AHTDP Assisted Reproductive Technologies 2014

Assisted Reproductive Technologies (ARTs)

FINALREPORT
revised February 2014
Submitted to: Prepared by:
The Alberta Health Technologies Decision Process Health Technology & Policy Unit
Clinical Advisory and Research Branch School of Public Health
Primary Health Care Division Department of Public Health Sciences
Alberta Health University of Alberta
Production of this document has been made possible by a financial contribution from Alberta Health and under the
auspices of the Alberta Health Technologies Decision Process: the Alberta model for health technology assessment
and policy analysis. The views expressed herein do not necessarily represent the official policy of Alberta Health.

Alberta Health Technologies Decision Process
Assisted Reproductive Technologies (ARTs) February 2014
Acknowledgements:

With thanks for their advice and support throughout the project:
 Dr. Ray Howard, Alberta Health
 Dr. Jason Lau, Alberta Health
 Dr. Charlotte Moore Hepburn, The Hospital for Sick Children
 Ms. Tammai Piper, Alberta Health Services
 Ms. Lori Querengesser, Alberta Health
 Ms. Kate Wagontall, Alberta Health

Special thanks to Dr. Tarek Motan, University of Alberta, Faculty of Medicine and Dentistry for his
unfailing assistance and advice on the many questions that arose during the course of this
review.

Many thanks also to:
 Ms. Nancy Aelicks, and for the data provided by the Alberta Perinatal Health Program, Alberta
Health Services
 Dr. Jill Boulton, University of Calgary
 Dr. Calvin Greene, Regional Fertility Program
 Dr. Reg Sauve, University of Calgary

And to the members of the Expert Advisory Group for this assessment:
 Ms. Denise Brind, Alberta Health Services
 Dr. Bernard Corenblum, Alberta Health Services
 Dr. Ken Gardener, College of Physicians & Surgeons of Alberta
 Ms. Selikke Janes‐Kelley, Alberta Health Services
 Dr. James Kellner, Alberta Health Services
 Dr. Carolyn Lane, Low Risk Maternity Clinic
 Dr. Ernest Phillipos, Alberta Health Services
 Dr. Margaret Sagle, University of Alberta &Alberta Health Services
 Dr. Suzanne Tough, University of Calgary & Alberta Health Services
 Dr. Eric Wasylenko, Alberta Health Services

Authors’ conflict of interest statements: None declared.
Prepared by the University of Alberta for the Government of Alberta, © 2014

Table of contents
Table of contents .......................................................................................................................................... 1
Abbreviations ................................................................................................................................................ 7
Glossary....................................................................................................................................................... 12
Questions & answers for policy makers ..................................................................................................... 21
Executive summary ..................................................................................................................................... 30
Background ................................................................................................................................................. 38
Objectives ............................................................................................................................................... 38

Policy questions.................................................................................................................................. 38
Research questions ............................................................................................................................ 38
Introduction ................................................................................................................................................ 40
Infertility ................................................................................................................................................. 40

Female infertility ................................................................................................................................ 41
Male infertility.................................................................................................................................... 42
Unexplained infertility........................................................................................................................ 42
Assisted reproductive technologies (ARTs) ............................................................................................ 42
Diagnostic tests .................................................................................................................................. 43
Fertility drugs ..................................................................................................................................... 44
Intrauterine insemination (IUI) .......................................................................................................... 46
Gamete intrafallopian transfer (GIFT)................................................................................................ 46
Zygote intrafallopian transfer (ZIFT) .................................................................................................. 46
In vitro fertilization (IVF) .................................................................................................................... 47
Assisted hatching................................................................................................................................ 48
Intracytoplasmic sperm injection....................................................................................................... 49
Preimplantation genetic testing......................................................................................................... 49
Sperm, egg, and embryo cryopreservation........................................................................................ 50
Health Canada approval ......................................................................................................................... 50
Methodology............................................................................................................................................... 52
Literature search..................................................................................................................................... 52
Selection and synthesis of literature ...................................................................................................... 53
Social and demographic review ......................................................................................................... 53
Environmental scan of ARTs policies.................................................................................................. 53
Clinical effectiveness review .............................................................................................................. 53
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Economic evaluation .......................................................................................................................... 54
Social systems and demographics (S) ......................................................................................................... 55
Burden of illness ..................................................................................................................................... 55

Prevalence and incidence ....................................................................................................................... 57
Risk factors.............................................................................................................................................. 59
Age...................................................................................................................................................... 59
Lifestyle issues.................................................................................................................................... 61
Patterns of care ...................................................................................................................................... 62
Social, legal and ethical issues ................................................................................................................ 63
Older parents ..................................................................................................................................... 63
Population fertility ............................................................................................................................. 63
Public health....................................................................................................................................... 64
Quality of life ...................................................................................................................................... 64
Knowledge and education.................................................................................................................. 64
Patient preferences............................................................................................................................ 65
Embryo donation................................................................................................................................ 67
Patient autonomy and responsibility ................................................................................................. 67
Cost and accessibility ......................................................................................................................... 68
Equity.................................................................................................................................................. 69
Eligibility for ARTs............................................................................................................................... 69
Prioritizing patients for ARTs.............................................................................................................. 70
Religious issues................................................................................................................................... 70
Legal issues......................................................................................................................................... 70
Commercialization of health care services and reproductive tourism .............................................. 71
Fertility preservation.......................................................................................................................... 71
Elective oocyte freezing ..................................................................................................................... 72
Population dynamics, diffusion and demand ......................................................................................... 72
Access to ARTs in Alberta ....................................................................................................................... 74
New developments................................................................................................................................. 75
Health system capacity........................................................................................................................... 77
Workforce and infrastructural capacity ............................................................................................. 77
Summary of recent health technology assessments .................................................................................. 78
Environmental scan of ARTs policies .......................................................................................................... 80
Policies in Canada ................................................................................................................................... 80

Alberta................................................................................................................................................ 81
Manitoba ............................................................................................................................................ 81
Quebec ............................................................................................................................................... 81
Ontario ............................................................................................................................................... 82
Policies internationally ........................................................................................................................... 82
Coverage............................................................................................................................................. 83
Maternal age ...................................................................................................................................... 83
Number of embryos ........................................................................................................................... 83
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ICSI, assisted hatching and other forms of micromanipulation ......................................................... 84

Oocyte maturation ............................................................................................................................. 84
Fetal reduction ................................................................................................................................... 84
Preimplantation genetic diagnosis..................................................................................................... 85
Cryopreservation................................................................................................................................ 85
Donation............................................................................................................................................. 85
Storage of embryos ............................................................................................................................ 85
Surrogacy............................................................................................................................................ 85
Technology effects and effectiveness (T) ................................................................................................... 87
Results of literature search..................................................................................................................... 87
Overall description of included studies .................................................................................................. 87
ARTs in comparison to spontaneous conception............................................................................... 87
IVF/ICSI in comparison to less invasive ARTs treatment options....................................................... 88
Number of embryos transferred ........................................................................................................ 88
Fresh versus frozen embryo transfer ................................................................................................. 89
Stage of embryo during transfer ........................................................................................................ 89
Donor embryo transfer ...................................................................................................................... 89
Maternal and paternal age................................................................................................................. 90
Maternal weight................................................................................................................................. 90
Maternal smoking status.................................................................................................................... 90
Several factors.................................................................................................................................... 91
Patient preferences............................................................................................................................ 91
Overall quality of included studies ......................................................................................................... 91
Safety ...................................................................................................................................................... 92
ARTs in comparison to spontaneous conception............................................................................... 92
IVF/ICSI in comparison to less invasive ARTs treatment options....................................................... 95
Number of embryos transferred ........................................................................................................ 95
Fresh versus frozen embryo transfer ................................................................................................. 96
Stage of embryo during transfer ........................................................................................................ 97
Donor embryo transfer ...................................................................................................................... 98
Maternal age ...................................................................................................................................... 98
Maternal weight................................................................................................................................. 98
Maternal smoking status.................................................................................................................... 99
Summary ............................................................................................................................................ 99
Efficacy/effectiveness........................................................................................................................... 100
ARTs in comparison to spontaneous conception............................................................................. 100
IVF/ICSI in comparison to less invasive ARTs treatment options..................................................... 100
Number of embryos transferred ...................................................................................................... 101
Fresh versus frozen embryo transfer ............................................................................................... 103
Stage of embryo during transfer ...................................................................................................... 103
Embryo quality ................................................................................................................................. 104
Maternal age .................................................................................................................................... 104
Paternal age ..................................................................................................................................... 106
Maternal weight............................................................................................................................... 107
Maternal smoking status.................................................................................................................. 108
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Nature and duration of infertility..................................................................................................... 109
Patient preferences.......................................................................................................................... 109
Summary .......................................................................................................................................... 110
Economic evaluation (E) ........................................................................................................................... 111
Economic studies of ARTs interventions .............................................................................................. 111

Review of economic studies............................................................................................................. 111
Economic studies of ARTs interventions .......................................................................................... 111
Studies of the effects of ARTs policies on costs ............................................................................... 112
Studies of utilization and outcomes of ARTs services ...................................................................... 115
Studies on actual costs related to ARTs services ............................................................................. 116
Studies estimating the costs and benefits of ARTs services and policies ........................................ 117
Studies of US state mandated insurance coverage of ARTs services............................................... 121
Budget impact and cost‐effectiveness analysis ........................................................................................ 123
Methods................................................................................................................................................ 123
Budget Impact Analysis .................................................................................................................... 123
Scenarios .......................................................................................................................................... 123
Patient population............................................................................................................................ 123
Technology mix ................................................................................................................................ 123
Time horizon..................................................................................................................................... 124
Perspective ....................................................................................................................................... 124
Model description ............................................................................................................................ 125
Input data ......................................................................................................................................... 125
Cost‐effectiveness analysis............................................................................................................... 125
Results .................................................................................................................................................. 130
Decision model ......................................................................................................................................... 1
Conclusions ............................................................................................................................................... 146
Appendices................................................................................................................................................ 149
Appendix ‐ Additional tables ................................................................................................................ 150

Appendix A – Environmental scan of ARTs policies.............................................................................. 152
Appendix B – Evidence tables: Included studies .................................................................................. 162
Appendix C – Evidence tables: Quality of included studies.................................................................. 186
Appendix D – Evidence tables: Safety .................................................................................................. 189
Appendix E – Evidence tables: Efficacy/effectiveness.......................................................................... 201
Appendix F – Economic studies ............................................................................................................ 223
Appendix G ‐ Tables for the decision model......................................................................................... 350
Appendix H ‐ Literature search............................................................................................................. 448
References ................................................................................................................................................ 472
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Figure 1. Natural conception ‐ trends in pregnancy & miscarriage according to age ................................ 60

Figure 2. PRISMA diagram of literature search results & study selection for clinical effectiveness review
.................................................................................................................................................................... 87
Figure 3. Quality of systematic reviews: Oxman and Guyatt index of scientific quality for systematic
reviews tool................................................................................................................................................. 91
Figure 4. Infertility diagnosis..................................................................................................................... 137
Figure 5. Treatment options for female infertility........................................................................................ 1
Figure 6. Treatment options for male infertility ........................................................................................... 1
Figure 7. Treatment options for unexplained and mixed infertility ............................................................. 1
Figure 8. Treatment outcomes ................................................................................................................. 145

Table 1. Drugs commonly used in ARTs in Canada ..................................................................................... 45

Table 2. PICOS elements of the clinical effectiveness review protocol ...................................................... 54
Table 3. Summary of data abstraction form elements ............................................................................... 54
Table 4. Cases of male and female infertility in Alberta 2005/2006 .......................................................... 57
Table 5. Delivery and birth outcomes of women in Alberta by method of conception: data from the
Alberta Perinatal Health Program............................................................................................................... 59
Table 6. Funding scenarios for budget impact analysis ............................................................................ 123
Table 7. Average per capita health care costs in Alberta ......................................................................... 124
Table 8. Funding allocation per child per year in Alberta 2011‐2012....................................................... 125
Table 9. Cost‐effectiveness analysis.......................................................................................................... 126
Table 10. Costs associated with the base case and 'regulate but do not fund' scenarios........................ 127
Table 11. QALYs associated with the base case and 'regulate but do not fund' scenarios ...................... 128
Table 12. Costs associated with scenarios involving some level of public funding for IVF ...................... 128
Table 13. QALYs associated with scenarios involving some level of public funding for IVF ..................... 130
Table 14. Health care costs associated with treatment, pregnancy, delivery, neonatal care, and postnatal
care up to 18 years of age under different embryo transfer policy options ............................................ 130
Table 15. Health care cost savings under different embryo transfer policy options in comparison to the
status quo in Alberta................................................................................................................................. 131
Table 16. Health care and societal costs associated with treatment, pregnancy, delivery, neonatal care,
and postnatal care under different embryo transfer policy options ........................................................ 132
Table 17. Health care and societal cost savings under different embryo transfer policy options in
comparison to the status quo in Alberta .................................................................................................. 133
Table 18. Cost per ongoing pregnancy and healthy live birth under different embryo transfer policy
options ...................................................................................................................................................... 134
Table 19. Additional health care costs associated with a parallel private system under different publicly
funded embryo transfer policy options .................................................................................................... 135
Table 20. Additional health care and societal costs associated with a parallel private system under
different publicly funded embryo transfer policy options........................................................................ 135
Table 21. Cost‐effectiveness of different embryo transfer policy options in comparison to the status quo
in Alberta................................................................................................................................................... 135
Table 22.The Oxman & Guyatt index of scientific quality scoring system for systematic reviews........... 150
Table 23. PRISMA statement checklist ..................................................................................................... 150
Table 24. ARTs policies in Canada & internationally................................................................................. 152
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Table 25. Included studies ........................................................................................................................ 162

Table 26. Quality of included studies using Oxman & Guyatt index of scientific quality scoring system for
systematic reviews.................................................................................................................................... 186
Table 27. Safety during pregnancy & delivery .......................................................................................... 189
Table 28. Neonatal/infant safety .............................................................................................................. 196
Table 29. Dose of gonadotropin stimulation ............................................................................................ 201
Table 30. Duration of gonadotropin stimulation ...................................................................................... 202
Table 31. Oocyte retrieval......................................................................................................................... 203
Table 32. Embryo cryopreservation rate .................................................................................................. 204
Table 33. Cycle cancellation rate .............................................................................................................. 205
Table 34. Implantation rate ...................................................................................................................... 207
Table 35. Pregnancy rate .......................................................................................................................... 208
Table 36. Multiple pregnancy rate............................................................................................................ 212
Table 37. Miscarriage rate ........................................................................................................................ 214
Table 38. Live birth rate ............................................................................................................................ 216
Table 39. Multiple birth rate..................................................................................................................... 221
Table 40. Economic studies of ARTs interventions ................................................................................... 223
Table 41. Studies of the effects of ARTs policies on costs ........................................................................ 250
Table 42. Studies of the effects of ARTs policies on utilization and outcomes ........................................ 254
Table 43. Studies of utilization and outcomes of ARTs services ............................................................... 272
Table 44. Studies on actual costs related to ARTs services ...................................................................... 278
Table 45. Studies estimating the costs and benefits of ARTs services and policies ................................. 304
Table 46. Studies of US state mandated insurance coverage of ARTs services........................................ 342
Table 47. Variable inputs for decision model 1 ‐ diagnosis of patients presenting with suspected ........ 350
Table 48. Variable inputs for decision model II ‐ treatment of couples with female factor infertility only
.................................................................................................................................................................. 354
Table 49. Variable inputs for decision model III ‐ treatment of couples with male factor infertility only369
Table 50. Variable inputs for decision model III ‐ ovarian stimulation + IUI for couples with male factor
infertility.................................................................................................................................................... 382
Table 51. Variable inputs for decision model III ‐ donor insemination for couples with male factor
infertility.................................................................................................................................................... 383
Table 52. Variable inputs for decision model IV ‐ treatment of couples with unexplained infertility ..... 384
Table 53. Variable inputs for decision model V ‐ pregnancy & delivery outcomes after surgical treatments
for male & female infertility ..................................................................................................................... 385
Table 54. Variable inputs for decision model IV ‐ pregnancy & delivery outcomes after & ovarian
stimulation ± IUI/DI................................................................................................................................... 387
Table 55. Variable inputs for decision model V‐IVF/ICSI outcomes ......................................................... 389
Table 56. Variable inputs for decision model V‐pregnancy & delivery outcomes after IVF/ICSI ............. 392
Table 57. Variable inputs for decision model V‐neonatal & long‐term outcomes after 1) surgical
treatments for male & female infertility, 2) ovarian stimulation +/‐ IUI/DI, and 3) IVF/ICSI ................... 396
Table 58. Variable inputs for utilities associated with different health states in the decision model ..... 398
Table 59. Estimation of average cost of ARTs........................................................................................... 436
Table 60. Unit costs of treatment, pregnancy, delivery, neonatal care, and postnatal care ................... 443
Table 61. Estimation of average cost of diagnosis and management of couples with infertility ............. 446

6

Abbreviations
ADHD = attention‐deficit/hyperactivity disorder
AFC = antral follicle count
AH = assisted hatching
AHTDP = Alberta Health Technologies Decision Process
AHRC = Assisted Human Reproduction Canada
AHRQ = US Agency for Healthcare Research and Quality
AHS = Alberta Health Services
AI = artificial insemination
AMH = antimüllerian hormone
ARTs = assisted reproductive technologies
ASD = autism spectrum disorder
ASSET = Australian Study of Single Embryo Transfer
BIA = budget impact analysis
BMI = body mass index
CARTR = Canadian Assisted Reproductive Technologies Register
CC = clomiphene citrate
CFAS = Canadian Fertility and Andrology Society
CI = confidence interval
COS = controlled ovarian stimulation
CP = cerebral palsy
CPAC = Clinical Priority Assessment Criteria
DD = developmental delay
7

DET = double embryo transfer
ECS = early childhood services
eSET = elective single embryo transfer
ESHRE = European Society of Human Reproduction and Embryology
ET = embryo transfer
FET = frozen embryo transfer
FSH = follicle‐stimulating hormone
GIFT = gamete intrafallopian transfer
GnRH = gonadotropinreleasing hormone
GnRHa= Gonadotropinreleasing hormone agonist
GP = general practitioner
HCG = human chorionic gonadotropin
HFEA = UK Human Fertilisation and Embryology Authority
HLA = human leukocyte antigens
hMG = human menopausal gonadotropin
HOM = higher order multiples
HOMB = higher order multiple births
HP‐hMG= highly purified human menopausal gonadotropin
HSG = hysterosalpingogram
HTA = health technology assessment
HyCoSY = hysterosalpingoconstrastsonography
ICER = incremental cost‐effectiveness ratio
ICMART = International Committee for Monitoring Assisted Reproductive Technology
ICSI = intracytoplasmic sperm injection
IFFS = International Federation of Fertility Societies
8

IUI = intrauterine insemination
IVA = intravenous albumin infusion
IVF = in vitro fertilization
IVM = in vitro maturation
LBW = low birth weight
LH = luteinizing hormone
LHRHa= luteinizing hormone‐releasing hormone agonist
MeSH = Medical Subject Headings developed by the US National Library of Medicine
MET = multiple embryo transfer
microTESE = microsurgical testicular sperm extraction
MZT = monozygotic twinning
NHS = UK National Health Service
NICE = UK National Institute for Health and Clinical Excellence
NICU = neonatal intensive care unit
nIUI= natural cycle IUI
NIVF = natural cycle in vitro fertilization
NPV = net present value
nr = not reported
OECD = Organisation for Economic Co‐operation and Development
OHSS = ovarian hyperstimulation syndrome
OI = ovulation induction
OR = odds ratio
OS = ovarian stimulation
ORT = ovarian reserve testing
PCOS = polycystic ovarian syndrome
9

PESA = percutaneous epididymal sperm aspiration
PGS = preimplantation genetic screening
PGD = preimplantation genetic diagnosis
PID = pelvic inflammatory disease
PIH = pregnancy induced hypertension
POI = primary ovarian insufficiency
PPROM = preterm prolonged rupture of membranes
PRISMA = Preferred Reporting Items for Systematic Reviews and Meta‐Analyses
PTB = preterm birth
PTD = preterm delivery
QALY = quality‐adjusted life year
QET = quadruple embryo transfer
RCT = randomized controlled trial
rFSH = recombinant follicle stimulating hormone
RR = risk ratio
SC = spontaneous conception
SD = standard deviation
SET = single embryo transfer
SGA = sub‐group analysis
sIUI= stimulated IUI
SOGC = Society of Obstetricians and Gynaecologists of Canada
TESA = testicular sperm extraction
TESE = see TESA
TET = triple embryo transfer
WHO = World Health Organization
10

WHSSC = Welsh Health Specialised Services Committee
ZIFT = zygote intrafallopian transfer
11

Glossary
Amenorrhea = the absence of menstruation
Aneuploidy = an abnormal number of chromosomes
Anovulation = failure to ovulate
Antimullerian hormone = a hormone test used to determine ovarian reserve
Antral follicle = an ovarian follicle at a later stage of development
Antral follicle count = the number of antral follicles, measured by ultrasound, at the beginning of the
menstrual cycle
Aromatase inhibitors = anti‐estrogen drugs used in the treatment of breast cancer; also used to treat
anovulation in female infertility
Artificial insemination = inserting sperm directly into the woman’s vagina or uterus (also called
intrauterine insemination); the sperm may be from the woman’s partner or donor sperm
Assisted hatching = thinning or perforation of the zona pellucida (outer membrane of the embryo) to
improve embryo implantation
Assisted reproductive technologies = any procedures that involve the in vitro manipulation of oocytes
and sperm, or embryos, to establish pregnancy…. [the ICMART definition goes on to include other
techniques not included in this assessment]. It does not include artificial insemination.
Autologous = from the same individual
Azoospermia = absence of sperm in the semen; may be caused by a blockage in the testicle (obstructive
azoospermia), hypothalamus or pituitary conditions (pre‐testicular azoospermia), or testicular failure
(non‐obstructive azoospermia)
Basal body temperature = daily monitoring of a woman’s body temperature to determine when
ovulation occurs
Biochemical pregnancy = see Chemical pregnancy
Blastocyst = an embryo at the stage 5 to 6 days post‐fertilization
Bootstrapping= a statistical method of estimating the distribution of an estimate or a test statistic by
‘resampling’ the data
12

Bromocriptine = a drugused in the treatment of hyperprolactinemia, including amenorrhea and female
infertility
Budget impact analysis = the financial impact of introducing a technology or service on capital or
operating budgets
Cancelled cycle = an ARTs cycle where ovarian stimulation or monitoring has been used, but where
aspiration of the follicle or embryo transfer do not occur
Chemical pregnancy = also called biochemical pregnancy; a pregnancy diagnosed only by a blood or
urine test, that does not continue to develop into a clinical pregnancy
Cleavage = cell division in the early embryo; a cleavage stage embryo is one at around the 2nd or 3rd day
post‐fertilization
Clinical pregnancy = a pregnancy diagnosed by ultrasound where one or more gestational sacs can be
seen (including ectopic pregnancy); multiple gestational sacs count as one clinical pregnancy
Clomiphene citrate = also called clomifene; an oral anti‐estrogen drug used for ovarian stimulation
Clomiphene citrate challenge test = a blood test of hormone levels that indicate the ovarian reserve, or
the quantity and quality of eggs
Consanguinity = common ancestry
Controlled ovarian stimulation = see ovarian stimulation
Cost analysis = Identification of current and anticipated costs associated with operating a service,
examining the impact of those costs on service rates
Cost‐effectiveness acceptability curve= a graph to show whether an intervention will provide value for
money (i.e., is cost‐effective) compared to an alternative intervention
Cost‐effectiveness analysis= the ratio of the cost of an option (health program, intervention, etc.)
divided by the health outcome
Cost‐minimization analysis= an economic analysis that determines the least costly of two options
(health program, intervention, etc.)
Cost‐utility analysis = a type of economic analysis that compares the benefits of different options
(health program, intervention, etc.) in terms of quality adjusted life years (QALYs)
Cryopreservation = freezing and storing cells or tissue at ultra‐low temperature for future use
Decision analysis= a transparent approach to decision making under uncertainty
Decision model= a framework for showing alternative scenarios
13

Discrete event simulation = the process of codifying the behavior of a complex system as an ordered
sequence of well‐defined events
Dizygotic twins = fraternal twins, resulting from the fertilization of 2 eggs
Ectopic pregnancy = when the fertilized egg implants outside of the uterus, usually in the fallopian tube
Elective embryo transfer = the transfer of one or more embryos from the available embryos
Elective single embryo transfer = the selection of only one embryo for transfer, to lower the risk of
multiple pregnancies
Embryo = a fertilized egg during the first 8 weeks (56 days) after fertilization, after which it is called a
fetus
Embryo quality = various methods are used to assess the quality of the embryos, based on the
morphology, rate of development, amount of fragmentation, and other features
Endometrial biopsy = a tissue sample taken from the lining of the uterus
Endometriosis = when the tissue lining the uterus grows outside the uterus, for example, onto the
ovaries or fallopian tubes, or elsewhere in the pelvic cavity
Epididymis = the tube connecting the testicle to the vas deferens
Extremely low birth weight = birth weight less than 1,000 grams
Fallopian tubes = the two canals that transport fertilized eggs from the ovaries to the uterus
Fecundity = enhanced fertility or ability to reproduce
Fetus = the developmental stage from 8 weeks (57 days) after fertilization until miscarriage or birth
Fibroids = benign tumours in the uterus; these may be asymptomatic or may cause pain or excessive
menstrual bleeding, or problems with reproduction (infertility, miscarriage or preterm birth)
Flare protocol = use of a short course birth control drugs, followed by a gonadotropinreleasing
hormone; used for women who have had a poor previous response to ovarian stimulation
Follicle = the oocyte and the cells that surround it
Fresh embryo transfer = when the embryo is transferred to the uterus within a few days of fertilization
Frozen embryo transfer = when embryos are cryopreserved for future use, then thawed before they are
transferred to the uterus
Gametes = human sperm or eggs
14

Gamete intrafallopian transfer = transfer of sperm and eggs into the fallopian tube allowing fertilization
to occur inside the woman’s body
Gestation = the time between conception and birth (i.e., pregnancy)
Gestational age = the length of pregnancy measured from the first day of the last menstrual cycle to
date; with assisted reproductive technologies an additional 2 weeks are added to calculate gestational
age
Gestational carrier = see Surrogate
Gestational diabetes = diabetes that occurs during pregnancy
Gonadal tissue = tissue from either the ovary or testis
Gonadatropin releasing hormone = a hormone which causes the pituitary gland to make luteinizing
hormone (LH) and follicle stimulating hormone (FSH) to stimulate ovulation
Gonadotropins = a class of fertility drugs that are used to stimulate ovulation or to treat hypogonadism
Hatching = the process of the blastocyst‐stage embryo separating from the zona pellucida
High‐order multiple = when 3 or more fetuses are present in a pregnancy
Hirsutism = the growth of excess facial or body hair in women
Human chorionic gonadotropin = a drug used for ovarian stimulation
Human leukocyte antigen = proteins on the surface of white blood cells that determine immunological
compatibility; used to “match” patients and donors for stem cell transplantation
Human menopausal gonadotropin = a drug used for ovarian stimulation
Hyperprolactenemia = when the pituitary gland produces too much prolactin, a hormone that regulates
milk production and other reproductive functions
Hypogonadism = in men, this affects the testes’ production of sex hormones causing impotence and
infertility
Hypothalamic pituitary failure / dysfunction = the hypothalamus of the brain controls the pituitary
gland, which regulates the functions of the ovaries and testes, and levels of reproductive hormones such
estrogen, prolactin and testosterone
Hysterosalpingogram = an x‐ray combined with a special dye that is used to assess the fallopian tubes
and uterus
15

Hysterosalpingoconstrastsonography = a dye and ultrasound based test to detect abnormalities of the
uterus, endometrium and fallopian tubes
Hysteroscopy = visual examination of the inside of the uterus using an endoscope inserted through the
vagina
Idiopathic = of unknown cause
Imprinting syndromes = mutations that allow genetic inheritance of a certain gene from one parent,
rather than one from each parent; imprinting allows rare genetic diseases to be passed on to the child
In vitro fertilization = an ARTs procedure where the egg is fertilized by the sperm outside of the
woman’s body. The steps involved in IVF include: ovarian stimulation, egg retrieval, egg fertilization,
embryo culture and embryo transfer.
Incremental cost‐effectiveness ratio = a health economics method that compares one health
technology to an alternative technology (or to no intervention), taking into account both its effects or
benefits (e.g., measured in terms of quality‐adjusted life years gained (QALY)), and the cost per QALY. A
high ICER indicates that the technology in question will result in higher costs to achieve the potential
benefits. A technology that offers both lower costs and more benefit is called the “dominant”
technology.
Infertility = also called subfertility; failure to achieve pregnancy after 12 months or more of regular,
unprotected sexual intercourse
Intracytoplasmic sperm injection = injection of a single sperm into a mature egg; with the embryo then
transferred to the fallopian tube or uterus
Intrauterine insemination = placing sperm into the uterine cavity so that fertilization occurs in utero,
rather than in vitro (outside the body)
Laparoscopy = minimally or less invasive surgery on the abdomen or pelvis, performed using a
laparoscope (an instrument inserted through small incisions to allow visualization of the organs during
surgery)
Letrozole = an aromatase inhibitor drug used to treat breast cancer; also used, off‐label, to treat
anovulation in female infertility
Low birth weight = birth weight of <2,500 grams (or approximately 5.5 pounds); this includes both
preterm babies and small‐for‐gestational age babies; moderate low birth weight is from 1,500‐2,500
grams; very low birth weight is <1,500 grams
Luteinizing hormone = a drug used for ovarian stimulation
Markov model= a statistical representation of events over time as part of a decision analysis
16

Menopause = the permanent cessation of menstruation
Meta‐analysis = the use of statistical methods in a systematic review to pool results from different
studies and gain an estimate of the overall effect of an intervention
Metabolomics = sampling embryonic fluid to test for certain molecules (metabolites) that may indicate
the most viable embryos
Metformin = an antidiabetic drug that is also used to treat gestational diabetes and insulin resistance in
polycystic ovarian syndrome
Microscopic epididymal sperm aspiration = a procedure involving a small incision for sperm retrieval
Microscopic TESE = use of magnification to retrieve sperm in cases of very low sperm count
Miscarriage = also called spontaneous abortion; loss of an embryo or fetus before the 20th week of
pregnancy
Mitochondria = structures that produce energy in cells
Mitochondrial disease = a maternally inherited mutation of the mitochondrial chromosome. The
condition can cause many disorders, including degenerative diseases that affect eyesight, hearing, the
brain, heart and other organs.
Monozygotic twins = identical twins, from a single fertilized egg that divides into two embryos
Monte Carlo simulation= a technique that uses a random selection of possible variables to test the
effects of these changes on the outputs of a decision model
Morula = the embryo just before the blastocyst stage (about day 4 post‐fertilization)
Multifetal reduction = random termination of a fetus in a multiple gestation to improve the viability of
the remaining fetuses; see also Selective fetal reduction
Natural cycle IVF = retrieval of an oocyte for IVF from a natural menstrual cycle without using fertility
drugs
Net present value = the current cost, after taking into account discounted future costs (losses and gains)
Oligozoospermia / oligospermia = low sperm count; defined as less than 20 million sperm per milliliter
of semen
Oocyte = a mature ovum (egg)
Ovarian drilling = a surgical procedure used to reduce testosterone production by the ovaries in women
with polycystic ovarian syndrome
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Ovarian hyperstimulation syndrome = systemic adverse effects from fertility drugs (mainly from the
gonadotropin drugs) used for ovarian stimulation; categorized as mild, moderate or severe by the
degree of symptoms such as: bloating, ovarian enlargement, respiratory, blood pressure and metabolic
complications
Ovulation induction = see Ovarian stimulation
Ovarian reserve = the woman’s egg supply
Ovarian response = tests used to determine the dosage or type of medications needed to induce
ovulation
Ovarian stimulation = also called controlled ovarian stimulation, the use of fertility drugs to stimulate
the ovaries to produce multiple eggs
Ovulation = release of an egg from one of the ovaries
Ovum = human egg or oocyte
Percutaneous epididymal sperm aspiration = a technique for sperm retrieval
Placenta praevia = a complication of pregnancy where the uterus covers the cervix causing bleeding
Polycystic ovarian syndrome = when a woman’s ovaries or adrenal glands produce an excess of male
hormones (androgens) ‐ the hormones cause fluid‐filled cysts to develop on the ovaries and prevent the
release of eggs during ovulation
Polyps = usually benign growths; in the uterus these can cause irregular menstruation or excessive
menstrual bleeding
Pre‐eclampsia = a complication of pregnancy marked by high blood pressure, swelling and protein in the
urine
Preimplantation genetic diagnosis = testing an embryo for selected genetic abnormalities before it is
transferred to the uterus
Premature ovarian failure = depletion of primordial follicles and cessation of normal ovarian functioning
before age 40
Preterm birth = birth at less than 37 weeks gestation
Primordial follicle = an immature ovarian follicle
Probabilistic sensitivity analysis= a way to quantify the level of confidence that one can place in the
conclusions reached by an economic evaluation
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Progesterone = a steroid hormone that prepares the uterus for fertilization; also used to prevent
miscarriage, treat menstrual disorders and as a component of some oral contraceptives
QALY= a measure of health improvement used in cost utility analysis; it combines quality of life gains
with death as an endpoint, or number of years of life saved adjusted for quality of those years
Reification = turning an abstraction or concept into something real or concrete
Reproductive tourism = travelling out of the country or province of residence to receive health services
Saline hysterogram = a pelvic ultrasound to visualize the uterus
Selective fetal reduction = selective termination of a fetus with a known abnormality in a multiple
gestation to improve the remaining fetus(es) chances of survival; see also Multifetal reduction
Semen analysis = a test for male infertility that assesses characteristics such as sperm motility, quantity
and morphology
Sensitivity analysis= a process to check how much the results of a study would change given the
inclusion or exclusion of certain data
Sertoli cells = cells in the testes that produce sperm
Small‐for‐gestational age = infants in the smallest 10th percentile for gender‐specific birth weight
Sonohysterogram = a diagnostic ultrasound that also uses an infusion of saline to visualize the uterus,
ovaries and fallopian tubes
Sperm washing = a process to remove the risk of passing on transmittable diseases, such as HIV or
hepatitis, to the child; may also be used to remove other components of semen to improve chances of
fertilization
Spontaneous miscarriage = also called spontaneous abortion; loss of pregnancy before 20 weeks
gestation
Sterility = inability to reproduce
Stillbirth = death of the fetus at or after the 20th week of gestation
Subfertility = see Infertility
Sub‐replacement fertility = when the number of children being born is less than that needed to replace
the existing population
Surrogate = also called a gestational carrier; a woman who carries the pregnancy for the intended
parents. The egg and sperm used for the pregnancy can be from the intended parent(s), or from a third
party (or parties).
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Testicular sperm extraction = taking a small sample of tissue from the testes for sperm retrieval
Tubal occlusion = blockage of one or both of the fallopian tubes
Unexplained infertility = infertility where the cause is unknown
Uterus = womb
Uterine fibroids = benign growths on the wall of the uterus
Varicocele = enlargement of the veins in the scrotum, along the spermatic cord, causing problems with
sperm production
Vas deferens = the ducts that carry sperm from the epididymis to the ejaculatory ducts
Vitrification = a form of cryopreservation that involves ultrarapid cooling
Wegener’s disease = a rare disease that causes inflammation of the blood vessels and other tissues, in
particular, the respiratory tract and kidneys, muscle and joint pain
Willingness to pay= the maximum $ that an individual is prepared to pay to achieve a specific health
intervention or outcome
Zona pellucida = the thick outer membrane around the egg that begins to thin once fertilization takes
place, allowing implantation in the lining of the uterus
Zygote = the single cell that forms when a sperm fertilizes an egg
Zygote intrafallopian transfer = fertilization of the egg occurs in the laboratory, with the early stage
embryo (zygote) transferred to the fallopian tube rather than to the uterus
Where available, definitions have been based on:
 International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the
World Health Organization (WHO) revised glossary of ART terminology1
 PharmacoEconomics guide chart2
 HTAi consumer glossary: a beginner’s guide to words used in health technology assessment3
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Questions & answers for policy makers
Policy questions to be answered in this review are:
 Should assisted reproductive technologies (ARTs) be regulated in Alberta? If so, what is an
appropriate standard?
In most Canadian provinces, including Alberta, ARTs practice is regulated by a “patchwork”of legislation,
clinical practice guidelines, and standards.
At the national level, the Assisted Human Reproduction Actcovers some of the broader ethical issues, in
particular, prohibiting human cloning and commerce involving human sperm, eggs, embryos and
surrogacy. However, since a Supreme Court challenge by the province of Quebec, other sections of the
Act concerning the licensing and regulation of ARTs clinics are no longer in effect. These are now
deemed to be outside the scope of federal jurisdiction over health care. The provinces have been left to
develop their own regulations or standards in a decentralized model. To date, Quebec is the only
province that has introduced ARTs legislation and regulations.
Variousguidelines issued by the Society of Obstetricians and Gynaecologists of Canadaprovide voluntary,
rather than mandatory, guidance for ARTs clinical practice.Training and competencies for ARTs
physicians and other healthcare professionals are outlined in standards issued by The Royal College of
Physicians and Surgeons of Canada, and the Canadian Fertility and Andrology Society (CFAS).
At the provincial level,the College of Physicians and Surgeons of Albertaprovides standards and
guidelines for non‐hospital surgical centres that provide in vitro fertilization (IVF). These centres must be
accredited by the College. The standards and guidelines cover physician credentialing and requirements
for record keeping at these centres, but do not specify standards for clinical practice.
Further regulations are unlikely to be forthcoming at the national level, and given the gaps in what is
covered under existing regulations, it is important that Alberta develop comprehensive provincial
regulations to guide ARTs practice. Without such regulations, ARTs willcontinue to operate as a
relatively independent market‐based health service outside of provincial health services.
Quebec’s ARTs regulations and policies cover the provision of ARTs services at both the healthcare
delivery and clinical level and these could be adapted to suit Alberta’s requirements. Other jurisdictions
with similar healthcare systems (in particular, the UK, Australia and New Zealand) have established
agencies, regulations, and standards to manage ARTs services. Aspects of their systems and regulations
may be relevant for Alberta.
See the section: Environmental scan of ARTs policies for further information.
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 Should ARTs be publicly funded in Alberta, and for whom?
Currently, Quebec is the only Canadian province that provides full public funding for ARTs, including
coverage of fertility drugs, intrauterine insemination (IUI), and IVF/ICSI (intracytoplasmic sperm
injection).Public funding for IUI and IVF, but not for fertility drugs, is provided in Ontario.However,
coverage for IVF is restricted to women with bilateral fallopian tube blockage and does not include ICSI.
In Manitoba, ART services are not directly covered but a tax credit for fertility treatment expenses is
offered. In other developed countries with healthcare systems similar to Canada’s (e.g., the UK, Australia
and New Zealand, most Scandinavian countries, and in the larger European countries), ARTs treatments
are publicly funded (either fully or substantially).
Utilization of ARTs has increased worldwide but increases have been most pronounced in jurisdictions
that provide public funding forARTs. Public funding increases the adoption of single embryo transfer
(SET) and decreases the number of multiple births. The costs savings associated with reducing multiple
births (e.g., fewer obstetrical complications, low birth weight, premature and small‐for‐gestational age
infants, shorter hospital stays, and reduced longterm disability costs) offset the costs of providing ARTs
treatments.
All jurisdictions that provide public funding of ARTs have developed eligibility requirements, and in some
countries (such as New Zealand), priority‐setting criteria. The main eligibility criterion is the maternal
age limit. Age limits used elsewhere vary ‐ in some jurisdictions these are included in regulations or
other policies, but in others (such as Quebec), they are left to clinical practitioners to determine. Some
jurisdictions put further “lifestyle” restrictions on access, such as attempting smoking cessation and
weight loss.
Alberta will also need such criteria to ensure that public funds budgeted for ARTs services are fairly
allocated and based on the best available evidence. The interests of all groups who may benefit from
ARTs (e.g., single women, same‐sex couples, couples who are not infertile but risk passing on genetic
diseases, etc.) should be considered. Again, Quebec’s initial experiences in providing ARTs will be
invaluable in planning these services in Alberta.
See the sections: Equity, Eligibility for ARTs, Prioritizing patients for ARTs, and Economic
evaluation for further information.
 What are the implications of funding without regulating and regulating without funding?
The status quo in Alberta, and in all Canadian provinces except for Quebec, is currently between both
scenarios. Limited regulations, at the national level and from the College of Physicians and Surgeons of
Alberta, do not provide comprehensive guidance to manage the provision of ARTs services. Currently,
Canadian clinical practice guidelines may or may not be followed in actual practice.
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Provincial regulation and public funding of ARTs may reduce reproductive tourism (individuals travelling
out of Alberta to other provinces or countries for treatment).
In terms of costs, Quebec’s regulation and funding of ARTs has enabled it to negotiate reduced fees for
publicly funded ARTs services through private clinics, allowing better control of costs.
All other jurisdictions that provide public funding for ARTs have introduced regulations, codes of
practice, or other restrictions to manage its delivery. The current system of neither funding nor
regulating ARTs perpetuates the delivery of these treatments through private clinics ‐ increasing the risk
that clinical practice may not adhere to evidence‐based standards and limiting access to those who can
afford to pay.
See sections: Environmental scan of ARTs policies and the Economic evaluation section (on
policy outcomes) for further information.
Research questions to be answered in this review are:
 What is the burden of infertility to couples, patterns of care and capacity to deliver care in
Alberta?
Estimates of the prevalence of infertility in Canada range from about 8.5% to 16%, depending on the
definition and duration of infertility used. According to Alberta Health billing data 11,513 Albertans
(4,659 men and 6,854 women) were diagnosed with infertility in 2005, and 12,490 (4,962 men and 7,528
women) were diagnosed with infertility in 2006.
We did not findany recent studies that examined the emotional or financial burden of infertility on
couples in Alberta. Studieselsewhere indicate that infertility decreases quality of life. Women aremost
affected, commonly describing feelings of psychological stress, depersonalization, guilt, sadness, and
stigma. In some couples, infertility caused marital tension, loss of libido and social isolation.Most
Canadians consider having children to be part of a full life.
Infertility treatments also impose significant physical and emotional suffering (mood swings, anxiety,
depression, pain, stress, and adverse effects from the fertility drugs and other interventions). They also
incur a financial burden for those affected as most of the costs associated with ARTs (fertility drugs, in
vitro fertilization and associated procedures, etc.) are not covered by provincial health insurance.
Indirect costs, such as time off work for frequent medical appointments and travel to receive ARTs
treatment add to this burden.
As there is little information on the burden of infertility in Alberta, public consultation on this issue could
ensure that patient experiences here are fully recognized.
See the section: Burden of illness for further information.
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The wait time for an initial consult with an infertility specialist in Alberta is currently up to 6
months.Based on studies of other jurisdictions, if public funding of ARTs is introduced the demand for
infertility treatments will increase substantially, at least in the first few years. Quebec used private
clinics to meet the increased demand for ARTs in the first years of their program,while additional public
clinics were being established.
Currently, there are two centres in Alberta that can provide IVF and other ARTs treatments, however,
there are other centres that offer non‐IVF ARTs procedures, such as intrauterine insemination. There
are10 reproductive endocrinologists practising in Alberta (four in Edmonton and six in Calgary), of whom
seven may perform IVF (one in Edmonton and six in Calgary).Further, there are five embryologists in
Calgary and one in Edmonton who perform ICSI.
The Calgary Regional Fertility Centre (a private clinic) recently expanded, but it will likely not be
sufficient to meet provincial demand if public funding for ARTs is introduced. Additional infertility
specialists and other healthcare staff trained in infertility nursing, counselling and embryology will be
needed. Provincial laboratory services that can handle preimplantation genetic testing may also be
needed, rather than continuing to rely on laboratory services elsewhere in Canada and the US.
See the section: Workforce and infrastructural capacity for further information.
 With respect to the mother, what are the safety, effectiveness and cost‐effectiveness of ARTs with
respect to short term and long term outcomes?
Safety: Compared to natural conception, IVF/ICSIwas associated with an increased risk for maternal
complications,during both pregnancy and childbirth. Some of these complications may be due to the
causes of infertility, rather than to the ARTs interventions.
More adverse events occurredduring pregnancy and delivery in women who received double embryo
transfer (DET), compared to women who receivedsingle embryo transfer (SET). Preterm deliveries and
caesarean section deliveries were noticeably increased after DET.
Compared to women who received SET, women who received DET during IVF/ICSI had higher rates of
adverse events during pregnancy and delivery, and DET infants had higher rates of complications. There
were significantly more preterm deliveries, caesarean section deliveries and low birth weight infants
with DET.
Evidence from studies in ARTs‐specific populations was limited, but increased maternal age (>35 to 40
years), maternal obesity, and smoking were associated with more complications duringpregnancy and
delivery, and more adverse health effects in theirinfants. Maternal smoking appeared to influence
pregnancy success rates, but ultimately, not live birth rates.Despite the higher doses of gonadotropins
and longer duration of stimulation usedfor IVF/ICSI in overweight and obese women, their live birth and
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pregnancy rates remained lower than in women with normal weight. Pregnancy rates per cycle,
however, were not significantly different among the groups.
Although some studies have suggested an increased risk for some types of cancer in women who receive
IVF/ICSIdue to the use of fertility drugs, the evidence in this area is inconclusive. However, the risk of
ovarian cancer appears to be higher in women affected by infertility.
Effectiveness: Compared to no treatment for infertility, IVF/ICSI showed a clear benefit in terms of
pregnancy and live birth rates in couples with endometriosis and unexplained infertility. Clinical
pregnancy rates after IVF/ICSI did not appear to be influenced by the use of ICSI in comparison to IVF
alone, but differences in the patient populations receiving IVF compared to ICSI were not discussed or
taken into account. Clinical pregnancy rates and live birth rates with fresh versus frozen embryos were
similar.
DET, rather than SET, improved both pregnancy and live birth rates, but also substantially increased
multiple pregnancy and multiple birth rates. The increases seen with DETwere also achieved through
two cycles of SET, or one fresh SET cycle and one frozen SET cycle. Regardless of the number of embryos
implanted, IVF/ICSI with top quality embryos resulted in better live birth rates than when less than top
quality embryos were used.
The chances of pregnancy and live birth were increased with blastocyst‐stage embryo cycles over
cleavage‐stage embryo cycles, particularly in women who were considered likely to have a good
prognosis with blastocyst transfers.There was no difference in the rate of multiple pregnancies between
the two groups.
Increased maternal age was associated with a reduced chance of pregnancy and live birth, and an
increased risk of miscarriage. Increased paternal age was associated with reduced semen volume, but
whether this translated into decreased reproductive function or decreased success with IVF/ICSI was not
clear.
Cost‐effectiveness:Over half of the economic studies reviewed for this assessment focussed on the cost‐
effectiveness of using different drug regimens for ovulation stimulation or induction. Most of these
studies used decision modelling and comparedhighly purified human menopausal gonadotropin (HP‐
hMG) to recombinant follicle stimulating hormone (rFSH) under different scenarios, with live birth rate
as the main outcome measure. Across the studies, the use of HP‐hMG was consistently shown to be
more effective and less costly than rFSH.
Two studies compared the cost‐effectiveness of accelerated versus step‐wise treatment protocols. In
one study, accelerated treatment used three cycles of clomiphene citrate/IUI and up to six cycles of IVF,
while step‐wise treatment used three cycles of clomiphene citrate/IUI, three cycles of gonadotropin/IUI
and up to six cycles of IVF. The median time to pregnancy was significantly shorter for accelerated
treatment, and as long as IVF costs per cycle were less than US$17,749, accelerated treatment was also
the less costly alternative.
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In the second study of an accelerated (IVF as the initial treatment) versus step‐wise treatment (three
cycles of gonadotropins before up to three cycles of IVF), while both protocols had a similar chance of
producing a live birth (over 80%), the step wise approach was found to be less costly. However, the step‐
wise approach had a four times greater risk of higher order multiples (HOMs), and the costs associated
with HOMs were not included.
One study examined a standard or “long” IVF/ICSI protocol (ovarian stimulation with a fertility drug
followed by up to three cycles of DET) compared to “mild” IVF/ICSI (ovarian stimulation with a fertility
drug followed by up to four cycles of SET). The mild protocol was more cost‐effective from a societal
perspective (i.e., more IVF/ICSI cycles were required, but overall treatment, pregnancy, obstetrical and
neonatal costs were lower).
What is more pertinent for policy development in Alberta is the information from economic studies of
single versus double embryo transfer, and the impact that this has on multiple birth rates and their
associated costs.Information on this was obtained from more than 40 studies that analyzed the effects
of policies restricting the number of embryos transferred per cycle on the costs and outcomes. The
policies studied were implemented through legislation, regulations or guidelines. These studies were
conducted in a number of countries at government or institution levels.
Overall, restrictions on embryo number results in lower transfer rates and reductions in costs. These
cost reductions are attributable to lower rates of multiple births. However, these policies vary, e.g., in
the number of embryos that may be transferredper cycle, whether the embryos are fresh or frozen, and
in the total number of cycles permitted. Consequently, there are differences in the detailed results from
study to study. Since the age criteria within policies are also different in each jurisdiction, the impacts on
costs and outcomes varied across age groups as well. It is important to note that although there was
general agreement that multiple birth rates fall with restrictive policies on embryo number, some
studies reported that pregnancy rates did not change after the policy, while other studies noted
significant reductions in clinical pregnancy rates, particularly in younger women.
About 20 studies estimated potential costs or outcomes, or both, of ARTs under certain assumptions.
Some of these were costing studies that produced the cost per IVF treatment in a jurisdiction, or
compared costs of different treatments. A number of them used modelling approaches to estimate the
potential cost‐effectiveness of different embryo transfer strategies. However, there was a wide range of
strategies using different decision models and representing different policies and practices. The studies
also varied in the types of costs that were included in their analyses. Consequently, closer examination
of an individual study would be needed to see if its results would apply to Alberta.
See the section: Economic evaluation for more information.
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 With respect to the child, what are the safety, effectiveness and cost‐effectiveness of ARTs with
respect to short term outcomes (such as preterm birth, low birth weight and multiple births) and
long term outcomes (such as special care and educational needs)?
Compared to natural conception, IVF/ICSIwas associated with an increased risk for infant
complications,including preterm birth, low birth weight and small for gestational age infants, birth
defects, and conditions such as cerebral palsy (in both singleton and multiple births). Some of these
complications result in lifetime disability. However, most children born through IVF/ICSI followed normal
childhood development. Nevertheless, more studies with longer follow‐up are needed as the effects of
IVF/ICSI may not be evident until maturity.
More adverse eventsoccurred in infants born after IVF/ICSI with DET, compared to infants born after
IVF/ICSI with SET. Rates of preterm and low birth weight infants were noticeably higher after DET.
Other than increasedrates of monozygotic twinning, blastocyst embryo transfer did not appear to cause
any significant safety issues compared to IVF/ICSI with cleavage stage embryos.
The health of infants born with IVF/ICSI with donor oocytes (eggs)was at least as good as that of infants
born after IVF/ICSI with autologous oocytes.
In comparison to fresh embryo transfer, frozen embryo transfer was associated with fewer adverse
events throughout pregnancy and delivery, and was at least as safe as fresh embryo transfer in terms of
infant outcomes.
Some studies suggest older paternal age increases the risk of miscarriage, and the child’s risk of certain
genetic diseases and conditions such as autism spectrum disorders.
A summary of the evidence on the effectiveness and cost‐effectiveness of ARTs with respect to both
mothers and children was summarized in the previous question.
 What is the most appropriate patient population for ARTs with respect to safety, effectiveness
and cost‐effectiveness?
The main patient population for ARTs in Alberta isheterosexual coupleswho have not been able to
conceive after one or two years of trying (or less for older women).
Jurisdictions that provide public funding for ARTs have access criteria in place. There may be defined
cut‐off ages for receiving ARTs through the public health care system (as in the UK), or this may be
broadly defined (as in Quebec) to “women of reproductive age” and left to physicians to determine
using accepted clinical practice guidelines.The use of donor eggs could extend the maternal age of the
patient population beyond women in their early 40s.
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No systematic reviews were identified that assessed the safety of IVF in older mothers. One analysis of
UK IVF registry data showed that women under 40 years of age had a higher risk for having preterm
births and low birth weight babies than women over 40 years of age. This may be due to the higher
likelihood of multiple births in younger women, regardless of the number of embryos transferred.
However, in non‐IVF singleton pregnancies in the general population, women over 35 to 40 years of age
have a higher risk of preterm delivery and low birth weight babies than younger women.
In general, there is an increase in pregnancy complications (such as ectopic pregnancy, gestational
diabetes, placenta praevia, and caesarean deliveries) with increasing maternal age. The risk of perinatal
mortality is also greater in women over 35 to 40 years of age. Aside from potentially higher rates of
malformations in infants conceived through IVF, evidence from the general population shows increasing
rates of chromosomal abnormalities (e.g., trisomies) and non‐chromosomal birth defects (e.g., heart
defects) with maternal age, even in singleton births.
The limited evidence available on the effect of paternal age suggests there may be higher rates of
specific congenital anomalies and cognitive or psychiatric disorders in the offspring of older men, but,
more studies that control for maternal age and other factors are needed.
Increased maternal age, particularly after age 40, is associated with a reduced chance of pregnancy and
live birth, and an increased risk of miscarriage. However, the use of donor embryos in women has
resulted in pregnancy rates in women in their 40s similar to those in women less than 40 years of age.
In addition, special patient groups may also need ARTs. These groups include single women, same‐sex
couples, individuals with physical or psychological disabilities that prevent sexual intercourse, cancer
patients who preserve their fertility before undergoing cancer treatment and may need ARTs in the
future, and couples who risk passing on a genetic disease (such as Huntington’s disease or cystic fibrosis)
or a transmissible disease (such as human immunodeficiency virus (HIV)).
See the sections: Infertility, Eligibility for ARTs, Prioritizing patients for ARTs, and Maternal
age for more information.
 What is the budget impact of providing ARTs with and without restrictions on their use?
The budget impact of different funding options for IVF/ISCI in Alberta was examined using eight
different resource utilization scenarios (implementing permissive, restrictive, and Quebec regulations
with and without funding, funding without regulating, and the current Alberta situation).
Health care and societal costs associated with treatment, pregnancy, delivery, neonatal care, and
postnatal care up to 18 years of age for the current cohort of 1,222 IVF/ICSI candidates, and, under
public funding scenarios, theexpected cohort of 3,055 IVF/ICSI candidates are presented inTable 16. The
cost savings under public funding policies (restrictive, permissive, Quebec, and no regulation) and
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regulation without funding policies (restrictive, permissive, Quebec) in comparison to the status quo in
Alberta are reported in Table 17.
In comparison to the current situation of no funding in Alberta, the net healthcare cost savings of
funding are $97 million following a restrictive policy, $7 million following a permissive policy, and $61
million following Quebec’s policy. In contrast, funding without regulating leaves Alberta with a net cost
$550 million. Healthcare and societal cost savings are about $179 million following a restrictive policy,
$15 million following a permissive policy, and $114 million following Quebec’s policy in comparison to
the status quo. Funding ARTs without regulating it results in a net cost of $990 million in comparison to
the status quo.
See the section: Budget impact analysis for more information.
 What are the current standards of regulation and provision of ARTs? What standard of regulation
and provision of ARTs with respect to patient outcomes are supported by available evidence?
This question was addressed in questions 1 through 3.
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Executive summary
Introduction: This assessment updates and expands earlier assessments on assisted reproductive
technologies (ARTs) prepared for Alberta Health as part of the Alberta Health Technologies Decision
Process. The focus is on the following ARTs:
 in vitro fertilization (IVF)
 intracytoplasmic sperm injection (ICSI)
 intrauterine insemination (IUI).
Gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT) are included if discussed in
relevant studies, but these procedures are rarely used in Canada.
Objectives: The purpose of this assessment is to help Alberta Health in their consideration of the
following policy questions:
 Should ARTs be regulated in Alberta, and if so, what are appropriate standards?
 Should ARTs be publicly funded in Alberta, and if so, for whom?
 What are the implications of funding ARTs without regulating it, and of regulating ARTs without
funding it?
Methods:Several literature searches were made to capture each of the main areas of focus (ARTs
policies and funding, clinical effectiveness, economic evaluations, searches for costs and utility values for
the decision model, and information for the social and demographics section). The searches used the
main biomedical literature databases: PubMed (MEDLINE and non‐MEDLINE sources), The Cochrane
Library, the Centre for Reviews & Dissemination (DARE, NHS EED, and HTA databases), EMBASE, Web of
Science, Scopus, CINAHL, PsycINFO and EconLit.
The policy and systematic reviews searches were limited to the most recent 5 years; the economics
searches were extended to cover the last 10 years and included all types of economic studies; the
primary studies search,used to complete and update gaps in the systematic reviews (run in PubMed
only), was limited to 2008 onwards. The most recent, reliable information available was used for values
in the decision model. Monthly update searches were run in PubMed throughout the project (until
February 2013). Searches were limited to English language studies.
The grey literature searches included web sites of ARTs‐related professional and patient associations,
guidelines, clinical trials, health technology assessment agencies, grey literature databases, and Google
searches. In the search for policies we checked the ministry of health web sites for each of the selected
countries (and where applicable, provinces and states within the countries). We also scanned the web
sites of key international and national organizations in this field, including the European Society of
Human Reproduction and Embryology (ESHRE), the International Federation of Fertility Societies (IFFS),
the American Society for Reproductive Medicine, the Society of Obstetricians and Gynaecologists of
30

Canada (SOGC), and the Canadian Fertility and Andrology Society (CFAS). Additional sources used
included web site links, references from relevant papers, and personal contacts in various provinces and
countries. Clinical experts in Alberta kindly provided essential information on clinical practice here.
For the clinical effectiveness review, search results were independently reviewed by two researchers.
Studies were appraised using accepted scoring instruments for study quality, and information was
extracted by two researchers using a standard data extraction form based on the PICOS questions
identified in the project work plan.
Similar methods were followed for the review of economic evaluations, which were independently
appraised by two researchers using validated guidelines for economic evaluations.
Several researchers compiled the information on ARTs policies and funding using sources identified in
the published and grey literature, and through personal contacts. The information was extracted into
tables to capture key details and allow for comparisons of regulations and policies, and their impact on
ARTs utilization and health care costs across jurisdictions.
For the budget impact assessment, the cost of services associated with provision of IVF/ICSI were
developed under four different policy scenarios. Unit costs for publicly funded services were obtained
from inpatient, outpatient, and physician claims data from Alberta Health. Costs associated with IVF/ICSI
were obtained from the twoARTs clinics in Alberta. A clinical pathway detailing the coursethat patients
follow from infertility diagnosis through to ARTs was constructed from a systematic review of published
literature and input from the Expert Advisory Group and local infertility specialists. A decision model was
constructed on the basis of this clinical path.
Results: Ultimately, over 1,400 papers, web pages and other documents were reviewed in the
preparation of this assessment. Over 250 systematic reviews and primary studies, and over 180
economic studies were assessed for inclusion. Most of the remaining documents were relevant for the
policy review or the summary of social and demographic information.
Technical aspects
This section is based on 37 systematic reviews of IVF/ICSI. They evaluated the effect of procedural
differences (such as the number of embryos transferred), patient characteristics, and IVF/ICSI in
comparison to less invasive ARTs (intrauterine insemination) or spontaneous conception, and patient
preferences. These were supplemented by seven primary studies and non‐systematic reviews where
information from systematic reviews was lacking.
Safety: Twenty seven reviews assessed different aspects of the safety of IVF/ICSI – mainly these
reported on adverse effects during pregnancy or delivery, or adverse effects in infants.
IVF/ICSI was associated with increased complications during pregnancy and delivery, and adverse effects
in infants. The most marked differences were increased rates of preterm delivery, low birth weight,
malformations, birth defects, and cerebral palsy in IVF/ICSI infants (both singletons and twins) compared
31

to spontaneously conceived infants. However, these increases may be due to greater surveillance of
IVF/ICSI pregnancies, maternal complications, or the root causes of infertility, rather than to IVF/ICSI.
Blastocyst embryo transfer increased rates of monozygotic twinning, but did not otherwise appear to
have safety issues compared to IVF/ICSI with cleavage stage embryos.
Infants born after donor IVF/ICSI were as healthy as those born using autologous oocytes.
Frozen embryo transfer was associated with fewer adverse events throughout pregnancy and delivery,
and was at least as safe as fresh embryo transfer in terms of infant outcomes.
Women who received DET during IVF/ICSI had higher rates of adverse events during pregnancy and
delivery, and their infants had higher rates of complications, compared to women who received SET and
their infants. Preterm deliveries, caesarean section deliveries and low birth weight infants were
significantly increased with DET.
Efficacy/effectiveness: Nineteen reviews assessed the effectiveness of IVF/ICSI.
IVF showed a clear benefit in pregnancy rates and live birth rates over no treatment in couples with
endometriosis and unexplained infertility. Frozen and fresh embryo cycles had similar pregnancy rates
and live birth rates.
DET increased both pregnancy and live birth rates, as compared to SET, but also substantially increased
multiple pregnancy and multiple birth rates. Using SET with two cycles (one fresh embryo transfer, when
necessary followed by one frozen embryo transfer) achieved pregnancy and live birth rates similar to
those with DET.
IVF/ICSI using top quality (grade A) embryos, defined by the number of blastomeres observed two to
three days after fertilization, results in better live birth rates than when lesser quality (grade B) embryos
are used, regardless of the number of embryos transferred. The chances of pregnancy and live birth
were also increased when blastocyst‐stage embryos were transferred, rather than cleavage‐stage
embryos.
Increasing maternal age is associated with a decreased chance of pregnancy and live birth, and a higher
risk of miscarriage. There is inconclusive evidence on the effect of increasing paternal age on
reproductive success with ARTs.
Despite higher doses of fertility drugs and longer periods of ovarian stimulation, pregnancy and live birth
rates were lower in overweight and obese women, compared to normal weight women. However,
pregnancy rates per cycle were not significantly different. Further studies are needed to determine the
effect of BMI while controlling for other factors, such as maternal age and number of embryos
transferred.
32

Economic aspects
Economic studies of ARTs interventions: Nineteen economic analyses of different treatment‐related
components of ARTs were identified. Fifteen of these studies focussed on the costs or cost‐effectiveness
of different fertility drugs used for ovulation stimulation or induction; three studies compared surgical
therapy to ARTs for varicoceles, obstructive azoospermia, or severe male factor infertility, and one study
compared the cost‐effectiveness of day three embryo transfer to blastocyst transfer.
The fertility drug studies reached similar conclusions – that highly purified human menopausal
gonadotropin (HP‐hMG) was more effective and less costly than recombinant follicle stimulating
hormone (rFSH).
Two studies compared the cost‐effectiveness of accelerated versus step‐wise treatment protocols. In
one study, accelerated treatment used three cycles of clomiphene citrate/IUI and up to six cycles of IVF,
while step‐wise treatment used three cycles of clomiphene citrate/IUI, three cycles of gonadotropin/IUI
and up to six cycles of IVF. The median time to pregnancy was significantly shorter for accelerated
treatment, and as long as IVF costs per cycle were less than US$17,749, accelerated treatment was also
the less costly alternative.
In the second study of an accelerated (IVF as the initial treatment) versus step‐wise treatment (three
cycles of gonadotropins before up to three cycles of IVF), while both protocols had a similar chance of
producing a live birth (over 80%), the step wise approach was found to be less costly. However, the step‐
wise approach had a four times greater risk of higher order multiples (HOM), and the costs associated
with HOM were not included.
One study examined a standard or “long” IVF/ICSI protocol (ovarian stimulation with a fertility drug
followed by up to three cycles of DET) compared to “mild” IVF/ICSI (ovarian stimulation with a fertility
drug followed by up to four cycles of SET). The mild protocol was more cost‐effective from a societal
perspective (i.e., more IVF/ICSI cycles were required, but overall treatment, pregnancy, obstetrical and
neonatal costs were lower).
Effects of ARTs policies on costs: Four studies reported the effects of policies on ARTs expenditures.
Overall, restrictions on embryo number resulted in lower transfer rates and reductions in costs. Two of
these studies demonstrated cost savings as a result of restrictions on multiple embryo transfers. The
other twostudies concluded that when IVF subsidies were reduced utilization dropped.
Effects of ARTs policies on utilization and outcomes: Twenty‐three studies examined the effects of ARTs
policies (legislation, regulation or guidelines) on the utilization or outcomes of IVF. These studies were
conducted in a number of countries and at government or institution levels.
Eighteen of the studies examined the impact of restricting multiple embryo transfer on outcomes and
utilization. Overall, the effect was to reduce the rate of multiple embryo transfers, and as a
consequence, to reduce the rate of multiple births. This was reported in Quebec, Australia, Belgium,
Italy, Spain and the United States. In most of jurisdictions,restrictions on multiple embryo transfers were
33

brought in through legislation or regulation. In Australia, a mandatory code of practice was established
instead of legislation. Inthe US,clinical practice guidelines recommend restricted use of multiple embryo
transfers.
The evidence is less clear on the effect of restrictions on clinical pregnancy rates. Two studies from
Belgium reported unchanged pregnancy rates after the law was introduced. However, a study from Italy
that comparedfive‐year periods before and after the law, reported a reduction in clinical pregnancy
rates. Studies from Quebec reached similar conclusions, particularly in women from 35 to 39 years of
age.
ARTs costs, utilization and outcomes:Twenty‐three studies presented actual cost, utilization and/or
costs data on ARTs services. The studies that examined the effect of age on IVF outcomes concluded
that IVF was less effective (in women older than 45 years of age) and less cost‐effective (in women over
39 years of age). Overall, the cost (reported variously in the studies) for multiple births was higher than
for singleton births. Infant outcomes were also reported to be worse for multiple births. In comparison
to SET, DET was more expensive. In other studies, the cost for an IVF birth increased with maternal age.
One study concluded that embryo donation was approximately twice as cost‐effective as oocyte
donation. Another concluded that there were no significant differences in the cost per live birth
between women of different weights. A number of the studies in this section reported on costs per
treatment or costs per birth; these figures are of limited use as they are jurisdiction‐specific, and
comprised different cost elements in each case. However, an international study concluded that the cost
per live birth in the 10 countries it compared was highest in the US and the UK, and lowest in
Scandinavia and Japan.
Studies estimating the costs and benefits of ARTs strategies:Twenty‐seven studies, from nine countries,
presented the results of models used to estimate potential costs and outcomes of ARTs strategies. These
studies varied in their approaches, and in the specific aspects of the treatment strategy. Nine of the
studies were based on models that used hypothetical cohorts of women. Although cost‐effectiveness
measures were used, it is hard to generalize from the studies because of differences in the models. The
single Canadian study in this group concluded that IVF‐DET was the most cost‐effective strategy across a
wide range of costs, compared to IVF‐SET and stimulated IUI, but the costs were limited to direct costs
only up until birth.
In the past few years, because of an increased interest in public funding of IVF in Canada, a number of
consultant reports have been produced and these have been included in this review. Their focus has
been on long‐term costs due to disability and health care for twins, triplets and HOMs from IVF. These
reports concluded that if public funding were made available in Quebec or Alberta with restrictions on
multiple embryo transfers, there would be tens of millions of dollars saved in lifetime costs due to the
multiple births that would not occur. These reports were not been peer‐reviewed, nor were they
presented in accordance with established guidelines for economic evaluations, and so though their
conclusions might be correct, the actual savings estimated requires further verification.
34

Another sub‐group of studies which used the same general accounting approach concluded that the tax
revenue for government generated by an IVF‐conceived child over his or her lifetime would produce an
overall benefit from the initial investment of publicly funding IVF. The model assumes that an IVF‐
conceived child would grow up to be as employable as a naturally conceived child.
Studies of US state mandated insurance coverage of ARTs services:Finally, six studies examined the
effects of state mandated insurance coverage of ARTs in the US. Four of the studies used regression
models to estimate the utilization of ARTs and birth rates under different types of insurance mandates.
Since the definitions of the extent of insurance coverage were not consistent in all the studies, the
results, some of which are contradictory, should be interpreted with caution. One study estimated fewer
multiple births per transfer and fewer births per cycle in stateswhich mandated insurance coverage of
ARTs compared to states with no mandate. Another study estimated lower rates of births per cycle and
higher multiple births per ARTs birth in states which mandated insurance coverage of ARTs.A third study
reported small but statistically insignificant increases in multiple births in states with strong mandates
for coverage of ARTs. The final modelling study concluded that women under 35 years of age had a
significantly lower birth rate in states with a “universal” mandate (where all insurers must cover ARTs),
compared to states with a “restricted” mandate (that only some insurers cover ARTs); the opposite was
true for older women. Twin birth rates appearedto be unaffected by the type of insurance mandate, but
the rate of HOMB was statistically significantly higher in both age groups in states with a universal
mandate.
The remaining two studies used actual clinic‐level data to compare the effects of different types of
insurance mandates. The first study concluded that for women less than 35 years of age, embryo
transfer rates and multiple birth rates were statistically significantly lower in states with a coverage
mandate than in states with no mandate. Multiple birth rates were also statistically significantly lower in
the 35 to 37 year age group.No statistically significant differences were observed in the outcomes for
the 38 to 42 year old group. The second study had similar findings.
What is more pertinent for policy development in Alberta is the information from economic studies of
single versus double embryo transfer, and the impact this has on multiple birth rates and their
associated costs. Information on this was obtained from more than 40 studies that analyzed the effects
of policies restricting the number of embryos transferred per cycle on costs and outcomes. The policies
studied were implemented through legislation, regulations or guidelines. The cost reductions were
attributed to lower rates of multiple births. However, these policies vary, e.g., in the number of embryos
that can be transferred at each cycle, whether the embryos are fresh or frozen, and in the number of
cycles permitted. Consequently, there are differences in the detailed results from study to study. Since
the age criteria within policies are also different in each jurisdiction, the impacts on costs and outcomes
varied across age groups as well. It is important to note that although there was general agreement that
multiple birth rates fall with restrictive policies on the number of embryos transferred, some studies
reported that pregnancy rates did not change after the policy, while other studies noted significant
reductions in clinical pregnancy rates, particularly in younger women.
35

About 20 studies estimated potential costs or outcomes, or both, of ART under certain assumptions.
Some of these were costing studies that produced the cost per IVF treatment in a jurisdiction, or
compared costs of different treatments. A number of them used modelling approaches to estimate the
potential cost‐effectiveness of different embryo transfer strategies. However, there was a wide range of
strategies analyzed using different decision models that represent different policies and practices. The
studies also varied in the types of costs that were included.Closer examination of each study would be
needed to see if its results could be applicable to Alberta.
Conclusions: Based on this extensive review and the accompanying decision modeland budget impact
analyses, several conclusions can be reached.
 IVF offers a clear benefit over no treatment in improving pregnancy rates.
 Fresh and frozen embryo transfers result in similar pregnancy rates.
 Frozen embryo transfer appears to have fewer adverse events than fresh embryo transfer, and
is at least as safe in terms of infant outcomes.
 The use of top quality embryos results in better live birth rates than those with lesser quality
embryos; success rates arealso better using blastocyst‐stage embryos than cleavage‐stage
embryos.
 ARTs is associated with increased complications during pregnancy and delivery, and increased
rates of multiple births, preterm delivery, low birthweight infants, birth defects and
malformations, and cerebral palsy compared to naturally conceived pregnancies. The underlying
causes of infertility, rather than ARTs procedures, may be responsible for some of these
complications.
 DET increases pregnancy and birth rates compared to SET, but it also substantially increases
multiple pregnancy and multiple birth rates. SET with two cycles (one fresh and, if necessary,one
frozen) achieves pregnancy and live birth rates similar to DET.
 Women who receive multiple embryos have higher rates of adverse events during pregnancy
and delivery compared to women receiving single embryos; similarly, infants conceived through
multiple embryo transfers have worse outcomes than infants conceived through SET.
 In jurisdictions with policies to limit the numbers of embryos transferred per cycle, multiple
births rates have been reduced. However, in some age groups clinical pregnancy rates have also
been reduced.
 Restricting the number of embryos transferred reduces the likelihood of multiple births and
their health and cost consequences.
 Total health care costs associated with pregnancy, delivery, neonatal care and postnatal care (up
to the age of 18 years) for the current cohort of 1,222 IVF/ICSI candidates in Alberta are
estimated to be approximately $316 million (the current Alberta situation without public
funding or regulation).
 Total health care costs associated with ARTs treatment, pregnancy, delivery, neonatal care and
postnatal care (up to the age of 18 years) for the expected cohort of 3,055 IVF/ICSI candidates in
Alberta are estimated to be approximately $219 million (with a restrictive funding policy), $309
36

million (with a permissive funding policy), $255 million (with Quebec's policy), and $866 million
(with a fund without regulation policy). If public funding is provided with regulations, there
would be an estimated total savings(over 18 years) savings to government of $97 million
(restrictive policy), $7 million (permissive policy) and $61 million (Quebec policy).
 Total health care and societal costs associated with pregnancy, delivery, neonatal care and
postnatal care (up to the age of 18 years) for the current cohort of 1,222 IVF/ICSI candidates in
Alberta are estimated to be approximately $609 million (the current Alberta situation without
public funding or regulation).
 Total health care and societal costs associated with ARTs treatment, pregnancy, delivery,
neonatal care and postnatal care (up to the age of 18 years) for the expected cohort of 3,055
IVF/ICSI candidates in Alberta are estimated to be approximately $430 million (with a restrictive
funding policy), $594 million (with a permissive funding policy), $495 million (with Quebec's
policy), and $1.6 billion (with a fund without regulation policy). If public funding is provided
along with regulations, there would be an estimated total savings(over 18 years) savings of $179
million (restrictive policy), $15 million (permissive policy) and $114 million (Quebec policy).
37

Background
The Alberta Health Technologies Decision Process (AHTDP) is part of the Alberta Government’s response
to advice from the Expert Advisory Panel to Review Publicly Funded Health Services to improve decision‐
making regarding providing public funding of health technologies and services.
Under the auspices of the AHTDP, the Health Technology and Policy Unit at the University of Alberta was
commissioned to prepare a health technology assessment on assisted reproductive technologies (ARTs)
for the treatment of infertility. This assessment is intended to update and expand on information
provided in earlier assessments prepared by the health technology assessment partners at the
University of Calgary4,5 and the Institute of Health Economics.6
For the purposes of this review, ARTs are limited to in vitro fertilization (IVF), intracytoplasmic sperm
injection (ICSI), and intrauterine insemination (IUI). Evidence on gamete or zygote intrafallopian transfer
(GIFT or ZIFT) is also included, where appropriate, though these procedures are seldom used in Canada.
Objectives
This assessment is intended to help address the following policy and research questions as specified in
the Project Charter.
Policy questions
The primary policy questions to be answered in this review are:
 Should ARTs be regulated in Alberta? If so, what is an appropriate standard?
 Should ARTs be publicly funded in Alberta, and for whom?
 What are the implications of funding without regulating and of regulating without funding?
Research questions
 To determine the burden of infertility to couples, patterns of care and capacity to deliver care in
Alberta.
 With respect to the mother, what are the safety, effectiveness and cost‐effectiveness of ARTs
with respect to short term and long term outcomes?
 With respect to the child, what are the safety, effectiveness and cost‐effectiveness of ARTs with
respect to short term outcomes (such as preterm birth, low birth weight and multiple births)
and long term outcomes (such as special care and educational needs)?
 What is the most appropriate patient population for ARTs with respect to safety, effectiveness
and cost‐effectiveness?
 What is the budget impact of providing ARTs with and without restrictions on their use?
38

 What are the current standards of regulation and provision of ARTs? What standard of
regulation and provision of ARTs with respect to patient outcomes are supported by available
evidence?
39

Introduction
Assisted reproductive technologies receive considerable media and public attention, and, more so than
most health technologies, they raisean array of social, ethical and legal issues. The public health
implications of ARTs include the clinical outcomes (risks for multiple birth pregnancies, preterm births,
obstetrical complications, and the health of the child); concerns about disease transmission through the
use of donor gametes;social and ethical issues.7
Of all the complex issues entwined with ARTs, multiple birthsis the foremost concern.8,9In a recent
comparison of 21 countries, the SOGC noted that Canada has one of the highest rates of multiple births
from ARTs.10Multiple births pose greaterhealth risks for both the mother and the infants.9 The rise in
multiple gestations, largely due to the increased use of fertility drugs and ARTs,is responsible for a
corresponding increase in maternal and neonatal morbidity and mortality rates, and consequently,
higher hospital and healthcare costs.11‐15In most of Canada (except for Quebec), infertile couples bear
most of the costs involved in trying to become pregnant, but the public health care system carries the
cost burden of multiple births.16
Among Canadian provinces, Alberta has the highest rates of multiple births and preterm births, and one
of the highest rates of small‐for‐gestational age babies, and these rates are increasing.17‐19Assisted
reproductive technologies are one of the forces driving these rates.20
Infertility
Infertility indicates a difficulty in conceiving or carrying a pregnancy to term, but it is not synonymous
with sterility (the inability to reproduce). The distinction is important as over 50% of young adults who
experience infertility may eventually conceive.21 In general, an estimated 84% of couples who have
regular sexual intercourse and do not use contraception will conceive within a year.22 About half of the
remaining couples will conceive in the second year, with a cumulative pregnancy rate of 92% after 2
years.22
This assessment uses the ICMART and WHO definition of infertility or subfertility:
A disease of the reproductive system defined by the failure to achieve a clinical pregnancy after
12 months or more of regular unprotected sexual intercourse.1
Other definitions may use different time spans to define infertility. The 2004 guidance from the UK’s
National Institute for Health and Clinical Excellence (NICE) defined infertility as the inability to become
pregnant after one 1 to 2 years, but their 2013 guidance has revised this definition to 1 year.23,24 The US
Centers for Disease Control and Prevention reduces this period to 6 months for women over 35 years of
age.25 NICE also recommends earlier referral for clinical assessment of infertility for women over 36
years of age.24
40

Various patient groups may be affected by clinical infertility, most commonly, heterosexual couples
where either or both partners may be affected. However, others may be candidates for ARTs due to
different circumstances, for example:
 same‐sex couples who have been unable to conceive with donor insemination
 individuals with physical or psychological conditions that prevent heterosexual intercourse
 young people who want to preserve their fertility before undergoing cancer treatments26‐28
 single women who want to have children, or women who want to postponehaving children for
some time in the future29
 couples who are not infertile, but who want preimplantation genetic diagnosis (PGD) of their
embryos to avoid passing on a known genetic disease
 couples seeking a sibling donor of stem cells for a child who needs a stem cell transplant (human
leukocyte antigen (HLA) matching)
 couples who use ARTs procedures to reduce the risk of passing on transmissible diseases, such
as HIV.30‐32
Some causes of infertility occur early in life.33In males, the Sertoli cells that produce sperm develop
mainly in the fetal and early neonatal period, and cease development at puberty. Environmental or
other conditions that affect the hormonal development of these cells may cause abnormal sperm
production in adulthood.33
In females, the germ cells that later become oocytes (eggs) develop before birth, and are affected by the
“maternal environment” (for example, by maternal smoking, alcoholism or obesity).33 At 4 months the
ovaries of the female fetus contain about 6 to 7 million oocytes. Over half of these oocytes disappear
before birth, and by puberty only about 300,000 to 400,000 remain. The numbers continue to decline
until menopause, when only a few hundred oocytes remain.34,35
Female infertility
Infertility is exclusively due to a female factor in 35 to 40% of couples.36,37Approximately21% to 45% of
female infertility (15% of all infertility in couples)is due to ovulatory disorders.22,38,39Ovulatory disorders
may be caused by various factors, including aging or premature ovarian failure, endocrine dysfunction,
stress, excessive exercise or weight loss, or tobacco use.38,40
The WHO classifies ovulatory disorders into 3 categories:
1. WHO Group 1 – Hypogonadotropic hypogonadal anovulation. These women usually have
amenorrhea and anovulation due to estrogen deficiencies caused by decreased secretion of
gonadotropinreleasing hormone (GnRH) by the hypothalamus, or lack of responsiveness to
GnRH by the pituitary gland. They may also have low levels of follicle stimulating hormone (FSH)
or prolactin (approximately 5% to 10% of anovulatory women are in this category).40,41
2. WHO Group 2 – Normogonadotropic normoestrogenic anovulation. These women are not
deficient in estrogen, and may have normal FSH and prolactin levels, but luteinizing hormone
(LH) levels may be normal or elevated. Most of the women in this group (over 90%) have
41

polycystic ovarian syndrome (PCOS).42Group 2 is the most common type of ovulation disorder
(approximately 70 to 85% of anovulatory women fall within this category).40
3. WHO Group 3 – Hypergonadotropic hypoestrogenic anovulation. This category includes women
with ovarian insufficiency (lack of ovarian follicles due to early menopause) or diminished
ovarian reserve (approximately 10% to 30% of anovulatory women are in this category).40,43,44
Other causes of female infertility include tubal obstruction, endometriosis, uterine polyps or fibroids,
and abnormal cervical mucus. Approximately 14% to 30% of infertile women have damaged fallopian
tubes, sometimesdue to blockage or scar tissue caused by pelvic inflammatory disease (PID).22,26,38
Endometriosis affects approximately 10% to 15% of infertile women. For about 3% to 10% of infertile
women, other conditions of the uterus or peritoneum, such as uterine polyps or fibroids, are the
cause.26,38,45
Male infertility
Male infertility affects 20% to 40% of infertile couples.26,38,46,47Primary hypogonadism (failure of the
testes to produce adequate levels of sex hormones), is the most common known cause of infertility in
men.38Azoospermia (absence of sperm in the semen) affectsbetween 10% to 20% of infertile
men.48,49,49Other causes of male infertility include secondary hypogonadism, varicocele (which affects
about 40% of infertile men), radiation therapy, mumps, trauma to the testicles, retrograde ejaculation,
sexually transmitted diseases (such as chlamydia), and genetic disorders.38,48,48,50
Certain drugs also affect male fertility, reducing sperm production or hormonal levels, orcausing erectile
dysfunction. The offending drugs include prescription drugs, such as antidepressants, beta‐blockers,
thiazide diuretics, and chemotherapy, andrecreational drugs, such as anabolic steroids, heroin, cocaine,
cannabis, and nicotine.50In about half of the cases of male infertility the cause is unknown.38
Unexplained infertility
Approximately 25% to 30% of couples with infertility have both female and male fertility, or have
unexplained infertility (where the cause is unknown).25,26,38,51 One study of couples on a Dutch waiting
list to receive IVF found a cumulative pregnancy rate of 9.1%.52 Pregnancy rates were highest amongst
couples with unexplained infertility, and lowest in those with infertility due to tubal factors or
endometriosis.52The cause and the duration of infertility also affected pregnancy rates.52
Assisted reproductive technologies (ARTs)
Assisted reproductive technologiesinvolve a gamut of health care services including:
 counselling (psychological and genetic)
 diagnostic and monitoring tests (e.g., blood tests, sperm counts, ultrasound scans)
 drug therapies
 procedures (e.g., sperm retrieval and washing,egg retrieval, the use of assisted hatching or ICSI,
and embryo quality assessment, transfer techniques and cryopreservation)
42

 preimplantation genetic diagnosis or screening.

The main concerns with ARTs are the increased rate of multiple births, and the associated risks for
preeclampsia, gestational diabetes, hypertension, miscarriage,obstetrical complications, preterm
delivery and low birth weight, as well as the increased healthcare costs these incur.
The success of ARTs is affected by this complex interplay, in addition to other factors, in particular:
 maternal age (or the age of the eggs)
 the underlying reason(s) for infertility
 lifestyle choices (smoking, alcohol or drug consumption, obesity)53
 the different combinations of ARTs drugs and procedures used by physicians or fertility centres
 whether the sperm, eggs or embryos used are fresh or frozen.25
Some studies have linked IVF(with or without ICSI) to increased risks for neurological disorders
(e.g.,cerebral palsy), birth defects,low birth weight, and infant mortality.11,12,54,55 There may also be a
slightly increased risk for certain rare imprinting disorders (e.g., Beckwith‐Wiedemann syndrome and
Angelman syndrome).54,56
It is important to notethat the risks associated with ARTs multiple births also apply to naturally
conceived multiple births, and that some of these risks are associated with the underlying causes of
infertility, rather than to ARTs.54
Most ARTs pregnancies are uncomplicated and most children conceived from ARTs are healthy in both
the short and longterm.7,57 Nevertheless, there are still gaps in our understandingof the longterm
maternal and child health outcomes associated with ARTs.12,54
Diagnostic tests
Initially, the couple’s physician will ask about their sexual histories and both partners will have a physical
examination (a pelvic exam and Pap test for the woman, and a testicular exam for the man).25,58Before
infertility is finally diagnosed, and during ARTs treatments, many different diagnostic and monitoring
tests are performed.59
Diagnostic tests for female infertility:
 monitoring of menstrual cycles, and at home urine and basal body temperature measurements
to determine when ovulation occurs25,39,58
 hormone profiling to check for hormonal imbalance60
 blood tests to assess ovulation60
 ovarian reserve tests, such as:
o the follicle‐stimulating hormone (FSH) ‐ elevated FSH levels are an early sign of ovarian
aging that typically occurs in women between 35 to 40 years of age
43

o an antral follicle count (AFC) ‐ using transvaginal ultrasound to visualize the number of
antral follicles (an indicator of the number of primordial follicles in the ovary)
o the clomiphene challenge test
o the antimullerian hormone (AMH) test34,35,61,62
 a sonohysterogram ‐ ultrasound combined with an infusion of saline to evaluate the uterus,
ovaries and fallopian tubes60
 a hysterosalpingogram (HSG) – an x‐ray that uses a contrast dye to image the inside of the
uterus and ensure the fallopian tubes are not blocked58
 endometrial biopsy – to test a sample of the tissue lining the uterus for changes indicating a
normal menstrual cycle58
 laparoscopy – examination of the uterus, fallopian tubes and ovaries through a laparoscope
inserted through a small incision, usually with the patient under general anaesthesia (it may also
be used to detect and sometimes treat cysts, fibroids, scar tissue or endometriosis)58
 hysteroscopy – examination of the inside of the uterus via a lighted scope inserted through the
vagina and cervix.58
Diagnostic tests for male infertility:
 semen analysisto check the number, motility and quality of sperm46
 testosterone test (low levels of testosterone can cause low sperm count)58
 testicular ultrasound or biopsy to check for abnormalities in the testicles that may affect sperm
production.58
Some tests may be used for the diagnosis of both female and male infertility. Antisperm antibody
testing, for example, assesses protein molecules produced by the woman’s or man’s immune system
that may prevent the sperm fertilizing the egg.60 Antisperm antibody testing involves a blood test for the
woman and a semen analysis for the man.63 Both partners may also undergo karotyping, a blood test for
chromosomal abnormalities that may cause infertility or recurrent miscarriage.58
Fertility drugs
Most ARTs use drug treatments in combination with the procedures. The earliest of the fertility drugs,
clomiphene citrate (Clomid®), has been in use for over 40 years.64Many ARTs procedures use different
combinations or sequences of drugs depending on the causes of infertility, or if one course of therapy
fails.38 Some of these drugs are approved for other indications and are used “off‐label” for fertility
treatments.38 Other drugs are intended to treat the underlying condition. For example, metformin, an
antidiabetic drug, may be used to treat insulin resistance in PCOS, and nafarelin acetate may be used to
treat endometriosis.25,65 Fertility drugs can be expensive, and may constitute approximately half of the
costs of IVF.66
Some of these drugs, such as clomiphene citrate or the gonadotropins, may be used to stimulate
ovulation, without the use of ARTs. Unfortunately,thesedrug treatments also increase the risk of
multiple pregnancies. Infertility treatments that use drugs alone have even higher rates of multiple
44

pregnancies than those associated with ARTs.9,25,67,68 The American Society for Reproductive Medicine
estimatedthat 21% to 32% of twin pregnancies were due to ovulation induction, and 8% to 16% were
due to ARTs (the remaining 60% resulted from natural conception).9 For higher order multiple
pregnancies (e.g., triplets), 39% to 67% were due to ovulation induction, 13% to 44% were due to ARTs,
and about 20% resulted from natural conception.9
Some fertility drugs, for example, human chorionic gonadotropin (hCG), may also be used to treat
certain kinds of male infertility, such as secondary hypogonadism.69
Table 1. Drugs commonly used in ARTs in Canada
Drug: generic name(s) Brand name(s) Mode of action [Mode of delivery]
Estrogen agonists & antagonists: Clomid®, Serophene®, Act on pituitary gland to stimulate ovulation or replace

clomiphene citrate, estradiol (estrogen Estrace® estrogen in women with ovarian failure [Oral]
tablet), oral contraceptives
Dopamine agonists: bromocriptine, Parlodel®, Dostinex®, Prolactin inhibitors; used to regulate high levels of

cabergoline, quinagolide Norprolac® prolactin (prolactinemia) ‐ a hormone that affects milk
production & ovulation, & to prevent ovarian
hyperstimulation syndrome. May also be used for male
infertility when high prolactin levels affect sperm
production [Oral]
Human menopausal gonadotropin (hMG): Repronex®, Act on ovaries to stimulate ovulation. May also be

menotropin Menopur® used for male infertility due to hypogonadism
[Injection]
Human chorionic gonadotropin (hCG) Ovidrel® Act on ovaries to stimulate ovulation [Injection]
Follicle‐stimulating hormone (FSH): Bravelle®, Gonal‐F®, Act on ovaries to stimulate ovulation [Injection]

urofollitropin, follitropin alfa, follitropin Puregon®
beta
Gonadotropinreleasing hormone (GnRH) – Lupron Depot®, Act on pituitary gland to regulate ovulation (either

agonists & antagonists: leuprolide acetate, Synarel®, Zoladex®, stimulating ovulation or suppressing premature
nafarelin acetate, goserelin acetate, Orgalutran®, Luveris®, ovulation) [Injection / Nasal spray / Skin implant]
ganirelix acetate, lutropin alfa, buserelin Suprefact®,
acetate, cetrorelix acetate, triptorelin Cetrotide™, Trelstar®
Antihyperglycemic agent: metformin Glucophage® Used for women with insulin resistance or polycystic

ovarian syndrome to lower levels of male hormones &
stimulate ovulation [Oral]
Progesterone Crinone®, Used to thicken the lining of the uterus for egg

Prometrium®, implantation [Vaginal gel or insert]
Endometrin®
Aromatase inhibitors: letrozole, Femara®, Arimidex® Used off‐label for hormone therapy in both male
45

anastrozole &female fertility treatments [Oral]
Note: The brand names of these drugs sometimes differ between countries and companies. The table shows some of the drugs
commonly used in ARTs treatments in Canada, but it may not be a complete list. Some of these drugs are approved in Canada
for other indications and used “off‐label” in infertility treatments.
Intrauterine insemination (IUI)
Artificial insemination involves placing the sperm into either the cervix or the uterus. The latter is known
as intrauterine insemination. In IUI the sperm is placed in the woman’s uterus using a catheter. It is an
option for some kinds of infertility, such as those due to endometriosis, unexplained infertility, problems
with ovulation, and mild male factor infertility.70 The woman mayalso receive controlled ovarian
stimulation (COS) with fertility drugs to increase the production of eggs – which also increases the risk
fora multiple pregnancy.57,71 Themultiple birth rate with IUI ranges from 21% to 29%.72 Although it is less
expensive and less invasive than IVF, IUI still requires frequent diagnostic tests (blood tests and
ultrasounds) to determine when the woman is ovulating.66
The success rate of IUI (10% to 15%) is considerably lower than that for IVF (20% to
30%).73Unfortunately, there is no registry of Canadian IUI outcomes.74However, the UK does collect data
on IUI “success rates” (which means pregnancy rates, rather than live birth or “take‐home baby” rates).
For 2008, the reported UK IUI success rates using donor sperm were:
 16% for women under 35 years of age
 11% for women from 35 to 39 years of age
 1% for women between 43 and 44 years of age
 0% for women over 44 years of age.71
For some kinds of infertility (e.g., unexplained infertility, mild endometriosis, or low sperm count), up to
6 cycles of IUI may be used before IVF is considered.71Intrauterine insemination is not used for women
with blocked or damaged fallopian tubes.70
Gamete intrafallopian transfer (GIFT)
In GIFT both the eggs and the sperm are transferred to the fallopian tube.1Because fertilization occurs
within the woman’s body this procedure is more acceptable to some religious faiths than other ARTs
treatments.75
Zygote intrafallopian transfer (ZIFT)
In ZIFT the zygote (the early, diploid stage embryo resulting from fertilization) is transferred into the
fallopian tube.1A particular disadvantage of both GIFT and ZIFT is that the woman must undergo
laparoscopic surgery with general anesthesia when the cells are transferred to the fallopian
tube(s).76Guidance from the UK National Institute for Health and Clinical Excellence (NICE) concluded
that there was insufficient evidence to recommend the use of GIFT or ZIFT, rather than IVF, to couples
with unexplained or male factor fertility.23Guidelines prepared by the SOGC excluded studies of GIFT and
46

ZIFT“since they are rarely used in Canada”.57A recent US review on infertility also notes that these
procedures are rarely used.76
In vitro fertilization (IVF)
Since the birth of the first IVF baby, in 1978, the European Society of Human Reproduction and
Embryology estimates that over 5 million IVF babies have been born worldwide, and between 1% to 4%
of babies born in developed countries are now conceived through IVF.12,77,78
In vitro fertilization involvesseveral steps, often referred to as a “cycle of treatment”, that take place
over a period of weeks:
1. Ovarian stimulation: the woman takes fertility drugs to stimulate the ovaries to produce more
egg cells (normally only one egg is produced each month). When these cells are mature she is
given another drug that causes the follicles to release the eggs.
2. Egg retrieval: the physician extracts the eggs from the woman’s body in an outpatient surgical
procedure called follicular aspiration or extraction.
3. Insemination and fertilization: the sperm is placed with the best quality eggs in a controlled
environment (insemination). Fertilization (when the sperm enters the egg) usually occurs within
a few hours.
4. Embryo culture: the fertilized eggs begin to divide and become embryos.
5. Embryo quality assessment:an embryologist evaluates the quality of the embryos based on their
morphology (e.g., number and size of cells, rate of development, symmetry, nucleation, zona
pellucida, and levels of fragmentation). The best quality embryo(s) are selected for transfer. The
Society for Assisted Reproductive Technology (SART) has developed a standardized embryo
grading system that can be applied to both cleavage and blastocyst stage embryos. On this scale,
embryos are classified as good, fair, or poor, depending on the number of cells and degree of
fragmentation, symmetry, and compaction.79While most American and Canadian fertility clinics
use the SART system in clinical practice, various grading systems are applied in the published
literature and internationally, making it difficult to compare IVF across research studies.80
6. Embryo transfer: about 3 to 5 days after fertilization the embryo(s) are placed in the woman’s
uterus via a catheter passed through the cervixusing ultrasound visualization.76,81,82
Delayed transfer of the embryo at the blastocyst stage (5 days post‐fertilization, rather than at the
earlier 2 to 3 day stage of the embryo) offers some advantages, particularly in patients with good
prognosis and those using donor eggs.83These advantages include improved ability to assess the quality
of the embryos to select for transfer,and higher implantation and pregnancy rates.83
Single embryo transfer (SET) refers to the transfer of one embryo to the uterus.In elective single embryo
transfer (eSET) one “high‐quality” embryo is selected for transfer from the embryos available.84 Double
embryo transfer (DET) is the transfer of 2 embryos, and in some cases, triple (TET) or quadruple (QET)
embryo transfer may be used. The risk of multiple pregnancy increases with the number of embryos
transferred.85Unused embryos are usuallycryopreserved (frozen) for use in subsequent cycles of IVF.
47

Depending on the wishes of the couple, unused embryos may be donated to other couples, for research
use, or discarded.81,86
Natural cycle IVF (NIVF) is in vitro fertilization without the use of fertility drugs to stimulate egg
production.Although it is less expensive and less risky(e.g., no danger of ovarian hyperstimulation
syndrome from the fertility drugs),NIVF is also less effective than IVF.The 2013 UK guidance
recommends that NIVF not be offered.24
Assisted reproductive technologies are expensive ‐ one cycle of ovarian stimulation in Canada can cost
from CDN $7,750 to $12,250 ‐ or more if the woman needs higher doses of fertility drugs.16,87,88The
drugs alone cost several thousand dollars, the IVF procedure costs approximately $5,000, and other
procedures, such as semen analysis, cryopreservation, ovulation monitoring and infertility
counsellingadd to the costs.87Despite the expenses involved there is no guarantee of a baby.
The success rates of IVF are often reported using different measures, making it difficult to compare
outcomes. For example, some studiesreport the clinical pregnancy rate rather than the live birth rate.89
Moreover, these rates may be reported per cycle or number of cycles, rather than per patient. A recent
Cochrane review concluded that future ARTs trials should provide both live birth rates and cumulative
live birth rates per patient (i.e., complete follow‐up through the use of both fresh and frozen
embryos).89
Many countries have data registries to track ARTs procedures and outcomes.90‐92The Canadian Fertility
and Andrology Society (CFAS) compiles annual statistics from 28 participating ARTs clinics in the
Canadian Assisted Reproductive Technologies Register (CARTR).93Preliminary results of Canadian live
birth rates (from 2010 cycles) were similar to those reported by registries in other countries, including
the US.94The overall Canadian live birth rate per IVF cycle (including ICSI‐IVF) was 34%.94The breakdown
of live birth rates per IVF cycle by maternal age was:
 43% for women under 35 years of age
 18% for women 40 years of age or older.94
Of these births, 75% were singletons, 23% were twins and 2% were triplets or other higher order
multiples.94For comparison, the rate of multiple pregnancies in the general Canadian population is
approximately 2%.95Registers from countries with policies that promote single embryo transfer show
markedly lower rates of multiple births. Australia and New Zealand, for example, increased the rates of
single embryo transfers from 48.3% in 2005 to 69.7% in 2009, which resulted in a decrease in the
number of ARTs‐related multiple births ‐ from 14.1% in 2005 to 8.2% in 2009.90Similarly, Sweden’s single
embryo transfer protocol has reduced ARTs‐related multiple births to less than 6%.95Singleembryo
transfer has a slightly lower live birth rate per cycle, but this can be redressed by subsequent frozen
single embryo transfer cycles.96
Assisted hatching
48

Assisted hatching is a laboratory procedure that uses either a chemical solution, mechanical or laser
techniques to thin the outer coating of the fertilized egg (the zona pellucida), making it easier for the
blastocyst to hatch and implant into the uterine lining.97 The 2013 UK guidance advises that assisted
hatchingis not recommended because it has not been shown to improve pregnancy rates.24A further
concern is apossible increase in multiple gestations in zona pellucida‐manipulated cycles.15,41,98
Intracytoplasmic sperm injection
Intracytoplasmic sperm injection (ICSI) involves injecting a single sperm directly into the egg to increase
the chances of fertilization in conjunction with IVF.1 It is used to treat some types of male infertility, for
exampleazoospermia, where the ejaculate does not contain enough sperm, or low sperm motility, or
when fertilization has not occurred in previous treatment cycles.41,99,100
Various techniques are used to retrieve the sperm for ICSI, including:
 percutaneous epididymal sperm aspiration (PESA), which uses a needle and syringe to aspirate
sperm from the head of the epididymis. The procedure may be performed by a urologist with
training in male infertility using a regional spermatic cord block with local anesthesia or under
general anesthesia.101
 testicular sperm aspiration (TESA) or microsurgical extraction (TESE) uses a needle to aspirate or
surgically remove sperm or tissue from the testis; usually performed under local anesthesia.
 microepididymal sperm extraction (microTESE)is a more invasive procedure in which the
scrotum is cut open and the epididymis dissected to allow aspiration of the sperm. It is
performed under general anesthesia and only used when other methods of sperm retrieval
fail.101
Open surgical biopsy may also be used to remove sperm from the testes. Adverse events (usually minor)
associated with these sperm retrieval procedures include bruising, bleeding, and pain.101
Most studies of ICSI have focused on possible adverse events in the children, particularly, chromosomal
abnormalities and birth defects. Recent studies suggest that these risks arelikely due to the association
between male infertility (in particular, azoospermia and oligozoospermia) and higher rates of
chromosomal defects and hereditary diseases, such as cystic fibrosis.50,57,102
Preimplantation genetic testing
Preimplantation genetic testing may be used for either diagnosis or for screening. This procedure
removes and biopsies a cell from an early stage embryo produced by IVF to test for the presence
ofspecific genetic diseases before it is implanted.30Preimplantation genetic diagnosis (PGD) was
introduced in 1990 as an alternative to prenatal diagnosis in early pregnancy (such as with
amniocentesis) for couples with a known risk of passing on a serious genetic disease to their
children.103Itis most often used to identify serious genetic diseases, such as Huntington’s disease,
thalassaemia, sickle cell disease, mitochondrial disease, and cystic fibrosis, or sex‐linked conditions, such
as Duchenne muscular dystrophy.104Less commonly, PGD is used for human leucocyte antigen (HLA)
tissue matching if an existing sibling has a medical condition requiring stem cell transplantation
49

(popularly called “saviour siblings”).104 The diagnostic accuracy of PGD is approximately 98%, and the
number of genetic diseases that can be detected by PGD is growing.30,104,105
Preimplantation genetic screening may be used to detect aneuploidy (an abnormal number of
chromosomes). Aneuploidy is the most common abnormality in human embryos. It includes many
different conditions caused by an extra or a missing chromosome – Down syndrome is one
example.30,106The risk of aneuploidy increases with maternal age.107 Preimplantation genetic screening
allows more viable embryos to be transferred and reduces the risk of miscarriage, but it is not yet used
in routine IVF practice.104
Sperm, egg, and embryo cryopreservation
Cryopreservation is a freezing method used to store sperm, eggs, testicular or ovarian tissue, and
blastocysts or embryos for future use.1 An IVF procedure may use a “fresh” embryo for the first cycle,
and store (freeze) any extra embryos for subsequent attempts.108 However, cryopreservation is not
alwayssuccessful in preserving viable tissue ‐ particularly for cryopreservation of eggs and ovarian
tissue.28
The question of whether fresh or frozen embryos produce better clinical results is discussed in the T
section of this report. Researchers in The Netherlands recently found that different commercial culture
media used during the in vitro process may affect subsequent birth weight.109,110
Health Canada approval
In Canada, the Assisted Human Reproduction Act prohibits:
 human cloning
 altering the genome of a human cell or in vitro embryo
 transplanting a non‐human sperm, egg, embryo or fetus into a human
 payment for surrogacy
 the sale of human eggs, sperm or embryos, and
 the use of PGDfor sex selection (other than to “prevent, diagnose or treat a sex‐linked
disorder”).111
Under the Act, the Assisted Human Reproduction Canada (AHRC)agency was set up to ensure
compliance and establish ethical principles regarding assisted reproduction, human rights, and privacy.
However, regulations for the Act, to enable the Agency to inspect and license ARTs facilities and enforce
the Act, were never put into effect, and the Agency is slated to close in March 2013.112,113 In 2010, the
Supreme Court of Canada ruled in favour of a Quebec appeal, basically, that “provision of medical
services and the professional regulation of the practice of reproductive medicine” falls under provincial
jurisdiction.114‐116Meanwhile, other sections of the Assisted Human Reproduction Act remain in effect
(e.g., the ban on cloning, etc.) and Health Canada will assume responsibility for other functions of the
agency, including “compliance and enforcement, and outreach”.112,115
50

The drugs used to treat infertility in Canada (Table 1) have received Health Canada Notices of
Compliance.117Though, for some drugs their use in infertility treatments may be an off‐label indication.
Donor semen is classed as a drug in Canada and regulated under the Food and Drugs Act and the
Processing and Distribution of Semen for Assisted Conception Regulations.118 Canadian ARTs centres
must comply with these regulations for storage, screening for disease, labeling, and tracking of donor
semen. This includes a 6‐month quarantine during which the sperm is frozen.119
Other than the medical devices used in ARTs procedures, the procedures themselves are not regulated
by Health Canada. Medical practice is regulated by provincial legislation and through the provincial
colleges of physicians and surgeons.The College of Physicians and Surgeons of Alberta has issued a
Standard & Guideline on the provision of IVF in non‐hospital settings.120
51

Methodology
Literature search
Several literature searches were performed for each of the main areas of focus for this assessment.
These areas were: ARTs funding, regulations and policies; systematic reviews of clinical effectiveness;
primary studies to update information from the clinical systematic reviews; economic studies; clinical,
economic and health utilities literature to inform the decision model, and searches for sub‐topics within
the social and demographics section. The searches combined Medical Subject Headings (MeSH) and
other controlled vocabulary terms (such as Reproductive Techniques, Assisted; Fertilization in Vitro;
Embryo Transfer; Single Embryo Transfer) with additional keywords (such as assisted reproduct* or IVF).
The searches were run in the mainbiomedical bibliographic databases, including: PubMed (MEDLINE and
non‐MEDLINE sources), The Cochrane Library, the Centre for Reviews & Dissemination (DARE, NHS EED,
and HTA databases), EMBASE, Web of Science, Scopus, CINAHL, PsycINFO, and EconLit (used for the
economics search only).
Searches were limited to English language studies published within the last 5 years, with the exception
of the economics search which was extended to cover the last 10 years. The PubMed search for primary
clinical studies to supplement and update the systematic reviews was limited to 2008 to date.No date
limits were applied in the searches for evidence to inform the decision model, but the most recent
literature that provided robust estimates for each component was sought.Monthly update searches
were run in PubMed throughout the project (until February 2012).Various filters were used for the
clinical and economics searches. Search results were collected in a Reference Manager (v. 12) database
and duplicate citations were removed.
The grey literature searches included web sites of ARTs‐related professional and patient associations,
guidelines, clinical trials, health technology assessment agencies, grey literature databases, and Google
searches. In the search for policies we checked the ministry of health web sites for each of the selected
countries (and, when possible, the provinces and states within the countries) using keywords such as
“assisted reproduct*”, IVF, and “in vitro fertili*”. Google searches for each country used the country
name in combination with the search terms: (IVF OR "assisted reproduct*" OR "in vitro fertili*") AND
(policy OR policies OR regulat* OR legislat* OR guideline*).
We checked the web sites of key international and national organizations in this field, including the
European Society of Human Reproduction and Embryology (ESHRE), the International Federation of
Fertility Societies (IFFS), the Society of Obstetricians and Gynaecologists of Canada (SOGC), and the
Canadian Fertility and Andrology Society (CFAS). We also used additional sources, such as web site links,
references from other papers, and personal contacts in various provinces and countries. Clinical experts
in Alberta were contacted for information on clinical practice here. Details of the searches are shown in
Appendix H.
52

Ultimately, over 1,400 papers, web pages and other documents were reviewed in the preparation of this
assessment.
Selection and synthesis of literature
Social and demographic review
The titles and abstracts of all search results were independently reviewed by two researchers to identify
information for the social and demographic section. Information from the studies was extracted by one
researcher and summarized narratively. No formal critical appraisal was performed on these studies.
Environmental scan of ARTs policies
For the comparison of ARTs policies in Canada and elsewhere, countries were selected from the top
ranked OECD nations and through discussion with Alberta Health. Four researchers compiled
information for a sub‐set of countries using two data extraction tables – one for policies (legislation,
regulations, guidelines, funding and coverage, etc.), and the other for studies of outcomes resulting
from these policies. For the policy outcomes review, studies from additional countries were
included.Note: information from the policy outcomes review is included in the Economic evaluation
section as these papers included both economic and utilization studies.
Language barriers may have prevented us from identifying some relevant legislation and other
information from countries where official documents are not available in English. Where original sources
could not be found we relied on information from other recent reviews, with the caveats that apply
when using secondary sources. We tried to use the most current information available, but ARTs policies
are constantly changing, andwhile some governments have recently decided to start funding ARTs,
others have decided to reduce funding.121‐123
Clinical effectiveness review
The titles and abstracts of all search results were independently reviewed by two researchers. Over 230
potentially relevant clinical papers were retrieved for full text review. Each paper was screened by two
researchers using a standard data abstraction form and the study inclusion and exclusion criteria
(seeTable 2). In addition, over 220 articles were selected to inform aspects of the decision model.
Each reviewer independently extractedinformation from the included studies using a standard, pre‐
tested data abstraction form and a set of decision rules. The form contained the elements for assessing
the purpose, methods, and findings of each study (seeTable 3). If these elements were not described in
the review, primary studies were pulled to complete missing information. Disagreements between
reviewers in either study inclusion or data extraction were resolved through discussion and third party
review. Information collected from studies was summarized in tabular form.
The quality of each systematic reviewwas assessed using two validated and widely used scales: the
Oxman and Guyatt index of scientific quality scoring system for systematic reviews124,125 and the PRISMA
statement checklist126 (seeAppendix,Table 22 and Table 23).
53

Table 2. PICOS elements of the clinical effectiveness review protocol
Parameter Inclusion Criteria Exclusion Criteria

Participants  Couples 18 years of age and older with infertility
Intervention  IVF
 ICSI
Comparator  Less invasive ARTs (ovulation induction (OI), intrauterine insemination
(IUI))
 Procedural differences, such as:
‐ number of embryo’s transferred
‐ blastocyst vs. cleavage embryo transfers
‐ frozen vs. fresh embryo transfers
‐ IVF with or without ICSI
 Population differences:
‐ maternal and/or paternal age
‐ other risk factors (body size, alcohol or tobacco use)
Outcomes  Any pregnancy‐related or maternal clinical outcomes, including but not  Studies without any
limited to, miscarriages, pregnancy and/or live births, multiple defined clinical
pregnancies, caesarean deliveries, preterm birth, quality of life outcomes
 Any neonatal clinical outcomes, including but not limited to,
prematurity, birth defects, low birth weight, quality of life
 Patient preferences
Study Design  Systematic reviews  Primary studies†
 Health technology assessments
†Primary studies will be included if there is not enough information found in reviews or HTAs to answer the questions
in this project. Further, reviews and HTAs will be updated with primary studies where necessary and if available.

Table 3. Summary of data abstractionform elements
Parameter Description of information collected
Design  country, objective, literature search, study selection, qualitative or quantitative analysis
Studies  characteristics of included studies (number, design, publication dates, publication countries)
 quality of included studies
 characteristics of population of included studies
 characteristics of procedure used in included studies
Outcomes  any pregnancy‐related, delivery‐related, or maternal clinical outcomes
 any neonatal, infant, childhood, and adulthood clinical outcomes
Review  Oxman & Guyatt index of scientific quality125
quality  PRISMA statement checklist126

Economic evaluation
Two reviewers independently reviewed the results of the economic literature searches and selected
studies for full review. Researchers also identified economics studies from the clinical, policy and grey
literature search results. All types of economic studies (e.g., costing studies, cost‐effectiveness analyses,
cost‐consequence analyses, and budget impact analyses) were considered for inclusion. Over 180
economic studies were retrieved for full review. The quality of each economic study was independently
assessed by two reviewers using an accepted checklist for economic evaluations.127
54

Social systems and demographics (S)
Burden of illness
Infertility decreases quality of life, preventing individuals from having what they may consider to be a
full and “good life”.128Those affected by infertilityoften describe feelings ofsadness, psychological stress,
depersonalization, guilt and social isolation.38,83,129,130Infertility may be a source of marital tension and
loss of libido.41Women who experience infertility report significantly lower quality of life scores for
“mental health, social functioning and emotional behaviour”, though infertility appears to have less of
an impact on men’s quality of life.131
Evidence from long term studies is limited, but the effects of infertility on quality of life may diminish
over time.132 A recent German study found that 10 years after infertility treatment, those who remained
childless and those who had become parents had similar levels of quality of life.133 The main reported
difference was in levels of self‐esteem, which were higher for couples and women with children, though
childless women reported higher levels of job satisfaction.133 A Swedish study of couples 20 years after
IVF, found that over 90% of those who remained together had either biological or adopted children, or
both.132 Most of the couples who remained together rated their relationship as good, whether or not
they had children.132
The UK’s Human Fertilisation & Embryology Authority (HFEA) web site describes many women’s
experiences of infertility and ARTs treatments.134 Patients reported feelings of disappointment, anger,
resignation, and of an “… emotional rollercoaster… [and] most importantly that your life feels like it is on
hold.”134 As well as the psychological burden of infertility, the underlying health conditions may also
cause physical symptoms that affect quality of life, such as pain, heavy menstrual periods, or
hirsutism.135
Infertility may also carry social stigma, though this may be decreasing as more couples seek treatment
for infertility.21,72,136In Australia, where a substantial portion of ARTs treatments are publicly funded, the
stigma associated with infertility has declined and support for public funding of IVF has grown.67,137,138A
Canadian survey of attitudes towards ARTs found “a very clear acceptance of IVF, [but otherwise]
participants … were not positively predisposed to the use of third‐party treatment options (e.g. donor
eggs, surrogacy, etc.)…”.139
Infertility treatments also impose a significant burden of pain and psychological distress.81,140Fertility
drugs can cause mood swings, anxiety, depression, headaches, bloating and abdominal pain.7,81Ovarian
hyperstimulation syndrome (OHSS) affects between 2% to 5% of women taking fertility drugs, and
women with PCOS are particularly at risk.21,40Recent studies suggest fertility drugs may increase the risk
for certain types of cancer (e.g., breast, uterine and ovarian), but this evidence is still inclusive.7,7,135
However, infertility has been linked to an increased risk for ovarian cancer.40Egg retrieval procedures
also carry risks from the anesthesia, bleeding, infection, and damage to adjacent tissue.73
55

Some ARTs procedures may ultimately involve other interventions that cause feelings of guilt, anxiety
and loss, such as the need to consider fetal reductionin the case ofhigh order multiple gestations.141‐143
A recent US study of patients’ reasons for terminating IVF treatments found that, rather than financial
pressures, the psychological or emotional burden of IVF was the most common reason.144 The
psychological burden was also cited by patients in European and Australian studies where public funding
of IVF is provided.144 A recent commentary on Israel’s funding of unlimited IVF questions the value of
endless cycles of IVF, and notes a “perseverance‐trap” for women who may feel pressured to continue
treatments despite the decreasing chance of success after the first 3 cycles.145
The fertility drugs used for ARTs increase the risk for multiple births, and these impose a significant
burden in terms of maternal and neonatal health.143Blastocyst transfer and manipulation of the zona
pellucida (such as for assisted hatching) mayalso increase the risks for monozygotic twins.15,143A section
of the Assisted Human Reproduction Canada web site describes the health risks associated with multiple
births, and the emotional, psychological and financial challenges couples may face.146
Increased maternal risks with multiple births include higher rates of gestational diabetes and
hypertension, placental abruption, pulmonary emboli and edema, hospitalization during pregnancy,
caesarean births, and longer hospital stays for both mothers and newborns.143
Increased risks to the babies of multiple births include higher rates of stillbirth, growth restriction, and
cerebral palsy.15The risk of cerebral palsy is estimated to be 4 times higher in twins, and 17 times higher
in triplets than in singleton births.15 The risk of death in the first year of life is 7 times higher for twins,
and 20 times higher for triplets than for singletons.15,143
Parents of children with disabilities experience long term, continual stress that may undermine their
marriage and their capacity to cope.147,148
The cost of infertility treatments also imposes an economic burden on couples and on the healthcare
system.135 A US systematic review estimated that annual costs for infertility treatments in the US were
over US$3 billion.135In countries where full or partial public funding is not provided, couples or
individuals face significant out‐of‐pocket costs to undertake ARTs treatment.73A couple’s household
income affects the likelihood that they will seek infertility treatment.149The Ontario review on infertility
found that the “single greatest barrier to assisted reproduction services is the cost…[which is] beyond
the reach of most Ontarians”.72 The review also noted that many Ontario couples are choosing to
undergo IUI, rather than IVF, because it is publicly funded. This is problematic asIUI may not be the most
effective treatment for their condition. Moreover, IUIresults in more multiple births, and wastes
precious time and resourcesif IVF is eventually needed.72
Fertility treatments also involve many indirect costs. For example, ARTsconsumeconsiderabletime due
to thenumerous medical appointments and tests that necessitate time off work or away from family and
regular daily activities.81,83
56

Prevalence and incidence
The prevalence of infertility in Canada is similar to that of other western countries, where it is estimated
that 10% to 15% of couples experience infertility.13Data from the infertility component of Statistics
Canada’s 2009‐2010 Canadian Community Health Survey, indicates the prevalence of infertility in
Canada ranged from approximately 12% to 16% depending on the definition of infertility used (for
example, the period of trying to conceive, or current versus lifetime infertility).13,150 About 16% of
couples reported “current infertility” or infertility over the past 12 months.13,150 This is an increase over
the 5.4% prevalence rate found in a 1984 Canadian survey.13 The Statistics Canada Canadian Community
Health Survey found that approximately 15% of Canadian couples that included a woman between the
ages of 18 to 44, reported seeking medical assistance for conception.150
Earlier Canadian studies, for the Royal Commission on New Reproductive Technologies, estimated the
prevalence of infertility in Canada was about 7% (based on the inability to conceive after 2 years), or
8.5% (based on the inability to conceive after 1 year).36 Assisted Human Reproduction Canada uses the
8.5% estimate.151
Alberta Health billing data (physician claims, ambulatory care and inpatient databases) provided the
following information on the incidence and prevalence of male and female infertility in Alberta.
Table 4. Cases of male and female infertility in Alberta 2005/2006
Number of incident cases Number of prevalent cases
Year Male Female Male Female
2005 4,659 6,854 6,058 11,393
2006 4,962 7,528 6,473 11,868
Incident cases = patients with no infertility diagnosis or testing in the year prior to the first diagnosis or testing in 2005/2006.
A 2007 review of ARTs estimated that the prevalence of male infertility in Alberta increased from 0.43%
in 2001 to 0.51% in 2006, while the prevalence of female infertility increased from 0.90% to 0.97% over
the same period.5 From 1998 to 2007, the number of Albertans diagnosed with infertility increased from
12,747 (3,625 men and 9,122 women) to 19,005 (7,069 men and 11,936 women).5
UK estimates are that one in six couples is affected by infertility.152 A US systematic review estimated
that approximately 7% of married couples in the US experience infertility.135 Worldwide, an estimated
9% of couples experience infertility, and about 50% to 60% of these couples seek treatment.135
A recent Canadian survey found no association between infertility and level of education or household
income, but did show a clear association between a woman’s age and infertility rates.13The survey also
found an increased prevalence of current infertility over the 1984 survey rate of 4.6% in couples where
the woman was aged 40 to 44, versus 14.3% to 20.7% for the same age group in 2009‐10.13 The
prevalence of infertility in younger women, aged 18 to 29, also increased over this period – from 4.9% in
1984 to from 7.0% to 13.7% in 2009 to 2010.13The increase in the prevalence of infertility over this
57

period may be due to various factors, including the trend for women to delay childbirth, and to
increasing rates of obesity, alcohol consumption, and sexually transmitted diseases.13,153
The US Centers for Disease Control and Prevention, which collects data on ARTs procedures and
outcomes from most US fertility clinics, found that preterm births and low birth weight infants are
disproportionately higher among ARTs births.82However, ARTs births constitute a relatively small
percentage of total births. Consequently, the increase in low birth weight and preterm births cannot be
attributed solely to ARTs, and other causes, such as the use of fertility drugs for ovulation stimulation,
and the impact of women delaying childbirth until their thirties, should also be examined.15,82
Although ARTs are only one of many possible causes, they may be contributing to Alberta’s rising rates
of multiple and preterm births, low birth weight and small‐for‐gestational age babies, and caesarean
sections.20Statistics Canada data show that, from 2004 to 2008, Alberta had the highest rate of multiple
births in Canada (an average of 3.3% of all live births and stillbirths), with the possible exception of
Ontario for which data were not available.17 The Alberta rate increased slightly in subsequent years, to
3.5% in 2009, and 3.4% in 2010.19 Alberta also had the highest rate of preterm births among the
provinces (an average of 8.6% from 2000 to 2009), and one of the highest rates of small‐for‐gestational
age babies (8.7% in 2006‐2007).18,19The rate of low birth weight babies in Alberta in 2010 was 6.8%,an
increasefrom 6.1% in 2001.19,20In 2009, 27.8% of hospital deliveries in Alberta involved caesarean
section, also an increase from 22.5% in 2001.19
Data from the Alberta Perinatal Health Program (APHP) show that of 113,359 babies born in the
province from April 1, 2009 to December 31 2011, almost 4,000 were a result of assisted conception,
with 2,385 (2%) babies born as a result of IVF/ICSI in particular (see Table 5). This number may, however,
be an underestimate, as APHP data is dependent on documentation of assisted conception at the time
of delivery.Twin and higher‐order multiple pregnancies made up 12% of pregnancies resulting from
ovulation induction or IUI, 30% of pregnancies from IVF/ICSI, and 1% of ‘spontaneous’ pregnancies (no
record of assisted conception). No higher‐order multiples were reported in women with no record of
assisted conception. The number of complicated pregnancies, preterm deliveries, caesarean deliveries,
and babies admitted to the NICU were also higher in women with a record of ovulation induction or IUI
and IVF/ICSI, compared to those with no record of assisted conception. Overall, out of all of the babies
born during this time period, about 4% were multiples, with just over 3% born to women with no record
of assisted conception, and the other 1% born to women with some form of assisted conception,
primarily IVF/ICSI. Further, about 8% of all preterm deliveries and 8% of all NICU admissions occurred in
women with a record of assisted conception.
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Table 5. Delivery and birth outcomes of women in Alberta by method of conception: data from the Alberta
Perinatal Health Program
Ovulation induction
No assisted conception and/or IUI IVF/ICSI
(N = 108,086 women; (N = 1,295 women; 1,445 (N = 1,807 women; 2,385
109,529 babies) babies) babies)
Total number (%) of women
<35 years: 90,942 (84%) 905 (70%) 845 (47%)
35‐39 years: 14,371 (13%) 320 (25%) 664 (37%)
≥40 years: 2,773 (3%) 70 (5%) 298 (16%)
Total number (%) of women with
singleton pregnancy: 106,663 (99%) 1,152 (89%) 1,262 (70%)
twin pregnancy: 1,403 (1%) 136 (11%) 513 (28%)
HOM pregnancy: 20 (<1%) 7 (1%) 32 (2%)
Number (%)of women with pregnancy
complications†: 18,532 (17%) 398 (31%) 611 (34%)
Number (%) of women with preterm
delivery: 8,865 (8%) 200 (15%) 526 (29%)
Number (%) of women with
spontaneous vaginal delivery: 66,260 (61%) 618 (48%) 637 (35%)
assisted vaginal delivery: 13,277 (12%) 184 (14%) 260 (14%)
caesarean delivery: 28,497 (26%) 492 (38%) 909 (50%)
Total number (%) of babies from
singleton pregnancy: 106,663 (97%) 1,152 (80%) 1,262 (53%)
twin pregnancy: 2,806 (3%) 272 (19%) 1,026 (43%)
HOM pregnancy: 60 (<1%) 21 (1%) 97 (4%)
Number (%) of stillborn babies: 853 (1%) 27 (2%) 29 (1%)
Number (%) of preterm babies: 9,705 (9%) 294 (20%) 913 (38%)
Number (%) of singletons born preterm:
8,045 (8%) 113 (10%) 172 (14%)
Number (%) of multiples born preterm:
1,660 (58%) 181 (62%) 741 (66%)
Number (%) of babies with NICU
admission: 11,786 (11%) 272 (19%) 787 (33%)
Number (%) of singletons with NICU
admission: 10,433 (10%) 125 (11%) 168 (13%)
Number (%) of multiples with NICU
admission: 1,353 (47%) 147 (50%) 619 (55%)
Data from the Alberta Perinatal Health Program from April 2009 to December 2011 (collected from the Alberta Provincial Delivery
Record).Reliability of data dependent on documentation of assisted conception at the time of delivery.
†Complications consist of bleeding, gestational hypertension, or gestational diabetes

Risk factors
Age
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Women in Canada and other developed countries are delaying childbirth – typically until their late 20s
or early 30s.35,139,154,155Recent Statistics Canada data indicates that nearly 1 in every 5 live births in
Canada is to a mother over the age of 35.156 This rate increased approximately 3% from 1998 to 2007,
and the trend is expected to continue. Over the same period, the live birth rate in women over the age
of 40 increased by 48%.156Even with natural conception,older women have higher rates of multiple
births.15,18Currently, almost one of every three first‐time mothers in Canada is over the age of 35.156
Women are most fertile in their early twenties, after which their fertility declines steadily until about
age 35 when a more marked decline occurs, followed by a further steep decline after the age of 40.129
Maternal age is associated with a decrease in the number of eggs and with lower quality eggs. It also
increases the risks for spontaneous miscarriage, chromosomal abnormalities (such as Down syndrome),
and stillbirths.15. Advanced maternal age (over the age of 35),also increases the risk of infertility,
obstetrical and perinatal complications.155,156These risks include gestational diabetes, hypertension, pre‐
eclampsia, placenta praevia, and the need for assisted vaginal delivery or caesarean section.35,155‐157
Women over the age of 35 also have an increased risk ofpreterm delivery (before 37 weeks of
pregnancy), low birth weight and small‐for‐gestational‐age babies.18,156
Figure 1. Natural conception ‐ trends in pregnancy & miscarriage according to age

Source: Reproductive aging: guidelines for first line physicians for investigation of infertility problems. Montreal
(QC): Canadian Fertility and Andrology Society; 2004.158
The age at which menopause occurs varies considerably.34,35 Some women remain fertile well into their
forties while others experience loss of fertility in their thirties.34Childbearing usually ends about 10 years
before menopause.35
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Premature ovarian failure affects about 1% of women before the age of 40, and 0.1% of women before
the age of 30.34 Causes of premature ovarian failure include genetic abnormalities, infections (such as
herpes zoster, cytomegalovirus, and mumps), autoimmune disorders, and iatrogenic causes (such asside
effects of cancer treatments or ovarian surgery).34
Male fertility declines with age too, but not usually to alevel that affects conception.157However, there
may be an association between paternal age and slightly increased rates of miscarriage, genetic
abnormalities, autism and schizophrenia.35,159
Lifestyle issues
Smoking: Smoking increases the risk of infertility in women (dose dependent), and decreases the success
of infertility treatments by an estimated 50%.61 This may be due to toxic effectson gametes of the
chemicals in tobacco.53,53,129Smoking also affects the levels of female hormones, the “follicular
environment”, and the density of the zona pellucida (which reduces the chance of sperm
penetration).129 Moreover, women who smoke reach menopause at an earlier age than non‐
smokers.129Essentially, the quality and quantity of oocytes is affected by smoking. In terms of IVF
outcomes, smoking may be equivalent to adding 10 years to a woman’s age.160A 2007 summary of
systematic reviews on lifestyle factors associated with infertility found numerous effects of smoking on
fertility, including an increased number of IVF cycles needed to conceive, higher rates of miscarriage,
lower birth weights, and lower rates of live births from ARTS.129 A meta‐analysis of the effect of
maternal smoking on ARTs outcomes found that smokers had significantly lower rates of clinical
pregnancies and live births, and significantly higher rates of miscarriage.161 Even for non‐smoking
women, exposure to secondhand smoke may affect fertility.53
Smoking also affects male fertility by reducing sperm quality and counts, though evidence in this area is
less conclusive.53
Obesity: In women, obesity (a BMI of ≥30) is associated with anovulation (failure to ovulate), increased
time to conceive, higher rates of miscarriage, and complications during pregnancy (including
preeclampsia, gestational diabetes and hypertension).33,41,53,61,129,162 Spontaneous conception rates are
about 50% less in women with moderate obesity, especially those with abdominal adiposity.53Obese
women undergoing ARTs may need higher doses of fertility drugs, increasing the risk of adverse effects.
Pregnancy rates are about 30% lower in obese women.53
Obesity is also associated with polycystic ovarian syndrome (PCOS) and insulin resistance.42,53 In PCOS
the ovaries develop many small cysts that can cause anovulation.33However, recent studies indicate that
although women with PCOS may take longer to conceive, it is usually women with both PCOS and
obesity who experience infertility, and that weight loss can help restore fertility.42
Maternal obesity also affects the infant’s health, and has been linked to higher rates of childbirth
complications, neonatal death, congenital, and cardiovascular abnormalities.53 Children born to obese
mothers are at an increased risk for childhood obesity and signs of metabolic syndrome (e.g., glucose
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intolerance and hypertension)which may predispose them for obesity, diabetes and other conditions in
adulthood.53
Conversely, underweight women, such as those suffering from anorexia nervosa, are also at a greater
risk for infertility as ovulation and menstruation usually cease.33
Recent studies have linked male obesity to infertility due to increased rates of erectile dysfunction,
higher scrotal temperatures, changes in sperm production, and hormonal imbalances (lower
testosterone levels and endocrine abnormalities).53Individuals with excess body fatare also more
susceptible to environmental toxins that affect fertility.163
Alcohol and drug consumption: The consumption of large quantities of alcohol, the use of recreational
drugs, and the use of some over‐the‐counter and prescription drugs can affect fertility.61,12938,41 Evidence
in this area is limited but alcohol appears to affect fertility in both sexes (dose‐dependent).53One US
study found an association between female drinking and lower rates of oocyte retrieval for IVF, and
recommended that couples abstain from alcohol for at least 1 month before IVF procedures.164 Another
study found a 21% decrease in the live birth rates following IVF in couples where each partner had 4 or
more drinks per week.165
Evidence on the effects of prenatal exposure to alcohol on pregnancy and birth outcomes is well
established. Alcohol is a known teratogen linked to higher rates of miscarriage, preterm labour, low
birth weight, birth defects, and fetal alcohol spectrum disorders.53,164,166
Other risk factors for infertility: Sexually transmitted diseases (STDs) are another risk factor for infertility
in both sexes.51Exposure to workplace or environmental toxins, such as radiation or agricultural
pesticides, may affect fertility, for example, by reducing sperm counts.38,51,129Sedentary activities or
occupations, such as driving, or disability requiring permanent use of a wheelchair, can increase scrotal
temperature and lower sperm production.33
Patterns of care
Family physicians in Alberta are able to perform infertility workups, however, many refer couples with
problems conceiving to an endocrinologist, an obstetrician‐gynaecologist, or a reproductive
endocrinologist (REI). After diagnosis, the clinical path that patients follow depends on the age of the
female partner and the type of infertility. Couples with female factor infertility only, with the exception
of ovarian failure and tubal obstruction (not from sterilisation), are candidates for less invasive ARTs or
surgical treatments prior to IVF/ICSI. Ovarian stimulation agents are a first line of treatment for women
with PCOS and non‐PCOS related ovulatory dysfunction, some of which (e.g., clomiphene citrate) can be
provided by the family physician, whereas others (e.g., gonadotropins, pulsatile GnRH) are administered
by an obstetrician‐gynaecologist, endocrinologist, or REI. Women who fail to ovulate with the use of
fertility drugs are treated for unexplained infertility, proceeding from ovarian stimulation with IUI and
then to IVF. For women with endometriosis, polyps, or fibroids, surgery is generally the first treatment
of choice. This may be supplemented with ovarian stimulation and IUI before continuing to IVF. Either
IVF or tubal reanastomosis may be performed in women who have had a tubal ligation.
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ICSI with or without sperm retrieval surgery is the first line of treatment in most couples with male
factor infertility. However, surgical treatments may be considered for some conditions (varicocele,
vasectomy, ejaculatory duct obstruction) depending on the severity of the male factor and the age of
the female partner. Further, IUI can be used to treat mild male factor infertility, such as that resulting
from a mild varicocele or an immunologic condition, and donor insemination can be used in most
patients. For a detailed overview of the clinical pathway that patients follow see the decision model
section.
Patients who experience infertility and subsequently get pregnant tend to receive more monitoring tests
(ultrasounds, office visits, etc.) than other pregnant women, though this is not necessarily evidence‐
based [personal communication: Tarek Motan, University of Alberta, Faculty of Medicine and Dentistry;
15 Jul 2012].
Social, legal and ethical issues
Older parents
For older women and those with reduced ovarian reserve the use of donor eggs may be the best
option.157Egg donation and other technological developments have made it possible for older women ‐
even after menopause ‐ to become pregnant, but the safety of ARTs treatments, pregnancy and
childbirth in postmenopausal women has not been fully determined.159There is evidence that pregnancy
and childbirth in older women increasesthe risks of miscarriage, hypertension and other cardiovascular
risks, gestational diabetes, placenta praevia, preterm birth, and caesarean section.159
Some countries that provide public funding for IVF have established limits on the woman’s age. For
example, in the UK, the 2013 guidance from the National Institute for Health and Clinical Excellence
(NICE) increased the age limit to receive IVF from 40 to 42.24 However, for those who can afford it, age
or other restrictions can be circumvented by seeking treatment in private clinics, or in other countries
(“reproductive tourism”).159
Older fathers do not face similar medical risks, but paternal age has been linked to declining fertilization
rates, and to increased risks to the child for genetic diseases and other conditions.35,159,167
Older parenthood also raises other issues for the child’s welfare, including the need to consider the
possibility of parental death while the child is still young.159
Population fertility
Postponing pregnancy is associated with smaller family sizes and with an overall decrease in population
fertility, or “sub‐replacement fertility”.156 In Canada, as of 2007, the average number of children per
woman was 1.6, below the 2.1 needed for population replacement.155,168
Studies by Connolly et al have examined IVF costs versus lifetime taxes in several countries.169‐171 Their
UK study examined the association between an IVF singleton birth and lifetime discounted value of net
taxes.169 The study mentions declining birth rates, aging populations and increasing life expectancies as
factors that contribute to the stresses placed on health care budgets and the tax revenues that finance
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these budgets.169 Their US study calculated the costs of funding IVF treatment and the estimated net
taxes paid to government over a lifetime and concluded that government would benefit ‐ both from the
additional taxes and from overall economic growth.170 (These studies are discussed further in the
economics section.)
A study of the economic impact of ARTs in the UK concluded that government funding could contribute
to improving the total fertility ratio and balancing the aging population trend, with the consequent
stresses this places on the workforce, healthcare and pension benefits.172 Moreover, the direct costs of
using ARTs as part of their population policy would be comparable to other government options, such as
increasing child benefits or encouraging immigration.172
From a population perspective, if the focus is on longterm benefits rather than short‐term costs, public
funding of IVF may be beneficial.171,173
Public health
Consanguinity is a possible public health risk with ARTs, particularly in Canada where there is a shortage
of sperm donors. Consanguinity means people with common ancestry. It may be an issue medically if
closely related individuals reproduce, increasing the risk of passing on hereditary diseases.7 A Canadian
surveillance system is needed to track donors and set limits to the number of offspring per donor.7 In
general, improved data collection of ARTs procedures and outcomes in Canada is needed.7 This may be
particularly important in future with the demise of Assisted Human Reproduction Canada.
Quality of life
Mothers of IVF twins often report higher levels of stress, exhaustion, and depression, and of having less
pleasure in their children than mothers of IVF singletons.174,175 Other studies found greater worry about
meeting the family’s basic material needs and lower quality of life, but did not report higher levels of
stress.176 Some mothers of multiples note feelings of social stigma because of the association between
ARTs and multiple births.142,177 Mothers of multiples were also less likely to be employed outside the
home, placing them more at risk for postpartum depression.174,175
Family quality of life is generally lower in families with multiple births compared to families with
singletons, regardless of whether the children were conceived via ARTs.177 However, most studies have
focussed on the mother, who is most affected, while little is known about the father’s quality of life.178 A
recent study from Finland found that the mental health of both mothers and fathers of twins, as
measured by levels of depression, anxiety, sleeping problems and “social dysfunction”, was lower during
the first year of parenthood.179
Knowledge and education
There is a general lack of awareness of how much aging affects fertility.72,129,180 A recent survey of over
3,000 Canadian women found that 72.9% of respondents believed health and fitness levels were better
indicators of fertility than age. Over 90% believed that until menopause ARTs could help most women to
have a child using their own eggs.180Less than 50% of the survey respondents knew that one IVF cycle
typically costs over $5,000.180 A BC study of female undergraduate students found that although most
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young women knew that fertility declines with age, they overestimated the chances of conception at all
ages, and were not aware of the marked decline in fertility for women in their 30’s. They were also
unaware that age also affects the success rates of IVF.181 Moreover, as one Alberta study found, many
men and women understand some, but not all of the increased risks associated with childbearing after
the age of 35.182
Family doctors and other healthcare professionals can help educate their patients about declining
fertility and the increased risks associated with pregnancy in older women.72,156 Some researchers have
called for public education programs to promote awareness of fertility, the limitations of ARTs, and the
possible consequences of delaying childbearing.180 The SOGC has called for pre‐conception counselling
and education campaigns to ensure that Canadians who are planning to have children can make
informed decisions about when to start trying to conceive.155
Patients also need to be fully informed of the treatment‐related risks of ARTs. This should include
discussion of the possible need for selective fetal reduction, and the increased risk of pregnancy loss
that it incurs.57,141 Informed consent for fertility treatments also involves consent for the use and storage
of sperm, eggs or embryos, and consent for disclosure of information.60
Patient education is also needed to ensure couples fully understand the risks involved with multiple
births.11,14,14 One US study found that 25% of women treated at 3 infertility clinics considered a multiple
birth to be the most desirable outcome, while only a minority were aware of all the risks involved.11
When fully informed about these risks couples are less inclined to request multiple embryo
transfers.183The Australian ASSET trial (Australian Study of Single Embryo Transfer) was unable to recruit
patients willing to risk being randomized to receive double embryo transfer because the patient
information handout clearly presented the less favourable outcomes with multiple births.67 As well as
the physical risks involved with multiple births couples should be informed of the potential impact that
multiples will have on their mental and financial wellbeing.142,142,174,175 Alternately, these risks could be
framed positively in terms of the benefits of singleton births.174
At a practical level patients should receive counselling before, during and after their diagnosis of and
treatments for infertility.41 Some jurisdictions require counselling be provided to all patients undergoing
ARTs, while others require it only for ARTs procedures that involve donors or surrogates.184 The concept
of “non‐directional” counselling is most widely accepted. This type of counselling provides information
to the patients, and helps them to understand their situation and what they need to know about further
steps.184Another type of counselling may be used to assess patients for eligibility for ARTs treatments or
as donors in the interests of protecting the “welfare of the child”.
Patient preferences
Several studies have demonstrated a preference for multiple births (mainly for twins) among couples
waiting for, undergoing, or who have undergone IVF/ICSI.185 The extent of this preference varies across
studies and isprobably due to differences in study methods (e.g., survey or interview, provision of
counselling, phrasing of questions), populations (e.g., age, infertility and treatment history, stage of
treatment at time of study), and context (e.g., country, embryo transfer policies, funding).
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In a study at a Quebec infertility clinic, prior to the initiation of public funding of IVF/ICSI, 41% of male
and female infertility patients reported a preference for twins.14 Similarly, in patients who were either
receiving NHS funding or paying for their own IVF/ICSI in the UK, 32% to 45% of couples reported that
they would prefer twins, and 90% would not mind having twins.14,186
In a public infertility clinic in Denmark, when up to 3 IVF/ICSI cycles with 1 or 2 embryos were
completely funded, 59% of couples at all stages of IVF/ICSI desired a twin birth.140 In comparison, only
20% of couples attending either a university‐based or private infertility clinic in the US selected multiple
pregnancies over singleton pregnancies as a preferred outcome of infertility treatment.11 When the
mothers of children born after IVF/ICSI were surveyed, 85% of twin‐moms and 62% of singleton‐moms
reported a preference for twins as their first children.185
Most North American women want more than one child, and this may partially explain the preference
for twins in couples with infertility.187A 2006 Canadian survey found that of married or common‐law
women who wanted children, the vast majority (87%) wanted 2 or more children; of these most (55%)
wanted 2 children, while only 13% wanted a single child.168
In infertile couples undergoing IVF/ICSI, especially older couples or those with a longer duration of
infertility, many saw twins as a chance to have an “instant family”, or more children with fewer IVF
treatments, or as their only chance of having 2 children.11,14,74,86,140,185,188A Canadian survey of 801
patients at the McGill Reproductive Center, conducted before Quebec began universal funding of IVF,
found that 41% of patients (female and male) considered multiple pregnancy to be an “ideal treatment
outcome”.14
In more recent studies the desire to increase the chances of pregnancy or live birth in the least number
of cycles appears to be the underlying reason for a preference for twins.140,183Some couples recognize
the risks associated with higher order multiple births but are not aware that the risks are also higher
with twins.185 One Danish study found that most patients (58.7%) preferred to have twins rather than a
singleton birth, possibly to minimize the psychological and physical stresses of IVF treatment by
undergoing as few cycles as possible.140 Other studies report even higher rates of women or couples
expressing a preference for twins – particularly when pregnancy rates per cycle remain lower with single
embryo transfer.175,189
In a few studies, many women did not explicitly state a preference for twins, but did preferDET to
maximise their chances of pregnancy.8,140,183,185 Similarly, when women undergoing or waiting to
undergo IVF were asked about the chances of no pregnancy or no live birth, almost all would prefer
twins over no pregnancy, and many chose having a child with a chronic disability over not having
achild.140,186,190
In some studies, whether the couples were paying for their own ARTs treatment or receiving funding did
not seem to affect their responses.140,186 However,other studies have suggested that if public funding for
IVF is available patients may be willing to accept SET, even if it required additional cycles,as long as
pregnancy rates approach those associated with DET.185,186,191
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Ethicists have expressed concern about the “reification” of the gene – the belief that genetic
parenthood is of utmost importance, rather than recognizing and promoting other options for having
children or creating a family.192,193But, these other options are not always readily available ‐ in
Canadaadoption is a complex and expensive process that can take years.72
Embryo donation
Using donor embryos is an option for some couples, but this can also be difficult in Canada. Other than
the Assisted Human Reproduction Act’s prohibition of payment for donor embryos, there are no laws
regulating embryo donation across Canada and, in the absence of provincial regulation, the process
appears to be left to IVF centres to manage. Some Canadian centres do not offer embryo donation,
while others maintain their own waiting list of couples wanting embryos.194 In one Australian clinic the
waiting list to “adopt embryos” was 3 years.195
Embryo donation is a difficult decision for most couples who have unused embryos remaining in storage.
Although over 70% of Canadian couples surveyed in one study supported embryo donation in
principleonly 12% of them would definitely consider donating their own embryos.196Studies in other
countries also found that only from 2% to 18% of couples were willing to consider embryo
donation.196Most couples eventually choose to dispose of their excess embryos, rather than donating
them to others or allowing them to be used in medical research.195,196Some couples express concern
about the level of personal information and involvement associated with donating embryos. For
example, they may have concerns about the psychological and medical screening tests required for
embryo donation, or about the conditions that may or may not be placed on the donation (such as
knowing the outcome of the pregnancy, or possible contact with the potential child ‐ as with adopted
children who trace their biological parents). For some embryo donation is more aptly called embryo
adoption, because they view the process as more like adoption (which also involves a child who is not
genetically related to the parents) than, for example, organ donation.196
A recent US systematic review of ARTs stressedthe need for further research on patient values and
decision making on infertility and treatment options.135
Patient autonomy and responsibility
Potentially modifiable lifestyle factors that have an impact on the cost‐effectiveness and outcomes of
ARTs, such as obesity, alcohol consumption and smoking, raise many ethical issues.Although fertility
treatments involve the physician and patient relationship and require respect for patient autonomy, the
health and wellbeing of the future childmust also be considered.53 Moreover, because these lifestyle
factors influence the outcomes and cost‐effectiveness of ARTs treatments, in publicly funded health
systems, the societal perspective should also be considered.53Physicians have an obligation to advise,
or,in publicly funded health systems,to insist that patients attempt lifestyle modifications before
receiving ARTs. However, the physician and the health care systemshould help patients make
theselifestyle changes by ensuring they have access tothe dietary counselling, exercise therapy, smoking
cessation programs, drug and surgical treatments that they need.53Access to such programsisparticularly
important because these lifestyle factors are more common in disadvantaged socioeconomic groups.
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This is a complex area and “policing” it will be difficult. Although decisions should be based on evidence,
in some cases the evidence is lacking (such as what the optimum cut‐off points should be for BMIor
levels of alcohol consumption).53The time required to make these lifestyle changes should also be
balanced along with the woman’s age. For women approaching the end of their reproductive years, age
may be more of a concern than the need for lifestyle changes.53
Cost and accessibility
Couples report that the cost of ARTs was a secondary consideration to their desire to have a child.185
Nevertheless, because of the expenses involved, couples may seek to maximize their chances of having
children by requesting multiple embryo transfers.16 Access to publicly funded infertility treatments and
the number of cycles that are funded influences patient choices – in part, because single embryo
transfer may increase the number of treatment cycles needed, and consequently, the costs
involved.185,197
The level of funding support for ARTs (whether through public or private insurance) has been shown to
increase the uptake of single embryo transfer and decrease the rate of multiple births, but funding also
increases utilization of ARTs.73,77,198 In one US study, states that mandated health insurance coverage of
IVF had higher rates of IVF utilization, but they also had lower rates of multiple births.149,199 The rate of
twin births from ARTs procedures in the US and Canada is more than double that of countries, such as
Sweden and Australia, which provide public funding for ARTs.10,142 In Ontario, where public funding of
IVF is only available to women with bilateral fallopian tube blockage, less than 3% of women agree to
single embryo transfer.72As a recent economic review concluded, “Reasonable reimbursement policies
can increase not only utilization of ART treatments but also the uptake of single embryo transfers.”198
One Australian study found a significant shift to single embryo transfer, and a corresponding decrease in
the rates of multiple births (approximately 54%) and associated costs over a 6‐year period after public
funding was introduced.77 The authors concluded:
…funding arrangements for ART not only affect who can afford to access ART treatment, but also
have the potential to alter the health outcomes of children born as a result. For the sake of the
health of children born following ART, we should be asking: “Can we afford not to fund it?”77
One comment on the 2004 UK guidance on fertility treatment noted that not being able to access
fertility treatments because of their cost is an important inequality that prevents people from
accomplishing something that is important and attainable to most of us – starting a family.200
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Equity
Equity means the fair allocation of resources between different individuals or groups.201Canadian health
researchers determined that equity in the allocation of ARTs requires consideration of the following four
groups: 1) those without fertility problems, 2) the infertile, 3) the wealthy, and 4) the poor.21 With these
groups in mind, the questions are:
 Whether infertility is a medical condition, or whether a social desire to have children should be
publicly supported. The World Health Organization defines infertility as a “disease”.1 Many
jurisdictions provide public funding for less effective, “lower‐tech” infertility treatments, such as
tubal surgery, ovulation induction, or IUI ‐ evidence that infertility has already been established
as a medical condition considered for public funding.21 There is a need for consistency here, in
other words,consideration of all relevant infertility treatments before rationing is applied to
ARTs.21
 Whether private or public funding of ARTs is desirable. Private funding allows inequitable
distribution of resources between the groups. It means that the wealthy can access ARTs while
others either cannot or impoverish themselves to do so. Public funding, including fertility drug
coverage, would ensure equitable access.21
A fifth group that should be considered are the “socially infertile” (rather than the medically infertile).
This includes two sub‐groups of potential ARTs users: same‐sex couples, and single women or men who
want to have children.137
The Ontario review on infertility noted that individuals or couples who need “third party reproduction
services” (i.e., donor eggs or sperm, embryos, or gestational surrogacy) face particular difficulties in
receiving infertility services, in part, because the Assisted Human Reproduction Act makes it a criminal
offense to pay for these services in Canada.72,111
Eligibility for ARTs
Ethical issues include the kinds of restrictions that may be applied to restrict eligibility for ARTs,
including marital status (are single women or men, common‐law, or same‐sex couples acceptable?) and
lifestyle issues. Some European countries restrict eligibility to heterosexual, married couples.202
Lifestyle criteria are sometimes used to determine eligibility for ARTs.53 Obesity and smoking are two
examples where access to ARTs may require weight loss or smoking cessation because this will improve
treatment outcomes and the health of the child.53 The ESHRE Task Force on Ethics and Law determined
that infertility physicians have a dual responsibility – to protect the welfare of both the parent and of
the “future child”.53Respect for individual patient autonomy must be balanced with societal interests,
particularly when health care for ARTs treatments, and for treating any adverse outcomes, are publicly
funded.53
The Ontario review of infertility and assisted reproduction suggested several criteria that might be used
if publicly funded ARTs were introduced.72 These includedan age limit of 42 for women to receive IVF or
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IUI, and the requirement to use frozen embryos (where extra, good quality embryos are available) after
the initial fresh embryo cycle to reduce the costs of subsequent cycles.72
Prioritizing patients for ARTs
New Zealand has developed eligibility criteria and a Clinical Priority Assessment Criteria (CPAC)“scoring”
system for ARTs patients.203 To qualify for publicly funded IVF women must be non‐smokers (for a
minimum of 3 months before treatment), and have a BMI of less than 32.203,204
Researchers in the UK proposed a “needs‐based” prioritization system for fertility patients based on 4
categories (ranked from highest to lowest):
1. Couples with no children (2 people are affected by infertility)
2. One partner has a child from a previous relationship while the other partner is childless, or a
single woman seeking a child (1 person is mainly affected by infertility)
3. Couples where both partners have children from previous relationships, but no children
together
4. Couples with one or more children from their present relationship.128
However, they conclude that many other priority‐setting criteria, such as the woman’s age, the duration
of infertility, and the likelihood of treatment success, should also be taken into consideration.128
Religious issues
Some religious faiths consider ARTs, or some ARTs procedures, to be in conflict with their tenets. The
Roman Catholic Church, for example, views IVF as “morally illicit” because it contravenes a number of
religious beliefs, including: the sanctity of marriage and conjugal relations, the divine intervention aspect
of conception (the child as the “supreme gift”), the destruction of human embryos (e.g., the “excess”
embryos derived from ovarian stimulation), and the Church’s view of masturbation as a form of moral
disorder.205 Prenatal genetic diagnosis, if used with the intent to abort an abnormal fetus rather than to
intervene with medical treatment, is also considered illicit by the Catholic Church.205
Other religions, such as Judaism, have a “pro‐natalist” approach that encourages its followers to “be
fruitful and multiply”. The use of ARTs is considered a legitimate means to this end. In the orthodox
Jewish faith “the soul does not enter the embryo until 40 days after conception”.206 Preimplantation
genetic diagnosis (PGD) is thus morally and ethically acceptable because it occurs within the 40 days.206
Egg and sperm donation is generally not accepted within orthodox Judaism, but ovarian tissue
transplantation is acceptable because ovulation (even with donor tissue) occurs within the woman’s
body and thus within the sanctity of marriage.206
Legal issues
Assisted reproductive technologies raise complex ethical and legal issues that include a woman’s right to
reproductive autonomy, respect for human life (the rights of the embryo or fetus, and the welfare of the
child), and the rights of same‐sex couples. They also involve addressing what constitutes a parent or a
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family. In Canada, these issues were identified in the report of the Royal Commission on Reproductive
Technologies, published in 1993.51
Ownership of stored eggs, sperm or embryos if a couple separates, or one partner dies can present legal
problems, particularly if there is no directive or will stipulating what is to be done with them.207 Thismay
involve balancing one individual’s right to have children versus another’s right not to be a parent.208 In
part, these issues arise from outmoded definitions of parenthood based on genetic ties that also entail
financial support for the child.208
Legal issues concerning parenthood and the rights of the child to know their biological parenthood may
arise if donors are involved (i.e., if donor sperm or eggs, or surrogacy are used).60 Commercial third party
reproductive services – intermediaries who charge a fee to arrange for donors or surrogates are
prohibited in Canada.111 This may be ethically laudable, but it makes it more difficult for patients to find
donor services in Canada, and may drive them to use international or “underground” services instead.72
Despite the restrictions, some Canadian web sites advertise surrogacy consulting and egg donation
services.209‐211
Commercialization of health care services and reproductive tourism
Assisted reproductive technologies have become an area of health care commercialization in Canada,
with private clinics providing most of these services outside of publicly funded provincial health
services.7,66
Cross‐border or “reproductive tourism” where individuals travel outside the country for infertility
treatments has raised additional issues. These includethe potential risks tothe individualsand their
offspring from receiving poor quality and perhaps unregulated healthcare services, and the need to
protect women in developing countries from exploitation (in the case of gamete donation or
surrogacy).7
Reproductive tourism also carries downstreamcosts for the Canadian health care system when the
mother and infant(s) return to Canada.7 The question of interprovincial reproductive tourism has also
been raised given the closure of Assisted Human Reproduction Canada and the lack of regulatory control
of ARTs in most provinces.212
Fertility preservation
A recent survey of Canadian ARTs clinics found that most clinics (80% of respondents) offer oocyte
cryopreservation, either for fertility preservation in patients undergoing cancer therapy, or “social egg
freezing”, in women who want to preserve eggs for possible future use.213
The Ontario review on infertility concluded that: “the fertility needs of young cancer patients are often
forgotten by treating cancer specialists”.72 A small retrospective survey of Canadian female cancer
patients found that for a third of the patients the question of fertility preservation was raised by the
patients or their family, rather than by their healthcare provider.214 Over 97% of the respondents
thought that it was important for young cancer patients to see a reproductive specialist for advice on
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fertility issues.214The survey identified “stress, time pressure, and costs” as the main factors influencing
patient decisions on fertility preservation. An Australian study reached similar conclusions ‐ that the
barriers to cancer patients’ use of ARTs were mainly due to cost (e.g., of egg and sperm
cryopreservation), time constraints before cancer treatment began, and lack of healthcare provider
awareness of these services.27
Relatively few Canadian women have used oocyte cryopreservation, and pregnancy success rates are
higher with embryo cryopreservation.72 Reports of live births resulting from the use of thawed oocytes
range from 2% to 4% per oocyte.213
Ovarian tissue cryopreservation is still considered “experimental” though at least 17 live births following
this procedure have been reported worldwide.214,215 Fertility preservation is costly.28 Canadian ARTs
clinics charge from $3,500 to $5,850 for elective oocyte cryopreservation, not including the drug
costsand annual storage fees.213
Elective oocyte freezing
Elective oocyte freezing, also called “social” or “non‐medical” egg freezing, is the voluntary
cryopreservation of eggs by women who want to delay having children until later in life.29 Whether the
costs involved in ovarian stimulation, egg retrieval and cryopreservation should be publicly funded for
fertile women who want to have the option of having children later may become an issue.29A Canadian
review highlighted the ethical issue of “extending fertility into old age” as a key concern with ARTs.7 But
a recent Belgian paper identified some possible benefits to elective oocyte freezing,mainly in terms of
having “younger” eggs available for IVF later on, and possibly a larger supply of donor eggs as
well.29Because younger eggs are more viable, elective oocyte freezing could potentially improve live
birth rates, lower rates of miscarriage and reduce rates of chromosomal abnormalities, which may offset
the costs of providing the service.29 However, a 2012 US analysis determined that currently neither
elective oocyte cryopreservation nor ovarian tissue transplantation are cost‐effective practices for
women who want to delay childbearing.216
Population dynamics, diffusion and demand
The trend for women to delay childbirth is expected to continue. This will increase the potential patient
population and demand for infertility treatments.7,154‐156A 2007 review of ARTs noted the number of
women treated for infertility in Alberta increased from about 7,500 (in 1998) to 11,000 (in 2007).5
Couples are also more likely to seek treatment for infertility than they were in the past.21,26,36,41 This may
be due to factors such as popular media coverage, wider availability of fertility drugs and other
technologies, and an increase in the number of doctors specializing in infertility treatments.36
The use of ARTs procedures in Canada has increased approximately 50% over a 10‐year period.Canadian
Fertility and Andrology Society registry data show an increase in the number of IVF procedures
(including ICSI) from 4,292 IVF cycles at 18 Canadian IVF centres in 1999, to 10,532 IVF cycles at 28
centres in 2009.217 Nevertheless, a recent review noted that utilization of ARTs in most developed
countries is below the estimated 1,500 cycles per million population that is a conservative estimate of
72

overall need.198 The discrepancy between ARTs utilization and estimated need is most pronounced in
countries where public funding is not provided, for example, ARTs utilization in Scandinavia, in 2005,
was from 5 to 7 times greater than Canadian utilization (1,450 to 2,209 per million population in
Scandinavian countries versus 353 per million in Canada).198
A 2012 report by Lindy Forte, commissioned by the Generations of Hope Fertility Assistance Fund,
estimated that 13% of the all IVF procedures performed in Canada are done in Alberta.218Her scenarios
projectthe number of Alberta IVF procedures will increase by approximately 4% to 5% per year over the
next 5 years if funding is not provided.218If IVF funding is provided, the number of procedures is
projected to almost double over the initial 5‐year period, but tosubsequentlydecline to 4% to 5%
increases per year (as in the no funding projections).218(The cost estimates developed in this report, and
those in an earlier report by Forte on funding IVF in Quebec, are discussed in the economics
section.)88,218
In the US, the number of ARTs proceduresperformed almost doubled from 1996 to 2005.135Registry data
show an increase in the use of ARTs from 2002 to 2003 of 13% (in Europe), 6.5% (in the US), and 16% (in
Australia).219 In Australia, where a large portion of ARTs costs are publicly funded, one study estimated
that the number of ARTs treatments increased an average of 10% each year from 2002 to
2008.77Meanwhile, Australian government expenditures on ARTs services more than doubled from 2000
to 2005.219Worldwide, the use of ARTs is increasing by 5 to 10% per year.73
There is alsoa trend towards greater use of ICSI.93,220 According to the European Society of Human
Reproduction and Embryology, in 2006 over 65% of cycles worldwide used ICSI.220The American Society
for Reproductive Medicine reports that approximately 60% of ARTs cycles in the US now involve ICSI.61
Reports from Australia and France also report increased use of ICSI.101,221
One European studyfound that about 60% of couples with genetic disorders want to have genetic
testing in future pregnancies.103 If no wait time are involved,74% of thesecouples would
preferpreimplantation genetic diagnosis (i.e., IVF with PGD)as opposed to natural conception followed
by prenatal diagnosis (e.g., amniocentesis), and the stress and grief they would face in the event that an
abortion was needed.103Unfortunately, 42% of couples with known genetic diseases were not aware of
PGD.103
A survey of the use of PGD at IVF clinics in Canada found that many centres lack the resources to offer
PGD, and those that did often used other centres in Canada or in the US to provide this service.105 With
the increased demand for IVF in Canada, more patients will be seeking this test and greater capacity to
provide PGD will be needed.105
Additional facilities for sperm, egg and embryo cryopreservation may also be needed, as well as
regulations and standards for the provision of these services.
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Access to ARTs in Alberta
The Canadian Fertility and Andrology Society lists 34 IVF centres in Canada, 2of which are in Alberta:
 the Regional Fertility and Women’s Endocrinology Clinic (Edmonton Fertility Centre) at the Royal
Alexandra Hospital in Edmonton
 the Regional Fertility Program in Calgary.222
Effective use of ARTs should begin withtimely referral to fertility specialists (after 12 months of trying to
conceive for women under the age of 30, and after 6 months for women over the age of 30).72In Alberta,
prior to a referral to one of the two IVF centres, some patients may receive non‐IVF infertility
treatments (e.g., ovulation induction, IUI, and surgical treatments)at centres in Red Deer, Medicine Hat,
and Peace River [personal communication: Tarek Motan, University of Alberta, Faculty of Medicine and
Dentistry; 15 Jul 2012].
The Edmonton centre performs services such as semen analysis and infertility counselling within Alberta
Health Services, but patients pay out‐of‐pocket for other procedures, including intrauterine
insemination and IVF.223The Edmonton centre performed 287 fresh IVF cycles and 101 frozen IVF
cyclesin 2011 [personal communication: Tarek Motan, University of Alberta, Faculty of Medicine and
Dentistry; 16 Jul 2012]. The wait time for an initial consult at the Edmonton centre is 5 to 6 months, and
2 months for a follow‐up consult [personal communication: Tarek Motan, University of Alberta, Faculty
of Medicine and Dentistry; 23 Nov 2012].
The Calgary centre was established in 1984 as a private fertility clinic. Patients need a physician referral
to be accepted for a consultation, and only Canadian residents are accepted for treatment.37 The usual
wait time for a consult is approximately 2 to 3 months and the treatment cycle typically starts 2 to 4
months after the initial consult.37 Teleconsultation can be arranged for patients who live outside of
Calgary. In 2010, the Program performed 935 fresh embryo transfers and 704 frozen embryo
transfers.37The expansion of laboratory facilities at the Calgary Regional Fertility Program will allow the
centre to perform more procedures in future [personal communication: Tarek Motan, University of
Alberta, Faculty of Medicine and Dentistry; 15 Jul 2012]. Should public funding of IVF be provided in
Alberta, Dr. Cal Greene, Medical Director of the Regional Fertility Program, estimates that demand for
IVF might increase by 30 to 50% ‐ an increase that could be handled by the Calgary and Edmonton
centres [personal communication: Cal Greene, Regional Fertility Program; 31 Jan 2013].
Public funding of ARTs in Alberta is limited to some physician visits, diagnostic testing for infertility, and
procedures used to treat underlying conditions (such as laparoscopic surgery for varicocele or
endometriosis).224 In Alberta, and most Canadian provinces, infertile couples face significant financial
barriers to accessing fertility treatments, and most associated costs are not covered by provincial health
insurance.173 The exceptions are Ontario (where IVF is funded only for women with bilateral fallopian
tube blockage), and Quebec (which provides full coverage of 6 natural cycles and 3 stimulated cycles of
IVF for all women “of childbearing age – including homosexual women”).225,226
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Preimplantation genetic diagnosis is also not publicly funded in Alberta. For couples in Alberta, embryos
are biopsied locally and are sent to US laboratories for genetic testing, an out‐of‐pocket cost to the
couple of approximately $5,500 in Edmonton and $6,500 in Calgary [personal communications: Tarek
Motan, University of Alberta, Faculty of Medicine and Dentistry; 13 Nov 2012;Cal Greene, Regional
Fertility Program; 18Nov 2012]. At the Edmonton fertility clinic, 4 or 5 patients per year pay privately for
PGD [personal communication: Tarek Motan, University of Alberta, Faculty of Medicine and Dentistry;
15 Jul 2012].
Health Canada requires that donor sperm be quarantined (frozen and stored for 6 months), and then re‐
tested to ensure it is free of transmissible diseases before it can be used.72This has contributed to
ashortage of sperm in Canada and sperm from the US or other sources are often used.68,72Health Canada
maintains a list of Canadian establishments (currently 10 agencies, all located in Ontario or Quebec) that
process or import semen for assisted conception.227
Prior to the Assisted Human Reproduction Act, some Canadian women were able to barter their eggs in
exchange for IVF treatments, which raises ethical questions, but did allow some women access to IVF.68
According to the Regional Fertility Program web site, embryo donation is an option for some couples
who have completed their infertility treatment at the Calgary centre and who want to donate their
remaining embryos to other couples.37However, both the donor and recipient couples must meet
certain criteria. As only a small number of embryos are donated, the waiting list can be long.37
Alberta cancer patients can access fertility preservation services (sperm or egg harvesting and
preservation) at a reduced cost through Alberta Health Services, although they still incur substantial out‐
of‐pocket costs.223 The Edmonton fertility clinic receives about 1 referral per week from the Cross Cancer
Institute for female fertility preservation, and also receives referrals from urologists (for example, for
patients with Wegener’s disease) [personal communication: Tarek Motan, University of Alberta, Faculty
of Medicine and Dentistry; 13 Jul 2012].
No information was found on access to infertility services for Albertans in rural or remote areas. As with
other health services, distance undoubtedly creates barriers for some patients. The Ontario review on
infertility recommended that the Ontario Telemedicine Network be used to improve access to infertility
treatments, and travel allowances be provided for women from remote areas to allow them to receive
infertility treatments.72
New developments
The DuoFertility system (Cambridge Temperature Concepts) is an over‐the‐counter device recently
launched in the US and the UK.228 It consists of a skin patch sensor, worn under the arm, which
continuously measures a woman’s basal body temperature to detect ovulation. The information is
displayed to the patient on a handheld device, and also transmitted to a specialist clinical service via the
Internet.229Early results of a 6‐month trial of DuoFertility by 99 couples reported a pregnancy rate of
19.5%,but live birth rates were not reported.228An expanded study, that included 242 couples, found a
patient‐reported pregnancy rate of 24% over 6 months and 38.8% over 12 months.229 DuoFertility may
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be more accurate than existing devices that take once‐daily temperature measurements, but evidence
to show a clear benefit for fertility outcomes is still lacking. Several small observational studies that
compare DuoFertility to other methods of monitoring ovulation (such as basal body temperature and
urine testing) and a further UK trial arenow underway.228
Ovarian tissue cryopreservation is available in many countries, mainly for women whose cancer
treatments may cause infertility. However, there are no registry counts of the number of women who
have undergone this procedure, andlittle information is available on the health outcomes of the few
children born followingovarian tissue transplantation.230 Some women who received ovarian tissue
transplants subsequently conceived spontaneously, while others used IVF.230
In future, testicular tissue cryopreservation may offer a way to preserve male fertility, particularly for
pre‐adolescent boys who undergo cancer treatments that affect sperm production in adulthood. Animal
studies have demonstrated the procedure is feasible, but the procedure has not yet been tested in
humans.231
Uterus transplantation is under investigation as a treatment for some women with uterine factor
infertility who want to have children.45 Although animal trials of uterus transplantation have been
successful, no human births have occurred.45 Surgeons in Sweden recently transplanted the uteruses of
two mothers to their daughters (one daughter had her uterus removed during cervical cancer
treatment, and the other was born without a uterus).232 After a recovery period, the women will receive
IVF. If they are able carry pregnancies to term the transplanted uteruses will be removed when their
families are complete, so that they will not need to be on lifelong immunosuppressant drugs.
In the future, “3‐parent IVF” may be used to avoidtransmitting mitochondrial disease.233 This procedure
involves transferringeither the maternal spindle (mother’s chromosomes) or the nucleus of the affected
woman’s egg, intoahealthy donor’s egg before it is fertilized by the partner’s sperm.The offspring would
inherit DNA from 3 people. The UK’s Human Fertilisation and Embryology Authority began a public
consultation on this technique in September 2012, with the results to be presented to parliament in
2013.234,235 Because it involves genetic modification to the embryo changes to the UK Human
Fertilisation and Embryology Act will be needed before mitochondrial replacement can be introduced
into clinical use.235
Improved techniques to assess embryo quality will enablebetterclinical decisions on the optimal number
of embryos to transfer.95 “Metabolomic” profiling involves sampling the embryonic culture media using
biospectroscopy to test for the presence of certain molecules, such as amino acids. These metabolites,
in addition to the morphology of the embryo, may improve the assessment ofwhich embryos are most
viable for transfer.236,237
Preimplantation genetic testingis likely toexpand to include complete chromosomal analysis.238It may
improvethe success rate of IVF by ensuring only viable blastocysts are transferred, and may become part
of standard IVF practice in the future [personal communication: Tarek Motan, University of Alberta,
Faculty of Medicine and Dentistry; 15 Jul 2012]. The use of ICSI with IVF may also become standard
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practice[personal communication: Tarek Motan, University of Alberta, Faculty of Medicine and
Dentistry; 15 Jul 2012].
Health system capacity
Workforce and infrastructural capacity
Infertility evaluations and treatments may be performed by an obstetrician‐gynaecologist with special
training in infertility. Reproductive endocrinologists are obstetrician‐gynaecologists with two further
years of specialization in the diagnosis and treatment of infertility. The College of Physicians and
Surgeons of Alberta stipulates physician requirements for IVF privileges include a medical specialization
in obstetrics and gynaecology, a sub‐specialty in reproductive endocrinology and infertility, or
equivalent training in this field.239 The Royal College of Physicians and Surgeons of Canada is updating
their 2010 credentialing requirements for reproductive endocrinology and infertility.240Alberta has over
220 obstetricians and gynecologists.241 Most of these physicians do not have the additional training
required for specialization in the treatment of infertility. Currently, Alberta has 10practicing
reproductive endocrinologists (6 in Calgary and 4 in Edmonton). All 6 Calgary reproductive
endocrinologists and 1 in Edmonton have IVF privileges from the College of Physicians and Surgeons of
Alberta. Further, there are 5 embryologists in Calgary and 1 in Edmonton whoare able to perform ICSI
[personal communication: Tarek Motan, University of Alberta, Faculty of Medicine and Dentistry; Cal
Greene, Regional Fertility Program; 15 Jan 2013].
Some urologists specialize in male infertility.46 Embryologists are laboratory specialists in embryo
development who may carry out procedures such as: sperm washing, IVF, ICSI, preimplantation genetic
diagnosis, and new techniques for egg freezing. Alberta Health Services’ Careers in Health Care includes
IVF Laboratory Technologist, a 4 year Bachelor of Science degree offered through the Universities of
Calgary, Lethbridge and Alberta.242
The American Society for Reproductive Medicine (ASRM), the Society for Assisted Reproductive
Technology, and other US organizations in this field recommend that ARTs programs include staff with
expertise in reproductive endocrinology, laparoscopic surgery, ultrasonography and tissue culture, and
that the physicians are board certified in reproductive endocrinology and infertility.61 The ASRM also
offers an accredited training program for nurses involved in infertility treatments [personal
communication: Tarek Motan, University of Alberta, Faculty of Medicine and Dentistry; 15 Jul 2012].
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Summary of recent health technology assessments
The UK’s National Institute for Health and Clinical Excellence (NICE) recently updated their 2004
guidance on infertility.23 The new guidance, published in 2013, provides a comprehensive review of the
clinical and economic implications of ARTs, including assessments of the evidence on tests for ovarian
reserve,the clinical and cost‐effectiveness of different fertility drugs and techniques for IVF, embryo or
blastocyst transfer, sperm washing and cryopreservation, as well as recommendations for eligibility and
provision of ARTs services to different patient groups.24 A pathway for implementing the guidance and a
costing analysis have also been issued.24
A 2010 UK health technology assessment which modelled single versus double embryo transfer
concluded that single SET transfer would likely result in about a third fewer live births than a double
embryo transfer. However, complete cycles of SET (using fresh followed by frozen embryo transfer)
could produce more live births than repeat DET.86 This strategy would require support from funders, and
acceptance by patients of the need for cryopreservation and potentially more transfer cycles.86
The 2008 US Agency for Healthcare Research and Quality (AHRQ) assessment of ARTs concluded that:
Despite the large emotional and economic burden resulting from infertility, there is relatively
little high‐quality evidence to support the choice of specific interventions. Removing barriers to
conducting appropriately designed studies should be a major policy goal.135
The AHRQ review also highlighted the need to examine the “political, regulatory, and financial barriers
to high‐quality research in infertility”.135
A 2006 assessment from the Ontario Medical Advisory Secretariat concluded that single embryo transfer
IVF is an effective treatment for infertility that avoids multiple pregnancies.74 However, unlike other
Canadian reviews88,218their economic analysis determined that the cost savings through reduction of
multiple births would not justify the cost of universal IVF with single embryo transfer. The assessment
noted that, for some types of infertility, IUI is as effective as IVF, and that IUI is significantly less
expensive ‐ moreover, IUI is already publicly funded in Ontario, though other procedures used in
conjunction with IUI, such as sperm washing, cost several hundred dollars and are not publicly
funded.72,74 Although these recommendations have not been implemented, based on the 2006
assessment, the Ontario Health Technology Advisory Committee recommended that coverage of IVF
should also be considered:
 IVF with ICSI for couples with “severe male factor infertility”
 IVFwith SET for infertile women who have “serious medical contraindications to multiple
pregnancy”.74
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Subsequently, the Ontario Expert Panel on Infertility and Adoption recommendations, issued in 2009,
concluded that for Ontario couples the main barrier to ARTs is the cost, which leads to choices that
result in higher rates of multiple births and worse health outcomes.66 The Panel also called for a
provincial regulatory framework to license and accredit ARTs services (including donor and surrogacy
services), and government funding and clinical guidance for fertility preservation (“freezing and storage
of eggs, sperm and embryos”) for those with medical conditions that may affect their fertility.66
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Environmental scan of ARTs policies
This section provides a summary comparison of policies (including legislation, regulations, guidelines,
funding and other mechanisms) that have been established in Canada and elsewhere to guide the
provision of ARTs services. Further details are included in Appendix A,Table 24.
Please note:The summary of studies that examine the outcomes of ARTs policies (for example, number
of embryos transferred, utilization and costs), are included in the Economic evaluation section and in the
tables shown in Appendix F.
Policies in Canada
The 2012 federal government budget cuts included closing the Assisted Human Reproduction Canada
(AHRC) agencyas of March 2013.112 Established in 2006, the agency was intended to oversee licensing
compliance and the regulations of the Assisted Human Reproduction Act. The Act prohibits cloning, sex
selection, and payment for sperm or egg donors, or surrogacy.111 However, with one exception,
regulations to accompany the Act were never passed and a system to license fertility clinics in Canada
has not been instituted.112Fertility clinics may voluntarily apply for accreditation from Accreditation
Canada, but thus far only a few have done so.243
After a 2009 Supreme Court challenge by the province of Quebec, some sections of the Act were
declared ultra vires or outside the scope of federal responsibility for health care.244 Health Canada’s
Assisted Human Reproduction Implementation Office will assume responsibility for the agency’s
remaining functions (for example, those concerning cloning and the commodification of human
reproduction).113The further regulation of ARTs has been left to each province to determine. Thus far,
Quebec is the only province that has regulations in place.244
Artificial insemination or intrauterine insemination is a publicly insured health benefit in some Canadian
provinces (BC, SK, ON, QC, PEI, and NF). Most Canadian provinces do not fund ARTswith the exceptions
of Quebec (which now provides full coverage), and Ontario (which provides coverage of IUI, and of up to
3 cycles of IVF only for women with bilateral blockage of the fallopian tubes).225
Certain medical procedures related to IVF, such as diagnostic tests for infertility, blood tests,
ultrasounds, and in‐hospital costs, are publicly funded by provincial health insurance. However, fertility
drug costs, IVF, ICSI, preimplantation genetic diagnosis and storage costs for sperm, eggs or embryo
cryopreservation are not covered.225,245
The SOGC has issued several clinical practice guidelines related to ARTs.35,155,246Some of thekey
recommendations are that:
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 as part of their primary health care, women in their 20s and 30s should be counseled about age‐
related infertility, the risks of pregnancy and the lower success rates of ARTs for older women
(in their late 30s and 40s)35,155
 women over the age of 35 should be referred for an infertility evaluation after six months of
trying to conceive, and earlier than this in women over the age of 3735,155
 to minimize twin or multiple pregnancies, elective single embryo transfer should be performed
selectively in “good prognosis patients”.246
The SOGC guidelines also state that public funding of IVF would increase the uptake of elective single
embryo transfer, and that oocyte donation is “the only effective treatment for ovarian aging”.35,246
The Canadian Fertility and Andrology Society (CFAS) guidelines outline the training and competencies
required for ARTs laboratory and nursing staff, and for counselling ARTs patients.247‐250
Alberta
The College of Physicians and Surgeons of Alberta has issued a Standard & Guideline on IVF which
stipulates that physicians in Alberta may provide IVF services in non‐hospital surgical facilities that have
been accredited by the College.120It must also be accredited as a diagnostic laboratory if bodily fluids or
tissue analysis are performedthere. The standard also outlines the requirements for IVF centre staff
qualifications, written procedures and patient record keeping (including informed consent, details of the
number of eggs retrieved, and eggs or embryos transferred, stored, and discarded). There is also a
requirement to contribute this data to the Canadian Assisted Reproductive Technology Registry.120 The
College of Physicians and Surgeons of Saskatchewan has issued similar standards, based on those of
Alberta.251
Manitoba
Manitoba does not directly fund ARTs but provides a tax credit for up to 40% (maximum of $20,000) of
eligible treatment costs related to infertility, including ovulation induction, therapeutic donor
insemination, IUI, IVF, and ICSI to a maximum tax credit of $8,000 per year.252
Quebec
Quebec is the only Canadian province withARTs legislation in place:An Act Respecting Clinical and
Research Activities Relating to Assisted Procreation (Bill 26, 2009), and the accompanying regulations
cover standards and ethical principles for ARTs in clinical and research practice, as well as the
regulations that cover application of the provincial Health Insurance Act to ARTs.226,253‐255
Quebec has provided public funding for ARTs since August 2010.256 All women of childbearing age
(including single women and same sex couples) are eligible to receive up to 3 cycles of IVF. No age limit
is specified by the provincial regulations. Women ≤ 36 years of age may receive eSET, or if their
physician determines it is necessary, DET. Women ≥ 37 years of age may receive a maximum of 3
embryos per transfer.257 Draft regulations, proposed in April 2012, will reduce the maximum number of
embryos transferred to 2 in women aged 37 and over.258The McGill Reproductive Centre, in Quebec, has
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revised its age limit and will now provide IVF to women 43 years of age or less using their own eggs, and
IVF using donor eggs to women 44 to 50 years of age.259
Quebec also covers natural IVF (without the use of fertility drugs) for up to 6 cycles.226 All costs for ARTs‐
related medical procedures (including preimplantation genetic diagnosis) and drugs are covered by
provincial health insurance.226,260Quebec also offers a refundable tax credit for 50% of infertility
treatment expenses not covered by public or private insurance, to a maximum of $10,000 per year.261
In the first year of the program the Quebec government budgeted $27 million and 4,867 IVF cycles were
funded. Most ARTs services were provided through private clinics and one public hospital (at
McGill).256,262 Initially, the government paid private clinics $7,100 per cycle but renegotiated this rate to
$4,600 per cycle in 2011.256,263 Public hospital costs ranged from $5,000 to $6,000.256 Four additional
Quebec public hospital sites will be offering ARTs services once the program has been fully implemented
in 2014‐15. At that time, approximately 7,000 IVF cycles will be provided each year, with an estimated
annual operating cost of $63 million.256,262
Preliminary reports indicate that Quebec’s multiple birth ratefrom ARTs has dropped from
approximately 26% to around 4%.256,264,265
Ontario
From 1983 to 1993, Ontario fully funded IVF when it was performed in a public hospital.266 In 1994,
provincial budget cuts included reduced public funding for IVF, which was subsequently limited to
women with bilateral fallopian tube blockage (a condition that affects only about 25% of infertile
women).260 The chair of the panel reviewing procedures for delisting health services admitted their
process was flawed. One of the main reasons given for removing funding was that IVF was not medically
necessary, yet Ontario continues to fund intrauterine inseminationand surgical interventions for
conditions that affect fertility, such as endometrial ablation and laparoscopic fallopian tube repair.267,268
As a recent economic review noted, the success rates withIVF interventions have “consistently”
improved over time, whereas the success rates with conventional treatments (IUI, etc.) have remained
the same – and their effectiveness should now be questioned.198
A 2011 poll, organized by an infertility patients support group, reported that approximately 75% of
Ontarians would support provincial funding of IVF similar to that in Quebec.269
Policies internationally
International healthcare systems vary and this is reflected in their approaches to regulating and funding
ARTs. Some countries have centralized national systems while others are regulated at the state or
provincial level. In some jurisdictions health care is predominantly publicly funded, while others have a
mixture of public and private funding. Consequently, the relationships between medical professionals
and payers also vary, for example, from employee‐employer relationships to that of independent
entrepreneurs.
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All of the countries surveyed have national legislation in place, but these range in scope from coverage
of clinical and research use of human tissue and embryos, prohibitions against cloning and
commercialization of human reproduction and surrogacy, preimplantation genetic testing, to more
specific guidance on ARTs. Some countries, such as Australia, have legislation at both the national and
the state level (most states have legislation in place).
In some countries, clinical practice guidelines for ARTs are mandatory, the Fertility Society of Australia’s
Code of Practice for Assisted Reproductive Technology Units, for example, while in others they are only
recommendations.270The following sections summarize ARTs‐related policies, regulations, and funding in
the international jurisdictions selected for this review.
Coverage:
The public funding of ARTs services in the countries reviewed is governed by legislative statutes,
guidelines and, in some cases, by administrative decree. There is currently full public coverage of ARTs in
France,271 Israel,272and Sweden.10In New Zealand273 and Belgium,274 ARTsare fully covered for women
who meet certain clinical criteria. In Brazil275 and Switzerland276 there is no public coverage. In most
jurisdictions public coverage of IVF treatment is partial. In Australia, 277 Austria,278 Germany,275 Italy,10
The Netherlands,10 Norway,10 and Spain10 a portion of the costs is reimbursable or publically funded,
with varying rates of coverage, procedures covered and eligibility requirements. In most jurisdictions the
costs of diagnosing infertility are publicly covered, while coverage of the drugs used to treat infertility
and during IVF procedures varies by jurisdiction.
Maternal age:
Most jurisdictions have age limits on both public funding of IVF treatment and on the number of
embryos transferred per IVF cycle. In younger patients, due to their fecundity, most recommendations
call for implanting fewer embryos per cycle to minimize chances of multiple births. The youngest age
group is defined as less than 30 years (Spain),275 35 years (Australia,270Belgium,279Brazil275 and Israel),275
36 years (in Canadian guidelines),275 37 years (Quebec),257 38 years (Germany),275 and 39 years (New
Zealand).275
In addition to the younger age specifications, many jurisdictions that offer full or partial coverage of
ARTs have upper maternal age limits (due to the loss of fertility in older women public funding for ARTs
becomes significantly less cost‐effective). No upper age limits were found for Australia, Brazil, Canada,
Finland, Norway, Spain or Switzerland. The upper age limits for public funding were 40 years (Austria,278
Denmark,280 and New Zealand),203 42 years (France),28143 (Belgium,279and UK NICE guidance282),and 45
years (the Netherlands280 and Israel).283Note that these upper age limits apply to publicly funded ARTs
treatments. Denmark recently reduced public coverage of IVF treatments and it is unclear if their age
restriction will apply to privately funded procedures.171
Number of embryos:
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Limits on the number of embryos transferred per cycle are controlled by statute or regulations in many
jurisdictions (Belgium,281 Brazil,275 Germany,275 Israel,275Quebec,254Spain,275 Sweden,257 Switzerland,284
and the UK285), through a mandatory code of practice (Australia),270 and through voluntary clinical
practice guidelines in 3 countries (Canada,246the Netherlands,286 and New Zealand287). No information
onthe number of embryos that may be transferred was found for Austria, Denmark or Finland.
Generally, the permissible number of embryos transferred increases with maternal age and the number
of unsuccessful IVF cycles to balance the chances of a successful pregnancy with the risk of multiple
births. For the youngest age group (in the age categories described above) a maximum of a single
embryo for at least the first cycle is mandated in Australia270 and Belgium,281 and recommended in New
Zealand.275 Elective single embryo transfer for this age group is also recommended in the Canadian
guidelines246(for the first 3 cycles) and in Sweden.257In the Canadian guidelines, double embryo transfer
is permitted where the likelihood of twins is small (due to poor quality embryos and other infertility
factors). Quebec permits eSET or DET in the first 3 cycles for younger patients, but implantation of more
than 1 embryo requires justification from the practicing physician.257 In Brazil, Germany and Israel the
maximum number of embryos that may be transferred is 2.275 The guidelines in the Netherlands also
prescribe a maximum of 2 embryos but the decision between SET and DET is left to the physician and
couple.286 In Spain288 and Switzerland289 a maximum of 3 embryos is permitted, but in Spain younger
patients are usually recommended to have SET or DET.Clinicians in Switzerland have voluntarily reduced
the number of embryos transferred to a maximum of 2 (below the limits of their statute).289In Italy the
decision is left to the physician, although guidelines recommend SET or DET where possible290
In all jurisdictions older women are permitted to have more embryos transferred; most jurisdictions
allow a maximum of 3 embryos to be transferred.
ICSI, assisted hatching and other forms of micromanipulation:
In all of the countries reviewed ICSI and assisted hatchingare permitted. Norway requires special
approval for assisted hatching.The 2013 UK guidance states that assisted hatching is not recommended
because the evidence does not show that it improves pregnancy rates.24Other forms of
micromanipulation are permitted only in Australia (under limited conditions), Belgium (where it is
considered as embryo research requiring appropriate ethics approval) and Norway (where special
approval is required). In other jurisdictions micromanipulation was either expressly prohibited, or
commonly, was not mentioned.275
Oocyte maturation:
Most countries permit oocyte maturation either through legislation (Australia, Belgium, Denmark,
France, Germany, Israel, Italy, Norway, Sweden and Switzerland) or professional guidelines (New
Zealand and Spain). No specific reference to oocyte maturation was found for the remaining
jurisdictions.275
Fetal reduction:
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Fetal reduction is permitted by law in most countries (Australia, Belgium, Denmark, France, Germany,
Israel, Italy, the Netherlands, Sweden and Switzerland), and through guidelines in New Zealand. It is
forbidden in Brazil and Norway.275
Preimplantation genetic diagnosis:
Most jurisdictions allow PGD for known or potential medical risks. It is normally permitted for the
identification of genetic diseases or chromosomal disorders (limited to testing for certain hereditary
cancers in the Netherlands291). In Australia292 and France293 it is allowed for tissue matching with a sibling
and sex‐selection for medical reasons, and in Australia294 for women who have had repeated
miscarriages. Sex‐selection for medical reasons is also permitted in Belgium, Italy and the Netherlands,
although it is unclear if this is done by PGD or by sperm sorting.291 Israel allows PGD for “social reasons”
(which are not specified) in exceptional circumstances,293 for carriers of severe genetic diseases, and for
women who have had multiple miscarriages.295Preimplantation genetic diagnosis is not permitted in
Austria275 or Switzerland.291
Cryopreservation:
Most jurisdictions allow the freezing of embryos (Australia,294 Austria,275 Belgium,296 Brazil,275
Denmark,275 Finland,275 Israel,275 Italy,290 Norway275 and Sweden275). Some of these countries also permit
the cryopreservation of oocytes, ovarian and testicular tissue. This allows fresh embryo implantation to
be used on the first IVF cycle and frozen embryo implantation on subsequent cycles, thereby eliminating
the need for multiple embryo extraction procedures.Only Germany275 and Switzerland289 expressly
forbid the cryopreservation of embryos.
Donation:
Legislation or guidelines in Belgium, Brazil, Denmark, Finland and New Zealand permit the donation of
sperm, oocytes and embryos.275 Italy290 and Sweden275 do not permit embryo donation. Denmark,275
Germany,275 Israel,275 Norway202 and Switzerland275 allow only sperm donation. Austria does not permit
any ARTs related donation.275
Storage of embryos:
Six countries have stated lengths of time for which embryos may be stored. Australia,294 Belgium,275
Denmark275 and Switzerland297 allow 5 years of storage (with possible extension in Belgium). Embryos
are allowed to be stored for 10 years in Israel275 and 15 years in Finland.275
Surrogacy:
Only Belgium275 and Israel272 permit surrogacy. Several countries ban surrogacy (Austria,275 Denmark,275
Finland,275 France,291 Germany,275 Italy291 and Switzerland291).Canada,111 the Netherlands291 and New
Zealand298 do not permit “commercial surrogacy”.
Several recent reviews compare ARTs policies internationally, including a 2010 survey of over 100
countries by the International Federation of Fertility Societies,275 a review of global uptake of single
embryo transfer,299 a Canadian review which compares Canadian policies and multiple birth rates to
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those of 21 other industrialized countries,10 and a 2012 review that compares Canadian and Australian
policies on ARTs.212 The 2010 survey notes that:
Generally speaking, countries that have long been the users of IVF do have some sort of
legislative regulation or guidelines with certainquasi‐official regulation concerning parts of the
operation. It will, therefore, probably never be possible to determine the effect of
regulations or guidelines, or lack thereof, on the clinical outcome of IVF programmes.275
Nevertheless, the evidence shows that multiple birth rates have declined in countries with policies that
require or encourage single embryo transfer.10
In the US, voluntary clinical practice guidelines, rather than regulations, guide the practice of ARTs. The
recent case of the Suleman octuplets (IVF with 6 embryos transferred, 2 of which produced monozygotic
twins) is cited as “an example of what happens when ET [embryo transfer] is not strictly regulated and
when professional societies ‘lack the resources, statutory empowerment, training and experience to
regulate clinical practice’. The Suleman case illustrates the appropriateness of ET regulation in countries
that practice it. The absence of legislation regarding ET in the United States makes future such cases
likely.”300,301
A recent Australian systematic review of ARTs, intended to inform disinvestment decisions, concluded
that:
Within ART, there is a large volume of research; however there are a number of ways in which
this evidence‐base could be developed in order to provide greater clinical certainty and increased
policy relevance. It may be necessary to involve policy makers in specifying howmore relevant
data might be generated; their expectations of the information and the areas in which they see
scope for policy participation. As it stands, this evidence‐base presents a substantial challenge to
evaluation in a manner that is relevant and timely in itscontribution to the development of
robust health policy funding decisions.302
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Technology effects and effectiveness (T)
Results of literature search
9,905 discrete citations were identified through the literature search and 234 potentially relevant
clinical articles were selected for full review (Figure 2). Of these, 37studies met the inclusion criteria.In
addition, several articles that did not fall under the scope of the clinical review were selected to inform
the clinical pathway/decision model. The results of the literature search are shown below. The included
studies are summarized in Appendix B.
Figure 2. PRISMA diagram of literature search results & study selection for clinical effectiveness review

Total search results

= 16,051 citations

After duplicates removed

= 9,905 citations

Not relevant
Titles and abstracts reviewed
= 9,670

Full papers selected for clinical effectiveness
review
= 235

Included studies = 37 Excluded studies = 198

Some of these studies did not fall under the scope of the clinical review, however were selected for inclusion for the clinical
pathway/decision tree
Overall description of included studies
This review is based on 37 systematic reviews on IVF/ICSI, of which, 27included meta‐analyses (see
Table 25). These reviews evaluated the effect of procedural differences, such as the number of embryos
transferred (15 reviews), maternal and paternal characteristics (8), IVF/ICSI in comparison to less
invasive ARTs (2), ARTs in comparison to spontaneous conception (11), and patient preferences
(1).Where information was missing these reviews were supplemented by 7 primary studies.
ARTs in comparison to spontaneous conception
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ARTs was compared to ‘natural’ or ‘spontaneous’ conception (i.e., conception that is not preceded by an
ARTs intervention) in 13 reviews, 9 of which performed quantitative analyses on at least some
outcomes.55,89,303‐313 Control groups were often from the general population, although some studies used
infertile couples who eventually achieved pregnancy without the use of assisted conception. Reviews
included primary studies published between 1989 and 2011, and most were retrospective and
prospective cohorts, with some randomized controlled trials (RCTs), registry reports, and cross‐sectional
studies. With the exception of 5 reviews that reported maternal and infant safety data, they focused on
short‐ and longterm infant outcomes, ranging from neonatal periods through infancy and childhood.
Few studies examined outcomes at adolescence and adulthood. Population and procedural
characteristics were rarely reported.
IVF/ICSI in comparison to less invasive ARTs treatment options
IVF/ICSI was compared to less invasive ARTs in 1 meta‐analysis and 1 review.89,314 The meta‐analysis
comprised 6 RCTs (published from 1993 to 2011) from Canada (2), the US (1), and the Netherlands (3),
comparing the effectiveness and safety of IVF/ICSI to IUI (4) or to expectant management/spontaneous
conception (2).89
Of studies that reported treatment protocols, IVF/ICSI was preceded by a GnRH agonist protocol with
hMG or FSH and involved the transfer of 1‐4 blastocyst or cleavage stage embryos, while clomiphene
citrate (CC) or gonadotropins (e.g., FSH) were used for controlled ovarian stimulation in IUI. In 3 of 4
studies comparing IVF/ICSI and IUI, women who had not previously received ARTs underwent: 1) up to 2
cycles of IVF (1 fresh cycle and 1 frozen‐thaw cycle) vs. up to 3 cycles of IUI, 2) up to 6 cycles of IVF vs. up
to 6 cycles of IUI, or 3) 1 cycle of IVF vs. up to 3 cycles of IUI. In the fourth study, all couples received up
to 3 cycles of IUI with CC as a first line of treatment. Subsequently, women who failed to achieve an
ongoing pregnancy after these 3 cycles underwent either: 1) up to 6 cycles of IVF, or 2) up to 3 cycles of
IUI with FSH and, if no pregnancy is achieved with FSH‐IUI, up to 6 cycles of IVF.
The other review, which included 47 primary studies (most were case‐control and cohort studies)
discussed pregnancy complications after different types of ARTs. However, no quantitative analysis was
performed and details regarding the primary studies were not provided.314
Number of embryos transferred
Five meta‐analyses comprising 23 unique primary studies (14 RCTs, 1 quasi‐RCT, and 8 cohorts)
evaluated the effect of the number of embryos transferred on the safety and effectiveness of
IVF/ICSI.96,313,315‐317 One review consisted of a meta‐analysis of individual patient data.96 DET was
compared to eSET in all 5 reviews, with 1 review also comparing higher order multiple embryo transfers.
All reviews limited analyses to fresh embryos only, 3 excluded blastocyst‐stage embryos, and 1 excluded
donor oocytes or embryos, although the use of donor oocytes was not explicitly stated in any of the
primary studies. Primary studies were published between 1994 and 2010, and with the exception of 3
studies (1 in the US, 1 in Australia, and 1 in Saudi Arabia), most were of European origin. Similar ovarian
stimulation protocols were used across studies (GnRH agonist + hMG or FSH in the majority) and most
studies only included 1 cycle of IVF/ICSI per couple. Over half of trials specified maternal upper age
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limits (ranging from 30 to 37 years) and 7 further limited inclusion to couples where the female partner
was deemed to have a “good prognosis” (i.e., younger women in their 1st or 2nd IVF/ICSI cycle with good
embryo quality).
Fresh versus frozen embryo transfer
The safety and effectiveness of frozen embryo transfers in comparison to fresh embryo transfers was
assessed in 4 reviews of 81 unique primary studies.318‐321 Meta‐analyses were performed in 3 reviews,
however, 1 of these reviews only included 1 study, an Italian RCT, that compared fresh and frozen
embryo transfer, and 1 review (including 1 single‐arm trial from China and 6 observational studies from
the US) focused exclusively on the incidence of 1 adverse event. Studies in this review used similar
ovarian stimulation protocols (GnRH agonist + hMG and/or FSH in the majority), and evaluated
autologous cleavage‐ and blastocyst‐stage embryo transfers in ‘unselected’ women. The effect of frozen
embryo transfer on maternal and infant safety in singleton pregnancies was assessed in the third
analysis, which comprised 11 cohort studies.321 In the last review, 67 studies were included, 25
comparing the transfer of frozen cleavage‐stage embryos to fresh cleavage‐stage embryos or
spontaneous conception (1 RCT, 12 retrospective cohorts, and 12 registry reports) and 42 non‐
comparative studies evaluating the transfer of frozen blastocyst‐stage embryos or the fertilization and
transfer of frozen oocytes (mostly single‐arm trials and case reports). Studies were published between
1993 and 2008 and most were performed in the US or European and Asian countries, with a few in
Australia (4), Argentina (3), Canada (1), and Brazil (1). IVF/ICSI procedural details were not reported in
most studies.
Stage of embryo during transfer
The effect of the developmental stage at which the embryo is at during transfer in IVF/ICSI was
evaluated in 4 meta‐analyses comparing cleavage‐stage embryo transfer, where embryos are
transferred 2‐3 days after fertilization (i.e., embryos are cultured for 2‐3 days), and blastocyst‐stage
embryo transfer, where embryos are transferred 5‐6 days after fertilization.322‐326 Three reviews limited
inclusion to RCTs only, however 1 of these expanded inclusion to any design for studies reporting on
monozygotic twinning, and 1 review, only looking at sex ratio and monozygotic twinning, included any
comparative study. Analyses were limited to fresh cycles only in all 4 reviews, and autologous oocytes
only in 2 reviews. Overall, these analyses yielded 38 distinct primary studies (18 RCTs) published
between 1987 and 2007, with the earliest RCT published in 1998. Most studies were of European origin,
with a few studies originating in Australia, Israel, and the US. There was little difference in the ovarian
stimulation protocols reported across studies (mainly GnRH agonist + hMG and/or FSH). While only
patients with autologous oocytes were included in 2 RCTs, the use of donor oocytes was not explicitly
reported in any study. The number of embryos per cycle and the number of cycles per woman were
often not reported, and where reported, were variable across studies. In 9 studies, only women
considered likely to succeed with blastocyst transfers were included, and in 2 studies, only women with
a poor prognosis were included. The rest of the studies comprised ‘unselected’ couples, however,
maternal upper age limits ranging from 35 to 44 years were employed in a number of studies.
Donor embryo transfer
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One systematic review assessed the safety of IVF/ICSI using donor embryos.327 Details of the 79 primary
studies included in this review were not provided.
Maternal and paternal age
The association between parental age and the effectiveness of IVF/ICSI was assessed in 2 reviews,
neither of which included meta‐analyses.302,328 These reviews included 28 unique studies published from
1996 to 2010, with most from the US or Europe. The effects of maternal and paternal age were
discussed in a review of 21 observational studies. The influence of paternal age was further evaluated in
a second review. Eighteen studies used autologous oocytes only, while 2 studies included both
autologous and donor oocytes and 1 study limited inclusion to donor cycles only. A standard ovarian
stimulation protocol involving administration of a GnRH agonist followed by hMG and/or FSH was used
in most studies. Several studies restricted inclusion to fresh cycles (14) and cleavage‐stage embryo
transfers (10), and 13 studies only considered 1 cycle per couple. The number of embryos transferred
per couple was variable across studies. In the review looking solely at paternal age, maternal age was
taken into account in all studies either through upper age limits, the use of oocyte donors, or
adjustment for maternal age in analyses.
Maternal weight
Four reviews evaluated the effect of being overweight or obese on the safety and effectiveness of
IVF/ICSI.162,329‐331 All four reviews included meta‐analyses. These reviews comprised a total of 47 unique
primary observational studies published between 1999 and 2011, most of which were retrospective
cohorts (some were prospective cohorts, case‐control studies, and cross‐sectional studies or registry
reports). Over half of the studies were of European origin, with most of the other half from the US (12),
and the rest from Asian countries (5), Australia (4), Canada (1), and Brazil (1). In most primary studies,
cycles using donor oocytes or frozen embryos were excluded. Embryos were transferred at the cleavage
stage in 13 studies, at the blastocyst stage in 2, and at either in 11 (not specified in others). Several
studies reported a common ovarian stimulation protocol (GnRH agonist + hMG and/or FSH), while a few
used a GnRH antagonist, or clomiphene citrate + hMG and/or FSH. Where reported, the number of
embryos transferred per cycle and the number of cycles per couple were variable, although 1 review
limited analyses to 1 cycle per couple. With the exception of 4 retrospective cohorts of women expected
to have a “good prognosis” with IVF, study populations encompassed unselected patients, however
many studies excluded older women (limits ranging from 35‐44 years).
Maternal smoking status
Women who were active smokers at the time of the IVF procedure were compared to non‐smokers in 1
meta‐analysis of 21 studies (10 prospective cohorts and 11 retrospective cohorts).161 These cohort
studies were published between 1986 and 2007 in Europe (12), the US (4), Canada (2), Australia (2), and
Israel (1). Other than in 1 study, all outcomes were reported for 1 IVF/ICSI cycle per couple (or GIFT/ZIFT
cycle in some patients). Ovarian stimulation protocols varied slightly across studies: GnRH agonist +
hMG and/or FSH in the majority, clomiphene citrate + hMG in 5 studies, LHRHa +hMG in 1 study, and
hMG alone in 1 study. Donor oocytes were excluded in nearly all studies (20), and only women under
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37‐40 years were selected in 7 studies. Characteristics of the embryo transfer were not reported in most
studies.
Several factors
One review evaluated the association between fresh, autologous IVF/ICSI and several factors pre‐
identified as predictors of IVF/ICSI success (maternal age, parity, basal FSH, duration and indication of
infertility, method of fertilization, number of embryos transferred, and embryo quality).332 A total of 14
studies were included, mainly retrospective cohorts, published 1997 to 2008 in European countries (12),
the US (1), and Australia and New Zealand (1). Maternal age was a predictor in 13 studies, indication for
IVF in 4, duration of infertility in 3, basal FSH in 7, number of embryos transferred in 7, and quality of
embryos transferred in 3.
Patient preferences
Patients’ attitudes towards multiple pregnancies and single embryo transfer were discussed in 1 review
of 20 interview and questionnaire studies.185 Studies were published between 1998 and 2008, and were
from Canada (2), the US (7), Belgium (2), Denmark (2), the Netherlands (2), Sweden (1), and the UK (4).
Half of the studies elicited views from patients who were waiting to undergo or had already undergone
treatment with IVF/ICSI, ovulation induction, or intrauterine insemination, 2 studies included mothers of
IVF‐conceived children (IVF‐conceived twins, specifically, in 1 study), while 4 studies recruited all
patients attending a fertility clinic within a specific time period and 4 studies interviewed or sent
questionnaires to patients with infertility.
Overall quality of included studies
Included studies consisted of systematic reviews with or without quantitative analyses. Reviews were
assessed using the Oxman and Guyatt index of scientific quality for systematic reviews (Figure 3 and
Appendix C) and the PRISMA statement checklist.124‐126
Figure 3. Quality of systematic reviews: Oxman and Guyatt index of scientific quality for systematic reviews tool
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In general, most reviews were of high quality, although some had minor flaws and a few had major
flaws. All reviews provided the details of their search strategy, which was reasonably comprehensive,
and nearly all clearly described their study inclusion criteria. Aside from 1 review that excluded studies
with 0% incidence of a primary outcome, bias in study selection was avoided. The most common
weakness of the reviews was failure to perform or report a validity assessment of included studies
(15/36). Where validity was assessed, appropriate criteria were used. Of reviews with meta‐analyses
(27/31), all recorded the methods they used to combine outcome data, and all used appropriate
methods. In between studies that pooled data and those that did not, there was some variation in the
degree of clinical heterogeneity that was considered too much to pool. Conclusions drawn in all reviews
were consistent with the data they collected and reported.
For most of the procedural comparisons, data from experimental trials was available and supplemented
with data from prospective and retrospective cohorts. Only observational data were available for
comparisons among population characteristics (e.g., age), however, often data were from large registry
reports, or large prospective and retrospective cohorts. The poorest quality data existed among studies
looking at short term, and specifically long term, infant outcomes after ARTs compared to spontaneous
conception. Studies were often small and typically compared ART‐conceived infants to either the
general population or ‘spontaneously’ conceived infants, making it difficult to rule out the use of less
invasive ARTs treatments in control groups and the influence of infertility itself.
Significant heterogeneity was present across most studies. This is likely due to the great variation in
couples who may be candidates for ARTs, the lack of clear clinical practice guidelines, and the wide
variability within and between countries and between individual clinics with respect to ARTs policies and
protocols. Within comparisons, there was overlap in studies included between the reviews. Further, the
majority of reviews did not identify or discuss overlap between primary studies (multiple reports on the
same studies or patients published by different investigators), which may be a source of bias.
Safety
Safety relating to pregnancy and delivery
In comparison to pregnancies resulting from spontaneous conception, pregnancies occurring after
IVF/ICSI are associated with several maternal complications. An increased risk of ectopic pregnancy (10%
vs. 2%), gestational diabetes (10% vs. 6%), pregnancy‐induced hypertension (6% vs. 3%), placenta
praevia and placental abruption (4% vs. 1 %), preterm premature rupture of membranes (proportions
not reported), caesarean delivery (proportions not reported), and preterm delivery (8% vs. 5%) were
found in women who underwent IVF/ICSI with SET or achieved a singleton pregnancy through IVF/ICSI in
comparison to those who conceived ‘spontaneously’.312,313A sensitivity analysis found no changes in
results after excluding studies with spontaneous pregnancies in infertile couples.312
A significant increase in the risk of preterm birth after IVF/ICSI in comparison to spontaneous conception
was further confirmed in 3 meta‐analyses of studies controlling for at least maternal age, among other
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potential confounding factors. The higher likelihood of preterm delivery (<37 weeks gestation) and
moderate preterm delivery (<33 weeks gestation) after IVF was more pronounced in singleton
pregnancies (OR: 1.84 (1.54, 2.21); 1.63 (1.17, 2.27)) than twin pregnancies (OR: 1.23 (1.09, 1.41); 2.27
(1.73, 2.97)).303,305,306 In studies controlling for basic maternal characteristics (e.g., age, parity), women
who conceived twins through an ARTs were more likely to receive a caesarean section delivery than
women who conceived twins spontaneously (61% vs. 51%; OR: 1.70 (1.35, 2.14)).303
Safety relating to infant
Infants born to couples who conceived via IVF/ICSI appear to be more likely to experience adverse
events than infants born to couples who conceived without ARTs. In a meta‐analysis of 2 studies,
approximately 5% of infants were born low birth weight and 1% very low birth weight, regardless of
whether they were conceived spontaneously, or through IVF/ICSI with SET.313 On the other hand, pooled
data from a larger group of studies controlling for at least maternal age, among other potential
confounders, in singletons and twins, separately, revealed a significantly increased odds of being born
low birth weight after IVF/ICSI in both groups, with a more distinct effect in singletons (OR singletons:
1.60 (1.29, 1.98); OR twins: 1.14 (1.06, 1.22)).305,306,312
Further, more IVF/ICSI singletons, but not twins, were small for their gestational age (birth weight <10th
percentile for gestational age) compared to spontaneously conceived singletons and twins (OR 1.45
(1.04, 2.00)).306,312 In another analysis of twins only, no significant differences in low birth weight or very
low birth weight rates were seen between IVF/ICSI twins and spontaneously conceived twins, with the
exception of differences seen in a subgroup of twins of different sexes.303
Monozygotic twining rates reported in non‐comparative studies after ARTs approached 2% (27 studies),
over double the rates reported after spontaneous conception (0.4%).308 This rate was further amplified
in frozen embryo transfers (3%), and blastocyst embryo transfers (5%).
Infants born after IVF/ICSI had similar neonatal mortality rates and NICU admission rates as infants born
without IVF/ICSI, however data was based on 1 study.313 In twin studies adjusting for basic maternal
characteristics, no significant differences in perinatal morality (3%) or NICU admissions (65‐66%) were
observed between IVF/ICSI twins and spontaneously conceived twins, aside from a subgroup of unlike
sex twins who had increased perinatal mortality rates after IVF/ICSI (4% vs. 2%; OR: 1.95 (1.41, 2.71)).303
Singletons conceived through IVF/ICSI, however, were at a significantly higher risk of perinatal mortality
and NICU admission than singletons conceived spontaneously (RRs: 1.87 (1.48, 2.37), and 1.58 (1.42,
1.77), respectively).312
The incidence of birth defects in ARTs and non‐ARTs infants was assessed in 2 analyses. In a pooled
analysis of 5 studies controlling for maternal characteristics, birth defect rates were 3% in both ARTs and
non‐ARTs twins.303 In contrast, in a large meta‐analysis (46 studies) including both singletons and
multiples, the odds of infants having a birth defect were increased after both IVF and ICSI (combined OR:
1.37 (1.26, 1.48)).55 The effects were particularly evident in the nervous system (OR: 2.01 (1.27, 3.20)),
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whereas differences were least noticeable in defects of the musculoskeletal system (OR: 1.48 (1.09,
2.02)), and eye/ear/face/neck (OR: 1.43 (1.01, 2.05)).
About 4% of singletons born after IVF/ICSI were reported to have congenital malformations in a meta‐
analysis of 7 studies, compared to about 3% of singletons born after spontaneous conception (OR: 1.67
(1.33, 2.09)).312 Differences remained significant after restricting analyses to studies that matched for at
least age and parity. In a review of congenital malformations, pooled data from older meta‐analyses
suggested significantly increased rates of all congenital malformations, in addition to major birth
defects, in all children born after IVF compared to children born after spontaneous conception (ORs: 1.3‐
1.4, and 2.0, respectively), consistent with findings from recent primary studies.309,311 The same effect
was not seen in ICSI children, however, in a recent large cohort, where ICSI was associated with slightly
higher rates of malformations in comparison to spontaneous conception after adjusting for maternal
age, and parental and sibling malformations (OR: 1.2 (1.0, 1.5)). The effect also appears to be higher
among twins, with 7% of IVF twins, 13% of ICSI twins, and 2% of spontaneously conceived twins
experiencing malformations (adjusted OR: 6.7 (2.1, 21.9)).309 No significant differences in imprinting
disorders were noted.309,311
Couples who conceived via IVF/ICSI were over 2 times as likely to have an infant with cerebral palsy, in
comparison to couples who conceived naturally (0.5% vs. 0.2%; OR: 2.18 (1.71, 2.77)).307 A further
analysis showed this difference was true for singletons, while no significant differences between twins
were observed.307,310 Out of 2 studies adjusting for preterm birth, 1 reported a lasting significant
difference. In studies that could not be combined, 5 of 5 showed a significant association between
cerebral palsy and IVF/ICSI, but again, a difference between singletons and multiples was apparent, with
3 of 4 studies in singletons and 0 of 5 studies in multiples reporting significant differences.307
Evidence around the risk of autism spectrum disorders (ASD) in IVF/ICSI children was variable. Out of 5
studies, 3 found no differences between IVF/ICSI conceived and spontaneously conceived infants, 1
study reported a significant increase in the incidence of a broader group of psychiatric disorders
altogether, of which 1 disorder was ASD, in IVF/ICSI children, and 1 study showed significantly reduced
chances of having ASD after IVF, adjusting for several factors.307
In a systematic review discussing motor, behavioral, cognitive, and mental developmental delay, very
few of 30 studies reported notable differences between children born from assisted conception
compared to those born after spontaneous conception.307 Similarly, no consistent effect of assisted
conception on neuromotor, cognitive, language, and behavioral development was observed in studies of
infants and/or school‐aged children.310 Further, no significant differences in growth or cognitive
development between ARTs‐conceived and spontaneously conceived adolescents and adults were
observed in most studies from another review, however this was from a few small size studies.304
Chronic disease profiles in adolescents were also similar irrespective of their conception history, with
the exception of a higher prevalence of attention‐deficit/hyperactivity disorder (ADHD) reported after
ARTs in 1 cross‐sectional study (27 vs. 3‐5%) and more cases of childhood cancer after ARTs in 1 cohort
study (OR: 1.42 (1.09, 1.87)).
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The incidence of OHSS was slightly higher in women after 6 or fewer cycles of IVF than after 6 or fewer
cycles of IUI with controlled ovarian stimulation (5.1% vs. 3.4%; 1 RCT). These differences were not
statistically significant.89
In a review of hypertensive complications, after adjusting for age and smoking status among other
factors, women who conceived through an invasive ART (IVF/ICSI or GIFT/ZIFT) were 2‐3 times more
likely to have preeclampsia than women who conceived spontaneously (ORs: 2.7 (1.7‐4.4), 1.8 (1.1,3.1)),
whereas no increased risk was shown in women who conceived through a less invasive ARTs (ovulation
induction or IUI) compared to women who conceived spontaneously.314
In contrast, in a cohort study of singleton pregnancies that matched patients on maternal age,
gestational age, and parity, not only were the odds of experiencing gestational diabetes, pregnancy‐
induced hypertension, and caesarean delivery significantly higher after IVF in comparison to
spontaneous conception, but also after IUI.314 The proportion of women experiencing gestational
diabetes, pregnancy‐induced hypertension, and caesarean delivery, however, appeared higher after IVF
(21%, 10%, and 47%, respectively) than after ovulation induction (13%, 9%, and 18%, respectively).
The safety of less invasive ART options was discussed in 1 review, however IVF/ICSI was not directly
compared to these treatments.311No significant differences in the rate of congenital malformations or
major malformations were found between women who conceived through ovulation induction alone or
ovulation induction with IUI and those who conceived spontaneously.311
DET was associated with higher rates of preterm rupture of membranes (8.5%), placental abruption
(2.2%), and preeclampsia (7.7%), in comparison to SET (0.8%, 0%, 7.0%, respectively), however results
were from 1 RCT (N = 270) and 1 cohort (N = 269), and statistical significance was not reported.313 In the
same review, the incidence of gestational diabetes was reported to be higher in women after DET in an
RCT and higher after SET in a cohort. No significant differences between SET and DET in ectopic
pregnancy (3 RCTs, 3 cohorts) and placenta praevia were found (1 cohort).313,315
The risk of preterm delivery (<37 weeks gestation) was significantly lower after SET (7% of pregnancies,
13% of deliveries) in comparison to DET (22% of pregnancies, 30% of deliveries) in 2 meta‐analyses of
RCTs (ORs: 0.33 (0.25, 0.55), 0.37 (0.20, 0.55)), but no significant difference was shown in cohort
studies.96,313 In one of these reviews, the risks of both early (<32 weeks gestation) and moderate (<34
weeks gestation) preterm delivery were also significantly lower after SET.96 In addition, more women
underwent caesarean section delivery after DET (24%) compared to SET (20%) in 1 cohort study
(significance not reported).313
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In 2 meta‐analyses, infants born after IVF/ICSI with SET were 2‐4 times less likely to be born with a low
birth weight (<2,500 grams) compared to infants born after DET (7‐8% vs. 24‐29% in RCTs; RR: 0.25
(0.15, 0.45), OR: 0.36 (0.15, 0.87); 9.5% vs. 4.8% in cohorts; RR: 0.51 (0.29, 0.91)).96,313 DET was also
associated with slightly higher rates of neonatal mortality (1.1% vs. 0%), perinatal mortality (1.0% vs.
0.7%), and congenital malformations (4.8% vs. 3.1%) in 1 RCT (significance not reported), but this RCT
also reported no difference in the proportion of ‘healthy’ newborns (rated by the Apgar score) born
after DET and SET.313 Combined results from cohorts in the same review showed no significant
difference in neonatal or perinatal mortality, or NICU admissions between SET and DET.313
Four reviews, 2 of which included meta‐analyses, evaluated the safety of IVF/ICSI with frozen embryos
compared to that with fresh embryos. The incidence of ectopic pregnancy was the focus of 1 meta‐
analysis of 7 studies, which reported no significant difference between women undergoing fresh embryo
transfer and frozen embryo transfer (OR: 1.66 (0.62, 4.41)).318 Further subgroup analyses showed similar
results regardless of the stage at which the embryo was transferred. There were no significant
differences in the number of women experiencing moderate to severe OHSS or the number of women
admitted to the hospital during their pregnancy after fresh versus frozen embryo transfers, although
these outcomes were only reported by 1 review of 1 study.319 In a comprehensive analysis limited to
singleton pregnancies, there was a significantly lower incidence of antepartum hemorrhage (including
placenta praevia and placental abruption) and preterm birth after frozen embryo transfer (9.4% and
3.2%, respectively) compared to fresh embryo transfer (10.5% and 5.1%, respectively), but a significantly
higher incidence of caesarean delivery after frozen cycles (35% vs. 29%).321 In a recent registry study,
lower rates of placenta praevia but higher rates of preeclampsia were found after frozen embryo
transfer in comparison to fresh embryo transfer.333
Half of the studies discussed in a review reported a significantly lower number of singleton preterm
births after frozen cleavage‐stage embryo transfers (9‐11%) compared to fresh cleavage‐stage embryo
transfers (12‐13%), while the other studies reported no differences.320 Results were similar between IVF
and ICSI cycles. In twins, 2 studies observed no difference in preterm births, 1 study reported
significantly less preterm births after frozen compared to fresh cleavage stage transfers (33% vs. 58%),
and 1 study reported a reduced number of preterm births in fresh cleavage stage transfers after IVF, but
not after ICSI.
Adverse effects in infants born after frozen embryo transfers were assessed in 1 meta‐analysis and 1
systematic review that did not include a meta‐analysis because of heterogeneity among studies.320,321 An
analysis of 8 studies revealed that singletons born after frozen embryo transfers were less likely to be
born low birth weight (6%) than singletons born after fresh embryo transfers (8%; RR: 0.69 (0.62,
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0.76))321,333. In 1 study discussed in the review, this was true for IVF but not ICSI. Frozen cleavage
transfers were also associated with a reduced incidence of low birth weight in twins (38‐47%) compared
to fresh cleavage transfers (50‐55%) in 3 studies, while 2 studies found similar rates between the 2
groups.320 Limited data on the freezing of blastocysts and oocytes were found and no differences in birth
weight were demonstrated between fresh and frozen transfers.
Perinatal mortality rates in singletons were slightly lower after frozen transfers (0.8% vs. 0.9%; RR: 0.68
(0.48, 0.96), while NICU admissions were similar between fresh and frozen IVF.321However, a recent
registry study in singletons born after IVF reported significantly higher rates of perinatal mortality and a
significantly higher proportion of ‘unhealthy’ newborns (rated by the Apgar score) after frozen
transfers.333 Comparable perinatal mortality rates in both singletons and twins were reported in 1 study,
however, another study found lower rates of stillbirths in singletons after frozen IVF and ICSI cycles
(0.5%, 0.4%) compared to fresh IVF and ICSI cycles (1.2%, 1.8%) and in twins after frozen ICSI cycles
(0.6%) compared to fresh ICSI cycles (2.1%).320
The rate of birth defects among singletons and multiples combined ranged from 1‐8% (13 studies) after
both fresh and frozen transfers, with only 2 studies reporting a significant difference – increased rate of
malformations after fresh embryo transfer in 1 study and after frozen embryo transfer in the other. An
additional 4 studies reported on defects in singletons and/or twins separately. Of these, 1 study
observed significantly more singletons with birth defects if conceived after frozen ICSI (6%) versus fresh
ICSI (3%). Further, the proportion of infants with chromosomal aberrations was shown to be similar
between fresh and frozen cycles (1 study). In an analysis of 3 studies, no significant difference was
shown in the rate of congenital malformations.321
Long term growth patterns in infants were discussed in 2 studies, following infants born after IVF/ICSI
with cleavage‐stage embryos up to 18‐24 months of age. In singletons, growth was not only normal and
similar between fresh and frozen embryo transfers, but also similar between these 2 groups and a group
of spontaneously conceived controls.320 In contrast, early delays in growth were demonstrated in both
fresh and frozen IVF/ICSI groups in comparison to spontaneously conceived multiples, however these
differences dissipated after 6 months of age. Further, few differences in mental development were seen
between infants born after frozen IVF/ICSI and those who were spontaneously conceived.
Very few studies were found that assessed differences in safety between blastocyst‐ and cleavage‐stage
embryo transfers. Aside from monozygotic twinning, blastocyst‐stage transfers are not expected to be
associated with any more safety issues than cleavage‐stage transfers.334
Monozygotic twinning rates reported in non‐comparative studies range from 0.4‐8.6% after IVF/ICSI,
overall.326 Rates reported in non‐comparative studies of blastocyst‐stage IVF/ICSI (1.2‐5.7%) fit into this
range. Only one of 9 comparative studies included in 1 review showed significantly higher rates of
monozygotic twinning after blastocyst transfers compared to cleavage transfers (1.6% vs. 0.4%; OR 3.04
(1.54, 6.01)).322 In a subgroup analysis by publication date, this difference was only significant in studies
published before 2002.
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Donor embryo transfer
Safety issues related to donor embryo transfer were addressed in 1 systematic review.327 Increased rates
of pregnancy‐induced hypertension and caesarean section deliveries were demonstrated in donor
IVF/ICSI in comparison to spontaneous conception pregnancies. In comparison to autologous IVF/ICSI
cycles, first trimester vaginal bleeding and hypertensive complications were significantly higher in
pregnancies resulting from donor IVF/ICSI cycles (even when age and parity were taken into account).
No significant differences in the proportion of women experiencing preterm delivery were reported.
No significant associations were apparent between IVF/ICSI with donor oocytes and low birth weight
rates, proportion of infants small for their gestational age, or congenital malformations.327
Maternal age
No reviews were found that assessed the influence of maternal age on the safety of IVF. A prospective
analysis of data from a UK registry showed that women under 40 years of age were at a higher risk of
preterm birth and having a low birth weight baby than women 40 years of age and older.333 This may, in
part, be a result of the higher likelihood of multiple births in women under 40 in comparison to women
40 and older, regardless of the number of embryos transferred.333 In singleton pregnancies in the
general population, however, women over 35‐40 years of age have a higher odds of preterm delivery
and of having a low birth weight baby than younger women.35
Further, although not studied in ARTs populations specifically, an increase in pregnancy complications
with increasing maternal age has been shown in women in general.35 For instance, 4‐8 fold increases in
the incidence of ectopic pregnancy are reported after 35 years of age, 3 fold increases in the incidence
of gestational diabetes and placenta praevia are in women over 40 years of age, and linear increases in
the rate of caesarean deliveries with increasing maternal (in women over 40, over half of infants are
delivered via caesarean section).35 The risk of perinatal mortality is also greater in women over 35‐40.
Aside from potentially higher rates of malformations in infants conceived through IVF, evidence from
the general population shows increasing rates of chromosomal abnormalities (e.g., trisomies) and non‐
chromosomal birth defects (e.g., structural heart defects) with maternal age, even in singleton
births.335The limited evidence available on the effect of paternal age suggests there may be higher rates
of specific congenital anomalies and cognitive or psychiatric disorders in the offspring of older men,
however, more studies controlling for maternal age and other factors are needed.335
Maternal weight
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Similar proportions of normal or underweight women (BMI <25) and overweight or obese women
combined (BMI ≥25) developed OHSS after ovarian stimulation.329,331 The incidence of OHSS was also
similar between overweight (BMI 25‐29) and obese women (BMI ≥30).331 No significant differences in
the risk of ectopic pregnancy were evident between normal or underweight women and overweight or
obese women.329 No studies on the influence of maternal weight on other pregnancy complications
after IVF/ICSI were found, although, evidence of the effect of obesity on pregnancy in general
populations was found.53 Obese women were significantly more likely to experience preeclampsia (2X
higher), gestational diabetes (2‐4X higher if obese, 8X higher if morbidly obese), and postpartum
hemorrhage (1.5X higher) than normal weight women, and were at a significantly higher risk of
caesarean delivery (2X higher) than normal weight women.53,336
No studies of the effect of maternal weight on ARTs infant safety were found. In general populations,
rates of stillbirth, admission to NICU, and perinatal death have been shown to be significantly higher in
infants born to obese women compared to non‐obese women.53,336 Metabolic disorders and congenital
abnormalities are also more common in infants born to obese women. Morbidly obese women (BMI>40)
are more likely to give birth to a child with a birth defect (4% of infants) than women who are obese
with BMIs of 30‐40 (2% of infants).53,336
The safety effects of smoking at the time of treatment with IVF/ICSI were assessed in 1 meta‐analysis.
Women who were active smokers at the time of IVF/ICSI treatment were much more likely to
experience an ectopic pregnancy than non‐smokers (OR: 15.69 (2.87, 85.76)), even in studies where age
was not likely to be a confounder.161 Studies on the effect of smoking on other maternal and neonatal
adverse events in IVF/ICSI populations were not found. In general populationssmoking during pregnancy
has been shown to increase placental complications and preterm delivery.53
Smoking during pregnancy is associated with higher risks of stillbirth, neonatal mortality, and fetal
growth restriction, in addition to Sudden Infant Death Syndrome and childhood respiratory disorders.53
Potential relations between smoking and congenital abnormalities, and behavioral or psychiatric
disorders have been suggested, but evidence is limited and inconclusive.53
Summary
The safety of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) was assessed in 27 reviews:
18 reporting on adverse events relating to pregnancy or delivery, and 19 on adverse events in infants
(Appendix D). In comparison to ‘natural’ conception, IVF/ICSI is associated with an increase in many
complications that occur during pregnancy and delivery, and may even have an adverse effect
throughout infancy, childhood and adulthood. Most obvious differences were increased preterm
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delivery, low birth weight, malformations and birth defects, and cerebral palsy in IVF/ICSI infants, in
both singletons and twins, compared to spontaneously conceived infants. However, these could be due
to increased surveillance in IVF/ICSI pregnancies, infertility itself, or associated with maternal
complications. The growth and development of IVF/ICSI children appeared to follow normal patterns,
but studies with longer follow‐up are needed as the effect may not be evident until maturity.
Other than increased monozygotic twinning rates, blastocyst embryo transfer did not appear to have
any significant safety issues over IVF/ICSI with cleavage stage embryos. Similarly, the health of infants
born after donor cycles is at least as good as that of infants born after IVF/ICSI with autologous oocytes.
Donor IVF is often associated with anovulation and advanced maternal age, therefore, studies of donor
cycles should take these into account. In comparison to fresh embryo transfer, overall, frozen embryo
transfer is associated with fewer adverse events throughout pregnancy and delivery, and is at least as
safe as fresh embryo transfer in terms of infant outcomes.
In general, in comparison to women undergoing SET, there were more adverse events during pregnancy
and delivery in women after DET and more safety issues in infants born after IVF/ICSI with DET. The
number of preterm deliveries, caesarean section deliveries, and low birth weight infants were noticeably
increased after DET.
Although evidence in ARTs‐specific populations was limited, increased maternal age (>35‐40 years),
maternal obesity, and smoking during pregnancy contributed to or were associated with more
complications throughout pregnancy and delivery, and in infants.
Efficacy/effectiveness
Pregnancy
The odds of achieving a clinical pregnancy after 1 cycle of IVF were over 3 times higher than after 3‐6
months of no treatment (12 vs. 29%; OR: 3.24 (1.07, 9.80)).89
Live births
Very few couples with unexplained infertility had a live birth after 3‐6 months of no treatment (4%).89 In
contrast, almost half of couples with unexplained infertility achieve a live birth after 1 cycle of IVF (OR:
22.00 (2.56, 189.37)).
Pregnancy
In 2 RCTs in couples with unexplained infertility, no significant differences were seen in pregnancy rates
after IVF and stimulated IUI (22‐24%), however, up to 3 cycles of IUI were required to achieve these
rates in comparison to 1 cycle of IVF (with some women receiving an additional frozen‐thaw cycle).89 In
contrast, pregnancy rates were substantially different between IUI and IVF as a second line of treatment
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in couples who were unable to succeed with 3 cycles of IUI with clomiphene citrate: 84% of women
became pregnant within 6 cycles of IVF in comparison to 30% of women within 3 cycles of IUI with FSH
(OR: 12.78 (7.54, 21.65)).
Miscarriage
Miscarriage rates were slightly higher in couples who had failed to achieve a pregnancy with CC‐IUI who
underwent 1‐6 cycles of IVF (19%) in comparison to those who had 1‐3 cycles of FSH‐IUI (14%).89 The
statistical significance was not reported.
Multiple pregnancy
Overall, similar multiple pregnancy rates were reported after stimulated IUI and IVF (9% vs. 13%; no
significant difference), however, multiple pregnancies in the IVF group occurred only in couples who
received more than 1 embryo.89 In contrast, multiple pregnancy rates were lower after IVF (14%)
compared to IUI (25%) in a recent pilot study that randomized women to 1 cycle of elective SET (transfer
of 1 good quality embryo, or 2 embryos if none of good quality available) or 3 cycles of ovarian
stimulation + IUI (with clomiphene citrate or FSH); statistical significance was not reported.337 Again, all
multiple pregnancies in the IVF group occurred in women who received 2 embryos.
Live births
Similar to pregnancy rates, no differences in live births were observed between stimulated IUI and IVF as
a first line of treatment for couples with unexplained infertility (29‐32%), but significantly higher live
birth rates occurred after IVF (58%) than after FSH‐IUI (22%) as a second line of treatment in women
who had failed CC‐IUI (OR: 2.66 (1.94, 3.63)).89
Implantation
Of 5 primary studies reporting implantation rate, none found significant differences between SET and
DET. Approximately 31‐35% of embryos transferred in IVF/ICSI cycles were successfully implanted,
regardless of whether 1 or 2 embryos were transferred.315,316
Pregnancy
Clinical pregnancy rates per couple after DET (50%) were almost 2 times greater than pregnancy rates
after SET (31‐37%) (RRs: 1.35 (1.08, 1.69), 2.21 (1.75, 2.79)).315,317 Similar findings were reported for
ongoing pregnancy rates after DET (45%) versus SET (24‐28%) (RRs: 1.89, (1.39, 2.56), 2.06 (1.64, 2.60)),
even in studies which only included women under 36 years of age.315,316 Further, in a single small study
included in one review, when compared to women undergoing 1 IVF/ICSI cycle with DET, no significant
differences in clinical pregnancy rates were seen in women undergoing 2 SET cycles, 1 fresh SET cycle
and 1 frozen SET cycle, 1 three embryo transfer (TET) cycle, or 1 four embryo transfer (QET) cycle.317
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Miscarriage
Although DET was associated with a higher likelihood of ongoing pregnancy in comparison to SET, the
risk of miscarriage was similar between the two groups in most studies (DET: 15‐18% of pregnancies, 8%
of women, vs. SET: 20‐25% of pregnancies, 7% of women), and also between 1 DET cycle and 2 SET
cycles.313,315,317 One meta‐analysis of individual patient data showed a slightly higher rate of miscarriage
(per pregnancy) after eSET (25%) compared to DET (18%) (RR: 1.52 (1.01, 2.28)).96
Live births
Live birth rates after DET (42‐43%) were significantly higher than live birth rates after SET (26‐28%), with
odds ratios among 4 analyses ranging from 1.61 to 2.10, one of which adjusted for the cause of
infertility, treatment characteristics, and the quality of embryos transferred.96,315‐317 No change in this
effect was seen in subgroup analyses of individual patient data comparing women under 33 years of age
to women 33 and older, couples with a history of infertility less than 3 years to couples with 3 or more
years of infertility, and top quality embryos to lesser quality embryos, although differences were greater
in transfers with less than top quality embryos (OR: 3.45 (1.41, 9.09)), in comparison to those with top
quality embryos (OR: 1.89 (1.49, 2.50)).96 Chances of live birth were also increased in TET (27%) and QET
(54%) in comparison to DET (13% and 29%, respectively), but differences did not reach statistical
significance.
In contrast, cumulative live birth rates (live birth rates per couple after all cycles/transfers) were
comparable between 1‐2 cycles of DET and SET96, 1 cycle of DET and either 2 cycles of SET or 1 cycle of
fresh SET and 1 cycle of frozen SET, 2 cycles of DET and 2 cycles of TET, and 3 cycles of DET and 3 cycles
of TET.317
Multiple pregnancies/multiple births
The odds of carrying multiples was far greater in women who achieved a clinical pregnancy through
IVF/ICSI with DET than in women who received SET (19% vs. 0.7% of women; OR: 25.00 (9.09,
100.00)).317 The incidence of multiple pregnancy rates was also heightened in TET compared to DET (RR:
0.17 (0.01, 3.85)) and QET compared to DET (RR: 0.44 (0.10, 1.97)), and after 1 cycle of DET compared to
2 cycles of SET (13% vs. 0%; RR: 0.06 (0.00, 1.02)), however these differences were not statistically
significant and were based on 1 small study.317
Correspondingly, multiple birth rates were not only significantly increased in women who underwent
DET (30% of live births) in comparison to women who underwent SET (2%) (RR: 17 (6, 50); OR: 25 (8,
100)), but also in women who received 1 cycle of DET (33%) compared to those who received 1 cycle of
fresh SET and 1 cycle of frozen SET (0.8%) (OR: 50).96,315,317 Findings were consistent regardless of
maternal age (<33 or ≥33), duration of infertility (<3 or ≥3), or embryo grade (A or B).
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Pregnancy
Clinical pregnancy rates per woman were comparable between fresh and frozen IVF/ICSI cycles,
although data was based on a single RCT.319
Live births
No significant differences in the proportion of women with live births were observed between fresh
(37%) and frozen (28%) IVF/ICSI cycles.319
Embryo cryopreservation
Significantly fewer embryos were cryopreserved (per couple) after blastocyst‐stage embryo transfers
(41‐53%) than after than cleavage‐stage embryo transfers (63‐71%) (ORs: 0.28‐0.45).323,325 This held true
in studies where more cleavage‐stage embryos than blastocyst‐stage embryos were transferred.325
Cycle cancellation
Out of women reaching the oocyte retrieval stage of IVF/ICSI, about 9% awaiting blastocyst transfers
cancelled their cycle compared to 5% of women awaiting cleavage transfers (OR: 2.21 (1.47, 3.32)).323
Further, significantly more couples undergoing blastocyst transfer failed to transfer any embryos (9%) in
comparison to couples undergoing cleavage transfer (3%), regardless of whether an equal number of
embryos were transferred between groups or if more embryos were transferred in the cleavage stage
group (OR: 2.86 (1.96, 4.17)).325 In women predicted to have a good prognosis, however, no significant
differences were observed.
Pregnancy
Slightly higher clinical pregnancy rates per woman were demonstrated after IVF/ICSI with blastocyst‐
stage embryos (39‐40%) compared to IVF/ICSI with cleavage‐stage embryos (34‐39%) in 2 meta‐
analyses.323,325 While these differences were significant in 1 review (OR: 1.27 (1.03, 1.55)), the other only
found significant differences in cumulative clinical pregnancy rates after all fresh and frozen IVF/ICSI
cycles. Further, subgroup analyses revealed no differences when an equal number of cleavage and
blastocyst stage embryos were transferred, or when more cleavage stage embryos than blastocyst stage
embryos were transferred.325
Miscarriage
No significant variation in the proportion of women experiencing miscarriages after blastocyst transfers
(10%) versus cleavage transfers was reported (8%).325
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Live births
IVF/ICSI with blastocyst‐stage embryos was associated with a higher likelihood of a live birth than
IVF/ICSI with cleavage‐stage embryos (35‐39% vs. 28‐31% of women; ORs: 1.35‐1.39).323,325 When only
studies considering women who were expected to have a good prognosis with blastocyst transfer,
differences were even greater, and, conversely, in studies of unselected women or women with a poor
prognosis, no significant differences were shown.325
Despite several studies transferring more cleavage than blastocyst stage embryos, there was no
significant difference in the multiple pregnancy rate between blastocyst‐ and cleavage‐stage embryo
transfer (28% vs. 26% of pregnancies; 11% vs. 10% women).323,325
Embryo quality
Pregnancy
In a meta‐analysis of predictors of IVF/ICSI success, several studies found embryo quality to be a
significant and valuable predictor of successful pregnancy. Results were not pooled because each study
used different criteria/criterion to assess embryo quality. Given the lack of consistency between the
quality assessment methods, which factor of the quality of the embryo is important remains unclear.332
Live births
In a pooled analysis of 8 RCTs, IVF/ICSI with fresh, autologous, cleavage‐stage embryos achieved a 21%
live birth rate with grade B embryos, in comparison to a 36% live birth rate with grade A (top quality)
embryos (OR: 1.93 (1.23, 3.04)).96 Embryos were considered top quality, or grade A, if they had4 or more
cells on day 2 or more than 6 cells on day 3 after fertilization. All other embryos were classified as grade
B.
Multiple births
No significant association between embryo grade and multiple birth rates were found.96
Maternal age
Pregnancy
Reduced pregnancy rates after IVF/ICSI were associated with increasing maternal age. Pooled data from
7 cohort studies indicated that for each one year increase in maternal age, the odds of a clinical
pregnancy after a fresh, non‐donor IVF/ICSI cycle was significantly decreased by 4‐6% (OR: 0.95 (0.94,
0.96)).332 Evidence from individual studies that separated women into age categories noted significantly
reduced chances of pregnancy in women over 38 years of age, 35 years of age, and even 30 years of
age.332 Although statistical significance was not reported, in the 3 most recent studies identified in a
systematic review, pregnancy rates per autologous IVF/ICSI cycle were considerably lower in women
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over 37 years of age (27%), compared to women under 37 (45%), and substantially lower in women over
40‐41 (3‐9%), compared to women under 40‐41 (17‐28%).302
Lower pregnancy rates in older women have been overcome through IVF/ICSI with donor oocytes. In a
few older studies of IVF/ICSI with oocytes from donors under 35 years of age, pregnancy rates per cycle
were 37‐49% in women in over 50, 25% in women 45‐50, 38% in women 40‐50, and 47% in women
under 40.332 In a more recent population‐based study, success rates of donor IVF were shown to be
dictated by the age of the oocyte donor.338 No significant differences in pregnancy rates (34‐36%) were
reported across recipient age groups (>35, 35‐39, 40‐44, >44), however rates were significantly lower
when oocytes were from donors 35‐39 years old (32%), or donors over 40 years of age (23%), compared
to donors 30‐34 or under 30 years of age (35‐37%).
Pregnancy has been shown to steeply decline after 40 years of age. Recent CARTR data (2010) reported
per cycle pregnancy rates of 8% in women 44‐45 and 0% in women over 45 years, compared to 13% in
women 42‐43 and 22% in women 40‐41 years of age. These trends were further supported by US
registry data, which also indicated increases in miscarriage ratesby about 9% per year between the ages
of 41 and 43until they reach almost 60% in women 44 and older. Pregnancy and miscarriage rates in
women over 40 undergoing IVF/ICSI with donor embryos, however, have been found to be similar to
those in women under 40 years of age. Pregnancy and miscarriage rates in 2010 CARTR data were 51%
and 15%, respectively, in women 40 years of age and older undergoing IVF/ICSI with donor embryos,
compared to corresponding rates of 42% and 13% in women under 40 years of age undergoing IVF/ICSI
with their own embryos.
Miscarriage
Recent comparative studies in women undergoing autologous IVF/ICSI showed higher rates of
miscarriages in older age groups compared to younger age groups, with 2 of 3 studies reporting
significant differences.302 The proportion of pregnancies resulting in miscarriage was highly variable
across both comparative and non‐comparative studies, ranging from 32‐64% in women aged 40 and up,
22‐27% in women under 40, and 9% in women under 37.
Live births
In autologous IVF/ICSI cycles, increasing maternal age was correlated with a decreased likelihood of live
birth. In a meta‐analysis of 8 observational studies, after fresh, autologous IVF/ICSI with cleavage stage
embryos, 37% of women under 33 years of age had a live birth, compared to 21% of women 33 years of
age or older (OR: 1.37 (1.05, 1.77)).96 Several studies discussed in a review of both fresh and frozen
autologous cycles reported a decline in both the proportion of women having a live birth and the
proportion of cycles resulting in a live birth with rising maternal age, particularly after age 40.302The
statistical significance was not reported and rates were highly variable across studies. Live birth rates of
37‐65% were demonstrated in women less than 35‐36 years of age, compared to 24‐46% in women over
34‐35 years, corresponding to 21‐35% and 7‐21% of cycles, respectively. After age 39‐40, 37‐60% of
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women (13‐24% of cycles) achieved live birth, while under age 40‐41, 3‐31% of women (1‐10% of cycles)
achieved live birth.
The effect of maternal age in donor IVF/ICSI cycles was assessed in 1 review in 2 registry‐based
studies.302 While no statistically significant differences were seen in the live birth rates amongst
recipient age categories (live births/woman >34‐35: 24‐46% vs. <33‐34: 37‐65%; >39‐40: 3‐31% vs. <40‐
41: 37‐60%), a greater number of cycles were required to reach a live birth in older women compared to
younger women, evident in the lower live birth rate per cycle in older age groups (>34‐35: 7‐21% vs.
<33‐34: 21‐35%; ≥37: 15% vs. <37: 32%; >39‐40: 1‐11% vs. <40‐41: 14‐24%).
Maternal age did not appear to influence the multiple birth rate after autologous IVF/ICSI in 1 meta‐
analysis, where 19% of live births in women under 33 were multiples, in comparison to 18% of live births
in women over 33 (no significant difference).96
Paternal age
Semen parameters
A significant linear decline in semen volume with increasing paternal age was observed in 4 of 5 studies,
also reflected in a reduction in total sperm count in 2 studies, and total motile sperm count in 3
studies.328 Most studies found no significant age‐effect on sperm concentration, motility, or
morphology.
Implantation
With the exception of 2 studies, no significant association was shown between implantation rates and
paternal age.328 In 1 of the 2 studies, implantation rates after IVF/ICSI were significantly lower in men
over 60 years of age, and in the other, in couples undergoing ICSI, a significant negative correlation
between age and low sperm concentration was reported.
Pregnancy
IVF/ICSI in couples where the male partner was of advanced age was shown to be significantly
associated with lower chances of clinical pregnancy in 3 of 10 studies.328 For each one year increase in
paternal age, the odds of unsuccessful pregnancy were increased by 11% in one study, and by 5%, only
in men with oligozoospermia, in the other. Pregnancy rates were 53% if men were no older than 35
years, 35% if men were 36‐40, and 13% if over 40. In the third study, couples where the male partner
was under 30 years of age were almost twice as likely to become pregnant as couples where the male
partner was over 40.
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Miscarriage
No significant variations in miscarriage rates with paternal age were evident in the majority of studies,
however, 1 study reported nearly half the risk of miscarriage if fathers were 50 years of age or younger
in comparison to over 50 years (RR: 0.61 (0.45, 0.84)).328
Live births
Two of four studies showed no significant differences between paternal age groups and live birth
rates.328 In one of the other studies, the proportion of women with a live birth after IVF/ICSI was
significantly lower if their partner was over 50 years of age (41%) than if their partner was 50 or under
(56%) (RR: 1.53 (2.24, 2.05)). In a study adjusting for the type of infertility and the number of embryos
transferred, among other potential confounders, live birth rates were 38%, 17%, and 7% in women with
partners less than 35, 36‐40, and greater than 40 years of age, respectively. In addition, the odds of a
live birth after IVF/ICSI were decreased by 12% with each year increase in paternal age.
Maternal weight
Dose and duration of gonadotropin stimulation
In obese women (BMI ≥30), overweight women (BMI 25‐29.9), and obese and overweight women
combined (BMI ≥25), significantly higher doses of gonadotropins, in addition to longer gonadotropin
stimulation duration, were required in comparison to normal weight women.162,339
Number of oocytes retrieved
Despite the higher doses of gonadotropin stimulation, a significantly lower number of oocytes were
retrieved in overweight and obese women combined compared to normal weight women (OR: 0.58
(0.22, 0.94)).331 The same analysis, however, in addition to a second meta‐analysis, found no significant
difference in the number of oocytes retrieved per cycle (rather than per woman) between these 3
groups.162,331
Cycle cancellation
In a pooled analysis of 3 studies in couples undergoing fresh, autologous IVF/ICS, 6% of women reaching
the oocyte retrieval stage with a BMI under 25 cancelled their cycle, in comparison to 9% of women with
a BMI of 25 or higher, and 6% of women with a BMI under 30 cancelled their cycle, in comparison to
10% of women with a BMI of 30 or higher.331 Differences were not statistically significant.
Pregnancy
Inconsistent findings were reported across 3 analyses assessing pregnancy rates after autologous
IVF/ICSI. In 1 review, neither clinical nor ongoing pregnancy rates were different when comparing
normal weight versus overweight and obese women, or normal and overweight women, versus obese
women.329 Conversely, the largest meta‐analysis, pooling pregnancy data from 25 studies, reported an
increased likelihood of clinical pregnancy in women with a normal weight (40‐41%) compared to:
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overweight and obese women combined (35%; RR: 0.90 (0.85, 0.94)), overweight women only (36%; RR:
0.91 (0.86, 0.96)), and obese women only (36%; RR: 0.87 (0.80, 0.95)).162 In the third review, pregnancy
rates per woman, including biochemical and clinical pregnancies, were slightly lower in overweight and
obese women (37%) than in normal weight women (39%) (OR: 0.81 (0.67, 0.98)), but were similar
between overweight and obese women.331 Pregnancy rates per cycle, however, were not significantly
different among groups.331
Miscarriage
The risk of miscarriage was significantly greater after IVF/ICSI in overweight or obese women (17% of
women, 23% of pregnancies, 24% of cycles) in comparison to normal weight women (13% of women,
19% of cycles, 19% of pregnancies) (ORs: 1.31‐1.67).162,330,331 When studies where age was considered to
be a confounder were excluded, rates were no longer different.330 IVF/ICSI cycles in overweight women
were associated with a higher chance of resulting in a miscarriage than cycles in normal weight women
(24% vs. 21%; OR 1.24 (1.13, 1.25)), and IVF/ICSI cycles in obese women were associated with a higher
chance of miscarriage than cycles in normal weight women (26% vs. 20%; OR: 1.36 (1.13, 1.64)) and in
normal weight women and overweight women combined (25% vs. 19%; OR: 1.53 (1.27, 1.84)).162,331
Live births
Women undergoing fresh or frozen IVF/ICSI were less likely to achieve a live birth if they had a were
overweight or obese (18%) than if they had a normal BMI (27%) (OR: 0.90, (0.82, 1.00)).329 Further, the
proportion of cycles resulting in a live birth was considerably lower in overweight women and obese
women, at 23% and 20%, respectively (versus 26%; RRs: 0.80‐0.90).162 In a smaller analysis of fresh
cycles only, no significant differences were demonstrated between BMI <25 vs. ≥25, or BMI <30 vs.
BMI≥30 groups.331
Pooled data from 5 studies indicated that after IVF/ICSI, women with a normal BMI, and overweight or
obese women have similar multiple pregnancy rates (32%).329
Pregnancy
In contrast to non‐smokers at the time of IVF/ICSI, women who were active smokers were almost half as
likely to become pregnant (18% vs. 33%; OR: 0.56 (0.43, 0.73)), regardless of whether they received IVF
alone (rather than IVF with ICSI), whether they used their own oocytes (rather than donor oocytes), and
even after excluding studies where age was considered to confound the findings.161
Miscarriage
About one third of IVF/ICSI cycles performed in smokers resulted in a miscarriage, about 15% higher
than the proportion of miscarriages in non‐smokers (OR: 2.65 (1.33, 5.30)). When only considering
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autologous cycles, this difference remained significant. Subgroup analyses excluding studies in women
undergoing ICSI, and studies where age was deemed an uncontrolled confounder did not reach
statistical significance.161
Live births
Active smoking at the time of IVF/ICSI was associated with a decreased odds of live birth (OR: 0.54 (0.30,
0.99)), however, this association was no longer significant after maternal age was taken into account.161
No data were found multiple pregnancies or births in smokers, however it is not expected that maternal
cigarette smoking would influence the order of the pregnancy.
Nature and duration of infertility
Pregnancy
In comparison to women with 1 year or less of infertility, no significant differences in clinical pregnancy
rates were seen at >1‐2 years, >2‐3 years, >3‐4 years, or >4‐5 years (only 1 study).332 Pooled data from 2
studies, however, demonstrated a 0‐2% decline in pregnancy with each year increase in the duration of
infertility.332
While statistical significance was not reported, couples with male factor infertility, tubal factor infertility,
or endometriosis had lower chances of achieving a successful pregnancy after IVF/ICSI than couples with
unexplained infertility (2 studies).332However, in 2 other studies, couples with endometriosis, male
factor or unexplained infertility had a higher likelihood of clinical pregnancy than couples with tubal
factor infertility.332
Live births
Live birth rates after IVF/ICSI were similar between women with a history of <3 years of infertility and
women with 3 or more years of infertility (33‐34%).96
Women with a longer history of infertility (3 or more years) were not reported to have any significant
differences in their chances of multiple pregnancy/birth after IVF/ICSI in comparison to women with a
shorter infertility history (18‐19% in both groups).96
Patient preferences
The studies that reported on patient preferences are discussed in the “S” section of this report.
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Summary
The effectiveness of in vitro fertilization with or without intracytoplasmic sperm injection (IVF/ICSI) was
assessed in 19 reviews (Appendix E).
IVF shows a clear benefit over no treatment for infertility in terms of pregnancy and live birth in couples
with endometriosis and unexplained infertility. Clinical pregnancy rates after IVF/ICSI did not appear to
be influenced by the use of ICSI in comparison to IVF, although, the differences in populations that are
predicted to benefit from ICSI in comparison to IVF were not discussed or taken into account. Clinical
pregnancy rates and live birth rates were similar after frozen embryo cycles, in comparison to fresh
embryo cycles. DET cycles, rather than SET cycles, greatly improved both pregnancy and live birth rates,
while also substantially increasing multiple pregnancy/birth rates. The same increases in likelihood of
pregnancy and live birth seen with DET, without the increases in multiple birth rates, can be achieved
through 2 cycles of SET, or 1 fresh SET cycle and 1 frozen SET cycle. Further, regardless of whether 1 or 2
embryos are implanted, IVF/ICSI with top quality embryos results in better live birth rates than less than
top quality embryos.
Increased chances of pregnancy and live birth were also associated with blastocyst‐stage embryo cycles
over cleavage‐stage embryo cycles, particularly when the transfer of an equal number of blastocysts and
cleavage stage embryos were compared, and when women who were considered likely to have a good
prognosis with blastocyst transfers were selected. No differences in the rate of multiple pregnancies
were observed between the two groups. Significantly fewer embryos were cryopreserved in women
undergoing blastocyst transfers, and significantly more women cancelled their cycle after oocyte
retrieval in blastocyst transfers.
Increasing maternal age is associated with a reduced chance of pregnancy and live birth, and an
increased risk of miscarriage. Increasing paternal age is associated with reduced semen volume,
however, there is insufficient evidence to suggest that this translates into decreased reproductive
function or decreased success with IVF/ICSI. In studies where age was not likely to be a confounder,
maternal smoking at the time of IVF treatment was negatively correlated with pregnancy rates, but not
live birth rates.
Despite the higher doses of gonadotropins and longer duration of stimulation required in overweight
and obese women in comparison to normal weight women, live birth and pregnancy rates were lower in
overweight and obese women. Pregnancy rates per cycle, however, were not significantly different
among the groups. Studies looking at the effect of BMI while controlling for maternal (e.g., age) and
procedural (e.g., number of embryos) characteristics are needed.
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Economic evaluation (E)
Economic studies of ARTs interventions
The following section presents economic implications of ARTs based on the review of existing economic
studies, and the findings of decision‐modeling and a budget impact analysis.
Review of economic studies
Studies identified through the literature search were grouped into the following seven categories, each
relating to a different economic effect of ARTs interventions or ARTs funding policies:
• Studies or economic evaluations of different interventions related to ARTs
• Studies of the effects of ARTs policies on costs
• Studies of the effects of ARTs policies on utilization and outcomes
• Studies of utilization and outcomes of ARTs services
• Studies of actual costs related to ARTs services
• Studies estimating the costs and benefits of ARTs services and policies
• Studies of US state mandated insurance coverage of ARTs services
The studies are discussed by category below.
(see Appendix F, Table 40)
Nineteen economic studies of different treatment‐related components of ARTs included in the decision
model for this HTA report were identified. Fifteen (79%) compared ovarian stimulating agents (fertility
drugs), primarily through cost‐effectiveness analyses. Three (16%) compared surgical therapy to ARTs
for varicoceles, obstructive azoospermia, or severe male factor infertility, and one determined the cost‐
effectiveness of day 3 embryo transfer to that of blastocyst transfer.
Studies of ovarian stimulating agents
Over half of the studies assessed the costs or cost‐effectiveness of pharmaceuticals used in
ovulationstimulation/induction.340‐350 Of these, the majority used decision modelling to compare HP‐
HMG to rFSH under different scenarios, and employed live birth rate as the main outcome measure.
While treatment events included in scenarios varied across studies (e.g., number of fresh and frozen
cycles, treatment failures, multiple births) the findings were similar. HP‐HMG was consistently shown to
be more effective and less costly than rFSH. However, none of the studies considered the costs of
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treatment failures or those beyond birth. Almost all of these studies assessed uncertainty in parameters
in the model through probabilistic sensitivity analyses, and found that HP‐HMG remained the most cost‐
effective approach.
Two studies compared the cost‐effectiveness of accelerated versus step‐wise treatment protocols.351,352
In one study, ‘accelerated’ treatment involved 3 cycles of clomiphene citrate/IUI and up to 6 cycles of
IVF, while ‘step‐wise’ treatment involved 3 cycles of clomiphene citrate/IUI, 3 cycles of gonadotropin/IUI
and up to 6 cycles of IVF.351 Median time to pregnancy was statistically significantly shorter for
accelerated treatment, and as long as IVF costs per cycle remained less than US$17,749, it was also the
less costly alternative.
In the second study, patients who received ‘accelerated’ treatment proceeded directly to IVF, whereas
those who received ‘step‐wise’ treatment started with 3 cycles of gonadotropins before undergoing up
to 3 cycles of IVF.352 While both treatments resulted in a greater than 80% chance of a live birth, the
step‐wise protocol was found to be less costly. However, the probability of higher order multiples
(HOM) was 4 times higher in the step‐wise arm, and the analysis, which only included costs up to birth,
did not take into account the costs associated with HOMs.
A third study compared ‘standard’ IVF/ICSI protocol (ovarian stimulation with GnRH agonist long
protocol followed by double embryo transfer up to 3 cycles) to ‘mild’ IVF/ICSI protocol (ovarian
stimulation with GnRH antagonist co‐treatment followed by single embryo transfer up to 4 cycles).353
From a societal perspective, the ‘mild’ protocol was found to be more cost‐effective. Although it was
associated with more IVF/ICSI cycles, the overall costs (including treatment, pregnancy, obstetric, and
neonatal) were lower.
Studies of interventions for male infertility
Two of the studies assessed the cost‐effectiveness of immediate ARTs compared to vasectomy reversal
in men with post‐vasectomy infertility.354,355 Both concluded that surgical treatment was more cost‐
effective than initial ARTs. However, they assessed pregnancy rates, rather than live birth rates, and did
not include multiple births.
Studies of interventions related to stage of embryo at transfer
A final study compared the cost of day 3 embryo transfer to blastocyst transfer using a decision model
that included fetal reduction.356 A higher chance of pregnancy, fewer multiple gestations, and a lower
average cost per transfer were associated with blastocyst transfer.
Studies of the effects of ARTs policies on costs
Four studies reported the effects of policies on ARTs expenditures. In Australia, 2002 guidelines from the
Reproductive Technology Accreditation Committee advocated the increased use of SET to reduce
multiple births and their consequences. Between 2002 and 2006, there was a reduction in multiple
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births, and an estimated cost savings of AU$47.6 million during the following 6 years.77 In Spain, 2003
legislation limited the number of embryos transferred to 3; subsequently, guidelines from the Spanish
Fertility Society specified recommendations regarding maternal age, embryo quality, and previous cycles
also be considered before transfer (details of these conditions were not available). The effects of both
the legislation and the guidelines on neonatal care costs were assessed using a model, and average
savings over the 2 years after the guidelines were reported to be €9,741,715 (the range was
from€890,187 to €18,593,242).357These studies demonstrate that restrictions on embryo transfer rates
have resulted in cost savings.
The other 2 studies report on the effects of restrictive funding policies on ARTs expenditures. When
Australia introduced a cap on extended Medicare benefit payments for ARTs, in 2010, the rates of fresh
embryo transfers for IVF fell due to the substantially increased out‐of‐pocket cost to patients. The cap
reduced Medicare spending on ARTs by an estimated AU$76 millionin the 12 months following the cap,
but an estimated 1,200 to 1,500 ARTs babies were not born in the first year of the policy as a result.73 In
Germany, when the reimbursement for ART services by statutory health insurance was reduced by 50%,
and conditions applied to age and number of embryos transferred, drastic reductions in IVF utilization,
pregnancies and costs resulted (the conditions were not specified). The reduction in reimbursement was
73% from 2002 (when the restriction was imposed) to 2005.358
Studies of the effects of ARTs policies on utilization and outcomes
Twenty‐three studies examined the effects of ARTs policies (legislation, regulation or guidelines) on the
utilization and/or outcomes of IVF. These present data from Australia, Belgium, Germany, Italy, Quebec,
Spain, the United Kingdom and the United States.
Australia: A study examined rates of birth by plurality after the 2002 Australian guidelines from the
accreditation committee (mentioned above) and reported that between 2002 and 2006 high order
multiple birth rates from SET was 0.2% and from DET was 1.0%. Although the study did not explicitly
demonstrate this, the authors concluded that multiple births fell during this period.359
Belgium: 2003legislation allowed for the public funding of up to 6 cycles of IVF for women until the age
of 42. For women < 35 years of age, at the 1st cycle, only 1 fresh embryo can be transferred, for the 2nd
cycle, either1 or 2 frozen embryos of poor quality can be transferred, and for the subsequent cycles, a
maximum of 2 fresh embryos is allowed. For women 35 to 39 years old, there is a maximum of 2 fresh
embryos allowed in the first 2 cycles, and a maximum of 3 fresh embryos in subsequent cycles. For
women between 40 and 42, no restriction was placed. One of the studies evaluating the impact of this
legislation showed that the mean number of embryos transferred dropped from 2.0 (before the law) to
1.98 (6 months after the law) and to 1.60 (1 year after). It also reported a reduction in multiple birth rate
from 29.4% to 6% to 3% in the same time periods, while the rate of ongoing pregnancies remained
unchanged in this time.360Brock et al. reached the same conclusions regarding pregnancy rates and
multiple births.361
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Germany: The effects of the 2004 Statutory Health Insurance Modernization Act were examined in one
study which compared the number of treatments and the birth rates prior to and following the act.358
The results demonstrated a statistically significant decrease occurred in both measures over this period.
Italy: Italy has seen 2 legislative actions regarding IVF since 2004. At that time, new legislation was
passed that limited the number of embryos transferred to a maximum of 3. Five studies have been
published examining the impact of this over different periods of time and in different populations. Three
studies were conducted sequentially by the same research group comparing patients in the 2 years
before and after the law was passed, the 3 years before and after the law, and the 5 years before and
after, respectively. The mean number of embryos transferred fell from 3.1 to 2.2 in the 2‐year study,
and from 3.1 to 1.7 in the 5‐year study. Multiple births were also shown to fall in these studies; these
reductions were statistically significant. The clinical pregnancy rate, which did not changes significantly
in the 1‐year study, was shown to fall statistically significantly in the 5‐year study (the rate of
pregnancies per cycle dropped from 17.3% to 14.8%).362‐364
Another Italian study focussed on the effects of the law on couples with severe male fertility factor. The
authors concluded that there was no change in the multiple birth rate (18.2% before and after the law),
but the clinical pregnancy rate per transfer dropped significantly from 33.4% to 23.0% in couples where
the male had severe non‐obstructive azoospermia.365 In the last study, women who had IVF in the year
before the law were compared to those who received IVF treatment the year after. It showed that there
were no significant changes in the mean number of embryos transferred or in clinical pregnancy rate per
cycle. However, in two subgroups (women who had received 2 embryos and men with very low motile
sperm count) the pregnancy rates dropped significantly after the law was passed.366
In 2009, the Constitutional Court in Italy declared parts of the 2004 legislation to be unconstitutional,
and decisions on the number of embryos transferred were left to the physician and patient. The effects
of this decree were examined in a study which compared 2,248 IVF cycles before the decree and 1,026
after it. The mean number of embryos transferred increased, but not statistically significantly (1.74 to
2.04); however the percentage of transfers of 2 or more embryos increased statistically significantly.
There were no significant differences found in pregnancy rates by plurality of birth.367
Quebec: Legislation was passed in 2010 which resulted in public funding of IVF, with conditions on the
number of embryos transferred. This provides funding for women of reproductive age to have up to 3
cycles of IVF with ovarian stimulation or 6 cycles of natural or modified natural cycle at no cost. Only one
embryo may be transferred in either a frozen or fresh cycle. However, up to 2 embryos may be
transferred in a woman 36 years or younger, and up to 3 in an older woman, but the physician mustbe
able to justify this decision. Five reports have examined the effect of this law. In one, data from all
women in Quebec who underwent IVF in the 6 months following the law were compared to the year
before the law. The rate of elective SET (eSET) increased from 1.6% in 2009 to 50% during the study
period. Overall multiple pregnancy rates fell from 25.6% to 3.7%. However, clinical pregnancy rates also
fell, from an overall average of 42.8% in 2009 to 32% in 2010.121 There were no statistical tests of
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significance reported in this study. A second study found a statistically significant increase in the rate of
eSET from 17.3% (one year pre‐law) to 85% (one year post‐law).368 Multiple pregnancy rates fell from
25.8% (one year pre‐law) to 1.6% (one year post‐law), while there was an “acceptable” decrease in
cumulative ongoing pregnancy rates from 31.9% (one year pre‐law) to 23.3% (one year post‐law). Three
reports were abstracts from a recent (October 2012) conference. The first reported similar findings to
the paper described above. There were reductions in the mean number of embryos transferred and in
multiple births. However, sub‐group analyses showed that in the 35 to 39 year age group, reducing the
number of embryos transferred by 1 significantly reduced multiple births (22% to 5.3%), but also
significantly reduced the clinical pregnancy rate (40% to 27.1%).369 A second study examined the effects
of the law on older women (40 to 42 years), and concluded that the multiple pregnancy rate stayed
above 10% after the law; one objective of the law had been to reduce multiple pregnancy rate to below
10%. Transferring 2 or 3 embryos in these women significantly improved pregnancy rates in this age
group.370. The last abstract examined women having in vitro maturation and reported similar trends as
in the other reports.371 Finally, a sixth study examined changes in the demographic characteristics of IVF‐
seeking patients in Montreal after the 2010 law, finding a greater diversity in ethnicity, level of
education, employment, and household income in the population accessing treatment.372
Spain: The effects of the 2003 decree limiting IVF treatment to TET and the 2004 Spanish Fertility Society
guidelines also limiting embryo transfer were examined in one study.357 The results showed reductions
in number of embryos transferred, multiple pregnancy rates, and multiple delivery rates. An increase in
singleton pregnancies and delivery rates was also found.
United Kingdom: In 2009, the United Kingdom began offering 3 NHS‐funded IVF treatment cycles to
women less than 40 years of age following NICE recommendation.373 The effects of these
recommendations were examined in one study based on the experiences of one fertility clinic.373 The
results showed an increase in cumulative pregnancy rates, but a decrease in cumulative pregnancy rates
as age increases.
United States: The effects of 1998 and 1999 transfer guidelines of the Society for Assisted Reproductive
Technologies and the American Society for Reproductive Medicine were examined in 2 studies. One
examined trends from 1996 to 2003, and the other from 1997 to 2003. Both studies showed reductions
in mean number of embryos transferred and in multiple births.374,375 One of the studies also examined
the percentage of transfers that fell outside the guidelines, and demonstrated reductions for all age
groups, suggesting that the guidelines have had an effect on practice.374
Studies of utilization and outcomes of ARTs services
(see Appendix F,Table 43)
Four studies reported on outcomes and utilization of ARTs services. Information from Australia and New
Zealand, Israel, Italy and France was analyzed in these studies.
The effects of eligibility criteria for women seeking ARTs treatment in New Zealand (which restricts
funding to women who are unlikely to achieve a pregnancy naturally, are < 40 years of age, and have a
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BMI <32 kg/m2) were assessed and compared to Australia, where no such criteria exist. The study period
was from 2004 to 2006. SET rates and live delivery rates were significantly higher in New Zealand for all
age groups); no significant differences were found in multiple birth rates between the 2 countries.376
In Israel, where there is unrestricted, free IVF treatment, 89.6% of women followed achieved a
pregnancy in the 7‐year period following the first IVF attempt. However, 81.3% required up to 8 cycles,
and the remainder required up to 19 cycles to achieve pregnancy.377
An Italian study which compared women who were pregnant through ARTs with a matched group who
conceived naturally concluded that the ART women and children had worse clinical outcomes, including
significantly shorter gestations, and lower birthweights. Rates of preterm birth, gestational hypertension
and gestational diabetes were all higher in the ARTs group.378
In the French study women undergoing eSET in a single institution were compared to those undergoing
DET. Overall, the DET children had worse outcomes than the eSET children. Significantly more twins
were born in the DET group than in the eSET group, and the mean birthweight of the DET children was
significantly lower than the eSET children. Significantly more DET children were hospitalized than eSET
children.379
Studies on actual costs related to ARTs services
Nineteen studies examined cost‐related aspects of IVF treatment. All but one of these studies reported
on actual programs in 8 countries, and the last was an international comparison. Although all of the
studies reported actual costs, different populations were compared in the different studies. Because of
this, and the different ways in which “costs” were defined, comparisons across studies should be made
with caution.
Five studies reported on the cost per cycle of IVF. In a Dutch study, the average costs of an eSET cycle
and a DET cycle were €4,431 ($6,377 CDN) and €4,513 ($6,494 CDN) (not statistically significant).380 An
average cost per cycle of £2,932 ($6,205 CDN) was reported in the UK.346 A study comparing women
with different BMI values, the average cost of a cycle was not statistically significantly different between
the group with lowest BMI (<18.5, £2,685 ($5,682 CDN)) and with the highest BMI (>35, £2,729 ($5,776
CDN)).381 Finally, an international comparison of costs reported a range of costs across 10 developed
countries reported the lowest cost in Japan (US$3,596) and the highest in the US (US$12,513).382The
definition of a cycle and the specific cost elements included in each case were not provided in detail,
and could explain some of the variations in costs.
The cost of a live birth was reported in 6 of the studies. In the UK, an average cost of £13,326 ($28,203
CDN) per live birth was reported.346 In Scotland, the effect of weight (based on BMI) did not have a
significant effect on the cost per live birth, ranging from £18,747 ($39,676 CDN) (BMI<18.5) to £20,282
($42,925 CDN) (BMI>35).381The effect of age was reported in 3 studies. In Scotland, the cost per live
birth increased from an average of £16,503 ($34,927 CDN) in women under 30 years of age to £40,320
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($85,333 CDN) in women 39 or older.381Two Australian studies reported on the costs per live birth for
older women. In the first, women 42 years or older had a much larger cost per live birth with fresh
cycles (US$307,559) than with frozen cycles (US$33,076).383The second study concluded that women 45
years or older undergoing autologous fresh cycles cost nearly 30 times more to achieve a live birth than
all women undergoing the same treatment.384Finally, the international comparison reported a range of
costs among countries, with the highest being in the US (US$41,132) and the UK(US$40,364) and the
lowest in Scandinavia (US$24,485) and Japan (US$24,329).382
Six studies reported on different categories of cost. Two studies compared the cost per singleton
pregnancy with the cost per twin pregnancy. In the Netherlands, a singleton pregnancy averaged€2,549
($4,238 CDN), compared to €13,469 ($22,398 CDN) for a twin pregnancy.385 In Finland, the analogous
figures were €5,778 ($9,608 CDN) and €15,579 ($25,907 CDN) respectively; this study also concluded
that the cost of singleton pregnancies through natural conception averaged €4496 ($7,476 CDN) and for
twin pregnancies €14,448 ($24,027 CDN).386
Three studies compared costs between SET and DET. A Swedish study reported that maternal health
care costs for SET averaged €6,857($9,485 CDN) compared to €6,767 ($9,360 CDN) for DET (not
statistically significant), while health care costs per live child were €23,798 ($32,919 CDN) and €21,572
($29,840 CDN) respectively.387 A Finnish study comparing 2 periods of time (the first when only 4.2% of
transfers were SET and the second when 46% were SET) concluded that the total cost for eSET averaged
€4,584 ($7,281 CDN) compared to €4,952 ($7,866 CDN) for DET.388 Finally, total costs (including
productivity losses) in the Netherlands per SET was €1,520 ($2,187 CDN) compared to €3,252 ($4,679
CDN). The difference was statistically significant.380
One study estimated the indirect costs associated with IVF treatment. The author concluded that out‐of‐
pocket costs for receiving IVF treatment cost could become significant.389
A US cost‐effectiveness analysis found the introduction of a policy on the number of embryos
transferred would reduce the number of HOMB from 13.9% to 4.5%, and costs to the US health care
system would be decreased by over US$1 millionper 100 cycles.390 However, it is not clear what costs
were included in the calculations; moreover, US costs are significantly higher than Canadian health care
costs.
As mentioned earlier in this section, comparisons between costs reported in these studies must take
into consideration the different definitions of “cost” and “cycle”. However, some conclusions can still be
drawn. The cost of producing a live baby with ARTs appears to increase substantially for women over 40
years of age. Singleton pregnancies cost less than twin pregnancies; however, the evidence is not clear
whether the difference is statistically significant. The woman’s BMI does not appear to have a significant
effect on costs related to ARTs services.
Studies estimating the costs and benefits of ARTs services and policies
(see Appendix F,Table 45)
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Twenty‐seven studies, from 9 countries, presented the results of models used to estimate potential
costs and outcomes of ARTs strategies.
Ten studies used modelling approaches to compare various ART strategies. Two of these compared
hypothetical groups of patients undergoing SET with those undergoing DET. In a Belgian study the cost
per child born was similar with SET and DET, ranging from €9,520 ($15,573 CDN)to €12,254 ($20,046
CDN) (with corresponding pregnancy rates of 53.8% and 42.0% respectively) for SET, and from €9,511
($15,624 CDN) to €12,934 ($21,158 CDN) (pregnancy rates of 77.7% and 43.0% respectively) for DET.391
By contrast, a Scottish study concluded that the additional cost of a live birth achieved with DET was
£38,047 ($64.535 CDN) and£3,781 ($6,413 CDN) for women aged 32 and 42 years respectively.392 It
should be noted that the Scottish study included long‐term disability costs, while the Belgian study did
not.
The other studies modelled different ART strategies. Primary IVF was compared with IUI (stimulated or
unstimulated) followed by IVF in a UK study with couples having unexplained male factor infertility. This
study concluded that a full cycle was more cost‐effective than any IUI followed by IVF. Any IUI followed
by IVF was estimated to cost between £174,200 ($353,085 CDN) and £438,000 ($887,782 CDN) more.393
A Canadian cost‐effectiveness analysis showed that IVF‐DET was the most cost‐effective strategy across
a wide range of costs, compared to IVF‐SET and stimulated IUI. Costs per live birth for the 3 strategies
averaged $14,409, $109,385 and $66,960 respectively. Only direct medical costs were included in this
analysis, and long‐term costs were not included.394 Seven IVF strategies were modelled ina Dutch study,
conducted alongside an RCT: 3 cycles of eSET, 3 cycles of DET, 3 cycles of “standard treatment policy”
(STP) (which was eSET in women < 38 years of age with at least 1 good quality embryo and DET for all
others), and 3 combinations of STP with eSET or DET. A maximum of 3 cycles was allowed. Three cycles
of eSET, DET (which cost €17,200 ($27,227 CDN) more than eSET per live birth) and STP (which
cost€8,190 ($13,009 CDN) more than eSET per live birth) were the most cost‐effective. The model
stopped at birth so long‐term costs were not included.395
In a second Dutch study, 4 IVF strategies were compared: no treatment, 3 cycles of IVF with no
conditions, starting with IVF in all women, and exclusion of poor responders (< 4 oocytes after
stimulation), and ovarian reserve testing and 3 cycles of IVF with hormonal dose adjustment based on
the testing. Ovarian reserve testing in all women prior to treatment was shown to be cost‐effective
compared to the other strategies (€19,483 ($28,858 CDN) compared to €21,935 ($32,490 CDN) with
exclusion of poor responders and€22,502 ($33,329 CDN) with 3 cycles of IVF). Only treatment costs
were included in this study.396
In a UK study the cost per live birth (based on age and number of cycles) for IVF was compared to IVF
with ICSI. In the age‐specific model, women were offered up to 6 cycles of treatment. The cost per live
birth with IVF alone was similar between the ages of 24 and 33, but went up drastically for older women
(24 year olds £11,917 ($29,004 CDN); 35 years – £12,931 ($31,472 CDN); 39 years – £20,056 ($48,814
CDN)). These trends were similar when sensitivity analyses were done with higher and lower costs for
IVF. The cost per live birth varied with number of cycles, ranging from £15,281 ($37,192 CDN), £16,169
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($39,353 CDN), £14,793 ($36,442 CDN) and £14,336 ($34,892 CDN), for 1 to 4 cycles. The cost of ICSI per
live birth was £14,002 ($34,079 CDN). These models were developed to estimate the cost of a birth
under different ART strategies in the NHS, and no long‐term costs were included.23
In another UK studydifferent embryo transfer strategies were examined (SET, SET, which if unsuccessful
is followed by a frozen SET (fzSET) and DET) in women in 3 age groups (< 30 years, 30 – 3 years, 36 – 39
years). The incremental cost‐effectiveness ratios (ICERs) for SET+fzSET varied from £18,463 ($36,139
CDN) in the youngest group to £21,029 ($41,162 CDN) in the oldest group compared to SET. * For the 35
to 39 year old group, DET dominated SET+fzSET. The authors conclude that the choice of embryo
transfer policy depends on maternal age, relevance of the SET option, the value of a live birth and the
importance of adverse events.397
A study from the Netherlands modelled a hypothetical cohort of 35 year old women wishing to
postpone their first pregnancy until the age of 40. Two strategies were compared to waiting until the
age of 40 to conceive naturally, and then receiving IVF if there is no natural conception in the year
following (the reference standard). In the first strategy, at the age of 35, all women undergo 3 cycles of
ovarian hyperstimulation to collect all obtained oocytes for cryopreservation. These are then thawed
and transferred at the age of 40. In the second strategy, women wait until the age of 40 and try to
conceive naturally. Oocyte freezing was shown to be the more cost‐effective strategy, provided at least
61% of women return to collect their frozen oocytes. The ICER for this strategy compared to the
reference was €13,156 ($18,002 CDN), and for the second strategy was €60,707 ($83,071 CDN). Only
direct IVF treatment costs were included; the costs of pregnancies and deliveries were not included.398
In the final study comparing ART strategies, the direct medical costs of IVF and ICSI were compared at a
Dutch IVF centre. The cost of an ongoing pregnancy was €10,482 ($15,476 CDN) with IVF compared to
€10,036 ($14,818 CDN)with ICSI; the costs of medications for both treatments increased with age. The
study only included procedure‐related costs.399
Four further studies examined (1) expected costs of IVF births by plurality, (2) costs and outcomes of IVF
with and without the option of embryo freezing, (3) the impact of obesity on costs and utilization, and
(4) the cost of ARTs for patients with a poor prognosis. The first of these studies, from the UK, estimated
the total cost to the NHS of singletons, twins and triplets following IVF were £3,313 ($6,715 CDN),
£9,122 ($18,489 CDN) and £32,354 ($65,578 CDN) respectively; these estimates were relatively robust
under sensitivity analysis. Triplets took up only 2% of all births, but incurred 10.6% of all costs. Since the

*
An ICER is a health economics method that allows comparison between interventions taking into
account the effects or benefits (e.g., measured in terms of quality‐adjusted life years gained (QALY)),
and the costs per QALY. A high ICER indicates that the technology in question will result in higher costs
to achieve the potential benefits. A technology that offers both lower costs and greater benefit is called
the “dominant” technology.
119

time horizon was only a year, this estimate will likely be low, because long‐term disability costs were not
included.400
A second study, from Italy, concluded that the ICER for a live birth was €23,863 ($32,897 CDN) with
embryo freezing compared to no treatment. The results of this study are difficult to interpret as they
were reported in an abstract with little detail.401
A US study, considering a hypothetical cohort of women with FSH levels below 13 UI/L on day 3,
concluded that the cost of a live birth in these women increased with FSH level and age, but in a non‐
linear manner. Assuming a cycle cost of US$10,803, the authors conclude that the cost per live birth can
exceed US$100,000 when the birth rate falls below 10%. There is no clear explanation of the costs
included in this study; the cost of multiple gestations does not appear to be included.402
In the last study in this group, 6 hypothetical cohorts of women (anovulatory or ovulatory, and in 3
weight groups – normal weight, overweight and obese) were included in a model comparing average
cost per live birth. The average costs for anovulatory women were €3,016 ($4,467 CDN), €4,653 ($6,892
CDN) and €6,045 ($8,953 CDN) as weight increased, and for ovulatory women were €6,096 ($9,029
CDN),€8,806 ($13,043 CDN) and €10,355 ($15,337 CDN). This was due to both an increased cost of
treatment by weight category and reduction in the number of pregnancies with weight.403
Five non‐peer reviewed Canadian reports are included in this summary. Four of these reports developed
models to estimate the cost savings in Canada if multiple births were reduced in number. Estimates
were obtained for both Canada as a whole, and for the provinces of Quebec and Alberta. Using
European studies to identify targets for rates of multiple births, 2 of these studies concluded that there
were potentially $266 million in savings (from hospitalization and disability savings) over 5 years and
$57.5 million in disability costs (time period not provided).404,405 In 2 other consultant reports, conducted
for the infertility community, both of which used the same methodology, it was projected that with
public funding of IVF in Alberta or Quebec, there would be substantial savings from the reduction of
multiple births: $27 to $36 million in Alberta, and $34 to $44 million in Quebec.88,218 In the last
document in this group, it was estimated that the total average cost of a stimulated IVF cycle in Canada
was $6,099.In this study a cost chain model was used to estimate costs from the point of the initial
consultation to the IVF treatment.406
In the last group of studies summarized, all 4studies used the same generational accounting approach to
estimate the tax revenues that could be generated from an ARTs‐conceived child over a lifetime. These
analyses included transfers from government to the individual (e.g., education costs, health care,
pensions) and the tax projected to be paid to government. The Net Present Value (the current cost,
taking into account discounted future costs)of the investment in the IVF to produce a child was
calculated. This was estimated to be US$155,870 in the US,170,407 £160,069 ($370,399 CDN) in the UK,407
and 254,000 SEK ($39,751 CDN) in Sweden.408 The authors conclude that ARTs funding is beneficial to
governments in the long run. Applying the same methodology in Denmark, the effects of cuts to IVF
funding were projected to cost the government from €74 million ($101,180,200 CDN) to €123 million
($168,177,900 CDN) over 20 years in lost tax revenue.171,409
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The summary above demonstrates the wide range of studies that have been reported on expected costs
and utilization and outcomes of various ART‐related strategies. The applicability of the results would
depend upon ARTs services and strategies available in a particular jurisdiction. In addition, because of
the different cost elements that are included in the different studies, and the different degree of detail
provided, caution must be exercised in considering the generalizability of the results.
The sub‐group of consultant reports that deal with potential cost savings due to reduced multiple births
with IVF funding merits further discussion. These 4 reports (2 of which are only available as conference
abstracts) have not been conducted or reported in compliance with any internationally accepted
standards for economic evaluations. This includes a lack of a structured and systematic approach to
obtaining and synthesizing evidence on clinical outcomes, details on the models used, and on the
validation of the disability costs used. Although the conclusion that a reduction in multiple births will
recoup costs has some support in the peer‐reviewed literature, the actual amounts that have been
projected are questionable.
The group of studies that predict the lifetime tax contribution of an IVF‐conceived individual would
exceed the cost of the original investment in IVF, have assumed that the potential employment capacity
and the resulting tax contribution is the same for an IVF‐conceived child as for a naturally conceived
child. Since the likelihood of long‐term disability is greater for IVF‐conceived children, this assumption
may not be valid. At best, the difference between the tax generated over a lifetime and the transfer
benefits from government may be considerably less than that predicted by the model.
Studies of US state mandated insurance coverage of ARTs services
Six studies which assessed the impact of US state government mandated insurance for ARTs services are
summarized below and in the accompanying table.
Four of the studies used regression models to estimate the utilization of ARTs and birth rates under
different types of insurance mandates. The authors of the first study concluded that clinics in states with
“comprehensive” mandates transferred fewer embryos per cycle, were associated with fewer multiple
births per transfer and fewer births per cycle than in states with no mandate. This was true for all age
groups; for women under 35 years of age, the differences were statistically significant.410 A second study
concluded that compared to states with no mandated insurance, births per cycle were lower, multiple
births per ART birth were higher and utilization (cycles per 1000 women) were all statistically
significantly higher than in “no mandate” states.411. A third study undertook analyses of multiple birth
rates, examining the effects of woman’s age, marital status, race and educational achievement.64
Married women and white women had a statistically significantly higher rate of multiple births in states
with strong mandates compared to states with no mandate (4.7% and 3.3% higher respectively). Overall,
there were small but statistically insignificant increases in multiple births in states with strong
mandates.64 The final modelling study concluded that women under 35 years of age have a significantly
lower birth rate in states with a “universal” mandate, compared to states with a “restricted”
mandate.The opposite was true for older women,twin birth rates were shown to be unaffected by the
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type of mandate, but the rate of HOMB was statistically significantly higher in both age groups in states
with a universal mandate.412
The remaining 2 studies used actual clinic‐level data to compare the effects of different types of
insurance mandates. The first study concluded that for women under 35 years of age, embryo transfer
rates and multiple birth rates were statistically significantly lower in mandated states than in states with
no mandate. Multiple birth rates were also statistically significantly lower in the 35 to 37 year group.413
The results from the second study were similar. In addition, no statistically significant differences were
observed in the outcomes for the 38 to 42 year old group.411
The type of insurance mandate varies considerably across the US states. In studies that reported this,
the mean number of embryos transferred was lower in strongly mandated states. In most of the studies
reviewed, a strong mandate was also associated with a reduction in multiple births; this was more
marked in younger women. However, there are exceptions to this, particularly among certain sub‐
groups.
It should be noted that in the studies reviewed, no information was provided as to whether a particular
state’s mandate included restrictions on embryo transfer. If such restrictions exist, they would have
contributed to the findings.
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Budget impact and cost‐effectiveness analysis
Methods
Budget Impact Analysis
Methods used for the budget impact analysis (BIA) and modelling of cost‐effectiveness complied with
internationally accepted, published guidelines for conducting BIAs and modelling.414‐416 Applying a worst‐
case scenario approach, the total cost of IVF/ICSI in Alberta, in addition to the cost per ongoing
pregnancy and healthy live birth,were calculated under different policy scenarios and cost perspectives.
Scenarios
Eight BIAs were conducted, each corresponding to a different funding option or scenario for IVF/ICSI.The
scenarios are described below (see Table 6). The base case assumes no change in the current policy and
funding of IVF/ICSI in Alberta, in other words, maintenance of the status quo. The first two options
(restrictive and permissive) were derived from the most common funding conditions identified through
the international review of IVF/ICSI policies. The third option, based on the Quebec scenario, reflects the
policy implemented in Quebec in 2010. The last two options represent funding without any restrictions
and regulation (restrictive, permissive, or following Quebec) without any funding.
Table 6. Funding scenarios for budget impact analysis
No change / Restrictive policy Permissive policy Quebec policy Funding without Regulation without

Current policy regulation funding
No funding <35 years of age: SET
<35 years of age: <35 years of age: Funding No funding
No restrictions all cycles SET first cycle, DET 0.89 SET, 0.11 DET No restrictions Restrictions as per
35‐39 years of age: second and third (all cycles) restrictive,
SET first two cycles,
cycles 35‐39 years of age: permissive, and
DET third cycle 35‐39 years of age: 0.59 SET, 0.38 DET, Quebec policy
≥40 years of age: DET
DET first cycle, TET 0.03 TET (all cycles) options
second and third
first cycle, TET second ≥40 years of age:
and third cycles cycles 0.3 SET, 0.56 DET,
≥40 years of age: 0.14 TET (all cycles)
TET all cycles
SET = single embryo transfer; DET = double embryo transfer; TET = triple embryo transfer
Patient population
Under each public funding scenario, it was estimated that a cohort of 3,055 patients would be eligible
for IVF in a given year. The number takes into account the 1,222 fresh IVF cycles performed in Alberta in
2011, and assumes that they took place in no more than 1,222 individuals. This figure was then
multiplied by 2.5 to reflect the increased demand for IVF/ICSI, measured in number of cycles,
experienced in Quebec following the introduction of public funding.
Technology mix
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The BIA is based upon an ARTs clinical pathway model. It was constructed using data on local treatment
patterns, published clinical practice guidelines, interviews with members of the Expert Advisory Group,
and the findings of a comprehensive systematic review of the effectiveness of IVF/ICSI and different
components of ARTs. The clinical pathway is presented in the next section showing the components of
the decision model (Decision model
Figure 4, Error! Not a valid bookmark self‐reference., Error! Not a valid bookmark self‐reference.,
Error! Not a valid bookmark self‐reference., and Figure 8).
Time horizon
The time horizon for the analysis was set at a maximum of 3 fresh and 3 frozen cycles per patient under
each of the regulated scenarios, and a maximum of 6 fresh and 6 frozen cycles per patient under the
base case and funding without regulation scenarios.
Perspective
A societal perspective, incorporating healthcare system costs, education costs, and caregiver costs, was
adopted for the analyses. Healthcare costs considered included direct costs associated with the
procedure, confirmation of pregnancy, pregnancy loss, ongoing pregnancy, delivery, neonatal care, post‐
natal care up to the age of 4 years, and average annual healthcare costs between 5 and 18 years of age.
Costs associated with IVF/ICSI were obtained from the 2 fertility clinics in Alberta. For the purposes of
the BIA, costs from these clinics were averaged. Costs associated with neonatal and post‐natal care (up
to 4‐5 years of age) were derived from a primary analysis of administrative data from Alberta Health for
infants born in the 2005/2006 fiscal year. Pregnancy and delivery costs were derived from data for the
mothers of these infants. Data captured included all inpatient and outpatient visits, as well as physician
fees. Costs were inflated by 5% per year to obtain 2012 Canadian dollars. Physician fees for
neonatologists were estimated from the salary of neonatologists and the average lengthofstay of
'unhealthy' babies in the NICU (obtained from Alberta Health data).
For the cost of healthcare beyond the first 5 years for healthy children, published Alberta data for
children between the ages of 5 and 19 years from the Canadian Institute for Health Information National
Health Expenditures Report 2011 were used (see Table 7).417An inflation rate of 5% per year was applied
to convert the values to 2011 dollars. For children with mild, moderate, or severe disabilities, published
studies of healthcare costs for children ages 5 to 19 years with congenital heart disease,
Downsyndrome, and cerebral palsy were used.418,419Once again, all values were inflated to 2011
Canadian dollars.
Table 7. Average per capita health care costs in Alberta
Years of Age Canadian dollars per capita (2009 current dollars)
5‐9 $1,513.67
10‐14 $1,613,48
15‐19 $1,988.49

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For education costs, information from the Government of Alberta’s Education Funding in Alberta:
Kindergarten to Grade 12, 2011‐2012report was used (Table 8).420
Table 8. Funding allocation per child per year in Alberta 2011‐2012
Type of Child ECS Grades 1 to 3 Grades 4 to 9 Grades 10‐12
Normal $3,248.35 $6,496.71 $6,496.71 $6,187.33
Mild to moderate $5,686.35 $6,496.71 $6,496.71 $6,187.33

disabilities
Severe disabilities $27,808.35 $22,961.71 $22,961.71 $22,961.71
ECS = early childhood services
For caregiver costs (costs to families including direct monetary costs, decline in hours worked, reduced
labour force participation, and reduced future earnings), figures from a 2012 US study based on census
data were used. In this study, costs in 2011 US dollars averaged across families with children with
disabilities ranged from a lower end estimate of $3,210 per year to a higher end estimate of $25,460 per
year. The average was $10,830.421
Model description
The basic structure of the BIA model is presented in the form of a decision tree (see Figure 4, Error! Not
a valid bookmark self‐reference., Error! Not a valid bookmark self‐reference., Error! Not a valid
bookmark self‐reference., and Figure 8). As described above, branches comprising different sequences
of procedures and outcomes were extracted from a systematic review of the published literature and
expert opinion. It estimates the proportion of patients requiring 1, 2, or 3 cycles of IVF/ICSI, where 1
cycle represents 1 fresh and 1 frozen embryo transfer. It then goes on to estimate the total number of
miscarriages and live births, and how the live births are distributed between singleton, twins, and
higher‐order multiples. Also, it explicitly models the distribution of live births between healthy and
unhealthy. Lastly, it provides estimates of the costs avoided for each stage of the clinical pathway or
branch in the decision tree (see Appendix G ‐ Tables for the decision model).
Input data
Parameters used to populate the model are presented inAppendix G ‐ Tables for the decision model).
Probabilities of undergoing a certain treatment pathway were based on expert opinion. Success and
failure rates and short and long term clinical outcomes were taken from results of the systematic review
of effectiveness completed for the “T” section of this report. Data from the Canadian Assisted
Reproductive Technologies (CARTR) database and the Alberta Perinatal Health Program were also used
to estimate clinical outcomes.
Cost‐effectiveness analysis
A cost‐effectiveness analysis comparing the base case or ‘do nothing’ alternative to the following
scenarios was performed (see Table 9).
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Table 9. Cost‐effectiveness analysis
Scenario Description
Base case (do nothing alternative) IVF treatment is neither publicly funded nor regulated in Alberta (i.e., number of cycles
performed and number of embryos transferred is at the physician’s discretion)
Funded and regulated ‐ Restrictive Patients undergo no more than three publicly funded cycles of IVF, where one cycle is
considered to be either a fresh‐egg only treatment, or a fresh‐egg and frozen‐egg treatment
AND:

i. Patients under 35 years of age receive single embryo transfer (SET) treatment for all three
cycles

ii. Patients 35 to 39 years of age receive SET treatment for their first two cycles, and double
embryo transfer (DET) treatment in the last cycle

iii. Patient over 39 years of age receive DET treatment for their first cycles, and triple embryo
transfer (TET) treatment for their second and third cycles
Funded and regulated ‐ Permissive Patients undergo no more than three publicly funded cycles of IVF, where one cycle is
considered to be either a fresh‐egg only treatment, or a fresh‐egg and frozen‐egg treatment
AND:

i. Patients under 35 years of age receive SET treatment for their first cycle, and DET treatment
for their second and third cycles

ii. Patients 35 to 39 years of age receive DET treatment for their first cycle, and TET treatment
for their second and third cycles

iii. Patients over 39 years of age receive TET treatment for all three cycles
Funded and regulated ‐ Quebec Assumes patients treated in Quebec are a representative sample of the patients who would
receive treatment in Alberta under a publicly‐funded scenario. Therefore, the following
recorded proportions of patients receiving a certain type of treatment in Quebec are applicable
to patients in Alberta:

i. Of patients under the age of 35, 89% receive SET treatment and 11% DET treatment

ii. Of patients between the ages of 35 and 39, 59% receive SET treatment, 38% receive DET
treatment, and 3% receive TET treatment

iii. Of patients over the age of 39, 30% receive SET treatment, 56% receive DET treatment, and
14% receive TET treatment
Regulated but not funded IVF treatment remains unfunded, but is regulated in a manner identical to the “Permissive”
scenario
Funded but not regulated IVF treatment is publicly funded but not regulated (i.e., number of cycles performed and
number of embryos transferred is at the physician’s discretion)

Patient level simulation, which uses the accumulating history of the patient to determine transitions,
costs, and health‐related quality of life through the model, was performed from both the healthcare
system and societal perspectives. For the healthcare system/payer perspective, costs captured in the ‘do
not fund’ scenarios (i.e., base case and ‘regulate but do not fund’) spanned those currently borne by the
healthcare system in Alberta. Costs comprising the remaining scenarios, all of which included some level
of public funding, related to the additional costs that would be borne by the healthcare system. For
analyses from the societal perspective, caregiver, education, and out‐of‐pocket costs, as well as those
126

associated with lost productivity, were included in all of the scenarios. Outcomes were measured in
QALYs. In order to assess differences in the number of QALYs gained across scenarios, all of those
accumulated during the time period of the model were included, regardless of whether they were
directly attributable to the treatment options (e.g., a healthy patient ineligible for IVF could gain a
similar number of QALYs through the model despite the fact that she is not pregnant). The following
tables (Table 10, Table 11, Table 12, Table 13) contain values for the costs and consequences used in the
model. All costs were measured in 2011 Canadian dollars, and all consequences were measured in
Quality‐adjusted life years (QALYs). Values beyond initial treatment and care were discounted by an
annual rate of 5%.
All alternative scenarios were compared incrementally to the “base” scenario, with both incremental
costs and incremental effectiveness being calculated. ICERs were produced for each alternative.
In all scenarios, uncertainty was modeled through the use of Dirichlet and Beta distributions. All
transition probabilities for which original n‐value data were available were modeled through these
distributions (e.g. if the probability of pregnancy for a given patient was modeled on data from 100
women, of whom 50 became pregnant, these values would be entered as ‘alpha’ and ‘beta’ in a Beta
distribution.) Probabilistic sensitivity analysis was then performed by running 1500 groups of 3000 trials,
wherein each group received a new and random value from each distribution. Confidence intervals and
standard deviations were then noted as outputs.
Table 10. Costs associated with the base case and 'regulate but do not fund' scenarios
Value
Name (annual discount rate in brackets) Distribution
Failed pregnancy after implantation $435.69 None
Clinical pregnancy $808.56 None
Miscarriage $3965.23 None
Singleton pregnancy $3657.50 None
Twin pregnancy $10736.41 None
Triplet pregnancy $17967.50 None
Vaginal delivery (singleton) $4042.41 None
Vaginal delivery (twins) $6162.59 None
Vaginal delivery (triplets) $12483.53 None
Cesarean delivery (singleton) $5633.00 None
Cesarean delivery (twins) $5483.66 None
Cesarean delivery (triplets) $19222.97 None
Healthcare for a healthy singleton’s first 18 $8634.03 (5%) Gamma
years of life
Healthcare for a healthy multiple’s first 18 $43552.36 (5%) Gamma
years of life
Healthcare for a unhealthy singleton’s first $114285.50 (5%) Gamma
18 years of life
Healthcare for a unhealthy multiple’s first $240533.3 (5%) Gamma
18 years of life
Educational costs for a healthy singleton’s $52136 (5%) None
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Value
first 18 years of life
Educational costs for a unhealthy $197001 (5%) None
singleton’s first 18 years of life
Educational costs for a healthy multiple’s $52136 (5%) None
Educational costs for a unhealthy multiple’s $197001 (5%) None
Caregiver costs for a healthy singleton’s $0 (5%) None
Caregiver costs for a unhealthy singleton’s $312497 (5%) None
Caregiver costs for a healthy multiple’s first $0 (5%) None
18 years of life
Caregiver costs for a unhealthy multiple’s $312497 (5%) None

Table 11. QALYs associated with the base case and 'regulate but do not fund' scenarios
Value
Undergoing a fresh cycle of IVF, undergoing Cycle 1: 0.094615385 None
a frozen cycle of IVF, retrieving an oocyte, Cycle 2: 0.085384615
cryopreserving an embryo, pregnancy Cycle 3 and higher: 0.080769231
failure after implantation
Clinically pregnant (first trimester) 0.219230769 None
Ongoing pregnancy (remainder of 0.365384615 None
pregnancy)
Miscarrying 0.061538462 None
Delivering (vaginal or cesarean) 0.015288462 None
A healthy child lives from birth to 18 years 11.69 (5% annual discount rate) None
An unhealthy child from birth to 18 years 8.18 (5% annual discount rate) None
Successful treatment and birth (mother) of 11.69 (5% annual discount rate) None
a child, subsequent 18 years
Failure of treatment (mother), subsequent 9.59 (5% annual discount rate None
18 years
Dropout from treatment (mother), 9.59 (5% annual discount rate) None
subsequent 18 years

Table 12. Costs associated with scenarios involving some level of public funding for IVF
Value
Undergoing a fresh cycle of IVF Initial cycle: None
Edmonton: $4200
Calgary: $5550
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Value
Subsequent cycles:
Edmonton: $4000
Calgary: $5250
Undergoing a frozen cycle of IVF Edmonton: $500 None
Calgary: $600
Oocyte retrieval and implantation Edmonton: $7182 None
Calgary: $8055
Cryopreserving an embryo Edmonton: $600 None
Calgary: $875
Failed pregnancy after implantation $435.69 None
Clinical pregnancy $808.56 None
Miscarriage $3965.23 None
Singleton pregnancy $3657.50 None
Twin pregnancy $10736.41 None
Triplet pregnancy $17967.50 None
Vaginal delivery (singleton) $4042.41 None
Vaginal delivery (twins) $6162.59 None
Vaginal delivery (triplets) $12483.53 None
Cesarean delivery (singleton) $5633.00 None
Cesarean delivery (twins) $5483.66 None
Cesarean delivery (triplets) $19222.97 None
Healthcare for a healthy singleton’s first 18 $8634.03 (5%) Gamma
years of life
Healthcare for a healthy multiple’s first 18 $43552.36 (5%) Gamma
years of life
Healthcare for a unhealthy singleton’s first $114285.50 (5%) Gamma
18 years of life
Healthcare for a unhealthy multiple’s first $240533.3 (5%) Gamma
18 years of life
Educational costs for a healthy singleton’s $52136 (5%) None
Educational costs for a unhealthy $197001 (5%) None
singleton’s first 18 years of life
Educational costs for a healthy multiple’s $52136 (5%) None
Educational costs for a unhealthy multiple’s $197001 (5%) None
Caregiver costs for a healthy singleton’s $0 (5%) None
Caregiver costs for a unhealthy singleton’s $312497 (5%) None
Caregiver costs for a healthy multiple’s first $0 (5%) None
18 years of life
Caregiver costs for a unhealthy multiple’s $312497 (5%) None

129

Table 13. QALYs associated with scenarios involving some level of public funding for IVF
Value
Undergoing a fresh cycle of IVF, undergoing Cycle 1: 0.094615385 None
a frozen cycle of IVF, retrieving an oocyte, Cycle 2: 0.085384615
cryopreserving an embryo, pregnancy Cycle 3 and higher: 0.080769231
failure after implantation
Clinically pregnant (first trimester) 0.219230769 None
Ongoing pregnancy (remainder of 0.365384615 None
pregnancy)
Miscarrying 0.061538462 None
Delivering (vaginal or cesarean) 0.015288462 None
A healthy child lives from birth to 18 years 11.69 (5% annual discount rate) None
An unhealthy child from birth to 18 years 8.18 (5% annual discount rate) None
Successful treatment and birth (mother) of 11.69 (5% annual discount rate) None
a healthy child, subsequent 18 years
Failure of treatment (mother), subsequent 9.59 (5% annual discount rate None
18 years
Dropout from treatment (mother), 9.59 (5% annual discount rate) None
subsequent 18 years

Results
Total health care costs associated with treatment, pregnancy, delivery, neonatal care, and postnatal
care up to 18 years of age for the full cohort of IVF/ICSI candidates in Alberta (1,222 under current and
no funding scenarios, and 3,055 under public funding scenarios) are presented in Table 14. The cost
savings under public funding policies (restrictive, permissive, Quebec, and no regulation) and regulation
without funding policies(restrictive, permissive, Quebec) in comparison to the status quo in Alberta are
reported in Table 15.
Table 14. Health care costs associated with treatment, pregnancy, delivery, neonatal care, and postnatal care up
to 18 years of age under different embryo transfer policy options
Ongoing pregnancy Neonatal and
and delivery postnatal care‡
Policy Treatment ($CDN)† ($CDN) ($CDN) Total ($CDN)
No regulation, no funding (N = 1,222)
Current policy: $2,991,458 $12,253,148 $300,999,151 $316,243,758
No restrictions, no funding (up to 6 cycles)
Funding with regulation (N = 3,055)
Restrictive policy: $77,790,114 $17,704,387 $123,604,589 $219,099,091
<35: SET all cycles
35‐39: SET first two cycles, DET third cycle
≥40: DET first cycle, TET second and third cycles
Permissive policy: $72,579,320 $20,030,266 $216,841,588 $309,451,174
<35: SET first cycle, DET second and third cycles
35‐39: DET first cycle, TET second and third cycles
≥40: TET all cycles
130

Quebec policy outcomes: $75,719,977 $18,580,120 $160,828,416 $255,128,513

<35: 0.89 SET, 0.11 DET (all cycles)
35‐39: 0.59 SET, 0.38 DET, 0.03 TET (all cycles)
≥40: 0.3 SET, 0.56 DET, 0.14 TET (all cycles)
Funding without regulation (N = 3,055)
No regulation: $83,100,695 $30,632,871 $752,497,878 $866,231,444
Funding with no restrictions (up to 6 cycles)

Regulation without funding (N = 1,222)
<35: SET all cycles
*Costs reflect the treatment of a cohort of 3,055 patients with up to 3 cycles of fresh and 3 cycles of frozen IVF/ICSI; it was assumed that 55% of couples received ICSI
(16.5% with ejaculated sperm and 38.5% with surgically retrieved sperm), and 5% of couples received PGS
†Treatment costs include procedural costs and costs of pregnancy confirmation and pregnancy loss
‡Neonatal and postnatal care costs include all healthcare costs from birth through to 18 years of age

Table 15. Health care cost savings under different embryo transfer policy options in comparison to the status
quo in Alberta
Policy Ongoing pregnancy Neonatal and

Treatment ($CDN)† ($CDN) ($CDN) Total ($CDN)
Funding with regulation
Restrictive policy: ‐$74,798,656 ‐$5,451,239 $177,394,562 $97,144,667
<35: SET all cycles
Permissive policy: ‐$69,587,862 ‐$7,777,117 $84,157,564 $6,792,584
Quebec policy outcomes: ‐$72,728,519 ‐$6,326,971 $140,170,735 $61,115,245
Funding without regulation
No regulation: ‐$80,109,237 ‐$18,379,723 ‐$451,498,727 ‐$549,987,686

Regulation without funding
Restrictive policy: $476,877 $5,171,393 $251,557,315 $257,205,586
<35: SET all cycles
Permissive policy: $498,521 $4,241,042 $214,262,516 $219,002,079
Quebec policy outcomes: $555,753 $4,821,101 $236,667,785 $242,044,638
131


Health care and societal costs associated with treatment, pregnancy, delivery, neonatal care, and
postnatal care up to 18 years of age for the full cohort of IVF/ICSI candidates in Alberta (1,222 under
current and no funding scenarios, and 3,055 under public funding scenarios) are presented in Table 16.
The cost savings under public funding policies (restrictive, permissive, Quebec, and no regulation) and
regulation without funding policies (restrictive, permissive, Quebec) in comparison to the status quo in
Alberta are reported in Table 17.
In comparison to the current situation of no funding in Alberta, the total cost of providing treatment is
approximately $78 million, $73 million, $76 million, and $83 million, under the restrictive, permissive,
Quebec, and fund‐without‐regulation policies, respectively. The cost savings, including healthcare costs
only, associated with pregnancy, delivery, neonatal care, postnatal care up to 18 years of age under
each of these policies is $172 million, $76 million, and $134 million, leaving Alberta Health with a net
cost savings of $97 million following a restrictive policy, $7 million following a permissive policy, and $61
million following Quebec’s policy. The fund without regulations policy will cost Alberta Health an
additional $470 million in pregnancy, delivery, neonatal care, postnatal care healthcare costs, leaving
Alberta Health with a total of $550 million in costs. The cost savings, including both societal and
healthcare costs, associated with pregnancy, delivery, neonatal care, postnatal care up to 18 years of
age under each of these policies is $254 million, $85 million, and $187 million, leaving Alberta Health
with a net cost savings of $179 million following a restrictive policy, $15 million following a permissive
policy, and $114 million following Quebec’s policy. The fund without regulations policy will cost Alberta
Health an additional $909 million in healthcare and societal costs, leaving Alberta Health with a total of
$990 million in costs.
In comparison to the current situation of no funding in Alberta, the net cost healthcare savings of
regulating without funding is about $257 million, $219 million, and $242 million, following restrictive,
permissive, and Quebec’s regulations, respectively. The net cost healthcare and societal cost savings of
regulating without funding under each of these scenarios is about $465 million, $398 million, and $439
million.
Table 16. Health care and societal costs associated with treatment, pregnancy, delivery, neonatal care, and
postnatal care under different embryo transfer policy options

No regulation, no funding (N = 1,222)
Current policy: $2,991,458 $12,253,148 $594,053,135 $609,297,742
No restrictions, no funding (up to 6 cycles)
Funding with regulation (N = 3,055)
132


<35: SET all cycles
Funding without regulation (N = 3,055)
No regulation: $83,100,695 $30,632,871 $1,485,132,839 $1,598,866,405

Regulation without funding (N = 1,222)
<35: SET all cycles
‡Neonatal and postnatal care costs include all healthcare costs, educational costs, and caregiver costs from birth through to 18 years of age

Table 17. Health care and societal cost savings under different embryo transfer policy options in comparison to
the status quo in Alberta

Funding with regulation
Restrictive policy: ‐$74,798,656 ‐$5,451,239 $259,681,632 $179,431,737
<35: SET all cycles
Permissive policy: ‐$69,587,862 ‐$7,777,117 $92,458,100 $15,093,121
Quebec policy outcomes: ‐$72,728,519 ‐$6,326,971 $193,334,037 $114,278,547
Funding without regulation
No regulation: ‐$80,109,237 ‐$18,379,723 ‐$891,079,703 ‐$989,568,663

Regulation without funding
Restrictive policy: $476,877 $5,171,393 $460,304,534 $465,952,805
<35: SET all cycles
133

Permissive policy: $498,521 $4,241,042 $393,415,121 $398,154,684
Quebec policy outcomes: $555,753 $4,821,101 $433,765,496 $439,142,350
‡Neonatal and postnatal care costs include all healthcare costs, educational costs, and caregiver costs from birth through to 18 years of age

The cost to achieve an ongoing pregnancy and a healthy live birth under the different public funding
policies (restrictive, permissive, Quebec, and no regulation) are reported inTable 18. The cost per
ongoing pregnancy under a restrictive policy, permissive policy, Quebec’s policy, and funding without
regulations is about $49 thousand, $41 thousand, $47 thousand, and $40 thousand, respectively. These
costs include all treatment and pregnancy costs. The cost per healthy live birth under each of these
scenarios is approximately $56 thousand, $51 thousand, $54 thousand, and $40 thousand. These costs
include all treatment, pregnancy, and delivery costs.
Table 18. Cost per ongoing pregnancy and healthy live birth under different embryo transfer policy options
Funding without
Restrictive Policy Permissive Policy Quebec policy outcomes regulation
Cost per ongoing pregnancy $49,178 $41,480 $47,146 $39,995
Cost per healthy live birth $55,895 $50,553 $53,516 $40,020
*Cost per ongoing pregnancy includes all treatment and pregnancy costs up to, but not including, delivery; cost per healthy live birth includes all
treatment, pregnancy, and delivery

The additional health care and societal costs that would be incurred by allowing a parallel private system
operate alongside a publicly funded system are presented inTable 19 and Table 20. Assuming the
patients who would access the private system are those who either: 1) fail to achieve a pregnancy after
3 publicly funded cycles, or 2) are over 43 years of age, the additional health care costs associated with
these patients are approximately $12 million under a restrictive policy, $8 million under a permissive
policy, and $11 million under Quebec’s policy. Including both the health care and societal costs, these
patients would cost an additional $25 million, $17 million, and $24 million under restrictive, permissive,
and Quebec policies, respectively.
134

Table 19. Additional health care costs associated with a parallel private system under different publicly funded
embryo transfer policy options
Additional Costs ($CDN)
Policy Total Cost
(Number of patients accessing Ongoing pregnancy Neonatal and (public + private)
parallel private system) Treatment† and delivery postnatal care‡ Total ($CDN)
Restrictive policy $417,190 $891,529 $10,391,793 $11,700,512 $230,799,603
(N = 202)
Permissive policy $349,268 $649,220 $7,126,626 $8,125,115 $317,576,288
(N = 168)
Quebec policy outcomes $422,281 $880,953 $10,169,082 $11,472,315 $266,600,828
(N = 203)
*Assumptions:
‐ patients that access the private system are comprised of: 1) patients who fail to achieve an ongoing pregnancy after 3 cycles of IVF/ICSI in the public system, and 2)
patients over 43 years of age who choose to attempt IVF/ICSI with their own eggs
‐ in a parallel private system, clinicians follow permissive embryo transfer guidelines

Table 20. Additional health care and societal costs associated with a parallel private system under different
publicly funded embryo transfer policy options
Additional Costs ($CDN)
Policy Total Cost
(Number of patients accessing Ongoing pregnancy Neonatal and (public + private)
parallel private system) Treatment† and delivery postnatal care‡ Total ($CDN)
Restrictive policy $417,189.61 $891,529.27 $23,446,003.86 $24,754,722.74 $454,620,727.82
(N = 202)
Permissive policy $349,267.94 $649,220.48 $16,399,463.30 $17,397,951.73 $611,602,572.76
(N = 168)
Quebec policy outcomes $422,280.92 $880,952.66 $23,015,413.48 $24,318,647.05 $519,337,842.13
(N = 203)
*Assumptions:
‐ patients that access the private system are comprised of: 1) patients who fail to achieve an ongoing pregnancy after 3 cycles of IVF/ICSI in the public system, and 2)
patients over 43 years of age who choose to attempt IVF/ICSI with their own eggs
‐ in a parallel private system, clinicians follow permissive embryo transfer guidelines

Table 21. Cost‐effectiveness of different embryo transfer policy options in comparison to the status quo in
Alberta
Base Case Quebec policy Funding without Regulation

(Current Policy) Restrictive Policy Permissive Policy outcomes regulation without funding
Healthcare perspective
Cost‐effectiveness ratio $2,787 $2,468 $3,255 $2,638 $3,816 $2,312
Incremental cost‐ N/A $4,351 ‐$2,398 $3,597 ‐ $8,055
effectiveness ratio Lower mean cost Higher mean cost Lower mean cost Higher mean cost Lower mean cost
(compared to base case) and lower mean and lower mean and lower mean and no difference and lower mean
effectiveness than effectiveness than effectiveness than in mean effectiveness than
current policy current policy current policy effectiveness than current policy
current policy
Societal perspective
135

Cost‐effectiveness ratio 6,317 4,565 6,323 4,935 7,344 5,381

Incremental cost‐ N/A $14,860 $6,248 $13,787 ‐ $16,717
effectiveness ratio Lower mean cost Lower mean cost Lower mean cost Higher mean cost Lower mean cost
(compared to base case) and lower mean and lower mean and lower mean and no difference and lower mean
effectiveness than effectiveness than effectiveness than in mean effectiveness than
current policy current policy current policy effectiveness than current policy
current policy
*Current policy = no restrictions, no funding (up to 6 cycles); Restrictive policy = <35: SET all cycles, 35‐39: SET first two cycles, DET third cycle,
≥40: DET first cycle, TET second and third cycles; Permissive policy = <35: SET first cycle, DET second and third cycles, 35‐39: DET first cycle, TET
second and third cycles, ≥40: TET all cycles; Quebec policy outcomes: <35: 0.89 SET, 0.11 DET (all cycles), 35‐39: 0.59 SET, 0.38 DET, 0.03 TET (all
cycles), ≥40: 0.3 SET, 0.56 DET, 0.14 TET (all cycles); Funding without regulation = funding with no restrictions (up to 6 cycles); Regulation without
funding = regulation as per permissive policy.

136

*Infertility workup:
‐ history and physical exam on both
partners
Decision model ‐ counselling on frequency and timing of
intercourse and lifestyle factors (BMI,
Figure 4. Infertility diagnosis drug and alcohol use, etc.)

Female tests:
‐ blood and urine tests: day 3 FSH and
estradiol, LH, progesterone prolactin, TSH
‐ pelvic ultrasound (with antral follicle
Part I: Infertility Diagnosis count)
‐ hysterosalpingography or
hysterosalpingocontrastsonography

Male tests:
‐ blood and urine tests: FSH, LH,
testosterone, prolactin, TSH, post‐
ejaculatory urinalysis
‐ semen analysis and test for anti‐sperm
antibodies
Abbreviations:
CBAVD = congenital bilateral absence of vas deferens; ENDO = endocrinologist; FSH = follicle‐
stimulating hormone; GP/FP = general practitioner/family physician; IF = infertility; LH =
luteinizing hormone; OBGY = obstetrics and gynecology specialist; OD = ovulatory
dysfunction; PCOS = polycystic ovarian syndrome; REI = reproductive endocrinology and
infertility specialist; TSH = thyroid‐stimulating hormone
Assumptions:
‐ Breakdown of infertility assumes type (e.g., tubal obstruction) is the sole cause of infertility
‐ *Further diagnostic workup may be indicated dependent on results of initial workup
‐ **90% of cases are treated at the same time as diagnostic procedure, while 10% of patients
are treated in a second, separate procedure; if fertility is not restored after medical or surgical
management, couple is referred to REI
‐ ***If no apparent female or male factor found, assume unexplained infertility, couple is
referred to REI; if both male and female factor present (mixed infertility), couple is referred to
REI

137

Notes:
‐ Success = ongoing pregnancy; failure = no pregnancy achieved or miscarriage experienced
after clinical pregnancy (for further outcomes, see part IV – treatment outcomes); success
after ‘natural conception’ (following a non‐ART surgical treatment for infertility) refers to
Figure 5. Treatment options for female infertility pregnancy within 6‐12 months after surgery with no further intervention
‐ “Dropout” includes patients who do not continue treatment for many reasons (the physical
and psychological stress of treatment, side effects (e.g., OHSS), the decision to adopt, they
experience a spontaneous pregnancy while awaiting treatment, etc.)
‐ *See part IV: treatment options for unexplained and mixed infertility
Part II: Treatment Options for Female Infertility
Notes:
‐ **For endometriosis: laparoscopic surgery includes cautery or ablation of endometriosis,
plus (for severe endometriosis), removal of any symptomatic or potentially malignant (>4cm)
endometrioma(s); may or may not include ovarian suppression
‐ ***For moderate‐severe endometriosis: the first cycle of IVF is preceded by up to 6 months
of ovarian suppression; subsequent cycles proceed with standard protocols

138

139


Abbreviations:
CC = clomiphene citrate; GnRH = gonadotropin releasing hormone; ICSI = intracytoplasmic
sperm injection; IUI = intrauterine insemination; IVF = in vitro fertilization; Laparoscopic
ovarian drilling (LOD); OD = ovulatory dysfunction; PCOS = polycystic ovarian syndrome

140


Notes:
Figure 6. Treatment options for male infertility after clinical pregnancy (for further outcomes, see part IV – treatment outcomes); success
after ‘natural conception’ (following a non‐ART surgical treatment for infertility) refers to
pregnancy within 6‐12 months after surgery with no further intervention
Part III: Treatment Options for Male Infertility experience a spontaneous pregnancy while awaiting treatment, etc.)
‐ For sperm retrieval techniques in men with obstructive azoospermia, PESA is preferred over
mTESE
141

142

Abbreviations:
CBAVD = congenital bilateral absence of vas deferens; Ejaculatory duct obstruction (EDO);
GnRH = gonadotropin releasing hormone; ICSI = intracytoplasmic sperm injection; IUI =
intrauterine insemination; IVF = in vitro fertilization; mTESE = microsurgical testicular sperm
143

Notes:
after clinical pregnancy (for further outcomes, see part IV – treatment outcomes); success
Figure 7. Treatment options for unexplained and mixed infertility after ‘natural conception’ (following a non‐ART surgical treatment for infertility) refers to
pregnancy within 6‐12 months after surgery with no further intervention
experience a spontaneous pregnancy while awaiting treatment, etc.)
Part IV: Treatment Options for Unexplained and Mixed Infertility ‐ Depending on the nature of male and female factors, ICSI may include donor eggs and/or
sperm retrieval techniques or donor sperm
Abbreviations:
ICSI = intracytoplasmic sperm injection; IUI = intrauterine insemination; IVF = in vitro
fertilization
144


Figure 8. Treatment outcomes
Part V: Treatment Outcomes
145

Conclusions
In this STE review many different sources of information were used to address the questions posed in
the Project Charter. This included a comprehensive review of peer‐reviewed and grey literature,
relevant websites, and contact with clinical experts in Alberta.
The scope of the material reviewed on ARTs and its utilization, health and cost consequences was very
broad. It included clinical studies examining the effectiveness and outcomes of specific treatments (e.g.,
drug therapies, IUI) and the outcomes of specific ARTs strategies (differing numbers of cycles, numbers
of embryos transferred, sequence of treatments, etc.). There were also studies that examined the
effects on the utilization and outcomes of ARTs services before and after legislation, regulation or
guidelines were imposed in a number of jurisdictions.
In addition to utilization and clinical outcomes, the economic aspects of ARTs use were also reviewed.
Studies determining the cost‐effectiveness of different components of ARTs treatments and those
comparing different ARTs strategies were included. The cost implications of policies restricting or
recommending restrictions on the number of embryos transferred were also reviewed. Two other
groups of studies – the first examining the impact of US state‐mandated insurance coverage of ARTs and
the second estimating the long‐term tax revenue to government from investment in ARTs‐conceived
births – were also included in this review.
In order to estimate the health and cost consequences of public funding of ARTs in Alberta, a detailed
and comprehensive decision model was developed. The inputs for this model were obtained from
literature, clinical experts and Alberta Health administrative datasets. Several public funding scenarios
were examined, including public funding with: 1) a “permissive” policy, 2) a “restrictive” policy,3) a
policy similar to that instituted in Quebec in 2010, and 4) no regulations. Further, the implementation of
these policies was examined in the absence of public funding. The budget impact of each of these
policies was estimated and compared to the current situation in Alberta of no funding and no regulation.
Based on this extensive review and the decision model, the following conclusions may be reached.
 ARTs is associated with increased complications during pregnancy and delivery, increased rates
of preterm delivery, low birthweights, malformations, birth defects and cerebral palsy compared
to naturally conceived pregnancies.
 IVF has a clear benefit over no treatment in pregnancy rates; fresh and frozen embryo transfers
result in similar pregnancy rates.
 Frozen embryo transfer is associated with fewer adverse events than fresh embryo transfer, and
is as safe in terms of infant outcomes.
 Women who receive multiple embryos have higher rates of adverse events during pregnancy
and delivery, and their infants have higher rates of complications compared to women who
receive single embryos, and their infants.
146

 DET increases pregnancy and birth rates (compared to SET) but it also substantially increases
multiple pregnancy and multiple birth rates. SET with 2 cycles (1 fresh and if necessary 1 frozen)
achieves pregnancy and live birth rates similar to DET, without the corresponding increase in
multiple pregnancy rates.
 The use of grade A embryos results in better live birth rates than lesser quality embryos; success
rates are better with blastocyst‐stage embryos than with cleavage‐stage embryos.
 Restrictions on the number of embryos transferred reduce the likelihood of multiple births and
their health and cost consequences.
 In jurisdictions where policies have been introduced to reduce the numbers of embryos
transferred per cycle, multiple birth rates have been reduced. However, clinical pregnancy rates
in some age groups have also been reduced.
 The cost to achieve an ongoing pregnancy under a publicly funded scenario ranges from nearly
$40 thousand (if there are no restrictions) to just over $49 thousand (under restrictive
regulations). The cost to achieve a healthy live birth under a publicly funded scenario ranges
from nearly $40 thousand (if there are no restrictions) to almost $56 thousand (under restrictive
regulations).
 Total health care costs associated with pregnancy, delivery, neonatal care and postnatal care (up
to the age of 18 years) for the current cohort of 1,222 IVF/ICSI candidates in Alberta are
estimated to be approximately $316 million (the current Alberta situation without public
funding or regulation).
 Total health care costs associated with ARTs treatment, pregnancy, delivery, neonatal care and
postnatal care (up to the age of 18 years) for the expected cohort of 3,055 IVF/ICSI candidates in
Alberta are estimated to be approximately $219 million (with a restrictive funding policy), $309
million (with a permissive funding policy), $255 million (with Quebec's policy), and $866 million
(with a fund without regulation policy). If public funding is provided with regulations, there
would be an estimated total savings(over 18 years) to government of $97 million (restrictive
policy), $7 million (permissive policy) and $61 million (Quebec policy).
 When the societal perspective is incorporated, total costs are estimated to be approximately
$609 million (the current Alberta situation without public funding), $430 million (with a
restrictive funding policy), $594 million (with a permissive funding policy), $495 million (with
Quebec's policy). If public funding is provided, there would be an estimated total savings(over
18 years) to government of $179 million (restrictive policy), $15 million (permissive policy), and
$114 million (Quebec policy).
 If funding were provided without regulations, it would cost $866 million in healthcare costs and
$1.6 billion in healthcare and societal costs to treat the full cohort of 3,055 IVF/ICSI candidates.
In contrast to the regulated scenarios, there would not be a cost savings, but rather this would
cost Alberta Health almost $550 million in healthcare costs and $990 million in healthcare and
societal costs.
 If public funding were provided with regulations, and patients who either failed to achieve a
pregnancy after 3 publicly funded cycles of IVF/ICSI or who exceeded upper age limits for
147

IVF/ICSI with their own eggs were allowed to access a parallel private system, Alberta Health
would incur an additional cost with these patients of approximately $12 million under a
restrictive policy, $8 million under a permissive policy, and $11 million under Quebec’s policy.
Including both health care and societal costs, these patients would cost an additional $25
million, $17 million, and $24 million under restrictive, permissive, and Quebec policies,
respectively.
148


Appendices
149

Appendix ‐ Additional tables

Table 22.The Oxman & Guyatt index of scientific quality scoring system for systematic reviews
Question Judgement
1 Were the search methods used to find evidence on the  Yes  No  Partially
primary question(s) stated?
2 Was the search for evidence reasonable comprehensive?  Yes  No  Can’t tell
3 Were the criteria used for deciding which studies to include  Yes  No  Partially
reported?
4 Was bias in the selection of studies avoided?  Yes  No  Can’t tell
5 Were the criteria used for assessing the validity of the  Yes  No  Partially
included studies reported?
6 Was the validity of all the studies referred to in the text  Yes  No  Can’t tell
assessed using appropriate criteria?
7 Were the methods used to combine the findings of the  Yes  No  Partially
relevant studies reported?
8 Were the findings of the relevant studies combined  Yes  No  Can’t tell
appropriately relative to the primary question of the overview?
9 Were the conclusions made by the author(s) supported by  Yes  No  Partially
the data and/or analysis reported in the overview?
10 How would you rate the scientific quality of this review? Flaws
(If “can’t tell” is used ≥ 1 time – review likely to have minor
flaws at best, difficult to rule out major flaws: score 4 or lower; Extensive Major Minor Minimal
if “no” is used on Qs 2, 4, 6, or 8 – review is likely to have 1 2 3 4 5 6 7
major flaws: score of 3 or less depending on number and
degree of flaws.)

Table 23. PRISMA statement checklist
Question Judgement
Are the results of the review valid?
Did the review explicitly address a sensible clinical question?  Yes  No  Unclear
Was the search for relevant studies detailed and exhaustive?  Yes  No  Unclear
Were the primary studies of high methodologic quality?  Yes  No  Unclear
Were assessments of studies reproducible?  Yes  No  Unclear
What where the results?
Were the results similar from study to study?  Yes  No  Unclear
What are the overall results of the review?
How precise were the results?
How can I apply the results to patient care?
How can I best interpret the results to apply them to the care of
patients in my practice?
Were all clinically important outcomes considered?
Are the benefits worth the costs and potential risks?
150

151

Appendix A – Environmental scan of ARTs policies

Table 24. ARTs policies in Canada & internationally
Details of legislation, guidelines, and Female partner age Number of cycles Assisted hatching or Embryo freezing and PGS/PGD Fetal reduction Oocyte, embryo, or Surrogacy

funding and number of other micro‐ storage sperm donation
embryos manipulation
Australia – national
Legislation:275,294
• None • no national legislation (legislation at • no legal restrictions • no legal restrictions • no legal restrictions • no legal restrictions • no legal • no legal restrictions • no legal restrictions • no legal
state level) restrictions restrictions
Guidelines:212,275,292,422‐425 Female partner age
• National Health & Medical • not mandatory but sets ‘national • no upper age limits • no limits • permitted • permitted • permitted for • permitted • permitted • permitted
Research Council (NHMRC) standards of acceptable practice’ present or future
Ethical Guidelines on the followed by most individual states in Number of embryos medical reasons
Use of ART in Clinical legislation • <35: 1 for first cycle, only
Practice & Research max of 2 for
• Fertility Society of subsequent cycles
Australia Reproductive • 35‐39: max of 2
Technology Accreditation • sets a code of practice for assisted • oocytes from donor
Committee reproductive technology units <40: max of 2
Funding:27,423‐427 Infertility diagnosis:
• Medicare Benefits • partial public coverage (75%) • no restrictions • no limits • no information • no public coverage • no public • no information • no information • no
Schedule (MBS) found coverage found found information
• Pharmaceutical Benefits Fertility drugs: found
Scheme IVF/GIFT Program • partial public coverage for some drugs
• Federal Medicare &
Extended Medicare Safety IUI and IVF/ICSI:
Net (EMSN) rebate program • partial public coverage (75%)
• includes all pharmaceuticals and
procedures
• includes sperm retrieval surgery
• rebate for 80% of out of pocket
expenses up to a maximum of $4,000 per
cycle (annual income threshold applies)
Australia – Victoria
294,428,429
Legislation:
• Assisted Reproductive • regulates use of assisted reproduction • no information • no information • no information • permitted • permitted for • no information • no information • no
Treatment Act (2008) procedures found found found • eggs & sperm stored present or future found found information
‐ regulations (2010) up to 10 years medical reasons found
• embryos stored up only (genetic
to 5 years diseases, older
women, or
women with
repeat
miscarriages or
IVF failures)
• sex selection
152


permitted for
medical reasons
only
Funding:
• National • public coverage at national level (see
above)
Australia – Western Australia
Legislation:30,430
• Human Reproductive • sets code for practice of, procedures • no information • no information • no information • no legal restrictions • permitted for • no information • no information • no
Technology Act (1991) used in, and ethics governing human found found found future medical found found information
• The Amendment Act reproductive technology reasons (risk of found
(1996) • regulates use of human reproductive serious genetic
technology for assisted reproduction and disease)
research • must be
approved by the
Reproductive
Technology
Council
Funding:
• National • public coverage at national level (see
above)
Austria
Legislation:275
• Reproductive Medicine • regulates methods of assisted • no legal restrictions • no legal restrictions • permitted • permitted for • not permitted • no legal restrictions • not permitted • not
Act (1992) reproduction fertilized eggs and permitted
oocytes
Funding:275,278 IUI: Female partner age
• IVF Fund Act (2004) • no public coverage • <40 • max of 4 cycles • no public coverage • no information • no information • no information • no public coverage • no
found found found information
IVF/ICSI: Embryo number found
• partial public coverage (70%) in couples • restricted by age and
with semen pathology and/or female number of previously
factor infertility due to tubal factor (not failed cycles; specific
due to sterilization), PCOS, or embryo number not
endometriosis found
• includes all pharmaceuticals and
procedures
Belgium
Legislation:275,296 Female partner age
• Law on Research into • ≤47 • no legal restrictions • AH permitted •permitted •permitted for •permitted • permitted •permitted
Embryos in vitro (2002) • other present or future • sperm donation
•Law on Medically Assisted micromanipulation medical reasons limited to men aged
Reproduction and the requires local and only 18‐44
Disposition of federal medical ethics •sex selection
Supernumerary Embryos approval permitted for
and Gametes (2007) medical reasons
only
Funding:274 IVF/ICSI: Female partner age
153


• Royal Decree (2003) • full public coverage • <43 • max of 6 cycles • no information • no information • no information • no information • no information • no
found found found found found information
Number of embryos found
•≤35: 1 for first cycle,
max of 2 for
subsequent cycles
• 36‐39: max of 2 for
first two cycles, max of
3 for subsequent
cycles
•40‐42: no limits
Brazil
• Resolution (1992) • no limit • no legal restrictions • permitted • permitted • permitted • not permitted • permitted • permitted

Number of embryos
• <35: 2
• >35: 3
• overall max of 4
Funding:
• None • no public coverage • no public coverage • no public coverage • no public coverage • no public coverage • no public • no public coverage • no public coverage • no public
coverage coverage
Canada – national level
Legislation:111,113,275
• Assisted Human • regulates activities related to assisted • no legal restrictions • no legal restrictions • permitted • permitted • permitted • permitted • permitted • permitted
Reproduction Act (2004) human reproduction • PGD/PGS for sex • payment for
• Assisted Human • provides basis for licensing, , selection is not surrogacy is
Reproduction Canada inspecting, and enforcing these activities permitted not permitted
(AHRC) (will be replaced by at a federal level
Health Canada ‐ Assisted
HumanReproduction
Implementation Office)
Funding: Infertility diagnosis:
• None • no public coverage at national level • no public coverage • no public coverage • no public coverage • no public coverage • no public • no public coverage • no public coverage • no public
at national level at national level at national level at national level coverage at at national level at national level coverage at
ARTs: national level national level
• no public coverage at national level
Canada – Alberta
Legislation:
• None • no provincial legislation or regulation;
must follow national legislation (see
above)
Funding:432,433 Infertility diagnosis:
• Schedule of Medical • full public coverage • no public coverage • no public coverage • no public coverage • no public coverage • no public • no public coverage • no public coverage • no public
Benefits ‐ medical coverage coverage
procedure list ARTs:
• no public coverage
Canada – Manitoba
Legislation:
154


above)
Funding:252 Infertility diagnosis:
• Fertility treatment tax • full public coverage
credit
ARTs:
• tax credit of 40% of total cost of • no restrictions • no restrictions • included in tax credit • included in tax credit • no information • no information • included in tax • included in
fertility treatments up to maximum tax reported reported found found credit tax credit
credit of $8,000
• includes fertility drugs, IUI, DI, IVF/ICSI,
sperm retrieval surgery
Canada – Ontario
Legislation:
above)
Funding:10,66,74,225,245 Infertility diagnosis: Female partner age
• Health Insurance Act • full public coverage • <40 years • max of 3 cycles • no public coverage • no public coverage • no public • full public coverage • no public coverage • no
(1990) coverage information
‐ regulation 552 Fertility drugs: found

IUI/DI:
• full public coverage for procedure
• no public coverage for drugs or sperm
preparation

IVF/ICSI:
• full public coverage for IVF procedure
in women with missing fallopian tubes or
bilateral tubal blockage (not due to
sterilization)
• no coverage for drugs
• no coverage for ICSI or sperm retrieval
surgery
Canada – Quebec
Legislation:253‐255 Female partner age IVF/ICSI
• An Act respecting clinical • mandates that fertility medications and • ≤36: 1‐2 • max of 3 cycles • permitted • permitted • permitted for • no information • permitted • no
and research activities ARTs are insured services • >36: max of 3 identifying serious found information
relating to assisted • regulates methods of assisted cleavage‐stage, max of Natural cycle IVF/ICSI monogenic found
procreation (2009) reproduction 2 blastocyst stage • max of 6 cycles diseases and
‐regulation on clinical chromosomal
activities related to assisted • must also follow national legislation abnormalities
procreation (see above)
‐ regulation modifying the
regulation respecting the
application of the Health
Insurance Act
155


Funding:255 Infertility diagnosis: Female partner age IVF/ICSI
• regulation modifying the • full coverage • ≤36: 1‐2 embryos • max of 3 cycles • full public coverage • full public coverage • full public • no information • full public coverage • no
regulation respecting the • >36: max of 3 coverage found information
application of the Health Fertility drugs: embryos IVF/ICSI and Frozen ET found
Insurance Act • full coverage cleavage‐stage, max of • max of 1 + 4, 2+2, or
2 blastocyst stage 3 + 6 cycles
IUI:
• full coverage Natural cycle IVF/ICSI
• max of 6 cycles
IVF/ICSI:
• full coverage for IVF/ICSI
• tax credit of 50% of total unpaid
expenses related to IVF (e.g., subsequent
cycles)
Denmark
Legislation:275 Female age
•Law of Artificial • level of public coverage reduced in • <45 in public clinics • no legal restrictions • permitted • permitted • permitted for • permitted • sperm and oocyte • not
Fertilization (1997) 2010171 • storage for up to 5 present or future donation permitted permitted
years medical reasons • embryo donation
only not permitted
Funding:434 IVF: Number of embryos
• Amendment to Law of • reduced public coverage (as of 2010)171 •<35: 1 in first cycle • max of 5 cycles • no information • no information • no information • no information • no information • no
Artificial Fertilization (2010) found found found found found information
found
Finland
Legislation:275
• Statute not specified • no information • no information • permitted • permitted • permitted for • not permitted • permitted • not
found found • storage for up to 15 present or future permitted
years medical reasons
only
Funding:433 ARTs:
• Act of Assisted • partial public and private coverage • no information • no information • no information • no information • no information • no information • no information • no
Reproduction (2006) found found found found found found found information
found
France
Legislation:275,293,435 Female partner age:
• Bioethics Law No. 94‐654 • ≤42 • no legal restrictions • AH permitted • permitted • permitted for • no information • permitted • not
• Bioethics Law No. 2004‐ medical reasons found permitted
800 (2004) Embryo Transfer: and
• 1‐2 preferable personal/family
• >2 requires history of serious
documented genetic disease
reasoning • sex selection for
medical reasons
permitted
Funding:436 IVF/ICSI: Female partner age
• Bioethics Law No. 2004‐ • full public coverage for heterosexual • ≤42 • no limits • no information • no information • no information • no information • no information • no
800 (2004) couples diagnosed with infertility or a found found found found found information
156


high risk of transmission of severe found
disease to the child
Germany
Legislation:275,437,438 • insemination of single women is
• Federal Embryo prohibited130 • no information • no information • AH permitted • cryopreservation of • permitted for • permitted • sperm donation • not
Protection Law (1990) found found • other embryos not polar body permitted permitted
• Adoption Brokerage Law micromanipulation permitted diagnosis • oocyte and embryo
(2006) not permitted • cryopreservation of • permitted for donation not
eggs at pronuclear embryo screening permitted
stage or oocytes if predisposition to
permitted serious genetic
illness
Funding:275 IVF: Number of embryos
• partial public coverage (50%) of related • <38: max of 2 • max of 3 cycles • no information • no information • no information • no information • no information • no
costs • ≥38: max of 3 found found found found found information
found
Israel
Legislation:272,275,291,293,295 Number of embryos
• National Health • <35: max of 2 • no legal restrictions • permitted • permitted • permitted for • permitted • sperm and oocyte • permitted
Regulations on IVF (1987) • storage of eggs for future medical donation permitted
• Agreements for the up to 10 years reasons only or in • embryo donation
Carriage of Fetuses Law exceptional not permitted
(1996) circumstances for • commercial use of
social reasons eggs for assisted
reproduction not
permitted
Funding:272,272,283 IVF/ICSI: Female age
• full public coverage • ≤45 • no limits on number • no information • no information • no information • no information • no information • no
of cycles found found found found found information
• public funding until a found
woman’s first two
children are born
Italy
Legislation:271,275,290,291 Embryo number
• Medically Assisted • use of ART restricted to heterosexual • no legal restrictions • no legal restrictions • permitted • permitted • permitted for • permitted • not permitted • not
Procreation Law 40 (2004), couples who live together, are of • decided by physician present or future permitted
amended May 2009 reproductive age (over 18), have based on age, quality medical reasons
documented infertility and have been of embryos, and only
first provided with opportunity for outcomes of previous • usage under
adoption treatment debate
Funding: ARTs:
• Partial public coverage10281 • either both phases are covered or less • no information • no information • no information • no information • no information • no information • no information • no
than 81% of total costs of IUI and IVF is found found found found found found found information
reimbursed (source does not specify) in found
married couples only

In‐vitro maturation and cross‐border
MAR:
157


The Netherlands
Legislation:275,291,439 Embryo number
• Commercial Surrogacy Act • max of 2 • no legal restrictions • permitted • permitted • permitted for • permitted • permitted • permitted
(1993) • 1 generally present or future • commercial use of • commercial
• Embryos Act (2002) recommended for medical reasons eggs for research is surrogacy is
young patients with • sex selection not permitted not permitted
good quality embryos permitted for
medical reasons
only
Funding:10,286,291,440 ARTs: Female partner age OI/IUI:
• partial public coverage for OI, IUI, and • <50 • no limits • no information • no information • no information • no information • no information • no
IVF found found found found found information
• includes pharmaceuticals and IVF: found
procedures • max of 3 cycles
• no public coverage for ICSI
New Zealand
Legislation:10,275,287,291,298
• Human Assisted • no legal restrictions • no legal restrictions • permitted • permitted • permitted for • permitted • permitted •permitted
Reproductive Act (2004) present or future • commercial •commercial
established 2 statutory medical reasons donation of eggs for surrogacy is
bodies: ACART (Advisory only research is not not
Committee on ART) issues • not permitted permitted permitted,
guidelines & advice, & for sex selection altruistic
ECART (Ethics Committee surrogacy is
on ART) oversees permitted441
applications for certain ART
procedures441
• Guidelines on Pre‐
implantation Genetic
Diagnosis (2005)
Funding:203,273,376,442 Female partner age
• Clinical Priority Access • partial public coverage available • <40 • max of 2 cycles • no information • no information • no information • no information • no information • no
Criteria (CPAC) Prioritization • patients are ranked with a CPAC score, found found found found found information
Guidelines (implemented by based on the following criteria: prognosis Embryo number found
the National Health without treatment, infertility duration, • <36: in order to be
Committee) number of children, age, and diagnosis eligible for a second
• Scored on a 100 point scale, with cycle, must use SET
women over 65 qualifying for coverage
of treatment

• Restrictions placed on BMI and patients
with a history of smoking

• Funding limited to couples who have
resided in New Zealand for at least 2
years
Norway
202,275,443
Legislation: Female partner age
• Norwegian Law on • no legal restrictions • no legal restrictions • no information • permitted • permitted, but • permitted • sperm donation • not
158


Artificial Reproduction found not for embryo permitted permitted
(1987, revised 1994) Embryo number screening • oocyte and embryo
• The Biotechnology Act • no legal restrictions donation not
(1994) • eSET preferred permitted
Funding:299 [personal IVF:
communication Nan B. • partial public coverage (80%) • no information • max of 3 cycles • no information • no information • no information • no information • no information • no
Oldereid, Oslo University found found found found found found information
Hospital, 20 Jun 2012] found
Spain
Legislation:288,357,435,444 Embryo number
• Spanish Decree 45 (2003) • max of 3 • no legal restrictions • permitted • permitted • permitted for • no information • permitted • not
present or future found permitted
medical reasons
only
Funding:275,288,357,445 IVF/ICSI: Embryo number
• Spanish Fertility Society • full public coverage for approximately • <30: 1‐2 • no information • no information • no information • no information • no information • no information • no
Guidelines (2007) 30% of IVF cycles performed • 30‐37: 1‐2 for first found found found found found found information
• includes pharmaceuticals and two cycles, 3 for found
procedures subsequent cycles if
no good quality
embryos
• ≥38: 2 for first cycle,
3 for subsequent
cycles if no good
quality embryos
Sweden
Legislation:246,257,275,299,446 Embryo number
• 2008 Law; SFS 2005:39, • eSET with max of 2 • AH permitted • permitted • permitted • no information • sperm and oocyte • not
SFS 2006:351, SFS 2009:262, • 2 only permitted • other found donation permitted permitted
SOFS 2002:13, SFS 2008:286 when risk of multiple micromanipulation • embryo donation
births is low not permitted not permitted

Funding:246,299 ARTs: Female partner age
• full public coverage in public hospitals • <39 • max of 3 cycles • no information • no information • no information • no information • no information • no
• reimbursement for drugs in private • must have at least 1 found found found found found information
clinics good quality embryo found
Switzerland
Legislation:275,289,291,293,297 Embryo number
• Embryonic Research Act • max of 3 (voluntary • no legal restrictions • permitted • cryopreservation of • not permitted • permitted • sperm donation • not
(2004) reduction to max of 2 embryos not permitted permitted
• Federal Law on Medically by medical permitted • oocyte and embryo
Assisted Reproduction community) • cryopreservation of donation not
(1998) • eSET not permitted pronucleate eggs permitted
permitted
• eggs stored up to 5
years
Funding:276,291 Fertility diagnosis:
• public coverage • not applicable • not applicable • no public coverage • no public coverage • no public • no public coverage • no public coverage • no public
coverage coverage
159


Fertility drugs:
• public coverage for up to 6 cycles of
ovulation induction

IVF/ICSI:
United Kingdom – national
Legislation:114,115,275,285,285,447,
Female partner age
448
• regulates treatment and research • no limits • no legal restrictions • permitted • permitted • permitted for • permitted • permitted • permitted
• Human Fertilization & involving human embryos • eggs & sperm stored patients with
Embryology Act (1990, • established the Human Fertilization & Embryo number up to 10 years serious inheritable
revised in 2008) Embryology Authority (HFEA) as the UK’s • <40: max of 2 • embryos stored up disorders
• Human Fertilization and independent regulator of ART • ≥40: max of 3 to 5 years • sex selection for
Embryology Authority Code • current potential UK reforms under the • oocytes from donor non‐medical
of Practice section 26(4) Public Bodies Bill may dissolve HFEA and <40: max of 2 reasons not
transfer its functions elsewhere permitted
Guidelines:10,24,302,449‐451 Female partner age
• National Institute for • funding recommendations only; • in 2004: 23‐39 • maximum of 3 cycles • no public coverage • no public coverage • no information • no information • no information • no
Health & Clinical Excellence funding determined at local level by • in 2013: ≤42 10 found found found information
(NICE) 2004 &2013 Primary Care Trusts found
guidance Number of embryos
Fertility Drugs: • <37: 1 for first cycle,
• no public coverage 1 top quality or 2 less
than top quality for
IVF/ICSI: subsequent
• full public coverage for procedure • 37‐39: 1 top quality
or 2 less than top
quality
• 40‐42: 2
• British Fertility Society &
Association of Clinical • eSET • no information • no information • no information • no information • no information • no information • no
Embryologists guidelines found found found found found found information
(2008) found
Funding:10,41,302,449‐451
• None • no national funding; funding • not applicable • not applicable • no public coverage • no public coverage • no public • no public coverage • no public coverage • no public
determined at local level by Primary Care at national level at national level coverage at at national level at national level coverage at
Trusts national level national level
United Kingdom – Northern Ireland
• Ministerial Decree (2009 • IVF/ICSI limited to patients with <3 • <39 with own eggs • no legal restrictions • permitted • no information • permitted for • no information • no information • no
and 2012) prior unsuccessful treatments (publicly • <49 with donor eggs found medical reasons found found information
or privately funded) only found
Funding:275,452 IVF/ICSI:
• Ministerial Decree (2009 • partial public coverage for patients • no information • max of 1 cycle • no information • no information • no information • no information • no information • no
and 2012) with a 3 year history of unexplained found • max of 1 FET cycle found found found found found information
infertility for new referrals found
United Kingdom – Scotland
Legislation:275
• must also follow national legislation • no information • no legal restrictions • permitted • no information • permitted for • no information • no information • no
160


(see above) found found medical reasons found found information
only found
Guidelines:275 IVF/ICSI: Female partner age
Guidelines of the Expert • limited to couples/singles where • <38 • max of 3 cycles (3 • no information • no information • no information • no information • no information • no
Advisory Group on Infertility neither partner has been previously fresh or 2 fresh and 1 found found found found found information
(2000) sterilized and there is no child living with frozen) found
the couple/single
Funding:
• no information found • no information • no information • no information • no information • no information • no information • no information • no
found found found found found found found information
found
United Kingdom – Wales
Legislation:453
• Welsh Health Specialised • must also follow national legislation • no information • no legal restrictions • permitted • permitted • permitted for • no information • permitted • permitted
Services Committee (see above) found medical reasons found
(WHSSC) only
Funding:447,453,454 • sets quality standards and clinical Female partner age
• Welsh Assembly governance arrangements • age limit for referral • max of 2 cycles (1 • public coverage • public coverage until • public coverage • no information • public coverage • public
st
Government (2005) • sets eligibility criteria for IVF funding, to infertility services: fresh and 1 frozen) 1 frozen cycle (under separate found coverage for
• Welsh Health Specialised which follows NICE guidance & the UK 38 years and 6 months • no public coverage policy) IVF/ICSI cycle
Services Committee HFEA Code of Practice • first treatment cycle thereafter with
(WHSSC) must be completed surrogate,
• All Wales Assisted Fertility IVF/ICSI: before age 40 where no
Working Group (2011) • partial public coverage for other fertility
couples/singles who meet the following treatment
criteria: available
‐ <3 prior embryo transfers (publicly or • WHSSC not
privately funded) involved in
‐ a female partner with a BMI of 19‐30 financial
who is a non‐smoker at the time of arrangements
treatment between
‐ no children living couple/singles surrogate and
‐ one partner has never had a biological couple
or adopted child
Note: no legal restrictions refers to restrictions on access, but not on funding (i.e., a service can be publicly funded for a specific population, however there may be no legal restrictions on treatments that are paid for privately)

161

Appendix B – Evidence tables: Included studies
Description of systematic reviews meeting initial inclusion/exclusion criteria grouped by their primary comparison
Table 25. Included studies
Review Details of Review Study Selection Characteristics of Included Studies Outcomes

Inclusion criteria Exclusion criteria General Population details Procedure details Pregnancy/delivery Neonatal/infant
IVF/ICSI in comparison to non‐invasive ART treatment options (N = 2)
Thomopoulos Country: Greece Population(s): ‐ Number of studies: 47 • age: ‐ • ovarian stimulation protocol: ‐ Primary: Primary:
314
et al. (2012) • 1 RCT Effectiveness: ‐ Effectiveness: ‐
Comparison: impact Intervention(s): • 33 case‐control studies • BMI: ‐ • number of cycles: ‐
of different ART • ART • 4 prospective cohorts Safety: Safety: ‐
modalities Comparator(s): ‐ • 9 retrospective cohorts • other: ‐ • donor or autologous oocytes: ‐ • hypertensive
complication rate
Date of literature Outcome(s): Publication dates • frozen or fresh embryos: ‐
search: up to Dec • hypertensive complications (range): 1992 ‐ 2010 Secondary: Secondary:
2010 Design: ‐ • stage of embryo during Effectiveness: ‐ Effectiveness: ‐
• reviews, case Countries: ‐ transfer: ‐
Meta‐analysis: no series, case reports, Safety: ‐ Safety: ‐
letters, editorials, Number of patients: ‐ • number of embryos
Sub‐group or commentaries, non‐ transferred: ‐
sensitivity analysis: human studies
no Other: • quality of embryos transferred:
• all published studies • non‐English ‐
providing evidence on the language
incidence of hypertensive
complications in ART‐initiated
pregnancies
Number of embryos transferred (N = 5)
Grady et al. Country: Canada Population(s): Number of studies: 15 • age: maternal upper • ovarian stimulation protocol: Primary: Primary:
313
(2012) (Ontario) • single, twin, or multiple‐ • 7* RCTs age limit in 7 RCTs varies slightly across RCTs: Effectiveness: ‐ Effectiveness: ‐
order infants conceived by • 1 quasi‐RCT (range 30‐38) and 5 GnRHa + hMG or FSH in most,
Comparison: eSET vs. IVF/ICSI • 4* prospective cohorts cohorts (range 36‐39) with 1 study using a GnRH Safety: Safety:
1) DET or MET, or 2) Intervention(s): • 4 retrospective antagonist in DET group; the • preterm birth rate • low birth weight rate
spontaneous • eSET cohorts • BMI: lower and same across all cohorts: GnRHa + • perinatal mortality
conception Comparator(s): *1 study with 2 arms: 1 RCT upper limit in 1 RCT FSH rate
• DET or MET and 1 prospective cohort (BMI 18‐28) Secondary:
Date of literature • spontaneous conception (SC) • number of cycles: analysis Effectiveness: Secondary:
search: 1978/1980 ‐ Outcome(s): Publication dates • other: study included 1 cycle only • miscarriage rate Effectiveness: ‐
Mar 2011 • perinatal mortality, preterm (range): 1999 ‐ 2010 population limited to

162


birth, birth weight Countries: Australia (1), women with a “good • donor or autologous oocytes: Safety:
Meta‐analysis: yes Design: Belgium (4), Finland (3), prognosis” (i.e., autologous only in 5 RCTs (not • ectopic pregnancy Safety:
• randomized controlled trials • editorials France (1), the younger women in specified in others) rate • very low birth weight
st nd
Sub‐group or • cohort studies • case reports Netherlands (3), Saudi their 1 or 2 IVF • preeclampsia rate rate
sensitivity analysis: • case‐control studies • letters Arabia (1), Sweden (2) cycle with good • frozen or fresh embryos: • placenta praevia rate • mean birth weight
no Other: embryo quality) in 5
analysis included fresh cycles • placental abruption • mean gestational age
• duplicate Number of patients: RCTs only rate at delivery
publications 79,084 • preterm prolonged • proportion of infants
• studies with very • eSET: 2,010 • stage of embryo during rupture of membranes small for gestational
small populations • DET: 2,175 transfer: cleavage in 4 RCTs and rate age
(N<10) • MET: 57 5 cohorts, blastocyst in 1 cohort, • gestational diabetes • proportion of infants
• SC: 74,842 cleavage or blastocyst in 1 RCT rate with Apgar score <7
and 1 cohort (not specified in • early preterm birth • NICU admission rate
others) rate • neonatal death rate
• caesarean section rate • congenital
• number of embryos abnormalities
transferred: 1 vs. 2 (primary
comparison)

• quality of embryos transferred:
at least good quality in 6 RCTs
and 1 cohort
McLernon et Country: Australia Population(s): Number of studies: 8 • age: maternal upper • ovarian stimulation protocol: Primary: Primary:
96
al. (2010) and several European • women undergoing • all RCTs age limit in 6 studies varies slightly across studies Effectiveness: Effectiveness: ‐
(Belgium, Finland, the autologous IVF/ICSI (range 34‐37); reporting a protocol: GnRHa + • live birth rate
Netherlands, Sweden, Intervention(s): Publication dates maternal age included hMG or FSH • multiple birth rate
the UK) • eSET with cleavage stage • blastocyst (day 5) (range): 1999 ‐ 2008 in model* • cumulative live birth
(day 2‐3) embryos embryo transfer • number of cycles: 1 cycle in 6 rate†
Comparison: eSET vs. Comparator(s): Countries: Australia (1), • BMI: included in studies, 1‐2 cycles in 2 studies; • cumulative multiple
DET • DET with cleavage stage (day • blastocyst (day 5) Belgium (1), Finland (1), model* outcomes for more than 1 cycle birth rate†
2‐3) embryos embryo transfer Netherlands (2), UK (1), analyzed separately
Date of literature Outcome(s): multiple (2‐Sweden, • other: study Safety: ‐ Safety: ‐
search: • live birth, multiple birth Denmark, Norway, the population limited to • donor or autologous oocytes:
up to 2008 Design: Netherlands) women with a “good autologous only in all studies Secondary: Secondary:
• randomized controlled trials • quasi‐randomized prognosis” (i.e., Effectiveness: Effectiveness: ‐
Meta‐analysis: yes (including crossover trials) controlled trials Number of patients: younger women in • frozen or fresh embryos: • miscarriage rate
st nd
(of individual patient • published and ongoing 1,367 their 1 or 2 IVF analysis included fresh cycles • term singleton birth
data) Other: • eSET: 683 cycle with good only rate
• intervention differs only by • trials with other • DET: 684 embryo quality) in 6
Sub‐group or number of embryos to be co‐interventions studies; type, cause, • stage of embryo during Safety: Safety:
sensitivity analysis: transferred (i.e., similar and duration of transfer: analysis included • preterm birth rate • low birth weight rate
yes protocols for controlled infertility included in cleavage stage transfers only; • early preterm birth • mean birth weight
(by maternal age, ovarian stimulation, embryo regression model* day of transfer included in rate
163


embryo grade, and culture, and embryo model* • moderate preterm
duration of infertility) replacement) *included as covariate in birth rate
regression model to • number of embryos
obtain adjusted OR (if transferred: 1 vs. 2 (primary
found to be significant)
comparison); number of
embryos available for transfer
included in model*

at least good quality in 7 studies

*included as covariate in regression
model to obtain adjusted OR (if found
to be significant)
Gelbaya, Country: the UK Population(s): Number of studies: 6 • age: maternal upper • ovarian stimulation protocol: Primary: Primary:
Tsoumpou, • women undergoing IVF/ICSI • 5 RCTs age limit in 5 studies varies slightly across studies: Effectiveness: Effectiveness: ‐
and Nardo Comparison: eSET vs. Intervention(s): • 1 quasi‐RCT (range 30‐36) GnRHa + hMG or FSH • live birth rate
315
(2010) DET • eSET • blastocyst embryo • multiple birth rate
transfer Publication dates • BMI: ‐ • number of cycles: analysis
Date of literature Comparator(s): (range): 1999 ‐ 2008 included 1 cycle only Safety: ‐ Safety: ‐
search: Jan 1974 ‐ • DET • blastocyst embryo • other: study
Sep 2008 transfer Countries: Belgium (1), population limited to • donor or autologous oocytes:
Outcome(s): Finland (1), the women with a “good autologous only in 5 studies (not Secondary: Secondary:
Meta‐analysis: yes • live birth, multiple birth Netherlands (2), Saudi prognosis” (i.e., specified in others) Effectiveness: Effectiveness: ‐
Design: Arabia (1), multiple (1‐ younger women in • implantation rate
st nd
Sub‐group or • randomized controlled trials • non‐randomized Sweden, Denmark, their 1 or 2 IVF • frozen or fresh embryos: • pregnancy rate
sensitivity analysis: studies Norway) cycle with good analysis included fresh cycles • clinical pregnancy rate
no Other: ‐ embryo quality) in 4 only • ongoing pregnancy
Number of patients: studies rate
1,354 • stage of embryo during • miscarriage rate
• eSET: 678 transfer: cleavage in 5 studies, Safety: ‐
• DET: 676 majority cleavage in 1 study Safety:
(98%) • ectopic pregnancy
rate
• number of embryos • preterm delivery rate
comparison)

Baruffi et al. Country: Brazil Population(s): Number of studies: 7 • age: maternal upper • ovarian stimulation protocol: Primary: Primary:
316
(2009) • women undergoing fresh • 6 RCTs age limit in 4 studies varies slightly across studies: Effectiveness: Effectiveness: ‐
Comparison: SET vs. IVF/ICSI • 1 quasi‐RCT (range 30‐35) GnRHa + hMG and/or FSH • implantation rate
DET Intervention(s): • ongoing pregnancy
164


• SET Publication dates • BMI: ‐ • number of cycles: 1 cycle in 5 rate
Date of literature Comparator(s): (range): 2001 ‐ 2008 studies, 1‐2 cycles in 2 studies • live birth rate
search: 1995 ‐ 2008 • DET • other: study Safety: ‐
Outcome(s): Countries: Belgium (1), population limited to • donor or autologous oocytes: Safety: ‐
Meta‐analysis: yes • implantation, pregnancy, live Finland (1), the women with a “good autologous only in 6 studies (not
birth Netherlands (2), Saudi prognosis” (i.e., specified in others)
Sub‐group or Design: Arabia (1), the US (1), younger women in
st nd
sensitivity analysis: • randomized controlled trials multiple (1‐Sweden, their 1 or 2 IVF • frozen or fresh embryos:
yes (of studies that • published and ongoing Denmark, Norway) cycle with good analysis included fresh cycles
only included younger Other: ‐ embryo quality) in 5 only
women) Number of patients: studies
1,402 • stage of embryo during
• SET: 701 transfer: cleavage in 5 studies,
• DET: 701 majority cleavage in 1 study
(98%), blastocyst in 1 study

• number of embryos
comparison)

Pandian et al. Country: Egypt and Population(s): Number of studies: 7 • age: maternal upper • ovarian stimulation protocol: Primary: Primary:
317
(2009) the UK • subfertile women • all RCTs age limit in 4 studies varies slightly across studies: Effectiveness: Effectiveness: ‐
undergoing fresh, autologous (range 34‐36); study GnRHa + hMG and/or FSH • live birth rate
Comparison: 1) DET or donor IVF/ICSI Publication dates population limited to
vs. SET, TET, or QET, Intervention(s): (range): 1994 ‐ 2006 older women (38‐45) • number of cycles: 1 cycle in 5 Safety: ‐ Safety: ‐
2) TET vs. DET or QET • 1) DET • blastocyst embryo in 1 study studies, 1‐2 cycles in 2 studies;
• 2) TET transfer Countries: Belgium (1), outcomes for more than 1 cycle Secondary: Secondary:
Date of literature • with cleavage stage embryos Finland (1), France (1), • BMI: ‐ analyzed separately Effectiveness: Effectiveness: ‐
search: 1970/1985 ‐ Comparator(s): the Netherlands (3), • clinical pregnancy rate
2008 • 1) SET, TET, or QET • blastocyst embryo multiple (1‐Sweden, • other: study • donor or autologous oocytes: • multiple
• 2) DET or QET transfer Denmark, Norway) population limited to autologous only in 5 studies (not pregnancy/birth rate
Meta‐analysis: yes • with cleavage stage embryos women with a “good specified in others) • miscarriage rate
Outcome(s): Number of patients: prognosis” (i.e., • cumulative live birth
Sub‐group or • live birth 1,374 younger women in • frozen or fresh embryos: rate‡
st nd
sensitivity analysis: Design: • SET: 638 their 1 or 2 IVF analysis included fresh cycles
no • randomized controlled trials • DET: 686 cycle with good only, except 1 study that Safety: ‐ Safety: ‐
(including crossover trials) • TET: 22 embryo quality) in 4 reported outcomes after an
• published and ongoing • QET: 28 studies additional frozen cycle ;
Other: outcomes for frozen cycle
• standard procedures (i.e., analyzed separately
standard protocols and
165


materials for ovarian • stage of embryo during
stimulation, ultrasound‐guided transfer: analysis included
oocyte retrieval, insemination, cleavage stage transfers only
embryo culture, embryo
replacement) • number of embryos
transferred: 1, 2, 3, or 4 (primary
comparison)

at least good quality in all studies
Fresh embryo transfer in comparison to frozen embryo transfer (N = 5)
Roque et al. Country: Population(s): Number of studies: • age: 27‐33 years • ovarian stimulation protocol: Primary: Primary:
455
(2012) • women undergoing IVF/ICSI • 3 RCTs FSH and GnRHa in 1, FSH and Effectiveness: Effectiveness: ‐
Comparison: frozen Intervention(s): • BMI: GnRH antagonist in 2. • clinical pregnancy rate
ET vs. fresh ET • frozen embryo transfer (FET) Publication dates • ongoing pregnancy
Comparator(s): (range): 2010‐2011 • other: • number of cycles: rate
Date of literature • fresh embryo transfer 1 cycle per patient •miscarriage rate
search: up to Outcome(s): Countries:
December 2011 • pregnancy, miscarriage USA, Iran, • donor or autologous oocytes: Safety: ‐ Safety: ‐
Design:
• RCTs Number of patients: • frozen or fresh embryos:
Meta‐analysis: • 633 Primary comparison Secondary: Secondary:
Yes Other: ‐ Effectiveness: ‐ Effectiveness: ‐
• stage of embryo during
Sub‐group or transfer: Safety: ‐ Safety: ‐
sensitivity analysis: One oocyte, two blastocyst
No
transferred:

Maheshwari Country: the UK Population(s): Number of studies: 11 • age: ‐ • ovarian stimulation protocol: ‐ Effectiveness: ‐ Effectiveness: ‐
et al. • singleton IVF/ICSI • 4 matched cohorts
321
(2012) Comparison: frozen pregnancies • 7 unmatched cohorts • BMI: ‐ • number of cycles: ‐ Safety: Safety:
ET vs. fresh ET Intervention(s): • preterm birth rate • low birth weight rate
• frozen embryo transfer (FET) • GIFT Publication dates • other: ‐ • donor or autologous oocytes: ‐ • early preterm birth • very low birth weight
Date of literature Comparator(s): (range): 1994 ‐ 2011 rate rate
search: 1984 ‐ 2012 • fresh embryo transfer • no comparator • frozen or fresh embryos: fresh • caesarean section rate • proportion of infants
Outcome(s): Countries: ‐ vs. frozen (primary comparison) • antepartum small for gestational
Meta‐analysis: yes • obstetric or perinatal • no obstetric or hemorrhage rate age
outcomes perinatal outcomes Number of patients: ‐ • stage of embryo during • congenital
Sub‐group or Design: transfer: cleavage only in 3 abnormalities
sensitivity analysis: • any observational study • case reports, case studies, blastocyst only in 1 • perinatal mortality
166


yes (matched vs. series study, both in 3 studies (not rate
unmatched cohort) Other: specified in others) • NICU admissions
• published • not possible to
differentiate • number of embryos
outcomes for transferred: ‐
singletons and
twins • quality of embryos transferred:
not specified in most studies
Jee, Suh, and Country: South Korea Population(s): Number of studies: 7 • age: no studies • ovarian stimulation protocol: Effectiveness: ‐ Effectiveness: ‐
318
Kim (2009) • women undergoing • 1 single‐arm trial employed maternal varies slightly across studies
Comparison: frozen autologous IVF • 4 retrospective cohorts age limits reporting a protocol: GnRHa + Safety: Safety: ‐
ET vs. fresh ET Intervention(s): • 1 case‐control study hMG and/or FSH • ectopic pregnancy
• frozen embryo transfer (FET) • 1 retrospective chart • BMI: ‐ rate
Date of literature Comparator(s): review • number of cycles: 1 or more
search: up to Feb • fresh embryo transfer • other: unselected per couple; actual number not
2008 Outcome(s): Publication dates patients in all studies specified in any study
• ectopic pregnancy (range): 1994 ‐ 2007 (i.e., all patients
Meta‐analysis: yes Design: ‐ undergoing IVF within • donor or autologous oocytes:
• registry reports Countries: China (1), the a certain time period autologous only in all studies
Sub‐group or Other: ‐ US (6) at a particular clinic or
sensitivity analysis: in a particular region) • frozen or fresh embryos: fresh
yes (by stage of Number of patients: vs. frozen (primary comparison)
embryo transfer) 13,059*
• FET: 2,125* • stage of embryo during
• fresh ET: 10,934* transfer: cleavage only in 3
*pregnancies studies, blastocyst only in 1
study, both in 3 studies

transferred: up to 4 in 2 studies,
mean of 2 in 1 study (not
reported in 3)

varies widely across studies
Wennerholm Country: several Population(s): Number of studies: 25 • age: ‐ • ovarian stimulation protocol: ‐ Effectiveness: ‐ Effectiveness: ‐
et al. European (Denmark, • single or multiple‐order • single and • 1 RCT
320
(2009) Finland, Norway, infants conceived by IVF/ICSI multiple births not • 12 retrospective • BMI: ‐ • number of cycles: ‐ Safety: Safety:
• part I Sweden) separated (except cohorts • preterm birth rate • low birth weight rate
birth defect studies) • 12 registry reports • other: ‐ • donor or autologous oocytes: ‐ • very low birth weight
Comparison: frozen Intervention(s): rate
ET with cleavage • frozen embryo transfer (FET) • donor and non‐ Publication dates • frozen or fresh embryos: fresh • perinatal mortality
stage embryos vs. 1) with early cleavage stage donor oocytes not (range): 1993 ‐ 2008 vs. frozen (primary comparison) rate
167


fresh ET, or 2) embryos (cryopreservation by separated • birth defect rate
spontaneous slow freezing or vitrification) Countries: Australia (2), • stage of embryo during • chromosome
conception Comparator(s): Belgium (1), Denmark transfer: ‐ aberration rate
• 1) fresh embryo transfer • no control group (1), India (1), Japan (1), • childhood morbidity
Date of literature • 2) spontaneous conception (SC(except vitrification) Sweden (4), Turkey (1), • number of embryos • growth pattern
search: 1984 ‐ Sep • none for vitrification studies the UK (3), the US (10), transferred: ‐ • mental development
2008 Outcome(s): multiple European (1)
• neonatal/perinatal or child • quality of embryos transferred:
Meta‐analysis: no outcomes Number of patients: ‐
Design: 170,874
Sub‐group or • comparative • non‐comparative • FET: 25,489
sensitivity analysis: (except vitrification) • fresh ET: 136,628
no Other: • SC: 8,757
• English language
• part II Comparison: frozen Population(s): Number of studies: • age: ‐ • ovarian stimulation protocol: ‐ Effectiveness: ‐ Effectiveness:
ET with blastocyst • single or multiple‐order blastocyst: 12
stage embryos or infants conceived by IVF/ICSI • 3 single‐arm trials • BMI: ‐ • number of cycles: ‐
oocytes (no Intervention(s): • 1 retrospective Safety: Safety:
comparator) • frozen embryo transfer (FET) • in vitro analyses • other: ‐ • donor or autologous oocytes: ‐ • preterm delivery rate • mean birth weight
with blastocyst stage embryos maturation • 8 case reports • congenital
or oocytes (cryopreservation oocyte: 30 • frozen or fresh embryos: frozen malformations
by slow freezing or • 1 non‐randomized cycles only
vitrification) controlled trial
Comparator(s): • 7 single‐arm trials • stage of embryo during
• none • 4 retrospective transfer: ‐
Outcome(s): analyses
• neonatal/perinatal or child • studies that do • 2 case series • number of embryos
outcomes not report on the • 16 case reports transferred: ‐
health of infants
born Publication dates • quality of embryos transferred:
Design: (range): blastocyst: ‐
• any (including case reports) 2000‐2007
Other: oocyte: 1999‐2008
Countries:
blastocyst: Argentina
(1), Japan (5), Korea (2),
Spain (1), Sweden (1),
the US (2)
oocyte: Argentina (2),
Australia (2), Brazil (1),
Canada (1), China (2),
Germany (1), Hungary
168


(1), Italy (10), Israel (1),
Japan (3), Korea (1),
Spain (1), Switzerland
(1), Taiwan (2), the US
(1)

Number of patients: ‐
D’Angelo and Country: the UK Population(s): Number of studies: 2 • age: ‐ • ovarian stimulation protocol: ‐ Primary: Primary:
Amso • reproductive‐age women • women • all RCTs Effectiveness: Effectiveness: ‐
319
(2007) Comparison: frozen undergoing IVF/ICSI with undergoing • BMI: 1) upper limit • number of cycles: 1 in both • clinical pregnancy rate
ET vs. 1) fresh ET, or GnRHa pituitary down‐ ovulation induction Publication dates of 30 studies
2) intravenous regulation and superovulation without (range): Safety: Safety: ‐
albumin + fresh ET Intervention(s): 1) 1999 • other: ‐ • donor or autologous oocytes: • incidence of
• frozen embryo transfer (FET) 2) 1996 autologous in both studies moderate‐severe OHSS
Date of literature (cryopreservation of all • incidence of nil‐mild
search: 1985 ‐ May embryos) Countries: • frozen or fresh embryos: 1) OHSS
2007 Comparator(s): 1) Italy fresh vs. frozen; 2) IVA vs. frozen
• 1) fresh embryo transfer 2) the UK (primary comparison) Secondary: Secondary:
Meta‐analysis: yes • 2) intravenous albumin Effectiveness: Effectiveness: ‐
infusion (IVA) + fresh embryo Number of patients: • stage of embryo during • live birth rate
Sub‐group or transfer 1) 125 transfer: 1) fresh ET: cleavage • mean number of
sensitivity analysis: Outcome(s): • FET: 58 stage (FET: zygotes frozen oocytes retrieved
no • OHSS, pregnancy • fresh ET: 67 immediately after fertilization); • mean number of
Design: 2) 26 2) IVA: blastocyst stage (FET: oocytes fertilized
• randomized controlled trials • crossover trials • FET: 13 pronucleate stage embryos • mean number of
Other: ‐ • IVA: 13 frozen) embryo’s transferred
• mean resolution time
• number of embryos (time to next menstrual
transferred: 1) 3‐4; 2) mean of 2 period)

• quality of embryos transferred: Safety: Safety: ‐
‐ • hospital admission
rate
Stage of embryo during transfer (N = 4)
Chang et al. Country: South Korea Population(s): Number of studies: • age: maternal upper • ovarian stimulation protocol: Effectiveness: ‐ Effectiveness:
322
(2009) • women undergoing and sex ratio: 4* age limit in 5 studies varies slightly across studies • sex ratio (number of
Comparison: infants born after fresh, • all retrospective (range 35‐44; only 1 reporting a protocol: GnRHa + male infants/number of
blastocyst stage ET vs. autologous IVF/ICSI cohorts study at 44, the rest hMG and/or FSH in most, with 1 female infants)
cleavage stage ET Intervention(s): *an additional 4 35‐37) study using a GnRH antagonist
• blastocyst embryo transfer unpublished studies Safety: ‐ Safety:
Date of literature included in a separate • BMI: ‐ • number of cycles: 1 or more • monozygotic twinning
Comparator(s):
analysis (characteristics of
search: Jan 1995 ‐ • cleavage embryo transfer per couple; actual number not rate
these studies not provided)
Nov 2007 Outcome(s): MZT: 9 • other: study specified in most studies
169


• sex ratio, monozygotic • 3 RCTs population limited to
Meta‐analysis: yes twinning (MZT) • 1 prospective cohort couples with a “good • donor or autologous oocytes:
Design: • 4 retrospective prognosis” (i.e., those analysis included autologous
Sub‐group or • any comparative study cohorts expected to do well only
sensitivity analysis: Other: • 1 case‐control study with blastocyst
yes (by publication • published in peer‐reviewed • non‐English culture) in 2 studies • frozen or fresh embryos:
year) journal language Publication dates and to couples with a analysis included fresh cycles
(range): 2001 ‐ 2007 “poor prognosis” (i.e., only
those who had
Countries: experienced multiple • stage of embryo during
sex ratio: Australia (1), failures with transfer: blastocyst vs. cleavage
the US (1) conventional (primary comparison)
MZT: Belgium (1), Brazil treatment or a poor
(1), Israel (2), the US (5) response to ovulation • number of embryos
induction) in 1 study; transferred: varies across studies
Number of patients: unselected patients in (mean of 2‐3 reported in 5
sex ratio: 2,487 the other 10 studies studies, max of 4 reported in 1
• blastocyst: 1,102 study)
• cleavage: 1,485
MZT: 40,917* • quality of embryos transferred:
• blastocyst: 9,316 varies widely across studies
• cleavage: 31,601
*pregnancies
Papanikolaou Country: Belgium Population(s): Number of studies: 8 • age: maternal upper • ovarian stimulation protocol: Primary: Primary:
et al. • women undergoing IVF/ICSI • all RCTs age limit in 6 studies varies slightly across studies Effectiveness: Effectiveness: ‐
323
(2008) Comparison: Intervention(s): (range 36‐43; only 1 reporting a protocol: GnRHa + • live birth rate
blastocyst stage ET vs. • blastocyst (day 5‐6) embryo Publication dates study at 43, the rest hMG and/or FSH in most, with 3
cleavage stage ET transfer (range): 2000 ‐ 2006 36‐41) studies using a GnRH antagonist Safety: ‐ Safety: ‐
Comparator(s):
Date of literature • cleavage (day 2‐3) embryo Countries: Belgium (5), • BMI: upper limit of • number of cycles: analysis Secondary: Secondary:
search: 1966/1980 ‐ transfer Italy (1), Israel (1), 30 in 1 study included 1 cycle only Effectiveness: Effectiveness: ‐
Jul 2007 Outcome(s): ‐ Sweden (1) • clinical pregnancy rate
• other: study • donor or autologous oocytes: • multiple pregnancy
Meta‐analysis: yes Design: Number of patients: population limited to autologous only in 1 study (not rate
• randomized controlled trials • pseudo‐ 1,654 couples with a “good specified in others) • cancellation rate
Sub‐group or (parallel only) randomization • blastocyst: 815 prognosis” (i.e., those • cryopreservation rate
sensitivity analysis: methods • cleavage: 839 expected to do well • frozen or fresh embryos: Safety: ‐
yes (including pseudo‐ Other: with blastocyst analysis included fresh cycles Safety: ‐
randomized studies) • equal number of embryos • not published as culture) in 6 studies; only
transferred between full manuscript in unselected patients in
blastocyst and cleavage groups peer‐reviewed the other 2 studies • stage of embryo during
journal transfer: blastocyst vs. cleavage
(primary comparison)

170


transferred: varies across studies
(range 1‐up to 3)

Glujovsky et Country: Argenitina Population(s): Number of studies: 23 • age: maternal upper • ovarian stimulation protocol: Primary: Primary:
325
al. (2012) and New Zealand • couples undergoing • all RCTs age limit in 14 studies varies slightly across studies Effectiveness: Effectiveness: ‐
and Blake et autologous or donor IVF/ICSI (range 35‐43; only 1 reporting a protocol: GnRHa + • live birth rate
324
al. (2007) § Comparison: Intervention(s): Publication dates study at 43, the rest hMG and/or FSH in most, with 3
blastocyst stage ET vs. • blastocyst (day 5‐6) embryo • in vitro (range): 1998 ‐ 2011 35‐40) trials using a GnRH antagonist Safety: ‐ Safety: ‐
cleavage stage ET transfer with single, sequential maturation
media culture • pre‐implantation Countries: Australia (1), • BMI: upper limit of • number of cycles: 1 or more Secondary: Secondary:
Date of literature genetic diagnosis Belgium (7), Brazil (1), 30 in 2 studies per couple; actual number not Effectiveness: Effectiveness: ‐
search: 1966/1980 ‐ • co‐culture Denmark (1), Egypt (1), specified in most • clinical pregnancy rate
Feb 2012 methods France (1) Greece (1), • other: study • multiple pregnancy
Comparator(s): Italy (2), Israel (3), population limited to • donor or autologous oocytes: rate
Meta‐analysis: yes • cleavage (day 2‐3) embryo Jordan (1), Sweden (1), couples with a “good autologous only in 2 studies (not • miscarriage rate
transfer with single, sequential the US (3) prognosis” (i.e., those specified in others) • cumulative pregnancy
Sub‐group or media culture expected to do well rate
sensitivity analysis: Outcome(s): Number of patients: with blastocyst • frozen or fresh embryos: • cryopreservation rate
yes (by distribution of • live birth, pregnancy, 3,823* culture) in 14 studies analysis included fresh cycles • failure to transfer any
embryos in blastocyst multiple pregnancy, embryo *couples and to couples with a only embryos rate Safety: ‐
vs. cleavage groups, freezing, failure of embryo “poor prognosis” (i.e.,
prognosis of study transfer those who had • stage of embryo during Safety: ‐
population, and time Design: experienced multiple transfer: blastocyst vs. cleavage
of randomization) • randomized controlled trials • quasi‐randomized failures with (primary comparison)
controlled trials conventional
Other: ‐ treatment or a poor • number of embryos
• no data available response to ovulation transferred: varies across studies
from fresh cycle induction) in 2 (range 1‐up to 5)
studies; unselected
patients in the other 7 • quality of embryos transferred:
studies varies widely across studies
Johnson, Country: New Population(s): Number of studies: 25 RCTs: RCTs: Primary: Primary:
Blake, and Zealand • couples undergoing • 6 RCTs • age: maternal upper • ovarian stimulation protocol: Effectiveness: ‐ Effectiveness: ‐
Farquhar autologous or donor IVF/ICSI • 19 non randomized age limit in 5 studies varies slightly across studies
326
(2007) § Comparison: Intervention(s): controlled trials (range 37‐43; only 1 reporting a protocol: GnRHa + Safety: ‐ Safety: ‐
blastocyst stage ET vs. • blastocyst (day 5‐6) embryo study at 43, the rest hMG and/or FSH
cleavage stage ET transfer Publication dates 37‐39) Secondary: Secondary:
Comparator(s): (range): 2002 ‐ 2004 • number of cycles: 1 or more Effectiveness: ‐ Effectiveness: ‐
Date of literature • cleavage (day 2‐3) embryo • BMI: ‐ per couple; actual number not
search: 1966/1980 ‐ transfer Countries: RCTs: specified in most Safety: ‐ Safety:
171


May 2005 Outcome(s): Australia (1), Belgium • other: study • monozygotic twinning
• live birth, pregnancy, (2), Israel (1), Jordan (1), population limited to • donor or autologous oocytes: rate§
Meta‐analysis: yes multiple pregnancy, the US (1); details on couples with a “good autologous only in 1 study (not
miscarriage, embryo freezing, other studies not prognosis” (i.e., those specified in others)
Sub‐group or failure of embryo transfer, reported expected to do well
sensitivity analysis: monozygotic twinning with blastocyst • frozen or fresh embryos:
no Design: Number of patients: ‐ culture) in 6 studies analysis included fresh cycles
• randomized controlled trials and to couples with a only
• non‐randomized studies for “poor prognosis” (i.e.,
monozygotic twinning (if those who had • stage of embryo during
monozygotic twins considered experienced multiple transfer: blastocyst vs. cleavage
separately from dizygotic failures with (primary comparison)
twins) conventional
Other: ‐ treatment or a poor • number of embryos
response to ovulation transferred: varies across studies
induction) in 2 (range 1‐up to 4)
studies; unselected
patients in the other • quality of embryos transferred:
studies varies widely across studies
Embryo donation (N = 1)
Van der Country: the Population(s): ‐ Number of studies: 79 • age: ‐ • ovarian stimulation protocol: ‐ Effectiveness: ‐ Effectiveness: ‐
Hoorn et al. Netherlands and
327
(2010) the US Intervention(s): Publication dates • BMI: ‐ • number of cycles: ‐ Safety: Safety:
• embryo donation (range): ‐ • maternal/pregnancy • fetal/neonatal
Comparison: embryo Comparator(s): ‐ • other: ‐ • donor or autologous oocytes: complication rate complication rate
donation (no Countries: ‐ donor • caesarean section rate
comparator) Outcome(s): • pregnancy‐induced
• pregnancy, pregnancy • exclusive focus on Number of patients: ‐ • frozen or fresh embryos: ‐ hypertension rate
Date of literature complications, placental ethics of egg • first or second
search: up to Jan pathology, immunologic donation • stage of embryo during trimester bleeding rate
2010 aspects transfer: ‐ • placental pathology
Design:
Meta‐analysis: no • original • case reports, • number of embryos
• review letters transferred: ‐
Sub‐group or Other: ‐
sensitivity analysis: • quality of embryos transferred:
no ‐
Maternal or paternal age (N = 2)
Watt et al. Country: Australia Population(s): Number of studies: 21 • age: primary • ovarian stimulation protocol: Effectiveness: Effectiveness: ‐
302
(2011) and the US • couples with infertility • 1 prospective cohort comparison varies slightly across studies • live birth rate
Intervention(s): • 17 retrospective reporting a protocol: GnRHa + • miscarriage rate
Comparison • autologous or donor IVF/ICSI • studies comparing cohorts • BMI: ‐ hMG and/or FSH in most, with 4
association between IVF/ICSI with • 2 case‐control studies studies using a GnRH antagonist Safety: ‐ Safety: ‐
172


maternal age, another fertility • 1 registry report • other: ‐ in some or all patients, and 1
paternal age, cycle treatment *an additional 48 studies reporting use of gonadotropins
rank and ART published before 2005 alone and natural IVF cycles in
Comparator(s):
outcomes included in a separate some patients
• effect of maternal or analysis (characteristics of
paternal age these studies not provided

Date of literature • effect of cycle rank and outcomes only reported • number of cycles: 1 cycle in 8
search: Jan 1994 ‐ Outcome(s): in detail for studies studies, 1 or more cycles in 5
Oct 2009 • safety, effectiveness published 2005‐2009) studies (not specified in others)
Design:
Meta‐analysis: no • systematic reviews • non‐systematic Publication dates • donor or autologous oocytes:
• cohorts reviews, case (range): 2005 ‐ 2009 autologous only in 18 studies,
Sub‐group or • case‐control studies reports, letters, donor only in 1 study, mixed in 2
sensitivity analysis: • cross‐sectional studies commentaries, Countries: Australia (1), (outcomes for donor cycles
no • registry studies (unique animal studies, cell Egypt (1), France (1), discussed separately)
analysis of registry data) culture studies Finland (1), Israel (5),
Other: Japan (1), the • frozen or fresh embryos: fresh
• • studies published Netherlands (1), cycles only in 10 studies, fresh
only as abstracts Singapore (1), Spain (2), and frozen cycles in 3 studies
• non‐English the US (7) (not specified in others)
language
• insufficient data Number of patients: • stage of embryo during
• Kaplan Meier or 145,962 transfer: cleavage in 8 studies,
other survival cleavage or blastocyst in 1 study
models of (not specified in others)
cumulative
outcomes • number of embryos
(range 1‐up to 7)

varies widely across studies;
unspecified in most
Dain, Country: Israel Population(s): ‐ Number of studies: 10 • age: maternal upper • ovarian stimulation protocol: Primary: Primary:
Auslander, • 1 prospective cohort age limit in 2 studies varies slightly across studies Effectiveness: Effectiveness: ‐
and Dirnfeld Comparison: Intervention(s): • 6 retrospective (38‐40); maternal age reporting a protocol: GnRHa + • fertilization rate
328
(2011) association between • ART¶ cohorts adjusted for in 6 hMG and/or FSH in most (4), • embryo development
paternal age and ART Comparator(s): • 2 case‐control studies studies (oocyte with 1 study using a GnRH • implantation rate
outcomes • effect of paternal age • 1 registry report donation by young antagonist and 1 reporting use of • pregnancy rate
Outcome(s): females in other 4 standard COS • spontaneous
Date of literature • fertilization, embryo Publication dates studies) miscarriage rate
search: 1990 ‐ 2009 development, implantation, (range): 1996 ‐ 2010 • number of cycles: 1 cycle in 8 • live birth rate
pregnancy, miscarriage, live • BMI: upper limit of studies, 1 or more cycles in 2
Meta‐analysis: no birth Countries: Brazil (1), 27 in 1 study studies Safety: ‐ Safety: ‐
173


Design: Egypt (1), France (1),
Sub‐group or • retrospective and • case reports, case Spain (2), the US (5) • other: study • donor or autologous oocytes: Secondary: Secondary:
sensitivity analysis: prospective series, anecdotal population limited to autologous only in 5 studies, Effectiveness: Effectiveness: ‐
no data Number of patients: couples where female donor only in 4 studies, mixed in • semen parameters
Other: 9,754 completely sterile 1
• English language (bilateral tubal Safety: ‐ Safety: ‐
• published in peer‐reviewed obstruction or • frozen or fresh embryos: fresh
journal absence) in 1 study cycles only in 4 studies (not
specified in others)

transfer: cleavage in 4 studies,
blastocyst in 2 studies (not

(range 1‐up to 5)

included as an outcome
Maternal weight/BMI (N = 4)
Koning et al. Country: the Population(s): Number of studies: 27* • age: maternal upper • ovarian stimulation protocol: Effectiveness: Effectiveness: ‐
329
(2012) †† Netherlands • women with infertility • 4 prospective cohorts age limit in 14 studies varies slightly across studies • live birth rate
Intervention(s): • 21 retrospective (range 35‐44; 3 studies reporting a protocol: GnRHa + • clinical pregnancy rate
Comparison: normal • IVF/ICSI • fertility treatment cohorts at 42‐44, the rest 35‐ hMG and/or FSH in most, with 3 • ongoing pregnancy
weight women (BMI other than • 2 case‐control studies 41) studies using a GnRH antagonist, rate
≤25) vs. overweight Comparator(s): *plus 4 additional studies 1 study using GnRHa or CC + • multiple pregnancy
and obese women • effect of maternal including women with PCOS • BMI: primary hMG, and 1 study using GnRHa + rate Safety: ‐
(BMI >25) only that are discussed but assessment hMG and/or LH
overweight/obesity (BMI)
not included in meta‐
Outcome(s): analysis
Safety:
Date of literature • effectiveness, complications • other: unselected • number of cycles: analysis • OHSS rate
search: Jan 1999 ‐ Jul Design: Publication dates patients in most included 1 cycle only • ectopic pregnancy
2011 • ‐ • reviews (range): 1999 ‐ 2011 studies; study rate
Other: population limited to • donor or autologous oocytes:
Meta‐analysis: yes • English • not enough data Countries: Australia (1), women with a “good autologous only in 17 studies,
reported to create a China (1), France (2), prognosis” (i.e., donor only in 1 study, mixed in 1
Sub‐group or 2x2 table India (1), Israel (2), the younger women <40 in study, which reported outcomes
st rd
sensitivity analysis: Netherlands (3), Norway their 1 – 3 IVF cycles for each separately (not
yes (overweight and (1), Spain (1), Turkey (2), with a good ovarian specified in others)
obese separated) the UK (4), the US (9) reserve…) in 3 studies
• frozen or fresh embryos: fresh
Number of patients: cycles only in 18 studies, frozen
174


89,051 cycles included in 3 studies (not

transfer: cleavage only in 9
studies, cleavage or blastocyst in
8 studies (not specified in others)

(range 1‐>4)

unspecified in many
Rittenberg et Country: the UK Population(s): Number of studies: 33 • age: maternal upper • ovarian stimulation protocol: Primary: Primary:
162
al. (2011) • women undergoing • 2 prospective cohorts age limit in 12 studies varies slightly across studies Effectiveness: Effectiveness: ‐
Comparison: normal autologous IVF/ICSI • 30 retrospective (range 35‐44; 1 study reporting a protocol: GnRHa + • clinical pregnancy rate
weight women (BMI Intervention(s): cohorts at 44, the rest 35‐41) hMG and/or FSH in most, with 6 • miscarriage rate
<25) vs. overweight • IVF/ICSI • natural cycle • 1 case‐control study studies using CC + hMG and/or • live birth rate
and obese women conception, OI, IUI, • BMI: primary FSH in some patients, 1 study
(BMI ≥25) oocyte donation Publication dates assessment using hMG or FSH alone in some Safety: ‐ Safety: ‐
Comparator(s): (range): 2000 ‐ 2011 patients, and 1 study using a
Date of literature • effect of maternal • parameters other • other: unselected GnRH antagonist in some Secondary: Secondary:
search: 1966 ‐ 2010 overweight/obesity (BMI) than BMI used to Countries: Australia (4), patients in most patients Effectiveness: Effectiveness: ‐
measure Austria (1), Brazil (1), studies; study • mean gonadotropin
Meta‐analysis: yes overweight/obesity China (1), Czech Republic population limited to • number of cycles: 1 or more stimulation dose
(e.g., waist‐to‐hip (1), France (3), Germany women with a “good per couple; actual number not • mean duration of
Sub‐group or ratio) (1), India (1), Iran (1), prognosis” (i.e., specified in most studies gonadotropin
sensitivity analysis: Outcome(s): Israel (2), the younger women <40 stimulation
st rd
yes (overweight and • pregnancy, miscarriage, live Netherlands (1), Norway in their 1 – 3 IVF • donor or autologous oocytes: • mean number of
obese separated) birth (2), Spain (2), Turkey (2), cycles with a good autologous only in all studies oocytes retrieved
Design: ‐ the UK (2), the US (6), ovarian reserve…) in 2 • mean peak oestradiol
Other: multiple (1‐Egypt, studies • frozen or fresh embryos: fresh Safety: ‐
• ‐ • WHO BMI criteria Germany, and the UK; 1‐ cycles only in 24 studies, frozen Safety: ‐
not used Canada and the US) cycles included in 3 studies (not
Number of patients:
47,967* • stage of embryo during
*cycles transfer: cleavage only in 9
studies, blastocyst only in 2
5 studies (not specified in others)
175



(range 1‐6)

unspecified in many
Metwally et Country: the UK Population(s): Number of studies: 12* • age: maternal upper • ovarian stimulation protocol: Effectiveness: Effectiveness: ‐
330
al. (2008) • women • underweight • 1 prospective cohort age limit in 3 studies varies slightly across studies • miscarriage rate
Comparison: normal women (BMI ≤19) • 11 retrospective (range 38‐40) reporting a protocol: GnRHa +
weight women (BMI Intervention(s): cohorts hMG and/or FSH in most, with 4 Safety: ‐ Safety: ‐
19‐24.9) vs. • ovulation induction *3 additional studies on • BMI: primary studies using CC + hMG and/or
overweight and obese • autologous or donor IVF/ICSI ovulation induction and 1 assessment FSH in some patients
women (BMI ≥25) with unspecified treatment
• none (spontaneous
not included for outcomes
conception) • other: unselected • number of cycles: 1 or more

Date of literature Comparator(s): patients in most per couple; actual number not
Publication dates
search: 1964/1974 ‐ • effect of maternal • no control group studies; study specified in most studies
(range): 2000 ‐ 2007
Sep 2006 overweight/obesity (BMI) of normal weight population limited to

women women with a “good • donor or autologous oocytes:
Countries: Australia (3),
Meta‐analysis: yes Outcome(s): prognosis” (i.e., autologous only in 9 studies,
France (1), the
• miscarriage younger women <40 donor only in 3 studies
Netherlands (1), Norway st rd
Sub‐group or Design: ‐ in their 1 – 3 IVF (outcomes for donor cycles
(2), Spain (2), the US (3)
sensitivity analysis: cycles with a good analyzed separately)

yes (age and BMI Other: ‐ ovarian reserve…) in 1
Number of patients:
classification) study • frozen or fresh embryos: fresh
11,267
cycles only in 9 studies (not

5 (not specified in others)

(range 1‐>3)

unspecified in many
Maheshwari Country: the UK Population(s): Number of studies: 12 • age: maternal upper • ovarian stimulation protocol: Primary: Primary:
et al. • women • studies including • 1 prospective cohort age limit in 3 studies varies slightly across studies Effectiveness: Effectiveness: ‐
176


331
(2007) Comparison: 1) selected • 10 retrospective (range 38‐40) reporting a protocol: GnRHa + • live birth rate
normal weight populations only cohorts hMG and/or FSH in most, with 4
women (BMI <25) vs. (e.g., women with • 1 case‐control study • BMI: primary studies using CC + hMG and/or Safety: ‐ Safety: ‐
overweight and obese PCOS, oocyte assessment FSH in some patients and 1 study
women (BMI ≥25), or recipients…) Publication dates using hMG or FSH alone in some Secondary: Secondary:
2) normal and Intervention(s): (range): 2000 ‐ 2006 • other: unselected patients Effectiveness: Effectiveness: ‐
overweight women • IVF/ICSI • natural cycle patients in all studies • pregnancy rate
(BMI <30) vs. obese conception, OI, IUI Countries: Australia (3), • number of cycles: 1 or more • miscarriage rate
women (BMI ≥30) Comparator(s): Czech Republic (1), per couple; actual number not • cancellation rate
• independent effect of • parameters other France (2), Germany (1), specified in most studies • mean gonadotropin
Date of literature maternal overweight/obesity than BMI used to the Netherlands (1), stimulation dose
search: 1966 ‐ 2006 (BMI) measure Norway (2), the US (2) • donor or autologous oocytes: • mean number of
overweight/obesity autologous only in all studies oocytes retrieved
Meta‐analysis: yes (e.g., waist‐to‐hip Number of patients: ‐
ratio) • frozen or fresh embryos: fresh Safety: Safety: ‐
Sub‐group or Outcome(s): cycles only in all studies • OHSS rate
sensitivity analysis: • live birth, pregnancy,
no miscarriage, cancellation, • stage of embryo during
gonadotropin dose, number of transfer: cleavage only in 3
oocytes/embryos, OHSS studies, cleavage or blastocyst in
Design: 3 (not specified in others)
• all observational studies
Other:
• published • WHO BMI criteria
(range 1‐>3)
not used

unspecified in many
Maternal smoking (N = 1)
Waylen et al. Country: the UK Population(s): Number of studies: 21 • age: maternal upper • ovarian stimulation protocol: Effectiveness: Effectiveness: ‐
161
(2009) • women • 10 prospective age limit in 7 studies varies slightly across studies • fertilization rate
Comparison: women Intervention(s): cohorts (range 37‐40); only reporting a protocol: GnRHa + • clinical pregnancy rate
who are active • IVF/ICSI • IUI, spontaneous • 11 retrospective women 35‐39 hMG and/or FSH in most, with 5 • spontaneous
cigarette smokers vs. • GIFT/ZIFT conception cohorts included in 1 study studies using CC + hMG in all or miscarriage rate
non‐smokers Comparator(s): some patients, 1 study using • live birth rate
• effect of active maternal • passive smoking Publication dates • BMI: ‐ hMG alone, and 1 study using
Date of literature cigarette smoking at the time • history of smoking (range): 1986 ‐ 2007 LHRHa + hMG Safety: Safety: ‐
search: 1806/1980 ‐ of treatment without active • other: • ectopic pregnancy
May 2007 smoking Countries: Australia (2), • number of cycles: 1 cycle in 19 rate
Outcome(s): Austria (3), Canada (2), studies, 1 or more cycles in 2
Meta‐analysis: yes • live birth, pregnancy, Czech Republic (2), studies
miscarriage, fertilization, France (1), Italy (2),
177


Sub‐group or ectopic pregnancy Israel (1), the • donor or autologous oocytes:
sensitivity analysis: • per cycle data Netherlands (1), Spain autologous only in 20 studies,
yes (age and oocyte Design: (1), Sweden (1), the UK donor only in 1 study
donation) • cohort studies (1), the US (4)
• case‐control studies • frozen or fresh embryos: fresh
Other: Number of patients: cycles only in 1 study
• published • unpublished 14,870
studies (not specified in others)

(range 1‐>4)

Maternal factors suggested to be predictive of success (N = 1)
Van Country: the Population(s): Number of studies: 14 • age: maternal upper • ovarian stimulation protocol: Effectiveness: Effectiveness: ‐
Loendersloot Netherlands • subfertile women • studies including • 3 prospective cohorts age limit in 3 studies • clinical pregnancy rate
et al. undergoing fresh, autologous selected • 11 retrospective (38, 39, and 44); • number of cycles: 1 cycle in 7 • ongoing pregnancy
332
(2010) Comparison: IVF/ICSI populations cohorts predictor in 13 studies studies; 1 or more cycles in 7 rate
association between (subpopulations) studies Safety: ‐
factors pre‐identified only Publication dates • BMI: predictor in 1 Safety: ‐
as potential Intervention(s): (range): 1997 ‐ 2008 study • donor or autologous oocytes:
predictors of success • IVF/ICSI with ovarian autologous only in all studies
and pregnancy stimulation (gonadotropins) Countries: Austria (1), • other: indication for
protocol with down regulation Denmark (2), France (1), IVF is a predictor in 4 • frozen or fresh embryos: fresh
Date of literature Comparator(s): Hungary (1), the studies; type of cycles only in all studies
search: 1978 ‐ Aug • effect of pre‐identified Netherlands (3), subfertility is a
2009 predictive maternal factors Sweden (1), the UK (3), predictor in 3 studies; • stage of embryo during
(maternal age, parity, basal the US (1), multiple (1; duration of transfer: cleavage embryos only
Meta‐analysis: yes FSH, duration of subfertility, Australia and New subfertility is a in 5 studies, blastocyst embryos
(some outcomes) indication for subfertility, Zealand) predictor in 3 studies; only in 1 study (not specified in
number of oocytes retrieved, smoking is a predictor others)
Sub‐group or method of fertilization, Number of patients: in 2 studies; basal FSH
sensitivity analysis: number of embryos 47,043 is a predictor in 7 • number of embryos
no transferred, embryo quality) studies transferred: varies across studies
Outcome(s): (range 1‐9); predictor in 2
• pregnancy studies (number of oocytes
Design: ‐ retrieved is a predictor in 7
studies)
Other:
178


• ‐ • unconditional OR • quality of embryos transferred:
not reported and predictor in 3 studies
not enough data
reported to
calculate
unconditional OR
ART in comparison to spontaneous conception (N = 11)
Pandey et al. Country: the UK Population(s): Number of studies: 30 • age: ‐ • ovarian stimulation protocol: ‐ Effectiveness: ‐ Effectiveness: ‐
312
(2012) • singleton IVF/ICSI • 20 matched cohorts
Comparison: frozen pregnancies • 10 unmatched cohorts • BMI: ‐ • number of cycles: ‐ Safety: Safety:
ET vs. fresh ET Intervention(s): • preterm birth rate • low birth weight rate
• IVF/ICSI • GIFT Publication dates • other: ‐ • donor or autologous oocytes: ‐ • early preterm birth • very low birth weight
Date of literature Comparator(s): (range): 1994 ‐ 2011 rate rate
search: 1978 ‐ 2012 • spontaneous conception (SC) • no SC comparator • frozen or fresh embryos: ‐ • caesarean section rate • proportion of infants
• 2 different Countries: ‐ • antepartum small for gestational
Meta‐analysis: yes aspects of IVF/ICSI • stage of embryo during hemorrhage rate age
compared Number of patients: ‐ transfer: ‐ • hypertensive • congenital
Sub‐group or Outcome(s): complication rate abnormalities
sensitivity analysis: • obstetric or perinatal • no obstetric or • number of embryos • PPROM • perinatal mortality
yes (matched vs. outcomes perinatal outcomes transferred: ‐ • gestational diabetes rate
unmatched cohort) Design: • NICU admissions
• any observational study • case reports, case • quality of embryos transferred:
series ‐
Other:
• published • not possible to
differentiate
outcomes for
singletons and
twins
Wen et al. Country: China Population(s): Number of studies: 56 • age: ‐ • ovarian stimulation protocol: ‐ Effectiveness: ‐ Effectiveness: ‐
55
(2012) • children conceived by
Comparison: 1) IVF/ICSI Publication dates • BMI: ‐ • number of cycles: ‐ Safety: ‐ Safety:
IVF/ICSI vs. Intervention(s): (range): 1989 ‐ 2011 • birth defects
spontaneous • IVF/ICSI • other: 36 studies • donor or autologous oocytes: ‐
conception, or 2) IVF Comparator(s): Countries: ‐ controlled for
vs. ICSI • 1) spontaneous conception (SC potential confounding • frozen or fresh embryos: ‐
• 2) ICSI Number of patients: ‐ factors (e.g., maternal
Date of literature Outcome(s): age, parity, sex, • stage of embryo during
search: up to Sep • birth defects • no control group smoking, …) transfer: ‐
2011 • inappropriate
control group • number of embryos
Meta‐analysis: yes Design: transferred: ‐
• ‐ • case reports
179


Sub‐group or Other: • quality of embryos transferred:
sensitivity analysis: • English language • not published as ‐
no • risk ratio and 95%CI directly full report
stated or calculable from
reported study data
Rossi and Country: Italy Population(s): Number of studies: 13 • age: maternal age • ovarian stimulation protocol: ‐ Effectiveness: ‐ Effectiveness: ‐
Addario • twins delivered at >21 • singletons • 2 prospective cohorts controlled for in 5
303
(2011) Comparison: ART vs. gestational weeks or >500 • twins reduced to • 11 retrospective studies • number of cycles: ‐ Safety: ‐ Safety:
spontaneous grams conceived by ART singleton (in utero cohorts • preterm birth rate • normal birth weight
conception multifetal reduction) • BMI: ‐ • donor or autologous oocytes: ‐ • moderate preterm rate
Intervention(s): Publication dates birth rate • low birth weight rate
Date of literature • ART‡‡ (range): 2000 ‐ 2009 • other: parity • frozen or fresh embryos: ‐ • caesarean section rate • very low birth weight
search: Jan 2000 ‐ Comparator(s): controlled for in 5 (vaginal delivery rate) rate
Sep 2010 • spontaneous conception (SC) Countries: Australia (1), studies; 1 study did • stage of embryo during • NICU admission rate
Outcome(s): Austria (1), Belgium (2), not report which transfer: ‐ • perinatal death rate
Meta‐analysis: yes • neonatal outcomes • reported per Germany (1), Greece variables were taken • birth defect rate
• reported per twins, pregnancy (1), Hungary (1), Israel into account; • number of embryos
Sub‐group or proportional rates (1), Lebanon (1), the unselected patients in transferred: ‐
sensitivity analysis: Design: Netherlands (1), Turkey all studies (i.e., all
yes (unlike sex twins) • ‐ • letters, personal (1), the United Arab twin • quality of embryos transferred:
communications Emirates (1), the US (1) pregnancies/deliverie ‐
Other: s within a certain time
• ‐ • non‐English Number of patients: period at a particular
language 23,031 clinic or in a particular
• ART: 7,506 region)
• SC: 15,525
Wilson et al. Country: Australia Population(s): Number of studies: 17* • age: majority of • ovarian stimulation protocol: ‐ Effectiveness: ‐ Effectiveness: ‐
304
(2011) • individuals of adolescent or • individuals of • 14 retrospective children school‐aged
Comparison: ART vs. older age (mean sample age of younger age or cohorts (range across studies: • number of cycles: ‐ Safety: ‐ Safety:
spontaneous ≥12 years or mean follow‐up studies with a mean • 3 cross‐sectional 0‐24) • growth and
conception period of ≥12 years) conceived follow‐up of <12yrs studies • donor or autologous oocytes: metabolism
by ART *represent only 9 different • BMI: ‐ inclusion of donor oocytes • general physical
Date of literature Intervention(s): populations – 7 reported in 2 studies health
search: Jan 1998 ‐ publications on 1 • other: ‐ • childhood cancer
• ART (IVF, GIFT, ZIFT, tubal ET, • artificial
Netherlands cohort, 3
Oct 2010 gamete or embryo insemination • frozen or fresh embryos: ‐ • cognitive
publications on 1 UK
cryopreservation, oocyte or • ART exposure not cohort) development
Meta‐analysis: no embryo donation, gestational made explicit • stage of embryo during • psychological
surrogacy) Publication dates transfer: ‐ adjustment and socio‐
Sub‐group or Comparator(s): ‐ (range): 2001 ‐ 2010 emotional functioning
sensitivity analysis: • number of embryos • parent‐adolescent
no Outcome(s): Countries: Belgium (2), transferred: ‐ relationship
• physical health and Germany (1),
development, psychosocial Netherlands (7*), • quality of embryos transferred:
180


health and adjustment Sweden (1), the UK (3*), ‐
Design: the US (2), multiple (1‐
• ‐ • clinical case several European)
studies
Other: Number of patients: ‐
• published in peer‐reviewed
journal
McDonald et Country: Canada Population(s): Number of studies: 12 • age: maternal age • ovarian stimulation protocol: ‐ Primary: Primary:
305
al. (2010) (Ontario) • twins conceived by IVF/ICSI • multifetal or • all retrospective controlled for in all Effectiveness: ‐ Effectiveness: ‐
selective reduction
cohorts studies • number of cycles: ‐
Comparison: IVF/ICSI Intervention(s): Safety: Safety:
vs. spontaneous • IVF/ICSI Publication dates • BMI: ‐ • donor or autologous oocytes: ‐ • preterm birth rate • low birth weight rate
conception Comparator(s): (range): 1992 ‐ 2005
• spontaneous conception (SC) • other: unselected • frozen or fresh embryos: fresh Secondary: Secondary:
Date of literature Outcome(s): Countries: Australia (1), patients in most cycles only in 1 study; frozen Effectiveness: ‐ Effectiveness: ‐
search: 1978/1980 ‐ • preterm birth, low birth Belgium (1), Denmark studies (i.e., all twin cycles only in 1 study
Jun 2008 weight (1), Finland (2), pregnancies/deliverie Safety: Safety:
Design: Germany (1), Greece s within a certain time • stage of embryo during • moderate preterm • mean birth weight
Meta‐analysis: yes • cohort studies (1), Hungary (1), Israel period at a particular transfer: ‐ birth rate • very low birth weight
• case‐control studies (1), Lebanon (1), clinic or in a particular • mean duration of rate
Sub‐group or Other: Sweden (1), the UK (1) region) • number of embryos gestation • extremely low birth
sensitivity analysis: • English language • duplicate transferred: ‐ weight rate
yes (ICSI, frozen ET, • matching or adjustment for publications Number of patients: • intra uterine growth
and low quality at least maternal age 16,178 • quality of embryos transferred: restriction
studies) • : 4,385 ‐
• SC: 11,793
McDonald et Country: Canada Population(s): Number of studies: 17 • age: maternal age • ovarian stimulation protocol: ‐ Primary: Primary:
306
al. (2009) (Ontario) • singletons conceived by • multifetal or • all retrospective controlled for in all Effectiveness: ‐ Effectiveness: ‐
IVF/ICSI selective reduction cohorts studies • number of cycles: ‐
Comparison: IVF/ICSI Intervention(s): Safety: Safety:
vs. spontaneous • IVF/ICSI Publication dates • BMI: ‐ • donor or autologous oocytes: ‐ • preterm birth rate • low birth weight rate
conception Comparator(s): (range): 1990 ‐ 2007
• spontaneous conception (SC) • other: unselected • frozen or fresh embryos: fresh Secondary: Secondary:
Date of literature Outcome(s): Countries: Belgium (2), patients in most cycles only in 2 studies; frozen Effectiveness: ‐ Effectiveness: ‐
search: 1978/1980 ‐ • preterm birth, low birth Denmark (1), Finland (3), studies (i.e., all cycles only in 1 study
Jun 2008 weight Hungary (1), Israel (2), singleton Safety: Safety:
Design: the Netherlands (1), pregnancies/deliverie • stage of embryo during • moderate preterm • mean birth weight
Meta‐analysis: yes • cohort studies Sweden (2), the UK (1), s within a certain time transfer: ‐ birth rate • very low birth weight
• case‐control studies the US (4) period at a particular • mean duration of rate
Sub‐group or Other: clinic or in a particular • number of embryos gestation • extremely low birth
sensitivity analysis: • English language • duplicate Number of patients: region) transferred: ‐ weight rate
yes (ICSI, frozen ET, • matching or adjustment for publications 112,151 • intra uterine growth
181


and low quality at least maternal age • reviews, • : 31,032 • quality of embryos transferred: restriction
studies) editorials, letters, • SC: 81,119 ‐
case reports
• studies published
only as abstracts
Hvidtjørn et Country: Denmark, Population(s): Number of studies: 41* • age: ‐ • ovarian stimulation protocol: ‐ Effectiveness: ‐ Effectiveness: ‐
307
al. (2009) Norway, Sweden, the • children conceived by ART • 3 prospective cohorts
US Intervention(s): • 36 retrospective • BMI: ‐ • number of cycles: ‐ Safety: ‐ Safety:
• ART (IVF/ICSI, intrauterine cohorts • cerebral palsy rate
Comparison: ART vs. insemination (IUI), ovulation • 2 case‐control studies • other: unselected • donor or autologous oocytes: ‐ • autism spectrum
spontaneous induction (OI)) *11 on CP and/or ASD patients in most disorder rate
conception Comparator(s): studies (i.e., all • frozen or fresh embryos: ‐ • motor development
• spontaneous conception (SC) Publication dates children conceived by • behavioral
Date of literature Outcome(s): (range): CP/ASD: 2002 ‐ an ART within a • stage of embryo during development
search: Jan 1996 ‐ • cerebral palsy (CP), autism 2008 certain time period at transfer: ‐ • cognitive
Apr 2008 spectrum disorder (ASD), a particular clinic or in development
developmental delay (DD) Countries: a particular region) • number of embryos • mental development
Meta‐analysis: yes Design: ‐ CP/ASD: Croatia (1), transferred: ‐
Denmark (5), Finland
Sub‐group or Other: (1), Israel (1), Sweden • quality of embryos transferred:
sensitivity analysis: • original data (3) ‐
yes (singles vs. • follow‐up period ≥1 year
multiples) Number of patients: ‐
Vitthala et al. Country: the UK Population(s): Number of studies: 27 • age: ‐ • ovarian stimulation protocol: ‐ Effectiveness: ‐ Effectiveness: ‐
308
(2009) • women undergoing ART • 2 prospective cohorts
Comparison: ART (no Intervention(s): • 21 retrospective • BMI: ‐ • number of cycles: ‐ Safety: ‐ Safety:
comparator) • ART§§ cohorts • monozygotic twinning
Comparator(s): ‐ • 4 cross‐sectional • other: ‐ • donor or autologous oocytes: ‐ rate
Date of literature studies (population
search: 1966/1974 ‐ Outcome(s): surveys) • frozen or fresh embryos: frozen
Jul 2007 • monozygotic twinning (MZT) • MZT not reported cycles only in 3 studies
as a proportion of total as a proportion of Publication dates
Meta‐analysis: yes number of pregnancies either total clinical (range): 1993 ‐ 2007 • stage of embryo during
pregnancies or live transfer: blastocyst embryos only
Sub‐group or births Countries: Belgium (1), in 9 studies
sensitivity analysis: • MZT reported as a Brazil (1), Denmark (1),
yes (by diagnostic proportion of Greece (1), Israel (4), • number of embryos
methods and type of multiple Japan (1), the transferred: varies across studies
ART) pregnancies Netherlands (1), Norway (range 1‐>4)
Design: ‐ (1), Poland (2), the UK
(2), the US (12) • quality of embryos transferred:
Other: ‐
• ‐ • method of Number of patients:
182


diagnosis or 87,932
confirmation of
zygosity after live
birth not reported
Bertelsmann Country: Germany Population(s): Number of studies: 27* • age: ‐ • ovarian stimulation protocol: ‐ Effectiveness: ‐ Effectiveness: ‐
et al. • children conceived by ICSI malformations: 15
309
(2008) Comparison: ICSI vs. Intervention(s): • 4 prospective cohorts • BMI: ‐ • number of cycles: ‐ Safety: ‐ Safety:
1) IVF, or 2) • ICSI • 6 retrospective • malformations
spontaneous Comparator(s): cohorts • other: unselected • donor or autologous oocytes: ‐ • imprinting disorders
conception • IVF • 2 cohorts with 1 patients in most
• spontaneous conception (SC) prospective and 1 studies (i.e., all • frozen or fresh embryos: ‐
Date of literature Outcome(s): retrospective arm children conceived by
search: up to May • malformations, imprinting • 3 registry reports an ART within a • stage of embryo during
2006 defects * plus 3 meta‐analyses certain time period at transfer: ‐
Design: imprinting defects: 12 a particular clinic or in
Meta‐analysis: no • cohort studies • retrospective cohorts, a particular region) • number of embryos
• case‐control studies case‐control studies, transferred: ‐
Sub‐group or Other: case series and case
sensitivity analysis: • odds ratio for major • studies published reports • quality of embryos transferred:
no malformations directly stated before Jan 1998 ‐
or calculable from reported Publication dates
study data (range): malformations:
1998 – 2005, imprinting
defects: 2000 ‐ 2005

Countries:
malformations: Australia
(3), Belgium (2),
Denmark (2), Germany
(2), Japan (1), Spain (1),
the US (2), multiple (2‐
several European and
the US)

Middelburg Country: the Population(s): Number of studies: 23 • age: maternal age • ovarian stimulation protocol: ‐ Effectiveness: ‐ Effectiveness: ‐
et al. Netherlands • children conceived by • >10% of children • 8 prospective cohorts controlled for in 7
310
(2008) autologous IVF/ICSI born following OI • 6 retrospective registry reports; lower • number of cycles: ‐ Safety: ‐ Safety:
Comparison: IVF/ICSI only cohorts infant age limit (1.5‐2) • cerebral palsy
vs. spontaneous • donor gametes • 9 registry reports in 3 registry reports • donor or autologous oocytes: • epilepsy or
conception • adopted children (range across studies: autologous only in all studies convulsions
• surrogate Publication dates 0‐20) • mental retardation
Date of literature mothers (range): 1989 ‐ 2007 • frozen or fresh embryos: frozen • neuromotor
183


search: 1978/1989 ‐ Intervention(s): • BMI: ‐ included in 2 registry reports development
Dec 2007 • IVF/ICSI Countries: ‐ • behavioral
Comparator(s): • other: several other • stage of embryo during development
Meta‐analysis: no • spontaneous conception (SC) • no SC control Number of patients: ‐ factors controlled for: transfer: ‐ • cognitive
Outcome(s): ‐parity (5), plurality development •
Sub‐group or • neurodevelopmental (7), smoking (3), • number of embryos speech/language
sensitivity analysis: no outcome socioeconomic status transferred: ‐ development
Design: ‐ (3), duration of
infertility (1) and • quality of embryos transferred:
Other: infant‐preterm birth ‐
• good external validity • sample size < 25 (6), birth weight (3),
• follow‐up not birth defects (1)
beyond neonatal
period
• non‐English
language
Farhi and Country: Israel Population(s): Number of studies: ‐ • age: ‐ • ovarian stimulation protocol: ‐ Effectiveness: ‐ Effectiveness: ‐
Fisch • children born to infertile
311
(2007) Comparison: ART vs. population Publication dates • BMI: ‐ • number of cycles: ‐ Safety: ‐ Safety:
spontaneous Intervention(s): (range): ‐ • congenital
conception, or ART • ART (ovarian stimulation, • other: ‐ • donor or autologous oocytes: ‐ malformations
(no comparator) intrauterine insemination (IUI), Countries: ‐ • birth defects
artificial donor insemination, • frozen or fresh embryos: ‐ • imprinting disorders
Date of literature IVF/ICSI) Number of patients: ‐
search: 1985 ‐ 2006 Comparator(s): • stage of embryo during
• spontaneous conception (SC) transfer: ‐
Meta‐analysis: no • none
Outcome(s): • number of embryos
Sub‐group or • major congenital transferred: ‐
sensitivity analysis: malformations
no Design: ‐ • quality of embryos transferred:
‐
Other: ‐

Patient preferences (N = 1)
Leese & Country: the UK Population(s): Number of studies: 20 • age: ‐ • ovarian stimulation protocol: ‐ Effectiveness: Effectiveness: ‐
Denton • women undergoing IVF and • 9 interview studies • couples’ views of SET
185
(2007) Comparison: couples’ their partners' • 11 questionnaire • BMI: ‐ • number of cycles: ‐
views of SET (no Intervention(s): studies Safety: ‐ Safety: ‐
comparator) • SET • other: unselected • donor or autologous oocytes:
Comparator(s): ‐ Publication dates patients in 4 studies donor
Date of literature (range): 1990‐2008 (i.e., all patients
search: up to 2009 Outcome(s): entering a particular • frozen or fresh embryos: ‐
184


• views on SET Countries: Belgium (2), clinic within a certain
Meta‐analysis: no Design: ‐ Canada (2), Denmark time period) • stage of embryo during
(2), the Netherlands (2), transfer: ‐
Sub‐group or Other: ‐ Sweden (1), the UK (4),
sensitivity analysis: the US (7) • number of embryos
no transferred: ‐
‐

List of abbreviations used in table (alphabetical order): ART = artificial reproductive technologies; BMI = body mass index; CC = clomiphene citrate; COS = controlled ovarian stimulation; DET = double embryo transfer; ET =
embryo transfer; EM = expectant management; eSET = elective single embryo transfer; FET = frozen embryo transfer; FSH = follicle‐stimulating hormone; GIFT = Gamete intrafallopian transfer; GnRHa =
Gonadotropinreleasing hormone agonist; hMG = human menopausal gonadotropin; ICSI = intracytoplasmic sperm injection (ICSI); IVF = in vitro fertilization; IUI = intrauterine insemination; LH = luteinizing hormone; LHRHa =
luteinizing hormone‐releasing hormone agonist; MET = multiple embryo transfer; MZT = monozygotic twinning; NICU = neonatal intensive care unit; nIUI = natural cycle IUI; OHSS = ovarian hyperstimulation syndrome; OI =
ovulation induction; OR = odds ratio; QET = four embryo transfer; RCT = randomized controlled trial; SC = spontaneous conception; SET = single embryo transfer; sIUI = stimulated IUI; TET = three embryo transfer; ZIFT =
Zygote intrafallopian transfer

† Baseline rates calculated after initial embryo transfer; cumulative rates calculated after both fresh and frozen transfers from a single oocyte retrieval
‡ Baseline rates calculated after a single treatment cycle; cumulative rates calculated after all cycles
§ Both Blake et al. (2007) and Johnson, Blake, and Farquhar (2007) are updates of a systematic review published in 2005 with Blake et al. (2007) providing the most recent update; for Johnson, Blake, and Farquhar (2007), only
additional data on monozygotic twinning, that was not provided in Blake et al. (2007), is reported
¶ ART included IVF/ICSI (9 studies) and IVF or GIFT/ZIFT (1 study‐62% IVF); results not separated by treatment type
†† Update of review by Maheshwari et al. (2007); results are presented for both reviews as the update by Koning et al. (2012) did not include several of the earlier studies included in the review by Maheshwari et al.
‡‡ ART included IVF/ICSI (6 studies), controlled ovarian stimulation (COS) (1 study), COS and IVF (2 studies), GIFT and IVF (1 study), and was not specified in 3 studies; results not separated by treatment type
§§ ART included IVF/ICSI (25 studies) and ovulation induction (OI) (2 studies); sub‐group analysis by treatment type

185


Appendix C – Evidence tables: Quality of included studies

Table 26. Quality of included studies using Oxman & Guyatt index of scientific quality scoring system for systematic reviews
Search Bias in study Criteria used to Validity assessed Methods used to Findings Conclusions

Search methods Inclusion criteria Scientific quality
Review reasonably selection assess validity using appropriate combine findings combined supported by
stated: reported: rating*:
comprehensive: avoided: reported: criteria: reported: appropriately: data:
IVF/ICSI in comparison to non‐invasive ART treatment options (N = 2)
Pandian,
Gibreel, and
Yes Yes Yes Yes Yes Yes Yes Yes Yes 7
Bhattacharya
89
(2011)
Thomopoulos
314 Yes Yes Partially Yes No Can’t tell N/A N/A Yes 3
et al. (2012)
Number of embryos transferred (N = 5)
Grady et al.
313 Yes Yes Yes Yes Yes Yes Yes Yes Yes 7
(2012)
McLernon et
al. (2010)
Gelbaya et al.
(2010)
Baruffi et al.
316 Yes Yes Yes Yes Partially Can’t tell Yes Yes Yes 4
(2009)
Pandian et al.
(2009)
Fresh embryo transfer in comparison to frozen embryo transfer (N = 5)
Roque et al.
(2012)
Maheshwari
et al. (2012)
Jee, Suh, and
318 Yes Yes Yes Yes No Can’t tell Yes Yes Yes 4
Kim (2009)
Wennerholm et
320 Yes Yes Yes Yes No Can’t tell N/A N/A Yes 4
al. (2009)
D’Angelo and
Amso (2007)
Stage of embryo during transfer (N = 4)
Chang et al.
322 Yes Yes Yes No No Can’t tell Yes Yes Yes 3
(2009)
186


Papanikolaou
323 Yes Yes Yes Yes Partially Yes Yes Yes Yes 6
et al. (2008)
Glujovsky et al.
(2012)
Johnson, Blake,
and Farquhar Yes Yes Yes Yes Yes Yes Yes Yes Yes 7
326
(2007)
Embryo donation (N = 1)
Van der Hoorn
327 Yes Yes Partially Yes No Can’t tell N/A N/A Yes 3
et al. (2010)
Maternal or paternal age (N = 2)
Watt et al.
302 Yes Yes Yes Yes Yes Yes N/A N/A Yes 7
(2011)
Dain,
Auslander, and
Yes Yes Yes Yes No Can’t tell N/A N/A Yes 4
Dirnfeld
328
(2011)
Maternal weight/BMI (N = 4)
Koning et al.
(2012)
Rittenberg et
al. (2011)
Metwally et al.
(2008)
Maheshwari et
al. (2007)
Maternal smoking (N = 1)
Waylen et al.
(2009)
Maternal factors suggested to be predictive of success (N = 1)
Van
Loendersloot et Yes Yes Yes Yes Yes Yes Yes Yes Yes 7
332
al. (2010)
ART in comparison to spontaneous conception (N = 10)
Pandey et al.
(2012)
Wen et al.
(2012)
Rossi and
Addario Yes Yes Yes Yes No Can’t tell Yes Yes Yes 4
303
(2011)
187


Wilson et al.
(2011)
McDonald et al.
(2010)
McDonald et al.
(2009)
Hvidtjørn et al.
(2009)
Vitthala et al.
308 Yes Yes Yes Yes Yes Can’t tell Yes Yes Yes 5
(2009)
Bertelsmann et
al. (2008)
Middelburg et
310 Yes Yes Yes Yes Yes Yes N/A N/A Yes 7
al. (2008)
Farhi and Fisch
(2007)
Patient preferences (N = 1)
Leese &
Denton Yes Yes Partially Yes No Can’t tell Yes Yes Yes 3
185
(2007)

*Scientific quality rating124:
‐ >1 “can’t tell” = review likely to have minor flaws at best, difficult to rule out major flaws = score 4 or lower
‐ “no” on Qs 2, 4, 6, or 8 = review is likely to have major flaws = score of 3 or less depending on number and degree of flaws
‐ extensive flaws: score 1‐3, minor flaws: score 4‐7 (if major 4‐5, if minimal 6‐7)

188


Appendix D –Evidence tables:Safety

Table 27. Safety during pregnancy & delivery
Review Study Groups Event Rate n/N (%), Odds Ratio (95%CI)*, and p‐value

OHSS Ectopic Gestational PIH or Placenta praevia Placental Preterm Early preterm Caesarean Other
pregnancy diabetes preeclampsia abruption delivery/birth delivery/birth section delivery
IVF/ICSI in comparison to non‐invasive ART treatment options
Pandian, Number of studies 1
Gibreel, and sIUI (≤6 cycles) (ref.) 2/59 (3.4%)
Bhattacharya IVF (≤6 cycles) 3/59 (5.1%)
89
(2011) OR (95% CI) 1.53 (0.25, 9.49)

p‐value 0.65
Grady et al. Number of studies 3 (RCTs) 1 (RCT) 1 (RCT) 4 (RCTs) 2 (RCTs) 1 (RCT)†
313
(2012) eSET 1/165 (0.6%) 1/128 (0.8%) 9/128 (7.0%) 27/388 (7.0%) 7/334 (2.1%) 1/128 (0.8%)
DET (ref.) 5/232 (2.2%) 5/142 (3.5%) 11/142 (7.7%) 96/446 (21.5%) 18/388 (4.6%) 12/142 (8.5%)
RR (95% CI) 0.42 (0.09,2.01) nr nr 0.37 (0.25,0.55) 0.53 (0.17,1.60) nr

p‐value nr nr nr <0.00001 nr nr
Number of studies 3 (cohorts) 1 (cohort) 1 (cohort) 1 (cohort) 1 (cohort) 3 (cohorts) 1 (cohort)
eSET 8/261 (3.1%) 28/269 (10.4%) 6/269 (2.2%) 7/269 (2.6%) 0/269 (0) 46/351 (13.1%) 11/56 (19.6%)
DET (ref.) 15/534 (2.8%) 17/230 (7.4%) 8/230 (3.5%) 6/230 (2.6%) 5/230 (2.2%) 44/325 (13.5%) 11/45 (24.4%)
RR (95% CI) 1.07 (0.45,2.51) 1.69 (1.19, 2.42) nr nr nr 0.99 (0.43,2.29) nr

p‐value nr nr nr nr nr 0.03 nr
McLernon et Number of studies nr nr nr§
96
al. (2010) ‡ eSET 23/181 (12.7%) 1/181 (0.6%) 6/181 (3.3%)
DET (ref.) 85/284 (29.9%) 16/284 (5.6%) 29/284 (10.2%)
0.08
OR (95% CI) 0.33 (0.20,0.55)¶ 0.30 (0.12,0.75)††
(0.01,0.65)**
p‐value nr nr
nr
Gelbaya et al. Number of studies 3 2
315
(2010) eSET 1/458 (0.2%) 3/36 (8.3%)
DET (ref.) 4/454 (0.9%) 11/47 (23.4%)
RR (95% CI) 0.39 (0.08,1.99) 0.36 (0.11,1.18)

p‐value 0.26 0.09
Fresh embryo transfer in comparison to frozen embryo transfer
Maheshwari Number of studies 2 2 9 4 5 2‡‡
189


et al. 2905/27686 4835/16740
(2012)
321 Fresh ET (ref.) nr nr nr 358/7000 (5.1%)
(10.5%) (28.9%)
941/10017 1910/5435
Frozen ET nr nr nr 124/3875 (3.2%)
(9.4%) (35.1%)
RR (95% CI) 0.71 (0.53‐0.95) 0.44 (0.24, 0.83) 0.84 (0.78, 0.90) 0.73 (0.50, 1.08) 1.10 (1.05, 1.15) 0.67 (0.55, 0.81)

p‐value nr nr <0.00001 nr <0.0001 <0.0001
Jee, Suh, and Number of studies 7
318
Kim (2009) 162/10934
Fresh ET (ref.)
(1.5%)
Frozen ET 49/2125 (2.3%)
OR (95% CI) 1.66 (0.62,4.41)

p‐value 0.31
• SGA: Number of studies 3
studies with Fresh ET (ref.) 81/2813 (2.9%)
cleavage Frozen ET 29/1244 (2.3%)
stage OR (95% CI) 0.83 (0.20,3.49)
embryos only
p‐value 0.80
cleavage and Frozen ET 15/701 (2.1%)
blastocyst OR (95% CI) 3.47 (0.51,23.63)
embryos
p‐value 0.20
blastocyst Frozen ET 5/180 (2.8%)
stage OR (95% CI) 1.58 (0.53,4.69)
embryos only
p‐value 0.41
D’Angelo and Number of studies 1 1§§
Amso Fresh ET (ref.) 4/67 (6.0%) 4/67 (6.0%)
319
(2007) Frozen ET 0/58 (0) 0/58 (0)
OR (95% CI) 0.12 (0.01, 2.29) 0.12 (0.01, 2.29)

p‐value 0.16 0.16
Maternal weight/BMI
Koning et al
Number of studies 4 5
329
(2012) BMI ≤25 (ref.) 149/1975 (7.5%) 50/1660 (3.0%)
BMI >25 109/1469 (7.4%) 21/760 (2.8%)
OR (95% CI) 1.00 (0.77,1.29) 0.96 (0.54, 1.70)

p‐value 0.99 0.89
Maheshwari Number of studies 4
et al. BMI <25 (ref.) 50/916 (5.5%)
190


331
(2007) BMI ≥25 53/868 (6.1%)
OR (95% CI) 1.12 (0.74,1.68)

p‐value 0.60
Number of studies 4
BMI <30 (ref.) 68/1363 (5.0%)
BMI ≥30 20/369 (5.4%)
OR (95% CI) 1.16 (0.69, 1.96)

p‐value 0.58
Maternal smoking
Waylen et al. Number of studies 3
161
(2009) Non‐smokers (ref.) nr
Smokers nr
15.69 (2.87,
OR (95% CI)
85.76)
p‐value
nr
studies Non‐smokers (ref.) nr
where age Smokers nr
not likely to 14.70 (1.53,
be a OR (95% CI)
141.15)
confounder p‐value
nr
ART in comparison to spontaneous conception
Grady et al. Number of studies 1 1 1 1 1 2 2
313
(2012) eSET 27/269 (10.0%) 28/269 (10.4%) 6/269 (2.2%) 7/269 (2.6%) 0/269 (0) 58/520 (11.2%) 5/520 (1.0%)
236/15037 924/15037 246/15037 576/74572
SC (ref.) 65/15037 (0.4%) 59/15037 (0.4%) 4335/74572 (5.8%
(1.6%) (6.1%) (1.6%) (0.8%)
RR (95% CI) 6.40 (4.38,9.35) 1.69 (1.19,2.42) 1.36 (0.61,3.04) 6.02 (2.79,13.01) 0.47 (0.03,7.55) 2.13 (1.26,3.61) 1.31 (0.54,3.15)

p‐value nr nr nr nr nr 0.005 nr
Pandey et al. Number of studies 6 15 13‡‡ 22 11 17 7†
312
(2012) 982/16923 879/20807 2204/27819
IVF/ICSI singletons nr nr nr nr
(5.8%) (4.2%) (7.9%)
17305/589391 4913/608731 31260/614400
SC singletons (ref.) nr nr nr nr
(2.9%) (0.8%) (5.1%)
RR (95% CI) 1.48 (1.33, 1.66) 1.49 (1.39, 1.59) 2.49 (2.30, 2.69) 1.54 (1.47, 1.62) 1.68 (1.48, 1.91) 1.56 (1.01, 1.60) 1.16 (1.07, 1.26)

p‐value nr <0.00001 <0.00001 <0.00001 nr nr nr
Rossi and Number of studies 5 (C) 4 (C) 3 (C)§
Addario ART 2576/4664 (55.2% 371/610 (60.8%) 351/4322 (8.1%)
303
(2011) *** SC (ref.) 3095/5837 (53.0% 365/722 (50.5%) 439/5495 (8.0%)
OR (95% CI) 1.30 (1.03, 1.65) 1.70 (1.35, 2.14) 1.11 (0.78, 1.59)

p‐value 0.03 <0.0001 0.56
191


Number of studies 6 (NC) 6 (NC) 4 (NC)§
ART 1789/2457 (70.2% 1186/1650 (71.8% 552/2356 (23.4%)
SC (ref.) 5598/9244 (60.5% 2895/5838 (49.6% 1607/8747 (18.4%)
OR (95% CI) 1.08 (0.76, 1.55) 2.34 (1.55, 3.54) 1.12 (0.80, 1.57)

p‐value 0.66 <0.0001 0.52
• SGA: Number of studies 3 (NC) 3 (NC)§
unlike sex ART 1459/2490 (58.6% 268/2490 (10.8%)
twins SC (ref.) 1717/3467 (49.5% 285/3467 (8.2%)
OR (95% CI) 1.51 (1.25, 1.83) 1.37 (0.94, 2.00)

p‐value <0.0001 0.10
McDonald et Number of studies 11 5§
al. IVF/ICSI twins nr nr
305
(2010) ††† SC twins (ref.) nr nr
OR (95% CI) 1.23 (1.09, 1.41) 1.63 (1.17, 2.27)

p‐value 0.003 nr
• SGA: IVF Number of studies 6
alone IVF twins nr
SC twins (ref.) nr
OR (95% CI) 2.17 (1.39, 3.38)

p‐value nr
IVF+ICSI ICSI twins nr
SC twins (ref.) nr
OR (95% CI) 1.25 (0.93, 1.68)

p‐value nr
• SGA: fresh Number of studies 1
embryos only IVF/ICSI twins nr
SC twins (ref.) nr
OR (95% CI) 1.00 (0.58, 1.73)

p‐value nr
• SGA: frozen Number of studies 1
SC twins (ref.) nr
OR (95% CI) 1.85 (0.81, 4.23)

p‐value nr
McDonald et Number of studies 15 5§
al. IVF/ICSI singletons nr nr
306
(2009) ††† SC singletons (ref.) nr nr
OR (95% CI) 1.84 (1.54, 2.21) 2.27 (1.73, 2.97)

p‐value <0.00001 nr
192


alone IVF singletons nr
SC singletons (ref.) nr
OR (95% CI) 2.14 (1.58, 2.89)

p‐value nr
IVF+ICSI ICSI singletons nr
OR (95% CI) 1.87 (1.34, 2.62)

p‐value nr
embryos only IVF/ICSI singletons nr
OR (95% CI) 2.23 (1.27, 3.93)

p‐value nr
OR (95% CI) 1.00 (0.39, 2.59)

p‐value nr
193



313 321 315 312
* Risk ratio in Grady et al. (2012) , Maheshwari et al. (2012) , Gelbaya et al. (2010) , and Pandey et al. (2012)
† Preterm prolonged rupture of membranes rate
‡ Meta‐analysis of individual patient data
§ Moderate preterm birth rate
¶ Adjusted OR; no significant covariates found
** Adjusted for significant covariates (maternal BMI and duration of infertility)
†† Adjusted for significant covariates (maternal age)
‡‡ Antepartum hemorrhage (placenta praevia and placental abruption)
§§ Hospital admission rate
*** “Controlled” studies (C) are those that controlled for basic maternal characteristics, such as age, and “non‐controlled” (NC) studies are those that did not control for potential confounding factors
††† Combined OR obtained by pooling adjusted ORs (studies matched or adjusted for at least age, and often other factors such as parity and smoking)

Abbreviations:
ART = assisted reproductive technology; CI = confidence interval; DET = double embryo transfer; eSET = elective single embryo transfer; ICSI = intracytoplasmic sperm injection; IVF = in vitro fertilization; OHSS = ovarian
hyperstimulation syndrome; OR = odds ratio; MZT = monozygotic twinning; NICU = neonatal intensive care unit; nr = not reported; PIH = pregnancy‐induced hypertension; PPROM = preterm prolonged rupture of membranes;
RCT = randomized controlled trial; SC = spontaneous conception; SET = single embryo transfer; SGA = sub‐group analysis; sIUI = stimulated IUI (with clomiphene citrate or Gonadotropins)

Definitions:
• Ectopic pregnancy: diagnosed in most studies by ultrasound visualization of gestational sac in fallopian tube; ectopic pregnancy rates reported per pregnancy in Grady et al. (2012), Jee et al. (2009) and Waylen et al. (2009), and
per woman/couple in Gelbaya et al. (2010) and Koning et al. (2010)
• Gestational diabetes = high blood sugar diagnosed during pregnancy
• Pregnancy‐induced hypertension (PIH) = high blood pressure during pregnancy
nd rd
• Preeclampsia = development of high blood pressure and protein in the urine during the 2 ‐3 trimesters of pregnancy
nd rd
• Placenta praevia = implantation of the placenta over or near the cervix during the 2 ‐3 trimesters of pregnancy
• Gestation: term birth/delivery = birth/delivery at >37 weeks; preterm birth/delivery (PTB or PTD) = birth or delivery at <37 weeks gestation; moderate preterm birth/delivery = birth or delivery at <34 weeks gestation (<33 in
313 96
McDonald et al.), early or very preterm birth/delivery = birth or delivery at <32 weeks gestation; preterm birth rates reported per pregnancy in Grady et al. (2012) , and per delivery or live birth in McLernon et al. (2010) ,
315
Gelbaya et al. (2010) , Rossi and Addario (2011), and McDonald et al. (2009; 2010)

194

195

Table 28. Neonatal/infant safety

Monozygotic Low birth Very low birth Extremely low Neonatal Perinatal NICU admission Birth defects Congenital Other
twinning weight weight birth weight mortality mortality malformations
Grady et al. Number of studies 3 (RCTs) 1 (RCT) 1 (RCT) 2 (RCTs) 1 (RCT) 1 (RCT)†
313
(2012) eSET 13/183 (7.1%) 5/129 (3.9%) 0/129 (0%) 1/141 (0.7%) 4/129 (3.1%) 4/129 (3.1%)
DET (ref.) 72/247 (29.1%) 14/189 (7.4%) 2/189 (1.1%) 2/199 (1.0%) 9/189 (4.8%) 8/189 (4.2%)
RR (95% CI) 0.25 (0.15, 0.45) nr nr 0.74 (0.09, 5.94) nr 0.73 (0.23, 2.38)

p‐value <0.00001 nr nr nr nr nr
Number of studies 3 (cohorts) 2 (cohorts) 3 (cohorts) 2 (cohorts) 3 (cohorts) 1 (cohort)‡
eSET 17/351 (4.8%) 3/295 (1.0%) 0/387 (0%) 4/295 (1.4%) 11/351 (3.1%) 10/269 (3.7%)
DET (ref.) 31/325 (9.5%) 3/280 (1.1%) 6/484 (1.2%) 3/280 (1.1%) 17/325 (5.2%) 10/230 (4.3%)
RR (95% CI) 0.51 (0.29, 0.91) 1.08 (0.23, 5.10) 0.23 (0.03, 2.00) 1.31 (0.28, 6.21) 0.59 (0.28, 1.24) 0.86 (0.36, 2.02)

p‐value 0.02 nr nr nr nr nr
McLernon et Number of studies nr
96
al. (2010) § eSET 14/181 (8%)
DET (ref.) 69/284 (24%)
0.36 (0.15,
OR (95% CI)
0.87)¶
p‐value
nr
Maheshwari Number of studies 8 4 6 4 3 2‡
et al. 2146/258000 151/17424
321 Fresh ET (ref.) nr nr nr 115/3141 (3.7%)
(2012) (8.3%) (0.9%)
Frozen ET 494/8536 (5.8%) nr 42/5546 (0.8%) nr nr 31/1933 (1.6%)
RR (95% CI) 0.69 (0.62, 0.76) 0.72 (0.50, 1.04) 0.68 (0.48, 0.96) 1.00 (0.92, 1.08) 1.05 (0.81, 1.35) 0.45 (0.30, 0.66)

p‐value <0.00001 nr 0.03 nr nr <0.0001
Chang et al. Number of studies 9
322
(2009) 130/31601
Cleavage ET (ref.)
(0.4%)
Blastocyst ET 153/9316 (1.6%)
OR (95% CI) 3.04 (1.54, 6.01)

p‐value 0.001
studies 118/30995
Cleavage ET (ref.)
published (0.4%)
before 2002 Blastocyst ET 144/8858 (0.6%)
OR (95% CI) 4.05 (3.16, 5.18)

p‐value <0.00001
196


studies Cleavage ET (ref.) 12/606 (2.0%)
published Blastocyst ET 9/458 (2.0%)
after 2002 OR (95% CI) 1.00 (0.43, 2.32)

p‐value 1.00
Grady et al. Number of studies 2 2 1 1 1‡
313
(2012) eSET infants 27/520 (5.2%) 5/520 (1.0%) 0/269 (0%) 8/269 (3.0%) 10/269 (3.7%)
3396/74572 552/74572 227/15037
SC infants (ref.) 21/15037 (0.1%) 315/15037 (2.1%)
(4.6%) (0.7%) (1.5%)
RR (95% CI) 1.46 (0.91, 2.33) 1.50 (0.62, 3.62) 1.30 (0.08, 21.33) 1.97 (0.98, 3.95) 1.78 (0.96, 3.30)

p‐value 0.11 nr nr nr Nr
Pandey et al. Number of studies 19 14 8 5 7 7‡
312
(2012) IVF/ICSI singletons nr nr 97/14054 (0.7%) nr 162/4382 (3.7%) 487/13207 (3.7%)
1433/580514 14037/580810
SC singletons (ref.) nr nr nr 141/5324 (2.6%)
(0.2%) (2.4%)
RR (95% CI) 1.65 (1.56, 1.75) 1.93 (1.72, 2.17) 1.87 (1.48, 2.37) 1.58 (1.42, 1.77) 1.67 (1.33, 2.09) 1.39 (1.27, 1.52)

p‐value nr nr <0.00001 nr nr <0.00001
Wen et al. Number of studies 46
55
(2012) ** IVF/ICSI infants nr
SC infants (ref.) nr
OR (95% CI) 1.37 (1.26, 1.48)

p‐value 0.000
alone IVF infants nr
OR (95% CI) 1.30 (1.17, 1.46)

p‐value 0.055
IVF+ICSI ICSI infants nr
OR (95% CI) 1.58 (1.27, 1.95)

p‐value 0.001
Rossi and Number of studies 3 (C) 3 (C) 6 (C) 5 (C) 4 (C)
Addario ART twins 2129/4366 (48.8% 397/4366 (9.1%) 147/4820 (3.0%) 3023/4628 (65.0% 53/1556 (3.4%)
303
(2011) †† SC twins (ref.) 2631/5427 (48.5% 480/5427 (8.8%) 148/5993 (2.5%) 3829/5801 (66.0% 83/2729 (3.0%)
OR (95% CI) 1.02 (0.94, 1.11)
1.05 (0.83, 1.33) 1.27 (1.00, 1.60) 0.99 (0.83, 1.18) 1.15 (0.80, 1.63)

p‐value 0.58 0.67 0.05 0.91 0.45
Number of studies 4 (NC) 4 (NC) 6 (NC) 5 (NC) 5 (NC)
173/1459
ART twins 702/1459 (48.1%) 103/2379 (4.3%) 220/950 (23.1%) 137/2426 (5.6%)
(11.8%)
197


554/5341
SC twins (ref.) 2219/5341 (41.5% 347/9025 (3.8%) 378/1741 (21.7%) 307/9138 (3.3%)
(10.4%)
OR (95% CI) 1.10 (0.77, 1.59) 1.18 (0.72, 1.95) 1.12 (0.89, 1.41) 1.13 (0.68, 1.86) 1.86 (0.58, 5.95)

p‐value 0.60 0.51 0.34 0.64 0.30
• SGA: Number of studies 3 (NC) 3 (NC) 3 (NC) 2 (NC)
unlike sex ART twins 1237/2490 (49.7% 234/2490 (9.4%) 90/2490 (3.6%) 63/1170 (5.4%)
twins SC twins (ref.) 1471/3467 (42.4% 256/3467 (7.4%) 64/3467 (1.8%) 84/2147 (4.0%)
OR (95% CI) 1.35 (1.19, 2.97) 1.28 (0.87, 1.88) 1.95 (1.41, 2.71) 1.38 (0.99, 1.93)

p‐value <0.0001 0.21 <0.0001 0.06
McDonald et Number of studies 10 7 2 6‡
al. IVF/ICSI twins nr nr nr nr
305
(2010) ‡‡ SC twins (ref.) nr nr nr nr
OR (95% CI) 1.14 (1.06, 1.22) 1.28 (0.73, 2.24) 0.88 (0.04, 19.40) 1.06 (0.72, 1.55)

p‐value 0.0002 nr nr nr
alone IVF twins nr
SC twins (ref.) nr
OR (95% CI) 1.71 (1.34, 2.18)

p‐value nr
IVF+ICSI ICSI twins nr
SC twins (ref.) nr
OR (95% CI) 1.08 (0.80, 1.46)

p‐value nr
SC twins (ref.) nr
OR (95% CI) 1.00 (0.58, 1.73)

p‐value nr
SC twins (ref.) nr
OR (95% CI) 1.49 (0.83, 2.68)

p‐value nr
McDonald et Number of studies 12 8 1 8‡
al. IVF/ICSI singletons nr nr nr nr
306
(2009) ‡‡ SC singletons (ref.) nr nr nr nr
OR (95% CI) 1.60 (1.29, 1.98) 2.65 (1.83, 3.84) 3.02 (0.12, 74.66) 1.45 (1.04, 2.00)

p‐value <0.0001 nr nr nr
alone IVF singletons nr
198


OR (95% CI) 1.85 (1.40, 2.43)

p‐value nr
IVF+ICSI ICSI singletons nr
OR (95% CI) 1.71 (1.26, 2.32)

p‐value nr
OR (95% CI) 1.93 (0.75, 4.97)

p‐value nr
OR (95% CI) 1.35 (0.46, 3.99)

p‐value nr
Hvidtjørn et Number of studies 3§§
307
al. (2009) IVF/ICSI children 88/19462 (0.5%)
SC children (ref.) 1063/432950 (0.2%
OR (95% CI) 2.18 (1.71, 2.77)

p‐value nr
• SGA: Number of studies 3§§
singletons IVF/ICSI singletons 41/12191 (0.3%)
SC singletons (ref.) 1081/479615 (0.2%
OR (95% CI) 1.82 (1.31, 2.52)

p‐value nr
• SGA: twins Number of studies 3§§
IVF/ICSI twins 39/7069 (0.6%)
SC twins (ref.) 72/14940 (0.5%)
OR (95% CI) 1.00 (0.65, 1.52)

p‐value nr
Vitthala et al. Number of studies 27
308
(2009) 10783/2369682
ART
1.7% (1.2, 2.2)***
alone 151/40682
IVF
0.89% (0.5, 1.3)
199


IVF+ICSI 11/1220
ICSI
1.2% (0.4, 2.2)
embryos only 4/163
IVF/ICSI
3.0% (0.96, 6.12)
blastocyst 173/9721
IVF/ICSI
embryos only 5.1% (2.9, 8.1)
spontaneous nr
SC
conception 0.4% (0.4, 0.4)

313 321 315 312
* Risk ratio in Grady et al. (2012) , Maheshwari et al. (2012) , Gelbaya et al. (2010) , and Pandey et al. (2012)
† Proportion of infants with an Apgar score <7 at 5 minutes
‡ Proportion of infants small for gestational age or with intrauterine growth restriction
§ Meta‐analysis of individual patient data
¶ Adjusted for significant covariates (gestational age)
** Combine OR obtained by pooling adjusted ORs, when available, and crude ORs, where adjusted not available (33 studies matched or adjusted for factors such as maternal age, parity, and smoking)
†† “Controlled” studies (C) are those that controlled for basic maternal characteristics, such as age, and “non‐controlled” (NC) studies are those that did not control for potential confounding factors
‡‡ Combined OR obtained by pooling adjusted ORs (studies matched or adjusted for at least age, and often other factors such as parity and smoking)
§§ Proportion of infants with cerebral palsy
*** Weighted average (95% CI)

Abbreviations:
ART = assisted reproductive technology; CI = confidence interval; DET = double embryo transfer; eSET = elective single embryo transfer; ICSI = intracytoplasmic sperm injection; IVF = in vitro fertilization; OR = odds ratio; MZT =
monozygotic twinning; NICU = neonatal intensive care unit; nr = not reported; RCT = randomized controlled trial; SC = spontaneous conception; SET = single embryo transfer; SGA = sub‐group analysis

Definitions:
• Monozygotic twinning (MZT): diagnosis used by most studies = ultrasound visualization of >1 fetus with cardiac activity in the same gestational sac or a greater number of fetal hearts than the number of embryos transferred; a
few studies used Weinberg’s method (rate estimated by the number of unlike sex twins at birth), post‐natal placental histology, DNA analysis, or blood group analysis
• Birth weight: normal birth weight = birth weight >2,500 grams; low birth weight (LBW) = birth weight <2,500 grams; very low birth weight = birth weight <1,500 grams; extremely low birth weight = birth weight <1,000 grams;
th 321
small for gestational age or intrauterine growth restriction (IUGR) = birth weight <10 percentile for gestational age (except 2 studies in Maheshwari et al. (2012) : 1‐<22% expected mean birth weight according to reference
population, and 1‐<2 standard deviations of the mean for that gestation)
• Perinatal mortality defined by Rossi and Addario (2011) as stillbirth and early neonatal mortality (within 1 week of birth); not defined in Grady et al. (2012)
• Apgar score: method of assessing the health of newborn child immediately after birth (score of <3 = critically low, 4‐6 = fairly low, 7‐10 = generally normal)

200

Appendix E – Evidence tables:Efficacy/effectiveness

Table 29. Dose of gonadotropin stimulation
Review Treatment Characteristics Study Groups Subgroups Number Mean gonadotropin stimulation dose Heterogeneity

of primary N Mean ± SD Mean difference P‐value I2 (%) P‐value
studies (95% CI)
Maternal weight/BMI
Rittenberg et al. • Fresh or frozen, autologous BMI <25 (ref.) nr nr
2 nr nr (not sig.) nr nr
(2011)162 IVF/ICSI with cleavage or blastocyst BMI ≥25 nr nr
stage embryos BMI <25 (ref.) nr nr 137.92
• 1‐6 embryos per cycle 5 0.005 61% nr
BMI 25‐29.9 nr nr (41.25, 234.60)
• 1 or more cycles per BMI <25 (ref.) nr nr 406.77
woman/couple 5 0.0008 81% nr
BMI ≥30 nr nr (169.26, 644.2)
Maheshwari et • Fresh, autologous IVF/ICSI with BMI <25 (ref.) 3851 nr 210.08
al. (2007)331 cleavage or blastocyst stage 2 <0.00001 10% 0.29
BMI ≥25 1557 nr (149.12, 271.05)
embryos BMI <30 (ref.) 4867 nr
• 1‐>3 embryos per cycle 361.94
• 1 or more cycles per 2 0.0006 66% 0.09
BMI ≥30 511 nr (156.47, 567.40)
woman/couple

List of abbreviations used in table (alphabetical order): BMI = body mass index; CI = confidence interval; ICSI = intracytoplasmic sperm injection; IVF = in vitro fertilization; nr = not reported; SD = standard deviation

201

Table 30. Duration of gonadotropin stimulation
Review Treatment Characteristics Study Groups Subgroups Number Mean gonadotropin stimulation duration Heterogeneity

studies (95% CI)
Maternal weight/BMI
2 0.88 (0.49, 1.27) <0.0001 nr nr
stage embryos BMI <25 (ref.) nr nr
• 1‐6 embryos per cycle 5 0.22 (0.21, 0.23) <0.00001 nr nr
BMI 25‐29.9 nr nr
• 1 or more cycles per BMI <25 (ref.) nr nr
woman/couple 5 0.27 (0.26, 0.28) <0.00001 nr nr
BMI ≥30 nr nr

List of abbreviations used in table (alphabetical order): BMI = body mass index; CI = confidence interval; ICSI = intracytoplasmic sperm injection; IVF = in vitro fertilization; nr = not reported; SD = standard deviation

202

Table 31. Oocyte retrieval
Review Treatment Characteristics Study Groups Subgroups Number Mean number of oocytes retrieved Heterogeneity

studies (95% CI)
D’Angelo and • Autologous IVF/ICSI with Fresh ET (ref.) 67 19.80±4.30
Amso (2007)319 cleavage stage (day 2‐3) embryos
1 nr nr ‐ ‐
• 3‐4 embryos per cycle
Frozen ET 58 20.80±5.50
• 1 cycle per woman/couple
Maternal weight/BMI
nr nr nr (not sig.) nr nr
stage embryos BMI <25 (ref.) nr nr
• 1‐6 embryos per cycle nr nr nr (not sig.) nr nr
BMI 25‐29.9 nr nr
woman/couple nr nr nr (not sig.) nr nr
BMI ≥30 nr nr
Maheshwari et • Fresh, autologous IVF/ICSI with BMI <25 (ref.) 2651 nr
Per woman/couple 4 0.58 (0.22, 0.94) 0.001 0% 0.71
al. (2007)331 cleavage or blastocyst stage BMI ≥25 1440 nr
embryos BMI <30 (ref.) 3454 nr
• 1‐>3 embryos per cycle 3 0.68 (0.11, 1.25) 0.02 0% 0.59
BMI ≥30 585 nr
woman/couple Per cycle nr ‐0.30 (‐1.62, 1.02) nr (not sig.) nr nr
BMI ≥25 nr nr
BMI <30 (ref.) nr nr
nr 0.46 (‐0.55, 1.47) nr (not sig.) nr nr
BMI ≥30 nr nr

List of abbreviations used in table (alphabetical order): BMI = body mass index; CI = confidence interval; ET = embryo transfer; ICSI = intracytoplasmic sperm injection; IVF = in vitro fertilization; nr = not reported;
SD = standard deviation

203

Table 32. Embryo cryopreservationrate
Review Treatment Characteristics Study Groups Subgroups Number Embryo cryopreservation rate per woman or couple* Heterogeneity

of primary n/N % Odds Ratio P‐value I2 (%) P‐value
studies (95% CI)
Papanikolaou et • Fresh, autologous or donor Cleavage stage ET (ref.) 515/727 70.8%
al. (2008)323 IVF/ICSI
7 0.28 (0.14, 0.55) 0.0002 84% <0.00001
Blastocyst stage ET 371/703 52.8%
Glujovsky et al. • Fresh, autologous or donor Cleavage stage ET (ref.) 571/910 62.7%
325
(2012)
11 0.35 (0.29, 0.43) <0.00001 72% 0.00011
IVF/ICSI Blastocyst stage ET 336/819 41.0%
• 1‐5 embryos per cycle Cleavage stage ET (ref.) Studies with equal number 387/564 68.6%
• 1 or more cycles per of cleavage and blastocyst 7 0.23 (0.11, 0.47) 0.000068 78% 0.00017
woman/couple Blastocyst stage ET stage embryos transferred 271/554 48.9%
Cleavage stage ET (ref.) Studies with more cleavage‐ 184/346 53.2%
stage embryos transferred 4 0.25 (0.13, 0.48) 0.000023 66% 0.03
Blastocyst stage ET than blastocyst stage 65/265 24.5%
Cleavage stage ET (ref.) Studies limited to patients 232/308 75.3%
6 0.16 (0.08, 0.32) <0.00001 55% 0.05
Blastocyst stage ET with a good prognosis 143/304 47.0%
Cleavage stage ET (ref.) Studies with unselected 260/440 59.1%
4 0.38 (0.19, 0.76) <0.00001 80% 0.002
Blastocyst stage ET patients 177/434 40.8%

List of abbreviations used in table (alphabetical order): CI = confidence interval; ET = embryo transfer; ICSI = intracytoplasmic sperm injection; IVF = in vitro fertilization; nr = not reported
* Number of embryos cryopreserved (frozen) per woman/couple

204

Table 33. Cycle cancellation rate
Review Treatment Characteristics Study Groups Subgroups Number Cycle cancellation rate per woman or couple* Heterogeneity

studies (95% CI)
325
(2012)
16 2.86 (1.96, 4.17) <0.00001 20% 0.26
• 1 or more cycles per of cleavage and blastocyst 7 2.70 (1.64, 4.35) 0.00010 0 0.74
Cleavage stage ET (ref.) Studies with SET in both 8/176 4.5%
1 1.41 (0.55, 3.57) 0.47 ‐ ‐
Blastocyst stage ET groups 11/175 6.3%
9 1.49 (0.79, 2.86) 0.22 0 0.47
2 5.00 (0.93, 25.00) 0.061 0 1.00
Blastocyst stage ET with a poor prognosis 6/34 17.6%
5 3.70 (2.33, 5.88) <0.00001 2% 0.40
8 2.21 (1.47, 3.32) 0.0001 0 0.45
Maternal weight/BMI
Maheshwari et • Fresh, autologous IVF/ICSI with BMI <25 (ref.) 147/2623 5.6%
Per woman/couple 3 1.32 (0.96, 1.82) 0.08 26% 0.26
al. (2007)331 cleavage or blastocyst stage BMI ≥25 120/1416 8.5%
embryos BMI <30 (ref.) 208/3454 6.0%
BMI ≥30 59/585 10.1%
woman/couple Per cycle nr 1.83 (1.36, 2.45) nr (sig.) nr nr
BMI ≥25 nr nr
nr 1.59 (0.53, 4.80) nr (not sig.) nr nr
BMI ≥30 nr nr
205

Review Treatment Characteristics Study Groups Subgroups Number Cycle cancellation rate per woman or couple* Heterogeneity

studies (95% CI)

List of abbreviations used in table (alphabetical order): BMI = body mass index; CI = confidence interval; ET = embryo transfer; ICSI = intracytoplasmic sperm injection; IVF = in vitro fertilization; nr = not reported
* Number of cycles cancelled per woman/couple reaching oocyte retrieval in Papanikolaou et al. (2008)323 and Maheshwari et al. (2007)331; Number of couples failing to transfer any embryos in Glujovsky et al.
(2012)325
206

Table 34. Implantation rate
Review Treatment Characteristics Study Groups Subgroups Number Implantation rate per number of embryos transferred* Heterogeneity

studies (95% CI)
Gelbaya et al. • Fresh, autologous IVF/ICSI with eSET (ref.) 169/501 33.7%
(2010)315 cleavage stage (day 2‐3) embryos 5 0.93 (0.79, 1.08)† 0.31 0 0.88
• 1 cycle per woman/couple DET 323/1036 31.2%
Baruffi et al. • Fresh, autologous IVF/ICSI with SET (ref.) 163/470 34.7%
(2009)316 cleavage (day 2‐3) or blastocyst 5 0.99 (0.78, 1.25) 0.96 0 0.85
DET 338/980 34.5%
(day 5‐6) stage embryos
• 1 cycle per woman/couple in SET (ref.) Studies with patients ≤35 124/373 33.2%
most (2 studies with 1‐2 cycles per 4 1.02 (0.78, 1.33) 0.90 nr (no het.) Nr
DET years 267/790 33.8%
woman)

List of abbreviations used in table (alphabetical order): CI = confidence interval; DET = double embryo transfer; eSET = elective single embryo transfer; ICSI = intracytoplasmic sperm injection; IVF = in vitro
fertilization; nr = not reported
* Number of implantations per total number of embryos transferred; the number of implantations was counted as the number of gestational sacs with a fetal heartbeat as seen on an ultrasound in Gelbaya et al.
(2010) and was not specified in Baruffi et al. (2009)
† Risk ratio

207

Table 35. Pregnancy rate
Review Treatment Characteristics Study Groups Subgroups Number Pregnancy rate per woman or couple Heterogeneity

studies (95% CI)
IVF/ICSI in comparison to non‐invasive ART treatment options
Pandian, • Fresh or frozen, autologous IVF sIUI (≤3 cycles) (ref.) Clinical pregnancy 26/116 22.4%
2 1.10 (0.60, 2.03) 0.76 0 0.76
Gibreel, and with cleavage stage (day 2‐3) or IVF (≤2 cycles) Treatment‐naïve women 28/116 24.1%
Bhattacharya blastocyst (day 5‐6) stage embryos Clinical pregnancy
FSH‐IUI (≤3 cycles) (ref.) 50/169 29.6%
(2011)89 • 1‐6 cycles per woman/couple Women who failed to
1 12.78 (7.54, 21.65) <0.00001 ‐ ‐
achieve pregnancy with ≤3
IVF (≤6 cycles) 145/172 84.3%
cycles of CC‐IUI
Biochemical pregnancy* 3 1.49 (7.30, 1.72)† <0.00001 nr nr
(2010)315 cleavage stage (day 2‐3) embryos DET 269/512 52.5%
• 1 cycle per woman/couple eSET (ref.) 71/194 36.6%
Clinical pregnancy* 4 1.35 (1.08, 1.69)† 0.010 nr nr
DET 95/191 49.7%
eSET (ref.) 43/180 23.9%
Ongoing pregnancy* 2 1.89 (1.39, 2.56)† <0.0001 nr nr
DET 82/181 45.3%
(2009)316 cleavage (day 2‐3) or blastocyst Ongoing pregnancy 6 2.06 (1.64, 2.60) <0.001 0 0.65
DET 294/660 44.5%
(day 5‐6) stage embryos
• 1 cycle per woman/couple in SET (ref.) Studies with patients ≤35 131/450 29.1%
most (2 studies with 1‐2 cycles per 3 1.91 (1.45, 2.53) <0.0001 nr (no het.) nr
DET years 201/452 44.5%
woman)
Pandian et al. • Fresh, autologous or donor 1 SET (ref.) 198/630 31.4%
Clinical pregnancy 5 2.21 (1.75, 2.79) <0.00001 0 0.80
(2009)317 IVF/ICSI with cleavage stage (day 2‐ 1 DET 313/627 49.9%
3) embryos 1 DET 7/23 30.4%
• 1‐2 cycles per woman/couple 1 1.17 (0.32, 4.25) 0.82 ‐ ‐
1 TET (ref.) 6/22 27.3%
1 DET 15/28 53.6%
1 0.75 (0.26, 2.16) 0.59 ‐ ‐
1 QET (ref.) 17/28 60.7%
1 DET (ref.) 25/53 47.2%
1 1.40 (0.65, 3.00) 0.39 ‐ ‐
2 x SET 30/54 55.6%
1 DET (ref.) 172/323 53.3%
1 0.78 (0.90, 1.07) 0.12 ‐ ‐
1 fresh SET + 1 frozen SET 152/322 47.2%
D’Angelo and • Autologous IVF/ICSI with Fresh ET (ref.) Clinical pregnancy 1 31/67 46.3% 1.08 (0.54, 2.19) 0.82 ‐ ‐
208


studies (95% CI)
• 3‐4 embryos per cycle Frozen ET 28/58 48.3%
Roque et al. • IVF/ICSI with cleavage or
Fresh ET (ref.) 121/316 38.3%
(2012)455 blastocyst stage embryos Clinical pregnancy 3 1.31 (1.10, 1.56) † 0.002 0% 0.74
Frozen ET 159/317 50.2%
Clinical pregnancy in RCTs 8 1.27 (1.03, 1.55) 0.02 27% 0.22
al. (2008)323 IVF/ICSI Blastocyst stage ET 323/826 39.1%
• 1‐5 embryos per cycle Cleavage stage ET RCTs and pseudo‐ 315/945 33.3%
• 1 cycle per woman/couple 9 1.29 (1.07, 1.56) 0.008 19% 0.28
Blastocyst stage ET randomized trial 375/954 39.3%
325
(2012)
Clinical pregnancy 23 1.14 (0.99, 1.32) 0.075 47% 0.01
3 1.24 (0.84, 1.82) 0.28 70% 0.04
Cleavage stage ET (ref.) Studies with more 313/742 42.2%
cleavage‐stage embryos
12 1.07 (0.86, 1.33) 0.54 55% 0.01
Blastocyst stage ET transferred than blastocyst 283/645 43.9%
stage
14 1.15 (0.83, 1.58) 0.41 57% 0.004
2 2.59 (0.75, 8.92) 0.13 0 0.39
7 1.01 (0.81, 1.25) 0.95 0 0.52
Cleavage stage ET Cumulative clinical 144/257 56.0%
4 1.58 (1.11, 2.25) 0.011 46% 0.14
Blastocyst stage ET (ref.) pregnancies‡ 122/270 45.2%
Maternal age
Van Loendersloot • Fresh, autologous IVF/ICSI with
et al. (2010)332 cleavage stage (day 2‐3) embryos
Each year increase in Clinical and/or ongoing
• 1‐9 embryos per cycle 10 nr nr 0.95 (0.94, 0.96) nr (sig.) 0% nr (not sig.)
maternal age pregnancy
• 1 or more cycles per
woman/couple
Maternal weight/BMI
Koning et al. • Fresh or frozen, autologous or BMI ≤25 (ref.) Clinical pregnancy 9 nr nr 0.94 (0.69, 1.30) nr (not sig.) nr nr
209


studies (95% CI)
(2012)329 donor with cleavage or blastocyst BMI >25 nr nr
stage embryos BMI ≤30 (ref.) nr nr
• 1‐>4 embryos per cycle 9 0.97 (0.59, 1.60) nr (not sig.) nr nr
BMI >30 nr nr
• 1 cycle per woman/couple BMI ≤25 (ref.) nr nr
Ongoing pregnancy 4 1.01 (0.75, 1.40) nr (not sig.) nr nr
BMI >25 nr nr
BMI ≤30 (ref.) nr nr
4 0.96 (0.64, 1.40) nr (not sig.) nr nr
BMI >30 nr nr
Rittenberg et al. • Fresh or frozen, autologous BMI <25 (ref.) 9510/23693 40.1%
Clinical pregnancy§ 25 0.90 (0.85, 0.94)† <0.0001 51% 0.002
(2011)162 IVF/ICSI with cleavage or blastocyst BMI ≥25 3950/11213 35.2%
stage embryos BMI <25 (ref.) 8032/19511 41.2%
• 1‐6 embryos per cycle 16 0.91 (0.86, 0.96)† 0.003 35% 0.08
BMI 25‐29.9 2184/6079 35.9%
• 1 or more cycles per BMI <25 (ref.) 8278/20145 41.1%
woman/couple 15 0.87, 0.80, 0.95)† 0.002 62% 0.0008
BMI ≥30 1466/4062 36.1%
Maheshwari et • Fresh, autologous IVF/ICSI with BMI <25 (ref.) Biochemical, clinical and/or 1964/5017 39.1%
al. (2007)331 cleavage or blastocyst stage ongoing pregnancy per 7 0.81 (0.67, 0.98) 0.03 59% 0.02
BMI ≥25 1074/2883 37.3%
embryos woman
• 1‐>3 embryos per cycle BMI <30 (ref.) 2615/6781 38.6%
6 0.86 (0.70, 1.05) 0.15 38% 0.15
• 1 or more cycles per BMI ≥30 402/1067 37.7%
woman/couple BMI 20‐25 (ref.) 1024/2366 43.3%
3 0.71 (0.56, 0.82) <0.00001 0% 0.51
BMI >25 528/1443 36.6%
BMI 20‐30 (ref.) 1424/3327 42.8%
3 0.68 (0.56, 0.83) 0.002 0% 0.79
BMI >30 168/482 34.9%
BMI <25 (ref.) Biochemical, clinical and/or nr nr
nr 1.01 (0.89, 1.14) nr (not sig.) nr nr
BMI ≥25 ongoing pregnancy per cycle nr nr
nr 0.95 (0.78, 1.15) nr (not sig.) nr nr
BMI ≥30 nr nr
Maternal smoking
Waylen et al. • Fresh or frozen, autologous or Non‐smokers (ref.) 1303/3959 32.9%
Clinical pregnancy§ 18 0.56 (0.43,0.73) <0.001 49% 0.01
(2009)161 donor IVF/ICSI with cleavage or Smokers 236/1284 18.4%
blastocyst stage embryos Non‐smokers (ref.) nr nr
• 1‐>4 embryos per cycle IVF patients only 13 0.57 (0.42, 0.77) nr (sig.) nr nr
Smokers nr nr
• 1 cycle per woman/couple in Non‐smokers (ref.) Studies where age not nr nr
most (2 studies with >1 cycle in 9 0.51 (0.32, 0.79) nr (sig.) nr nr
Smokers likely to be a confounder nr nr
some women) Non‐smokers (ref.) Studies limited to nr nr
17 0.57 (0.43, 0.75) nr (sig.) nr nr
Smokers autologous oocytes only nr nr
Duration of infertility
Van Loendersloot • Fresh, autologous IVF/ICSI with Duration of infertility ≤1 Clinical and/or ongoing
1 nr nr ‐ ‐
et al. (2010)332 cleavage stage (day 2‐3) embryos year (ref.) pregnancy
210


studies (95% CI)
• 1‐9 embryos per cycle Duration of infertility >1
• 1 or more cycles per nr nr 0.83 (0.55, 1.27) nr (not sig.)
and ≤2 years
woman/couple Duration of infertility >2
nr nr 0.81 (0.54, 1.23) nr (not sig.)
and ≤3 years
Duration of infertility >3
nr nr 0.77 (0.50, 1.18) nr (not sig.)
and ≤4 years
nr nr 0.79 (0.49, 1.27) nr (not sig.)
and ≤5 years
nr nr 0.82 (0.55, 1.25) nr (not sig.)
years
Each year increase in
2 N=1077 nr 0.99 (0.98, 1.00) nr 0% nr (not sig.)
duration of infertility
Pandian, • Fresh, autologous IVF with
SC (3‐6 months) (ref.) 5/41 12.2%
Gibreel, and cleavage stage (day 2‐3) or
Clinical pregnancy 2 3.24 (1.07, 9.80) 0.037 80% 0.03
Bhattacharya blastocyst (day 5‐6) stage embryos
89 IVF 13/45 28.9%
(2011) • 1 cycle per woman/couple

List of abbreviations used in table (alphabetical order): BMI = body mass index; CI = confidence interval; DET = double embryo transfer; ET = embryo transfer; eSET = elective single embryo transfer; ICSI =
intracytoplasmic sperm injection; IVF = in vitro fertilization; nr = not reported; QET = four embryo transfer; RCT = randomized controlled trial; SC = spontaneous conception; SET = single embryo transfer; sIUI =
stimulated IUI (with clomiphene citrate or Gonadotropins); TET = three embryo transfer;
* Biochemical pregnancy = positive urine or serum β‐hCG levels 14 days after embryo transfer; clinical pregnancy = ultrasound visualization of gestational sac(s) with fetal pole and fetal heart
movements/activity/beat; ongoing pregnancy = ultrasound visualization of gestational sac(s) with a visible fetal heart beat after 12 weeks gestation
† Risk ratio
‡ Cumulative clinical pregnancy rate per woman from all fresh and frozen cycles
§ Pregnancy rate per cycle

211

Table 36. Multiple pregnancy rate
Review Treatment Characteristics Study Groups Subgroups Number Multiple pregnancy rate* Heterogeneity

studies (95% CI)
IVF in comparison to other treatment options
Pandian, • Fresh or frozen, autologous IVF
sIUI (≤6 cycles) (ref.) 23/175 13.1%
Gibreel, and with cleavage stage (day 2‐3) or Clinical pregnancy
3 0.64 (0.31, 1.29) 0.21 0 1.00
Bhattacharya blastocyst (day 5‐6) stage embryos Treatment‐naïve women
IVF (≤6 cycles) 16/176 9.1%
(2011)89 • 1‐6 cycles per woman/couple
5† 0.04 (0.01, 0.11) <0.00001 0 0.67
3) embryos 1 DET 0/23 0
• 1‐2 cycles per woman/couple 1 0.17 (0.01, 3.85) 0.27 ‐ ‐
1 TET (ref.) 2/22 9.1%
1 DET 3/28 10.7%
1 0.44 (0.10, 1.97) 0.28 ‐ ‐
1 QET (ref.) 6/28 21.4%
1 DET (ref.) 7/53 13.2%
1 0.06 (0.00, 1.02) 0.052 ‐ ‐
2 x SET 0/54 0
7 0.86 (0.58, 1.29) 0.46 0 0.57
325
(2012)
16 0.92 (0.71, 1.19) 0.50 27% 0.15
1 0.20 (0.01, 4.17) 0.30 ‐ ‐
Blastocyst stage ET groups 0/175 0
8 0.75 (0.49, 1.13) 0.16 20% 0.27
stage
11 0.88 (0.63, 1.22) 0.45 35% 0.12
Cleavage stage ET (ref.) Studies limited to patients 1 3/31 9.7% 0.89 (0.14, 5.81) 0.90 ‐ ‐
212

Review Treatment Characteristics Study Groups Subgroups Number Multiple pregnancy rate* Heterogeneity

studies (95% CI)
4 0.96 (0.62, 1.47) 0.84 0 0.70
Cleavage stage ET (ref.) Higher‐order (>2) multiple 9/1031 0.9%
12 0.44 (0.15, 1.33) 0.15 0 0.68
Blastocyst stage ET pregnancy rate 3/1004 0.3%
Cleavage stage ET (ref.) Studies with equal number 1/846 0.1%
of cleavage and blastocyst 8 0.33 (0.01, 8.28) 0.50 0 1.00
Blastocyst stage ET stage embryos transferred 0/826 0
4 0.46 (0.14, 1.49) 0.19 0 0.52
stage
9 0.29 (0.08, 1.06) 0.061 0 1.00
Cleavage stage ET (ref.) Studies limited to patients 0/31 0
1 4.20 (0.16, 107.89) 0.39 ‐ ‐
Cleavage stage ET (ref.) Studies with unselected 0/296 0
2 ‐ ‐ ‐ ‐
Blastocyst stage ET patients 0/300 0
Maternal weight/BMI
Koning et al. • Fresh or frozen, autologous or
(2012)329 donor IVF/ICSI with cleavage or BMI ≤25 (ref.) 3545/11013 32.2%
blastocyst stage embryos 5 0.97 (0.91, 1.04) 0.45 0 0.60
• 1‐>4 embryos per cycle BMI >25 2179/6879 31.7%

intracytoplasmic sperm injection; IVF = in vitro fertilization; nr = not reported; QET = four embryo transfer; SET = single embryo transfer; TET = three embryo transfer;
* Number of multiple pregnancies per clinical pregnancy in Papanikolaou et al. (2008); number of multiple pregnancies per woman in Pandian et al. (2011), Pandian et al. (2009) (†except 1 study out of 5 comparing
SET to DET that reported the number of multiple births per live birth), Blake et al. (2007), and Koning et al. (2012)

213

Table 37. Miscarriage rate
Review Treatment Characteristics Study Groups Subgroups Number Miscarriage rate* Heterogeneity

studies (95% CI)
Pandian, • Fresh, autologous IVF with Clinical pregnancy
Gibreel, and cleavage stage (day 2‐3) or Women who failed to
1 nr nr ‐ ‐
Bhattacharya blastocyst (day 5‐6) stage embryos achieve pregnancy with ≤3
IVF (≤6 cycles) 27/145 18.6%
(2011)89 • 1‐6 cycles per woman/couple cycles of CC‐IUI
Fresh vs. Frozen embryo transfer
Roque et al. IVF/ICSI with cleavage or blastocyst Fresh ET (ref.) 18/316 5.7%

Miscarriage rate 3 0.83 (0.43, 1.60) † 0.57 0% 1.00
(2012)455 embryos Frozen ET 15/317 4.7%
Grady et al. • Fresh, autologous or donor eSET (ref.) 44/216 20.4%
RCTs 4 0.74 (0.43, 1.27)‡ nr (not sig.) 38% nr
(2012)313 IVF/ICSI with cleavage or blastocyst DET 46/305 15.1%
stage embryos eSET (ref.) 53/361 14.7%
• 1 cycle per woman/couple Cohorts 4 0.88 (0.58, 1.33)‡ nr (not sig.) 30% nr
DET 87/656 13.3%
McLernon et al. • Fresh, autologous IVF/ICSI with eSET (ref.) 60/245 24.5% nr (sig.
(2010)96† cleavage stage (day 2‐3) embryos nr 0.66 (0.44, 0.99) 0.06 nr
DET 63/355 17.7% het.)
(2010)315 cleavage stage (day 2‐3) embryos 4 1.10 (0.74, 1.64)‡ 0.65 nr nr
• 1 cycle per woman/couple DET 46/608 7.6%
3 1.18 (0.75, 1.86) 0.48 61% 0.08
3) embryos 1 DET (ref.) 5/53 9.4%
1 1.67 (0.51, 5.48) 0.40 ‐ ‐
• 1‐2 cycles per woman/couple 2 x SET 8/54 14.8%
Glujovsky et al. • Fresh, autologous or donor
(2012)325 IVF/ICSI Cleavage stage ET (ref.) 86/1069 8.0%
• 1‐5 embryos per cycle 14 1.14 (0.84, 1.55) 0.39 0 0.64
• 1 or more cycles per Blastocyst stage ET 97/1058 9.5%
woman/couple
Maternal weight/BMI
Rittenberg et al. • Fresh or frozen, autologous BMI <25 (ref.) 2444/12724 19.2%
22 1.31 (1.18, 1.45) <0.00001 48% 0.01
(2011)162 IVF/ICSI with cleavage or blastocyst BMI ≥25 1207/5072 23.8%
214


studies (95% CI)
stage embryos BMI <25 (ref.) 1529/7413 20.6%
14 1.24 (1.13, 1.35) 0.001 22% 0.26
• 1‐6 embryos per cycle BMI 25‐29.9 472/1989 23.7%
• 1 or more cycles per BMI <25 (ref.) 1837/9206 20.0%
woman/couple 14 1.36 (1.13, 1.64) 0.001 56% 0.005
BMI ≥30 306/1198 25.5%
Metwally et al. • Fresh or frozen, autologous or BMI 19‐24.9 (ref.) 991/7621 13.0%
12 1.67 (1.25, 2.25) 0.0006 84% <0.00001
(2008)330 donor IVF/ICSI with cleavage or BMI ≥25 603/3646 16.5%
blastocyst stage embryos BMI 19‐24.9 (ref.) 647/5546 11.7%
• 1‐>3 embryos per cycle Autologous oocytes 9 1.52 (0.88, 2.6) nr (not sig.) nr nr
BMI ≥25 425/2857 14.9%
• 1 or more cycles per BMI 19‐24.9 (ref.) Studies where age not nr nr
woman/couple 4 1.41 (0.96, 2.06) nr (not sig.) nr nr
BMI ≥25 likely to be a confounder nr nr
BMI 19‐24.9 (ref.) Studies using WHO criteria nr nr
6 1.95 (0.76, 5.01) nr (not sig.) nr nr
BMI ≥25 for BMI classification nr nr
BMI 19‐24.9 (ref.) 344/2075 16.6%
Donor oocytes 3 1.52 (1.10,2.09) nr (sig.) nr nr
BMI ≥25 178/789 22.6%
BMI 19‐24.9 (ref.) Studies using WHO criteria nr nr
3 1.59 (0.89, 2.88) nr (not sig.) nr nr
BMI ≥25 for BMI classification nr nr
Maheshwari et • Fresh, autologous IVF/ICSI with BMI <25 (ref.) 813/4222 19.3%
al. (2007)331 cleavage or blastocyst stage 10 1.33 (1.06, 1.68) 0.01 46% 0.05
BMI ≥25 483/2117 22.8%
embryos BMI <30 (ref.) 996/5149 19.3%
• 1‐>3 embryos per cycle
• 1 or more cycles per 8 1.53 (1.27, 1.84) <0.00001 0% 0.86
BMI ≥30 186/747 24.9%
woman/couple
Maternal smoking
Waylen et al. • Fresh or frozen, autologous or Non‐smokers (ref.) 268/1688 15.9%
Spontaneous miscarriage 7 2.65 (1.33, 5.30) 0.006 45.4% 0.09
(2009)161 donor IVF/ICSI with cleavage or Smokers 66/211 31.3%
blastocyst stage embryos Non‐smokers (ref.) nr nr
• 1‐>4 embryos per cycle IVF patients only 4 2.99 (0.94, 9.47) nr (not sig.) nr nr
Smokers nr nr
• 1 cycle per woman/couple in Non‐smokers (ref.) Studies where age not nr nr
most (2 studies with >1 cycle in 3 1.88 (0.55, 6.37) nr (not sig.) nr nr
Smokers likely to be a confounder nr nr
some women) Non‐smokers (ref.) Studies limited to nr nr
6 3.05 (1.74, 5.73) nr (sig.) 30.3% nr
Smokers autologous oocytes only nr nr
215


studies (95% CI)

intracytoplasmic sperm injection; IVF = in vitro fertilization; nr = not reported; SET = single embryo transfer
* Number of miscarriages per pregnancy in Grady et al. (2010), McLernon et al. (2010), Maheshwari et al. (2007), and Pandian et al. (2009), and per woman/couple in Gelbaya et al. (2010) and Glujovsky et al.
(2012)325, and per cycle in Rittenberg et al. (2011) and Waylen et al. (2009)
† Meta‐analysis of individual patient data
‡ Risk ratio

Table 38. Live birth rate
Review Treatment Characteristics Study Groups Subgroups Number Live birth rate per woman or couple Heterogeneity

studies (95% CI)
Pandian, • Fresh or frozen, autologous IVF sIUI (≤6 cycles) (ref.) Cumulative live birth rate* 34/117 29.1%
2 1.09 (0.74, 1.59) 0.66 0 0.99
Gibreel, and with cleavage stage (day 2‐3) or IVF (≤6 cycles) Treatment‐naïve women 37/117 31.6%
Bhattacharya blastocyst (day 5‐6) stage embryos Cumulative live birth rate*
(2011)89 • 1‐6 cycles per woman/couple Women who failed to
1 2.66 (1.94, 3.63) <0.00001 ‐ ‐
achieve pregnancy with ≤3
IVF (≤6 cycles) 100/172 58.1%
cycles of CC‐IUI
McLernon et al. • Fresh, autologous IVF/ICSI with eSET 181/683 26.5%
8 0.50 (0.39, 0.63)‡ <0.001 0 0.77
(2010)96† cleavage stage (day 2‐3) embryos DET (ref.) 285/683 41.7%
• 1 cycle per woman/couple eSET 131/461 28.4%
Age <33 years 0.48 (0.36, 0.63) nr ‐ ‐
DET (ref.) 205/454 45.2%
8
eSET 50/219 22.8%
Age ≥33 years 0.54 (0.36, 0.83) nr ‐ ‐
DET (ref.) 80/277 28.9%
eSET 164/571 28.7%
Grade A embryos 0.53 (0.40, 0.67) nr ‐ ‐
DET (ref.) 259/597 43.4%
8
eSET 10/79 12.7%
Grade B embryos 0.29 (0.11, 0.71) nr ‐ ‐
DET (ref.) 17/51 33.3%
eSET Duration of infertility <3 60/234 25.6%
0.49 (0.33, 0.72) nr ‐ ‐
DET (ref.) years 93/226 41.2%
8
eSET Duration of infertility ≥3 115/432 26.6%
0.51 (0.38, 0.69) nr ‐ ‐
DET (ref.) years 183/441 41.5%
216


studies (95% CI)
• 1‐2 cycles per woman/couple eSET 132/350 37.7%
Cumulative live birth rate* 2 0.85 (0.62, 1.15) nr nr nr
DET (ref.) 149/353 42.2%
Gelbaya et al. • Fresh, autologous IVF/ICSI with eSET 171/652 26.2%
(2010)315 cleavage stage (day 2‐3) embryos 5 0.62 (0.53, 0.72)‡ <0.00001 37% 0.17
• 1 cycle per woman/couple DET (ref.) 275/649 42.4%
(2009)316 cleavage (day 2‐3) or blastocyst 5 1.87 (1.44, 2.42) <0.001 0 0.40
DET 222/522 42.5%
(day 5‐6) stage embryos SET (ref.) 127/450 28.2%
• 1 cycle per woman/couple in Studies with patients ≤35
most (2 studies with 1‐2 cycles per 3 1.91 (1.45, 2.53) <0.0001 nr (no het.) nr
DET years 194/452 42.9%
woman)
Pandian et al. • Fresh, autologous or donor SET (ref.) 166/630 26.3%
5 2.10 (1.65, 2.66) <0.00001 0 0.51
(2009)317 IVF/ICSI with cleavage stage (day 2‐
DET 268/627 42.7%
3) embryos DET 3/23 13.0%
• 1 cycle per woman/couple 1 0.40 (0.9, 1.85) 0.24 ‐ ‐
TET (ref.) 6/22 27.3%
DET 8/28 28.6%
1 0.35 (0.11, 1.05) 0.61 ‐ ‐
QET (ref.) 15/28 53.6%
• 1‐3 cycles per woman/couple 1 DET (ref.) 19/53 35.8%
Cumulative live birth rate* 1 1.23 (0.56, 2.69) 0.60 ‐ ‐
2 x SET 22/54 40.7%
1 DET (ref.) 140/323 43.3%
2 x DET (ref.) 7/23 30.4%
2 x TET 8/22 36.4%
3 x DET (ref.) 9/23 39.1%
3 x TET 10/22 45.5%
D’Angelo and • Autologous IVF/ICSI with Fresh ET (ref.) 25/67 37.3%
1 1.03 (0.50, 2.12) 0.94 ‐ ‐
Frozen ET 22/58 37.9%
6 1.39 (1.10, 1.76) 0.005 17% 0.30
12 1.40 (1.13, 1.74) 0.0021 40% 0.07
(2012)325 IVF/ICSI Blastocyst stage ET 292/751 38.9%
217


studies (95% CI)
2 1.46 (0.98, 2.19) 0.064 29% 0.24
8 1.43 (0.99, 2.07) 0.058 49% 0.06
2 1.99 (0.49, 8.04) 0.33 0 0.48
2 1.05 (0.56, 1.97) 0.88 43% 0.19
Embryo quality
McLernon et al. • Fresh, autologous IVF/ICSI with Grade A embryos 423/1168 36.2%
(2010)96† cleavage stage (day 2‐3) embryos
8 1.93 (1.23, 3.04) 0.004 0 0.77
• 1‐2 embryos per cycle Grade B embryos (ref.) 27/130 20.8%
Maternal age
McLernon et al. • Fresh, autologous IVF/ICSI with Age <33 years 336/915 36.7%
(2010)96† cleavage stage (day 2‐3) embryos
8 1.37 (1.05, 1.77) 0.02 0 0.77
Age ≥33 years (ref.) 130/446 29.1%
Maternal weight/BMI
Koning et al. • Fresh or frozen, autologous or BMI ≤25 (ref.) 1786/6709 26.6%
(2012)329 donor IVF/ICSI with cleavage or 7 0.90 (0.82, 1.00) 0.04 0 0.58
BMI >25 850/3249 17.9%
blastocyst stage embryos BMI ≤30 (ref.) nr nr
• 1‐>4 embryos per cycle 6 0.89 (0.76, 1.03) nr (not sig.) nr nr
• 1 cycle per woman/couple BMI >30 nr nr
Rittenberg et al. • Fresh or frozen, autologous 2882/10270
BMI <25 (ref.) 28.1%
(2011)162 IVF/ICSI with cleavage or blastocyst 9 § 0.84 (0.77, 0.92)** 0.0002 21% 0.19
stage embryos BMI ≥25 776/3226§ 24.1%
• 1‐6 embryos per cycle 2754/10616
• 1 or more cycles per BMI <25 (ref.) 25.9%
5 § 0.91 (0.85, 0.98)** 0.01 0% 0.86
woman/couple BMI 25‐29.9 667/2831§ 23.6%
218


studies (95% CI)
2754/10616
BMI <25 (ref.) 25.9%
5 § 0.80 (0.71, 0.90)** 0.0002 0% 0.77
BMI ≥30 256/1264§ 20.3%
Maheshwari et • Fresh, autologous IVF/ICSI with BMI <25 681/2522 27.0%
Per woman 2 0.93 (0.79, 1.09) 0.34 0% 0.34
al. (2007)331 cleavage or blastocyst stage BMI ≥25 (ref.) 397/1355 29.3%
embryos BMI <30 907/3321 27.3%
BMI ≥30 (ref.) 171/556 30.8%
• 1 or more cycles per BMI <25 nr nr
woman/couple Per cycle 2 1.35 (0.50, 3.70) nr (not sig.) nr nr
BMI ≥25 (ref.) nr nr
Maternal smoking
Waylen et al. • Fresh or frozen, autologous or Non‐smokers (ref.) nr nr
(2009)161 donor IVF/ICSI with cleavage or 4 0.54 (0.30, 0.99) nr (sig.) nr nr
blastocyst stage embryos Smokers nr nr
• 1‐>4 embryos per cycle
Non‐smokers (ref.) nr nr
• 1 cycle per woman/couple in Studies where age not likely
3 0.41 (0.14, 1.14) nr (not sig.) nr nr
most (2 studies with >1 cycle in to be a confounder
Smokers nr nr
some women)
McLernon et al. • Fresh, autologous IVF/ICSI with Duration of infertility <3
153/460 33.3%
(2010)96† cleavage stage (day 2‐3) embryos years
8 1.02 (0.79, 1.32) 0.87 0 0.77
• 1‐2 embryos per cycle Duration of infertility ≥3
298/873 34.1%
• 1 cycle per woman/couple years (ref.)
Pandian, • Fresh, autologous IVF with
IVF (ref.) 1/27 3.7%
Gibreel, and cleavage stage (day 2‐3) or
Clinical pregnancy 1 22.00 (2.56, 189.37) 0.0049 ‐ ‐
Bhattacharya blastocyst (day 5‐6) stage embryos
SC (3‐6 months) 11/24 45.8%
(2011)89 • 1 cycle per woman/couple
219


studies (95% CI)

intracytoplasmic sperm injection; IVF = in vitro fertilization; MET = multiple embryo transfer; nr = not reported; QET = four embryo transfer; SC = spontaneous conception; SET = single embryo transfer; TET =
three embryo transfer;
* Cumulative rates include all cycles (transfers) per woman resulting from a single oocyte retrieval; in McLernon et al. (2010), 1 additional frozen SET cycle after a single fresh SET cycle was compared to a single DET
cycle in both studies; in Pandian et al. (2009), 1 additional frozen SET cycle after a single fresh SET cycle was compared to a single DET in 1 study, 2 fresh SET cycles were compared to a single DET cycle in 1
study, and 2‐3 fresh DET cycles were compared to 2‐3 fresh TET cycles in 1 study
† Meta‐analysis of individual patient data
‡ Adjusted for significant covariates (grade of the embryos transferred, type of Treatment Characteristics, and the primary cause of infertility)
§ Live birth rate per cycle
** Risk ratio

220

Table 39. Multiple birth rate
Review Treatment Characteristics Study Groups Subgroups Number Multiple birth rate per live birth Heterogeneity

studies (95% CI)
McLernon et al. • Fresh, autologous IVF/ICSI with eSET 3/181 1.7%
8 0.04 (0.01, 0.12)† <0.001 nr nr
(2010)96* cleavage stage (day 2‐3) embryos DET (ref.) 84/285 29.5%
• 1 cycle per woman/couple eSET 3/131 2.3%
Age <33 years nr nr ‐ ‐
DET (ref.) 61/205 29.8%
8
eSET 0/50 0%
Age ≥33 years nr nr ‐ ‐
DET (ref.) 23/80 28.8%
eSET 3/164 1.8%
Grade A embryos nr nr ‐ ‐
DET (ref.) 78/259 30.1%
8
eSET 0/10 0%
Grade B embryos nr nr ‐ ‐
DET (ref.) 4/17 23.5%
eSET Duration of infertility <3 1/60 1.7%
0.04 (0.01, 0.29) nr ‐ ‐
DET (ref.) years 27/93 29.0%
8
eSET Duration of infertility ≥3 2/115 1.7%
0.04 (0.01, 0.17) nr ‐ ‐
DET (ref.) years 54/183 29.5%
eSET 1/132 0.8%
Cumulative multiple births‡ 2 0.02 (0.002, 0.12) nr nr nr
DET (ref.) 47/149 31.5%
Gelbaya et al. • Fresh, autologous IVF/ICSI with eSET 2/171 1.2%
(2010)315 cleavage stage (day 2‐3) embryos 5 0.06 (0.02, 0.18)§ <0.00001 0 0.91
• 1 cycle per woman/couple DET (ref.) 82/275 29.8%
Pandian et al. • Fresh, autologous or donor 1 DET (ref.) 46/141 32.6%
(2009)317 IVF/ICSI with cleavage stage (day 2‐
1 0.02 (0.00, 0.12) 0.000064 ‐ ‐
3) embryos
• 1‐2 cycles per woman/couple
Embryo quality
McLernon et al. • Fresh, autologous IVF/ICSI with Grade A embryos 81/423 19.1%
(2010)96* cleavage stage (day 2‐3) embryos
8 1.59 (0.49, 5.17) 0.44 nr nr
Grade B embryos (ref.) 4/27 14.8%
Maternal age
McLernon et al. • Fresh, autologous IVF/ICSI with Age <33 years 8 64/336 19.0% 1.06 (0.58, 1.91) 0.86 nr nr
221

Review Treatment Characteristics Study Groups Subgroups Number Multiple birth rate per live birth Heterogeneity

studies (95% CI)
(2010)96* cleavage stage (day 2‐3) embryos
• 1‐2 embryos per cycle Age ≥33 years (ref.) 23/130 17.7%
McLernon et al. • Fresh, autologous IVF/ICSI with Duration of infertility <3
28/153 18.3%
(2010)96* cleavage stage (day 2‐3) embryos years
8 0.97 (0.55, 1.72) 0.91 nr nr
• 1‐2 embryos per cycle Duration of infertility ≥3
56/298 18.8%
• 1 cycle per woman/couple years (ref.)

List of abbreviations used in table (alphabetical order): CI = confidence interval; DET = double embryo transfer; eSET = elective single embryo transfer; ICSI = intracytoplasmic sperm injection; IVF = in vitro
fertilization; nr = not reported; SET = single embryo transfer
* Meta‐analysis of individual patient data
† Adjusted OR; no significant covariates found
‡ Multiple births per cumulative live birth; cumulative rates include all cycles (transfers) per woman resulting from a single oocyte retrieval (1 additional frozen SET cycle after a single fresh SET cycle was compared
to a single DET cycle in both studies)
§ Risk ratio

222

Appendix F – Economic studies

Table 40. Economic studies of ARTs interventions
Author/Country/
Year of Purpose of
publication study Study methods Costs Outcomes measured Findings Comments
Studies comparing ovarian stimulation agents
Al‐ To compare the Study type Costs included Main outcome Ongoing pregnancy rate Conclusions
Inany456/Egypt/200 cost effectiveness Cost‐effectiveness • Pharmaceuticals (HP‐HMG, Number of ongoing • HMG: 40.89% after 3 The average cost per
6 of ongoing analysis rFSH, and all other pregnancies cycles ongoing pregnancy
pregnancy with pharmaceuticals) • rFSH: 35.9% after 3 cycles with HMG is lower than
IVF/ICSI using Patient population • IVF/ICSI treatment Information source with rFSH. The authors
HMG versus rFSH Hypothetical cohort of (including monitoring, oocyte Published meta‐analysis Discontinuation of IVF: conclude that HMG has
100,000 patients, age retrieval, laboratory of 8 RCTs showing no • HMG: 53.2% dominance over rFSH
distribution unspecified procedures, luteal phase significant difference • rFSH: 57.5%
support, and pregnancy between rFSH and HMG Limitations
Analysis determination) in ongoing pregnancy Cost per ongoing pregnancy • Only cost up to a
Constructed a Markov • Hospital admissions for rate, live birth rate, after 3 cycles: pregnancy were
model with 2 treatment OHSS multiple pregnancy • HMG: 13,946 EGP included (no long‐term
arms (HMG and rFSH) rate, or incidence of • FSH: 18,721 EGP costs)
• Used Monte Carlo Information source OHSS • Frozen cycles were
simulation to examine • Egyptian ministry of health Sensitivity analysis showed not considered
potential impact of • 1 Egyptian IVF clinic that rFSH would have to be • Egyptian costs based
assumptions and reduced in price by almost on one clinic may not
uncertainties Other 60% for it to be as cost‐ be generalizable
Costs reported in 2005 effective as HMG
Sensitivity analysis Egyptian pounds (EGP)
Varied cost of HMG
versus rFSH

Perspective
Patient

Time horizon
223

Author/Country/
Year of Purpose of
Up to 3 cycles before
pregnancy

Lloyd et To compare the Study type Costs included Main outcome Ongoing pregnancy rate Conclusions
al.350/United costs of achieving Cost‐minimization • Pharmaceuticals (HP‐HMG, • Ongoing pregnancy • HP‐HMG: 22% (95%CI: 18‐ • HP‐HMG and rFSH
Kingdom/2003 a pregnancy analysis rFSH, and all other (at 10 weeks or more) 27%) achieved similar
through IVF/ICSI pharmaceuticals) • rFSH: 19% (95%CI: 15‐ ongoing pregnancy
with HP‐HMG to Patient population • IVF/ICSI treatment Secondary outcomes 23%) rates
IVF/ICSI with rFSH • 781 women from 22 (including visits/consultations, • NA Difference between HP‐ • Average cost of HP‐
centres in 6 countries visits requiring injections, HMG and rFSH not HMG was significantly
(Belgium, Germany, ultrasound examinations, Information sources statistically significant lower than that of rFSH
Israel, the Netherlands, blood tests and other • RCT
Switzerland, and the UK) diagnostic procedures, oocyte Total cost per patient Limitations
• Patient eligibility retrieval, fertilization and • HP‐HMG: £2,423 • Cost and outcomes of
criteria: infertility for > 1 embryo transfer) (95%CI: £2,356‐2,495) failed treatments were
year and history of ≤3 • Any other healthcare • rFSH: £2,745 not considered
unsuccessful IVF/ICSI resource use associated with (95%CI: £2,356‐2,495) • Did not include live
cycles; female partner IVF/ICSI procedure, including Difference between HP‐ births
with normal menstrual the costs of managing adverse HMG and rFSH statistically
cycle between the ages events significant
of 18‐36 years and a BMI
of 18‐28, and no history Information sources Total cost per ongoing
of severe OHSS • Published literature pregnancy
• All received GnRH • University Hospitals • HP‐HMG: £10,781
agonist protocol with Coventry and Warwickshire (95%CI: £9,056‐12,919)
either highly purified (UHCW) finance department • rFSH: £14,284
HMG (396 women) or • British National Formulary (95%CI: £11,883‐17,891)
rFSH (385 women) (pharmaceutical costs)
• Social Services Research
Analysis Unit, University of Kent
Analyzed costs alongside • National Health Service
an international RCT Reference costs
• Average cost per
outcome was calculated
• Analysed using
intention to treat
224

Author/Country/
Year of Purpose of
protocol

Perspective
Payer/healthcare system

Time horizon
From treatment to
ongoing pregnancy (at 10
or more weeks)

Sensitivity analysis
• Aggregate UK charges
per cycle versus
“bottom‐up costing” of
individual procedures
pooled from medical
resources in different
countries
• British National
Formulary cost estimates
versus discounted prices
• Confidence intervals
were generated using
nonparametric
bootstrapping
Wechowski et To determine the Study type Costs included Main outcome Mean cost including Conclusions
al.347/United cost‐effectiveness Cost‐effectiveness • Pharmaceuticals (HP‐HMG, Ongoing pregnancy rate maternal and neonatal cost HP‐HMG after 1 fresh
Kingdom/2007 of HP‐HMG analysis rFSH, and all other per started cycle • HP‐HMG: ₤14,301 cycle of IVP offered
compared to rFSH pharmaceuticals ) • rFSH: ₤17,407 significant cost savings
Patient population • IVF treatment (including Information sources Difference statistically
• RCT recruiting women visits associated with Data from MERiT Trial significant Limitations
21‐37 years of age with retrieval, fertilization, and (Menotrophin versus • Effectiveness data
regular menstrual cycles embryo transfer recombinant FSH in‐ Incremental ratios came from a
and presumed to have • Specialist consultations vitro fertilization trial) comparing HP‐HMG to rFSH randomized trial which
ovulatory, tubal, or (stimulation and pregnancy • Multi‐national, open‐ • Cost savings per cycle: included patients with
unexplained infertility determination) label, assessor‐blind ₤237 favourable ovarian
225

Author/Country/
Year of Purpose of
• Excluded women with • Hospital admissions as a RCT • Incremental cost per response profiles
more than 3 previous result of OHSS • Based on intention‐ delivery: ‐ ₤5,187
consecutively • Hospital admissions for to‐treat population • Incremental cost per • Cost and outcomes of
unsuccessful IVF cycles delivery and neonatal care baby: ‐ ₤4,804 failed treatments were
and recurrent • Varying costs for singleton, • Incremental cost per not considered
miscarriage twins, and triplets delivery including maternal
and neonatal costs: ‐ ₤740 • Non‐medical costs
Analysis Information sources were not included
Constructed a discrete • British National Formulary Probabilistic sensitivity
event simulation model • Published UK sources analysis
• Included stimulation, • Expert opinion • Mean and median values
oocyte retrieval, embryo of ICERs were negative for
transfer, ongoing both cost per delivery and
pregnancy, and live birth cost per baby
• Confidence intervals • HP‐HMG was cost saving
around estimates were in > 92% of patients for
produced by both measures of
bootstrapping effectiveness

Perspective

Time horizon
Up to pregnancy or a live
birth

Probabilistic to assess
uncertainty in
probabilities of success at
each stage of simulation

Connolly et To determine the Study type Costs included Main outcome After 1 fresh cycle only Conclusions
al.345/Belgium/20 cost‐effectiveness Cost‐effectiveness • IVF treatment (oocyte Live birth rate Incremental live birth rate: HP‐HMG resulted in
08 of HP‐HMG analysis retrieval, laboratory • HP‐HMG: 0.255 lower average costs
compared to rFSH procedures, embryo transfer, Other outcomes • rFSH (high dose): 0.216 per fresh cycle, lower
226

Author/Country/
Year of Purpose of
Patient population and freezing, storing, and • rFSH (low dose): 0.216 average costs for 1
Hypothetical cohort of thawing embryos) Information sources fresh and 1 frozen
women • Pharmaceuticals used in IVF Published meta‐analysis Average cost per live birth cycle, and lower
Analysis • Treatment‐related adverse • HP‐HMG: €10,288 average costs per live
Constructed a decision events (ovarian • rFSH (high dose): €13,515 birth
model incorporating the hyperstimulation syndrome • rFSH (low dose): €13,017
following events: start Limitations
fresh treatment, cryo‐ Information sources After 1 fresh and 1 frozen • Did not include costs
preserved cycle, live • Published literature cycle of treatment
birth, and treatment • Genk Institute for Fertility Incremental live birth rate: withdrawals, ongoing
withdrawal Technology • HP‐HMG: 0.365 pregnancies, and
• Scenarios assessed • Expert opinion • rFSH (high dose): 0.0.315 deliveries. These were
were cycle 1: 1 fresh • rFSH (low dose): 0.315 considered to be
cycle for all patients; Other irrelevant for a Belgian
cycle 2: second Costs reported in 2007 Euros Average cost per live birth analysis, but may affect
consecutive fresh cycle after 1 cycle (through the generalizability of
or 1 frozen cycle based probabilistic sensitivity the findings.
on probability of cryo‐ analysis:
preserved embryo being • HP‐HMG: €10,293 Study sponsor
available • rFSH (high dose): €13,520 Ferring
• Two dosing regimens • rFSH (low dose): €13,020 Pharmaceuticals
were examined: ‘low The difference between
dose’ obtained from HMG and rFSH was
practice at a Belgian statistically significant
fertility centre, and ‘high
dose’, which was based
on the weighted mean
dose per cycle calculated
from a published meta‐
analysis.
• Treatment withdrawal
included: cancellation of
fresh cycle, unsuccessful
fertilization, unsuccessful
embryo implantation or
miscarriage following
227

Author/Country/
Year of Purpose of
clinical pregnancy
• Assessed uncertainty in
individual outcomes
using Monte Carlo first‐
order microsimulation
techniques

Perspective

Time horizon
Time for 2 IVF cycles

Probabilistic (second‐
order analysis) to assess
uncertainty in drop‐out
rates, frequency of clinic
visits, availability of
frozen embryos, live birth
rates achieved using HP‐
HMG and rFSH and live
birth rates using cryo‐
preserved embryos
Wechowski et To assess the cost Study type Costs included Main outcome Live birth rate after 1 fresh Conclusions
al.344/United effectiveness of Cost‐effectiveness • Pharmaceuticals (HP‐HMG, • Number of live births IVF cycle: HP‐HMG appeared to
Kingdom/2009 HP‐HMG analysis rFSH, and all other • Number of babies • HP‐HMG: 26.6% be more effective and
compared to rFSH pharmaceuticals ) born per patient • rFSH: 20.6% less costly than rFSH
Patient population • IVF treatment (including initiating treatment (Odds ratio: 1.4; CI 1.04‐
Women 18‐38 years of visits associated with 1.88) Including maternal and
age with unexplained retrieval, fertilization, and Information source neonatal costs
infertility recruited at 53 embryo transfer • Combined individual Babies per 1,000 cycles reduced cost savings
fertility clinics in 13 • Specialist consultations patient data from 2 initiated, adjusting for associated with HP‐
European countries and (stimulation and pregnancy multinational RCT multiple births HMG because of more
Israel determination) • Results based on • HP‐HMG: 338 live births, but HP‐
• Hospital admissions as a intention‐to‐treat data • rFSH: 268 HMG still remained
228

Author/Country/
Year of Purpose of
Analysis result of ovarian (Odds ratio: 1.4; CI 1.06‐ cost‐effective
Constructed a discrete hyperstimulation syndrome 1.83)
event simulation model • Hospital admissions for Limitations
• Modeled stimulation, delivery and neonatal care Mean cost per live birth • Cost and outcomes of
oocyte retrieval, embryo considered separately including maternal and failed treatments were
transfer, pregnancy, neonatal costs not considered
pregnancy loss, and live Information sources • HP‐HMG: ₤14,804 • Did not include long
birth, single or multiple • Resource data from UK • rFSH: ₤18,909 term costs
delivery established treatment Difference statistically • Probability of
• Produced confidence practices and the 2 trials significant fertilization and
intervals by • University Hospitals of implantation success
bootstrapping Coventry and Warwickshire Incremental cost‐ was implicitly included
• British National Formulary effectiveness ratio per live • No systematic review
Perspective • Published UK sources birth for HP‐HMG was conducted, making
Payer/healthcare system • Expert opinion compared to rFSH it unclear whether all
‐ ₤4,180, indicating that relevant sources of
Time horizon Other HP‐HMG is more effective efficacy data were
Not specified Costs reported in pounds and less costly captured
sterling in 2006
Sensitivity analysis Probabilistic sensitivity Study sponsor
Probabilistic: to assess analysis Ferring
uncertainty in Probability of HP‐HMG Pharmaceuticals
probabilities of success at being cost‐effective was
each stage of simulation 98.4% for a ceiling ratio of
based on 95% confidence ₤20,000 per live birth
intervals exclusive and inclusive of
• Results summarized neonatal and maternal
using cost‐effectiveness costs
acceptability curves

Wex‐Wechowski et To compare HP‐ Study type Costs included Main outcome Cumulative live birth rate Conclusion
al.342/United HMG and rFSH in Cost‐effectiveness • Pharmaceuticals (HP‐HMG, • Cumulative live birth HP‐HMG HP‐HMG is more cost‐
Kingdom/2010 IVF treatments analysis rFSH, and all other rate • 1 fresh + up to 2 frozen effective than rFSH at
with pharmaceuticals) • Babies per 1,000 cycles: 53.7% producing live births in
cryopreserved Patient population • IVF treatment (including treatments • 1 fresh + 1 frozen cycle: women undergoing
embryos Pooled patients from 2 visits associated with 32.6% conventional IVF and,
229

Author/Country/
Year of Purpose of
prospective multinational retrieval, fertilization, and Other outcomes • 1 fresh + 2 frozen cycles when available, frozen
To assess the RCTs: embryo transfer • Number of oocytes (based on frozen success embryo transfer cycles
economic • 986 women between • Specialist consultations retrieved rate from trial): 36.4%
implications of the ages of 18 to 39 (stimulation and pregnancy • Fertilization rates Limitations
choice of recruited from 53 fertility determination) rFSH • Cost and outcomes of
gonadotropin centres in Europe and • Hospital admissions as a Information sources • 1 fresh + up to 2 frozen failed treatments were
Israel result of ovarian • Pooled patient level cycles: 44.6% not considered
• Primary cause of hyperstimulation syndrome from the 2 clinical trials • 1 fresh + 1 frozen cycle: • Did not include long
infertility was tubal and • Hospital admissions for (number of oocytes 27.0% term costs (only
unexplained infertility delivery and neonatal care retrieved, number of • 1 fresh + 2 frozen cycles treatment costs were
• All treated in fresh twins and triplets (based on frozen success considered)
cycles, and received Information sources • Published literature rate from trial): 32.1%
either highly purified • British National Formulary • Expert opinion Study sponsor
HMG (491 women) or (pharmaceutical costs) Difference between HP‐ Ferring
recombinant FSH (495 • Other published UK sources HMG and rFSH statistically Pharmaceuticals
women), plus 1 or 2 • Expert opinion significant for 1 fresh + up
frozen embryos if to 2 frozen cycles scenario Note
available. This is a supplement to
Babies per 1,000 Wechowski et al.
Analysis treatments (2009) which modelled
• Constructed a discrete HP‐HMG a fresh cycle scenario
event simulation model • 1 fresh + up to 2 frozen only.
to determine number of cycles: 679
patients with live births • 1 fresh + 1 frozen cycle:
and number of babies 414
born per patient • 1 fresh + 2 frozen cycles
initiating treatment (based on frozen success
under different scenarios rate from trial): 460
• Model incorporated 1
fresh and 2 frozen cycles rFSH
• Monte Carlo • 1 fresh + up to 2 frozen
simulations with a total cycles: 580
of 30,000 patients • 1 fresh + 1 frozen cycle:
• Base case scenario: 350
patients offered second • 1 fresh + 2 frozen cycles
fresh cycles unless (based on frozen success
230

Author/Country/
Year of Purpose of
cryopreserved embryos rate from trial): 419
were available
• In 2008 Pounds Sterling Difference between HP‐
• No discounting was HMG and rFSH statistically
applied significant for 1 fresh + up
to 2 frozen cycles scenario
Perspective
Payer/healthcare system Required number of
patients needed to be
Time horizon treated to achieve 1
Not specified additional live birth when
using HP‐HMG instead of
Sensitivity analysis rFSH varied in different
Probabilistic scenarios from 11 to 24

Mean cost per live birth
using 1 fresh and up to 2
frozen cycles excluding
maternal and neonatal
costs:
• HP‐HMG: £10,046
• rFSH: £14,055

Mean cost per baby using 1
fresh and up to 2 frozen
cycles including maternal
and neonatal costs
• HP‐HMG: £12,635
• rFSH: £15,563

Mean total per patient
treatment costs
• HP‐HMG: £5,393
• rFSH: £6,269
Difference attributable to
lower cost of
231

Author/Country/
Year of Purpose of
gonadotropins using HP‐
HMG

Incremental cost‐
effectiveness ratio for HP‐
HMG vs rFSH
• Incremental cost per live
birth: ‐ £9,632
• Incremental cost per
baby: ‐ £8,856
Indicates that HP‐HMG is
less costly and more
effective

Probabilistic sensitivity
analysis
HP‐HMG was cost saving in
100% of patients, both
exclusive and inclusive of
neonatal and maternal
costs
Fragoulakis et To determine the Study type Costs included Main outcome Birth rate Conclusions
al.340/Greece/2012 cost‐effectiveness Cost‐effectiveness • Pharmaceuticals used in IVF Live birth rate • rFSH: 44.6% rFSH is cost‐effective
of Gonal‐F,(rFSH) analysis • IVF treatment (including • uHMG: 39.4% when compared to
compared to initial examination and Information sources Difference statistically uHMG
Menopur (uHMG) Patient population preparation, cost of oocytes, Published observational significant (amounting to
Hypothetical cohort of needle puncture, fertilization, data validated by a 52 more births per 1000 Limitations
women (age not transfer, cryopreservation, local expert panel patients treated) • Costs beyond IVF
specified) undergoing up and frozen embryo thawing) treatment were not
to 3 cycles of IVF with Cost per birth: included
either rFSH or uHMG Information sources • rFSH: €16,906 • Did not take into
• Ministry of Health 2011 • uHMG: €17,287 account potential
Analysis Price Bulletin Difference not statistically differences in
Constructed a decision • 3 selected IVF clinics significant singletons, twins, and
tree with Markov • Expert opinion higher order multiples
modelling comparing Incremental cost‐ across treatment arms
232

Author/Country/
Year of Purpose of
rFSH arm with uHMG Other effectiveness ratio for rFSH
arm Costs reported in 2011 Euros compared to uHMG Note: authors
• Model treated all births • €14,541 per additional acknowledged
the same, regardless of birth inconsistencies in
plurality • Based on a cost‐ results compared to
• Ran 5,000 simulations effectiveness acceptability previous studies and
curve at an ICER threshold attributed them to the
Perspective of €20,000 there is a 95% use of observational
• Payer/healthcare probability that rFSH is rather than RCT data
system cost‐effective
• Patient

Time horizon
Three consecutive cycles
of IVF

Probabilistic –
constructed cost‐
effectiveness
acceptability curves to
deal with uncertainty
based on results of
Monte Carlo simulations
(5,000 runs)
Hatoum et To assess costs Study type Costs included Main outcomes Probability of a continuing Conclusions
al.348/United and effectiveness Cost‐effectiveness Defined categories of costs: •Continuing pregnancy pregnancy with 1 treatment hFSH was found to be
States/2005 of human FSH analysis start of cycle cost, oocyte cycle more effective in 65%
(Bravelle) with retrieval, embryo success, Secondary outcomes; • hFSH: 0.40 + 0.05 of cases and less costly
rFSH (Fullistim) Patient population embryo failure, chemical and • Live birth • rFSH: 0.37+0.05 in 100% of cases
Hypothetical group of clinical pregnancies, and OHSS • Multiple birth (authors concluded
women undergoing • Clinical pregnancy Costs of 1 treatment cycle that hFSH is cost‐
infertility treatment with Information sources • Premature birth • hFSH: $11,584 + $211 effective compared to
either hFSH or rFSH 2003 published study • OHSS • rFSH: $12,762 + $170 rFSH)

Time horizon Other Information source Probability of a continuing Limitations
233

Author/Country/
Year of Purpose of
Not specified Costs reported n 2003 US 2 recent RCTs pregnancy with 3 treatment • Assumed patient
dollars cycles population similar to
Perspective • hFSH ‐0.78 + 0.05 those in the RCTs;
Payer/health system • rFSH – 0.75+0.05 therefore, results may
not be generalizable
Analysis Costs of 3 treatment cycles
Constructed a Markov • hFSH ‐ $22,712 + $1107 • Limited information
model • rFSH ‐ $24,935 + $1205 on methods used in
• States included: oocyte cost‐effectiveness
retrieval, successful were analysis provided
embryo transfer,
chemical, clinical and • The comparators may
ongoing pregnancies, and be applicable in the US
OHSS only
• Ran model 10,000
times
Holman et To assess the Study type Costs included Main outcome Clinical pregnancy rate Conclusions
al.346/United utilization, cost Cost analysis Not specified • Clinical pregnancy 36.4% IVF/ICSI outcomes in
Kingdom/2008 and outcomes of rate Ongoing pregnancy rate clinical setting were
ART and Patient population Information source • Ongoing pregnancy 24.4% similar to UK averages
Abstract determine Women receiving fresh Financial audit of ART unit rate per cycle Live birth rate
whether they are cycles of IVF/ICSI from • Live birth rate 22% Cost of rFSH per cycle
consistent with October 2001 to January Other Average cost of rFSH per were lower than that
that estimated by 2006 at UK ART unit; all Costs reported In 2007 Information sources cycle estimated in the NICE
the National women received rFSH for pounds sterling Clinical records of ₤646 guidelines
Institute for ovarian stimulation patients at ART unit
Health and Average total cost per cycle Limitations
Clinical Excellence Analysis ₤2,932 •Elements included in
(NICE) Cost per case calculated cost of “clinical
Average total cost per procedures” were not
Perspective clinical pregnancy clearly specified
Not specified ₤8,058
• Based on data from a
Time horizon Average total cost per single unit; therefore,
Not specified ongoing pregnancy findings may not be
₤12,017 generalizable
234

Author/Country/
Year of Purpose of
Not specified Average total cost/ live
birth
₤13,326
Ledger et To assess Study type Costs included Main outcomes Average rFSH dose per cycle Conclusion
al.343/United utilization, costs, Cost analysis • Pharmaceuticals (rFSH and • Clinical pregnancies • 1,855 IU Average rFSH doses
Kingdom/2009 and economic all other pharmaceuticals for per cycle and costs per cycle,
consequences of Patient population treatment cycle) • Ongoing pregnancies Clinical pregnancy rate per and average total costs
IVF/ICSI with rFSH • 1001 women 22‐49 • IVF/ICSI treatment per cycle cycle per cycle were found
years attending fertility (including visits/consultations • Live births • 36.4% to be lower than those
clinic in England (both and tests, retrieval, (95%CI: 33.9‐38.9%) estimated in UK
private and NHS funded fertilization and preparation, Secondary outcomes • Antagonist cycles: 39% guidance. Lower
patients) and embryo transfer) • rFSH dose average total costs may
• All treated in fresh Ongoing pregnancy rate be, in part, due to use
cycles • All treated with Information sources Information sources per cycle of rFSH.
recombinant FSH with • British National Formulary • clinical records • 24.4%
either short or long GnRH 2007 (pharmaceutical costs) (95%CI: 22.1‐26.5%) Limitations
agonist protocol (30%), • Financial audit of fertility • Antagonist cycles: 27% • Pharmaceutical costs
or GnRH antagonist clinic may have been
protocol (66%) Live birth rate per cycle overestimated
• Majority of women Other • 22.0% • Cost and outcomes of
transferred 2 embryos • Costs reported in 2007 UK (95%CI: 19.7‐24.2%) failed treatments were
prices • ≤29 years: 24% not reported
Analysis • For abandoned cycles, cost • 30‐34 years: 28% • Findings were based
• Outcomes calculated of fertilization and • 35‐39 years: 22% on 1 clinic with a
from clinical records implantation subtracted from • >40 years: 15% focused protocol;
• Average cost per cost of cycle • Antagonist cycles: 24% therefore, they may
outcome was calculated not be generalizable
• Ad hoc subgroup Average cost per cycle
analysis of women who • rFSH: £646 (≤29 years:
received antagonist £576; 30‐34 years: £611;
protocol 35‐39 years: £643; >40
years: £716)
Perspective • Concomitant
Payer (healthcare system medications: £159 (≤29
or patient) years: £174; 30‐34 years:
235

Author/Country/
Year of Purpose of
£160; 35‐39 years: £272;
Time horizon >40 years: £133)
From treatment to birth • Clinical procedures:
£2,127 (≤29 years: £2,251;
Sensitivity analysis 30‐34 years: £2,155; 35‐39
None specified years: £2,125; >40 years:
£2,050)
• Total: £2,932 (≤29 years:
£3,001; 30‐34 years:
£2,926; 35‐39 years:
£2,939; >40 years: £2,899)
• Total for antagonist
cycles: £2,67

Average total cost per
clinical pregnancy
• £8,085

Average total cost per
ongoing pregnancy
• £12,017

Average total cost per live
birth
• £13,326
Reindollar et To compare cost‐ Study type Costs included Main outcome measure Time to pregnancy Conclusion
al.351/United effectiveness of Cost‐effectiveness • Treatment (e.g., physician Time to pregnancy • Median time to FSH/IUI was found to
States/2010 accelerated analysis and healthcare professional pregnancy: be of no added value
versus step wise time, medication, medical Othery outcomes Accelerated treatment: 8
treatment Patient population equipment, diagnostic tests, Complications months As long as IVF costs per
• 503 couples attending a etc.) Step‐wise treatment: 11 cycle <$17,749
Accelerated private infertility centre • Pregnancy Information source RCT months accelerated treatment
treatment: in which women were • Newborn care (Fast track and was the less costly
3 cycles of 21‐39 years of age and • Out‐of‐pocket costs standard treatment Statistically significantly alternative
clomiphene (CC) had unexplained (including prescription co‐ trial) shorter in accelerated arm
IUI and up to 6 infertility payments, mental health compared to step‐wise Limitations
236

Author/Country/
Year of Purpose of
cycles of IVF • Patient eligibility services, transportation costs, treatment arm (hazard • Analysis based on
criteria: lost wages, etc.) ratio: 1.25) charges rather than
Step‐wise at least one ovary, costs, which may not
treatment: 3 ipsilateral patent Information sources Cumulative % of reflect actual costs
cycles of fallopian tube confirmed • Blue Cross Blue Shield of pregnancies • Trial performed
comiphene/IUI, 3 by hysterosalpingogram Massachusetts, Harvard • At 6 months: almost entirely at 1
cycles of or laparoscopy, and no Pilgrim Health Care, Tufts Accelerated treatment: treatment center,
gonadotropin pelvic pathology or Health Plan (charges reflected 43.2% affecting
(FSH)/IUI and up ectopic pregnancy all health care items and Step‐wise treatment: 31.9% generalizability
to 6 cycles of IVF services for women covered • At 9 months:
Analysis by insurance during the time Accelerated treatment:
Cost‐effectiveness of the trial, from 54.7%
analysis alongside randomization through Step‐wise treatment: 43.8%
randomized controlled delivery hospital discharge of • At 12 months:
trial (RCT) both mother and baby) Accelerated treatment:
• Cost diaries, provided after 65.4%
247 couples randomized first cycle for each stage of Step‐wise treatment: 55.4%
to step‐wise treatment process (also recorded time
and 256 couples lost from work) Per cycle pregnancy rate
randomized to • CC/IUI: 7.6%
accelerated treatment • FSH/IUI: 9.8%
course (when patients • IVF: 30.7% (includes live
who were not pregnant births and ongoing viable
after 3 cycles of drug/IUI pregnancy > 20 weeks)
went directly to IVF
without Multiple birth rates
gonadotropin/IUI • Accelerated treatment:
treatment first) 45/199
• Step‐wise treatment:
493 couples initiated and 38/185
417 followed treatment Difference not statistically
protocol significant

Analysed using intention Charges per delivery
to treat protocol Accelerated treatment:
$61,553 (US dollars)
237

Author/Country/
Year of Purpose of
Step‐wise treatment:
2007 US dollars $71,399 (US dollars)

Perspective Incremental difference in
Payer/healthcare system charges per couple
and patient Savings of $2,624 US per
couple for accelerated
Sensitivity analysis treatment
Varied average costs per
cycle (+ 5% from base Increase in proportion of
case) couples with delivery
0.06 with accelerated
treatment

Average charge per delivery
$5,802 (US dollars) lower in
accelerated arm

Out‐of‐pocket costs per
couple
Accelerated treatment:
$485 (US dollars)
Step‐wise treatment:
$495 (US dollars)

Sensitivity analysis of costs
per delivery did not affect
results

Results of simulation Cost
of IVF cycle would need to
exceed $17,749 for step‐
wise treatment arm to have
a lower cost per delivery
Beresniak et To determine the Study type Costs included Main outcomes Live birth rate Conclusion
238

Author/Country/
Year of Purpose of
al.349/United cost‐effectiveness Cost‐effectiveness Not specified • Live birth rate •r‐HCG: 25.97% r‐HCG was found to be
States/2003 of recombinant analysis • Singleton live birth •u‐HCG: 23.58% more cost‐effective
HCG compared to Information sources rate Difference statistically than u‐HCG
Abstract urinary HCG Patient population Not specified significant (p‐value < 0.001)
Hypothetical cohort of Other outcomes Limitations
100,000 patients None Singleton birth rate • No information on
•r‐HCG: 21.25% costs included or
Analysis Information sources •u‐HCG: 16.00% source of cost
Constructed a Markov • Meta‐analysis of 3 Difference statistically information was
model comparing trials significant (p‐value < 0.001) provided
recombinant HCG with • Statistical reports and • Analysis was specific
urinary HCG surveys Cost‐effectiveness to the 3 drug products
• Performed 5,000 Cost per live birth (in US (Ovidrel and Novorel)
Monte Carlo simulations dollars) from the societal • ART and antenatal
on cohort of 100,000 perspective: costs were derived
patients • r‐HCG: $72,761 from
• Model included fresh • u‐HCG: $87,376 ‘statistical surveys’
and frozen cycles in any and, therefore, may
sequence (after the 1st Cost per singleton birth (in not be generalizable
fresh embryo transfer US dollars from the societal
cycle) over 3 successive perspective:
ART attempts • r‐HCG: $89,005
• u‐HCG: $130,007
Perspective
Societal and healthcare Cost per live birth (in US
management dollars) from the
organization (HMO) healthcare system/ payer
perspective:
Time horizon • r‐HCG: $49,444
Not specified • u‐HCG: $59,741

Sensitivity analysis Cost per singleton birth (in
Not specified US dollars from the
healthcare system/payer
perspective:
• r‐HCG: $60,562
239

Author/Country/
Year of Purpose of
• u‐HCG: $88,894
Kansal‐Kalra et al.352 To determine the Study type Costs included Main outcome Total number of live births Conclusions
/United cost‐effectiveness Cost‐effectiveness • Gonadotropin •Probability of a live per cycle • Both treatment arms
States/2005 of proceeding analysis • IVF therapies (included birth • Gonadotropin arm: 14% appeared to be similar
directly to IVF personnel, equipment, • Immediate IVF arm: 42% in terms of
compared to Patient population materials, and medication) Other outcomes effectiveness, resulting
starting with 3 • Hypothetical cohort of • Inpatient hospitalization for • Probability of higher Rates of live birth by in >80% chance of live
cycles of 10,000 women <35 years mothers and infants order multiple plurality birth
gonadotropins of age with unexplained • Antepartum and pregnancy • Gonadotropin arm
followed by 3 infertility who have failed intrapartum medical costs • Risk of cerebral palsy Singleton: 71.2% • Gonadotropins prior
cycles of IVF 3 cycles of IUI Twin: 27.7% to IVF is less costly than
• Assumed all patients Information sources Information sources HOMP: 4.1% proceeding directly to
had already failed 3 Published literature Society for Assisted IVF
cycles of clomiphene Reproductive • IVF arm
citrate with IUI Other Technology Singleton: 66.1% • If success rate of
In 2003 US dollars Twin: 33.1% gonadotropins
Analysis HOMP: 0.8% decreases to only 10%,
• Constructed a decision the cost per live birth
model comparing Probability of singletons in each arm would be
gonadotropin arm (3 and twins similar in both equal
cycles of gonadotropins) arms
to IVF arm (immediate Limitations
IVF with potential to Gonadotropin arm 4 times • Not clear what the
undergo 3 cycles of IVF) more likely to result in inclusion criteria for
• Accounted for HOMP patients were
probability and costs • Couples in
associated with Cost per live birth gonadotropin arm had
singleton, twin, or higher • Gonadotropin arm: more potential cycles
order multiple pregnancy $58,401 of infertility
(HOMP) • IVF arm: $61,930 treatments, resulting in
• Accounted for a greater total birth
likelihood of cerebral One‐way sensitivity analysis rate
palsy with each plurality Point at which cost of IVF • Did not include
and costs incurred by live birth would be the indirect costs (e.g., lost
child same as cost of wages or childcare)
gonadotropin live birth: • Only included costs
240

Author/Country/
Year of Purpose of
Perspective When: up to birth
Payer/healthcare system • IVF birth rate = 55.1% • • Sensitivity analyses
Gonadotropin birth rate = showed that small
Sensitivity analysis 10% adjustments to
•One‐way sensitivity • Cost of IVF = $11,432 pregnancy rates or
analysis • Cost of gonadotropins = costs might shift
•Two‐way sensitivity $4,189 cost/live birth in favour
analysis to determine • Cost of HOMP: $245,200 of IVF
point at which IVF • Cost of cerebral
algorithm is equally palsy:$6,500,000
costly per live birth to
the gonadotropin Two‐way sensitivity
algorithm for varying analysis
probabilities of IVF and Point at which for a given
gonadotropin birth rates IVF birth rate the
gonadotropins birth rate
would equalize the cost per
live birth for the immediate
IVF strategy: when IVF birth
rate is 25% and
gonadotropin birth rate is
5.5%
Polinder et • To compare the Study type Costs included Main outcome Cumulative term live birth Conclusion
al.353/The economic • Cost‐effectiveness IVF treatment costs: Term live birth rate (as rate from pregnancies From a societal
Netherlands/2008 consequences of analysis • in‐hospital medical costs a proportion of within 1 year perspective, mild
a ‘standard’ • Cost analysis (pharmaceuticals, procedures, pregnancies) • standard: 44.7% protocol is more cost‐
IVF/ICSI protocol outpatient visits, personnel • mild: 43.4% effective than standard
(ovarian Patient population time, and complications) Secondary outcomes protocol; mild protocol
stimulation with • 404 couples attending • out‐of‐hospital medical Mean number of cycles Mean number of cycles associated with more
GnRH agonist 1 of 2 university medical costs (e.g., GP visits) within 12 months within 12 months: IVF/ICSI cycles but
long protocol centres • non‐medical costs (e.g., • standard: 2.3 lower overall costs
followed by DET; • patient eligibility absence from work, travel) Information sources • mild: 1.7 (treatment, pregnancy,
up to 3 cycles criteria: patients with Pregnancy and obstetric care • RCT • difference statistically obstetric, neonatal)
reimbursed) to a tubal factor, male factor, costs: significant (p<0.001)
mild IVF/ICSI or unexplained infertility; • in‐hospital medical costs Limitations
protocol (ovarian female partner with (secondary care) Drop‐out rate per cycle: • Cost and outcomes of
241

Author/Country/
Year of Purpose of
stimulation with normal menstrual cycle, • out‐of‐hospital medical Mean number of cycles failed treatments not
GnRH antagonist age of <38 years, and costs (primary care) within 12 months: considered
co‐treatment BMI 18‐28 • standard: 2.3
followed by SET; Information sources • mild: 1.7
up to 4 cycles Analysis • Fee schedule • difference statistically
reimbursed) Cost‐effectiveness • Pharmacotherapeutic cost significant (p<0.001)
analysis alongside prices
randomized controlled • Hospital/institution In‐hospital medical costs
trial (RCT) • Published literature
• 199 couples Treatment:
randomized to standard Other • standard: €576
protocol Costs reported in 2004 Euros • mild: €750
• 205 couples • difference statistically
randomized to mild significant (p=0.006)
protocol
Pregnancy:
Analysed using intention • standard: €1,061
to treat protocol • mild: €530
• difference statistically
27 patients switched significant (p=0.03)
protocol (12 in mild
group, 15 in standard Obstetric/post‐natal costs
group) per ongoing pregnancy:
• standard: €4,136
Perspective • mild: €1,947
Societal • difference statistically
significant (p=0.001)
Time horizon
From treatment to 6 Total treatment,
weeks post‐delivery pregnancy, and neonatal
(occurring within 12 costs
months after • standard: €10,745
randomization) • mild: €8,333
• difference statistically
Sensitivity analysis significant (p=0.006)
• All treatment cycles
242

Author/Country/
Year of Purpose of
(reimbursed and non‐ Cost effectiveness
reimbursed) versus
treatments occurring Cost per ongoing pregnancy
within 12 months after leading to term live birth
randomization • standard: €24,000
• Costs per live birth • mild: €19,200
(counting twins as 1 live
birth) versus costs per Cost per term live born
live born child (counting child
twins as 2 live born • standard: €20,197
children) • mild: €19,200

Incremental cost‐
effectiveness of standard
versus mild:
• €185,000 per extra
pregnancy leading to term
live birth
• €24,600 per term live
born child
• €13,500 per live born
child

including all cycles
• per term live birth: mild
dominant (both cheaper
and more effective than
standard)
• €46,035 per term live
born child
• €19,097 per live born
child
Nunez et To determine the Study type Costs included Main outcome Rate of ovulation induction Conclusions
al.341/Mexico/2011 cost‐effectiveness Cost‐utility analysis • Pharmaceuticals to induce Quality adjusted life • Clomiphene citrate: Based on average
of anastrozole ovulation years (QALYs) 67.5% rather than
243

Author/Country/
Year of Purpose of
versus to Patient population • Pharmaceuticals to treat • Anastrozole: 66.2% incremental cost‐
clomiphene Hypothetical cohort of adverse events Other outcomes Difference not statistically effectiveness ratios,
citrate for 10,000 patients with • Medical visits • Rate of ovulation significant clomiphene citrate was
ovulation sociodemographic and • Diagnostic and laboratory induction found to be cost‐
induction clinical characteristics tests • Clinical pregnancy Clinical pregnancy rat: effective compared to
similar to a group of • Laparoscopic surgery rate • Clomiphene citrate: 7.4% anastrozole
patients who were part a • Hospital admissions • Anastrozole: 10.5% ($405/QALY vs.
pilot study • Transportation Information sources Difference not statistically $427/QALY)
• Work loss • Meta‐analysis of 2 significant
Analysis • Patient out‐of‐pocket clinical trials Limitations
Constructed a decision expenses • Small primary study Cost per patient • No information on
tree with Markov (pilot study) at same Cost per patient (in US how utilities were
modelling comparing Information sources institution dollars) determined or QALYs
clomiphene citrate to • Mexican department of • Source of utility • Clomiphene citrate: were calculated was
anastrozole finance estimates not reported $1,644 provided
• Patients entered 1 of 3 • Government reports • Anastrozole: $1,816 • Conclusions were
states after treatment: • Private clinic based on average cost‐
pregnancy, ovulation, or • Patient questionnaire utility ratios, rather
anovulation Cost‐effectiveness (in US than incremental cost‐
Other dollars) utility ratios; this
Perspective Costs reported in 2009 dollars • Clomiphene citrate: $405 makes interpretation
Societal per QALY difficult
• Anastrozole: $427 per • No quality
Time horizon QALY assessment of
1 year effectiveness data was
One‐way sensitivity analysis performed
Sensitivity analysis Did not change cost‐ • Most of the data
One‐way varying cost of effectiveness came from a single
drug treatment and small pilot study;
probabilities of therefore, the findings
pregnancy and ovulation may not be
generalizable
Studies of interventions related to stage of embryo at transfer
Alvero et To compare the Study type: Costs included Main outcome Pregnancy rate Conclusion
al.356/United cost of day 3 Cost‐effectiveness Prenatal and neonatal care Pregnancy rate • Day 3 embryo transfer: Blastocyst transfer was
States/2003 embryo transfer analysis costs – no further details 34% found to result in a
244

Author/Country/
Year of Purpose of
to blastocyst provided Information source • Blastocyst transfer: higher chance of
Abstract transfer Patient population • Published literature 55% pregnancy and fewer
Not specified Information source Difference statistically multiple gestations
• Charges from local significant
Analysis experience Limitations
Constructed a decision • Published literature Average cost per transfer • Limited information
model comparing day 3 (assuming no fetal provided in the
embryo transfer to reduction) (in US dollars) abstract
blastocyst transfer and • Day 3 embryo transfer: • Cost elements
included fetal reduction $28,116 included were not
as an option – no further • Blastocyst transfer: clearly specified
details provided $23,420 • Assumptions about
•Different analyses were selective fetal
run under various Average cost per transfer reduction may not be
assumptions about (assuming fetal reduction generalizable
whether a couple would and, therefore, no higher
undergo selection order multiple births) (in US
reduction from a HOM to dollars)
twins • Day 3 embryo transfer:
$22,470
Perspective • Blastocyst transfer:
Not specified $21,260

Time horizon Sensitivity analysis
Not specified Under a wide range of
probabilities (not provided
Sensitivity analysis in the abstract), blastocyst
Probabilistic – no further transfer remained cheaper
information provided
Studies of interventions for male infertility
Meng et To estimate the Study type Costs included Main outcomes Post‐vasectomy infertility Conclusion
al.355/United cost‐effectiveness Cost‐effectiveness • Microsurgical vasovasotomy • Probability of reversal Vasectomy reversal was In general, surgical
States/2005 of surgical analysis • Microsurgical patency of vasectomy more cost‐effective than treatment is more cost‐
therapy and ART varicocelectomy • Pregnancy rates after ICSI except at low reversal effective than ART
for varicocele and Patient population • IVF/ICSI cycle and IUI cycle IVF treatment patency rates – observed
vasectomy Hypothetical groups of across all pregnancy rates Limitations
245

Author/Country/
Year of Purpose of
reversal males seeking fertility Information source Other outcomes (from 10% to100%) if • Limited information
after varicocelectomy or Published data from • Cost per pregnancy patency rates were>79% on methods provided
vasectomy institution where treatments • No rationale for
took place Information source Varicocele‐associated success rates selected
Analysis Published literature infertility: from the publish
Created two decision Cost‐effectiveness literature for the model
models for depended on both the were provided
varicocelectomy and post‐operative pregnancy • Did not provide
vasectomy patients rate and the sperm count evidence to support
• Included IUI, along with the validity of the
sperm retrieval/ICSI in Surgical repair was more treatment pathway for
the ART treatment cost‐effective than ART the model
• Assumed 50% of when the post‐operative • Did not include
couples would pursue pregnancy rate was > 15% patient costs (social or
additional therapy after in men with a pre‐operative monetary) in the
primary treatment failure sperm count of < 10 female partner or
million, and when the indirect costs to the
Perspective pregnancy rate was > 45% male (e.g., time lost
Payer/healthcare system and the sperm count < 10 from work)
million • Did not include the
Time horizon effects of age on
Not specified maternal reproductive
potential
Sensitivity analysis • The cost‐
Performed one‐way and effectiveness appeared
two‐way sensitivity to depend on the
analyses on reversal patency rate being
patency rates and >79%, which may not
pregnancy rates be achievable in all
centres.
Hsieh et To determine the Study type Costs included Main outcome Cumulative pregnancy rate Conclusions
al.354/United cost‐effectiveness Cost‐effectiveness Out‐of‐pocket costs Clinical pregnancy • Immediate ART: 99.4% At a willingness to pay
States/2006 of ARTs compared analysis • Vasectomy reversal first: up to $65,000
with vasectomy Other outcomes 95.3% vasectomy reversal
reversal Patient population Information sources N/A was more cost‐
Hypothetical cohort of • Published national averages Average number of IVF effective than
246

Author/Country/
Year of Purpose of
100,000 men with post‐ • Institutional costs Information sources cycles immediate IVF
vasectomy infertility • Published literature • Immediate ART: 2.5
undergoing either ART or • Expert opinion • Vasectomy reversal first: Limitations
vasectomy reversal • SART National 1.6 • Assessed pregnancy
(50,000 in each Summary Mean costs: rates rather than live
treatment a • Immediate ART: $31,399 birth rates
• Vasectomy reversal first: • Did not include
Analysis $29,274 multiple births
Constructed a Markov • Did not include
model comparing initial One‐way sensitivity analysis indirect costs
ARTs with vasectomy • Female partner age • Assumed a cross over
reversal affected cost‐effectiveness to ART after 2 failed
• Assumes after 2 failed more profoundly than vasectomy reversal
vasectomy attempts, the obstructive interval attempts
latter arm crosses over to
ART (1 year interval Net Health Benefit (NHB)
between second failed At a willingness to pay of
reversal attempt and $100,000:
cross‐over to ART) • When female partner age
• ART cycles performed was varied from 25 to 50
every 3 months as years, NHB for vasectomy
needed reversal varied from 0.82 to
• Assumed infertility in 0.38
men was solely due to • When female age was
obstruction and held constant and
pregnancy rates after obstructive interval varied
subsequent IVF cycles from 0 to 20 years, NHB for
and vasectomy reversals vasectomy reversal varied
were the same as those from 0.681 to 0.683
after initial IVF cycles and
vasectomy reversals At a willingness to pay up
to $65,000 vasectomy
Perspective reversal was more cost‐
Patient effective than immediate
IVF
Time horizon
247

Author/Country/
Year of Purpose of
Until pregnancy is
achieved or for 3 years,
whichever comes first

One‐way performed on
all variables (including
age of female partner
and obstructive interval)
Hollingsworth et • To estimate the Study type Costs included Main outcome Cost per live birth if birth Conclusion
al.99/Australia/2007 incremental cost‐ • Cost‐effectiveness • Treatment costs (including Live birth rate rate is 10% (in 2003 For some indications,
effectiveness of analysis procedure, embryologist, Australian dollars) ICSI was found to offer
intracytoplasmic • Cost analysis disposable and capital costs, Othery outcomes • ICSI with ejaculated additional benefits, but
sperm injection etc.) Fertilization sperm: $22,000 to $35,000 at a substantial cost
(ICSI) using Patient population • Hospital admissions • ICSI with surgical sperm
ejaculated versus Two groups of patients • Pharmaceuticals Information sources resection: $35,000 to Limitations
surgically • ICSI with surgical sperm • Published literature $50,000 • Assumed pregnancy
extracted sperm collection for obstructive Information sources (systematic review and rates remained
azoospermia • Private fees at 2 IVF clinics meta‐analysis of trials Cost per live birth if birth constant
• To estimate the • ICSI with ejaculated in Australia comparing fertilization rate is 15% (in 2003 • Assumed number of
total costs of ICSI sperm for severe male • Australia Department of outcomes for ICSI Australian dollars) cycles stayed constant
factor infertility or Health and Ageing (Medical • Government report • ICSI with ejaculated • Long‐term costs were
patients unsuitable for Benefits Schedule) sperm: $14,667 to $23,333 not included
IVF Assumptions • ICSI with surgical sperm
Assumptions • Typical number of resection: $23,333 to
Analysis • Additional cost of surgical cycles is 4‐5 $33,333
• Assessed additional sperm retrieval (above • Half of the treatments
costs and live births standard IVF cycle) was may involve a frozen Cost per live birth if birth
compared with current between $1,959 and $2,298 embryo rate is 20% (in 2003
services for the 2 patient • Cost of ICSI with ejaculated • Absolute risk of at Australian dollars)
groups identified above sperm was between $2,200 least 1 live birth per • ICSI with ejaculated
and $3,500 cycle under ICSI was sperm: $11,000 to $17,500
• Used resource‐based between 0.10 and 0.27 • ICSI with surgical sperm
costing to estimate costs resection: $17,500 to
$25,000
• In 2003 Australian
248

Author/Country/
Year of Purpose of
dollars Total cost
• ICSI with ejaculated
Perspective sperm: $2,200 to $3,500
• Payer/healthcare • ICSI with surgical sperm
system resection: $3,500 to $5,000
• Patient
Budget impact (per annum)
Time horizon • ICSI with ejaculated
Not specified sperm: $2.8 to 6 million
(10‐15% of ICSI cycles)
Sensitivity analysis • ICSI with surgical sperm
One‐way resection: $25‐25.3 million

Incremental cost‐
effectiveness of ICSI with
surgical sperm retrieval
(incremental cost per birth):
• In patients who are not
candidates for standard
IVF: $8,500 to $13,400
• In patients with
subnormal semen
indication: $3,636 (no
benefits)

249

Table 41. Studies of the effects of ARTs policies on costs

Author/Country/Year
of publication Study details Findings Comments
Chambers et al.77 Description •Savings over the period of 2003‐2008 • This study could significantly

Australia/2011 • Study type: cost analysis due to theoretically predicted underestimate the long‐term
• Costs included: reductions in multiple births compared health care costs associated
• Hospital costs—cost of caring for mothers and to 2002 were estimated to be AU$47.6 with multiple birth infants,
their infants, born as a result of ART treatment, million since only hospital birth‐
during hospitalization from admission for birth to • The estimated saving was attributable admission costs were included
first separation for singleton, twin and triplet to savings from reduced twin deliveries • Note: the cost of pregnancy
births. These costs were adjusted to correct for of AU$54.4 million and from reduced was not included
private‐public patients and private‐public hospital triplet deliveries of AU$11.3 million
mix, and reflects only the government’s portion of • There was also an increase in public
these costs expenditure of an estimated AU$21.0
• ARTs costs—cost to the Australian Medicare million due to increased number of
Program for one ART treatment (1 fresh embryo singleton deliveries
transfer plus 1 frozen/thawed embryo transfer
cycle) calculated from annual service counts and
benefits paid for ART service, ART planning and
management, oocyte retrieval, semen preparation,
fresh embryo transfer, frozen/thawed embryo
transfer, and ICSI
• An estimate of the cost of drugs borne by
government was also included
•Method: theoretical cost savings were determined by
first estimating the cost savings for each year after 2002
(by calculating the number of multiple births that would
theoretically have resulted if the 2002 rates of multiple
births had persisted in years 2003‐2008) and then
subtracting the theoretical numbers for each year from
250


Author/Country/Year
the actual number for that year

Purpose
• To measure cost savings from the reduction of
multiple births associated with IVF since 2002 and
determine the theoretical number of IVF treatments
publicly funded through these savings
Chambers et al.73 Description •Assuming that trends in numbers of • Note: this study included
Australia/2012 • Study type: cost analysis cycles undertaken prior to 2010 would ARTs procedure‐related costs
• Costs included: costs to the Australian Medicare have continued unchanged if the policy only, and did not appear to
system of cancelled ART treatment before oocyte had not been implemented, it was include any costs of hospital
retrieval, planning & management of ART with IUI, estimated that AU$84.2 million would care or the long‐term effects
ovulation induction for IUI, oocyte retrieval, semen have been saved in the year following of treatment
preparation, fresh embryo transfer cycles, frozen its implementation
embryo transfer cycles, and ICSI • The estimated AU$84.2 million
• The costs comprised benefits paid to the provider, savings was compromised of AU$68.2
fees charged, Medicare benefits paid, and out‐of‐ million in fresh cycles, AU$8.5 million in
pocket expenses for each treatment cycle type frozen cycles, and AU$7.6 million in IUI
•Overall costs to the Medicare program between 2008 cycles
and 2010 were anticipated from two sources: first, from • When adjustment for anticipatory
the cap policy limiting reimbursement, and second, behaviour was made, the overall
from reduced Medicare benefits for certain services savings dropped to AU$76.2 million
between 2008 and 2010
• Cost savings were estimated in three steps:
(1) Calculating the difference between the actual
number of cycles in 2010 and the theoretical
number that have taken place if the 2008
EMSN cap policy had not been introduced, and
then multiplying this difference by the average
Medicare benefits before the policy
(2) Multiplying the difference between the actual
251


Author/Country/Year
(2010) and theoretical (on the basis of 2008)
Medicare benefits per cycle by the actual
number of 2010 cycles
(3) Adding the resulting values together to achieve
total costs
• Cost savings calculations were repeated to adjust for
“anticipatory behaviour”, i.e. since three months
passed between announcement and implementation of
the policy, there may have been an incentive for
patients to try and obtain treatment before 2010

Purpose
• To evaluate the impact of the 2009 Extended
Medicare Safety Net (EMSN) caps, which limit
reimbursement to 80% (once an annual threshold of
outpatient medical services is reached), including the
savings achieved and the reduction in the number of
IVF and IUI births
Dietrich358 Description • Between 2002 and 2005, the cost of
Germany/2010 • Study type: cost analysis reimbursement for medical benefits fell
• Costs included: physicians’ services for all individual by about €42.2 million (73%) in the SHI
treatments for reproductive treatments, a fixed group, and €2.8 million (63%) in the TK
percentage for additional general medical services, and group
drug prescriptions • Drug expenditures in the TK group
•Methods: Data were analyzed for all members of the declined by about €14 million (72%)
SHI (covering 86% of the German population) and the from 2002 to 2005
members of the Techniker Krankenkasse subgroup (TK;
or technicians insurance) separately

Purpose
• To measure the impact of the Statutory Health
252


Author/Country/Year
Insurance Modernization Act (2004) on the German
Statutory Health Insurance system, mandating a 50%
reimbursement reduction for ARTs while adding
restrictions on age and cycle number
Cabello357 Description • Estimated costs for the 2005/2006 • Both legislation and
Spain/2010 • Study type: cost analysis year: guidelines resulted in a
• Costs included: exclusively neonatal costs Own eggs: reduced mean estimated cost
•Methods: the average costs of neonatal care for No legislation or guidelines— €90.0 of deliveries
singleton, twin, and triplet or HOM deliveries precisely million • The average reduction since
published was used Legislation but no guidelines— €79.6 the inception of the guidelines
• Numbers of deliveries were obtained from the million was €9,741,715, with a range
assisted reproductive treatment register of the Spanish Legislation and guidelines— €74.8 of € 890,187 and €18,593,242
Fertility Society, and adjusted for deliveries occurring in million
centres that are not ART clinics
Donated eggs:
Purpose No legislation or guidelines— €28.6
• To measure the impact of (a) a 2003 Spanish decree million
limiting the number of embryos transferred to 3, and Legislation but no guidelines— €30.6
(b) 2004 guidelines of the Spanish Fertility Society for million
the number of embryos to transfer depending on Legislation and guidelines— €25.7
maternal age, embryo quality, previous cycles, year and million
type of technique on costs and outcomes
Total:
No legislation or guidelines— €118.6
million
Legislation but no guidelines— €110.2
million
Legislation and guidelines— €100.5
million

253

Table 42. Studies of the effects of ARTs policies on utilization and outcomes
Studies of the effects of ARTs policies on utilization & outcomes
Author/Country/Year
of publication Study details Findings Conclusions
Chambers et al.77 Description (1) Change in birth rates
Australia/2011 • Study type: cost analysis and outcome • Singleton: 81.2% to 91.4%
study • Twins: 18.4% to 8.3%
• Outcomes measured: (1) reduction in • Higher order multiples (HOM): 0.6% to 0.2%
multiple birth rate

Purpose
• To determine the reduction in rates of
multiple births from 2002 to 2008
Chambers et al.73 Description (1) Impact on percentage of fresh cycles •The authors conclude that
Australia/2012 • Study type: cost analysis and outcome • Pre‐law: rates increased by 12% in 2008 and by approximately 1200‐1500
study 17% in 2009 ART‐conceived infants were
• Outcomes measured: (1) change in • Post‐law: rates decreased by: 33 years of age – not born in 2010 as a result of
percentage of fresh embryo transfer cycles, 14% (p<0.001), 34‐39 years of age – 21% (p<0.001), the reductions in IVF and IUI
(2) change in percentage of frozen embryo and 40 years of age ‐ 38% (p<0.001) cycles after the EMSN caps
transfer cycles, (3) change in percentage of were introduced
IUI cycles, (4) impact on overall number of (2) Impact on percentage of frozen cycles:
transfer cycles, and (5) impact on overall • Pre‐law: rates increased by 5% in 2008, and by 9%
percentage of transfer cycles in 2009

• Post‐law: rates decreased by: 33 years of age –
Purpose
6%, 34‐39 years of age – 8% , and 40 years of age
• To evaluate the impact of the Extended
– 7%
Medicare Safety Net (EMSN) caps

(introduced in 2009) on fresh and frozen IVF
(3) Impact on percentage of IUI cycles
cycles, IUI cycles, and overall number of
• Pre‐law: rates stayed the same in 2008 and 2009
transfers, and to determine the reduction in
the number of IVF and IUI births associated • Post‐law: rates decreased by: 33 years of age –
254

Author/Country/Year
with the cap policy 4%, 34‐39 years of age – 6%, and 40 years of age
– 12%

(4) Impact on overall number of transfer cycles
• Post‐law: number of cycles decreased by: 33
years‐ 732 cycles, 34‐39 year‐ 704 cycles, and 40
years‐ 1748 cycles

(5) Impact on overall percentage of transfer cycles
• Post‐law: rates decreased by 21% from 2009‐2010
Note: adjusting for anticipatory behavior (due to
time lag between announcement and
implementation of policy) decrease was measured
as 16% (or 8600 cycles)
Wang et al.359 /Australia Description (1) % of SET procedures: • The policy of shifting
and New Zealand/2009 • Study type: outcome study • 28.4% (2002), 32.0% (2003), 40.5% (2004), 48.2% towards SET has been
• Outcomes measured: % of SET procedures (2005), 48.2% (2006) successful in reducing
multiple embryo transfers
Purpose
• To compare the proportions of SET
procedures performed annually between
2002 (when the Reproductive Technology
Accreditation Committee advocated
reduction in number of embryos
transferred) and 2006
Gordts360/Belgium/2005 Description (1) Mean number of embryos transferred
• Study type: outcome study • Pre‐law: 2.00
• Outcomes measured: (1) mean number of • 6 months post‐law: 1.98
embryos transferred, (2) ongoing • 12 months post‐law: 1.60
pregnancies, and (3) multiple births
(2) Ongoing pregnancy rate
Purpose • Pre‐law: 29%
• To measure the impact of 2003 legislation • 6 months post‐law: 29%
255

Author/Country/Year
allowing the public funding of laboratory • 12 months post‐law: 29%
services for up to 6 cycles IVF on
pregnancies and multiple births (3) Multiple births
• The legislation set conditions: • Pre‐law: 29.4%
• Women < 35 years, the 1st IVF cycle • 5 months post‐law: 6%
must be SET; for the 2nd, it must be • 12 months post law: 3%
SET if a good quality embryo is
available (DET if not); for the third
cycle on, DET is permitted
• Women aged 36 to 39, the 1st cycle
can be DET and TET is permitted
subsequently
• Women 40 to 42 years of age, no
restrictions
Debrock et Description (1) Mean number of embryos transferred • The authors conclude that
al.361/Belgium/2005 • Study type: outcome study • Pre‐law: 1.66 + 0.77 introduction of the legislation
• Outcomes measured: (1) embryo transfer • Post‐law: 1.27 + 0.61 (p<0.0001) resulted in a 3‐fold reduction
rate, (2) clinical pregnancy rate, and (3) of multiple pregnancy rate
multiple pregnancy rate (2) Clinical pregnancy rate per transfer (overall) per clinical pregnancy in their
• Pre‐law: 37.5% centre while the pregnancy
Purpose • Post‐law: 32.5% rate per embryo transferred
• To measure the impact of the 2003 did not change significantly
Belgian legislation limiting the number of (3) Multiple pregnancies per clinical pregnancy
embryos transferred • Overall: pre‐law – 25.9%, post‐law – 8.0%
(p<0.0001)
• < 36 years: pre‐law – 26.5%, post‐law – 6.6%,
(p<0.0001)
• 36 – 39 years: pre‐law – 23.8%, post‐law – 17.9%
• 40 – 42 years: pre‐law – 20%, post‐law – 0%
Bissonnette et Description (1) Clinical pregnancy rate (per embryo transfer) • Note:No statistical analyses
al.121/Quebec/2011 • Study type: outcome and utilization study • 42.8% in 2009, 32% in 2010 (< 35 years – 40%, 35‐ of data were reported
• Outcomes measured: (1) clinical 39 years – 32%, > 39 years – 17%)
pregnancy rates, (2) use of eSET, and (3)
256

Author/Country/Year
multiple pregnancy rates (2) Rate of eSET
• 1.6% in 2009, 50% in 2010 (< 35 years – 79%, 35‐
Purpose 39 years – 45%, > 39 years – 12%)
• To measure pregnancy rates in the first 3
months following provincial legislation in (3) Multiple pregnancy rate
2010 providing public funding of IVF, with • 25.6% in 2009, 3.7% in 2010 (< 35 years – 1.1%,
the following restrictions: 35‐39 years – 5.6%, > 39 years – 8.5%)
• The policy provides for any woman
of reproductive age to have up to 3
cycles of IVF with ovarian stimulation
or 6 cycles of natural or modified
natural cycle at no cost
• Only 1 embryo can be transferred in
either a fresh or frozen cycle; up to 2
embryos may be transferred in a
woman 36 years or younger and up to
3 embryos (including no more than 2
blastocysts) may be transferred in a
woman 37 years or older
Ouhilal et Description (1) Mean number of embryos transferred • After the law, the risk of
al.370/Quebec/2012 • Study type: outcome study • < 35 years: pre‐law – 2.0, post‐law – 1.0 multiple pregnancies
• Outcomes measured: (1) mean number of • 35 – 39 years: pre‐law – 2.4, post‐law – 1.3 decreased in women less
embryos transferred, (2) clinical pregnancy • ≥40: pre‐law – 3.0, post‐law – 2.0 than 35 years of age without
rates and (3) multiple pregnancy rates compromising clinical
(2) Clinical pregnancy rate pregnancy rates, however,
Purpose • Overall: pre‐law – 38%, post‐law – 29% (p=0.002) women between 35 and 39
• To determine the effect of the 2010 • < 35 years: pre‐law – 46.6%, post‐law – 41.2% years experienced a
Quebec law on clinical pregnancy rates in (p=0.34) significant reduction in the
specific age groups • 35 – 39 years: pre‐law – 40%, post‐law – 27.1% chance of a pregnancy
(p=0.008) • Note:This is an abstract
• ≥40: pre‐law – 22.1%, post‐law – 17.3% (p=0.4)

(3) Multiple pregnancy rate
257

Author/Country/Year
• Overall – pre‐law: 30.2%, post‐law: 4.8% (p<0.001)
• < 35 years: pre‐law – 41%, post‐law – 1.6%
(p<0.001)
• 35 – 39 years: pre‐law – 22%, post law – 5.3%
(p<0.01)
• ≥40: pre‐law – 21.1%, post law – 12.8% (p=0.3)
Dahan et Description (1) Pregnancy rate • Having 2 or 3 embryos
al.369/Quebec/2012 • Study type: outcome study • SET: 40 years – 11%, 41 years – 8%, 42 years – 5%, transferred improved
• Outcomes measured: (1) clinical 43 years – 11% pregnancy rates compared to
pregnancy rates and (3) multiple pregnancy • DET: 40 years – 21%, 41 years – 16%, 42 years – SET (p<0.05)
rates 9%, 43 years – 9% • The authors conclude that
• TET: 40 years – 33%, 41 years – 17%, 42 years – the chances of pregnancy
Purpose 17%, 43 years – 12% increase with the transfer of
• To determine the effect of the 2010 more than 1 embryo;
Quebec law on clinical pregnancy rates in (2)Multiple pregnancy rate however, the multiple
women 40 years and older; one objective of • SET: 0% pregnancy rate in this age
the law was to keep multiple pregnancy • DET:40 years – 20%, 41 years – 14%, 42 years – groups remains over 10%
rates below 10% 28%, 43 years – 0% • Note: This is an abstract
• TET: 40 years – 11%, 41 years – 13%, 42 years –
16%, 43 years – 0%
Son et Description (1) Mean number of embryos transferred • It was concluded that
al.371/Quebec/2012 • Study type: outcome study • Pre‐law: 3.5 + 0.9 further studies are required
• Outcomes measured: (1) mean number of • Post‐law: 1.5 + 0.5 (p<0.001) to choose a viable embryo “to
embryos transferred, (2) clinical pregnancy reduce multiple pregnancy
rates, and (3) multiple pregnancy rates (2) Embryo implantation rate rate even in the IVM
• Pre‐law: 17.0% program”
Purpose • Post‐law: 23.8% • Note: This is an abstract,
• To determine the effect of the 2010 and the analysis and
Quebec law on clinical pregnancy rates in (3) Clinical pregnancy rate conclusions are not
women with polycystic ovaries undergoing • Pre‐law: 43.3% consistent with each other
in vitro maturation (IVM) • Post‐law: 31.7%

258

Author/Country/Year
• Pre‐law: 29.9%
• Post‐law: 11.5%
Vélez et Description (1) Rate of SET •It was concluded that
al.368/Quebec/2013 •Study type: outcome study •One year pre‐law: 17.3% Quebec’s law providing public
•Outcomes measured: (1) Rate of SET, (2) •One year post‐law: 85.0% (vs. pre‐law p<0.001) funding with restrictions has
ongoing pregnancy rates, and (3) multiple decreased multiple
pregnancy rates (2) Ongoing pregnancy rate after fresh IVF cycle pregnancy rates and
•Pre‐law (2009): 31.9% maintained an acceptable
Purpose •One year post‐law: 23.3% (vs. pre‐law p=0.001) cumulative ongoing
•To determine the effect of the 2010 pregnancy rate.
Quebec law on ongoing pregnancy rates (3) Multiple pregnancy rate after fresh IVF cycle •Note: in the pre‐law cohort
and multiple pregnancy rates •Pre‐law (2009): 25.8% and the post‐law cohort, the
•One year post‐law: 1.6% (vs. pre‐law p<0.001) average patient ages were
35.2±4.4 years and 35.4±4.4
years
Tulandi et Description (1) Patients with household income < CAN$65,000 • The demographic
al.372/Quebec/2013 • Study type: utilization study • Pre‐law: 36.7% characteristics of IVF patients
•Outcomes measured: change in • Immediately post‐law: 42.5% (vs. pre‐law p=0.05) at the two fertility clinics in
demographic characteristics of IVF patients: • 8 months post‐law: 47.4% (vs. pre‐law p=0.02) Montreal were affected by
(1) patients with household income < the change in reimbursement
CAN$65,000, (2) unemployed patients, (3) (2) Unemployed patients policy as access to treatment
patients without a university education, (4) • Pre‐law: 3.6% was provided to a more
patients receiving treatment for secondary • Immediately post‐law: 3.7% diverse patient population
infertility and (5) Caucasian patients • 8 months post‐law: 11.6% (vs. pre‐law p<0.001; vs.
immediately post‐law p<0.001)
Purpose
• To determine the effect of the 2010 (3) Patients without a university education
Quebec law on the demographic • Pre‐law: 68%
characteristics of patients seeking IVF • Immediately post‐law: 59.3% (vs. pre‐law p=0.007)
treatment at two fertility clinics in Montreal • 8 months post‐law: 63.1%

(4) Patients with secondary infertility
• Pre‐law: 14%
259

Author/Country/Year
• Immediately post‐law: 29%
• 8 months post‐law: 30%

(5) Proportion of Caucasian patients
• Pre‐law: 66.9%
• Immediately post‐law: 74.5% (vs. pre‐law p=0.03)
• 8 months post‐law: 62.8% (vs. immediately post‐
law p<0.001)
Dietrich358 Description (1) Number of treatments
Germany/2010 • Study type: cost analysis, outcome and • SHI: in 2002 – 73405, in 2003 – 104542 (42%
utilization study increase), in 2004 – 35352 (61% reduction), in 2005
• Outcomes measured: (1) number of –32099 (9% reduction)
treatments and (2) number of babies born • TK: in 2002 – 7089, in 2003 – 8723 (23% increase),
in 2004 – 4059 (53% reduction), in 2005 – 3191 (23%
Purpose reduction)
• To measure the impact of the Statutory
Health Insurance Modernization Act (2004); (2) Number of babies born
which mandated a 50% reimbursement • SHI: in 2002 – 12479, in 2003 – 20296 (63%
reduction for ARTs and added restrictions increase), in 2004 – 6851 (64% reduction), in 2005 –
on age and cycle number 6066 (11% reduction)
• Effects were measured in outpatient
health insurance members of the Statutory
Health Insurance (SHI) in total and in a
subgroup of the Techniker Krankenkasse
(TK; or technicians insurance)
Ciriminna et Description (1) Number of embryos transferred • The multiple pregnancy rate
al.365/Italy/2007 • Study type: outcome study • SET: pre‐law – 9.6%, post‐law – 22.9% (p<0.001) dropped statistically
• Outcomes measured: (1) number of • DET: pre‐law – 43.6%, post‐law – 35.1% (p<0.001) significantly after the law was
embryos transferred, (2) clinical pregnancy • TET: pre‐law – 34.2%, post‐law – 31.9% passed; however, the clinical
rate by number of embryos transferred, (3) • >TET: pre‐law – 6.7%, post‐law – 0% pregnancy rate also dropped
clinical pregnancy rate per transfer, (4) significantly
multiple pregnancy rate and (5) abortion • It was concluded that the
rate (2) Clinical pregnancy rate by number of embryos law imposes a restriction,
260

Author/Country/Year
transferred particularly on men with
Purpose severe non‐obstructive
• To measure the impact of the 2004 • SET: pre‐law – 12.3%, post‐law – 10.4%% azoospermia
legislation that restricts the maximum
number of embryos transferred to 3 and • DET: pre‐law – 33.1%, post‐law – 22.8% (p<0.01)
prohibits embryo selection and
cryopreservation • TET: pre‐law – 39.9%, post‐law – 34.6%
• >TET: pre‐law – 32.1%, post‐law – 0%

(3) Clinical pregnancy rate per transfer
• pre‐law: 33.4%
• post‐law: 23.8% (p<0.001)
• pre‐law: 33.4%
• post‐law: 23.8% (p<0.001)
(5) Abortion rate
• pre‐law: 17.2%
• post‐law: 22.5%
261

Author/Country/Year
Levi Setti et Description (1) Number of embryos transferred • Overall, there were no
al.366/Italy/2008 • Study type: outcome and utilization study significant changes in the
• Outcomes measured: (1) number of • Overall: SET – pre‐law :13.70%, post‐law: 10.19%; mean number of embryos
embryos transferred, (2) pregnancy rate, (3) DET – pre‐law: 35.71%, post‐law: 23.53% (p<0.001); transferred/cycle, and the
take home babies, (4) number of cancelled TET – pre‐law: 28.73%, post‐law: 37.56% (p<0.05) pregnancy rate/cycle,
cycles, (5) fertilization rate, (6) fertilization however, sub‐group analyses
failures, and (7) implantation rate • Mean number: pre‐law – 2.32, post‐law – 2.29 showed that in the case of
women who received 2
Purpose • <36: SET – pre‐law: 5.28%, post‐law: 11.06%; DET embryos and men who had
• To measure the impact of 2004 legislation – pre‐law: 90.38%, post‐law: 43.81%; TET – pre‐ severe male fertility factor
on pregnancy rates and implantation rates (very low motile sperm
law: 3.90%, post‐law: 45.12%
in a single IVF centre count), the pregnancy rate
dropped significantly after
• ≥36: SET – pre‐law: 10.44%, post‐law: 16.22%;
the law was passed
DET – pre‐law: 16.70%, post‐law: 41.95%; TET –
pre‐law: 72.86%, post‐law: 41.83%
(2) Pregnancy rate/cycle
• Overall:pre‐law – 23.3%, post‐law – 23.1%
• <36: SET – pre‐law: 8.70%, post‐law: 14.47%; DET
– pre‐law: 41.16%, post‐law: 30.90% (p<0.05); TET –
pre‐law: 47.06%, post‐law: 48.71%
• ≥36: SET – pre‐law: 16.00%, post‐law: 7.86%; DET
– pre‐law: 8.75%, post‐law: 17.40%; TET – pre‐law:
28.37%, post‐law: 27.98%
262

Author/Country/Year
(3) Take home babies (per cycle)
• Pre‐law: 19.1%

(4) Cancelled cycles
• Pre‐law: 15.01%
• Post‐law: 9.89% (p<0.001)

(5) Fertilization rate
• Pre‐law: 66.12%
• Post‐law: 75.36%

(6) Fertilization failures
• Pre‐law: 6.49%
(7) Implantation rate
• Pre‐law: 16.50%
263

Author/Country/Year
• Post‐law: 14.77%
La Sala et Description (1) Number of embryos transferred/cycle • Multiple birth rates fell

al.362/Italy/2008 • Study type: outcome and utilization study statistically significantly after
• Outcomes measured: (1) number of • IVF: pre‐law – 3.1 + 1.7, post‐law – 2.2 + 0.8 the law was passed, with no
embryos transferred, (2) pregnancy rates, (p<0.05) reduction in clinical
and (3) multiple births
pregnancy rates for all age
• ICSI: pre‐law – 3.1 + 1.7, post‐law – 2.2 + 0.7
Purpose groups.
(p<0.05)
• To measure the impact of the 2004
legislation after 2 years on an IVF program • Note: two years before and

at a single centre two years after the law were
(2) Pregnancy rate/cycle compared
• Overall: pre‐law – 19.8%, post‐law – 26.7%
(statistically significant)
• < 35 years: pre‐law – 15.4%, post‐law – 17.4%
• 35‐37 years: pre‐law – 15.5%, post‐law – 20.2%
(3) Birth rate
• Singleton: pre‐law – 69.0%, post‐law – 76.7%
264

Author/Country/Year
• Multiple: pre‐law – 31.0%, post‐law – 23.4%
La Sala et Description (1) Birth rates • Overall, outcomes were

al.363/Italy/2009 • Study type: outcome and utilization study improved after the law was
• Outcomes measured: (1) birth rates, (2) • Singletons: pre‐law – 49.7%, post‐law – 64.7% passed. In particular, multiple
gestational age, (3) birthweight, (4) (statistically significant) birth rates fell statistically
embryonic fetal loss and (5) neonatal
significantly
deaths • Twins: pre‐law – 39.1%, post‐law – 29.9%
(statistically significant) • Note:This was an extension
Purpose
• To measure the impact of the 2004 of the La Sala (2008) study
• HOM: pre‐law – 11.1%, post‐law – 5.4%
legislation after 3 years on an IVF program summarized above, and
at a single centre compared date from 3 years
before the law to 3 years
(2) Birthweight after the law
• < 1500 g: pre‐law – 7.7%, post‐law – 7.8%
• < 2500 g: pre‐law – 41.1%, post‐law – 34.8%
(3) Gestational age
• < 32 weeks: pre‐law – 3.2%, post‐law – 7.8%
265

Author/Country/Year
• ≤37 weeks: pre‐law – 52.5%, post‐law – 43.5%
(4) Embryonic and fetal loss
• Pre‐law: 30.7%
• Post‐law: 21.5% (statistically significant)
(5) Neonatal deaths/1000
• Pre‐law: 9.9
• Post‐law: 15.6
Levi Setti et Description (1) Mean number of embryos transferred • The ruling resulted in an

al.367/Italy/2010 • Study type: outcome and utilization study • Pre‐law: 1.74 + 1.11 increase in the mean number
• Outcomes measured: (1) number of • Post‐law: 2.04 + 1.20 of embryos transferred while
embryos transferred, (2) type of transfer, there were no significant
(3) fertilization rate, (4) fertilization failures, (2) Type of transfer differences in pregnancy rate
and (5) pregnancy rates • SET: pre‐law – 23.34%, post‐law – 16.14% (p<0.05) by plurality
• DET: pre‐law – 37.42%, post‐law – 24.02% • Note: This study compared
Purpose (p<0.001) a 17‐month period before the
• To measure the impact of a 2009 • >DET: pre‐law – 39.24%, post‐law – 59.85% ruling with a 7‐month period
Constitutional Court ruling that declared the (p<0.001) after
2004 law restricting the number of embryos
to be partially unconstitutional and leaving (2) Fertilization rate
the decision to patients and physicians • Pre‐law: 76.00 + 29.30
• Post‐law: 73.37 + 27.15 (p<0.001)

266

Author/Country/Year
(3) Fertilization failures
• Pre‐law: 5.38%

(4) Pregnancy rate/started cycle
• Overall: pre‐law – 20.42%, post‐law – 23.49%
(p<0.05)
• Singletons: pre‐law – 74.11%, post‐law – 71.43%
• Twins: pre‐law – 23.44%, post‐law – 26.98%
• Triplets: pre‐law – 2.46%, post‐law – 1.68%
La Sala et Description (1) Proportion of ART with IVF by age • Compared to the 5‐year
al.364/Italy/2012 • Study type: outcome and utilization study • < 35 years: pre‐law – 52.7%, post‐law – 50.9%; period before the law was
• Outcomes measured: (1) proportion of • 35‐37 years: pre‐law – 64.7%, post‐law – 47.2%; passed, the mean number of
IVF/ICSI treatments, (2) embryo transfer • 38 years: pre‐law – 70.5%, post‐law – 49.3%; embryos transferred and
rate, (3) clinical pregnancy rate and (4) birth • 39 years: pre‐law – 72.4%, post‐law – 44.9%; multiple birth rates dropped
rate • > 39 years: pre‐law – 66.5%, post‐law – 42.1% statistically significantly in the
5 years after, while clinical
Purpose (2) Mean embryo transfer rate pregnancy rates also dropped
• To measure the impact of the 2004 • Pre‐law: 3.1 + 2.1 statistically significantly
legislation after 5 years on an IVF/ICSI • Post‐law: 1.7 + 1.1 (p<0.01)
program at a single centre
(3) Clinical pregnancy rate (/ cycle)
• Pre‐law: 17.3%
• Post‐law: 14.8% (statistically significant)

(4) Birth rates
• Singletons: pre‐law – 58.3%, post‐law – 71.6%
• Twins: pre‐law – 31.4%, post‐law – 24.3%
• HOM: pre‐law – 10.3%, post‐law – 4.1%
267

Author/Country/Year
357
Cabello Description (1) Number of transfers
Spain/2010 • Study type: cost analysis, outcome and • 2002/2003 – 31387, 2004 – 27481, 2005/2006 –
utilization study 57758
• Outcomes measured: (1) number of
transfers, (2) number of embryos (2) Mean number of embryos transferred
transferred, (3) type of transfer, (4) number • 2002/2003 – 2.4, 2004 – 2.2, 2005/2006 – 2.1
of deliveries, and (5) number of pregnancies
(3) Type of transfer
Purpose • SET: 2002/2003 – 11.8%, 2004 – 13.3% (p<0.05),
• To measure the impact of (a) a 2003 2005/2006 – 14.5% (p<0.05)
Spanish decree limiting the number of • DET: 2002/2003 – 40.3%, 2004 – 49.8%,
embryos transferred to 3, and 2005/2006 – 56.8%
(b) 2004 guidelines of the Spanish Fertility • TET: 2002/2003 – 39.1%, 2004 – 36.9% (p<0.05),
Society for the number of embryos to 2005/2006 – 28.6% (p<0.05)
transfer depending on maternal age, • >TET: 2002/2003 – 8.8%, 2004 – no data,
embryo quality, previous cycles, year and 2005/2006 – no data
type of technique on costs and outcomes
(4) Number of deliveries
• Single: 2002/2003 – 70.2%, 2004 – 73.1%,
2005/2006 – 74.6%
• Twin: 2002/2003 – 29.8%, 2004 – 26.9% (p<0.05),
2005/2006 – 25.4%;
• HOM: 2002/2003 – 2.8%, 2004 – 1.8%, 2005/2006
– 1.4%

(5) Number of pregnancies (% per transfer)
• Singleton: 2002/2003 – 68.5%, 2004 – 72.6%,
2005/2006 – 74.6%;
• Multiple: 2002/2003 – 31.5%, 2004 – 27.4
(p<0.05), 2005/2006 – 25.4 (p<0.05)
Goswami et al.373 Description (1) Cumulative pregnancy rates •The outcome per treatment
/United Kingdom/2013 • Study type: outcome and utilization study • 23‐29 years: cycle 1 – fresh: 29.5%, fresh + frozen: reflects national data (28.9%
• Outcomes measured: (1) cumulative 33.6%; cycle 2 – fresh: 49.3%, fresh + frozen: 52.2%; vs. 33.4% clinical pregnancy
268

Author/Country/Year
pregnancy rates ( cycle 3 – fresh: 67.9%, fresh + frozen: 69.8% rate per embryo transfer,
• 30‐34 years: cycle 1 – fresh: 29.8%, fresh + frozen: 2010)
Purpose 34.61%; cycle 2 – fresh: 54.97%, fresh + frozen: • The freezing of embryos
•To measure the impact of the NICE 58.05%; cycle 3 – fresh: 65.14%, fresh + frozen: provides a small benefit in
recommendation that all sub‐fertile women 67.52% achieving pregnancy.
of <40 years of age receive three IVF • 35‐37 years: cycle 1 – fresh: 32.69%, fresh + •90.2% of women were likely
treatment cycles funded by NHS after its frozen: 33.97%; cycle 2 – fresh: 47.75%, fresh + to complete all 3 NHS‐funded
implementation at The Newcastle Fertility frozen: 51.71%; cycle 3 – fresh: 53.78%, fresh + cycles, with a median interval
Centre of Life in 2009 frozen: 57.28% of 11 months
• Additional limitations to qualify include: • 38‐39 years: cycle 1 – fresh: 28.23%, fresh + •Note: the study is limited by
the man must be over 23 years of age, the frozen: 29.84%; cycle 2 – fresh: 45.45%, fresh + its well‐defined geographical
woman must have a BMI between 19 and frozen: 46.68%; cycle 3 – fresh: 52.27%, fresh + population
30, the couple must be in a stable union of frozen: 53.34%
over 2 years and have at least 2‐years of
unexplained subfertility, neither partner
may have had previous children, and
neither had been sterilized
374
Stern et al. /United Description (1) Change in the % of transfers by embryo number • There were reductions in
States/2007 • Study type: outcome and utilization study • SET or DET: <35 years – 13% to 54% (p<0.001), 35‐ the number of embryos
• Outcomes measured: (1)rates of embryo 37 years and 38‐40 years –similar but less transferred over the 1996 to
transfer by number transferred, (2) HOM pronounced reductions, ≥40 years – 27% to 16% 2003 period, as well as in the
birth rates by age, (3)delivery rates by clinic • TET: <35 years – 30% to 34% (p<0.001), 35‐40 percentage of transfers for all
quartile, (4) birth rates by clinic quartile, years – similar but less pronounced reductions, ≥40 age groups that fell outside
and (5) % of transfers falling outside the years 17% to 14% the guidelines
1998 guidelines • >TET: <35 years – 58% to 12% (p<0.001), 35‐37 • There were reductions in
years and 38‐40 years –similar but less pronounced multiple births over this
Purpose reductions, ≥40 years – 56% to 67% period of time as well in
• To evaluate trends in numbers of embryos women less than 40 years of
transferred in SART member clinics (2) Change in % of HOM births age
between 1996 and 2003, and resulting HOM • < 35 years: 8.8% to 3.4% (p<0.01)
pregnancies, and to examine the • 35‐37 years: 6.0% to 3.2% (p<0.001)
relationship to SART‐ASRM embryo transfer • 38‐40 years and > 40 years: no change
guidelines of 1998 and 1999
269

Author/Country/Year
• The hypothesis was that there is a (3) Change in deliveries per cycle
temporal relationship between the • Quartile 1: 30.0% to 40.0%
publication of the 1998 and 1999 guidelines • Quartile 2: 28.4% to 37.7%,
and ART outcomes at SART member clinics • Quartile 3: 26.8% to 35.4%
• Quartile 4: 28.5% to 35.5%

(4) Change in birth rate
• Singletons: Quartile 1 – 58.0% to 63.6%, Quartile 2
– 58.8% to 62.1%, Quartile 3 – 55.2% to 59.8%,
Quartile 4 – 54.9% to 56.9%
• Twins: Quartile 1 – 33.7% to 34.2%, Quartile 2 –
31.5% to 34.7%, Quartile 3 – 36.5% to 35.4%,
Quartile 4 – 36.1% to 36.3%
• Triplets: Quartile 1 – 7.9% to 2.2%, Quartile 2 –
9.1% to 3.1%, Quartile 3 – 7.2% to 4.7%, Quartile 4 –
7.6% to 6.6%
• > triplets: Quartile 1 – 0.4% to 0.0%, Quartile 2 –
0.6% to 0.1%, Quartile 3 – 1.0% to 0.1%, Quartile 4 –
1.4% to 0.3%

(5) Change in % of transfers falling outside the 1998
guideline
• <35 years: 57% to 15%
• 35‐37 years: 28% to 7%
• 38‐40 years: 34% to 16%
• > 40 years: 20% to 14%
Dickey375/United Description (1) Change in multiple birth rates (per 1000) • Following the guidelines,
States/2007 • Study type: outcome and utilization study • Twins: ART – 436.1 to 431.9, all United States – the rate of high order
• Outcomes measured: (1) change in 26.8 to 31.5 multiple births as a fraction of
multiple birth rates from 1997‐2003, and (2) • Triplets: ART – 120.9 to 66.2, all United States – all ART births dropped
change in % of multiple births from 1997 to 1.58 to 1.74
2003 • Quadruplets: ART – 12.7 to 3.4, all United States –
0.15 to 0.14
270

Author/Country/Year
Purpose
• To assess how multiple births due to ARTs (2) Changes in % of multiple births
have changed since publication of the 1998 • Twins: ART – 10.5% to 16.3% of all multiple births,
SART guidelines recommending restriction natural conception – 73.2% to 62.7%, ‘unexplained’
in the number of embryos transferred – 16.2% to 21.0%
• Triplets: ART – 49.3% to 45.4% of all multiple
births, natural conception – 19.5% to 17.7%,
‘unexplained’ – 31.2% to 36.9%
• ≥ quadruplets: ART – 53.6% to 29.6% of all
multiple births, natural conception – 7.1% to 8.0%,
‘unexplained’ – 39.2% to 62.4%
Ryan et al.8/United Description (1) Mean number of embryos transferred • After the policy, multiple
States/2007 • Study type: outcome study • Pre‐mSBT: 2.1 + 0.6 gestation rates dropped
• Outcomes measured: (1)number of • Post‐mBST: 1.9 + 0.7 (p<0.05) statistically significantly,
embryos transferred, (2) ongoing while the ongoing pregnancy
pregnancies, (3) ongoing gestations, and (2) Ongoing pregnancy rate rates stayed similar
(4)embryo implantation rate • Pre‐mSBT: 57% • Note:This was an
• Post‐mSBT: 51% institutional policy, not a
Purpose national or system‐wide one
• To assess the impact of a strategy to (3) Ongoing gestations
reduce twin birth rates at 1 IVF program • Singleton: pre‐mSBT – 65%, post‐mSBT – 81%
using (1) an educational campaign, and (2) a • Multiple: pre‐mSBT – 35%, post‐mSBT – 19%
mandatory single‐blastocyst transfer in (p<0.05)
(mSBT) couples identified as high risk for
twins (4) Embryo implantation rate
• Pre‐mSBT: 43%
• Post‐mSBT: 42%
271

Table 43. Studies of utilization and outcomes of ARTs services
Author/Country/Year Outcomes
of publication Purpose of study Study design measured Findings Comments
Caserta et To compare maternal Study type Main outcomes 1) Mean gestational • Authors state that because
al.378/Italy/2008 and neonatal outcomes Outcome and utilization • Gestational age: ART group – 38.6 + the ART pregnancies have a
of ART‐conceived study age 1.6, control group – worse outcome in this study
pregnancies following compared to a matched
39.3 + 2.1 (p< 0.05)
the 2004 Italian law to Patient population • Birthweight control group, all ART
naturally conceived 358 women who were pregnancies should be
2) Mean birthweight:
pregnancies pregnant following ART • Major considered as high‐risk
ART group – 2650 g +
between February 2004 congenital
and October 2006, and a malformation 665 g, control group ‐
matched control group of 3241g + 351 g
304 women who had • Spontaneous (p<0.001)
spontaneous abortion
pregnancies. 3) Major congenital
• Preterm birth, malformation: ART
group ‐ 0.5% (1 baby),
• Gestational
control group ‐ 0%
hypertension
4) Preterm birth: ART
• Gestational
group – 13.9%, control
diabetes
– 10.5% (p<0.05)
• Placental
abruption 5) Gestational
hypertension: ART
Information group – 3.3%, control
source group – 1.3%
• Not specified
6) Gestational diabetes:
ART group – 1.1%,
272

control group – 0.6%
7) Placental abruption:
ART group – 1.1%,
control – 3.2%
Farquhar et To compare ART Study type Main outcomes 1) Rates of procedures: Conclusion

al.376/Australia and utilization and outcomes Outcomes study • Types of <35 years: ICSI – • The authors conclude that
New Zealand/2010 between New Zealand procedures by Australia 61.5%, NZ the eligibility criteria in NZ,
(where there are explicit Patient population age 60.4%; Blastocyst which limits funding to
eligibility criteria: All patients in ANZARD transfer – Australia infertile women who are
infertile women who are receiving ART services • Number of 27.7%, NZ 8.0% unlikely to conceive
unlikely to conceive between 2004 and 2007 embryos (p<0.01); SET – spontaneously, who are <40
2
spontaneously, who are transferred Australia 59.6%, NZ years old, with BMI<32 kg/m ,
<40 years of age, with Analysis 75.1% (p<0.01) and who do not smoke, have
2
BMI<32 kg/m , and who Comparison of • Live deliveries 35‐39 years: ICSI – resulted in a healthier
do not smoke) and differences in Australia 59.2%, NZ population of women
Australia (without such demographics and • Multiple births 55.0% (p<0.01); undergoing treatment and
criteria) treatment factors Blastocyst transfer – improved pregnancy
between Australia and Information Australia 26.7%, NZ outcomes.
New Zealand using the t‐ source 4.9% (p<0.01) SET –
2
test or X test; compared • ANZARD Australia 47.1%, NZ
rates of clinical 40.5% (p<0.01)
pregnancy, multiple >39 years: ICSI –
pregnancy and live Australia 57.9%, NZ
delivery rates ratios 51.1% (p<0.01);
Blastocyst transfer –
Australia 22.2%, NZ
2.8% (p<0.01): SET –
Australia 35.8%, NZ
20.3% (p<0.01)
2) Live deliveries/cycle
<35 years: SET cleavage
273

embryo – Australia
27.6%, NZ 35.5%
(p<0.01); SET blastocyst
– Australia 37.4%, NZ
44.5% (p<0.01); DET
cleavage embryo –
Australia 33.8%, NZ
41.7% (p<0.01); DET
blastocyst – Australia
33.8%, NZ 55.6%
35‐39 years: SET
cleavage embryo –
Australia 16.8%, NZ
26.2% (p<0.01); SET
27.8%, NZ 32.0%; DET
cleavage embryo –
Australia 23.3%, NZ
34.4% (p<0.01); DET
25.6%, NZ 41.9%
(p<0.02)
>39 years: SET cleavage
embryo – Australia
4.6%, NZ 8.2% (p<0.05);
SET blastocyst –
Australia 12.1%, NZ
44.4% (p<0.05); DET
cleavage embryo –
Australia 8.6%, NZ
17.5% (p<0.001); DET
13.6%, NZ 26.3%
274

3) Multiple births:
<35 years: Twins –
Australia 25.3%, NZ
18.6%; HOM – Australia
0.9%, NZ 0.7%
35‐39: Twins –
Australia 23.3%, NZ
0.8%, NZ 0.2%
>39: Twins – 15.2%, NZ
0.2%, NZ 0%
Lande et Measure long‐term Study type Main outcome 1) In the follow‐up Conclusions
al.377/Israel/2010 success rates (based on Outcome study • Live births period (5‐7 years) 120 • The authors conclude that
live births) of women (89.6%) had a young women in a cost‐free
unrestricted, free IVF Patient population Information live birth, with no IVF system have a very high
treatment in Israel 134 women under the source triplets recorded chance of birthing a child.
age of 35 years with • Patient files
primary infertility who 2) In the first year, over
st
started their 1 IVF cycle • Follow‐up 60% had a live birth;
at one IVF centre telephone within 4 years 85.1%
between January 2001 interviews from had a live birth; within
and December 2002 with one IVF centre 6 years 88.5% had a live
a minimum of 12 months in Israel birth
infertility before
treatment 3) 54.5% had a live
birth after 3 cycles;
Analysis 81.3% after 8 cycles;
Descriptive statistical remaining live births
analyses, with a t‐test to achieved by cycle
evaluate differences number 19
between study
participants and those 4) 76.7% of live births
275

who were lost to follow were achieved by IVF or
up or refused to ICSI, and 9.2% with
participate. Cumulative thawed embryos; 2.5%
probability of the first live by IVF with donor
birth was estimated sperm; 1.7% from IUI
according to the Kaplan‐ with donor sperm, and
Meier method, according 0.8% from egg
to IVF cycle number and donation. 9.2%
years of treatment. resulted from
spontaneous
pregnancies.
Gremeau et To assess the outcome of Study type Main outcome 1) Average embryo • The authors explain the
al.379/France/2011 an eSET policy for the 1st Outcome and utilization • Number of transfer : eSET‐ 1.2 + finding of significantly higher
and 2nd IVF/ICSI cycles in study embryos 0.6, DET – 1.5 + 0.7 length of stay in the eSET
transferred
one institution, and to (p<0.001) group as being due to 2
Patient population
assess the feasibility of 611 women (undergoing • Birth rates extremely long
applying this policy 2) Singletons: eSET – hospitalizations for singletons
a total of 783 attempts)
97.8%, DET – 65.7% with cardiac defects. The
under the age of 36 years • Birthweight
at their 1st and 2nd (p<0.001) authors speculate regarding
IVF/ICSI cycles, and had 2 • Malformations the feasibility of
embryos of good quality 3) Twins – eSET – 2.2%,
implementing an eSET policy.
observed at day 2. Either • Neonatal DET – 34.3% (p<0.001)
Based on previous work, in
eSET or DET was death
performed 4)Birthweight: eSET ‐ 41% of cases, women
• Hospitalization 3135.1 g + 525 g, DET – entering an ART course are
Analysis 2808.3 g + 746 g inclined to desire twins. Most
The group undergoing • Length of stay (p<0.001) women also do not see a twin
eSET (442 attempts) was pregnancy as a complication.
compared to the group Information 5) Malformations: eSET The authors conclude that an
undergoing DET (341 source – 2.2%, DET – 0.7%
2 incentive system might have
attempts), using or • Not specified,
Fisher’s exact test, and presumably to be instituted in Belgium
6) Hospitalization: eSET
276

the t‐test institutional – 6.6%, DET – 18.9% too create a functional policy.
source (p<0.05)
7) Length of stay: eSET ‐
37.5 + 59.5 days, DET –
12.1 + 11.0 days
(p<0.05)
8)Neonatal death: eSET
– 0.7%, DET – 4.3%

277

Table 44. Studies on actual costs related to ARTs services
Studies on actual costs related to ART services
of publication Purpose of study Study design Costs included measured Findings Comments
390
Alvero et al. / • To assess the impact of Study type Costs included Main outcome • Introduction of a Limitations
United States/2003 blastocyst transfer and Cost‐effectiveness • “Direct and •Number of policy on embryo • Very limited data
reduction in number of analysis. indirect costs” HOM deliveries number transferred provided in the
embryos transferred on (January 1998) abstract.
higher order multiple Patient population Information resulted in a
births 1622 patients who sources reduction in higher‐ • Unclear what costs
initiated an ART cycle • Not specified order multiple were included, and
from Jan 1997 to Dec gestations, from the authors refer to a
2000. 13.9% to 4.5%, “family charge”,
between 1998 and without explaining
Perspective 2000. how this was
Payer/health system computed.
• The estimated
Time horizon charge for a triplet
3 years gestation is
$109,765; if the
Analysis HOM rate is reduced
The charge to a from 13.9% to 4.5%,
family for a triplet it is estimated that
IVF gestation and the the costs to the
impact of a reduction medical system will
in HOM pregnancies be decreased by
were calculated. $1,031,791 per 100
cycles.
Lukassen et al.385/ • To determine the Study type Costs included Main outcome • The number of low Limitations
Netherlands/2004 difference in costs Cost‐effectiveness • Hospital charges • Plurality of birth weight (<2500 • This analysis
between singleton and analysis. for antenatal care birth g) babies was stopped at 6 weeks
twin pregnancies after (gynecologist or significantly higher after delivery and so
IVF treatment Patient population midwifery services) Information among twins than longer term disability
278

A representative source singletons (51% vs. costs were not
sample of 135 • Delivery costs • Hospital 3%); for very low included.
singleton (home delivery, birth weight (<1500
pregnancies and 144 complicated and g) the rates of 5.9% • As well,
twin pregnancies complicated (singletons) and productivity costs
from one centre delivery and 1.5% (twins) were during pregnancy
after IVF treatment caesarian section) also statistically were also not
(IVF/ICSI/cryo‐ significantly included.
IVF/cryo‐ICSI) • Maternal different.
hospitalization and • Finally, the authors
Perspective NICU costs. • Maternal age at note that if costs of
Payer/heath system delivery averaged pregnancies resulting
• Costs up to 6 33.2+3.6 for still births are
Analysis weeks after singletons and included, the
The two groups of delivery were 34.5+3.4 for twins. estimated
pregnancies were included and differences would be
compared using the adjusted to 2003 • The mean total a conservative
Mann‐Whitney U‐ values. Cost of the cost per twin estimate of the true
test fertility treatment pregnancy was difference. The
itself was not significantly higher experience at their
Sensitivity analyses included. than per singleton centre is that 5% of
Conducted on the pregnancy (€13469 twin pregnancies
cost per maternal or Information vs. €2549). This was resulted in stillbirth
neonatal hospital sources due mainly to (between 1995 and
day • Danish National increased number of 2001) compared to
Health Tariffs maternal and 2% for singletons.
Authority and a neonatal admissions
published source. and increased
Cost of antenatal lengths of stay.
care based on
charges. • Sensitivity analysis
on hospital days (the
• Hospitalization major cost driver)
279

and ICU costs were did not affect the
determined from differences in cost to
tariff rates and a large degree.
rates published in
earlier work.
Koivurova et al.386/ • To compare prenatal Study type Costs included Main outcome • Health care costs • The study
Finland/2004 and neonatal health care Cost‐effectiveness • 2003 cost of IVF • Live birth for singletons were concludes that health
costs after IVF and analysis treatment (oocyte €5778.1 (IVF) vs. care costs are higher
spontaneous conception retrieval, embryo €4495.6 (control) for IVF births than for
Perspective transfer, related and for twins were natural births.
Payer/health system visits to the €15579.6 vs. However, the study is
infertility clinic) €14447.7 limited to costs faced
Patient population by the payers. No
• 215 IVF mothers • Costs of ovulation • Costs of additional costs, such
and 255 IVF medication (1996‐ unsuccessful cycles as sickness during
neonates treated 1998) were €3290.7 (IVF) pregnancy and
between 1990 and vs. €3290.7 (control) travelling costs were
1995 • Mean costs of included. Sensitivity
• 662 control sickness allowance • Total costs for analysis did not
mothers (matched (due to treatment) singletons were change the trends
for sex, year of birth, from published €22571.3 (IVF) vs. shown in the base
area, parity, data €4765.4 (control) case. The authors
maternal age, social and for twins, conclude that if the
class) and 388 • Costs of €32446.1 (IVF) vs. rate of multiple
control neonates unsuccessful cycles €14598.9 (control) births was reduced
(singletons and twins estimated from 46.2% to 10.0%,
only) assuming 1 costs would drop
• Controls were successful cycle in from about €3.1
randomly chosen 5.26 cycles million to €2.0
from the Finnish million.
Medical Register Information
sources
Analysis • Hospital records;
280

The cost for an IVF the National Health
singleton and an IVF Research and
twin until the end of Development
the neonatal period Centre
were calculated;
similarly the costs for • The Infertility
the control Clinic in Oulu
singletons and twins
were also calculated. •Social Insurance
Foundation of
Time horizon Finland
Short, up to the end
of the neonatal
period
Kjellberg et al.387/ • To compare costs of Study type Costs included Main outcomes: • Quality of life was • This study showed
Sweden/2005 live births from eSET to Cost‐effectiveness • Health costs ‐ • Birth rates not significantly that total costs were
DET analysis alongside an Costs for the IVF, different between lower with SET than
RCT drugs, • Gestational the groups. with DET. SET is also
complications, and age related to fewer
Patient population pregnancies were • The gestational premature births and
661 women, under calculated for each • Neonatal age was significantly more NICU days.
36 years of age, patient at a single complications lower in the DET However, this
st
undergoing their 1 hospital; antenatal group (265 days) analysis in only up to
nd
or 2 IVF cycle and care, including lab Secondary than in the SET 6 months after birth,
having at least 2 tests, midwifery, outcomes group (276 days), and other
good quality visits to a physician • Quality of life while the preterm complications and
embryos available. and ultrasound (using SF‐36 and rate and the low disabilities can arise
tests. the Swedish birth weight rate later in the child’s
Perspective Parenthood were significantly life.
Societal • Costs for Stress lower in the SET
miscarriages were Questionnaire) group (11.6% vs.
Time horizon divided into 3 29.1% for preterm
Until the child categories: rate, and 7.8% vs.
281

reaches 6 month of biochemical, early 27.5% for low birth
age not requiring weight).
curettage, and late,
requiring • Fewer children in
Analysis curettage. the SET group
331 women suffered severe
randomized to eSET • Costs outside neonatal
and330 to DET. health: absence complications
Intention‐to‐treat from work. This demanding neonatal
analyses were done. cost for hospital care (17.8%
Comparison of costs unemployed vs. 33.9%).
was done using the t‐ persons, students
test. For continuous and women • Treatment costs
or discrete variables, working at home, for SET were
the Mann‐Whitney were set to zero. significantly higher
U‐test was used, and than for DET, due
Fisher’s exact test for Information mainly to the cost of
comparison of sources the frozen cycles
proportions. • The Nord DRG (€3675 vs. €3142),
system, calculated but the cost of
Sensitivity analyses for 2004 at a single maternal antenatal
Two one‐way hospital. care and delivery
sensitivity analyses Questionnaires and were significantly
were done: one in medical records. lower for the SET
which the actual group.
IVF/ICSI treatment
cost was doubled, • The mean total
and the other, where maternal health care
NICU costs were cost did not differ
increased by 50% significantly (€6857
for SET vs. €6767 for
DET). Health care
costs for women for
282

pediatric care and
re‐admission to
hospital during the 6
months for the
child(ren) were
significantly lower
for the SET group
(€2445 vs. €5551).

• Health care cost
per live‐born child
was €21572 in the
DET group and
€23798 in the SET
group. With respect
to productivity, on
average, women in
the SET group had
significantly fewer
days of sick leave
during pregnancy
(14.1 days compared
to 23.0 days for DET
women), and also
significant lower loss
of productivity
(€1602 vs. €2359).

• The ICER was
€91702 per extra
delivery of a live
born child with DET
283

over SET; if
productivity losses
are excluded, this
becomes €73307.

• Sensitivity analysis
did not make a
difference in the
directionality of the
findings.
Chambers et al.383/ • To determine the costs Study type Costs included Main outcome • Average cost per •This study confirms
Australia/2006 and outcomes of ART Cost‐effectiveness • Medical • Live birth rates live birth from non‐ that ART is less cost‐
treatment in Australia in analysis procedures, donor cycles: effective in older
2002 counselling, Information women. The authors
Patient population ultrasound, source Fresh cycles: suggest that in
All women initiating scientific services, • ANZARD <30 years ‐ $29,811 addition to economic
non‐donor ART pathology, database 30‐34 years ‐ considerations,
treatments in medications $30,744 community values,
Australia in 2002 35‐39years – ethical judgement
• Average private $41,742 and clinical factors
Perspective insurance benefits .39 years ‐ $133,705 should influence
Societal, patient paid for OR, policy‐making.
hospital Frozen cycles:
Analysis accommodation <30 years ‐ $12,542
Five age‐specific and anesthetist 30‐34 years ‐
decision models charges, $12,491
were created to 35‐39years –
represent each • Other published $15,259
clinically and out‐of‐pocket .39 years ‐ $26,905
economically expenses borne by
significant stage of patients according All cycles:
ART treatment, to clinic fee rates. <30 years ‐ $24,809
including cycles • Costs expressed 30‐34 years ‐
284

discontinued before in 2005 Australian $24,905
oocyte removal or dollars. 35‐39years –$33,636
embryo transfer, .39 years ‐ $97,884
ICSI, surgical sperm • To take into
collection, assisted account inter‐ • Cost per live birth
hatching, oocyte jurisdictional rates for women aged >
culture and across Australia, 42 years: $307,559
cryopreservation. baseline costs were (fresh cycles) and
adjusted to $33,076(frozen
Time horizon account for cycles)
1 year different rates and
utilization of IVF
services across the
country.

Information
sources
• Medicare
schedules

•Pharmaceutical
Benefits Scheme,

• Published
literature,
insurance
companies, IVF
clinics

Fiddelers et al.380/ • To compare costs and Study type Costs included: Main outcomes • After 1 cycle, Limitations
Netherlands/2006 outcomes of women Cost‐effectiveness •Health costs: • Birth rate 33.1% of the SET • The costs relied on
undergoing eSET to analysis alongside an Hospital costs patients and 47.4% the use of
those undergoing DET RCT. related to the IVF • Pregnancies of the DET patients questionnaires
285

treatment and had a positive completed by
Patient population subsequent • Multiple birth pregnancy test, and patients and
308 women starting pregnancy rate 21.4% and 40.3% returned 6 months
their first IVF cycle (personnel costs, achieved an ongoing post‐partum.
between January costs of material, pregnancy. Secondly, the ICER
2002 and December equipment and was calculated only
2004 at one centre, medications); other • There were no for one cycle of IVF.
with at least 2 health care costs twins with SET and
embryos available (GP visit, midwife 19.6% were twins • They also
care), overhead after DET. acknowledge that a
Perspective costs. Markov model would
Societal • The costs for one be more appropriate
• Costs outside cycle of IVF for this analysis.
Analysis health: productivity treatment were Essentially, their
Couples were costs, out‐of‐ €4431 for eSET and€ conclusion is that
randomized between pocket costs like 4513 for DET (not one cycle SET is less
eSET and DET, travel. statistically expensive but less
regardless of age and All costs were significantly effective than DET;
embryo quality, with adjusted to the different). therefore, a decision
154 women in each year 2003. will depend on
group • Costs during society’s valuation of
Information source: pregnancy (5 to 40 the ICER as they have
Time horizon • University weeks) included calculated it.
42 weeks after Hospital, hospital and other
embryo transfer Maastricht; patient health care costs as
questionnaires well as indirect costs
such as productivity
losses, and differed
significantly
between the eSET
group (€1520) and
the DET group
(€3252).
286


• The total societal
costs were €7334 for
one cycle eSET
compared to €10924
for one cycle DET;
the difference was
statistically
significant

• The ICER for one
cycle DET compared
to one cycle eSET
was €19096 (base
case analysis).
Depending on the
ICER threshold, the
probability of DET
being cost‐effective
compared to eSET
ranged from 0% (at a
threshold of €15000)
to 100% (at €32500).
Kelly et al.389/ • To estimate indirect Study type Costs included Not relevant • Out‐of‐pocket • The author
Ireland/2006 costs associated with Cost analysis • Travel, parking, costs per visit contends that out‐of‐
receiving IVF treatment accommodation, ranged from an pocket costs for IVF,
Patient population food, telephone average of 104 especially if there is
All women receiving and dog/child‐ (individuals living travel and living
their first cycle of IVF minding within the County away from home
in one centre in Dublin area), to 219 involved, could
Dublin. Information source (within 50 miles), become significant.
• Individual 539 (50‐130 miles) This is not often
Analysis patients and 703 (> 130 included in economic
287

Patients were to miles). analyses of IVF. This
record information could also be a
on each of their • Time off work and barrier to accessing
visits. This included for travel in the 4 specialized IVF
actual expenditures groups averaged 40 centres.
and time for travel hours/visit, 48
and time off work. hours, 95 hours and
Patients were 214 hours.
grouped into 4,
depending upon the
distance from home
to clinic.
Holman et al. 346/ • To assess utilization, Study type Costs included Main outcome • Mean duration of Conclusions
United Kingdom/2008 costs and outcomes of Cost consequence • Drugs used, clinic • Ongoing ovarian stimulation: • Outcomes similar
IVF in a real‐world clinic analysis. procedures pregnancy 9.1 days (9.0‐9.3) to UK average.
setting rate/cycle
Patient population • Reported in UK • Clinical • Cost of rFSH/cycle
1001 women (both 2007 prices • Live birth rate pregnancy/cycle: was lower than that
NHS patients and 36.4 (33.9‐39) estimated by NICE.
private patients) Information
receiving fresh cycles Information source source • Ongoing • Note: All patients
of IVF/ICSI at UK • Financial audit of • Clinic medical pregnancy rate: 24.4 treated with rFSH.
fertility clinic clinic, and records (22.2‐26.7)
between October pharmacy
2001 and January • Live birth rate: 22
2006. (19.7‐24.2)

Cost and outcomes • Average dispensed
data were collected rFSH dose/cycle:
and averages 1891 units
calculated
• Average cost/cycle
£646
288


• Concomitant
medications £159
• Procedures:
£2,127

• Average total
cost/cycle: £2,932

• Average
cost/clinical
pregnancy: £8,058.

• Cost/ongoing
pregnancy: £12,017

• Cost/live birth:
£13, 326
Sullivan et al.384/ • To determine the costs Study type Costs included Main outcomes • Less than 1% of
Australia/2008 of live births and Cost analysis • Direct healthcare • Clinical embryo transfer
outcomes following ART costs, including pregnancy rates cycles resulted in
in women > 45 years of Patient population private and public by donor status live birth.
age Women over 45 who payer and patient
underwent ART out of pocket costs • Live birth rates • >40% of fresh
procedures between by donor status autologous
2202 and 2004 • Costs captured in treatment cycles did
Australian dollars not proceed to
Perspective 2005 and Information embryo transfer.
Payer/health system expressed in 2005 source
and patient Euros • Australia and • Clinical pregnancy
New Zealand rate: 1.9/100
Analysis Information source Assisted initiated cycles
A decision model • Not specified Reproduction
289

was created, Database Results following
including IVF, ICSI, (ANZARD) fresh autologous
assisted hatching, transfer:
surgical sperm • 71% ended in early
collection, blastocyst pregnancy loss.
culture and
cryopreservation. • Live birth rate was
The number of cycles 0.5 per 100 initiated
to reach each stage cycles and 0.9 per
of the model was 100 fresh autologous
multiplied by the embryo transfers.
average cost of each
type of partial and • Results following
complete cycle to initiated recipient
obtain the average donor cycles:
cost per birth. 29% resulted in
clinical pregnancy
Includes stimulated 32% ended in early
and natural cycles of pregnancy loss
IVF and ICSI Live birth rate was
19.1/100 initiated
Definition clinical cycles
pregnancy:
visualization of • Fresh donor
gestational sac by recipients had
ultrasound, presence increased odds
of chorionic villi on (43.2) of a live birth
examination of compared with
products of women having fresh
conception or autologous cycles.
diagnosis of ectopic
pregnancy • Average cost of a
live birth following
290

Time horizon fresh autologous
Not specified cycle was 753 107
Euros – 28.9 times
higher than for all
women undergoing
fresh autologous
ART treatment.
Finger et al.457/ • To compare the cost‐ Study type Costs included Main outcome • After 3 cycles, Limitations
United States/2008 effectiveness of embryo Cost effectiveness • Costs of a single • Live birth there were 361 • This study is not
donation with oocyte analysis. cycle of oocyte deliveries, at a cost very well‐described.
donation donation – donor of US$11,316,874 in Its conclusions are
Patient population and recipient the oocyte transfer not base on
525 women medications, fees group. incremental cost‐
undergoing oocyte paid to the egg effectiveness but the
donation and 186 donor • There were 108 cost to achieve the
undergoing embryo deliveries at a cost same outcome
donation in 5 centres • Charges for of US$1,458,564 in through the two
offering both clinical services the embryo transfer means. They
services. group. These conclude that
• Short‐term represent overall embryo donation is
Perspective medical insurance cost‐effectiveness approximately twice
Unclear and administrative ratios of US$31,349 as cost‐effective as
cost for oocyte transfer oocyte donation.
Analysis and US$13,505 for
The average cost per Information embryo transfer
cycle was calculated sources
from data from 15 15 IVF centres.
IVF centres

The cost per live
delivery for oocyte
donation and
embryo donation
291

were calculated
separately and
compared.
Veleva et al.388/ • To compare the costs Study type Costs included Main outcome • In aggregate, the • The authors state
Finland/2009 and outcomes between Cost‐effectiveness • Direct costs of • Live birth rate cumulative that their
2 periods of time: one analysis. the IVF, ICSI pregnancy rate populations reflect
when eSET was rarely • Term birth rate stayed relatively actual practice
used, and one when it Patient population • Medications, similar between the (unlike trial
was much more • 826 women under progesterone • Multiple birth 2 periods (51.8% in conditions). They
commonly used. the age of 40 who support, the FET rate the DET period and conclude on the basis
had DET between cycle and hormonal 55.7% in the eSET of this that an eSET
1995 and 1999 at support • Stillbirth rate period). policy with effective
one centre (when cryopreservation will
eSET was used • An annual Secondary • Pregnancy rates result in better
experimentally, only discount rate of 3% outcomes between the 2 outcomes and at
for 4.2% of the was applied to • Ectopic periods were not lower costs for
women) – referred costs. pregnancy significantly women less than 40
to as the DET period different in the years of age.
• 684 women under Information source • Miscarriage group receiving However, they did
40 many of whom • Oulu University fresh cycles. not comment on
had eSET between Hospital limitations of the
2000 and 2004 • With frozen study.
(46.2% of all women) embryo transfer,
at the same centre – cumulative
referred to as the pregnancy rates and
eSET period live pregnancy rates
were statistically
Perspective significantly higher
Hospital in the eSET period.

Sensitivity analyses • Multiple births
“Best‐case” (most were 18.7% in the
favourable to eSET first period and 8.7%
292

and “worst‐case” in the second
(least favourable to
eSET) were modelled • Average
to reflect joint (discounted) total
uncertainty in all cost in women in the
parameters. eSET period (when
the proportion of
eSET was 46.2%) was
€4,584, and in the
DET period (when
the eSET proportion
was 4.2%) was
€4942.

• The ICER (cost
saved per term live
birth during the eSET
period compared to
the DET period) was
€19889.

• eSET stayed
superior to DET
under sensitivity
analyses in which
the no. of fresh
cycles in the period,
the no. of transfer
cycles in the period,
and live birth rates
were varied.

Maheshwari et al.381/ • To determine the Study type Costs included Main outcome • Rate of live births • No significant
293

Scotland/2009 effect of maternal Cost‐effectiveness • Medical costs – • Rate of live by BMI group – differences were
weight on cost of live analysis oocyte recovery, births by BMI 25.6% (<18.5), 25.9% found in the cost per
births ultrasound scans, (18.5‐24.9), 23.2% live birth between
Patient population blood tests, • Multiple (25‐29.9), 23.0% (30‐ women of different
1756 women who medications, pregnancies 34), 22.1% (>34); weights. This raises
underwent their first embryo transfer, multiple pregnancies the question of
cycle of IVF in ICSI (costed Information in the same groups – whether obesity
Aberdeen between bottom‐up) source 36.4%, 27.7%, should be a factor
1997 and 2006, • Aberdeen 25.4%, 32.4%, considered while
grouped according to • Staff, equipment, Reproduction 33.3%. developing IVF
BMI (<18.5 (n=43), space and Unit Database policy.
18.5‐24.9 (n=988), consumables • The cost of the IVF
25‐29.9 (n=491), 30‐ (based on market cycle was similar
34 (n=148), >35 prices). across the weight
(n=86) groups, ranging from
• Costs were £2685 to €2789
Perspective adjusted to
Payer/health system 2006/07 values, • Cost per live birth
and capital items – £18747 (95% CI =
Analysis were annualized at £15374 to £27361)
Average costs per a 3.5% discount for BMI<18.5,
live births were rate. £16497 (£15374 to
calculated for each £17817) BMI 18.5 to
group and compared Information source 24.9, £18575
both parametric and • “Bottom‐up (£16648 to £21081)
non‐parametric test costing”, Aberdeen BMI 25 to 29.9,
Reproduction Unit £18805 (£15397 to
Sensitivity analyses budget £23554) BMI = 30 –
Reported as having • Aberdeen 34.5, 20282 (15288
been done, but no Maternity Hospital, to 28424) BMI>35.
detail provided • University of
Aberdeen pay • Sensitivity analyses
scales had little impact on
294

• Expert opinion the findings.

.

Chambers et al.382/ To compare regulatory Study type Costs included Main outcome • The cost of a • Birth of singleton,
Multi‐national/2009 and economic aspects of Outcomes, utilization • Societal: cost of • Live birth rate standard IVF cycle twin, or other
ART in 10 developed and cost comparison standard IVF cycle per initiated ranged between multiple counted as
countries as percentage of cycle. $12,513 in the US to one live birth
Patient population gross national $3,956 in Japan.
Women who income per capita Secondary • One woman could
received autologous in 2006. outcome • The cost/live birth contribute more than
(non‐donor oocyte • Multiple birth was highest in the one fresh or frozen
or embryo) IVF and • Patient: cost of rates per live US ($41,132) and the embryo cycle to an
ICSI in 2003 whose standard IVF cycle birth UK ($40,364) and annual ART registry
info was entered into as a percentage of lowest in cohort
national registries in disposable income • Number of Scandinavia
US, Canada, UK, for a single worker fresh and frozen ($24,485) and Japan
Japan, Australia and without children cycles initiated ($24,329)
Scandinavia earning 100% of per million
(Sweden, Denmark, average earnings population and • The cost of an IVF
Finland, Norway, and (total labor costs per million cycle after
Iceland) multiple by country women of government
specific OECED tax reproductive age subsidization ranged
Perspective wedge per annum in from 50% of
Patient and societal each disposable annual
• Used purchasing country/region. income in the US to
Analysis power parity to 6% in Australia
Compared economic equalize purchasing Information
aspects of ARTs in power between source • The cost of ART
selected developed currencies – gross • National treatment did not
countries: cost of standard Registry data. exceed 0.25% of
295

• Costs of treatment. cycle before total healthcare
• Affordability. government expenditure
• Cost‐effectiveness subsidization anywhere
ratio.
• Utilization. • Effect of • Australia and
• Total expenditure. subsidization: Scandinavia were
Used standardized applied rate of the only countries
model of national publicly funded where levels of
registry data cycles to the cost of utilization
a standard cycle approximate
Time horizon and then demand; North
from initiated estimating the America meets only
treatment through to residual level of 24% of estimated
pregnancy leading to copayments. demand
a live birth
• Total cost:
summed all direct
treatment costs
and expressed then
as percentage of
total public and
private healthcare
expenditures in
each country.
Price elasticity of
demand: allows
changes in demand
and revenue to be
predicted with
changes in
consumer price.
• Based on USD
2006
296


Information
sources
• Canada, Japan,
UK, and US: web‐
based survey of
fertility clinics

• Australia and
Scandinavia:
published
estimates

Chambers et al.458/ • To compare a strategy Study type Costs included Main outcomes • Clinical • The authors
Australia/2010 of 2 cycles of Cost‐effectiveness • Direct costs • Pregnancy pregnancies (% of conclude that 1 IVF
(IUI/controlled analysis related to providing rate initiated cycles): program is more
hyperstimulation(COH)) treatment up to a IUI/COH – 18.5% effective, but more

with IVF (1 fresh plus 1 Patient population pregnancy • Birth rate IVF – 50.0 costly than 2 cycles
associated frozen 448 couples meeting of IUI/COH.
embryo transfer) the criteria (woman • Indirect costs of • Live birth rate • All live births (% of
<39 years of age, had treatment initiated cycles): • This is a well‐
not undergone (pertaining to • Multiple birth IUI/COH – 15.5% described study, but
previous IVF/ICSI, complications of rate IVF – 39.2% no sensitivity
had at least 1 patent fertility treatment analyses were done.
tube, having and maternal and Information • Singletons (% of
unexplained, mild infant birth‐ sources live births):
male or mild female admission costs) • Not specified IUI/COH ‐ 86.7%
infertility) from 2 IVF – 89.9%
297

private fertility • Details provided
clinics. in an earlier • Multiples:
Between July 2003 publication. IUI/COH ‐ 13.3%
and June 2005. IVF – 10.1%

Mild female factor • Cost‐effectiveness
included mild (2 cycles IUI/COH vs.
endometriosis, 1 IVF):
unilateral tube Intention to treat:
disease, serum $46,325 ($37,139 to
sperm antibodies, $55,073)
cycle disorders and Per‐protocol
Polycystic Ovary analysis: $43,184
Syndrome (PCOS). ($34,166 to $52,698)
Male mild infertility
was due to poor
sperm
concentration.

Two decision models
were created to
reflect the intention‐
to‐treat and per
protocol analysis.

Perspective
Payer/health system

Analysis
Cumulative live
births per couple in
each group and
2
differences by the χ
298

test. The Kaplan‐
Meier test was used
to estimate the
cumulative
proportion of
patients with a live
birth after the mean
time to undertake 2
cycles of IUI/COH.
The Mantel‐Cox Log
Rank test was used
to test the equality
of these survival
distributions

Time horizon
2 years
459
Maheshwari et al. / • To estimate the Study type Costs included Main outcome • Live birth rate:
Scotland/2010 average health care costs Cost‐effectiveness • Staff (including • Live births by <30 years – 26.1%,
per live birth across analysis salary, maternal age 30‐34 years – 27.2%,
different age groups of superannuation 35‐39 years – 25.0%,
women receiving ART Patient population and national Secondary 39 years – 9.4%
treatment 1854 women who insurance outcomes
had their first fresh contributions) • Gestational • Median number of
IVF cycle between age inpatient days: < 30
1997 and 2006 at the • Equipment, years – 8 (4 to 13),
Aberdeen consumables • Number of 30‐34 years – 7 (5 to
Fertility Clinic • Administration inpatient days 10), 35‐39 years – 7
and clinic (4 to 10), > 39 years
Perspective appointments • Admission to – 10 (5 to 14)
Payer/health system neonatal unit
•Ovarian • Admission to
Analysis hyperstimulation • Multiple birth neonatal unit: < 30
299

Cost was determined syndrome rate years – 46.3%, 30‐35
by a bottom‐up years – 35.1%, 35‐39
approach. All • Pregnancies. Information years – 30.7%, > 39
resource inputs Average daily source years – 36.4%
required for inpatient costs; • Aberdeen
individual ultrasounds, Reproduction • Multiple births: <
procedures were amniocentesis Unit database 30 years – 28.9%,
identified and 39‐34 years – 28.7%,
measured through Information • Aberdeen 35‐39 years – 23.9%,
consultation with sources Maternity and > 39 years – 13.3%
appropriate • Aberdeen Neonatal
clinicians and valued budgets and salary Databank • Cost per live birth:
using 2006/07 scales < 30 years – £16,503
market price. (95% CI: £14,798 –
Staffing costs were • Information £17,609), 30‐35
included. Time Services Division years – £16,058
horizon was less than (£14,836 – £17,609),
1 year. • National Health 35‐39 years –
Service sources £17,096 (£15,635 –
Sensitivity analyses £18,937), > 39 years
One‐way sensitivity •Aberdeen – £40,320 (£27,105 –
analysis was Maternity Hospital £65,036)
performed on some
items, e.g., replacing
the cost of antenatal
and delivery care in
multiple births with
the mean cost
incurred for
singleton
pregnancies
Katz et al.460/ • To examine costs of Study type Costs included Main outcomes • Mean number of Conclusions
United States/2011 women presenting for Cost analysis using a • Medications, lab • Mean number cycle‐based • Higher costs
300

infertility evaluation and prospective cohort services, physician of cycle‐based treatments by attributable to
treatment, regardless of fees, procedures, treatments by treatment group: greater proportion of
treatment pursued Patient population maternal and treatment group Overall: multiple births.
398 patients from 8 neonatal hospital 1. MED: 2.7
reproductive costs • Mean number 2. IUI‐CC: 3.1 Limitations:
endocrinology of per person 3. IUI‐FSH: 3.8 • Homogeneous
practices that were • Birth weight, treatment cycles 4. IVF: 3.7 sample from
visiting the gestational age, with success 5. IVF‐DE: 3.5 California
recruitment clinic for and maternal and (delivery or
the first time and neonatal hospital ongoing • Mean number of • Did not include
had no prior IVF, lengths of stay pregnancy) per person costs of treatments
hysterectomy, or from telephone treatment cycles prior to entry into
sterilization interviews with • Rate of with success the study
procedures. mothers. deliveries (delivery or ongoing
pregnancy): • Study limited to 18
Diagnoses: Information • Rate of 1. MED: 1.0 months.
Male factor sources ongoing 2. IUI‐CC: 3.1
infertility: 37.7% • 2006 National pregnancies 3. IUI‐FSH: 3.4 Strengths:
Tubal: 14.6% Physician Fee 4. IVF: 3.4 • Examined costs of
Uterine: 12.8% Schedule relative • Rate of 5. IVF‐DE: 2.8 full spectrum of
Ovarian: 39.0% value file. “successful” fertility treatments
Ovulatory: 28.2% • 2006 Centers for outcome • Percent deliveries:
Medicare and 1. MED: 17.6 • Cost estimates
Analysis Medicaid Services 2. IUI‐CC: 35.9 derived from actual
Compared resource clinical laboratory Information 3. IUI‐FSH: 46.7 services
utilization and costs fee schedule. source 4. IVF: 32.3
across 5 treatment • Red Book, 2006 • Interviews and 5. IVF‐DE: 29.2
groups: (medication except questionnaires
1) No cycle‐based for gonadotropin – at baseline, 4, • Percent ongoing
treatment average wholesale 10, and 18 pregnancy
2) Medication only prices). months; 1. MED: 5.9
(MEDS) • Online sources resource used 2. IUI‐CC: 2.6
3) IUI with (gonadotropin). from medical 3. IUI‐FSH: 8.9
301

clomiphene citrate . records. 4. IVF: 15.1
(IUI‐CC) 5. IVF‐DE: 25.0
4) IUI with
gonadotropins (IUI‐ • Percent
FSH) “successful”
5) IVF outcome:
6) IVF with donor egg 1. MED: 23.5
(IVF‐DE) 2. IUI‐CC: 38.5
3. IUI‐FSH: 55.6
Treatment use and 4. IVF: 47.3
costs calculated 5. IVF‐DE: 54.2
separately for
women who had • Per person Median
successful outcomes treatment cost (US$
(treatment‐related 2006) per outcome:
delivery or ongoing Overall: $15,388
treatment related 1. MED: $1,182
pregnancy 2. IUI‐CC: $3,595
3. IUI‐FSH: $8,594
4. IVF: $24,373
5. IVF‐DE: $38,015

Successful:
• Overall: $19,765
1. MED: $925
2. IUI‐CC: $4,121
3. IUI‐FSH: $8,542
4. IVF: $24,010
5. IVF‐DE: $38,545

• Unsuccessful:
Overall: $4,448
1. MED: $1,519
302

2. IUI‐CC:$2,543
3. IUI‐FSH:$ 9,379
4. IVF: $25,921
5. IVF‐DE: $3,7485

•Overall cost per
success: $48,424

• Per successful
outcome treatment
costs:
1. MED: $5,894
2. IUI‐CC: $10,696
3. IUI‐FSH: $19,566
4. IVF: $60,151
5. IVF‐DE: $72,642

• Per successful
outcome treatment
and delivery costs:
1. MED: $14,045
2. IUI‐CC: $19,898
3. IUI‐FSH: $29,119
4. IVF: $76,395
5. IVF‐DE: $89,202

303

Table 45. Studies estimating the costs and benefits of ARTs services and policies
Studies estimating the costs and benefits of ARTs servicesand policies
Author/Country/Year
of publication Purpose of study Study design Costs included Outcomes measured Findings Comments
De Sutter et Hypothetical cohort Study type Costs included Main outcome • The cost per child Conclusion
al.391/Belgium/2002 of 1000 patients Cost‐effectiveness • IVF cycle; freezing • A child born; data born with SET ranged • Cost per child born
with a good analysis and thawing cycles obtained from 4 from €9520 to is similar between

prognosis (no published studies €12254 (with a SET and DET.
Perspective • Miscarriage (which
cancelled pregnancy rate of
Hospital includes sick‐time Limitations
stimulation cycles, 53.8% and 42.0%
no retrievals costs) respectively), • This model did not
Analysis
without oocytes Decision analytic compared to €9511 include neonatal
• Pregnancy and mortality and long‐
and no fertilization model in Excel to €12934 for DET
delivery term disability costs.
failures), and all comparing SET with (with corresponding
mothers had a DET, limited to 3 pregnancy rates of
• Neonatal hospital • The authors
cycles. Assumed that
transfer performed. stay. 77.7% and 43.0%
each patient stays in acknowledge that the
the treatment respectively)
study is limited to
originally assigned Information source
neonatal costs only.
(i.e., SET or DET), and • Gent University
pregnancy rates Hospital (2001)
remained constant
for each cycle. Also,
pregnancies that
result from frozen
embryos are
assumed to result in
singletons.

Time horizon
The model ends with
the birth of the
304

Author/Country/Year
child(ren)
Gerris et Patients recruited Study type Costs included Main outcome • Live birth rate was Conclusion
al.461/Belgium/2004 into 2 IVF/ICSI • Prospective 2 • Hospitalization, • Birth rate 37.4% for SET and • SET with a top
programs, <38 centre cost delivery and 36.6% for DET. SET quality embryo is as
effectiveness analysis and DET groups effective as, but
years at time of outpatient costs.
differed significantly cheaper than, DET
embryo transfer, Perspective in 2 factors: for women less than
first IVF/ICSI Information source:
Unclear prematurity (SET: 38 years in their first
treatment ever or • Unclear, but
8.5%, DET: 23.8%) IVF/ICSI cycle.
after a previous Patient population hospital bills and IVF and mean
delivery (whether Calculated from data costs from the hospitalization Limitations
through infertility on 118 patients on Belgian health duration (SET: 6.3 • Data is limited up
an intention‐to‐treat insurance system days, DET: 10.3 days) to 3 months after
treatment or not).
basis were included. birth, and longer
• Total cost after DET term effects might
262 patients from
Description: was higher than with change the
centre A and 146 SET (€8613+10105 conclusions.
Patients had the
from centre B; a choice of SET or DET. vs. €4700+3239), due
total of 375 SET was performed to significantly higher • Complete costs
patients (91.9%) exclusively when the neonatal costs were available only
had embryo embryo met (€3453+8154 vs. for 118 women, 71
transfer, and 367 of morphological €451+957, p<0.001),
with SET and 47 with
and not maternal
these (89.9% of the criteria of high DET.
competence. If no costs.
total no. of cycles)
high quality embryo
were used in this
was available, • When the cost for
analysis. patients received 2 IVF/ICSI is included,
embryos, except the average costs
when only one was become €7126 and
available. 31 patients €10004 respectively.
who had chosen SET The cost differences
and did not have a arise from twin births
high quality embryo in the DET group.
305

Author/Country/Year
maintained their
wish for SET. The
observation period
ended 3 months after
delivery. Either IVF or
ICSI was the
procedure used.
RCOG23/United • Hypothetical Study type Costs included Input data for the • In the age specific • These models were
Kingdom/2004 groups of women in Cost‐effectiveness • IVF per fresh cycle model were obtained model, the cost per provided as part of
different age analysis (without from the HFEA and live birth with IVF guidelines produced
by the National
groups. medications) the Oxford Fertility alone was very
Perspective Collaborating Centre
Unit. similar between the for Women’s and
Not specified • Frozen embryo ages of 24 and 33, Children’s Health in
explicitly, but would transfer after which it went the UK.
appear to be the NHS up dramatically. In
• IVF medications (u‐
the base case model, Limitations
Analysis FSH and r‐FSH)
Using decision the cost per live birth • The analyses are
limited to direct
models to estimate • Treatment of for ages 24 years, 35
medical costs and
(1) age‐specific and ovarian years, and 39 years merely attempts to
(2) cycle‐specific hypersensitivity were £11917, calculate the cost of
costs per live birth £12931 and £20056. a birth.
syndrome
following IVF alone
or IVF with ICSI. • ICSI • Sensitivity analyses • Costs that might
Sensitivity analyses using higher and accrue after birth are
were performed. In • Ectopic pregnancy lower values (£3500 not included.
the age‐specific
model, couples were and £1771 cf. £2771)
• Miscarriage
offered up to 6 cycles for the IVF treatment
of treatment. In the Information Source cost resulted in cost
cycle‐specific model, per live birth of
• NHS data
couples were offered £14697 and £8103
3 or 4 fresh cycles
306

Author/Country/Year
and no frozen • Fertility (24 years), £15943
embryo transfers. In Confidential and £8800 (35 years)
the latter case, 2 and £24673 and
separate models • Human Fertilization £13723 (39 years).
were used. and Embryology
Authority • For the cycle
specific model, two
• Published literature analyses were run,
using 2 different data

sets for
effectiveness. In the
first (with data from
the HFEA), the base
case cost per live
birth with IVF alone
with 1, 2, 3 and 4
cycles respectively,
were £15281,
£16169, £14793 and
£14336. With the
higher IVF cost
(£3500 cf. £2771),
these figures were
£19287, £20408,
£18671 and £18094.
With lower IVF costs
(£1771 cf. £2771),
these became £9787,
£10356, £9474 and
307

Author/Country/Year
£9181.
• In the second
analysis (with data
from the Oxford
Fertility Unit), the
costs were calculated
for 2 age groups: < 39
years and 39 years or
older. For the
younger group, the
cost per live birth
with 1, 2 or 3 cycles
were £11694,
£11548 and £12758,
while for the older
group; these were
£27611, £28938 and
£12835. Cost trends
generally stayed the
same within
sensitivity analyses.
The cost of ICSI per
live birth was
£14002.
Ledger et al.400/United • Not specified. Study type Costs included Main outcome • Total NHS cost for Conclusions

Kingdom/2006 Cost analysis • Not reported as • The probability of a singleton, twin and • In this model,
individual items, but singleton, twin or triplet births are although triplets
Perspective triplet surviving to at make up just 2% of
only in categories of £3313, £9122 and
308

Author/Country/Year
Healthcare system “maternal cost” and least one year. £32354 respectively. all births, they incur
“neonatal cost (per 10.6% of the costs.
family)”. Information source • The maternal costs The authors suggest
Cost analysis, using a • From published for these were this to be an
decision model Information source sources and £3122, £6058 and underestimate, since
comparing the costs extrapolated to the their time horizon is
• Unclear but are £11534 respectively.
of multiple UK. only 1 year. If twins
pregnancies as a stated to be “NHS
costings based on
• Neonatal costs (per are included, the
result of IVF to the result is that 27% of
information for family) were £191,
costs of singleton births (which would
pregnancies resulting 2002.” £3064 and £20820 be multiple births)
from IVF. The model respectively. would consume 54%
starts with the of the costs. It is
pregnancy, and costs • These findings were expected that with
of the preceding IVF relatively robust with multiple births and
are not included in respect to sensitivity low birth‐weight,
the analysis; these analyses. there will be
are assumed to be additional conditions
the same for both that will arise in later
singleton and years; this would
multiple pregnancies. result in higher costs
than a 1 year
estimate provides.

Limitations
• The data sources.
• Limited data.
• The assumption
that the number of
visits for singleton,
twin and triplet
mothers is the same.
309

Author/Country/Year
462
Little et al. / United Study type Costs included Main outcomes • Clinical outcomes Conclusion
States/2006 Cost analysis • Parental costs • Percentage of were better with • The difference in
included the full cost women who would single embryo the cost per birth
Patient population be able to transfer transfer. between the payer
of the IVF treatment
Hypothetical patients frozen embryos and the parents
(obtained by demonstrated in this
in 5 age groups: <35 • Societal
averaging the costs • Estimates of perspective: The study shows the
years, 35‐37 years, obtained from 5 preterm birth rates least expensive importance of the
38‐40, 41‐42, >42 centres). by gestational option is to transfer 1 parents’ perspective
years. number embryo in all age in treatment
• This included costs groups (< 35 years decisions.
Perspective of the procedure, • Estimates of and 35‐37 years:
Societal, family and medications, cerebral palsy rates US$21661, 38‐40: Limitations
insurer by preterm birth US$24501, 41‐42: • This paper does not
cryopreservation,
status US$25479, >42: present detailed
and 56% of the US$25723). costs, except for the
Analysis
Using a Markov sperm microinjection Information sources costs of transferring
model to estimate cost (this is the • CDC statistical • For women under different numbers of
costs of transferring percentage of reports 35 years, the embryos.
1 to 5 embryos per women estimated by incremental cost to
transfer from 3 the CDC as using this • Published literature achieve 1 more live • Actual costs per live
perspectives: society, technology); birth by transferring birth are not
the couple and the 2 embryos rather provided for all age
insurer. The woman than 1 is groups.
• A $2000 charge for
starts the model approximately
a live birth was also US$300000. • In this study,
undergoing 1 cycle of
fresh embryo included, assuming parental costs
transfer (1 to 5 they have insurance • For women > 42 included all costs of
embryos); if she coverage with a years, the cost of an the IVF treatment, as
failed to get pregnant $2000 deductible. additional live birth well as insurance
or miscarried, she for 2 rather than 1 deductible. It is not
nd
underwent a 2 • Insurer costs embryo is about clear how these
cycle with the same included the short US$8000 and for 2 results would
310

Author/Country/Year
no. of embryos, and long‐term costs rather than 3 transfer to a single‐
which could be fresh of live births, less the embryos, about payer first dollar
or frozen (depending $2000 deductible. US$23000. system.
on embryos
available). If she • Short term costs • Parental
failed again, she perspective:
were assumed to be
would have a 3rd Transferring 1
hospital charges.
cycle, with fresh embryo is the most
embryos, failing expensive option in
• Long‐term costs
which she would all age groups,
have a 4th cycle like included lifetime increasing with age
the 2nd one. Finally, if medical and indirect from US$26401 to
she failed the 4th costs for children US$51069.
cycle, she would have who develop cerebral
a 5th cycle with fresh palsy. • The incremental
embryos. cost to achieve 1
• The societal more live birth by
perspective included transferring 1 more
embryo, increases
both parental and
dramatically with
insurance costs, with age.
charges being
adjusted to reflect • Insurer perspective:
costs, by using a Costs are lowest for
national average for women of all ages to
transfer 1 embryo at
the ratio of costs to
a time. This is also
charges for inpatient true for cost per live
care. All costs were birth.
adjusted to 2005
dollars.
RAND Comparison of Study type Costs included Main outcome • Success rate (per Conclusions
311

Author/Country/Year
463
Europe /United potential IVF/ICSI • Cost benefit • Costs of 1 cycle of • Success rate per cycle) by age: • Increased number
Kingdom/2006 policies with analysis IVF or ICSI only cycle <30: 0.21 of IVF/ICSI births will
registry data from (medication, 30‐34: 0.20 not impact labour
Denmark and UK administration, lab Information Source 35‐39: 0.10 population for 15
from 2002. work and procedure) • Office for Statistics 40‐44: 0.05 years until entering
(for fertility rates; 45‐49: 0.01 labour force
Information source data restricted to IVF population, when
• Published literature and ICSI) • Scenario 1: If they will contribute
for UK. IVF/ICSI is provided to reducing ratio of
to all women: total old age dependents
fertility rate (TFR) to working age
increases by 0.0423 population.
at a cost of 427
million. • Increase in IVF/ICSI
will not bring TFR
• Scenario 2: If above replacement
women ≥ 44 years level.
excluded TFR
increases to 0.0419 • Cost per IVF/ICSI
at cost of 385 million. birth estimated to be
£15,000 to £25000.
• Scenario 3: If
IVF/ICSI only • Success rate across
provided to women < all ages categories
40 years TFR is 15%.
0.0366 at a cost of
259 million.

• Effect of increasing
child benefit by 25%:
TFR increased 0,07 at
a cost of 1.5 to 2.5
billion
312

Author/Country/Year
401
Dale/2006/Italy Decision analytic Study type Costs included Main outcomes • The estimated cost Conclusion
Abstract model comparing Cost‐effectiveness •Costs of fresh and • Cumulative birth per treatment was • Providing 3 cycles
IVF with and analysis frozen cycles, rate €4905 with no frozen of IVF with
without the option cryopreservation
including drugs and embryo transfer and
of embryo freezing Perspective favoured comparably
over 3 cycles of IVF. Health care system hospitalization €5453 with frozen to allowing only 3
rd
A 3 option of no embryo transfer. cycles of IVF. It is
Information sources
treatment was also Analysis unclear from the
included. • Micro‐costing. • The model limited data in this
Decision analytic
model. predicted a abstract how this
• Published sources. cumulative birth rate conclusion could be
of 30.9% with reached.

freezing and 25.3%
• Mention was made
without.
of sensitivity analysis
but no results were
• The IVF without
presented.
freezing was
“extensively
dominated by the
combination of no
treatment and IVF
plus
cryopreservation”.
• The incremental
cost per additional
live birth was €21863
with freezing
compared to no
treatment.
313

Author/Country/Year
Pashayan et al. To estimate the Study type Costs included Main outcome • Live birth rates: U‐ Conclusions
393
/United cost‐effectiveness Cost‐effectiveness •Cost of IVF (fresh •Live birth IUI – 3.5%, S‐IUI – • For couples with
Kingdom/2006 of IVF and IUI. analysis and frozen) and IUI 7%, C‐IUI – 3% unexplained or mild
cycles Information sources: male factor infertility,
Patient population •HFEA • Cost‐effectiveness a full IVF cycle is cost‐
Hypothetical cohort Information source: ratios (cost per live effective compared
of 100 couples with •NICE’s economic • Peer‐reviewed birth): IVF – £12,600, to any IUI followed
unexplained or mild model literature U‐IUI+IVF – £13,100, by IVF.
male infertility S‐IUI+IVF – £15,100
• Local activity data
Limitations
Perspective • For 100 infertile • There is not much
•‘Informed
Health system couples with detail on how the
judgement’
unexplained or mild clinical data was used
Analysis male factor
in the model, were
A decision model was infertility, providing 6 synthesized from the
created to compare cycles of U‐IUI+IVF or various sources
primary IVF and of S‐IUI+IVF would listed.
primary IUI (1 to 6 cost and additional;
cycles of clomifene‐ £174,200 and • There is no
stimulated IUI (C‐IUI) £438,000, description of age‐
or un‐stimulated IUI representing an dependence of the
(U‐IUI) or 3 cycles of opportunity cost of results.
stimulated IUI (S‐IUI) 136 additional IVF
and to compare cycles and 14 to 35
IUI+IVF with primary live‐birth producing
IVF. It was assumed pregnancies
that 90% of couples respectively.
who fail IUI will
proceed to IVF. • Under the
sensitivity analyses
314

Author/Country/Year
Sensitivity conducted, primary
analysesOne‐way IVF remained more
sensitivity analyses cost‐effective that
on live birth rates for IUI+IVF, and had less
the 3 types of IUI opportunity cost.
cycles.

Time horizon
Not specified,
presumably until
birth
Connolly et Net tax Data sources Costs included • NPV = £160,069

al.407/United contributions to the Not specified •NPV in the UK
Kingdom/2007 British government
attributed to a Data elements
successful IVF birth. Education costs,
child‐tax credits,
pensions, and age‐
specific income.
Analysis
Generational
accounting model for
an IVF conceived
child in 2005.
Bhatti and Comparison of Study type Costs included Main outcome Results: Conclusion

Baibergenova394/Canad cost‐effectiveness Cost‐effectiveness •Short term costs • Live births Total cost of • IVF‐DET most cost
a/2008 of IVF‐SET, IVF‐DET analysis only; long term costs drugs/cycle: effective strategy.
and IUI with associated with • Pregnancy rate sIUI: $500‐$1500
315

Author/Country/Year
gonadotropin Patient population multiple births were IVF: $2500‐$4500 Assumptions
stimulation (sIUI) Hypothetical female excluded • IVF treatment
using a Markov cohort (all < 36 years Base case: midpoint provided was a
decision model. of age) with no •Costs for ovarian of ranges for costs. combination of fresh
previous sIUI or IVF stimulation drugs, as and cryopreserved
treatment and a well as those used in • IVF‐DET: embryo transfers to a
good fertility conjunction with IVF $14,409/live birth maximum of 3 cycles.
prognosis. were also included IVF‐SET:
$109,385/live birth • Probability of
Perspective Information source sIUI: $66,960/live pregnancy and live
Healthcare system/ • Expert opinion birth births lower for
public payer cryopreserved cycle.
• Websites of • Sensitivity analysis:
Sensitivity analysis infertility clinics. IVF‐DET remained • sIUI: Small
Scenario; proportion most cost‐effective in proportion of women
of women for whom each of the 3 do not continue on
cryopreservation was scenarios, followed to undergo a cycle of
not possible – 50%‐ by sIUI, followed by sIUI.
50%; one‐way IVF‐SET, as well as
sensitivity analysis on when proportion of • Probability of
costs; varied women with limited success in achieving
probability of ability to employ pregnancy and
pregnancies and cryopreserved successful delivery is
delivery for each of embryos was the same regardless
the 3 interventions. changed of stage of
Below cost of 14000 treatment.
per cycle, IVF DET
remained most cost‐ • Small proportion of
effective strategy; vaginal and
>14,000/cycle, s IUI caesarean deliveries
dominated as most leads to infants being
cost‐effective admitted to NICU for
When cost of fresh observation
316

Author/Country/Year
cycle was varied and IVF‐SET or IVF‐DET:
cryopreserved cycles initial treatment
remained constant, cycle performed
IVF‐DET remained using fresh embryos
most cost –effective while subsequent
cycles performed
using cryopreserved
embryos – therefore
the cycle a patient is
in affects the
probability of a
successful pregnancy
and birth.

• In 25% of cases,
cryopreservation is
not possible
‐probability of higher
order birth is zero.
‐ Disregarded cost of
miscarriages,
maternal morbidity,
or costs
Svensson408/Sweden/2 Effect of A modified Costs included • NPV = 254,000 SEK Conclusion
008 restrictions on IVF generational • NPV in Sweden, • Therefore, state‐
on long‐term accounting model to assuming a life funded IVF does not
taxation and calculate the net expectancy of 80 negatively impact the
revenue to present value of years. long‐term budget,
government. average investment and an IVF child will
costs needed to return a positive net
achieve an IVF child value to the state.
317

Author/Country/Year
in Sweden.
Connolly et Public subsidization Data sources Costs included • NPV = US$155,870.

al.170407/United of IVF treatment in Current Population • NPV in the US
States/2008 the US. Survey, Consumer • The net projected
Expenditure Survey, lifetime tax
US Statistical contribution is US
Abstract, Digest of $606,200. The net
Education Statistics, present value of the
and US Congressional investment in IVF is
Budget Office. US $155,870.
Data elements
Mean cost/IVF cycle,
government
transfers, and tax
revenues.
Analysis
A modified
generational
accounting model for
an IVF‐conceived
child in 2000.
Dixon et To estimate the Study type Costs included Main outcome • For all 3 age Conclusions

al.397/England/2008 cost‐effectiveness Cost‐effectiveness Antenatal, neonatal • Live birth groups, the least • The choice of
of different embryo study and maternal costs effective strategy embryo transfer
strategies for a by plurality, obstetric (based on number of policy (from a cost‐
single cycle when 2 Patient population hospital per diem live births) was SET, effectiveness
318

Author/Country/Year
embryos are Women with 2 costs, pediatric followed by SET+fzET perspective) depends
available. embryos available for hospital costs (up to and then by DET. on 4 factors:
transfer, in 3 age 5 yrs. after birth). maternal age,
groups (< 30 yrs., • The probabilities of relevance of the SET
30—35 years and 36‐ Information sources any live births were option, the value of a
39 years) Six local providers of for women live birth, and the
IVF services and < 30 years of age: SET importance of
Perspective published literature – 0.171, for SET+fzET adverse outcomes.
Health service – 0.208, and for DET
– 0.307 • This study used
Analysis actual birth
Cost‐effectiveness 30‐35 years of age: probabilities instead
analysis comparing SET – 0.156, for of values from RCTs
different embryo SET+fzET – 0.189, and so probably
transfer strategies for and for DET – 0.284 represents real‐world
a single cycle. A outcomes. Costs are
strategy was defined 36‐39 years of age:
also from IVF centres.
as a combination of SET – 0.114, for
The probabilistic
single/double, SET+fzSET – 0.175,
fresh/frozen embryo and for DET – 0.213.
are well‐described.
transfer within a
• The probability of a
cycle. The outcomes Limitations
multiple pregnancy
were: no transfer, no • The results are
was highest with DET
live birth, singleton limited to the specific
in all age groups,
live birth, twin strategies identified
ranging from 0.079
multiple birth or in the study; these
for the youngest
HOMP birth. Live may not represent
group to 0.040 for
birth means any type practice elsewhere.
the oldest.
of live birth. The
main comparison
319

Author/Country/Year
was between DET • Premature births
and SET, which if (per 1000 cycles) also
unsuccessful leads to increase from 21 to
a transfer of a 66 (<30 yrs.), 19 to
previously frozen 59 (30‐35 yrs.) and
embryo (fzET). Birth 14 to 40 (36‐39 yrs.)
probabilities were in going from SET to
obtained from 5 IVF DET.
centres.
• The ICERs of
Sensitivity analyses SET+fzSET compared
Probabilistic to SET vary from
sensitivity analyses £18463 in the
using 4000 runs youngest group to
£21029 in the oldest
Time horizon group. If these are
5 years after birth considered to be
“cost‐effective”
ICERs, then DET is
more cost‐effective
than SET+fzSET.
• Finally, for the 35‐
39 year old group,
DET is less costly and
more effective than
SET+fzSET. The
model also shows
that adverse events
increase when going
320

Author/Country/Year
from SET to
SET+fzSET to DET,
and costs will
therefore increase as
well.
• Cumulative
cerebral palsy cases
per 1000 cycles
increase from 0 in all
age groups with SET
to 1 in the <35 year
old group with
SET+fzSET, to 2, 1
and 1 in the 3 age
groups with DET.
NICU days per cycle
also increase from 34
to 250 (< 35 years),
from 26 to 191 (35‐
39 years) and from
20 to 123 (35‐39
years) in going from
SET to DET.
• Cost‐effectiveness
acceptability curves
show that the
probability of
SET+fzSET being cost‐
321

Author/Country/Year
effective decrease
with age, if SET is not
considered. When
SET is included in the
analysis, SET+fzSET is
no longer cost‐
effective at any
threshold for any
age.
Bouwmans et To estimate the Study type Costs included Main outcome • Average cost of IVF Conclusions
al.399/Netherlands/200 cost per cycle of IVF Cost study •Cost of the fertility •Ongoing pregnancy and ICSI hormonal • Total cost of IVF
8 and ICSI. department, of stimulation were per cycle was 8.3%
Patient medication, the IVF €1630 and €1585 higher than for ICSI
population:Women lab, cost of respectively. per cycle. The main
starting their 1st complications contribution to cost
treatment cycle with (limited to cost of • The cost of oocyte was hormonal
IVF or ICSI in 4 Dutch inpatient days), cost retrieval was €500 stimulation.
centres. of oocyte retrieval and €25respectively.
Limitations
Analysis Information sources: • Cost per IVF and • This study is limited
Micro‐costing study •Hospital financial ICSI cycle started was to costing the
using a combination records €2381 and €2578 procedures
of top‐down and respectively. themselves, and
bottom‐up •Hospital purchase provides no
approaches, prices • The cost of embryo
information on the
depending on data transfer was €185.
effect of plurality,
availability. For the •National Health
Tariffs Authority • The cost of ongoing etc. The costs used
top‐down approach, may not be
pregnancy was
cost data were generalizable to
•Actual salary scales €10482 (IVF) and
obtained from the other situations.
€10036 (ICSI).
hospitals’ finance •Dutch wholesale
322

Author/Country/Year
department. For the drug prices • The costs of
bottom‐up approach, medication increased
volumes and prices with age, for both IVF
of resources were and ICSI.
used. ‘Housing’ and
overhead costs were
calculated on the
basis of a 45% of
personnel and
material costs
Perspective
Healthcare system
(direct medical costs
only)
Sensitivity
analysesNot reported
Time horizon
Not specified,
presumably until
birth
Henne et al.402/United • To estimate the Study type Costs included Main outcome • Live birth rate: 34% Conclusions

States/2008 cost of ART in poor Cost analysis • Direct medical •Live birth overall The authors conclude
prognosis patients. costs only this information is
Patient population Information sources • The cost of a live useful in patient
Women between 26 Information source •Institutional chart birth increased with counseling.
and 42 years of age •Published studies review age and FSH, but
323

Author/Country/Year
(with FSH levels < 12 non‐linearly. This can Limitation
IU/L on day 3) exceed $100,000 This paper does not
undergoing a first when the live birth describe what costs
stimulated fresh non‐ rate falls below 10% were included, but
donor ART cycle (assuming a cycle indicates that the
between January costs $10,803). cost of multiple
1999 to December gestations is not
2003. This comprised • Below a pregnancy included. As well, the
a total of 2,391 rate of 5%, the cost effect of reduced
cycles. increases pregnancy rates on
exponentially with costs has been
Analysis age. The paper demonstrated
Retrospective chart provides graphs of elsewhere. This
review for clinical cost per live birth as paper essentially
data; expected live a function of age and concludes that with
birth rates per cycle FSH level. high FSH, this effect
depending on age is accentuated.
and FSH were
modeled using a logit
transformation.
Logistic regression
with fractional
polynomials was
used.
Perspective
Health system
Time horizon
Not specified,
324

Author/Country/Year
presumably until
birth
Zowall & Estimated potential Study type Costs included Main outcome • Age specific

Brewer404/Canada/200 cost savings of Cost‐effectiveness • Clinical • Live birth incremental costs per
9 reducing number of analysis management costs (reductions in live birth.
multiple births in multiple births)
Abstract Canada over the Patient population • Hospital delivery • Over next 5 years,
next 5 years Hypothetical patient costs for mothers Information source proportion of
cohort and offspring • Published European singleton, twins, and
studies HOMs could be
Perspective • Costs of disabilities reduced from: 71.2
Third party payer due to preterm/low to 86.6, 27.5 to 12.8,
birth‐weight. and 1.3 to 0.6.
Conducted but no Information source • Potential cost
further information • “Recently savings estimated to
provided published papers” reach 266 million.

Time horizon • Overall incremental
5 years cost per live birth
reduced by 15,228.

• Incremental cost
reductions in
women:
< 35: $17,023
35‐39: $13,860
> 40: $10,749.

• Bulk of cost
reductions
attributable to
325

Author/Country/Year
reductions in
disability costs.
Forte/2009/Canada 88 To determine to Study type Costs included Main outcomes Total annual savings Conclusions:
what extent Cost‐benefit analysis Hospital costs, Multiple birth rate in disability costs The author concludes
Quebec average disability with public funding that there will be an
government Patient population cost of a disabled of IVF in Quebec estimated overall
funding of IVF Hypothetical cohort child resulting from a savings of $282
could be offset by of women in Quebec reduction in multiple million in the first 5
savings due to a (age unspecified) Information sources births was estimated years after public
reduction in who would undergo CIHI, grey literature to range from funding of IVF is
multiple births IVF in the future approximately $34 made available.
million in year 1 to This will offset the
Analysis approximately $44 cost of funding IVF in
The number of cycles million in year 5. the province.
in Quebec with and Savings in hospital
without funding over delivery and neonatal Limitations
5 years was costs were estimated A number of
projected, based on to be from assumptions have
national trends and approximately $15 been made for this
the assumption that million in year 1 to calculation.
IVF utilization will approximately $19 • The comparison
double over 5 years. million in year 5. with European and
Rates of live births Australian trends,
were obtained from from which it is
the Canadian Fertility concluded that the
and Andrology number of IVF cycles
Society. will double in the 5
Hospitalization costs years is questionable.
and disability costs • The methodology is
were estimated for a not sufficiently clear
5 year period. to give confidence in
the estimates.
Information sources: • There is no analysis
326

Author/Country/Year
Canadian Fertility by age of the woman.
and Andrology • The estimated cost
Society, CIHI, of disability, which
published literature contributes
significantly to the
projected savings, is
obtained from grey
literature.

Note:
• Since Quebec’s
introduction of public
funding in 2010, the
demand has been
quite different from
what this report
projected.
Ovo Study type Costs included • Cost structure of
Consulting406/Canada/ Cost structure •General IVF‐ICSI and sIVF
2009 analysis administration costs processes similar.

Analysis •Costs for physicians, • Total average cost
Analysed a cost chain nurses, other health of stimulated IVF
model by taking specialists and lab cycle in Canada:
every step in the work $5,254.07.
process phase of
treatment, from the •Coordination, • Total average cost
first consultation quality control, of simulated IVF‐ICSI
through to screening, training, research cycle in Canada:
virology and then and development, $6,099.20.
through IVF and overhead costs.
coordination and into
the procedure Information source
327

Author/Country/Year
Tagged specific costs •On‐site visit with
associated with every practicing clinic
process •National survey of
Canadian clinics
Fiddelers et To determine the Study type Costs included Main outcomes • Mean cost per Conclusion
al.395/Netherlands/200 cost‐effectiveness Cost effectiveness • IVF treatment • Live birth couple for each • 3 cycles of eSET,
9 of 7 different IVF analysis treatment strategy DET, or STP most
strategies. • Singleton and twin • No pregnancy (Euros): cost‐effective
Patient population pregnancy achieved (defined as 1) 3 eSET: 16 381
308 patients (complicated and cancellation of 2 (12544‐21861) • Model took into
(enrolled in a non‐complicated) subsequent IVF 2) eSET + 2 STP: 16 account: cancelled
randomized control cycles, patient 655 (12 893 – 21 819) cycles, availability of
trial (RCT); 222 • Delivery of decision to drop out 3) eSET + STP + DET: none or only one
patients declined to singleton and twins for personal reasons 17 092 (13 198 – embryo for transfer,
participate) who or patient received 22736) declining pregnancy
became pregnant • Period from birth maximum of 3 cycles 4) eSET + 2 DET: 17 rates in subsequent
following IVF and until 6 weeks after in all strategies and a 440 (13 440 ‐ 22 702) cycles, FETs, and
delivered at the birth for mothers and maximum of 2 frozen 5) 3 STP: 16 999 (13 treatment drop‐outs.
hospital between children embryo transfers per 308 – 22 505)
1995 and 2003 IVF cycle) 6) STP + 2 DET: 17 • Model
Information source 444 (13 681 – 22 546) incorporated: RCT
Perspective • Diaries kept by Information source 7) 3 DET: 18 046 (13 participants and
Patient and couples (beginning 2 • RCT data 733 – 24 210) eligible non‐
payer/healthcare weeks prior to participants to better
system randomization and • Retrospective case • Probability of live reflect general IVF
up to 6 weeks after series of all live births birth for each population
Analysis birth or 2 weeks after following IVF in a treatment strategy:
Compared 7 different last oocyte pickup) single hospital 1) 3 eSET: 0.396 Limitations
IVF strategies using (0.312‐0.475) • Subsequent IVF
Markov modelling •Hospital 2) eSET + 2 STP: treatments of
with first and second administrative/ 0.433 (0.364‐0.499) patients with a live
order Monte Carlo costing data 3) eSET + STP + DET: birth were not
simulation: 0.443 (0.384‐0.507) included.
328

Author/Country/Year
1) 3 consecutive 4) eSET + 2 DET:
elective single 0.457 (0.386‐0.530) • Societal
embryo transfer 5) 3 STP: 0.475 (0.414 consequences of
(eSET) – 0.537) additional IVF
2) 3 consecutive 6) STP + 2 DET: 0.499 attempts following
cycles of double (0.442‐0.561) live birth not
embryo transfer 7) 3 DET: 0.534 included.
(DET) (0.444‐0.618)
3) 3 consecutive • Difficult to
cycles of standard • ICER (Euros/live determine threshold
treatment policy birth): for society’s
(eSET in patients <38 1) 3 eSET: n/a willingness to pay for
years of age with at 2) eSET + 2 STP: 7405 one extra live birth
least 1 good quality 3) eSET + STP + DET: because outcome
embryo and DET in 43 700 measure of live birth
remaining patients) 4) eSET + 2 DET: 24 cannot be compared
4) 1 cycle of eSET + 2 857 directly to QALY.
cycles of STP 5) 3 STP: 8190
5) 1 cycle of eSET + 2 6) STP + 2 DET: 18 • Time horizon short,
cycles of DET 542 ending at live birth or
6) 1 cycle of eSET + 1 7) 3 DET: 17 200 if one of the other
cycle of STP + 1 cycle stop criteria was met
of DET • From cost‐ – did not take into
7) 1 cycle of STP + 2 effectiveness account future
cycles of DET acceptability curve: effects and costs
Ceiling ratio associated with
Time horizon (society’s willingness singletons and twins
Maximum of 3 cycles to pay for a QALYs of children
successful IVF born, patients and
attempt) family members
< €7350: 3 eSET (involuntary
highest probability of childlessness,
being most cost‐ severely
329

Author/Country/Year
effectiveness handicapped child,
€7350‐€15 250: 3 STP etc.
highest probability of
most cost‐effective
>€15 250: 3 DET
highest probability of
most cost‐effective
Moolenaar et al.396/ Comparison of the Study type Costs included Main outcome • Ongoing pregnancy Conclusion
Netherlands/2010 cost‐effectiveness Cost‐utility analysis • Treatment costs •Ongoing pregnancy rates for each • Ovarian reserve
of 4 different IVF rate treatment strategy: testing in all women
Abstract strategies using Patient population Information source 1) no treatment: prior to IVF is cost‐
Hypothetical female • Published literature 24.9% effective over no
cohort 2) 3 cycles of IVF: treatment or
55.5% selective
Perspective 3) Exclusion of poor continuation of IVF
Healthcare system/ responder: 51.7% after poor response.
public payer 4) 3 cycles of IVF
after hormone dose
Analysis adjustment: 61.8%
Markov modelling
used to compare: • Note: the reference
1) No treatment case was no
2) 3 cycles of IVF treatment
without any Additional costs per
conditions live birth
3) Start of IVF in all
women, but • All strategies tested
exclusion of poor for effect of exclusion
responders (< 4 on age
oocytes after
hormonal stimulation • ICER:
in whom ovarian 1) 3 cycles IVF:
reserve confirmed 22,502 Euros
330

Author/Country/Year
poor ovarian reserve 2) Exclusion of poor
after first cycle of IVF responder: 21,935
4) Ovarian reserve Euros
testing and 3 cycles 3) 3 cycles of IVF
of IVF with hormone after hormone dose
does adjustment adjustment: 19,483
based on ovarian Euros
reserve testing
• Withholding IVF in
women >41 in all
strategies resulted in
a minimal cost in
pregnancy reduction
of 2% and 1%
respectively.

• Limiting IVF to
women <39 resulted
in 7% gain in cost
reduction and 4%
gain in pregnancy
loss.
Koning et al.403/ Study type Costs included • Anovulatory Conclusions
Netherlands/2010 Cost analysis • Direct costs of the women: The model • Overweight leads
IVF, IUI and ovulation predicts that of 1000 to fewer pregnancies
Patient Population and more expensive
induction pregnant women,
6 hypothetical groups IVF treatments. It
900 will have might be suggested
of 1000 women: • Costs of caesarean pregnancies, of that weight reduction
anovulatory women delivery, which 90 will result in be attempted before
(normal weight, hypertensive miscarriages, 203 will IVF is performed.
overweight and disorder, gestational have other
obese) and ovulatory diabetes mellitus and complications, and
331

Author/Country/Year
women (normal miscarriage there will be 4
weight, overweight stillbirths. As weight
and obese). Information source increases, the
• Published Dutch numbers of
Perspective studies pregnancies and live
Hospital births fall, and the
rate of complications
Analysis
For each group of increases.
women, a decision
analytic model was • A similar pattern is
created. Sensitivity seen with ovulatory
analyses were women.
performed with
varying values for IVF • Anovulatory
success rate, women: average cost
ovulation induction of a pregnancy was
and IUI. €3001 (normal
weight), €4618
(overweight) and
€5982 (obese);
average cost of a live
birth for the same
groups were €3016,
€4653 and €6045.
• For ovulatory
women: these figures
were for a
pregnancy, €6066,
€8743 and €10246,
332

Author/Country/Year
and for a live birth
€6096, €8800 and€
10355.
• Sensitivity analyses
showed that as
success rates of
ovulation induction,
IUI and IVF increase,
the cost per birth
falls in all groups, by
25% to 50%.
Griffiths et al.219/ To estimate the Study type Costs included Main outcomes • For women in the Conclusions

Australia/2010 incremental costs Cost‐effectiveness • Direct costs of the • Pregnancy rates 30 to 33 year age • Essentially, this
and benefits of an analysis IVF treatment (fresh group, the cost per study seems to show
• Birth rates live birth went from that the age of the
additional IVF cycle and frozen
Patient population AU$27373 for woman is a more
treatment under Hypothetical groups cycle treatment, Program 1 to important factor in
• Rate of ovarian
certain conditions. of women in miscarriage, ectopic AU$30098 for costs than the
hypersensitivity
different maternal pregnancy, stillbirth) Program 2 and number of programs
syndrome
age groups (30‐33, and of managing the AU$31896 for she tries. This could
34‐37, 38‐41, 42‐45). outcomes were used. • Proportion of Program 3. For the have policy
age groups 34 to 37 implications.
singleton, twin and
Perspective • “Patient borne gap years and 38 to 41
“Limited societal” HOM births years groups, the Limitations
payments” were
perspective cost per live birth • A major limitation,
included, though not • Weights of babies
stayed the same in all from a policy
Analysis specified in the 3 programs (34‐37: perspective, is the
paper. Information source
Cost‐effectiveness AU$32564, 38‐41: failure to include
analysis using a • Australian New AU$51635) For the neonatal costs.
decision model to Information source Zealand Assisted 42 to 45 years group,
333

Author/Country/Year
estimate the • Australian Reproduction the cost per live birth
incremental costs Department of Database (ANZARD) went from $130951
and benefits of an Health and Ageing for the first program
additional IVF to AU$187515 for
treatment the second. The
conditional on government’s share
maternal age and of these costs was
previous IVF calculated: the costs
treatments. ICSI was were approximately
not included. Women 55% to 60% of total
could attempt up to costs in each age
3 ‘programs”. The group and for each
programs differed in program. A
fresh‐cycle sensitivity analysis
pregnancy rates, which took into
fresh‐cycle live birth account neonatal
rates and inpatient costs
discontinuation showed that the cost
rates. Pregnancy and per live birth would
live births rates be higher in all age
decreased from groups. This would
Program 1 to have implications for
Program, while multiple births.
discontinuation rates
decreased.

One‐way and
probabilistic
(with probabilities
being modelled on a
beta distribution and
cost estimates on a
334

Author/Country/Year
gamma distribution)
were conducted. The
time horizon was
stated as being
“short”, but
otherwise was not
specified;
consequently no
discounting was
performed.
Scotland et Study type Costs included Main outcomes • DET associated Conclusion
al.392/United Cost effectiveness • Costs of social and • QALY for women with higher • DET is associated
Kingdom/2011 analysis health care and infants cumulative live birth with a favorable cost
• Live birth rate in all age groups utility ratio in women
Abstract Patient population Information source >36 years of age.
6153 patients (aged • Not specified Information source • Additional cost per
32, 36, or 39 years) • Medical records of live birth achieved
who were treated at patients treated at with DET:
1 of 3 IVF clinics IVF clinics 32 years of age:
between January 38,047 GBP
1997 and June 2007 • Published literature 40 years of age:
3,781
Analysis
Comparison of the • DET strategy
cost‐effectiveness of generated more
DET versus eSET in QALYs than eSET
women 32, 36, and across all age groups
39 years of age using
a micro‐simulation • DET Cost/QALY:
model. 32 years of age:
eSET: could receive 38,477 GBP
up to 3 fresh eSET 40 years of age:
cycles 8,225 GBP
335

Author/Country/Year
DET: could receive up
to 3 fresh DET cycles.
Outcomes
incorporated into the
model: early loss,
miscarriage, stillbirth,
live birth, twin live
birth, neonatal
deaths, and long
term infant/family
outcomes.

Time horizon
20 years
Zowall To estimate Study type Information source Main outcomes • Cost savings: Conclusion
andBrewer464/Canada/ potential decrease Incremental net • Canadian Cost • Pregnancy rates <35 years: $31 M • Switching from
2011 in lifetime disability benefit analysis Fertility Model. • Multiple birth rates 35‐39 years: $22 M private to public
resulting from • Reduction in ≥ 40 years: $ 4.5 m provision, lifetime
reduction in Patient population lifetime disability disability rates for
multiple births. Hypothetical female costs • Multiple birth rates women ≥ 40 years of
cohort, ages 28 to 45 expected to be age is lower due to
years Information source reduced from 28.8% low birth success
• Published European to 13.4% rates.
Perspective literature.
Not specified • Net reductions in • Majority of cost
lifetime disability due savings accrues in
Time horizon to decreases in women less than 40
Not specified multiple births: years of age.
< 35 years: 3.6%
Sensitivity analysis 35‐39 years: 3.2% • Note: based on
Probabilistic – ≥ 40 years:2.6% Canadian Fertility
around lifetime Cost Model, for
disability rates/costs. which no information
336

Author/Country/Year
was provided.

Assumptions
• Reductions in
multiple birth rates
were similar to those
in selected European
countries.

• Pregnancy rates
unaffected by
decreases in multiple
birth rates.

van Loendersloot et Study type Costs included Main outcomes • IVF cycle: €3042, Conclusions
al.398/Netherlands/201 Cost‐effectiveness • Direct medical • Pregnancy rate oocyte freezing (3 • The authors
1 costs – cost of after natural cycles) €9126 (both conclude that oocyte
Perspective conception is more cost‐effective
ovarian estimates from
Health system than IVF. However,
hyperstimulation, • Clinical pregnancy literature); oocyte this is true only for
oocyte retrieval, rate storage/year €40, the strategy they
Patient population
Hypothetical group laboratory costs, embryo have defined
of 35 year old embryo transfer, • Miscarriage rate transfer/cycle €400, (strategy 1), and if
oocyte freezing and miscarriage €740 the percentage of
women who wish to
storage, transfer of Information sources (these 3 were based women returning to
postpone •Published literature collect their frozen
childbearing until frozen/thawed on institutional costs)
oocytes is 61%.
they are 40. oocytes and cost of •CDC
miscarriage. Costs • ICERs were
Limitations
were adjusted to •Human Fertilization calculated comparing • The authors
Analysis and Embryology the first 2 strategies acknowledge that the
337

Author/Country/Year
A Markov model was 2008 values. Authority with the reference limited amount of
used, comparing 2 standard, with and data available on
strategies with the Information sources without discounting natural conception at
reference case where • Institution and 40 years of age; the
(at 4% annually for
women receive IVF published literature limited data on
treatment only. The 2 10 years for costs, oocyte freezing; the
strategies were: (1) and at 1.5% for 5 fact that the costs of

women undergo 3 years for effects). pregnancies and
cycles of ovarian Both one‐way and deliveries are not
hyperstimulation at probabilistic included.
age 35 to collect and sensitivity analyses
freeze all obtained • The authors also
were performed with
oocytes. Between 35 acknowledge that
years and 40 years, undiscounted costs there is no absolute
no pregnancies and effects. value of the ICER that
occur, and the frozen might be acceptable
oocytes are thawed • The ICER of to society.
and used at age 40. If strategy compared to
there is no pregnancy the reference
after 1 year of IVF standard was €19534
with the oocytes, the (undiscounted) and
women try to
€13156 (discounted).
conceive naturally for
the remaining 4 For strategy 2, the
years; (2) women ICERs were €47874
wait until the age of and €60717.
40 to try and
conceive for the first • The probabilistic
time. If they do not sensitivity analyses
succeed within 1 (undiscounted)
year, they are resulted in mean
considered infertile,
ICERs for strategy 1
but do not seek any
against the reference
338

Author/Country/Year
treatment for this. In standard of €19587
the reference (95% CI = ‐€12728 to
standard women €111841), and for
delay active
strategy 2, €50137
conception until the
age of 40, and if they (€17888 to €221021).
fail in the first year,
• In the sensitivity
seek treatment with
IVF. If they do not analyses, the
conceive within percentage of
another year, they women who return
attempt to conceive to collect their frozen
naturally again. embryos was varied,
and Strategy 1
remained cost‐
effective when this
exceeds 61%.
• If the cumulative
live birth rate after
oocyte freezing drops
below 53%, the
reference standard
becomes more cost‐
effective. And if the
cost of IVF is more
than €4475 or of
oocyte freezing
becomes less than
€5058, Strategy 1
becomes more cost‐
339

Author/Country/Year
effective.
Connolly et Effect of cuts in IVF Data sources • By age 25, with the

al.171,409/Denmark/201 coverage in Demark Government sources, reductions in
1 on long‐term Registry of the government payment
taxation and Danish Fertility for IVF, it will have
revenue to Society cost savings of €67 to
government. €111 million.
Data elements
Government • By age 50, with
transfers (family fewer IVF children
allowances, born (and so fewer
education, etc.), tax tax payers), it is
revenue, and estimated that the
cost/cycle of IVF. government would
lose €74 to €123
Analysis million.
A modified
generational
accounting model,
for a hypothetical
IVF‐conceived child
born in 2010.
Forte218/2012/Canada To determine to Please see Forte Please see Forte Main outcome Total annual savings Conclusions

what extent Alberta (2009) above (2009) above Multiple birth rate in disability costs The projected savings
government with public funding in hospitalization and
of IVF in Alberta disability costs will
funding of IVF
Information source resulting from a more than offset the
could be offset by Private clinic in reduction in multiple cost of funding IVF in
savings due to a Calgary births was estimated the province.
340

Author/Country/Year
reduction in to range from
multiple births approximately $27 Limitations
million in year 1 to Similar to Forte
approximately $36 (2009) above. The
million in year 5. sources of
Savings in hospital information seem to
delivery and neonatal have been selective,
costs were estimated and may not
to be approximately represent what might
$6 million annually. happen in Alberta.

341

Table 46. Studies of US state mandated insurance coverage of ARTs services
Studies of US state mandated insurance coverage of ARTS services
410
Banks et al. /United To evaluate the Data sources Main outcomes
States/2010 outcomes of state CDC data on use and outcomes of ART • Embryo transfer • Comprehensive –
government clinics, 1997 to 2006. rate <35 years: 0.21 fewer embryos
mandated (p<0.001)
insurance Data elements 35 – 39 years: 0.26 fewer (p<0.001)
coverage of ARTs. Number of embryos transferred, no. of >39 years: 0.22 fewer (p<0.05)
cycles, no. of births (singletons,
multiples). • Limited and Offer only categories‐
Similar trends but not statistically
Analysis significant in most age groups
Multivariate least‐squares regression
at the clinic‐year level to estimate
separate models for each dependent • Multiple birth • Comprehensive –
variable. Three levels of insurance rate/transfer <35 years: fewer multiple
were defined: Comprehensive, births/transfer (p<0.05)
Limited, Offer only. Relationship less clear for older
women
Martin et To evaluate the Data sources Main outcomes
al.413/United outcomes of state SART/CDC data on all fresh, non‐donor • Pregnancy rate < 35 years ‐ group 1: 43%, group 2:
States/2010 mandated IVF cycles in the US in 2006. 47.3% (p<0.05)
insurance 35 – 37 years ‐ group 1: 36.2%,
coverage of ARTs. Data elements group 2: 37.3%

Pregnancy rates, live birth rates,
• Embryo transfer < 35 years ‐ group 1: 2.2, group 2:
embryo transfer rates, singleton, twin
rate 2.6 (p<0.05)
and multiple live birth rates. 35 – 37 years ‐ group 1: 2.3, group
2: 2.6 (p<0.05)
Analysis
Comparison between 2 groups of • Twin rate < 35 years ‐ group 1: 31.8%, group
342

clinics – group 1 (n=74 in states with 2: 34.2% (p<0.05)
mandated insurance), group 2 (n=352 35 – 37 years ‐ group 1: 25.8%,
in states without mandates). group 2: 26.3%

• Triplet rate < 35 years ‐ group 1: 3.5%, group 2:
4.1% (p<0.05)
35 – 37 years ‐ group 1: 3.4%, group
2: 4.6% (p<0.05)

• Multiple birth < 35 years ‐ group 1: 33.6%, group
rate 2: 36.3% (p<0.05)
35 – 37 years ‐ group 1: 27.2%,
group 2:29.6%(p<0.05)
Banks et al.410/United To evaluate the Study type Main outcomes • Clinics in states with
States/2011 relationship Outcome and utilization study • Embryo transfer “comprehensive”” insurance
between embryo rates, births and mandates transfer fewer embryos
Patient population multiple per cycle than clinics in states
transfer rates,
Women who have undergone ART without mandates:
birth outcomes births/transfer,
treatments between 1997 and 2006. < 35 years: 0.21 fewer
and state births/cycle embryos/cycle (p<0.01)
mandated Analysis 35‐37 years: 0.29 fewer

insurance status. US states were categorized as having embryos/cycle (p<0.001)

“comprehensive”, “limited” and “offer 38‐40 years: 0.26 fewer
Information
only” insurance mandates. embryos/cycle (p<0.05)
source
Multivariate least‐squares regression 41‐42 years: 0.22 fewer
• Centre for
analysis was used at the clinic‐year embryos/cycle (p<0.01)
Disease Control
level. Separate models were
(CDC)
estimated for each dependent • “Comprehensive” mandates were
variable. The regressions included all also associated with fewer multiple
control variables, including population births per transfer:
of women aged 25 to 44 years, < 35 years: 1.8% fewer (p<0,01)
minority rate, mean per capita 35‐37 years: 0.3 % fewer
income, percentage of working age 38‐40 years: 1.3% fewer (p<0.01)
343

adults with private insurance, 41‐42 years: 0.3% fewer
unemployment rates and year fixed
effects. • “Comprehensive” mandates were
also associated with fewer
births/cycle:
< 35 years: 3% fewer (p<0.05)
35‐37 years: 1.6% fewer
38‐40 years: 1.4% fewer
41‐42 years: 2.2% fewer (p<0.01)
Henne et To examine the Study type Main outcomes • Overall trends between 1990 and
al.411/United relationship Outcome and utilization study • Number of ART 2001:
States/2011 between cycles/1000 ART cycles/1000 women – 0.68 to
Patient population women (aged 25 2.36 (+246%)
insurance
This study was based on clinic‐level, to 44 years) Births/cycle – 14% to 29% (+104%)
mandates for IVF not patient‐level data. Multiple births/cycle – 0.04 to 0.10
and utilization • Number of live (+154%)
and outcomes. Analysis births/1000 cycles Singleton births/cycle – 0.11 to 0.18
Using clinic‐level data in the US from (+69%)
1990 to 2001, the differences in ART • Number of Multiple births/live birth – 27% to
utilization and outcomes between multiple 36% (+31%)
states with and without mandated births/live birth Increase in the number of multiple
insurance were examined using birth rate per capita increased
multivariate least squares regression. Information nearly 7‐fold
sources
• SART • In states with comprehensive
mandates, births/cycle were 4%
• CDC lower, and multiples/ART birth were
2% lower in states with no
• A fertility mandate; Utilization was higher by
organization for 1.3 cycles/1000 women in states
state mandate with comprehensive mandates than
information in states with no mandate. These
findings were all statistically
344

significant.
Martin et To measure the Study type Main outcomes • Mean number of embryos
al.413/United impact of state Outcome and utilization study • Embryo transfer transferred:
States/2011 mandated IVF rates < 35 years: 2.2 (mandated), 2.6
Patient population
insurance (non‐mandated) (p<0.05)
All women with fresh, non‐donor IVF • Live birth rates
coverage on 35‐37 years: 2.3 (mandated), 2.6
cycles performed in 426 infertility
embryo transfer • Cancellation (non‐mandated) (p<0.05)
clinics in the US in 2006.
practices and rates 38‐40 years: 2.6 (mandated), 2.8
multiple births. Analysis (non‐mandated)
Compared data from 74 clinics in • Births by 41‐42 years: 3.0 (mandated), 2.9
states with mandated IVF insurance plurality (non‐mandated)
with data from 352 clinics with no

mandated IVF coverage using Information
source • Live birth rates:
descriptive statistics. A mandated
• SART < 35 years: 37.6% (mandated), 41.6
state is defined as one in which at
least 1 IVF cycle is covered. There • CDC (non‐mandated) (p<0.05)
were 64188 cycles performed in 2006 35‐37 years: 29.7% (mandated),
in non‐mandated states and 27565 in 30.6% (non‐mandated)
mandated states. The Mann‐Whitney 38‐40 years: 19.5% (mandated),
U‐test was used for continuous 20.7% (non‐mandated)
variables, and χ2 tests were used for
41‐42 years: 10.2% (mandated),
categorical variables.
10.6% (non‐mandated)

• Cancellation rates:
< 35 years: 7.1% (mandated), 8.2%
(non‐mandated) (p<0.05)
13.97% (non‐mandated) (p<0.05)
345


• Multiple birth rates:
< 35 years: 33.6% (mandated),
Buckles64/United Impact of strongly Data sources Main outcome • Number of infants per 1000

States/2012 mandated state National Center for Health Statistics • Number of births:
insurance policies Natality Data Files, 1980 to 2002. infants per1000 All women: 1013.5
on ARTs.
births <30 years: 1011.4
Data elements
Maternal age, number of births >29 years: 1018.5
(singletons, multiples).
• These are not statistically

Analysis significant increases over singleton
Development of a model to estimate births
the effects of strongly‐mandated laws
on multiple births using a differences‐
in‐differences strategy.
Buckles64/United To estimate birth Study type Main outcomes • With a strong mandate, it is • The study
States/2012 rates in states Outcome study • Mean number estimated that married women and concludes that
with “strong” of babies per white women have a statistically strong mandates
Patient population 1000 births had a small and
infertility significantly higher multiple births
Births in the US between 1980 and statistically
treatment 2002. than in non‐mandated states. The insignificant
346

mandates and • Births by increases in these 2 groups are 4.7% impact on
states with no Analysis plurality and 3.3% respectively. Among multiple births.
mandated An ordinary least‐squares linear women with a college degree, there
regression model was developed, Information
coverage. is the same trend, but it is
using a difference‐in‐differences source
estimation strategy. This allows marginally statistically significant.
• National Center
determination of the effect of a strong for Health

insurance mandate on multiple births. Statistics’ Natality
The model incorporates maternal age, Detail Files
• Among women with less than 16
education, marital status and race.
years of education, who are
unmarried, or non‐white, there is
no statistically significant impact of
the mandate on multiple births
• Based on numbers of multiple
births, it is estimated that a strong
mandate increases multiple births
by about 4% in married women
(p<0.05). This trend is also true for
women over 30 years of age and for
white women, but not statistically
significantly.
Hamilton and To assess the Study type Main outcomes Utilization

McManus412/United differences in Outcome study • Number of ART • Universal mandate results in an
States/2012 utilization and cycles increase of ART utilization in women
Patient population of all ages, by approximately 90%;
outcomes of IVF
Clinic‐level data on ART from 1995 to • Birthrates the effect is slightly larger for
in states with 2003 were used instead of patient‐ women older than 35.
347

different level information. • Numbers of
insurance embryos • A restricted mandate has a small,
mandates. Analysis transferred but statistically insignificant,
Two regression models were created, positive effect on IVF utilization
one to estimate the effect of the • Multiple births
extent of the mandate on number of • In states with ‘other’ mandate
ART cycles/1000 women, and the Information laws (e.g., offering a mandate, or
other to estimate other effects due to sources covering non‐IVF treatments) IVF
clinic‐level practice. These included • SART
utilization is significantly below
whether the clinic was a SART member
or whether it provided ART services to • CDC states with no mandates for women
single women. under 35
• CMS
Birthrates
• US Census • Women under the age of 25 in
Bureau states with universal mandate has a
significantly lower birthrate than
• A national those in other states
infertility
association • Women 35 years or older have a
significantly lower birthrate in
states with restricted mandates
than in states with universal
mandates
• Women in both age groups have
higher birthrates in clinics with a
high rate of ICSI
Embryos transferred
• Women in both age groups have a
lower number of embryos
transferred in states with universal
348

mandates

• Clinics with high IVF rates transfer
fewer embryos, and clinics that
treat single women are associated
with higher embryo rates
Multiple births
• Twin rates are unaffected by type
of mandate
• In states with a universal
mandate, the rate of HOMB is
statistically significantly lower in
both age groups when compared to
other states; the effect is more
significant in the 35 or younger age
group than in the older age group.
349

Appendix G ‐ Tables for the decision model

Table 47. Variable inputs for decision model 1 ‐ diagnosis of patients presenting with suspected
Branch of Variable Estimate (probabilities) Information Sources and Assumptions

decision model
Couples present to general practitioner/family physician (GP/FM) with suspected infertility
A GP/FP performs infertility workup on couple Overall: 0.45* • The proportion of couples that present to their GP/FP with suspected infertility who receive a
By female age: no complete ‘infertility workup’ prior to being either 1) treated by the GP/FP, or 2) referred to an
differences (although, a appropriate specialist
faster workup and referral • Assumes a ‘complete infertility workup’ includes:
should be provided for ‐ history and physical exam on both partners
women ≥35 years of age) ‐ counselling on frequency and timing of intercourse and lifestyle factors (BMI, drug and
alcohol use, etc.)
‐ female tests: blood and urine testing (day 3 FSH and estradiol, LH, progesterone prolactin,
TSH), pelvic ultrasound (with antral follicle count), hysterosalpingography or
hysterosalpingocontrastsonography
‐ male tests: blood and urine testing(FSH, LH, testosterone, prolactin, TSH, post‐ejaculatory
urinalysis), semen analysis and test for anti‐sperm antibodies
• Expert opinion* (consensus among experts could not be achieved for this input; about half of
experts suggested 90‐100% of patients should receive an appropriate workup and counselling
from a GP before being referred to a specialist, while the other half suggested that patients
should be referred to a specialist for this workup (as specialists have the expertise needed)
B, C, D GP/FP refers couple to specialists for infertility workup: Couple referred to: • The proportion of couples that present to their GP/FP with suspected infertility are referred to
‐ male to urologist (UROL) or reproductive endocrinology REI: 0.40 an appropriate specialist for an ‘infertility workup’
and infertility specialist (REI) OBGY/UROL: 0.10 • Of these couples, the proportion of female partners who are referred to:
‐ female to endocrinologist (ENDO), obstetrics and ENDO/UROL: 0.05 ‐ an endocrinologist (ENDO),
gynecology specialist (OBGY), or reproductive ‐ an obstetrics and gynecology specialist (OBGY), or
endocrinology and infertility specialist (REI) ‐ a reproductive endocrinology and infertility specialist (REI)
• Of these couples, the proportion of male partners who are referred to:
‐ a urologist (UROL), or
‐ a reproductive endocrinology and infertility specialist (REI)
• Expert opinion*
E Suspected female factor infertility only Overall: 0.35 • The proportion of couples with suspected infertility that have:
By female age: ‐ female factor infertility only,
<35: 0.35 ‐ male factor infertility only,
35‐40: 0.35 ‐ both female and male factor infertility (mixed factor infertility), or
>40: 0.30 ‐ unexplained infertility
350


decision model
36,37
F Suspected male factor infertility only Overall: 0.30 • Literature
By female age:
<35: 0.30
35‐40: 0.30
>40: 0.25
G Suspected mixed factor (male and female) infertility Overall: 0.20
By female age:
<35: 0.20
35‐40: 0.20
>40: 0.35
H Unexplained infertility Overall: 0.15
By female age:
<35: 0.15
35‐40: 0.15
>40: 0.10
I Suspected ovulatory dysfunction Overall: 0.45 • The proportion of women with female factor infertility only that have:
By female age: ‐ ovulatory dysfunction,
<35: 0.40 ‐ tubal obstruction,
35‐40: 0.45 ‐ endometriosis, or
>40: 0.45 ‐ polyps/fibroids
36‐38,41,44,76
J Suspected tubal obstruction Overall: 0.40 • Literature
By female age: • Expert opinion
<35: 0.40
35‐40: 0.40
>40: 0.45
K Suspected endometriosis (moderate‐severe) Overall: 0.10
By female age:
<35: 0.15
35‐40: 0.10
>40: 0.05
L Suspected polyps or fibroids Overall: 0.05
By female age:
<35: 0.05
35‐40: 0.05
>40: 0.05
P WHO group I ovulatory dysfunction (Non‐PCOS) Overall: 0.10 • The proportion of women with ovulatory dysfunction that is caused by:
By female age: ‐ hypogonadotropic hypogonadism (non‐PCOS or WHO group I),
<35: 0.15 ‐ polycystic ovarian syndrome (PCOS or WHO group II), or
35‐40: 0.10 ‐ premature ovarian failure (WHO group III)
40,44,465‐467
>40: 0.05 • Literature
351


decision model
Q WHO group II ovulatory dysfunction (PCOS) Overall: 0.75
By female age:
<35: 0.80
35‐40: 0.70
>40: 0.25
R WHO group III ovulatory dysfunction (ovarian failure) Overall: 0.15
By female age:
<35: 0.05
35‐40: 0.20
>40: 0.70
S Proximal or distal tubal obstruction (not from sterilisation) Overall: 0.98 • The proportion of women with tubal obstruction that is caused by
By female age: ‐ a proximal or distal obstruction,
<35: 0.99 ‐ a tubal ligation
35‐40: 0.98 • Expert opinion
>40: 0.96 • Assumes diagnosis based on laparoscopy
T Tubal ligation Overall: 0.02
By female age:
<35: 0.01
35‐40: 0.02
>40: 0.04
U Polyps Overall: 0.10 • The proportion of women with suspected polyps or fibroids that have:
By female age: no ‐ polyps,
differences ‐ type 0 or 1 fibroids, or
V Type 0 or 1 fibroids (submucosal or <50% within uterine Overall: 0.45 ‐ type 2 fibroids
wall) By female age: no • Expert opinion
differences
W Type 2 fibroids(intramural or >50% of fibroid within Overall: 0.25
uterine wall) – symptomatic or small By female age: no
differences
X Type 2 fibroids(intramural or >50% of fibroid within Overall: 0.20
uterine wall) – asymptomatic and small By female age: no
differences
M Obstructive azoospermia or oligozoospermia (post‐ Overall: 0.05 • The proportion of men with male factor infertility only that have:
testicular) By female age: no ‐ obstructive azoospermia or oligozoospermia (post‐testicular causes),
differences ‐ a non‐obstructive condition (pre‐testicular or testicular causes), or
N Non‐obstructive condition (pre‐testicular or testicular) Overall: 0.65 ‐ male factor infertility of unknown cause
468‐470
By female age: no • Literature
differences
O Male factory infertility of unknown origin Overall: 0.30
By female age: no
differences
352


decision model
Y Vasectomy Overall: 0.04 • The proportion of men with obstructive azoospermia or oligozoospermia that is caused by:
By female age: no ‐ a vasectomy,
differences ‐ a congenital or acquired obstruction of the ejaculatory duct
Z Congenital or acquired obstruction of the ejaculatory duct Overall: 0.02 ‐ congenital bilateral absence of the vas deferens (CBAVD), or
By female age: no ‐ some other obstruction (e.g., trauma, infection, …)
468,471
differences • Literature
AA Congenital bilateral absence of vas deferens (CBAVD) Overall: 0.02
By female age: no
differences
BB Other obstruction Overall: 0.92
By female age: no
differences
CC Hormonal abnormalities Overall: 0.02 • The proportion of men with non‐obstructive infertility that is caused by:
By female age: no ‐ hormonal abnormalities (e.g., hypogonadotropic hypogonadism, Cushing syndrome)
differences ‐ a clinical varicocele(s)
DD Clinical varicocele Overall: 0.33 ‐ an immunologic condition
By female age: no ‐ a genetic abnormality (e.g., Klinefelter syndrome)
differences ‐ some other acquired condition (e.g., ejaculatory or sexual dysfunction, iatrogenic, ...)
469,470
EE Immunologic condition Overall: 0.08 • Literature
By female age: no
differences
FF Genetic abnormality Overall: 0.005
By female age: no
differences
GG Other acquired condition Overall: 0.565
By female age: no
differences
353


Table 48. Variable inputs for decision model II ‐ treatment of couples with female factor infertility only
decision model
Ovulatory dysfunction – Non‐PCOS (WHO group I)
First line of treatment
A Pulsatile GnRH Overall: 0.85‐0.90 • The proportion of women with hypogonadotropic hypogonadism (non‐PCOS or WHO group I
By female age: no ovulatory dysfunction) who:
differences ‐ are treated with pulsatile GnRH injections, or
B Dropout Overall: 0.10‐0.15 ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
By female age: no decision to adopt, etc.)
differences • Expert opinion
E Successful ovulation with pulsatile GnRH Overall: 0.80‐0.93 • The proportion of women with non‐PCOS (WHO group I) ovulatory dysfunction who:
By female age: ‐ ovulate after treatment with pulsatile GnRH injections, or
<35: 0.87‐0.93 ‐ do not ovulate after treatment with pulsatile GnRH injections
472,473
35‐40: 0.85 • Literature (note: results after up to 6 cycles of ovulation induction with pulsatile GnRH per
>40: 0.80 woman) and expert opinion
F No ovulation with pulsatile GnRH 1 – successful ovulation
I Successful clinical pregnancy with pulsatile GnRH Overall: • The proportion of women with non‐PCOS (WHO group I) ovulatory dysfunction who:
0.65‐0.90 per woman ‐ achieve a clinical pregnancy after treatment with pulsatile GnRH injections, or
By female age: ‐do not achieve a clinical pregnancy after treatment with pulsatile GnRH injections
472
<35: 0.80‐0.90 • Literature (note: results after up to 6 cycles of ovulation induction with pulsatile GnRH per
35‐40: 0.74‐0.85 woman) and expert opinion
>40: 0.22‐0.57 • Note: women who achieve successful ovulation, however fail to achieve or maintain a
J No clinical pregnancy with pulsatile GnRH 1 – successful clinical pregnancy will be treated as unexplained infertility
pregnancy
P Miscarriage after clinical pregnancy with pulsatile GnRH Overall: 0.09 • The proportion of women with non‐PCOS (WHO group I) ovulatory dysfunction who achieved a
By female age: clinical pregnancy after treatment with pulsatile GnRH injections, who:
<35: 0.08 ‐ do not maintain this pregnancy (experience a miscarriage), or
35‐40: 0.11 ‐ maintain this pregnancy (successful ongoing pregnancy)
472
>40: 0.20 • Literature and expert opinion (reported miscarriage rates were the same as those in general
O Successful ongoing pregnancy with pulsatile GnRH 1 – miscarriage population, therefore Alberta general population estimates were used)
• Note: women who achieve successful ovulation, however fail to achieve or maintain a
pregnancy will be treated as unexplained infertility
Second line of treatment (after failure to ovulate)
C Gonadotropins after failure to ovulate with pulsatile GnRH Overall: 0.85‐0.90 • The proportion of women with hypogonadotropic hypogonadism (non‐PCOS or WHO group I
By female age: no ovulatory dysfunction) who either did not achieved a clinical pregnancy or were unable to
differences maintain a pregnancy after treatment with pulsatile GnRH injections who:
K Dropout after failure to ovulate with pulsatile GnRH Overall: 0.10‐0.15 ‐ are treated with gonadotropin injections, or
By female age: no ‐ ‘dropout’
354


decision model
G Successful ovulation with gonadotropins Overall: 0.96 • The proportion of women with non‐PCOS (WHO group I) ovulatory dysfunction who:
By female age: ‐ ovulate after treatment with gonadotropins, or
<35: 0.96 ‐ do not ovulate after treatment with gonadotropins
474
35‐40: 0.90 • Literature and expert opinion
>40: 0.60 • It was assumed that ability to ovulate with gonadotropins was not influenced by a previous
H No ovulation with gonadotropins 1 – successful ovulation failure to ovulate with pulsatile GnRH
L Successful clinical pregnancy with gonadotropins Overall: • The proportion of women with non‐PCOS (WHO group I) ovulatory dysfunction who:
0.63‐0.87 per couple ‐ achieve a clinical pregnancy after treatment with gonadotropin injections, or
By female age: ‐ do not achieve a clinical pregnancy after treatment with gonadotropin injections
472,474‐476
<35: 0.75‐0.87 • Literature (note: results after up to 6 cycles of ovulation induction with hMG, or FSH +
35‐40: 0.71‐0.82 LH, per woman) and expert opinion
>40: 0.21‐0.55 • It was assumed that success with gonadotropins was not influenced by a previous failure to
M No clinical pregnancy with gonadotropins 1 – successful clinical ovulate with pulsatile GnRH
pregnancy • Note: women who achieve successful ovulation, however fail to achieve or maintain a
R Miscarriage after clinical pregnancy with gonadotropins Overall: 0.27 • The proportion of women with non‐PCOS (WHO group I) ovulatory dysfunction who achieved a
By female age: clinical pregnancy after treatment with gonadotropin injections, who:
472
>40:0.27 • Literature and expert opinion
Q Successful ongoing pregnancy with gonadotropins 1 – miscarriage • Note: women who achieve successful ovulation, however fail to achieve or maintain a
Third line of treatment (after failure to ovulate)
D IVF after failure with gonadotropins or pulsatile GnRH Overall: 0.85‐0.90 • The proportion of women with non‐PCOS (WHO group I) ovulatory dysfunction who either did
By female age: no not achieved a clinical pregnancy or were unable to maintain a pregnancy after treatment with
differences gonadotropin injections or pulsatile GnRH injections who:
N Dropout after failure with pulsatile GnRH Overall: 0.10‐0.15 ‐ are treated with IVF, or
Ovulatory dysfunction – PCOS (WHO group II)
A Clomiphene citrate ± metformin 0.95 • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who:
(0.20 with metformin) ‐ are treated with clomiphene citrate (Clomid® or Serophene®) ± metformin, or
By female age: no ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
differences decision to adopt, etc.)
B Dropout 0.05 • Expert opinion
By female age: no
differences
G Successful ovulation with clomiphene citrate ± metformin Overall: 0.64‐0.80 • The proportion of women with PCOS (WHO group II) ovulatory dysfunction who:
By female age: ‐ ovulate after treatment with clomiphene citrate ± metformin, or
<35: 0.80 ‐ do not ovulate after treatment with clomiphene citrate ± metformin
42,467,477
35‐40: 0.75 • Literature (note: number of cycles needed to ovulate variable – with most studies
>40: 0.50 reporting provision of up to 6 cycles) and expert opinion
355


decision model
H No ovulation with clomiphene citrate ± metformin 1 – successful ovulation
O Successful clinical pregnancy with clomiphene citrate ± Overall: 0.24‐0.49 per • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who:
metformin woman ‐ achieve a clinical pregnancy after treatment with clomiphene citrate ± metformin, or
By female age: ‐ do not achieve a clinical pregnancy after treatment with clomiphene citrate ± metformin
42,467,477‐483
<35: 0.40‐0.49 • Literature (note: number of cycles needed in order to achieve clinical pregnancy
35‐40: 0.36‐0.42 variable – with most studies reporting provision of up to 6 cycles; however studies have shown
467
>40: 0.10‐0.25 that the majority of pregnancies achieved with CC occur within the first 3 cycles ) and expert
P No clinical pregnancy with clomiphene citrate ± 1 – successful clinical opinion
metformin pregnancy • Note: women who achieve successful ovulation, however fail to achieve or maintain a
BB Miscarriage after clinical pregnancy with clomiphene Overall: 0.20 • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who achieved a
citrate ± metformin By female age: clinical pregnancy after treatment with clomiphene citrate ± metformin, who:
<35: 0.08‐0.11 ‐ do not maintain this pregnancy (experience a miscarriage), or
35‐40: 0.11‐0.17 ‐ maintain this pregnancy (successful ongoing pregnancy)
42,467,478,480‐482,484
>40: 0.20‐0.30 • Literature and expert opinion
AA Successful ongoing pregnancy with clomiphene citrate ± 1 – miscarriage • Note: women who achieve successful ovulation, however fail to achieve or maintain a
metformin pregnancy will be treated as unexplained infertility
Second line of treatment (after failure to ovulate with CC ± Mt)
C Aromatase inhibitors after failure with clomiphene citrate Overall: 0.65‐0.75 • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who either did not
± metformin By female age: achieved a clinical pregnancy or were unable to maintain a pregnancy after treatment with
<35: 0.85‐0.90 clomiphene citrate ± metformin who:
35‐40: 0.75‐0.85 ‐ are treated with aromatase inhibtirs
>40: 0 ‐ are treated with gonadotropins, or
D1 Gonadotropins after failure with clomiphene citrate ± Overall: 0.15‐0.20 ‐ ‘dropout’
metformin By female age: • Expert opinion
<35: 0
35‐40: 0.05‐0.10
>40: 0.85‐0.90
Q Dropout after failure with clomiphene citrate ± metformin Overall: 0.10‐0.15
By female age: no
differences
I Successful ovulation with an aromatase inhibitor Overall: 0.55‐0.91 • The proportion of women with PCOS (WHO group II) ovulatory dysfunction who:
By female age: ‐ ovulate after treatment with an aromatase inhibitor, or
<35: 0.84‐0.91 ‐ do not ovulate after treatment with an aromatase inhibitor
485‐487
35‐40: 0.72‐0.82 • Literature (note: results after up to 3 cycles of ovulation induction with Letrozole per
>40: N/A woman, although most studies use 1‐2 cycles) and expert opinion
J No ovulation with an aromatase inhibitor 1 – successful ovulation • These probabilities reflect the success of aromatase inhibitors as a second line of treatment in
clomiphene citrate‐resistant women (women who have failed to achieve ovulation and/or
pregnancy with clomiphene citrate)
356


decision model
R Successful clinical pregnancy with an aromatase inhibitor Overall: 0.25‐0.38 per • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who:
woman ‐ achieve a clinical pregnancy after treatment with an aromatase inhibitor, or
By female age: ‐ do not achieve a clinical pregnancy after treatment with an aromatase inhibitor
485‐487
<35: 0.27‐0.38 • Literature (note: results after up to 3 cycles of ovulation induction with Letrozole per
35‐40: 0.22‐0.31 woman, although most studies use 1‐2 cycles) and expert opinion
>40: N/A • These probabilities reflect the success of aromatase inhibitors as a second line of treatment in
S No clinical pregnancy with an aromatase inhibitor 1 – successful clinical clomiphene citrate‐resistant women (women who have failed to achieve ovulation and/or
pregnancy pregnancy with clomiphene citrate)
DD Miscarriage after clinical pregnancy with an aromatase Overall: 0.20 • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who achieved a
inhibitor By female age: clinical pregnancy after treatment with an aromatase inhibitor, who:
488
>40: N/A • Literature and expert opinion
CC Successful ongoing pregnancy with an aromatase inhibitor 1 – miscarriage • Note: women who achieve successful ovulation, however fail to achieve or maintain a
K Successful ovulation with gonadotropins Overall: 0.90 • The proportion of women with PCOS (WHO group II) ovulatory dysfunction who:
<35: N/A ‐ do not ovulate after treatment with gonadotropins
42
35‐40: 0.85 • Literature (notes: number of cycles needed to ovulate variable, although most studies
>40: 0.55 reported at least up to 3 cycles; most studies reported using FSH or hMG)
L No ovulation with gonadotropins 1 – successful ovulation • These probabilities reflect the success of gonadotropins as a second line of treatment in
U Successful clinical pregnancy with gonadotropins Overall: 0.41‐0.70 per • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who:
woman ‐ achieve a clinical pregnancy after treatment with gonadotropins, or
By female age: ‐ do not achieve a clinical pregnancy after treatment with gonadotropins
42,65,482,489
<35: N/A • Literature (notes: number of cycles needed in order to achieve clinical pregnancy
35‐40: 0.62‐0.71 variable, although most studies reported at least up to 3 cycles; most studies reported using FSH
>40: 0.17‐0.44 or hMG) and expert opinion
V No clinical pregnancy with gonadotropins 1 – successful clinical • These probabilities reflect the success of gonadotropins as a second line of treatment in
pregnancy clomiphene citrate‐resistant women (women who have failed to achieve ovulation and/or
FF Miscarriage after clinical pregnancy with gonadotropins Overall: 0.16‐0.40 • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who achieved a
By female age: clinical pregnancy after treatment with gonadotropins, who:
<35: N/A ‐ do not maintain this pregnancy (experience a miscarriage), or
482,490
>40: 0.28‐0.40 • Literature and expert opinion
EE Successful ongoing pregnancy with gonadotropins 1 – miscarriage • Note: women who achieve successful ovulation, however fail to achieve or maintain a
357


decision model
Third line of treatment (after failure to ovulate with aromatase inhibitors)
D2 Gonadotropins after failure with aromatase inhibitors Overall: 0.83‐0.89 • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who either did not
By female age: achieved a clinical pregnancy or were unable to maintain a pregnancy after treatment with
<35: 0.83‐0.89 clomiphene citrate or an aromatase inhibitor who:
35‐40: 0.85‐0.90 ‐ are treated with gonadotropins (e.g., FSH/Gonal F® or Puregon® plus hCG),
>40: N/A ‐ are treated with laparoscopic ovarian drilling (LOD), or
E Laparoscopic ovarian drilling (LOD) after failure with Overall: 0.01‐0.02 ‐ ‘dropout’
aromatase inhibitors By female age: • Expert opinion
<35: 0.01‐0.02
35‐40: 0
>40: N/A
T Dropout after failure with aromatase inhibitors Overall: 0.10‐0.15
By female age: no
differences
K Successful ovulation with gonadotropins Overall: 0.90 • The proportion of women with PCOS (WHO group II) ovulatory dysfunction who:

<35: 0.90 ‐ do not ovulate after treatment with gonadotropins
42
35‐40: 0.85 • Literature (notes: number of cycles needed to ovulate variable, although most studies
>40: N/A reported at least up to 3 cycles; most studies reported using FSH or hMG)
L No ovulation with gonadotropins 1 – successful ovulation • These probabilities reflect the success of gonadotropins as a second line of treatment in
U Successful clinical pregnancy with gonadotropins Overall: 0.41‐0.70 per • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who:
woman ‐ achieve a clinical pregnancy after treatment with gonadotropins, or
By female age: ‐ do not achieve a clinical pregnancy after treatment with gonadotropins
42,65,482,489
<35: 0.70‐0.80 • Literature (notes: number of cycles needed in order to achieve clinical pregnancy
35‐40: 0.62‐0.71 variable, although most studies reported at least up to 3 cycles; most studies reported using FSH
>40: N/A or hMG) and expert opinion
V No clinical pregnancy with gonadotropins 1 – successful clinical • These probabilities reflect the success of gonadotropins as a second line of treatment in
pregnancy clomiphene citrate‐resistant women (women who have failed to achieve ovulation and/or
FF Miscarriage after clinical pregnancy with gonadotropins Overall: 0.16‐0.40 • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who achieved a
By female age: clinical pregnancy after treatment with gonadotropins, who:
482,490
EE Successful ongoing pregnancy with gonadotropins 1 – miscarriage • Note: women who achieve successful ovulation, however fail to achieve or maintain a
358


decision model
M Successful ovulation with LOD Overall: 0.67‐0.80 • The proportion of women with PCOS (WHO group II) ovulatory dysfunction who:
By female age: ‐ ovulate after treatment with LOD, or
<35: 0.75‐0.80 ‐ do not ovulate after treatment with LOD
489,491
35‐40: 0.67‐0.75 • Literature
>40: N/A • These probabilities reflect the success of LOD either as a first line of treatment or a second line
N No ovulation with LOD 1 – successful ovulation of treatment in clomiphene citrate‐resistant women (women who have failed to achieve
ovulation and/or pregnancy with clomiphene citrate)
X Successful clinical pregnancy with LOD Overall: 0.28‐0.56 • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who:
By female age: ‐ achieve a clinical pregnancy after treatment with LOD, or
<35: 0.47‐0.58 ‐ do not achieve a clinical pregnancy after treatment with LOD
42,483,491,492
35‐40: 0.33‐0.48 • Literature
>40: N/A • These probabilities reflect the success of LOD either as a first line of treatment or a second line
Y No clinical pregnancy with LOD 1 – successful clinical of treatment in clomiphene citrate‐resistant women (women who have failed to achieve
pregnancy ovulation and/or pregnancy with clomiphene citrate)
HH Miscarriage after clinical pregnancy with LOD Overall: 0.17‐0.29 • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who achieved a
By female age: clinical pregnancy after treatment with LOD, who:
491,492
>40: N/A • Literature
GG Successful ongoing pregnancy with LOD 1 – miscarriage • Note: women who achieve successful ovulation, however fail to achieve or maintain a
Third or fourth line of treatment (after failure to ovulate with gonadotropins or LOD)
F IVF after failure with gonadotropins or LOD 0.85‐0.90 • The proportion of women with PCOS (WHO group II ovulatory dysfunction) who either did not
By female age: no achieved a clinical pregnancy or were unable to maintain a pregnancy after treatment with
differences gonadotropins ± metformin or LOD who:
W Dropout after failure with gonadotropins or LOD 0.10‐0.15 ‐ are treated with IVF, or
Ovulatory dysfunction – ovarian failure (WHO group III)
A Donor IVF Overall: 0.20‐0.50 • The proportion of women with ovarian failure (WHO group III ovulatory dysfunction) who:
By female age: no ‐ are treated with donor IVF (IVF with donor oocytes), or
differences ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
B Dropout Overall: 0.50‐0.80 decision to adopt, etc.)
By female age: no • Expert opinion
differences
Tubal obstruction (distal or proximal)
A IVF Overall: 0.85‐0.90 • The proportion of women with a distal tubal obstruction who:
By female age: no ‐ are treated with IVF, or
differences ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
359


decision model
B Dropout Overall: 0.10‐0.15 decision to adopt, etc.)
differences
Tubal obstruction – tubal ligation
A Tubal reanastomosis Overall: 0.425‐0.45 • The proportion of women with a tubal ligation who:
By female age: ‐ undergo a reversal (tubal reanastomosis),
<35: 0.65‐0.75 ‐ are treated with IVF, or
35‐40: 0.04‐0.05 ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
>40: 0 decision to adopt, etc.)
• Expert opinion
B IVF Overall: 0.425‐0.45
By female age:
<35: 0.15‐0.20
35‐40: 0.80‐0.86
>40: 0.85‐0.90
C Dropout Overall: 0.10‐0.15
By female age: no
differences
D Successful clinical pregnancy with tubal reanastomosis Overall: 0.50‐0.85 • The proportion of women with a tubal ligation who:

By female age: ‐ achieve a clinical pregnancy after tubal reanastomosis, or
<35: 0.73‐0.92 ‐ do not achieve a clinical pregnancy after tubal reanastomosis
466,493‐495
35‐40: 0.52‐0.86 • Literature
>40:N/A •These probabilities reflect the success of tubal ligation reversal with no further intervention;
E No clinical pregnancy with tubal reanastomosis 1 – successful clinical follow‐up not reported in most studies, but where reported, pregnancy occurred within 12‐18
pregnancy months after tubal reanastomosis
G Miscarriage after clinical pregnancy with tubal Overall: 0.12‐0.31 • The proportion of women with a tubal ligation who achieved a clinical pregnancy after
reanastomosis By female age: treatment with tubal reanastomosis, who:
493‐495
>40:N/A • Literature
F Successful ongoing pregnancy with tubal reanastomosis 1 – miscarriage • Expert opinion
Second line of treatment
I IVF after failure with tubal reanastomosis Overall: 0.85‐0.90 • The proportion of women with a tubal ligation who either did not achieved a clinical pregnancy
By female age: no or were unable to maintain a pregnancy after tubal reanastomosis who:
differences ‐ are treated with IVF, or
H Dropout after failure with tubal reanastomosis Overall: 0.10‐0.15 ‐ ‘dropout’
differences
360


decision model
Endometriosis – moderate‐severe (includes endometriomas)
A Laparoscopic surgery + natural conception Overall: 0.60 • The proportion of women with moderate‐severe endometriosis who:
By female age: ‐ undergo laparoscopic surgical treatment (during diagnostic laparoscopy or as a separate
<35: 0.825 procedure after diagnosis) + attempt to conceive naturally,
35‐40: 0.125 ‐ undergo laparoscopic surgical treatment (during diagnostic laparoscopy or as a separate
>40: 0.0 procedure after diagnosis) + ovarian stimulation + IUI, or
B Laparoscopic surgery + ovarian stimulation + IUI Overall: 0.35 ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
By female age: decision to adopt, etc.)
<35: 0.125 • Expert opinion
35‐40: 0.825
>40: 0.95
C Dropout Overall: 0.05
By female age: no
differences
E Successful clinical pregnancy with natural conception Overall: 0.20‐0.28 • The proportion of women with surgically treated moderate‐severe endometriosis who:

(after surgical treatment) By female age: ‐ achieve a clinical pregnancy without any further intervention (natural conception), or
<35: 0.22‐0.27 ‐ do not achieve a clinical pregnancy without any further intervention (natural conception)
496‐500
35‐40: 0.16‐0.18 • Literature
>40: N/A • These probabilities reflect success 6‐12 months after laparoscopic ablation in women with
F No clinical pregnancy with natural conception (after 1 – successful clinical moderate‐severe endometriosis with no further intervention; 2 studies reported on success after
499,500
surgical treatment) pregnancy the surgical removal of endometrioma(s) greater than 2cm (0.428‐0.537)
J Miscarriage after clinical pregnancy with natural Overall: 0.20‐0.40 • The proportion of women with surgically treated moderate‐severe endometriosis who
conception (after surgical treatment) By female age: achieved a clinical pregnancy with no further intervention, who:
498,501
I Successful ongoing pregnancy with natural conception 1 – miscarriage
(after surgical treatment)
G Successful clinical pregnancy with ovarian stimulation + Overall: • The proportion of women with surgically treated moderate‐severe endometriosis who:
IUI 0.10‐0.36 per couple ‐ achieve a clinical pregnancy after ovarian stimulation + IUI, or
(0.06‐0.26 per cycle) ‐ do not achieve a clinical pregnancy after ovarian stimulation + IUI
502‐504
By female age: • Literature
<35: 0.09‐0.26 per cycle
35‐40: 0.09‐0.22 per cycle
>40: 0.04‐0.12 per cycle
H No clinical pregnancy with ovarian stimulation + IUI 1 – successful clinical
pregnancy
361


decision model
O Miscarriage after clinical pregnancy with ovarian Overall: 0.20‐0.40 • The proportion of women with surgically treated moderate‐severe endometriosis who
stimulation + IUI By female age: achieved a clinical pregnancy after ovarian stimulation + IUI, who:
498,501,502,504
>40: 0.30‐0.40 • Literature
N Successful ongoing pregnancy with ovarian stimulation + 1 – miscarriage
IUI
First or second line of treatment (after laparoscopic surgery ± natural conception)
L Ovarian stimulation + IUI after failure with laparoscopic Overall: 0.525‐0.55 • The proportion of women with surgically treated moderate‐severe endometriosis who either
surgery By female age: did not achieved a clinical pregnancy or were unable to maintain a pregnancy after attempted
<35: 0.70‐0.80 natural conception who:
35‐40: 0.15‐0.25 ‐ are treated with ovarian stimulation + IUI,
>40: N/A ‐ are treated with IVF, or
M IVF after failure with laparoscopic surgery Overall: 0.325‐0.35 ‐ ‘dropout’
<35: 0.10‐0.15
35‐40: 0.65‐0.70
>40: N/A
K Dropout after failure with laparoscopic surgery Overall: 0.10‐0.15
By female age: no
differences
G Successful clinical pregnancy with ovarian stimulation + Overall: • The proportion of women with surgically treated moderate‐severe endometriosis who:

502‐504
<35: 0.09‐0.26 per cycle • These probabilities reflect the success of up to 3 cycles of IUI in women with moderate to
35‐40: 0.09‐0.22 per cycle severe endometriosis who failed to achieve a successful pregnancy 6‐12 months after
>40: N/A laparoscopic ablation
pregnancy
O Miscarriage after clinical pregnancy with ovarian Overall: 0.20‐0.40 • The proportion of women with surgically treated moderate‐severe endometriosis who
stimulation + IUI By female age: achieved a clinical pregnancy after ovarian stimulation + IUI, who:
498,501,502,504
IUI
Second or third line of treatment (after failure with laparoscopic surgery + ovarian stimulation + IUI)
S IVF after failure with laparoscopic surgery + ovarian Overall: 0.85‐0.90 • The proportion of women with moderate‐severe endometriosis who have a normalized pelvis
stimulation + IUI By female age: no after laparoscopic surgical treatment who either did not achieved a clinical pregnancy or were
differences unable to maintain a pregnancy after ovarian stimulation + IUI who:
362


decision model
R Dropout after failure with laparoscopic surgery + ovarian Overall: 0.10‐0.15 ‐ are treated with IVF, or
stimulation + IUI By female age: no ‐ ‘dropout’
Polyps
A Polypectomy + natural conception Overall: 0.59 • The proportion of women with polyps who:
By female age: ‐ undergo polypectomy (during diagnostic hysteroscopy or as a separate procedure after
<35: 0.89 diagnosis) + attempt to conceive naturally,
35‐40: 0.09 ‐ undergo polypectomy (during diagnostic hysteroscopy or as a separate procedure after
>40: 0.0 diagnosis) + ovarian stimulation + IUI, or
B Polypectomy + ovarian stimulation + IUI Overall: 0.39 ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
35‐40: 0.89
>40: 0.98
By female age: no
differences
E Successful clinical pregnancy with polypectomy + natural Overall: 0.32‐0.80 • The proportion of women with surgically treated polyps who:

conception By female age: ‐ achieve a clinical pregnancy without any further intervention (natural conception), or
505
35‐40: 0.51‐0.65 • Literature
>40: N/A • These probabilities reflect the success of polypectomy in women with polyps with no further
F No clinical pregnancy with polypectomy + natural 1 – successful clinical intervention within 6 months in 1 study (0.321), 12 months in 1 study (0.800), 18 months in 2
conception pregnancy studies (0.614‐0.783), and 9 years in 1 study (0.423)

J Miscarriage after clinical pregnancy with polypectomy + Overall: 0.10‐0.17 • The proportion of women with surgically treated polyps who achieved a clinical pregnancy with
natural conception By female age: no further intervention, who:
505
I Successful ongoing pregnancy with polypectomy + natural 1 – miscarriage
conception
G Successful clinical pregnancy with ovarian stimulation + Overall: • The proportion of women with surgically treated polyps who:
504,506
<35: 0.09‐0.26 per cycle
35‐40: 0.09‐0.22 per cycle
>40: 0.02‐0.12 per cycle
363


decision model
pregnancy
O Miscarriage after clinical pregnancy with ovarian Overall: 0.20‐0.40 • The proportion of women with surgically treated polyps who achieved a clinical pregnancy
stimulation + IUI By female age: after ovarian stimulation + IUI, who:
504,506
>40: 0.30‐0.40 • Literature
IUI
Second line of treatment (after failure with laparoscopic surgery + natural conception)
L Ovarian stimulation + IUI after failure with laparoscopic Overall: 0.525‐0.55 • The proportion of women with surgically treated polyps who either did not achieved a clinical
surgery + natural conception By female age: pregnancy or were unable to maintain a pregnancy after attempted natural conception who:
<35: 0.70‐0.80 ‐ are treated with ovarian stimulation + IUI,
35‐40: 0.15‐0.25 ‐ are treated with IVF, or
>40: N/A ‐ ‘dropout’
M IVF after failure with laparoscopic surgery + natural Overall: 0.325‐0.35 • Expert opinion
conception By female age:
<35: 0.10‐0.15
35‐40: 0.65‐0.70
>40: N/A
K Dropout after failure with laparoscopic surgery + natural Overall: 0.10‐0.15
conception By female age: no
differences
G Successful clinical pregnancy with ovarian stimulation + Overall: • The proportion of women with surgically treated polyps who:

504,506
<35: 0.09‐0.26 per cycle
35‐40: 0.09‐0.22 per cycle
>40: 0.02‐0.12 per cycle
pregnancy
O Miscarriage after clinical pregnancy with ovarian Overall: 0.20‐0.40 • The proportion of women with surgically treated polyps who achieved a clinical pregnancy
stimulation + IUI By female age: after ovarian stimulation + IUI, who:
504,506
>40: 0.30‐0.40 • Literature
IUI
Second or third line of treatment (after failure with laparoscopic surgery + ovarian stimulation + IUI)
364


decision model
S IVF after failure with laparoscopic surgery + ovarian 0.85‐0.90 • The proportion of women with surgically treated polyps who either did not achieved a clinical
stimulation + IUI By female age: no pregnancy or were unable to maintain a pregnancy after ovarian stimulation + IUI who:
differences ‐ are treated with IVF, or
R Dropout after failure with laparoscopic surgery + ovarian 0.10‐0.15 ‐ ‘dropout’
stimulation + IUI By female age: no • Expert opinion
differences
Fibroids – type 2 (intramural or >50% of fibroid within uterine wall): symptomatic or large
A Myomectomy + natural conception Overall: 0.25 • The proportion of women with symptomatic or large type 2 fibroids who:
By female age: ‐ undergo myomectomy (during diagnostic hysteroscopy or as a separate procedure after
35‐40: 0.10 ‐ undergo myomectomy (during diagnostic hysteroscopy or as a separate procedure after
>40: 0 diagnosis) + IVF,
B Myomectomy + IVF Overall: 0.25 ‐ are treated with ovarian stimulation + IUI, or
By female age: ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
<35: 0.20 decision to adopt, etc.)
35‐40: 0.30 • Expert opinion
>40: 0.50
C Ovarian stimulation + IUI Overall: 0.20
By female age:
<35: 0.30
35‐40: 0.30
>40: 0
D IVF Overall: 0.20
By female age:
<35: 0.05‐0.10
35‐40: 0.15‐0.20
>40: 0.35‐0.40
E Dropout Overall: 0.10‐0.15
By female age: no
differences
F Successful clinical pregnancy with myomectomy + natural Overall: 0.25‐0.57 • The proportion of women with surgically treated type 2 fibroids who:

507‐511
35‐40: 0.25‐0.38 • Literature (note: some couples had other infertility factors in addition to type 2 fibroids)
>40: N/A • These probabilities reflect the success of myomectomy in women with type 2 fibroids with no
365


decision model
G No clinical pregnancy with myomectomy + natural 1 – successful clinical further intervention; follow‐up not reported in most studies, but where reported, pregnancy
conception pregnancy occurred within 12‐18 months
510,511
• Only 2 studies reported pregnancy rates by ESHRE type (0.250‐0.313) ; other studies
reported success in women with intramural (>50% of fibroid within uterine wall) type 2 fibroids
(0.361‐0.565); studies did not separated by results by symptomatic vs. asymptomatic, or by size

K Miscarriage after clinical pregnancy with myomectomy + Overall: 0.14‐0.31 • The proportion of women with surgically treated type 2 fibroids who achieved a clinical
natural conception By female age: pregnancy with no further intervention, who:
507‐509
J Successful ongoing pregnancy with myomectomy + 1 – miscarriage
natural conception
H Successful clinical pregnancy with ovarian stimulation + Overall: • The proportion of women with symptomatic or large type 2 fibroids who:
504,507‐509
<35: 0.09‐0.26 per cycle
35‐40: 0.09‐0.22 per cycle
>40: N/A
I No clinical pregnancy with ovarian stimulation + IUI 1 – successful clinical
pregnancy
O Miscarriage after clinical pregnancy with ovarian Overall: 0.20‐0.40 • The proportion of women with symptomatic or large type 2 fibroids who achieved a clinical
stimulation + IUI By female age: pregnancy after ovarian stimulation + IUI, who:
504,507‐509
IUI
Second line of treatment (after failure with myomectomy + natural conception)
M IVF after failure with myomectomy + natural conception Overall: 0.85‐0.90 • The proportion of women with surgically treated type 2 fibroids who either did not achieved a
By female age: no clinical pregnancy or were unable to maintain a pregnancy after attempting to conceive naturally
differences who:
L Dropout after failure with myomectomy + natural Overall: 0.10‐0.15 ‐ are treated with IVF, or
conception By female age: no ‐ ‘dropout’
Second line of treatment (after failure with ovarian stimulation + IUI)
S IVF after failure with ovarian stimulation + IUI Overall: 0.85‐0.90 • The proportion of women with type 2 fibroids who either did not achieved a clinical pregnancy
By female age: no or were unable to maintain a pregnancy after attempting to conceive through ovarian
differences stimulation + IUI who:
R Dropout after failure with ovarian stimulation + IUI Overall: 0.10‐0.15 ‐ are treated with IVF, or
366


decision model
Fibroids – type 2 (intramural or >50% of fibroid within uterine wall): asymptomatic or small
A Ovarian stimulation + IUI Overall: 0.70 • The proportion of women with symptomatic or large type 2 fibroids who:
By female age: ‐are treated with ovarian stimulation + IUI,
<35: 0.80 ‐ are treated with IVF, or
35‐40: 0.40 ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
>40: 0.0 decision to adopt, etc.)
B IVF Overall: 0.20 • Expert opinion
By female age:
<35: 0.10
35‐40: 0.50
>40: 0.90
By female age: no
differences
D Successful clinical pregnancy with ovarian stimulation + Overall: • The proportion of women with asymptomatic and small type 2 fibroidswho:

504,507‐509
<35: 0.09‐0.26 per cycle
35‐40: 0.09‐0.22 per cycle
>40: N/A
E No clinical pregnancy with ovarian stimulation + IUI 1 – successful clinical
pregnancy
G Miscarriage after clinical pregnancy with ovarian Overall: 0.20‐0.40 • The proportion of women with asymptomatic and small type 2 fibroids who achieved a clinical
stimulation + IUI By female age: pregnancy after ovarian stimulation + IUI, who:
504,507‐509
F Successful ongoing pregnancy with ovarian stimulation + 1 – miscarriage
IUI
K IVF after failure with ovarian stimulation + IUI Overall: 0.85‐0.90 • The proportion of women with asymptomatic and small type 2 fibroids who either did not
By female age: no achieved a clinical pregnancy or were unable to maintain a pregnancy after ovarian stimulation +
differences IUI who:
J Dropout after failure with ovarian stimulation + IUI Overall: 0.10‐0.15 ‐ are treated with IVF, or
Fibroids – type 0‐1 (submucosal or <50% within uterine wall)
367


decision model
A Myomectomy + natural conception Overall: 0.70 • The proportion of women with type 0‐1 fibroids who:
By female age: ‐ undergo myomectomy (during diagnostic hysteroscopy or as a separate procedure after
35‐40: 0.35 ‐ undergo myomectomy (during diagnostic hysteroscopy or as a separate procedure after
>40: 0.0 diagnosis) + IVF, or
B Myomectomy + IVF Overall: 0.25 ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
35‐40: 0.60
>40: 0.95
By female age: no
differences
D Successful clinical pregnancy with myomectomy + natural Overall: 0.43‐0.57 • The proportion of women with surgically treated type 0‐1 fibroids who:

507‐511
35‐40: 0.35‐0.47 • Literature (note: some couples had other infertility factors in addition to fibroids)
>40: N/A • These probabilities reflect the success of myomectomy in women with fibroids with no further
E No clinical pregnancy with myomectomy + natural 1 – successful clinical intervention; follow‐up not reported in most studies, but where reported, pregnancy occurred
conception pregnancy within 12‐18 months
510,511
• Only 2 studies reported pregnancy rates by ESHRE type (0.428‐0.571) ; other studies
reported success in women with submucosal (<50% of fibroid within uterine wall) fibroids (0.433‐
0.450)
G Miscarriage after clinical pregnancy with myomectomy + Overall: 0.14‐0.31 • The proportion of women with surgically treated type 0‐1 fibroids who achieved a clinical
507
F Successful ongoing pregnancy with myomectomy + 1 – miscarriage • Expert opinion
natural conception
I IVF after failure with natural conception (after surgical 0.85‐0.90 • The proportion of women with surgically treated type 0‐ fibroids who either did not achieved a
treatment) By female age: no clinical pregnancy or were unable to maintain a pregnancy after attempting to conceive naturally
differences who:
H Dropout after failure with natural conception (after 0.10‐0.15 ‐ are treated with IVF, or
surgical treatment) By female age: no ‐ ‘dropout’
General Assumptions:
‐ All treatments are publicly funded, with the exception of sterilization reversal (tubal reanastomosis)
‐ Approximately 10‐20% of couples “dropout” after each cycle of IVF/ICSI, 5% after each cycle of ovarian stimulation + IUI using clomiphene citrate, 10% after each cycle of ovarian stimulation + IUI using
gonadotropin injections, and 10‐15% after each cycle of donor insemination
368

Table 49. Variable inputs for decision model III ‐ treatment of couples with male factor infertility only
decision model
Obstructive azoospermia or oligozoospermia – vasectomy
A Surgical treatment: vasectomy reversal (vasovasotomy Overall: 0.20 • The proportion of couples with male factor infertility due to a vasectomy who:
(VV) or vasoepididymostomy (VE)) By female age: ‐ undergo surgical treatment (vasectomy reversal: vasovasotomy (VV) or
<35: 0.30 vasoepididymostomy (VE)),
35‐40: 0.15 ‐ are treated with donor insemination,
>40: 0 ‐ are treated with ICSI with surgical sperm retrieval, or
B Donor insemination Overall: 0.05‐0.10 ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
<35: 0.05‐0.10 • Expert opinion
35‐40: 0.05‐0.10
>40: 0
C ICSI with PESA or mTESE Overall: 0.60
By female age:
<35: 0.50
35‐40: 0.65
>40: 0.85‐0.90
D Dropout Overall: 0.10‐0.15
By female age: no
differences
E Successful clinical pregnancy with VV or VE + natural Overall: 0.30‐0.75 • The proportion of couples with surgically reversed vasectomy who:

<35: 0.54‐0.57 ‐do not achieve a clinical pregnancy without any further intervention (natural conception)
512‐515
35‐40: 0.32‐0.53 • Literature
>40: N/A • These probabilities reflect the success of VV/VE in couples with no further intervention;
F No clinical pregnancy with VV or VE + natural conception 1 – successful clinical although follow‐up was variable, most pregnancies occurred within 24 months after surgery;
pregnancy pregnancy rates were 0.54 in 1 study limited to 12 months of follow‐up
J Miscarriage after clinical pregnancy with VV or VE + Overall: 0.08‐0.11 • The proportion of couples with surgically reversed vasectomy who achieved a clinical
>40: N/A • Expert opinion; assumed miscarriage rates were the same as those in the general population,
I Successful ongoing pregnancy with VV or VE + natural 1 – miscarriage therefore Alberta general population estimates were used
conception
G Successful clinical pregnancy with donor insemination *See Table below • The proportion of couples with male factor infertility due to a vasectomy who:
H No clinical pregnancy with donor insemination *See Table below ‐ achieve a clinical pregnancy after donor insemination, or
‐ do not achieve a clinical pregnancy after donor insemination
N Miscarriage after clinical pregnancy with donor *See Table below • The proportion of couples with male factor infertility due to a vasectomy who achieved a
insemination clinical pregnancy with donor insemination, who:
369


decision model
M Successful ongoing pregnancy with donor insemination *See Table below ‐ do not maintain this pregnancy (experience a miscarriage), or
‐ maintain this pregnancy (successful ongoing pregnancy)
Second line of treatment (after failure with surgery – VV or VE)
L ICSI with PESA or mTESE after failure with VV or VE + Overall: 0.85‐0.90 • The proportion of couples with surgically reversed vasectomy who either did not achieved a
natural conception By female age: no clinical pregnancy or were unable to maintain a pregnancy after attempting to conceive naturally
differences who:
K Dropout after failure with VV or VE + natural conception Overall: 0.10‐0.15 ‐ are treated with ICSI with surgical sperm retrieval, or
Second line of treatment (after failure with donor insemination)
R ICSI with PESA or mTESE or donor sperm after failure with Overall: 0.85‐0.90 • The proportion of couples with male factor infertility due to a vasectomy who either did not
donor insemination By female age: no achieved a clinical pregnancy or were unable to maintain a pregnancy after donor insemination
differences who:
Q Dropout after failure with donor insemination Overall: 0.10‐0.15 ‐ are treated with ICSI with surgical sperm retrieval, or
Obstructive azoospermia or oligozoospermia – ejaculatory duct obstruction (EDO)
A Surgical treatment: transurethral resection of the Overall: 0.20‐0.25 • The proportion of couples with male factor infertility due to an ejaculatory duct obstruction
ejaculatory duct (TURED) By female age: who:
<35: 0.30 ‐ undergo surgical treatment (transurethral resection of the ejaculatory duct (TURED)),
35‐40: 0.15 ‐ are treated with donor insemination,
>40: 0.0 ‐ are treated with ICSI with surgical sperm retrieval, or
B Donor insemination Overall: 0.05‐0.10 ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
<35: 0.05‐0.10 • Expert opinion
35‐40: 0.05‐0.10
>40: 0.0
C ICSI with PESA or mTESE Overall: 0.60‐0.65
By female age:
<35: 0.50
35‐40: 0.65
>40: 0.85‐0.90
By female age: no
differences
E Successful clinical pregnancy with TURED + natural Overall: 0.13‐0.29 • The proportion of couples with surgically treated ejaculatory duct obstruction who:

<35: 0.16‐0.29 ‐do not achieve a clinical pregnancy without any further intervention (natural conception)
513,516‐518
35‐40: 0.13‐0.24 • Literature
>40: N/A • These probabilities reflect the success of TURED in couples with male factor infertility caused
370


decision model
F No clinical pregnancy with TURED + natural conception 1 – successful clinical by an EDO with no further intervention; follow‐up not reported in most studies, but where
pregnancy reported, pregnancy occurred within 12 months
• In one review, it was suggested that the success of TURED may be related to whether or not
the EDO is congenital or was acquired (higher pregnancy rates if congenital), and whether the
516
obstruction was partial or complete (higher pregnancy rates if partial)

J Miscarriage after clinical pregnancy with TURED + natural Overall: 0.09 • The proportion of couples with surgically treated ejaculatory duct obstruction who achieved a
conception By female age: clinical pregnancy with no further intervention, who:
>40: 0.20 • Expert opinion; assumed miscarriage rates were the same as those in the general population,
I Successful ongoing pregnancy with TURED + natural 1 – miscarriage therefore Alberta general population estimates were used
conception
G Successful clinical pregnancy with donor insemination *See Table below • The proportion of couples with male factor infertility due to an ejaculatory duct obstruction
H No clinical pregnancy with donor insemination *See Table below that achieve a clinical pregnancy after donor insemination
N Miscarriage after clinical pregnancy with donor *See Table below • The proportion of couples with male factor infertility due to an ejaculatory duct obstruction
insemination who achieved a clinical pregnancy with donor insemination, who:
Second line of treatment (after failure with surgery – TURED)
L ICSI with PESA or mTESE after failure with TURED + natural Overall: 0.90 • The proportion of couples with male factor infertility due to an ejaculatory duct obstruction
conception By female age: no who either did not achieved a clinical pregnancy or were unable to maintain a pregnancy after
differences attempting to conceive naturally who:
K Dropout after failure with TURED + natural conception Overall: 0.10 ‐ are treated with ICSI with surgical sperm retrieval, or
R ICSI with PESA or mTESE or donor sperm after failure with Overall: 0.75 • The proportion of couples with male factor infertility due to an ejaculatory duct obstruction
donor insemination By female age: no who either did not achieved a clinical pregnancy or were unable to maintain a pregnancy after
differences donor insemination who:
Q Dropout after failure with donor insemination Overall: 0.25 ‐ are treated with ICSI with surgical sperm retrieval, or
Obstructive azoospermia or oligozoospermia – congenital bilateral absence of vas deferens (CBAVD)
A Donor insemination Overall: 0.10‐0.20 • The proportion of couples with male factor infertility due to CBAVD who:
By female age: ‐ are treated with donor insemination,
<35: 0.20‐0.25 ‐ are treated with ICSI with surgical sperm retrieval, or
371


decision model
B ICSI with mTESE Overall: 0.30‐0.40 • Expert opinion
By female age:
<35: 0.30‐0.325
35‐40: 0.35‐0.375
>40: 0.40‐0.45
C ICSI with donor sperm Overall: 0.30‐0.40
By female age:
<35: 0.30‐0.325
35‐40: 0.35‐0.40
>40: 0.40‐0.45
By female age: no
differences
E Successful clinical pregnancy with donor insemination *See Table below • The proportion of couples with male factor infertility due to CBAVD who:

F No clinical pregnancy with donor insemination *See Table below ‐ achieve a clinical pregnancy after donor insemination, or
H Miscarriage after clinical pregnancy with donor *See Table below • The proportion of couples with male factor infertility due to CBAVD who achieved a clinical
insemination pregnancy with donor insemination, who:
G Successful ongoing pregnancy with donor insemination *See Table below ‐ do not maintain this pregnancy (experience a miscarriage), or
L ICSI with mTESE or donor sperm after failure with donor Overall: 0.85‐0.90 • The proportion of couples with male factor infertility due to CBAVD who either did not
insemination By female age: no achieved a clinical pregnancy or were unable to maintain a pregnancy after donor insemination
differences who:
K Dropout after failure with donor insemination Overall: 0.10‐0.15 ‐ are treated with ICSI with donor sperm,
By female age: no ‐ are treated with ICSI with surgical sperm retrieval, or
differences ‐ ‘dropout’
• Expert opinion
Obstructive azoospermia or oligozoospermia – other congenital or acquired obstruction
A Donor insemination Overall: 0.05‐0.10 • The proportion of couples with male factor infertility due to some other obstruction (e.g.,
By female age: acquired as a result of infection or trauma) who:
<35: 0.05‐0.10 ‐ are treated with donor insemination,
35‐40: 0.05‐0.10 ‐ are treated with ICSI with surgical sperm retrieval, or
>40: 0 ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
B ICSI with PESA or mTESE Overall: 0.80‐0.85 decision to adopt, etc.)
<35: 0.80
35‐40: 0.80
>40: 0.85‐0.90
372


decision model
By female age: no
differences
D Successful clinical pregnancy with donor insemination *See Table below • The proportion of couples with male factor infertility due to some other obstruction who:

E No clinical pregnancy with donor insemination *See Table below ‐ achieve a clinical pregnancy after donor insemination, or
G Miscarriage after clinical pregnancy with donor *See Table below • The proportion of couples with male factor infertility due to some other obstruction who
insemination achieved a clinical pregnancy with donor insemination, who:
F Successful ongoing pregnancy with donor insemination *See Table below ‐ do not maintain this pregnancy (experience a miscarriage), or
K ICSI with PESA or mTESE or donor sperm after failure with Overall: 0.75 • The proportion of couples with male factor infertility due to CBAVD who either did not
donor insemination By female age: no achieved a clinical pregnancy or were unable to maintain a pregnancy after donor insemination
differences who:
J Dropout after failure with donor insemination Overall: 0.25 ‐ are treated with ICSI with surgical sperm retrieval, or
Non‐obstructive male factor – hormonal
A Gonadotropins or pulsatile GnRH Overall: 0.60‐0.70 • The proportion of couples with male factor infertility due to hormonal abnormalities who:
By female age: ‐ are treated with gonadotropin or pulsatile GnRH injections,
<35: 0.70 ‐ are treated with donor insemination,
35‐40: 0.60 ‐ are treated with ICSI with surgical sperm retrieval, or
>40: 0.15‐0.20 ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
B Donor insemination Overall: 0.05‐0.10 decision to adopt, etc.)
<35: 0.05‐0.10
35‐40: 0.05‐0.10
>40: 0
C ICSI with mTESE Overall: 0.10‐0.20
By female age:
<35: 0.10
35‐40: 0.20
>40: 0.70
By female age: no
differences
373


decision model
E Successful clinical pregnancy with pulsatile GnRH Overall: 0.46‐0.67 • The proportion of couples with male factor infertility due to hormonal abnormalities who:
By female age: ‐ achieve a clinical pregnancy with pulsatile GnRH injections, or
<35: 0.57‐0.67 ‐ do not achieve a clinical pregnancy with pulsatile GnRH injections
519‐523
35‐40: 0.46‐0.55 • Literature
>40: 0.27‐0.31 • These probabilities represent the success of pulsatile GnRH (duration of 6‐12 months) within 12
F No clinical pregnancy with pulsatile GnRH 1 – successful clinical months after treatment was stopped (0.46‐0.67 pregnancy rates); female partners were normal
pregnancy and received no treatment;
• Gonadotropins may be used instead, however literature reports 0.09‐0.13 pregnancy rates
after 3 months of gonadotropins within 3 months after treatment was stopped
J Miscarriage after clinical pregnancy with gonadotropins or Overall: 0.09 • The proportion of couples with male factor infertility due to hormonal abnormalities who
pulsatile GnRH By female age: achieved a clinical pregnancy with pulsatile GnRH injections, who:
>40: 0.20 • Expert opinion; assumed miscarriage rates were the same as those in the general population,
I Successful ongoing pregnancy with gonadotropins or 1 – miscarriage therefore Alberta general population estimates were used
pulsatile GnRH
G Successful clinical pregnancy with donor insemination *See Table below • The proportion of couples with male factor infertility due to hormonal abnormalities who:
N Miscarriage after clinical pregnancy with donor *See Table below • The proportion of couples with male factor infertility due to hormonal abnormalities who
Second line of treatment (after gonadotropins or pulsatile GnRH)
L ICSI with mTESE after failure with gonadotropins or 0.85‐0.90 • The proportion of couples with male factor infertility due to hormonal abnormalities who
pulsatile GnRH By female age: no either did not achieved a clinical pregnancy or were unable to maintain a pregnancy after
differences gonadotropin or pulsatile GnRH injections who:
K Dropout after failure with gonadotropins or pulsatile 0.10‐0.15 ‐ are treated with ICSI with surgical sperm retrieval, or
GnRH By female age: no ‐ ‘dropout’
R ICSI with mTESE or donor sperm after failure with donor 0.85‐0.90 • The proportion of couples with male factor infertility due to hormonal abnormalities who
insemination By female age: no either did not achieved a clinical pregnancy or were unable to maintain a pregnancy after donor
differences insemination who:
Q Dropout after failure with donor insemination 0.10‐0.15 ‐ are treated with ICSI with surgical sperm retrieval, or
Non‐obstructive male factor – immunologic
374


decision model
A Ovarian stimulation + IUI with sperm washing Overall: 0.75 • The proportion of couples with male factor infertility due to an immunologic condition who:
By female age: ‐ are treated with ovarian stimulation + IUI with sperm washing,
<35: 0.85‐0.90 ‐ are treated with ICSI, or
>40: 0 decision to adopt, etc.)
B ICSI Overall: 0.10‐0.15 • Expert opinion
By female age:
<35: 0
35‐40: 0.15‐0.20
>40: 0.85‐0.90
By female age: no
differences
D Successful clinical pregnancy with ovarian stimulation + *See Table below • The proportion of couples with male factor infertility due to an immunologic condition who:

IUI with sperm washing ‐ achieve a clinical pregnancy with ovarian stimulation + IUI with sperm washing, or
E No clinical pregnancy with ovarian stimulation + IUI with *See Table below ‐ do not achieve a clinical pregnancy with ovarian stimulation + IUI with sperm washing
524‐527
sperm washing • Literature
• These probabilities reflect the success of up to 6 cycles of IUI with sperm washing in couples
with male factor immunologic infertility
G Miscarriage after clinical pregnancy with ovarian *See Table below • The proportion of couples with male factor infertility due to an immunologic condition who
stimulation + IUI with sperm washing achieved a clinical pregnancy with ovarian stimulation + IUI with sperm washing, who:
F Successful ongoing pregnancy with ovarian stimulation + *See Table below ‐ do not maintain this pregnancy (experience a miscarriage), or
IUI with sperm washing ‐ maintain this pregnancy (successful ongoing pregnancy)
K ICSI after failure ovarian stimulation + IUI with sperm 0.85‐0.90 • The proportion of couples with male factor infertility due to an immunologic condition who
washing By female age: no either did not achieved a clinical pregnancy or were unable to maintain a pregnancy after
differences Ovarian stimulation + IUI with sperm washing who:
J Dropout after failure with ovarian stimulation + IUI with 0.10‐0.15 ‐ are treated with ICSI with surgical sperm retrieval, or
sperm washing By female age: no ‐ ‘dropout’
Non‐obstructive male factor – varicocele, mild
A Surgical treatment: varicocelectomy Overall: 0.05‐0.10 • The proportion of couples with male factor infertility due to a varicocele who:
By female age: ‐ undergo surgical treatment (varicocelectomy),
35‐40: 0.05‐0.10 ‐ are treated with ICSI with or without surgical sperm retrieval, or
375


decision model
B Ovarian stimulation + IUI Overall: 0.65 decision to adopt, etc.)
<35: 0.80
35‐40: 0.70
>40: 0.10
C ICSI with or without mTESE Overall: 0.15
By female age:
<35: 0
35‐40: 0.10
>40: 0.75‐0.80
By female age: no
differences
E Successful clinical pregnancy with varicocelectomy + Overall: 0.20‐0.44 • The proportion of couples with surgically treated varicocele who:

natural conception By female age: ‐ achieve a clinical pregnancy without any further intervention (natural conception), or
512,528‐533
35‐40: 0.24‐0.39 • Literature
>40: N/A • These probabilities reflect the success of varicocelectomy within 12 months of surgery in
F No clinical pregnancy with varicocelectomy + natural 1 – successful clinical couples with male factor infertility caused by a varicocele with no further intervention
conception pregnancy • Studies did not specify whether mild vs. severe semen parameters were associated with the
varicocele, although 1 study reported results by grade of varicocele, pregnancy rates of 0.29‐0.30
532,532
if grade II or III vs. 0.41 with grade I
J Miscarriage after clinical pregnancy with varicocelectomy Overall: 0.09 • The proportion of couples with surgically treated varicocele who achieved a clinical pregnancy
+ natural conception By female age: with no further intervention, who:
I Successful ongoing pregnancy with varicocelectomy + 1 – miscarriage therefore Alberta general population estimates were used
natural conception
G Successful clinical pregnancy with ovarian stimulation + *See Table below • The proportion of couples with male factor infertility due to a varicocele who:
IUI ‐ achieve a clinical pregnancy with ovarian stimulation + IUI, or
H No clinical pregnancy with ovarian stimulation + IUI *See Table below ‐ do not achieve a clinical pregnancy with ovarian stimulation + IUI
N Miscarriage after clinical pregnancy with ovarian *See Table below • The proportion of couples with male factor infertility due to a varicocele who achieved a clinical
stimulation + IUI pregnancy with ovarian stimulation + IUI, who:
M Successful ongoing pregnancy with ovarian stimulation + *See Table below ‐ do not maintain this pregnancy (experience a miscarriage), or
IUI ‐ maintain this pregnancy (successful ongoing pregnancy)
Second line of treatment (after failure with surgery – varicocelectomy)
L ICSI with or without mTESE after failure with natural Overall: 0.85‐0.90 • The proportion of couples with surgically treated varicocele who either did not achieved a
conception (after varicocelectomy) By female age: no clinical pregnancy or were unable to maintain a pregnancy after attempting to conceive naturally
differences who are treated with ICSI with or without surgical sperm retrieval
376


decision model
K Dropout after failure with natural conception (after Overall: 0.10‐0.15 • Expert opinion
varicocelectomy) By female age: no
differences
Second line of treatment (after failure with IUI)
R ICSI with or without mTESE after failure with ovarian Overall: 0.85‐0.90 • The proportion of couples with surgically treated varicocele who either did not achieved a
stimulation + IUI By female age: no clinical pregnancy or were unable to maintain a pregnancy after attempting to conceive with
differences ovarian stimulation + IUI who are treated with ICSI with or without surgical sperm retrieval
Q Dropout after failure with ovarian stimulation + IUI Overall: 0.10‐0.15 • Expert opinion
By female age: no
differences
Non‐obstructive male factor – varicocele, severe
A Surgical treatment: varicocelectomy Overall: 0.20 • The proportion of couples with male factor infertility due to a varicocele who:
By female age: ‐ undergo surgical treatment (varicocelectomy),
<35: 0.25 ‐ are treated with donor insemination,
35‐40: 0.10 ‐ are treated with ICSI with surgical sperm retrieval, or
B Donor insemination Overall: 0.05‐0.10 decision to adopt, etc.)
<35: 0.05‐0.10
35‐40: 0.05‐0.10
>40: 0
C ICSI with mTESE Overall: 0.60
By female age:
<35: 0.55
35‐40: 0.70
>40: 0.85‐0.90
By female age: no
differences
E Successful clinical pregnancy with varicocelectomy + Overall: 0.20‐0.44 • The proportion of couples with surgically treated varicocele who:

natural conception By female age: ‐ achieve a clinical pregnancy without any further intervention (natural conception), or
512,528‐533
35‐40: 0.24‐0.39 • Literature
>40: N/A • These probabilities reflect the success of varicocelectomy within 12 months of surgery in
F No clinical pregnancy with varicocelectomy + natural 1 – successful clinical couples with male factor infertility caused by a varicocele with no further intervention
conception pregnancy • Studies did not specify whether mild vs. severe semen parameters were associated with the
varicocele, although 1 study reported results by grade of varicocele, pregnancy rates of 0.29‐0.30
532
if grade II or III vs. 0.41 with grade I
377


decision model
J Miscarriage after clinical pregnancy with varicocelectomy Overall: 0.09 • The proportion of couples with surgically treated varicocele who achieved a clinical pregnancy
+ natural conception By female age: with no further intervention, who:
I Successful ongoing pregnancy with varicocelectomy + 1 – miscarriage therefore Alberta general population estimates were used
natural conception
G Successful clinical pregnancy with donor insemination *See Table below • The proportion of couples with male factor infertility due to a varicocele who:
M Successful ongoing pregnancy with donor insemination *See Table below • The proportion of couples with male factor infertility due to a varicocele who achieved a clinical
pregnancy with donor insemination
N Miscarriage after clinical pregnancy with donor *See Table below • The proportion of couples with male factor infertility due to a varicocele who achieved a clinical
insemination pregnancy with donor insemination, who:
‐ do not maintain this pregnancy (experience a miscarriage), or
Second line of treatment (after failure with surgery – varicocelectomy)
L ICSI with mTESE after failure with natural conception Overall: 0.85‐0.90 • The proportion of couples with surgically treated varicocele who either did not achieved a
(after varicocelectomy) By female age: no clinical pregnancy or were unable to maintain a pregnancy after attempting to conceive naturally
differences who:
K Dropout after failure with natural conception (after Overall: 0.10‐0.15 ‐ are treated with ICSI with surgical sperm retrieval, or
varicocelectomy) By female age: no ‐ ‘dropout’
R ICSI with mTESE after failure with donor insemination Overall: 0.85‐0.90 • The proportion of couples with male factor infertility due to a varicocele who either did not
By female age: no achieved a clinical pregnancy or were unable to maintain a pregnancy after donor insemination
differences who:
Q Dropout after failure with donor insemination Overall: 0.10‐0.15 ‐ are treated with ICSI with surgical sperm retrieval, or
Non‐obstructive male factor – genetic
A Donor insemination Overall: 0.75‐0.85 • The proportion of couples with male factor infertility due to a genetic abnormality who:
By female age: ‐ are treated with donor insemination,
<35: 0.80 ‐ are treated with ICSI with surgical sperm retrieval, or
B ICSI with mTESE or donor sperm Overall: 0.05‐0.10 • Expert opinion
By female age:
<35: 0.05‐0.10
35‐40: 0.15‐0.20
>40: 0.20‐0.25
378


decision model
By female age: no
differences
E Successful clinical pregnancy with donor insemination *See Table below • The proportion of couples with male factor infertility due to a genetic abnormality who:

F No clinical pregnancy with donor insemination *See Table below ‐ achieve a clinical pregnancy after donor insemination, or
G Successful ongoing pregnancy with donor insemination *See Table below • The proportion of couples with male factor infertility due to a genetic abnormality who
achieved a clinical pregnancy with donor insemination that maintain this pregnancy (do not
experience a miscarriage)
• 1 – miscarriage
H Miscarriage after clinical pregnancy with donor *See Table below • The proportion of couples with male factor infertility due to a genetic abnormality who
‐ do not maintain this pregnancy (experience a miscarriage), or
L ICSI with mTESE or donor sperm after failure with donor Overall: 0.85‐0.90 • The proportion of couples with male factor infertility due to a genetic abnormality who either
insemination By female age: no did not achieved a clinical pregnancy or were unable to maintain a pregnancy after Donor
differences insemination who:
K Dropout after failure with donor insemination Overall: 0.10‐0.15 ‐ are treated with ICSI with surgical sperm retrieval, or
Non‐obstructive male factor – other acquired condition
A Ovarian stimulation + IUI Overall: 0.40‐0.50 • The proportion of couples with male factor infertility due to some other acquired condition
By female age: who:
<35: 0.60 ‐ are treated with ovarian stimulation + IUI,
35‐40: 0.40‐0.50 ‐ are treated with ICSI with or without electro‐ejaculation or surgical sperm retrieval, or
>40: 0.05‐0.10 ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
B ICSI with or without electro‐ejaculation or mTESE Overall: 0.40‐0.45 decision to adopt, etc.)
<35: 0.25‐0.30
35‐40: 0.40‐0.45
>40: 0.80
By female age: no
differences
D Successful clinical pregnancy with ovarian stimulation + *See Table below • The proportion of couples with male factor infertility due to some other acquired condition

IUI who:
379


decision model
E No clinical pregnancy with ovarian stimulation + IUI *See Table below ‐ achieve a clinical pregnancy with ovarian stimulation + IUI, or
‐ do not achieve a clinical pregnancy with ovarian stimulation + IUI
G Miscarriage after clinical pregnancy with ovarian *See Table below • The proportion of couples with male factor infertility due to some other acquired condition
stimulation + IUI who achieved a clinical pregnancy with ovarian stimulation + IUI, who:
I ICSI with or without electro‐ejaculation or mTESE after Overall: 0.85‐0.90 • The proportion of couples with male factor infertility due to some other acquired condition
failure ovarian stimulation + IUI By female age: no who either did not achieved a clinical pregnancy or were unable to maintain a pregnancy after
differences ovarian stimulation + IUI who:
H Dropout after failure with ovarian stimulation + IUI Overall: 0.10‐0.15 ‐ are treated with ICSI with or without electro‐ejaculation or surgical sperm retrieval, or
Unknown male factor (male factor of unknown etiology)
A Ovarian stimulation + IUI Overall: 0.40‐0.50 • The proportion of couples with idiopathic male factor infertility who:
By female age: ‐ are treated with ovarian stimulation + IUI,
<35: 0.60 ‐ are treated with ICSI with or without surgical sperm retrieval, or
>40: 0.05‐0.10 decision to adopt, etc.)
B ICSI with or without surgical sperm retrieval Overall: 0.40‐0.45 • Expert opinion
By female age:
<35: 0.25‐0.30
35‐40: 0.40‐0.45
>40: 0.80
By female age: no
differences
D Successful clinical pregnancy with ovarian stimulation + *See Table below • The proportion of couples with idiopathic male factor infertility who:

IUI ‐ achieve a clinical pregnancy with ovarian stimulation + IUI, or
E No clinical pregnancy with ovarian stimulation + IUI *See Table below ‐ do not achieve a clinical pregnancy with ovarian stimulation + IUI
G Miscarriage after clinical pregnancy with ovarian *See Table below • The proportion of couples with idiopathic male factor infertility who achieved a clinical
stimulation + IUI pregnancy with ovarian stimulation + IUI, who:
I ICSI with or without surgical sperm retrieval after failure Overall: 0.85‐0.90 • The proportion of couples with idiopathic male factor infertility who either did not achieved a
ovarian stimulation + IUI By female age: no clinical pregnancy or were unable to maintain a pregnancy after ovarian stimulation + IUI who:
differences ‐ are treated with ICSI with or without surgical sperm retrieval, or
380


decision model
H Dropout after failure with ovarian stimulation + IUI Overall: 0.10‐0.15 ‐ ‘dropout’
differences
‐ All treatments are publicly funded, with the exception of sterilization reversal (vasovasotomy or vasoepididymostomy)
‐ Approximately 10‐20% of couples “dropout” after each cycle of IVF/ICSI, 5% after each cycle of ovarian stimulation + IUI using clomiphene citrate, 10% after each cycle of ovarian stimulation + IUI using
gonadotropin injections, and 10‐15% after each cycle of donor insemination

381


Table 50. Variable inputs for decision model III ‐ ovarian stimulation + IUI for couples with male factor infertility
decision model
See above table Successful clinical pregnancy with ovarian stimulation + Overall: • The proportion of couples with male factor infertility who:
IUI 0.09‐0.12 per cycle ‐ achieve a clinical pregnancy after ovarian stimulation + IUI, or
By female age: ‐ do not achieve a clinical pregnancy after ovarian stimulation + IUI
41,503,534,535
<35: 0.07‐0.11 per cycle • Literature
35‐40: 0.06‐0.09 per cycle • These probabilities reflect the success of up to 6 cycles of ovarian stimulation (with
>40: 0.02‐0.04 per cycle gonadotropins) + IUI in couples with male factor infertility only (normal female); most
See above table No clinical pregnancy with ovarian stimulation + IUI 1 – successful clinical pregnancies occurred within the first 3 cycles
pregnancy
See above table Miscarriage after clinical pregnancy with ovarian Overall: 0.12‐0.31 • The proportion of couples with male factor infertility who achieved a clinical pregnancy with
stimulation + IUI By female age: ovarian stimulation + IUI, who:
41,534
>40: 0.25‐0.31 • Literature
See above table Successful ongoing pregnancy with ovarian stimulation + 1 – miscarriage
IUI
General Assumptions:Success with IUI is not influenced by the underlying cause of male factor infertility

382


Table 51. Variable inputs for decision model III ‐ donor insemination for couples with male factor infertility
decision model
See above table Successful clinical pregnancy with donor insemination Overall: • The proportion of couples with male factor infertility who:
0.12‐0.27 per cycle ‐ achieve a clinical pregnancy after donor insemination, or
By female age: ‐ do not achieve a clinical pregnancy after donor insemination
503,536,537
<35: 0.17‐0.27 per cycle • Literature and expert opinion
35‐40: 0.09‐0.22 per cycle • These probabilities reflect the success of up to 6 cycles of ovarian stimulation (with CC or
>40: 0.08‐0.13 per cycle gonadotropins) + donor insemination (via intrauterine insemination) in couples with male factor
See above table No clinical pregnancy with donor insemination 1 – successful clinical infertility only (normal female); most pregnancies occurred within the first 3 cycles; most studies
pregnancy used frozen sperm
• Success rates were higher after cycles stimulated with gonadotropins (0.629 per couple)
compared to those stimulated with CC (0.487 per couple)

See above table Miscarriage after clinical pregnancy with donor Overall: 0.12‐0.18 • The proportion of couples with male factor infertility who achieved a clinical pregnancy with
insemination By female age: donor insemination, who:
538,539
>40: 0.18 • Literature and expert opinion
See above table Successful ongoing pregnancy with donor insemination 1 – miscarriage
* Success with donor insemination is not influenced by the underlying cause of male factor infertility

383


Table 52. Variable inputs for decision model IV ‐ treatment of couples with unexplained infertility
decision model
A Ovarian stimulation + IUI Overall: 0.75 • The proportion of couples with unexplained infertility who:
By female age: ‐ are treated with clomiphene citrate,
35‐40: 0.60 ‐ are treated with IVF/ICSI, or
>40: 0.10 ‐ ‘dropout’/choose not to have treatment (for example, due to spontaneous conception, or
B IVF/ICSI Overall: 0.10‐0.15 decision to adopt, etc.)
<35: 0
35‐40: 0.25‐0.30
>40: 0.75‐0.80
By female age: no
differences
D Successful clinical pregnancy with ovarian stimulation + Overall: • The proportion of couples with unexplained infertility who:
IUI 0.07‐0.11 per cycle ‐ achieve a clinical pregnancy after ovarian stimulation + IUI, or
By female age: ‐ do not achieve a clinical pregnancy after ovarian stimulation + IUI
41,89,503,504,540
<35: 0.07‐0.14 per cycle • Literature
35‐40: 0.06‐0.12 per cycle • These probabilities reflect the success of up to 6 cycles of IUI in couples with unexplained
>40: 0.02‐0.07 per cycle infertility who were either treatment naïve or had failed to achieve a successful pregnancy with
E No clinical pregnancy with ovarian stimulation + IUI 1 – successful clinical clomiphene citrate alone
pregnancy
G Miscarriage after clinical pregnancy with ovarian Overall: 0.12‐0.31 • The proportion of couples with unexplained infertility who achieved a clinical pregnancy with
stimulation + IUI By female age: ovarian stimulation + IUI, who:
41,89
>40: 0.25‐0.31 • Literature
F Successful ongoing pregnancy with ovarian stimulation + 1 – miscarriage
IUI
Second line of treatment (after ovarian stimulation + IUI)
K IVF/ICSI after failure with ovarian stimulation + IUI Overall: 0.85‐0.90 • The proportion of couples with unexplained infertility who either did not achieved a clinical
By female age: no pregnancy or were unable to maintain a pregnancy after treatment with ovarian stimulation +
differences IUI, or who failed to ovulate after treatment with clomiphene citrate who:
J Dropout after failure with ovarian stimulation + IUI Overall: 0.10‐0.15 ‐ are treated with IVF/ICSI, or

384


Table 53. Variable inputs for decision model V ‐ pregnancy & delivery outcomes after surgical treatments for male & female infertility
decision model
A Singleton pregnancy Overall: 0.98‐0.99 • The proportion of ongoing pregnancies that are:
By female age: no ‐ singleton
differences ‐ twin
B Twin pregnancy Overall: 0.01‐0.02 ‐ HOM
By female age: no • Data from Alberta Perinatal Health Program April 2009 ‐ Dec 2011 (collected from provincial
differences delivery records) for women with no record of ovulation induction, IUI, or IVF/ICSI (surgical
C Higher‐order multiple (HOM) pregnancy Overall: <0.01 treatments not reported); reliability of ART history dependent on documentation of ART at the
By female age: no time of delivery
differences
D Singleton pregnancy with complications Overall: 0.17‐0.25 • The proportion of singleton pregnancies that are:
By female age: ‐ complicated/’high‐risk’
<35: 0.16‐0.24 ‐ uncomplicated
35‐39: 0.21‐0.31 • Expert opinion
≥40: 0.27‐0.40 • Assumption: all twin/HOM pregnancies are complicated/high‐risk (expert opinion); this
E Singleton pregnancy without complications Overall: 0.75‐0.83 assumption was consistent with numbers found in Alberta Health Billing data
By female age:
<35: 0.76‐0.84 • The incidence of bleeding, gestational hypertension, and/or gestational diabetes were obtained
35‐39: 0.69‐0.79 from data from Alberta Perinatal Health Program April 2009 ‐ Dec 2011 (collected from provincial
≥40: 0.60‐0.73 delivery records) for women pregnant with singletons vs. twins/HOMs with no record of
ovulation induction, IUI, or IVF/ICSI (surgical treatments not reported); reliability of ART history
dependent on documentation of ART at the time of delivery
‐ singletons: 0.17 (<35: 0.16, 35‐39: 0.21, ≥40: 0.27)
‐ twins/HOMs: 0.26 (<35: 0.25, 35‐39: 0.26, ≥40: 0.30)
J Vaginal delivery after singleton pregnancy Overall: 0.84 • The proportion of singleton pregnancies that result in:
By female age: ‐ vaginal delivery
<35: 0.76 ‐ caesarean delivery
35‐39: 0.66
≥40: 0.61 • Data from Alberta Perinatal Health Program April 2009 ‐ Dec 2011 (collected from provincial
L Caesarean delivery after singleton pregnancy Overall: 0.26 delivery records) for women pregnant with singletons with no record of ovulation induction, IUI,
By female age: or IVF/ICSI; reliability of ART history dependent on documentation of ART at the time of delivery
<35: 0.24 ‐ vaginal delivery can be further broken down into: spontaneous vaginal ‐ 0.62 (<35: 0.63, 35‐39:
35‐39: 0.34 0.55, ≥40: 0.51) and assisted vaginal ‐ 0.12 (<35: 0.13, 35‐39: 0.11, ≥40: 0.10)
≥40: 0.39
M Vaginal delivery after twin pregnancy Overall: 0.46 • The proportion of twin pregnancies that result in:
35‐39: 0.46
O Caesarean delivery after twin pregnancy Overall: 0.54 delivery records) for women pregnant with twins with no record of ovulation induction, IUI, or
By female age: IVF/ICSI; reliability of ART history dependent on documentation of ART at the time of delivery
<35: 0.54 ‐ vaginal delivery can be further broken down into: spontaneous vaginal ‐0.39 (<35: 0.39, 35‐39:
385


decision model
35‐39: 0.54 0.38, ≥40: 0.36) and assisted vaginal: 0.07 (<35: 0.07, 35‐39: 0.08, ≥40: 0.07)
≥40: 0.55
P Vaginal delivery after HOM pregnancy Overall: 0.10 • The proportion of HOM pregnancies that result in:
35‐39: 0
≥40: 0 • Data from Alberta Perinatal Health Program April 2009 ‐ Dec 2011 (collected from provincial
R Caesarean delivery after HOM pregnancy Overall: 0.90 delivery records) for women pregnant with HOMs with no record of ovulation induction, IUI, or
By female age: IVF/ICSI; reliability of ART history dependent on documentation of ART at the time of delivery
<35: 0.89 ‐ vaginal delivery can be further broken down into: spontaneous vaginal ‐0.10 (<35: 0.11, 35‐39:
35‐39: 1.00 0, ≥40: 0) and assisted vaginal: 0 (<35: 0, 35‐39: 0, ≥40: 0)
≥40: 1.00
‐ Outcomes of surgical treatments for infertility past ongoing pregnancy are not influenced by the underlying cause of infertility, and are assumed to be the same as those in couples who conceive
‘spontaneously’ (no OI, OI/IUI, IVF/ICSI, or other ART)
‐ The same proportions of women undergoing different types of delivery (spontaneous vaginal, assisted vaginal, or caesarean section) were used for both complicated and uncomplicated pregnancies

386


Table 54. Variable inputs for decision model IV ‐ pregnancy & delivery outcomes after & ovarian stimulation ± IUI/DI
decision model
A Singleton pregnancy Overall:0.89 • The proportion of ongoing pregnancies that are:
By female age: no ‐ singleton
differences ‐ twin
‐ HOM
B Twin pregnancy Overall:0.10 • Data from Alberta Perinatal Health Program April 2009 ‐ Dec 2011 (collected from provincial
By female age: no delivery records) for women with a record of conception through ovulation induction ± IUI;
differences reliability of ART history dependent on documentation of ART at the time of delivery
42,478,479,482,490,536,541
• Literature :
C Higher‐order multiple (HOM) pregnancy Overall:0.01 ‐ Clomiphene citrate ± IUI/DI
By female age: no Singletons:0.90, Twins: 0.09, HOMs: 0.01
differences ‐ Gonadotropins ± IUI/DI
Singletons:0.81‐0.88, Twins: 0.09‐0.19, HOMs: 0.05
D Singleton pregnancy with complications Overall: 0.30‐0.44 • The proportion of singleton pregnancies that are:
35‐39: 0.35‐0.52 • Expert opinion
assumption was consistent with numbers found in Alberta Health Billing data

E Singleton pregnancy without complications Overall: 0.56‐0.70 • The incidence of bleeding, gestational hypertension, and/or gestational diabetes were obtained
By female age: from data from Alberta Perinatal Health Program April 2009 ‐ Dec 2011 (collected from provincial
<35: 0.55‐0.70 delivery records) for women pregnant with singletons vs. twins/HOMs with record of conception
35‐39: 0.48‐0.65 through ovulation induction ± IUI; reliability of ART history dependent on documentation of ART
≥40: 0.57‐0.71 at the time of delivery
‐ singletons: 0.30 (<35: 0.30, 35‐39: 0.35, ≥40: 0.29)
‐ twins/HOMs: 0.35 (<35: 0.35, 35‐39: 0.35, ≥40: 0.29)
35‐39: 0.61
L Caesarean delivery after singleton pregnancy Overall: 0.35 delivery records) for women pregnant with singleton with record of conception through
By female age: ovulation induction ± IUI; reliability of ART history dependent on documentation of ART at the
<35: 0.32 time of delivery
35‐39: 0.39 ‐ vaginal delivery can be further broken down into: spontaneous vaginal ‐0.50 (<35: 0.53, 35‐39:
≥40: 0.48 0.48, ≥40: 0.33) and assisted vaginal: 0.15 (<35: 0.15, 35‐39: 0.14, ≥40: 0.19)
35‐39: 0.42
387


decision model
O Caesarean delivery after twin pregnancy Overall: 0.63 delivery records) for women pregnant with twins with record of conception through ovulation
By female age: induction ± IUI; reliability of ART history dependent on documentation of ART at the time of
<35: 0.64 delivery
35‐39: 0.58 ‐ vaginal delivery can be further broken down into: spontaneous vaginal ‐0.28 (<35: 0.27, 35‐39:
≥40: 0.86 0.33, ≥40: 0.14) and assisted vaginal: 0.09 (<35: 0.09, 35‐39: 0.09, ≥40: 0)

P Vaginal delivery after HOM pregnancy Overall: 0 • The proportion of HOM pregnancies that result in:
<35: 0 ‐ caesarean delivery
35‐39: 0
≥40: 0 • Data from Alberta Perinatal Health Program April 2009 ‐ Dec 2011 (collected from provincial
R Caesarean delivery after HOM pregnancy Overall: 1.00 delivery records) for women pregnant with HOMs with record of conception through ovulation
By female age: induction ± IUI; reliability of ART history dependent on documentation of ART at the time of
<35: 1.00 delivery
35‐39: 1.00
≥40: 1.00
‐ Outcomes of OI/IUI for infertility past ongoing pregnancy are not influenced by the underlying cause of infertility

388


Table 55. Variable inputs for decision model V‐IVF/ICSI outcomes
decision model
IVF/ICSI with fresh, autologous oocytes
Fertilization and embryo transfer
Q Embryo selected for implantation; left over embryos Overall: 0.49‐0.69 • The proportion of couples undergoing embryo transfer who:
cryopreserved By female age: ‐ have embryos left over for cryopreservation
<35: 0.49‐0.69 ‐ do not have embryos left over for cryopreservation
35‐39: 0.49‐0.69 ‐ cryopreserve all embryos due to OHSS (or other reasons)
323,325,542
≥40: 0.21‐0.52 • Literature
R Embryo selected for implantation; no left over embryos Overall: 0.28 • Cycle cancellation due to OHSS slightly lower with GnRH antagonist protocol compared to
542
By female age: GnRH agonist protocol
<35: 0.28‐0.48 ‐ Overall: 0.03; GnRHa ‐ 0.04; GnRHantag ‐ 0.02
35‐39: 0.28‐0.48
≥40: 0.45‐0.76
S All embryos cryopreserved (due to OHSS) Overall: 0.03
By female age: no
differences
H Proceed with frozen cycle after fresh cycle cancellation Overall: 0.97‐0.99 • The proportion of couples who cancel a fresh IVF/ICSI cycle due to OHSS who:
due to OHSS By female age: no ‐ proceed with a frozen cycle
differences ‐ dropout
P Dropout after fresh cycle cancellation due to OHSS Overall: 0.01‐0.03 • Expert opinion
By female age: no
differences
Clinical pregnancy after embryo transfer
BB Clinical pregnancy SET: 0.33 • The proportion of IVF/ICSI cycles with assisted hatching that result in a clinical pregnancy
543
By female age: • 2009 CARTR data
<35: 0.45 • The same per cycle pregnancy rate was used for each cycle
35‐39: 0.26
≥40: 0.13
DET: 0.48
By female age:
<35: 0.54
35‐39: 0.45
≥40: 0.25
TET: 0.41
By female age:
<35: 0.49
35‐39: 0.46
≥40: 0.25
CC No clinical pregnancy 1 – clinical pregnancy
389


decision model
EE Miscarriage SET: 0.17 • The proportion of clinical pregnanciesafter IVF/ICSI cycles with assisted hatching that result in a
By female age: miscarriage
543
<35: 0.13 • 2009 CARTR data
35‐39: 0.20
≥40: 0.33
DET: 0.17
By female age:
<35: 0.13
35‐39: 0.22
≥40: 0.30
TET: 0.25
By female age:
<35: 0.19
35‐39: 0.20
≥40: 0.44
DD Ongoing pregnancy 1 – clinical pregnancy
IVF/ICSI with frozen, autologous oocytes
Clinical pregnancy after frozen‐thawed embryo transfer
JJ Clinical pregnancy SET: 0.19 • The proportion of IVF/ICSI cycles with assisted hatching that result in a clinical pregnancy
543
By female age: • 2009 CARTR data
<35: 0.26 • The same per cycle pregnancy rate was used for each cycle
35‐39: 0.15
≥40: 0.07
DET: 0.31
By female age:
<35: 0.35
35‐39: 0.29
≥40: 0.16
TET: 0.33
By female age:
<35: 0.39
35‐39: 0.36
≥40: 0.20
KK No clinical pregnancy 1 – clinical pregnancy
390


decision model
MM Miscarriage SET: 0.26 • The proportion of clinical pregnanciesafter IVF/ICSI cycles with assisted hatching that result in a
By female age: miscarriage
543
<35: 0.24 • 2009 CARTR data
35‐39: 0.41
≥40: 0.61
DET: 0.24
By female age:
<35: 0.15
35‐39: 0.23
≥40: 0.46
TET: 0.29
By female age:
<35: 0.13
35‐39: 0.16
≥40: 0.31
LL Ongoing pregnancy 1 – clinical pregnancy
Dropouts
Dropout after fresh cycle before frozen cycle
I Proceed with a frozen cycle after failure with a fresh cycle Overall: 0.95 • The proportion of couples who either did not achieved a clinical pregnancy or were unable to
By female age: no maintain a pregnancy after a fresh IVF/ICSI cycle, who:
differences ‐ proceed with a subsequent frozen cycle, or
AA Dropout after fresh cycle Overall: 0.05 ‐ dropout
differences
Dropout after fresh and/or frozen cycle before subsequent fresh cycle
J Proceed with a fresh cycle after failure with a fresh and/or Overall: 0.80‐0.85 • The proportion of couples who either did not achieved a clinical pregnancy or were unable to
frozen cycle By female age: no maintain a pregnancy after their a fresh and/or frozen IVF/ICSI cycle, who:
differences ‐ proceed with a subsequent fresh cycle, or
BB Dropout after fresh cycle Overall: 0.15‐0.20 ‐ dropout
differences

391


Table 56. Variable inputs for decision model V‐pregnancy & delivery outcomes after IVF/ICSI
Branch of Variable Estimate (probabilities)* Information Sources and Assumptions
decision model
IVF/ICSI with fresh, autologous oocytes
A Singleton pregnancy SET: 0.98 • The proportion of ongoing pregnancies that are:
By female age: ‐ singleton
<35: 0.97 ‐ twin
35‐39: 1.00 ‐ HOM
543
≥40: 1.00 • 2009 CARTR data for IVF/ICSI with fresh embryos
DET: 0.67 • IVF/ICSI with fresh embryos; no significant difference in cleavage and blastocyst transfers
323,325
By female age: (when the same number of cleavage stage as blastocyst stage embryos are transferred)
<35: 0.63
35‐39: 0.72 • The incidence of multiples after IVF/ICSI overall (no information with regards to number of
≥40: 0.86 embryos transferred or other procedural details) was obtained from data from Alberta Perinatal
TET: 0.67 Health Program April 2009 ‐ Dec 2011 (collected from provincial delivery records) for women
By female age: with a record of conception through IVF/ICSI; reliability of ART history dependent on
<35: 0.61 documentation of ART at the time of delivery
35‐39: 0.74 ‐ singletons: 0.70 (<37: 0.66, 35‐39: 0.75, ≥40: 0.70)
≥40: 0.84 ‐ twins: 0.28 (<37: 0.32, 35‐39: 0.23, ≥40: 0.29)
B Twin pregnancy SET: 0.02 ‐ HOMs: 0.02 (<37: 0.02, 35‐39: 0.01, ≥40: 0.01)
By female age:
<35: 0.03
35‐39: 0
≥40: 0
DET: 0.323
By female age:
<35: 0.363
35‐39: 0.273
≥40: 0.133
TET: 0.31
By female age:
<35: 0.37
35‐39: 0.25
≥40: 0.15
392


decision model
C Higher‐order multiple (HOM) pregnancy SET: 0
By female age:
<35: 0
35‐39: 0
≥40: 0
DET: 0.007
By female age:
<35: 0.007
35‐39: 0.007
≥40: 0.007
TET: 0.02
By female age:
<35: 0.02
35‐39: 0.01
≥40: 0.01
IVF/ICSI with frozen, autologous oocytes
A Singleton pregnancy SET: 0.98 • The proportion of ongoing pregnancies that are:
By female age: ‐ singleton
<35: 0.97 ‐ twin
35‐39: 1.00 ‐ HOM
543
≥40: 1.00 • 2009 CARTR data for IVF/ICSI with frozen embryos
DET: 0.79
By female age:
<35: 0.74
35‐39: 0.85
≥40: 1.00
TET: 0.69
By female age:
<35: 0.63
35‐39: 0.77
≥40: 0.87
393


decision model
B Twin pregnancy SET: 0.02
By female age:
<35: 0.03
35‐39: 0
≥40: 0
DET: 0.208
By female age:
<35: 0.258
35‐39: 0.148
≥40: 0
TET: 0.28
By female age:
<35: 0.34
35‐39: 0.22
≥40: 0.12
C Higher‐order multiple (HOM) pregnancy SET: 0
By female age:
<35: 0
35‐39: 0
≥40: 0
DET: 0.002
By female age:
<35: 0.002
35‐39: 0.002
≥40: 0
TET: 0.03
By female age:
<35: 0.03
35‐39: 0.01
≥40: 0.01
IVF/ICSI
D Complicated singleton pregnancy Overall: 0.40‐0.50 • The proportion of singleton pregnancies that are:
35‐39: 0.40‐0.50 • Expert opinion
394


decision model
E Uncomplicated singleton pregnancy Overall: 0.50‐0.60 assumption was consistent with numbers found in Alberta Health Billing data
By female age:
<35: 0.56‐0.65 • The incidence of bleeding, gestational hypertension, and/or gestational diabetes were obtained
35‐39: 0.50‐0.60 from data from Alberta Perinatal Health Program April 2009 ‐ Dec 2011 (collected from provincial
≥40: 0.30‐0.44 delivery records) for women pregnant with singletons vs. twins/HOMs with record of conception
through IVF/ICSI; reliability of ART history dependent on documentation of ART at the time of
delivery:
‐ singletons: 0.32 (<35: 0.28, 35‐39: 0.32, ≥40: 0.45)
‐ twins/HOMs: 0.37 (<35: 0.35, 35‐39: 0.41, ≥40: 0.37)
35‐39: 0.59 • Data from Alberta Perinatal Health Program April 2009 ‐ Dec 2011 (collected from provincial
≥40: 0.48 delivery records) for women pregnant with singleton with record of conception through IVF/ICSI;
L Caesarean delivery after singleton pregnancy Overall: 0.42 reliability of ART history dependent on documentation of ART at the time of delivery
By female age: ‐ vaginal delivery can be further broken down into:spontaneous vaginal ‐ 0.41 (<35: 0.47, 35‐39:
<35: 0.38 0.40, ≥40: 0.28) and assisted vaginal ‐ 0.17 (<35: 0.15, 35‐39: 0.19, ≥40: 0.20)
35‐39: 0.41
≥40: 0.53
35‐39: 0.30 • Data from Alberta Perinatal Health Program April 2009 ‐ Dec 2011 (collected from provincial
≥40: 0.15 delivery records) for women pregnant with twins with record of conception through IVF/ICSI;
O Caesarean delivery after twin pregnancy Overall: 0.68 reliability of ART history dependent on documentation of ART at the time of delivery
By female age: ‐ vaginal delivery can be further broken down into: spontaneous vaginal ‐ 0.23 (<35: 0.29, 35‐39:
<35: 0.62 0.21, ≥40: 0.09) and assisted vaginal ‐ 0.08 (<35: 0.09, 35‐39: 0.09, ≥40: 0.06)
35‐39: 0.70
≥40: 0.85
P Vaginal delivery after HOM pregnancy Overall: 0.03 • The proportion of HOM pregnancies that result in:
35‐39: 0 • Data from Alberta Perinatal Health Program April 2009 ‐ Dec 2011 (collected from provincial
≥40: 0 delivery records) for women pregnant with HOMs with record of conception through IVF/ICSI;
R Caesarean delivery after HOM pregnancy Overall: 0.97 reliability of ART history dependent on documentation of ART at the time of delivery
By female age: ‐ vaginal delivery can be further broken down into: spontaneous vaginal ‐0.03 (<35: 0.05, 35‐39:
<35: 0.95 0, ≥40: 0) and assisted vaginal: 0 (<35: 0, 35‐39: 0, ≥40: 0)
35‐39: 1.00
≥40: 1.00
‐ Outcomes of IVF/ICSI for infertility past ongoing pregnancy are not influenced by the underlying cause of infertility
395


Table 57. Variable inputs for decision model V‐neonatal & long‐term outcomes after 1) surgical treatments for male & female infertility, 2) ovarian
stimulation +/‐ IUI/DI, and 3) IVF/ICSI
decision model
Liveborn baby from singleton pregnancy 0.98 • The proportion of singleton pregnancies that result in:
‐ a liveborn baby
Still born baby from singleton pregnancy 0.02 ‐ a still born baby
• Data from Alberta Perinatal Health Program April 2009 ‐ Dec 2011 (collected from provincial
delivery records) for women pregnant with singletons
Two liveborn babies from twin pregnancy 0.97 • The proportion of twin pregnancies that result in:
‐ two liveborn babies
One liveborn baby from twin pregnancy 0.015 ‐ one liveborn baby
‐ two stillborn babies
Two stillborn babies from twin pregnancy 0.015
All liveborn babies from HOM pregnancy 0.97 • only data on triplets were available, therefore proportions are based on triplets only

• The proportion of triplet pregnancies that result in:
More than half, but not all, liveborn babies from HOM 0.0075
‐ all liveborn babies
pregnancy
‐ 2 liveborn babies
Less than half liveborn babies from HOM pregnancy 0.0075 ‐ 1 liveborn baby
All stillborn babies from HOM pregnancy 0.015 ‐ all stillborn babies
Neonatal death after live birth from singleton pregnancy 0.0005 • The proportion of liveborn babies from singleton pregnancies that:

‐ die during neonatal period
Neonatal death after live birth from singleton pregnancy 0.9995 ‐ survive neonatal period
544
• Alberta Reproductive Health Pregnancies and Births – surveillance report
545
• Literature
Neonatal death after live birth(s) from twin pregnancy 0.0016 • The proportion of liveborn babies from twin pregnancies that:
Neonatal survival after live birth(s) from twin pregnancy 0.9984 ‐ survive neonatal period
544
545
• Literature
Neonatal death after live birth(s) from HOM pregnancy 0.0025 • The proportion of liveborn babies from HOM pregnancies that:
Neonatal survival after live birth(s) from HOM pregnancy 0.9975 ‐ survive neonatal period
544
545
• Literature
Healthy neonatal survivor from singleton pregnancy Surgical tx, OI, or OI/IUI: • The proportion of neonatal survivors from singleton pregnancies that are:
0.967 ‐ healthy
‐ unhealthy
545
IVF/ICSI: • Literature (trends confirmed with series of EPICURE studies) – general population estimates
0.965 used for babies born after surgical treatment, OI, or OI/IUI (expert opinion)
Unhealthy neonatal survivor from singleton pregnancy Surgical tx, OI, or OI/IUI: • No estimates of the general health of infants born after IVF/ICSI compared to those in the
0.033 general population were found, however, trends of increased birth defects, congenital
396


decision model
malformations, and NICU admissions among IVF/ICSI infants (controlling for multiple gestations)
IVF/ICSI: were reported in the literature; proportions of unhealthy infants were increased by 1.05 (expert
0.035 opinion)
Healthy neonatal survivor(s) from twin pregnancy Surgical tx, OI, or OI/IUI:
0.925

IVF/ICSI:
0.921
Unhealthy neonatal survivor(s) from twin pregnancy Surgical tx, OI, or OI/IUI:
0.075

IVF/ICSI:
0.079
Healthy neonatal survivor(s) from HOM pregnancy Surgical tx, OI, or OI/IUI:
0.82

IVF/ICSI:
0.81
Unhealthy neonatal survivor(s) from HOM pregnancy Surgical tx, OI, or OI/IUI:
0.18

IVF/ICSI:
0.19

397

Table 58. Variable inputs for utilities associated with different health states in the decision model
Variable inputs for utilities associated with different health states in the decision model
Utility state Value Source Rationale
Condition related (female)
WHO Group 1 ovulatory dysfunction ‐ Non‐ 0.82 Published literature From published studies of utility associated with infertility, in general546
polycystic ovarian syndrome
WHO Group 2 ovulatory dysfunction – Poly‐ 0.82 Published literature From published studies of utility associated with infertility, in general546
cystic ovarian syndrome
WHO Group 3 ovulatory dysfunction – Ovarian 0.77 Based on published Published value for general infertility reduced by 0.05 to account for limited
failure literature and expert treatment options which involve donor eggs (no possibility of a child biologically
546
opinion related to the mother)
Proximal or distal tubal obstruction 0.82 Published literature From published studies of utility associated with infertility, in general547
Infertility from tubal ligation 0.82 Published literature From published studies of utility associated with infertility, in general546
Moderate to severe endometriosis 0.80 Published literature From published studies of utility associated with infertility, in general546
Polyps 0.82 Published literature From published studies of utility associated with infertility, in general546
Fibroids – Type 0 or 1 (sub‐mucosal) 0.82 Published literature From published studies of utility associated with infertility, in general546
Fibroids – Type 2 (> 50% intramural) 0.82 Published literature From published studies of utility associated with infertility, in general546
Unexplained female factor infertility 0.82 Published literature From published studies of utility associated with infertility, in general546
Condition related (male)
Infertility from vasectomy 0.82 Published literature From published studies of utility associated with infertility, in general546
Congenital bilateral absence of vas deferens 0.77 Published literature Published value for general infertility reduced by 0.05 to account for limited
(CBAVD) and expert opinion treatment options which involve donor sperm (no possibility of a child biologically
related to the father)546
Congenital or acquired obstruction of the 0.82 Published literature From published studies of utility associated with infertility, in general547
ejaculatory duct
Other acquired obstructions 0.82 Published literature From published studies of utility associated with infertility, in general546
Hormonal abnormalities 0.82 Published literature From published studies of utility associated with infertility, in general546
Clinical varicocele 0.82 Published literature From published studies of utility associated with infertility, in general546
Immunologic 0.82 Published literature From published studies of utility associated with infertility, in general546
Genetic 0.82 Published literature From published studies of utility associated with infertility, in general546
Other acquired non‐obstructive conditions 0.82 Published literature From published studies of utility associated with infertility, in general546
Unexplained male factor infertility 0.82 Published literature From published studies of utility associated with infertility, in general546
Pharmacological treatments
Pregnant after treatment with clomiphene 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
citrate pregnant548
Not pregnant after treatment with clomiphene 0.82 Expert opinion Assumes utility is the same as that for infertility, in general546
398

citrate
Pregnant after treatment with aromatase 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
548
inhibitors pregnant
Not pregnant after treatment with aromatase 0.82 Expert opinion Assumes utility is the same as that for infertility, in general546
inhibitors
Pregnant after treatment with gonadotropin 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
injections pregnant548
Not pregnant after treatment with 0.80 Expert opinion Based on published utility value for infertility adjusted for estimated utility
gonadotropin injections decrement associated with treatment546
Pregnant after treatment with pulsatile GnRH 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
injections pregnant548
Not pregnant after treatment with pulsatile 0.80 Expert opinion Based on published utility value for infertility adjusted for estimated utility
GnRH injections decrement associated with treatment546
ARTs‐related
Pregnant after IVF/ICSI – first cycle 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
pregnant548
Not pregnant after IVF/ICSI – first cycle 0.78 Expert opinion Assumes that the utility decrement associated with treatment failure is 0.04
Pregnant after IVF/ICSI – second cycle 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
pregnant548
Not pregnant after IVF/ICSI – second cycle 0.74 Expert opinion Assumes that the utility decrement associated with subsequent treatment failures is
also 0.04
Pregnant after IVF/ICSI – third cycle 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
548
pregnant
Not pregnant after IVF/ICSI – third cycle 0.70 Expert opinion Assumes that the utility decrement associated with subsequent treatment failures is
also 0.04
Pregnant after IVF/ICSI – first cycle with donor 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
eggs pregnant548
Not pregnant after IVF/ICSI – first cycle with 0.75 Expert opinion Assumes that the utility decrement associated with treatment failure is 0.0233
donor eggs
Pregnant after IVF/ICSI – second cycle with 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
donor eggs pregnant548
Not pregnant after IVF/ICSI – second cycle with 0.72 Expert opinion Assumes that the utility decrement associated with subsequent treatment failures is
donor eggs also 0.0233
Pregnant after IVF/ICSI – third cycle with donor 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
548
eggs pregnant
Not pregnant after IVF/ICSI – third cycle with 0.70 Expert opinion Assumes that the utility decrement associated with subsequent treatment failures is
donor eggs also 0.0233
Pregnant after ICSI – first cycle with donor 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
399

sperm pregnant548
Not pregnant after ICSI – first cycle with donor 0.75 Expert opinion Assumes that the utility decrement associated with treatment failure is 0.0233
sperm
Pregnant after ICSI – second cycle with donor 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
sperm pregnant548
Not pregnant after ICSI – second cycle with 0.725 Expert opinion Assumes that the utility decrement associated with subsequent treatment failures is
donor sperm also 0.0233
Pregnant after ICSI – third cycle with donor 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
sperm pregnant548
Not pregnant after ICSI – third cycle with donor 0.70 Expert opinion Assumes that the utility decrement associated with subsequent treatment failures is
sperm also 0.0233
Pregnant after Ovarian stimulation + IUI – first 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
cycle pregnant548
Not pregnant after Ovarian stimulation + IUI – 0.807 Expert opinion Assumes a utility decrement associated with treatment failure of 0.013 (smaller than
first cycle that for ICSI/IVF because procedure is less involved)
Pregnant after Ovarian stimulation + IUI – 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
548
second cycle pregnant
second cycle that for ICSI/IVF because procedure is less involved)
Pregnant after Ovarian stimulation + IUI – third 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
548
cycle pregnant
third cycle that for ICSI/IVF because procedure is less involved)
Pregnant after Donor insemination – first cycle 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
548
pregnant
Not pregnant after Donor insemination – first 0.76 Expert opinion Assumes utility decrement associated with treatment failure of 0.01 (slightly smaller
cycle than that for ovarian stimulation + IUI because procedure is less involved)
Pregnant after Donor insemination – second 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
cycle pregnant548
Not pregnant after Donor insemination – 0.75 Expert opinion Assumes utility decrement associated with subsequent treatment failure of 0.01
second cycle
Pregnant after Donor insemination – third cycle 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
pregnant
Not pregnant after Donor insemination – third 0.74 Expert opinion Assumes utility decrement associated with subsequent treatment failure of 0.01
cycle
Non‐ARTs related (female)
Pregnant after treatment with laparoscopic 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
548
ovarian drilling pregnant
400

Not pregnant after treatment with laparoscopic 0.80 Expert opinion Based on published utility values for infertility, adjusted for a decrement of 0.02
ovarian drilling associated with failure of laparoscopic procedure546
Pregnant after tubal ligation reversal 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
pregnant548
Not pregnant after tubal ligation reversal 0.79 Expert opinion Based on published utility values for infertility, adjusted for a decrement of 0.02
associated with failure of laparoscopic procedure546
Pregnant after treatment of endometriosis with 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
laparoscopic surgery pregnant546
Not pregnant after treatment of endometriosis 0.79 Expert opinion Based on published utility values for infertility, adjusted downward by 0.03 to reflect
with laparoscopic surgery utility decrement associated with failure of laparoscopic procedure more involved
546
than ovarian drilling
Pregnant after treatment with polypectomy 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
pregnant548
Not pregnant after treatment with polypectomy 0.80 Expert opinion Based on published utility values for infertility, adjusted downward by 0.02 to reflect
utility decrement associated with failure of laparoscopic procedure546
Pregnant after treatment with myomectomy 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
pregnant548
Not pregnant after treatment with 0.79 Expert opinion Based on published utility values for infertility, adjusted downward by 0.03 to reflect
myomectomy utility decrement associated with failure of laparoscopic procedure more involved
than ovarian drilling546
Non‐ARTs related (male)
Pregnant after vasectomy reversal 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
pregnant548
Not pregnant after vasectomy reversal 0.79 Expert opinion Based on published utility values for infertility, adjusted for a decrement of 0.03
associated with failure of surgical procedure546
Pregnant after transurethral resection of the 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
ejaculatory duct pregnant548
Not pregnant after transurethral resection of 0.79 Expert opinion Based on published utility values for infertility, adjusted for a decrement of 0.03
546
the ejaculatory duct associated with failure of surgical procedure
Pregnant after varicocelectomy 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
548
pregnant
Not pregnant after varicocelectomy 0.80 Expert opinion Based on published utility values for infertility, adjusted downward by 0.02 to reflect
utility decrement associated with failure of surgical procedure, but with an option for
546
IUI first rather than proceeding directly to IVF/ICSI
Outcome of fertility treatment – (amount by which the above utility values associated with a successful clinical pregnancy should be adjusted)
Clinical pregnancy – singleton 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
548
pregnant
Clinical pregnancy – twins 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
401

pregnant548
Clinical pregnancy – higher order multiple 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
548
pregnant
Discontinuation of treatment – spontaneous 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
pregnancy pregnant548
Discontinuation of treatment ‐ not related to 0.70 Expert opinion Based on utility value associated with failure of 3 cycles of ICSI/IVF549
spontaneous pregnancy
Outcome of fertility treatment – long term
Uncomplicated ongoing pregnancy ‐ singleton 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
pregnant548
Uncomplicated ongoing pregnancy ‐ twin 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
pregnant548
Uncomplicated ongoing pregnancy – higher 0.95 Expert opinion Assumes same utility as that found in the published literature for women who are
order multiple pregnant548
Complicated ongoing pregnancy ‐ singleton 0.65 Expert opinion Based on published utility values for symptomatic gestational diabetes550
Complicated ongoing pregnancy ‐ twin 0.65 Expert opinion Based on published utility values for symptomatic gestational diabetes550
Complicated ongoing pregnancy – higher order 0.65 Expert opinion Based on published utility values for symptomatic gestational diabetes550
multiple
Miscarriage ‐ singleton 0.80 Expert opinion Based on published values for pregnancy loss (0.80)549
Miscarriage – twin – one fetus 0.875 Expert opinion Based on published value for utility decrement associated with pregnancy loss of
0.05 and published value for miscarriage with future birth of 0.85549,551
Miscarriage – twin – both fetuses 0.80 Expert opinion Based on published values for pregnancy loss549
Miscarriage – higher order multiple – all fetuses 0.80 Expert opinion Based on published values for pregnancy loss549
Miscarriage – higher order multiple – more 0.85 Expert opinion Based on published value for pregnancy loss adjusted upwards based on published
549,552
than half of the fetuses value for miscarriage with future birth of 0.85
Miscarriage – higher order multiple – less than 0.875 Expert opinion Based on published value for utility decrement associated with pregnancy loss of
half of the fetuses 0.05 and published value for miscarriage with future birth of 0.85549,552
Outcome of fertility treatment – delivery
Uncomplicated vaginal delivery 0.89 Expert opinion Based on published utility value for well health after vaginal delivery (0.86)553 and
published value for utility decrement associated with uncomplicated vaginal delivery
(0.08)554
Complicated vaginal delivery 0.795 Published literature555 Based on the average value of published utility estimates for different complications
related to vaginal delivery (0.795)555
Uncomplicated caesarean section 0.78 Published literature Based on published utility value for well health after caesarean delivery555
Complicated caesarean section 0.76 Published literature Based on published utility value for adverse events associated with caesarean
555
delivery
Outcome of delivery
Singleton – still or neonatal death Baby: 0.01 Published literature Baby: Based on published utility values for still birth (0.0) and neonatal death
402

(0.01)556
Mom: 0.543
Mom: Based on published utility value for neonatal death: 0.543556
Singleton – live and healthy Baby: 1.0 Published literature Baby: Based on published utility value for healthy newborn (1.0)556

Mom: 0.93 Mom: Based on published utility value for mom of a healthy newborn (0.93)552
Singleton – live and unhealthy – cognitive Baby: 0.74 Published literature Baby: Based on average of published values for a baby with mild to moderate
(0.80)557 or severe cognitive delay (0.6)557 and published values for Down syndrome
Mom: 0.775 at birth (0.75‐0.81)552

Mom: Based on average of published values for mother of newborn with preterm
delivery and severe morbidity (0.75) and mother of newborn with preterm delivery
and moderate morbidity (0.80)558
Singleton – live and unhealthy – motor Baby: 0.75 Published literature Baby: Based on average of published values for severe motor delay (0.80)557, and
cerebral palsy (0.70)552
Mom: 0.775
558
and moderate morbidity (0.80)
Singleton – live and unhealthy ‐ physical Baby: 0.70 Published literature Baby: Based on published values for a baby with moderate neonatal morbidity
559
(0.70)
Mom: 0.775
and moderate morbidity (0.80)558
Singleton‐ live and unhealthy – cognitive and Baby: 0.55 Published literature Baby: Based on average of published values for a baby with mild‐to‐moderate
motor and expert opinion cognitive delay and mild‐to‐moderate motor delay (0.7), mild‐to‐moderate cognitive
Mom: 0.745 delay and severe motor delay (0.6), mild‐to‐moderate motor delay and severe
cognitive delay (0.5), and severe motor and severe cognitive delay (0.4)559‐561

558
and moderate morbidity (0.80) adjusted downwards by 0.03 to account for the
presence of both conditions
Singleton‐ live and unhealthy – cognitive and Baby: 0.65 Published literature Baby: Based on average of published values for moderate neonatal morbidity (0.70),
physical and expert opinion mild‐to‐moderate cognitive delay (0.80) and severe cognitive delay (0.60) adjusted
559‐561
Mom: 0.745 downwards by 0.05 to account for the presence of both conditions

403

and moderate morbidity (0.80)558 adjusted downwards by 0.03 to account for the
Singleton – live and unhealthy – physical and Baby: 0.68 Published literature Baby: Based on average of published values for moderate neonatal morbidity (0.70),
motor and expert opinion severe motor delay (0.80) and cerebral palsy (0.70) adjusted downwards by 0.05 to
559‐561
Mom: 0.745 account for the presence of both conditions

558
and moderate morbidity (0.80) adjusted downwards by 0.03 to account for the
Singleton‐ live and unhealthy – cognitive, Baby: 0.525 Published literature Baby: Based on average of published values for a baby with mild‐to‐moderate
physical, and motor and expert opinion cognitive delay and mild‐to‐moderate motor delay (0.7), mild‐to‐moderate cognitive
Mom: 0.725 delay and severe motor delay (0.6), mild‐to‐moderate motor delay and severe
cognitive delay (0.5), and severe motor and severe cognitive delay (0.4), adjusted
559‐561
downwards by 0.025 to account for presence of other physical issues

558
and moderate morbidity (0.80) , adjusted downwards by 0.05 to account for the
presence of all three conditions
Twins – both still Baby: 0.01 Published literature Baby: Based on published utility values for still birth (0.0) and neonatal death
(0.01)190,556
Mom: 0.543
Twins – one live and healthy Baby: 1.0 Expert opinion Baby: Assumes same as that for singleton

Mom: 0.92 Mom: Based on published values for mother of a healthy newborn (0.93)548 adjusted
downwards by 0.01 to account for loss of one baby
Twins – one live and unhealthy – cognitive Baby: 0.74 Expert opinion Baby: Same as that for singleton

Mom: 0.765 Mom: Based on average of published values for mother of newborn with preterm
and moderate morbidity (0.80)558, adjusted downwards by 0.01 to account for loss of
one baby
Twins – one live and unhealthy – physical Baby: 0.70 Expert opinion Baby: Same as that for singleton

404

and moderate morbidity (0.80)558 adjusted downwards by 0.01 to account for loss of
one baby
Twins – one live and unhealthy – motor Baby: 0.75 Expert opinion Baby: Same as that for singleton

and moderate morbidity (0.80) adjusted downwards by 0.01 to account for loss of
one baby
Twins – one live and unhealthy – motor and Baby: 0.55 Expert opinion Baby: Same as that for singleton
cognitive
and moderate morbidity(0.80)558, adjusted downwards by 0.04 to account for the
presence of both conditions and loss of one baby
Twins – one live and unhealthy – physical and Baby: 0.65 Expert opinion Baby: Same as that for singleton
cognitive
and moderate morbidity(0.80), 558 adjusted downwards by 0.04 to account for the
Twins – one live and unhealthy – physical and Baby: 0.68 Expert opinion Baby: Same as that for singleton
motor
and moderate morbidity (0.80) 558, adjusted downwards by 0.04 to account for the
Twins – one live and unhealthy – physical, Baby: 0.525 Expert opinion Baby: Same as that for singleton
motor, and cognitive
558
presence of all three conditions and loss of one baby
Twins – both live and healthy Baby: 1.0 Expert opinion Baby: Same as that for singleton

Mom: 0.93 Mom: Assumes same as that for singleton
Twins – both live, one healthy and one Baby: 0.74 Expert opinion Baby: Same as that for singleton
405

unhealthy ‐ cognitive
delivery and severe morbidity (0.75), mother of newborn with preterm delivery and
moderate morbidity (0.80)558, and mother of a healthy newborn (0.93)
unhealthy ‐ physical
558 548
moderate morbidity (0.80) , and mother of a healthy newborn (0.93)
unhealthy ‐ motor
548
moderate morbidity (0.80), and mother of a healthy newborn (0.93)
unhealthy – cognitive and motor
558
presence of both conditions in one baby
unhealthy – cognitive and physical
and moderate morbidity (0.80)558, adjusted downwards by 0.03 to account for the
unhealthy – motor and physical
unhealthy – cognitive, motor and physical
558
presence of all three conditions in one baby
406

Twins – both live and unhealthy – both Baby: 0.74 Expert opinion Baby: Same as that for singleton
cognitive
and moderate morbidity (0.80)558, adjusted downwards by 0.1 to account for two
babies
Twins – both live and unhealthy – both physical Baby: 0.70 Expert opinion Baby: Same as that for singleton

558
and moderate morbidity (0.80) , adjusted downwards by 0.1 to account for two
babies
Twins – both live and unhealthy – both motor Baby: 0.75 Expert opinion Baby: Same as that for singleton

558
and moderate morbidity (0.80) , adjusted downwards by 0.1 to account for two
babies
cognitive and physical
558
presence of both conditions in two babies
cognitive and motor
Twins – both live and unhealthy – both physical Baby: 0.68 Expert opinion Baby: Same as that for singleton
and motor
cognitive, physical, and motor
407

Twins – both live and unhealthy – each has Baby: 0.73 Expert opinion Baby: Average of utility values for singleton with physical, cognitive, or motor delay
different condition
and moderate morbidity (0.80), adjusted downwards by 0.1 to account for two
babies
Higher order multiples – all still Baby: 0.01 Published literature Baby: Based on published utility values for still birth (0.0) and neonatal death
(0.01)556
Mom: 0.543
190
Higher order multiples – all live and healthy Baby: 1.0 Expert opinion Baby: Same as that for singleton

Mom: 0.93 Mom: Assumes same as that for singleton
Higher order multiples – less than half live and Baby: 0.74 Expert opinion Baby: Same as that for singleton
unhealthy – cognitive
558
and moderate morbidity (0.80) , adjusted downwards by 0.02 to account for loss
of at least two babies
unhealthy – physical
558
unhealthy – motor
558
408

presence of both conditions and loss of at least two babies
558
unhealthy – cognitive, physical, and motor
558
Higher order multiples – more than half live and Baby: 0.74 Expert opinion Baby: Same as that for singleton
unhealthy – all cognitive
babies and the loss of at least one baby
unhealthy – all physical
unhealthy – all motor
409

unhealthy – all cognitive and motor
presence of both conditions in two babies and the loss of at least one baby
unhealthy – all cognitive and physical
unhealthy – all motor and physical
unhealthy – all cognitive, physical, and motor
558
presence of all three conditions in two babies and the loss of at least one baby
Higher order multiples – more than half live and Baby: 0.73 Expert opinion Baby: Average of utility values for singleton with physical, cognitive, or motor delay
unhealthy – each with different conditions
affected babies and the loss of at least one baby
Higher order multiples – all live and unhealthy – Baby: 0.74 Expert opinion Baby: Same as that for singleton
all cognitive
558
and moderate morbidity (0.80) , adjusted downwards by 0.15 to account for three
affected babies
410

all physical
and moderate morbidity (0.80)558, adjusted downwards by 0.15 to account for three
affected babies
all motor
affected babies
all cognitive and motor
babies with both conditions
all cognitive and physical
558
all motor and physical
all cognitive, motor, and physical
558
each with different conditions
411

babies with different conditions
Higher order multiples ‐ all live, some healthy Baby: 0,74 Expert opinion Baby: Same as that for singleton
and some unhealthy ‐ cognitive
moderate morbidity (0.80)558, and mother of a healthy newborn (0.93)548, adjusted
downwards by 0.02 to account for caring for a third baby
Higher order multiples ‐ all live, some healthy Baby: 0.75 Expert opinion Baby: Same as that for singleton
and some unhealthy ‐ motor
558 548
moderate morbidity (0.80) , and mother of a healthy newborn (0.93) , adjusted
downwards by 0.02 to account for caring for a third baby
Higher order multiples – all live, some healthy Baby: 0.70 Expert opinion Baby: Same as that for singleton
and some unhealthy – physical
558 548
downwards by 0.02 to account for needing to care for a third baby who may be
healthy or unhealthy
and some unhealthy – cognitive and motor
downwards by 0.10 to account for at least one baby with both conditions and
needing to care for a third baby who may be healthy or unhealthy
and some unhealthy – cognitive and physical
558 548
and some unhealthy – motor and physical
412

and some unhealthy – cognitive, motor, and
physical Mom: 0.567 Mom: Based on average of published values for mother of newborn with preterm
downwards by 0.16 to account for at least one baby with all three conditions and
and some unhealthy – each with different
conditions Mom: 0.787 Mom: Based on average of published values for mother of newborn with preterm
558 548
downwards by 0.04 to account for at least one baby with all three conditions and
Outcomes at one year after birth
Singleton – live and healthy Baby: 1.0 Expert opinion Baby: Assumes same utility as that for healthy newborn

Parent: 0.93 Parent: Assumes same utility as that for mother of a healthy newborn
Singleton – live and unhealthy – cognitive Baby: 0.74 Expert opinion Baby: Assumes same utility as that at birth

Parent: 0.775 Parent: Assumes same utility as that at birth because any gains associated with
coping are lost after taking into account greater care‐giving responsibilities
Singleton – live and unhealthy – physical Baby: 0.85 Expert opinion Baby: Assumes many of the physical issues resolve within the first year and utility
value increases by 0.15
Parent: 0.895
Parent: Assumes many of the physical issues resolve within the first year and utility
Singleton – live and unhealthy – motor Baby: 0.75 Expert opinion Baby: Assumes same utility as that at birth

learning to cope are lost after taking into account greater care‐giving responsibilities
Singleton ‐ live and unhealthy – cognitive and Baby: 0.55 Expert opinion Baby: Assumes same utility as that at birth
motor
413

Singleton – live and unhealthy – cognitive and Baby: 0.65 Expert opinion Baby: Assumes same utility as that at birth
physical
Singleton – live and unhealthy – motor and Baby: 0.68 Expert opinion Baby: Assumes same utility as that at birth
physical
Singleton – live and unhealthy – cognitive, Baby: 0.525 Expert opinion Baby: Assumes same utility as that at birth
motor and physical
Twins – one live and healthy Baby: 1.0 Expert opinion Baby: Assumes same utility as that for healthy newborn

Parent: 0.92 Parent: Assumes same utility as that for mother at birth
Twins – one live and unhealthy – cognitive Baby: 0.74 Expert opinion Baby: Assumes same utility as that at birth

Twins – one live and unhealthy – physical Baby: 0.85 Expert opinion Baby: Assumes many of the physical issues resolve within the first year and utility
Parent: 0.885
Twins – one live and unhealthy – motor Baby: 0.75 Expert opinion Baby: Assumes same utility as that at birth

Twins – one live and unhealthy – physical and Baby: 0.65 Expert opinion Baby: Assumes same utility as that at birth
cognitive
Twins – one live and unhealthy – motor and Baby: 0.55 Expert opinion Baby: Assumes same utility as that at birth
cognitive
414

Twins – one live and unhealthy – physical and Baby: 0.68 Expert opinion Baby: Assumes same utility as that at birth
motor
Twins – one live and unhealthy – physical, Baby: 0.525 Expert opinion Baby: Assumes same utility as that at birth
cognitive, and motor
Twins – both live and healthy Baby: 1.0 Expert opinion Baby: Assumes same utility as that for healthy newborn

Twins – both live and unhealthy – both Baby: 0.74 Expert opinion Baby: Assumes same utility as that at birth
cognitive
Twins – both live and unhealthy – both physical Baby: 0.85 Expert opinion Baby: Assumes many of the physical issues resolve within the first year and utility
Parent: 0.795
Twins – both live and unhealthy – both motor Baby: 0.75 Expert opinion Baby: Assumes same utility as that at birth

cognitive and motor
Twins – both live and unhealthy – both physical Baby: 0.68 Expert opinion Baby: Assumes same utility as that at birth
and motor
cognitive, motor, and physical
415

Twins – both live and unhealthy – each with Baby: 0.73 Expert opinion Baby: Assumes same utility as that at birth
different conditions
Higher order multiples – all live and healthy Baby: 1.0 Expert opinion Baby: Assumes same utility as that for healthy newborn

Higher order multiples – less than half live and Baby: 0.74 Expert opinion Baby: Assumes same utility as that at birth
Higher order multiples – less than half live and Baby: 0.85 Expert opinion Baby: Assumes many of the physical issues resolve within the first year and utility
unhealthy – physical value increases by 0.15
Parent: 0.875
unhealthy – motor
unhealthy – cognitive, motor, and physical
416

Higher order multiples – more than half live and Baby: 0.74 Expert opinion Baby: Assumes same utility as that at birth
Higher order multiples – more than half live and Baby: 0.85 Expert opinion Baby: Assumes many of the physical issues resolve within the first year and utility
unhealthy – all physical value increases by 0.15
Parent: 0.775
unhealthy – all cognitive, physical, and motor
Higher order multiples – all live and unhealthy – Baby: 0.74 Expert opinion Baby: Assumes same utility as that at birth
all cognitive
Higher order multiples – all live and unhealthy – Baby: 0.85 Expert opinion Baby: Assumes many of the physical issues resolve within the first year and utility
417

all physical value increases by 0.15
Parent: 0.745
all motor
all cognitive, motor, and physical
Higher order multiples ‐ all live, some healthy Baby: 0,74 Expert opinion Baby: Assumes same utility as that at birth
Higher order multiples ‐ all live, some healthy Baby: 0.75 Expert opinion Baby: Assumes same utility as that at birth
Higher order multiples – all live, some healthy Baby: 0.85 Expert opinion Baby: Assumes many of the physical issues resolve within the first year and utility
and some unhealthy – physical value increases by 0.15
418

Parent: 0.927
Higher order multiples – all live, some healthy Baby: 0.55 Expert opinion Baby: Assumes same utility as that at birth
and some unhealthy – cognitive, motor, and
physical Parent: 0.567 Parent: Assumes same utility as that at birth because any gains associated with
conditions Parent: 0.787 Parent: Assumes same utility as that at birth because any gains associated with
Outcomes at 5 years after birth
Singleton – live and healthy Child: 1.0 Expert opinion Child: Assumes same utility as that for healthy newborn

Singleton – live and unhealthy – cognitive Child: 0.74 Expert opinion Child: Assumes same utility as that at birth

Singleton – live and unhealthy – physical Child: 0.85 Expert opinion Child: Assumes many of the physical issues resolve within the first year and utility
Parent: 0.895
Singleton – live and unhealthy – motor Child: 0.75 Expert opinion Child: Assumes same utility as that at birth

419

Singleton – live and unhealthy – Child: 0.49 Expert opinion Child: Based on average of published values for child 5‐16 years of age with
psychiatric/behavioral behavioral issues (0.463), hyperactivity (0.417) or a learning disability(0.583)
Parent: 0.775
Parent: Assumes same utility as that assigned to a parent of a child with cognitive or
motor delay
Singleton ‐ live and unhealthy – cognitive and Child: 0.55 Expert opinion Child: Assumes same utility as that at birth
motor
Singleton – live and unhealthy – cognitive and Child: 0.65 Expert opinion Child: Assumes same utility as that at birth
physical
Singleton – live and unhealthy – motor and Child: 0.68 Expert opinion Child: Assumes same utility as that at birth
physical
Singleton – live and unhealthy – Child: 0.49 Expert opinion Child: Assumes same utility value as that for child with only psychiatric or behavioral
psychiatric/behavioral and cognitive issues
Parent: 0.745
Parent: Assumes same utility as that assigned to a parent of a child with cognitive
and motor delay
psychiatric/behavioral and physical issues
Parent: 0.745
and motor delay
psychiatric/behavioral and motor issues
Parent: 0.745
and motor delay
psychiatric/behavioral, cognitive and motor issues
Parent: 0.725
Parent: Assumes same utility as that assigned to a parent of a child with cognitive,
420

motor, and lasting persistent physical disability
Twins – one live and healthy Child: 1.0 Expert opinion Child: Assumes same utility as that for healthy newborn

Twins – one live and unhealthy – cognitive Child: 0.74 Expert opinion Child: Assumes same utility as that at birth

Twins – one live and unhealthy – physical Child: 0.85 Expert opinion Child: Assumes many of the physical issues resolve within the first year and utility
Parent: 0.885
Twins – one live and unhealthy – Child: 0.49 Expert opinion Child: Based on average of published values for child 5‐16 years of age with
562
psychiatric/behavioral behavioral issues (0.463), hyperactivity (0.417) or a learning disability(0.583)
Parent: 0.765
Parent: Assumes same utility as that assigned to a parent of a single surviving twin
with cognitive or motor delay
Twins – one live and unhealthy – physical and Child: 0.65 Expert opinion Child: Assumes same utility as that at birth
cognitive
Twins – one live and unhealthy – motor and Child: 0.55 Expert opinion Child: Assumes same utility as that at birth
cognitive
Twins – one live and unhealthy – physical and Child: 0.68 Expert opinion Child: Assumes same utility as that at birth
motor
Twins – one live and unhealthy – Child: 0.49 Expert opinion Child: Assumes same utility value as that for child with only psychiatric or behavioral
Parent: 0.725
with cognitive and motor delay
Parent: 0.725
421

Parent: 0.725
with cognitive and motor delay
Twins – one live and unhealthy –cognitive, Child: 0.49 Expert opinion Child: Assumes same utility value as that for child with only psychiatric or behavioral
motor, physical, and psychiatric/behavioral issues
Parent: 0.715
with physical, cognitive and motor delay
Twins – both live and healthy Child: 1.0 Expert opinion Child: Assumes same utility as that for healthy newborn

Twins – both live and unhealthy – both Child: 0.74 Expert opinion Child: Assumes same utility as that at birth
cognitive
Twins – both live and unhealthy – both physical Child: 0.85 Expert opinion Child: Assumes many of the physical issues resolve within the first year and utility
Parent: 0.795
Twins – both live and unhealthy – both motor Child: 0.75 Expert opinion Child: Assumes same utility as that at birth

Twins – both live and unhealthy – both Child: 0.49 Expert opinion Child: Based on average of published values for child 5‐16 years of age with
psychiatric/behavioral behavioral issues (0.463), hyperactivity (0.417) or a learning disability(0.583)562
Parent: 0.675
Parent: Assumes same utility as that for parent of twins with cognitive or motor
delay
cognitive and motor
422

Twins – both live and unhealthy – both physical Child: 0.68 Expert opinion Child: Assumes same utility as that at birth
and motor
Twins – both live and unhealthy – both Child: 0.49 Expert opinion Child: Assumes same utility value as that for child with only psychiatric or behavioral
Parent: 0.615
Parent: Assumes same utility as that for parent of twins with cognitive and motor
delay
Parent: 0.615
delay
Parent: 0.615
delay
cognitive, motor, physical, and issues
psychiatric/behavioral Parent: 0.585
Parent: Assumes same utility as that for parent of twins with cognitive, motor, and
physical disability
Twins – both live and unhealthy – each with Child: 0.73 Expert opinion Child: Assumes same utility as that at birth
Higher order multiples – all live and healthy Child: 1.0 Expert opinion Child: Assumes same utility as that for healthy newborn

Higher order multiples – less than half live and Child: 0.74 Expert opinion Child: Assumes same utility as that at birth
Higher order multiples – less than half live and Child: 0.85 Expert opinion Child: Assumes many of the physical issues resolve within the first year and utility
unhealthy – physical value increases by 0.15
423

Parent: 0.875
unhealthy – motor
Higher order multiples – less than half live and Child: 0.49 Expert opinion Child: Based on average of published values for child 5‐16 years of age with
unhealthy – psychiatric/behavioral behavioral issues (0.463), hyperactivity (0.417) or a learning disability(0.583)562
Parent: 0.755
Parent: Assumes same utility as that for motor or cognitive delay
Higher order multiples – less than half live and Child: 0.49 Expert opinion Child: Assumes same utility as that for psychiatric/behavioral issues only
unhealthy – psychiatric/behavioral and
cognitive Parent: 0.725 Parent: Assumes same utility as that for motor or cognitive delay
unhealthy – psychiatric/behavioral and physical
Parent: 0.725 Parent: Assumes same utility as that for cognitive and physical disability
unhealthy – psychiatric/behavioral and motor
Parent: 0.725 Parent: Assumes same utility as that for motor and physical disability
unhealthy – cognitive, motor, physical, and
psychiatric/behavioral Parent: 0.715 Parent: Assumes same utility as that for cognitive, motor and physical disability
Higher order multiples – more than half live and Child: 0.74 Expert opinion Child: Assumes same utility as that at birth
424

Higher order multiples – more than half live and Child: 0.85 Expert opinion Child: Assumes many of the physical issues resolve within the first year and utility
unhealthy – all physical value increases by 0.15
Parent: 0.775
Higher order multiples – more than half live and Child: 0.49 Expert opinion Child: Based on average of published values for child 5‐16 years of age with
unhealthy – all psychiatric/behavioral behavioral issues (0.463), hyperactivity (0.417) or a learning disability(0.583)562
Parent: 0.655
Parent: Assumes same utility as that for parent with higher order multiples in which
more than half have cognitive delay
Higher order multiples – more than half live and Child: 0.49 Expert opinion Child: Assumes same utility as that for psychiatric/behavioral issues only
unhealthy – all psychiatric/behavioral and
cognitive Parent: 0.615 Parent: Assumes same utility as that for parent with higher order multiples in which
more than half have cognitive and motor delay
physical Parent: 0.615 Parent: Assumes same utility as that for parent with higher order multiples in which
more than half have cognitive and physical disability
motor Parent: 0.615 Parent: Assumes same utility as that for parent with higher order multiples in which
425

more than half have cognitive and motor delay
unhealthy – all cognitive, physical, motor, and
psychiatric/behavioral Parent: 0.567 Parent: Assumes same utility as that for parent with higher order multiples in which
more than half have physical, cognitive and motor delay
Higher order multiples – all live and unhealthy – Child: 0.74 Expert opinion Child: Assumes same utility as that at birth
all cognitive
Higher order multiples – all live and unhealthy – Child: 0.85 Expert opinion Child: Assumes many of the physical issues resolve within the first year and utility
all physical value increases by 0.15
Parent: 0.745
all motor
Higher order multiples – all live and unhealthy – Child: 0.49 Expert opinion Child: Based on average of published values for child 5‐16 years of age with
all psychiatric/behavioral behavioral issues (0.463), hyperactivity (0.417) or a learning disability(0.583)562
Parent: 0.625
Parent: Assumes same utility as that for parent of higher order multiples who all
have cognitive or motor delay

426

Higher order multiples – all live and unhealthy – Child: 0.49 Expert opinion Child: Assumes same utility as that for psychiatric/behavioral issues only
all psychiatric/behavioral and cognitive
Parent: 0.575 Parent: Assumes same utility as that for parent of higher order multiples who all
have cognitive and motor delay
all psychiatric/behavioral and physical
have physical and cognitive delay
all psychiatric/behavioral and motor
have cognitive and motor delay
all cognitive, motor, physical, and
psychiatric/behavioral Parent: 0.545 Parent: Assumes same utility as that for parent of higher order multiples who all
have physical, cognitive and motor delay
Higher order multiples ‐ all live, some healthy Child: 0,74 Expert opinion Child: Assumes same utility as that at birth
Higher order multiples ‐ all live, some healthy Child: 0.75 Expert opinion Child: Assumes same utility as that at birth
Higher order multiples – all live, some healthy Child: 0.85 Expert opinion Child: Assumes same utility as that at one year
Parent: 0.927 Parent: Assumes same utility as that at one year
Higher order multiples – all live, some healthy Child: 0.49 Expert opinion Child: Based on average of published values for child 5‐16 years of age with
562
and some unhealthy – psychiatric/behavioral behavioral issues (0.463), hyperactivity (0.417) or a learning disability(0.583)
Parent: 0.807
Parent: Assumes same utility as that for parent of higher order multiples in which
some have cognitive or motor delay
427

Higher order multiples – all live, some healthy Child: 0.55 Expert opinion Child: Assumes same utility as that at birth
Parent: 0.727 Parent: Assumes same utility as that at one year because any gains associated with
Parent: 0.727 Parent: Assumes same utility as that at one year because any gains associated with
Higher order multiples – all live, some healthy Child: 0.49 Expert opinion Child: Assumes same utility as that for psychiatric/behavioral issues only
and some unhealthy – motor and
psychiatric/behavioral Parent: 0.727 Parent: Assumes same utility as that for parent of higher order multiples in which
some have cognitive and motor delay
and some unhealthy – cognitive and
some have cognitive and motor delay
and some unhealthy – physical and
some have physical and cognitive delay
and some unhealthy – cognitive, motor,
psychiatric/behavioral and physical Parent: 0.567 Parent: Assumes same utility as that for parent of higher order multiples in which
some have physical, motor, and cognitive delay
Higher order multiples – all live, some healthy Child: 0.73 Expert opinion Child: Assumes same utility as that at birth
conditions Parent: 0.787 Parent: Assumes same utility as that at birth because any gains associated with
Outcomes at 18 years after birth
Singleton – live and healthy Child: 1.0 Expert opinion Child: Based on published values for a healthy 18 year old

Parent: 0.93 Parent: Assumes same utility as that for mother of a healthy child
Singleton – live and unhealthy – cognitive Child: 0.74 Expert opinion Child: Assumes same utility as that after 5 years

428

Parent: 0.775 Parent: Assumes same utility as that after 5 years
Singleton – live and unhealthy – physical Child: 0.85 Expert opinion Child: Assumes same utility as that after 5 years

Singleton – live and unhealthy – motor Child: 0.75 Expert opinion Child: Assumes same utility as that after 5 years

Singleton – live and unhealthy – Child: 0.49 Expert opinion Child:Assumes same utility as that after 5 years
psychiatric/behavioral
Singleton ‐ live and unhealthy – cognitive and Child: 0.55 Expert opinion Child: Assumes same utility as that after 5 years
motor
Singleton – live and unhealthy – cognitive and Child: 0.65 Expert opinion Child: Assumes same utility as that after 5 years
physical
Singleton – live and unhealthy – motor and Child: 0.68 Expert opinion Child: Assumes same utility as that after 5 years
physical
Singleton – live and unhealthy – Child: 0.49 Expert opinion Child: Assumes same utility as that after 5 years
psychiatric/behavioral and cognitive
Singleton – live and unhealthy – Child: 0.49 Expert opinion Child: Assumes same utility as that after 5 years
psychiatric/behavioral and physical
psychiatric/behavioral and motor
psychiatric/behavioral, cognitive, and motor
Twins – one live and healthy Child: 1.0 Expert opinion Child: Assumes same utility as that after 5 years

Twins – one live and unhealthy – cognitive Child: 0.74 Expert opinion Child:Assumes same utility as that after 5 years

Twins – one live and unhealthy – physical Child: 0.85 Expert opinion Child: Assumes same utility as that after 5 years
429


Twins – one live and unhealthy – Child: 0.49 Expert opinion Child: Assumes same utility as that after 5 years
Twins – one live and unhealthy – physical and Child: 0.65 Expert opinion Child: Assumes same utility as that after 5 years
cognitive
Twins – one live and unhealthy – motor and Child: 0.55 Expert opinion Child:Assumes same utility as that after 5 years
cognitive
Twins – one live and unhealthy – physical and Child: 0.68 Expert opinion Child: Assumes same utility as that after 5 years
motor
Twins – one live and unhealthy – Child: 0.49 Expert opinion Child:Assumes same utility as that after 5 years
Twins – one live and unhealthy – Child: 0.49 Expert opinion Child: Assumes same utility as that after 5 years
Twins – one live and unhealthy – Child: 0.49 Expert opinion Child:Assumes same utility as that after 5 years
Twins – one live and unhealthy –cognitive, Child: 0.49 Expert opinion Child: Assumes same utility as that after 5 years
motor, physical, and psychiatric/behavioral
Twins – both live and healthy Child: 1.0 Expert opinion Child: Assumes same utility as that after 5 years

Twins – both live and unhealthy – both Child: 0.74 Expert opinion Child: Assumes same utility as that after 5 years
cognitive
Twins – both live and unhealthy – both physical Child: 0.85 Expert opinion Child:Assumes same utility as that after 5 years

Twins – both live and unhealthy – both motor Child: 0.75 Expert opinion Child: Assumes same utility as that after 5 years

430

Twins – both live and unhealthy – both Child: 0.49 Expert opinion Child:Assumes same utility as that after 5 years
cognitive and motor
Twins – both live and unhealthy – both physical Child: 0.68 Expert opinion Child:Assumes same utility as that after 5 years
and motor
cognitive, motor, physical, and
psychiatric/behavioral Parent: 0.585 Parent: Assumes same utility as that after 5 years
Twins – both live and unhealthy – each with Child: 0.73 Expert opinion Child: Assumes same utility as that after 5 years
Higher order multiples – all live and healthy Child: 1.0 Expert opinion Child:Assumes same utility as that after 5 years

Higher order multiples – less than half live and Child: 0.74 Expert opinion Child: Assumes same utility as that after 5 years
Higher order multiples – less than half live and Child: 0.85 Expert opinion Child:Assumes same utility as that after 5 years
unhealthy – physical
unhealthy – motor
431

unhealthy – psychiatric/behavioral
unhealthy – psychiatric/behavioral and
cognitive Parent: 0.725 Parent: Assumes same utility as that after 5 years
unhealthy – psychiatric/behavioral and physical
unhealthy – psychiatric/behavioral and motor
unhealthy – cognitive, motor, physical, and
Higher order multiples – more than half live and Child: 0.74 Expert opinion Child: Assumes same utility as that after 5 years
unhealthy – all physical
unhealthy – all psychiatric/behavioral
Higher order multiples – more than half live and Child: 0.55 Expert opinion Child:Assumes same utility as that after 5 years
432

Higher order multiples – more than half live and Child: 0.68 Expert opinion Child:Assumes same utility as that after 5 years
cognitive Parent: 0.615 Parent: Assumes same utility as that after 5 years
physical Parent: 0.615 Parent: Assumes same utility as that after 5 years
motor Parent: 0.615 Parent: Assumes same utility as that after 5 years
unhealthy – all cognitive, physical, motor, and
Higher order multiples – all live and unhealthy – Child: 0.74 Expert opinion Child:Assumes same utility as that after 5 years
all cognitive
Higher order multiples – all live and unhealthy – Child: 0.85 Expert opinion Child: Assumes same utility as that after 5 years
all physical
all motor
all psychiatric/behavioral
433

all psychiatric/behavioral and cognitive
all psychiatric/behavioral and physical
all psychiatric/behavioral and motor
all cognitive, motor, physical, and
Higher order multiples ‐ all live, some healthy Child: 0,74 Expert opinion Child: Assumes same utility as that after 5 years
Higher order multiples ‐ all live, some healthy Child: 0.75 Expert opinion Child: Assumes same utility as that after 5 years
Higher order multiples – all live, some healthy Child: 0.85 Expert opinion Child: Assumes same utility as that after 5 years
Higher order multiples – all live, some healthy Child: 0.49 Expert opinion Child:Assumes same utility as that after 5 years
and some unhealthy – psychiatric/behavioral
434

and some unhealthy – motor and
and some unhealthy – cognitive and
and some unhealthy – physical and
and some unhealthy – cognitive, motor,
psychiatric/behavioral and physical Parent: 0.567 Parent: Assumes same utility as that after 5 years
conditions Parent: 0.787 Parent: Assumes same utility as that after 5 years
435

Table 59. Estimation of average cost of ARTs
Item Unit Cost ($CDN) Quantity Total Cost ($CDN) Information Sources and Assumptions

Fertility medications
Ovarian stimulation: • Administration assumptions:
st
Clomiphene Citrate (CC) $30.36 for 1 cycle Up to 3 cycles Average: $106.26 ‐ 50mg/day for 5 days for each cycle
nd st nd
$30.36‐$60.72 for 2 cycle ($30.36 ‐ $182.16) ‐ if resistant and/or obese, start with 50mg/day for 5 days for 1 cycle; if no ovulation  2
rd rd
$30.36‐$91.08 for 3 cycle cycle at 100mg/day for 5 days; if no ovulation  3 cycle at 150mg/day for 5 days
563
• Price list from Edmonton pharmacy ($6.07 per 50mg tablet Clomid®)
• Expert opinion and product monographs for dosage/administration information
Gonadotropins (Gn) FSH + hCG • Gonadotropins + hCG
$501.90‐$3,362.03 per Up to 3 cycles Average: $5,294.00 • Administration assumptions:
cycle ($501.90 ‐ $10,086.09) ‐ Gonadotropins – FSH (e.g., Puregon®): 7‐21 days for each cycle (most patients 7‐8 days; very
few patients >16 days); start with 50IU/day for the first 5 days; if no response, increase dose
FSH+LH + hCG (Non‐PCOS by 25‐50IU every 3‐5 days thereafter, up to a max of 200IU (very few patients >150IU)
patients) ‐ Gonadotropins for non‐PCOS (WHO group I) patients –FSH + LH (e.g., Luveris® + Puregon®):
$1,042.44‐$5,065.87 per Average: $8,160.35 7‐21 days for each cycle (most patients 7‐8 days; very few patients >16 days), 75IU
cycle $1,123.08 ‐ $15,197.61 Luveris®/day + 50‐200IU Puregon®/day (same as above)
‐ hCG (Ovidrel® or generic chorionic gonadotropin): 5,000‐10,000IU (one‐time injection after
gonadotropins)
563
• Price list from Edmonton pharmacy ($60.18 per 50IU Puregon®; $77.22 per 75IU Luveris®;
$80.64‐$82.22 per 10,000IU hCG)
• Expert opinion and product monographs for dosage/administration information
st
Aromatase Inhibitors (AI) $32.55 for 1 cycle Up to 3 cycles Average: $97.65 • Administration assumptions:
nd
$32.55‐$65.10 for 2 cycle ($32.55 ‐ $162.75) ‐ 2.5mg/day for 5 days for each cycle
rd st nd
$32.55‐$65.10 for 3 cycle ‐ if resistant and/or obese, start with 2.5mg/day for 5 days for 1 cycle; if no ovulation  2
rd
cycle at 5mg/day for 5 days; if no ovulation  3 cycle at 5mg/day for 5 days
563
• Price list from Edmonton pharmacy ($6.51 per 2.5mg tablet Femara®)
Pulsatile GnRH agonist $926.44 per month Up to 6 months Average: $3,242.54 • Administration assumptions:
($926.44 ‐ $5,558.64) ‐GnRHa:15mg/month(slow release)
‐ hCG (Ovidrel® or generic chorionic gonadotropin): 5,000‐10,000IU (one‐time injection after
GnRHa)
563
• Price list from Edmonton pharmacy ($424.61 per 7.5mg slow‐release injection Lupron®;
$80.64‐$82.22 per 10,000IU hCG)
Ovarian stimulation + IUI
Ovarian stimulation CC‐IUI (+hCG) • See above (costs for CC + hCG, FSH±LH + hCG)
st
$111.00‐$112.58 for 1 1 cycle $111.00‐$173.30
cycle
nd
$111.00‐$142.94 for 2
cycle
rd
$111.00‐$173.30 for 3
cycle
436


Gn‐IUI (+hCG)
$501.90‐$3,362.03 per $501.90‐$3,362.03
cycle
Endometrial preparation Calgary: 1 cycle Calgary: • Personal communication
$600.00 $600.00

Edmonton: Edmonton:
$400.00‐$600.00 $400.00‐$600.00
37
IUI with fresh, non‐donor Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
sperm $365.00 $365.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
communication (2012)
Edmonton: Edmonton:
$250.00 $250.00
Total cost per cycle Calgary: • Cost of ovarian stimulation + insemination
Average: $2,002.58
CC: $1,076.00‐$1,138.30
Gn: $1,466.90‐$4,327.03

Edmonton:
Average: $1,787.06
CC: $761.00‐$1,023.30
Gn: $1,151.90‐$4,212.03
Donor insemination – registration
37
Initial registration fee Calgary: 1 Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
$460.00 $300.00 • Basic charge includes assistance with donor selection, 1 hour visit with psychologist, infectious
disease screening, and administration costs
Edmonton: Edmonton:
‐ ‐
Donor insemination
Ovarian stimulation CC‐IUI (+hCG) 1 cycle • See above (costs for CC + hCG, FSH±LH + hCG)
st
$111.00‐$112.58 for 1 $111.00‐$173.30
cycle
nd
$111.00‐$142.94 for 2
cycle
rd
$111.00‐$173.30 for 3
cycle

Gn‐IUI (+hCG)
$501.90‐$3,362.03 per $501.90‐$3,362.03
cycle
Endometrial preparation Calgary: 1 cycle Calgary: • Personal communication
$600.00 $600.00

Edmonton: Edmonton:
437

$400.00‐$600.00 $400.00‐$600.00
37
Donor sperm Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
$550.00‐$700.00 $550.00‐$700.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: Edmonton: • Does not include Health Canada documentation fees (one‐time cost of $100.00), shipment, or
$725.00‐$825.00 $725.00‐$825.00 ongoing storage ($225.00 per year after the first year)
37
Donor insemination Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
Edmonton: Edmonton:
$250.00 $250.00
Total cost per cycle Calgary: • Cost of ovarian stimulation + donor sperm + donor insemination (does not include initial
Average: $2,702.06 registration cost)
CC: $1,651.00‐$1,963.30
Gn: $2,041.90‐$5,152.03

Edmonton:
Average: $2,562.13
CC: $1,486.00‐$1,848.30
Gn: $1,876.90‐$5,037.03
IVF/ICSI – registration
37
Initial registration fee Calgary: 1 Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
$300.00 $300.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: Edmonton: • Basic charge includes provision of initial information, maintaining wait list, tracking menstrual
$200.00 $200.00 cycles, ordering, tracking, and interpreting tests required to do IVF/ICSI, and administration costs
IVF cycle with fresh, non‐donor eggs
37
Basic IVF cycle Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
$6,050.00 $6,050.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: Edmonton: • Includes pretreatment evaluation, consultation, organization of treatment, provision of
$5,400.00 $5,400.00 information, monitoring of ovulation, surgical and anesthetic fees, laboratory fees, and overhead
charges
37
Drug costs Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
$3,500.00‐$7,000.00 $3,500.00‐$7,000.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: Edmonton:
$2,500.00‐$5,500.00 $2,500.00‐$5,500.00
Total Cost per cycle 1 cycle Calgary: • Cost of basic cycle + drug costs (does not include initial registration cost)
$9,550.00‐$13,050.00

Edmonton:
$7,900.00‐10,900.00
IVF cycle with donor eggs (known donor)
37
Basic donor IVF cycle Calgary: 1 cycle • Calgary Regional Fertility Program webpage and personal communication (2013)
438

$8,100.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton:
$6,400.00
37
Edmonton: Edmonton:
$2,500.00‐$5,500.00 $2,500.00‐$5,500.00
Total Cost per cycle 1 cycle Calgary: • Cost of basic donor cycle + drug costs (does not include initial registration cost)
$11,600.00‐$15,100.00

Edmonton:
$8,900.00‐$11,900
IVF cycle with donor sperm
37
Basic IVF cycle Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
$6,050.00 $6,050.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: Edmonton: • Includes pretreatment evaluation, consultation, organization of treatment, provision of
$5,400.00 $5,400.00 information, monitoring of ovulation, surgical and anesthetic fees, laboratory fees, and overhead
charges
37
Edmonton: Edmonton:
$2,500.00‐$5,500.00 $2,500.00‐$5,500.00
37
Donor sperm Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
Edmonton: Edmonton: • Does not include Health Canada documentation fees (one‐time cost of $100.00), shipment, or
$725.00‐$825.00 $725.00‐$825.00 ongoing storage ($225.00 per year after the first year)
Total Cost per cycle 1 cycle Calgary: • Cost of basic cycle + drug costs + donor sperm (does not include initial registration cost)
$10,100.00‐$13,750.00

Edmonton:
$8,625.00‐$11,725.00
IVF cycle with frozen embryos (after failure to transfer any embryos in first fresh cycle, e.g., due to OHSS)
37
Drugs for frozen‐thaw Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
cycle $600.00 $600.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: Edmonton: • Includes drugs to prepare the uterus for implantation
$400.00‐600.00 $400.00‐$600.00
Total Cost per cycle 1 cycle Calgary:
$600.00

439

Edmonton:
$400.00‐600.00
IVF cycle with frozen embryos (after failure to achieve pregnancy/ongoing pregnancy with fresh embryo transfer)
37
Thawing and replacing Calgary: 1 cycle • Calgary Regional Fertility Program webpage and personal communication (2013)
frozen embryo(s) $1,150.00‐$1,350.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: • Includes set up of a frozen embryo cycle and thawing and replacing the embryos (cycle
$750.00 monitoring, surgical, and laboratory fees)
37
cycle $600.00 $600.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
$400.00‐$600.00 $400.00‐$600.00
$1,750.00‐$1,950.00

Edmonton:
$1,150.00‐$1,350.00
ICSI cycle with frozen eggs (after fertility preservation with egg freezing) ‐ e.g., chemotherapy patients
37
Egg freezing cycle Calgary: 1 cycle • Calgary Regional Fertility Program webpage and personal communication (2013)
$6,700.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: • Includes egg freezing cycle for preservation of fertility, embryo cryopreservation, and first year
$2,700.00 of storage
37
Drugs for egg freezing Calgary: 1 cycle • Calgary Regional Fertility Program webpage and personal communication (2013)
cycle $3,500.00‐$7,000.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton:
$2,500.00‐$5,500.00
37
ICSI cycle* (upon return Calgary: 1 cycle • Calgary Regional Fertility Program webpage and personal communication (2013)
for transfer) $2,700.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: • Includes set up of a frozen embryo ICSI cycle (*must use ICSI) and thawing and replacing the
$1,500.00 embryos (cycle monitoring, surgical, and laboratory fees)
37
ICSI cycle (upon return $600.00 $600.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
for transfer) communication (2012)
$400.00‐$600.00 $400.00‐$600.00
$13,500.00‐$17,000.00

Edmonton:
$7,100.00‐$10,300.00
Additional costs
440

37
Embryo cryopreservation Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
Additional $870.00 Additional $870.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: Edmonton: • Includes embryo cryopreservation and first year of storage
Additional $600.00 Additional $600.00
37
Semen cryopreservation Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
Edmonton: Edmonton: • Includes semen cryopreservation and first year of storage
Additional $100.00‐ Additional $100.00‐
$150.00 $150.00
37
Ongoing storage of Calgary: 1 year Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
embryos or sperm Additional $225.00 Additional $225.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: Edmonton: • Ongoing storage beyond first year (per year)
37
ICSI with ejaculated Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
sperm Additional $1,725.00 Additional $1,700.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: Edmonton: • Basic ICSI cycle with ejaculated sperm; includes laboratory preparation
Additional $1,500.00 Additional $1,500.00
37
ICSI with surgically Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
retrieved sperm Additional $2,025.00 Additional $2,025.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: Edmonton: • ICSI cycle with sperm retrieved through PESA, MESA, or TESE
Additional $1,800.00 Additional $1,800.00
37
Surgical sperm retrieval Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
Additional $1,500.00‐ Additional $1,500.00‐ • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
$1,700.00 $1,700.00 communication (2012)
• Surgical sperm retrieval (through PESA or TESE) performed in Calgary fertility clinic
Edmonton: Edmonton:
Not done in Edmonton Not done in Edmonton
37
Electro‐ejaculation Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
Additional $1,600.00‐ Additional $1,600.00‐
$3,300.00 $3,300.00

Edmonton: Edmonton:
N/A N/A
37
Assisted hatching Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
Edmonton: Edmonton:
37
Preimplantation genetic Calgary: 1 cycle Calgary: • Calgary Regional Fertility Program webpage and personal communication (2013)
diagnosis Additional $6,500.00 Additional $6,500.00 • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
441

Edmonton: Edmonton: • Includes embryo biopsy (performed in Edmonton or Calgary) and laboratory services
Additional $4,000.00‐ Additional $4,000.00‐ (performed at reference lab outside of Alberta)
5,000.00 5,000.00
IVF/ICSI cycle cancellation
37
Cancellation prior to Calgary: 1 Calgary: • Calgary Regional Fertility Program webpage
initiation of treatment $700.00 + registration $700.00 + registration • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
Edmonton: Edmonton:
$500.00 + registration $500.00 + registration
37
Cancellation prior to egg Calgary: 1 Calgary: • Calgary Regional Fertility Program webpage
retrieval $1,100.00 + registration + $1,100.00 + registration + • Edmonton Regional Fertility and Women’s Endocrinology Clinic price list and personal
drug costs drug costs communication (2012)

Edmonton: Edmonton:
$1,000.00 + registration + $1,000.00 + registration +
drug costs drug costs

442

Table 60. Unit costs of treatment, pregnancy, delivery, neonatal care, and postnatal care
Item Cost ($CDN) Information sources and assumptions

Treatment
IVF/ICSI – one‐time registration fee $250 • All IVF/ICSI costs reflect average of costs from Calgary Regional Fertility Program
($200‐$300) and Edmonton Regional Fertility and Women’s Endocrinology Clinic
• Includes provision of initial information, maintaining wait list, tracking menstrual
cycles, ordering, tracking, and interpreting tests required to do IVF/ICSI, and
administration costs
IVF/ICSI – fresh cycle $12,243 • Includes pretreatment evaluation, consultation, organization of treatment,
($11,182‐$13,305) provision of information, monitoring of ovulation, surgical and anesthetic fees,
laboratory fees, overhead charges, and drug costs
• Average reflects 5% of couples using PGS, 16.5% of couples using ICSI with
ejaculated sperm, and 38.5% of couples using sperm retrieval + ICSI with retrieved
sperm
IVF/ICSI – cryopreservation of $735 • Includes embryo cryopreservation and first year of storage
embryos ($600‐$870)
IVF/ICSI – frozen cycle after failure to $550 • Includes drug costs
transfer any embryos ($500‐$600)
IVF/ICSI – frozen cycle after fresh $3,168 • Includes set up of a frozen embryo cycle, thawing and replacing the embryos (cycle
embryo transfer ($2,807‐$3,530) monitoring, surgical, and laboratory fees), and drug costs
• Average reflects 5% of couples using PGS, 16.5% of couples using ICSI with
ejaculated sperm, and 38.5% of couples using sperm retrieval + ICSI with retrieved
sperm
Pregnancy confirmation $809 • Alberta Health billing data (physician claims, ambulatory care, and inpatient
databases) for mothers of infants born between April 1, 2005 to March 31, 2006
(costs were inflated by 5% per year to obtain 2012 dollars)
• Includes pregnancy testfollowed by ultrasound confirmation
Miscarriage $3965 • Includes pregnancy costs after confirmation up to loss
Pregnancy and delivery – healthcare costs
Pregnancy – uncomplicated $3,638 • All pregnancy and delivery costs obtained from Alberta Health billing data
singleton (physician claims, ambulatory care, and inpatient databases) for mothers of infants
born between April 1, 2005 to March 31, 2006 (costs were inflated by 5% per year to
obtain 2012 dollars)
• Includes all pregnancy costs after confirmation up to labour
Pregnancy – complicated singleton $6,509 • Includes all pregnancy costs after confirmation up to labour
Pregnancy – twin $10,736 • Includes all pregnancy costs after confirmation up to labour; assumes all twin
pregnancies are complicated/high‐risk (expert opinion); this assumption was
consistent with numbers found in Alberta Health Billing data
Pregnancy – HOM $17,968 • Includes all pregnancy costs after confirmation up to labour; assumes all HOM
pregnancies are complicated/high‐risk (expert opinion); this assumption was
consistent with numbers found in Alberta Health Billing data
443

Delivery, vaginal – singleton $4,043 • Includes all delivery costs and maternal care up to 1 month after delivery

Delivery, caesarean – singleton $5,633 • Includes all delivery costs and maternal care up to 1 month after delivery
Delivery, vaginal – twin $6,122 • Includes all delivery costs and maternal care up to 1 month after delivery
Delivery, caesarean – twin $5,484 • Includes all delivery costs and maternal care up to 1 month after delivery
Delivery, vaginal – HOM $12,484 • Includes all delivery costs and maternal care up to 1 month after delivery
Delivery, caesarean – HOM $19,223 • Includes all delivery costs and maternal care up to 1 month after delivery
Neonatal and postnatal (up to 4 years of age) – healthcare costs
Healthy infant from singleton $8,596 • All neonatal and postnatal healthcare costs up to 4 years of age were obtained
pregnancy from Alberta Health billing data (physician claims, ambulatory care, and inpatient
databases) for infants born between April 1, 2005 to March 31, 2006 (costs were
inflated by 5% per year to obtain 2012 dollars)
• Costs are per infant and include all healthcare costs from birth up to 4 years of age
Healthy infant from multiple $21,410 • Costs are per infant and include all healthcare costs from birth up to 4 years of age
pregnancy
Unhealthy infant from singleton $783,368 • Costs are per infant and include all healthcare costs from birth up to 4 years of age;
pregnancy fees for neonatologists were estimated using an annual salary and the average length
of NICU stay
• Infants were considered unhealthy if they were very low birth weight or extremely
low birth weight
Unhealthy infant from multiple $1,351,718 • Costs are per infant and include all healthcare costs from birth up to 4 years of age;
pregnancy fees for neonatologists were estimated using an annual salary and the average length
of NICU stay
• Infants were considered unhealthy if they were very low birth weight or extremely
low birth weight
Early childhood up to adulthood (5‐18 years of age) – healthcare costs
Healthy child from singleton $11,795 • Published Alberta‐specific data from the Canadian Institutes for Health Information
pregnancy National Health Expenditures Report 2011 (costs were inflated by 5% per year to
• Costs are per child and include all health care costs from 5 to 18 years of age
Healthy child from multiple $26,892 • Published Alberta‐specific data from the Canadian Institutes for Health Information
pregnancy National Health Expenditures Report 2011 (costs were inflated by 5% per year to
• Costs are per child and include all healthcare costs from 5 to 18 years of age
Unhealthy child from singleton $65,150 • Published data (Australia and US) for children with congenital heart disease, downs
pregnancy syndrome, and cerebral palsy (costs were converted to Canadian dollars and inflated
by 5% per year to obtain 2012 dollars)
Unhealthy child from multiple $116,629 • Published data (Australia and US) for children with congenital heart disease, downs
pregnancy syndrome, and cerebral palsy (costs were converted to Canadian dollars and inflated
by 5% per year to obtain 2012 dollars)
Early childhood up to adulthood (5‐18 years of age) – educational costs
Healthy child $80,281 • Published data from the Government of Alberta’s Education Funding in Alberta:
Kindergarten to Grade 12 2011‐2012 Report
• Costs are per child and include educational costs from kindergarten to grade 12
444

Unhealthy child $303,349 • Published data from the Government of Alberta’s Education Funding in Alberta:

Kindergarten to Grade 12 2011‐2012 Report
• Costs are per child and include educational costs from kindergarten to grade 12
Birth up to adulthood – caregiver costs
Healthy child $0
Unhealthy child $481,194 • Published study using 2011 US census data (costs were converted to Canadian
dollars and inflated by 5% per year to obtain 2012 dollars)
• Costs take into account direct monetary costs, decline in hours worked, reduced
labour force participation, and reduced future earnings

445

Table 61. Estimation of average cost of diagnosis and management of couples with infertility
Item Unit Cost ($CDN) Quantity Total Cost ($CDN) Information Sources and Assumptions

Infertility diagnosis
GP referral to specialist, $46.10 1 $46.10 • Alberta Healthbilling data (physician claims, ambulatory care, and inpatient databases) for men
or specialist referral to and women with a diagnosis of infertility or some form of fertility assessment from January 1,
other specialist 2005 to December 31, 2006
• Referral: $32.76 (SOMB 03.03A, 03.07A)
Initial infertility workup $2,178.44 1 $2,178.44 • Alberta Healthbilling data (physician claims, ambulatory care, and inpatient databases) for men
and women with a diagnosis of infertility or some form of fertility assessment from January 1,
2005 to December 31, 2006
• Female infertility workup includes:
‐ patient history and physical exam: $85.66 (SOMB 03.08A)
‐ blood tests (day 3 follicle‐stimulating hormone (FSH) and estradiol, estrogen, luteinizing
hormone (LH), estrogen, progesterone, prolactin, and thyroid‐stimulating hormone (TSH)):
$308.99 (SOMB E550A, E550B, E550E, E550Q, E550R, E550P, E750)
‐ pelvic ultrasound: $163.35 + $348.48 (SOMB X314, X315; CCHI 3RF10^^, 3RZ30^^, 5AB03^^)
‐ hysterosalpingography (HSG) or hysterosalpingocontrastsonography (HyCoSy): $76.44 +
$176.68 (SOMB 80.85A, 80.85B, X 80; CCHI 3RK10^^)
‐ follow‐up visit after workup: $34.46 (03.03A, 03.04A, 03.07A)
• Male infertility workup includes:
‐ patient history and physical exam: $98.44 (SOMB 03.08A)
‐ blood and urine tests (follicle‐stimulating hormone (FSH), luteinizing hormone (LH),
testosterone, prolactin, thyroid‐stimulating hormone (TSH), post‐ejaculatory urinalysis):
$218.19 (SOMB E550E, E550R, E550S, E550P, E750)
‐ semen analysis and test for anti‐sperm antibodies: $77.19 (SOMB E305, E305A, E305B, E313)
‐ follow‐up visit after workup: $34.46 (03.03A, 03.04A, 03.07A)
Extended workup for $1,045.07 1 $1,045.07 • Alberta Healthbilling data (physician claims, ambulatory care, and inpatient databases) for men
suspected tubal and women with a diagnosis of infertility or some form of fertility assessment from January 1,
obstruction: laparoscopy 2005 to December 31, 2006
• Laparoscopic diagnosis: $165.99 + $576.72 (SOMB 66.83, 81.09; CCHI 2OT70^^)
suspected endometriosis: and women with a diagnosis of infertility or some form of fertility assessment from January 1,
laparoscopy + biopsy 2005 to December 31, 2006
• Laparoscopic diagnosis: $165.99 + $576.72 (SOMB 66.83, 81.09; CCHI 2OT70^^)
• Laparoscopic diagnosis without treatment is only performed in 10% of patients; 90% of patients
are treated at the time of diagnosis (see cost for diagnosis + treatment below)
suspected and women with a diagnosis of infertility or some form of fertility assessment from January 1,
polyps/fibroids: 2005 to December 31, 2006
hysteroscopy • Hysteroscopy: $90.76+ $813.44 (SOMB 80.81; CCHI 2RM70^^)
• Hysteroscopic diagnosis of polyps or submucosal fibroids without treatment is only performed
446

in 10% of patients; 90% of patients are treated at the time of diagnosis (see cost for diagnosis +
treatment below)
Non‐ART (surgical) fertility treatments for female partner
Ovarian drilling $1,009.26 1 $1,009.26 • Alberta Healthbilling data (physician claims, ambulatory care, and inpatient databases) for men
• Laparoscopic diagnosis: $140.54 + $576.72 (SOMB 77.99A; CCHI 2OT70^^)
Tubal ligation reversal $4,000.00 1 $4,000.00 • Personal communication
(tubal reanastomosis)
Laparoscopic ablation of $1,866.71 1 $1,866.71 • Alberta Healthbilling data (physician claims, ambulatory care, and inpatient databases) for men
endomteriosis and women with a diagnosis of infertility or some form of fertility assessment from January 1,
• Hysteroscopy: $332.60+ $984.03 (SOMB 81.29C, 80.19D, 80.19E; CCHI 1RM59^^)
Hysteroscopic $1,424.48 1 $1,424.48 • Alberta Healthbilling data (physician claims, ambulatory care, and inpatient databases) for men
polypectomy and women with a diagnosis of infertility or some form of fertility assessment from January 1,
• Hysteroscopy: $90.76+ $825.59 (SOMB 80.81, 81.09; CCHI 2RM70^^)
Myomectomy $2,149.36 1 $2,149.36 • Alberta Healthbilling data (physician claims, ambulatory care, and inpatient databases) for men
• Myomectomy: $274.18+ $1,253.33 (SOMB 80.81, 81.09; CCHI 1RM87^^)
Non‐ART (surgical) fertility treatments for male partner
Vasectomy reversal $3,500.00 1 $3,500.00 • Personal communication
(vasovasotomy or
vasoepididymostomy)
Transurethral resection $3,316.41 1 $3,316.41 • Alberta Health billing data (physician claims, ambulatory care, and inpatient databases) for men
of the ejaculatory duct and women with a diagnosis of infertility or some form of fertility assessment from January 1,
(TURED) 2005 to December 31, 2006
• Expert opinion (similar costs as varicocelectomy)
Varicocelectomy $3,316.41 1 $3,316.41 • Alberta Health billing data (physician claims, ambulatory care, and inpatient databases) for men
• Varicocelectomy: $231.02 + $265.06+ $1860.83 (SOMB 75.0; CCHI 1QP51^^)
Notes:
‐ costs were obtained from Alberta Health billing data and consist of the sum of the average physician fee costs, outpatient costs, and inpatient costs per patient (from the SOMB/physician claims database, the
ambulatory care database (ACCS), and the inpatient database (DAD))
‐ all costs are in 2012 Canadian dollars; costs obtained from 2005/2006 Alberta Health billing data were inflated by 5% per year for 7 years

447

Appendix H‐ Literature search

Searches conducted from November 2011 – October 2012
Part A. ARTs – Policies
Date limit: 5 years
Language limit: none
1. PubMed search (www.pubmed.gov, Nov 21 2011)
#115 Search #110 OR #113 Limits: published in the last 5 years 1341
#114 Search #110 OR #113 5169
#113 Search #111 AND #112 626
#112 Search #89 OR #90 OR #91 OR #92 OR #93 OR #94 OR #96 OR #97 OR #98 OR #99 OR #100 697698
OR #102 OR #103 OR #104 OR #105 OR #106 OR #107 OR #108 OR #109
#111 Search #82 OR #83 OR #84 OR #85 OR #86 OR #87 14996
#110 Search #70 OR #71 OR #73 OR #74 OR #75 OR #76 OR #80 OR #81 4885
#109 Search legal*[ti] 18966
#108 Search legislat*[ti] 9588
#107 Search insurer*[ti] 1107
#106 Search insurance[ti] 16509
#105 Search private[ti] 11216
#104 Search public[ti] 63922
#103 Search government[ti] 6493
#102 Search "cost sharing"[ti] 270
#100 Search copayment[ti] 69
#99 Search co‐payment[ti] 27
#98 Search regulat*[ti] 295704
#97 Search payment*[ti] 5728
#96 Search reimburs*[ti] 3998
#94 Search funding[ti] 4386
#93 Search coverage[ti] 8802
#92 Search policy[ti] OR policies[ti] 31374
#91 Search costs and cost analysis[mh] 158840
#90 Search insurance coverage[mh] 8609
#89 Search insurance[mh] 139029
#87 Search "assisted reproduction"[ti] OR "assisted reproductive"[ti] 2546
#86 Search intracytoplasmic[ti] 2384
#85 Search "embryo transfer"[ti] 2542
#84 Search "in vitro fertilisation"[ti] 461
#83 Search "in vitro fertilization"[ti] 6275
448

#82 Search IVF[ti] 2788

#75 Search infertility AND (economics[sh] OR legislation and jurisprudence[sh] OR standards[sh] 2059
OR utilization[sh])
#81 Search infertility, male AND (economics[sh] OR legislation and jurisprudence[sh] OR 1009
standards[sh] OR utilization[sh])
#80 Search infertility, female AND (economics[sh] OR legislation and jurisprudence[sh] OR 1652
#76 Search sperm injections, intracytoplasmic[mh] AND (economics[sh] OR legislation and 162
jurisprudence[sh] OR standards[sh] OR utilization[sh])
#74 Search single embryo transfer[mh] AND (economics[sh] OR legislation and 14
#73 Search embryo transfer[mh] AND (economics[sh] OR legislation and jurisprudence[sh] OR 731
#71 Search fertilization in vitro[mh] AND(economics[sh] OR legislation and jurisprudence[sh] OR 1719
#70 Search reproductive techniques, assisted[mh] AND (economics[sh] OR legislation and

2. The Cochrane Library (John Wiley & Sons; issue 11 of 12, 2011)
Cochrane Reviews [1] | Other Reviews [1] | Clinical Trials [13] | Methods Studies [0] | Technology Assessments [0]
| Economic Evaluations [0] | Cochrane Groups [0]
#1 MeSH descriptor Reproductive Techniques, Assisted explode all trees 2482
#2 MeSH descriptor Fertilization in Vitro explode all trees 1644
#3 MeSH descriptor Embryo Transfer explode all trees 790
#4 MeSH descriptor Single Embryo Transfer explode all trees 7
#5 MeSH descriptor Sperm Injections, Intracytoplasmic explode all trees 388
#6 MeSH descriptor Infertility, Female, this term only 905

#7 MeSH descriptor Infertility, Male, this term only 381
"assisted reproduction" OR "assisted reproductive":ti or (IVF):ti or "in vitro fertilization"
#8 2090
OR "in vitro fertilisation":ti
#9 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8) 4095
#10 (insur*):ti or (policy):ti or (policies):ti or (coverage):ti or (funding):ti 1140

#11 (reimburs*):ti or (payment*):ti or (regulat*):ti or (co‐pay*):ti or (copay*):ti 1783
#12 "cost shar*":ti or (government):ti or (public):ti or (private):ab and (insurance):ti 1040
#13 (insurer):ti or (legislat*):ti or (legal*):ti 95
#14 (#10 OR #11 OR #12 OR #13) 3978
449

#15 (#9 AND #14), from 2006 to 2011 15

3. Centre for Reviews & Dissemination (CRD) – DARE, NHS EED, HTA databases
(http://www.crd.york.ac.uk/crdweb/; Nov 21 2011)
H
1 MeSH DESCRIPTOR Reproductive Techniques, Assisted EXPLODE ALL TREES 258
2 MeSH DESCRIPTOR Infertility, Female EXPLODE ALL TREES 76
3 MeSH DESCRIPTOR Infertility, Male EXPLODE ALL TREES 40
4 MeSH DESCRIPTOR Embryo Transfer EXPLODE ALL TREES 55
("assisted reproduction") OR ("assisted reproductive") OR (IVF):TI OR ("in vitro
5 238
fertilization"):TI OR ("in vitro fertilisation"):TI
6 #1 OR #2 OR #3 OR #4 OR #5 378
7 * FROM 2006 TO 2011 25116
8 #6 AND #7 204
(insurance) OR (policy) OR (policies) OR (coverage) OR (funding) FROM 2006 TO
9 1976
2011
10 (reimburs*) OR (payment*) OR (regulat*) OR ("co‐payment*") OR (copayment*) 1884
11 ("cost shar*") OR (government) OR (public) OR (private) OR (insurer) 3204
12 (legislat*) OR (legal*) 392
13 #9 OR #10 OR #11 OR #12 6321
14 #8 AND #13 22

4. EMBASE (Ovid, 1980 to 2011 Week 46)
1 exp infertility therapy/ 64395
2 exp fertilization in vitro/ 32951
exp female infertility/ or exp intracytoplasmic sperm injection/ or exp embryo
3 73655
transfer/ or exp male infertility/ or assisted reproductive technologies.mp.
4 1 or 2 or 3 106196
exp insurance/ or exp public health insurance/ or exp health insurance/ or exp
5 186069
private health insurance/ or exp national health insurance/
6 exp reimbursement/ 29245
7 exp health care policy/ 118894
450

8 exp government regulation/ or exp government/ 106198
9 exp policy/ 57768
10 exp public health service/ or exp public health insurance/ 48055
11 exp private health insurance/ 1603
12 exp law/ 70371
13 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 490231
14 4 and 13 3782
15 limit 14 to yr="2006 ‐Current" 1014
16 limit 15 to human 800

5. Web of Science (Thomson Reuters, searched 23 Nov 2011)
# 4 349 #3
Databases=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH Timespan=2006‐2011
Lemmatization=On
# 3 841 #2 AND #1
Databases=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH Timespan=All Years
Lemmatization=On
# 2 843,857 Title=(insurance OR coverage OR costs OR funding) OR Title=(policy OR policies OR
regulat*) OR Author=(payment* OR government* OR insurer* OR legal* OR legislat*)
Lemmatization=On
# 1 37,267 Topic=("assisted reproduction" OR "assisted reproductive") OR Topic=(IVF OR "in vitro
fertilization" OR "in vitro fertilisation") OR Topic=("embryo transfer*" OR "intracytoplasmic
sperm")
Lemmatization=On

6. Scopus (searched 23 Nov 2011)
4 (((TITLE‐ABS‐KEY("assisted reproduct*") OR TITLE‐ABS‐KEY(ivf) OR TITLE‐ABS‐KEY("in vitro
fertilization") OR TITLE‐ABS‐KEY("in vitro fertilisation") OR TITLE‐ABS‐KEY("embryo transfer")
OR TITLE‐ABS‐KEY("intracytoplasmic sperm"))) AND ((TITLE(insurance) OR TITLE(coverage) OR
396
TITLE(costs) OR TITLE(funding) OR TITLE(policy) OR TITLE(policies) OR TITLE(payment*) OR
TITLE(government*) OR TITLE(insurer*) OR TITLE(legal*) OR TITLE(legislat*) OR
TITLE(regulat*)))) AND (#6) *(#6=2006‐2011)
3 ((TITLE‐ABS‐KEY("assisted reproduct*") OR TITLE‐ABS‐KEY(ivf) OR TITLE‐ABS‐KEY("in vitro
fertilization") OR TITLE‐ABS‐KEY("in vitro fertilisation") OR TITLE‐ABS‐KEY("embryo transfer")
OR TITLE‐ABS‐KEY("intracytoplasmic sperm"))) AND ((TITLE(insurance) OR TITLE(coverage) OR
1,240
TITLE(costs) OR TITLE(funding) OR TITLE(policy) OR TITLE(policies) OR TITLE(payment*) OR
TITLE(government*) OR TITLE(insurer*) OR TITLE(legal*) OR TITLE(legislat*) OR
TITLE(regulat*)))
451

2 (TITLE(insurance) OR TITLE(coverage) OR TITLE(costs) OR TITLE(funding) OR TITLE(policy) OR
TITLE(policies) OR TITLE(payment*) OR TITLE(government*) OR TITLE(insurer*) OR 788,590
TITLE(legal*) OR TITLE(legislat*) OR TITLE(regulat*))
1 (TITLE‐ABS‐KEY("assisted reproduct*") OR TITLE‐ABS‐KEY(ivf) OR TITLE‐ABS‐KEY("in vitro
fertilization") OR TITLE‐ABS‐KEY("in vitro fertilisation") OR TITLE‐ABS‐KEY("embryo transfer") 45,197
OR TITLE‐ABS‐KEY("intracytoplasmic sperm"))

7. CINAHL (EBSCOHost; searched 24 Nov 2011)
S6 S4 and S5 131
S5 Limiters ‐ Published Date from: 20060101‐20111231; Exclude MEDLINE records 719588
S4 S1 or S2 or S3 1027
S3 (MH "Embryo Transfer/EC/EI/EV/LJ/ST/UT") 54
S2 (MH "Fertilization in Vitro/EC/EI/EV/LJ/ST/UT") 299
S1 (MH "Reproduction Techniques+/EC/EI/EV/LJ/ST/UT") 1027

8. Proquest Dissertation & Theses (searched 24 Nov 2011)
(assisted reproduct*) OR (IVF OR in vitro fertilization) OR (embryo transfer) AND 222
PDN(>11/24/2006)Dissertations & Theses: Full Text
Look for terms in: Citation and abstract
Publication type: All publication types

Additional policy search 24 Jun 2012 (for outcomes related to policies)
1. PubMed www.pubmed.gov
#9 Add Search #1 OR #2 OR #7 Filters: published in the last 5 years 1010
#10 Add Search #9 AND (in process[sb] OR publisher[sb] OR pubmednotmedlne[sb]) Filters: 115

published in the last 5 years
#8 Add Search #1 OR #2 OR #7 3004
#7 Add Search #5 AND #6 2314
#6 Add Search impact*[ti] OR outcome*[ti] OR effect*[ti] OR policy[ti] OR policies[ti] OR cost[ti] 1707761

OR costs[ti] OR budget[ti]
#5 Add Search "assisted reproduction"[ti] OR "assisted reproductive"[ti] OR "assistive 12119

reproduction"[ti] OR IVF[ti] OR "in vitro fertilisation"[ti] OR "in vitro fertilization"[ti]
#2 Add Search single embryo transfer/economics 9
#1 Add Search reproductive techniques, assisted/economics 792

452

Part B – ARTs – Systematic reviews
Limits: 5 years (i.e., 2007 to date)
English language

1. PubMed (www.pubmed.gov; searched 17 Jan 2012)
* used both the CADTH and MEDLINE filters for systematic reviews
* tried using human & animal filters but these eliminated some potentially useful references
#38 Search #33 OR #37 960
#37 Search #34 OR #35 Limits: English, Publication Date from 2007 to 2012 524
#36 Search #34 OR #35 548
#35 Search #32 AND (systematic[sb] OR meta‐analysis[pt] OR meta‐analysis as topic[mh] OR meta 548

analy*[tw] OR metanaly*[tw] OR metaanaly*[tw] OR met analy*[tw] OR integrative
research[tiab] OR integrative review*[tiab] OR integrative overview*[tiab] OR research
integration*[tiab] OR research overview*[tiab] OR collaborative review*[tiab] OR collaborative
overview*[tiab] OR systematic review*[tiab] OR technology assessment*[tiab] OR
"Technology Assessment, Biomedical"[mh] OR HTA[tiab] OR HTAs[tiab] OR "Cochrane
Database Syst Rev"[Journal:__jrid21711] OR "health technology assessment winchester,
england"[Journal] OR "Evid Rep Technol Assess (Full Rep)"[Journal] OR "Evid Rep Technol
Assess (Summ)"[Journal] OR "Int J Technol Assess Health Care"[Journal] OR evidence
based[tiab] OR best practice*[tiab] OR best evidence[tiab]) [CADTH systematic review filter]
#34 Search #32 AND systematic[sb] [MEDLINE systematic review filter] 456
#33 Search #32 AND (in process[sb] OR publisher[sb] OR pubmednotmedline[sb]) Limits: 459

Publication Date from 2007 to 2012
#32 Search #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #25 OR #26 OR 11969

#27 OR #28 OR #29 OR #30 Limits: Publication Date from 2007 to 2012
#31 Search #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #25 OR #26 OR 58931

#27 OR #28 OR #29 OR #30
#30 Search "embryo transfer*"[ti] 2560
#29 Search ICSI[ti] 1091
#27 Search "assisted reproductive"[ti] OR "assisted reproduction"[ti] OR "assistive 2570

reproductive"[ti] OR "assistive reproduction"[ti]
#22 Search infertility, male/th 5165
453

#21 Search infertility, female/th 9639
#20 Search infertility/th 17344
#19 Search sperm injections, intracytoplasmic[mh] 3798
#18 Search single embryo transfer[mh] 73
#17 Search embryo transfer[mh] 11506
#16 Search fertilization in vitro[mh] 25039
#15 Search reproductive techniques, assisted[mh] 46922

2. The Cochrane Library (issue 12 of 12, 2011)
* only Cochrane Database of Systematic Reviews, other reviews, technology assessments and economic
evaluations used
Cochrane Reviews [92] | Other Reviews [97]Technology Assessments [13] | Economic Evaluations [35]
#1 MeSH descriptor Reproductive Techniques, Assisted explode all trees 2484
#2 MeSH descriptor Fertilization in Vitro explode all trees 1644
#3 MeSH descriptor Embryo Transfer explode all trees 790
#4 MeSH descriptor Single Embryo Transfer explode all trees 7
#5 MeSH descriptor Sperm Injections, Intracytoplasmic explode all trees 387
#6 MeSH descriptor Infertility explode all trees 1668
#7 MeSH descriptor Infertility, Female explode all trees 905

#8 MeSH descriptor Infertility, Male explode all trees 520
(IVF):ti or (in vitro fertilization):ti or (in vitro fertilisation):ti or (assisted reproductive):ti or
#9 2129
(assisted reproduction):ti
(assistive reproductive):ti or (assistive reproduction):ti or (intracytoplasmic):ti or (icsi):ti or
#10 1116
(embryo transfer):ti
#11 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10), from 2007 to 2011 1072

3. Centre for Reviews & Dissemination (DARE, HTA, NHS EED) databases (http://www.crd.york.ac.uk/crdweb/;
searched 17 Jan, 2012)
2 MeSH DESCRIPTOR Fertilization in Vitro EXPLODE ALL TREES 173
3 MeSH DESCRIPTOR Embryo Transfer EXPLODE ALL TREES 55
4 MeSH DESCRIPTOR undefined EXPLODE ALL TREES 0
454

5 MeSH DESCRIPTOR Sperm Injections, Intracytoplasmic EXPLODE ALL TREES 48
6 MeSH DESCRIPTOR Infertility EXPLODE ALL TREES 156
(IVF):TI OR (in vitro fertilization):TI OR (in vitro fertilisation):TI OR (assisted reproductive):TI
9 165
OR (assisted reproductiion):TI
(assistive reproductive):TI OR (assistive reproduction):TI OR (intracytoplasmic):TI OR
10 72
(icsi):TI OR (embryo transfer):TI
11 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 370
12 * FROM 2007 TO 2012 22024
13 #11 AND #12 168

4. EMBASE (Ovid, 1980‐2012 Week 02)
* used BMJ Clinical Evidence filter for systematic reviews
3 exp embryo transfer/ 17046
4 exp intracytoplasmic sperm injection/ 9652
5 exp infertility/th [Therapy] 11167
6 female infertility/th 4663
7 male infertility/th 2509
8 1 or 2 or 3 or 4 or 5 or 6 or 7 67785
9 exp review/ 1750362
10 (literature adj3 review$).ti,ab. 166432
11 exp meta analysis/ 58505
12 exp systematic review/ 46604
13 9 or 10 or 11 or 12 1892520
(medline or medlars or embase or pubmed or cinahl or amed or psychlit or psyclit or
14 71610
psychinfo or psycinfo or scisearch or cochrane).ti,ab.
15 retracted article/ 5390
16 14 or 15 76957
17 13 and 16 55480
455

18 (systematic$ adj2 (review$ or overview)).ti,ab. 43278

19 (meta?anal$ or meta anal$ or meta‐anal$ or metaanal$ or metaanal$).ti,ab. 51153
20 17 or 18 or 19 112325
21 8 and 20 920
22 limit 21 to (human and english language and yr="2007 ‐Current") 452

5. MEDLINE (Ovid MEDLINE In‐Process & Other Non‐Indexed Citations, 1946 to present)
*using BMJ Clinical Evidence filter for systematic reviews
1 exp Reproductive Techniques, Assisted/ 47011
2 exp Fertilization in Vitro/ 25089
3 exp Embryo Transfer/ 11520
4 exp Single Embryo Transfer/ 74
5 infertility/th 2604
6 infertility, female/th 4567
7 infertility, male/th 2410
8 exp Sperm Injections, Intracytoplasmic/ 3826
9 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 50553
10 (review or review, tutorial or review, academic).pt. 1650735
11 (medline or medlars or embase or pubmed or cochrane).tw,sh. 60735
12 (scisearch or psychinfo or psycinfo).tw,sh. 6406
13 (psychlit or psyclit).tw,sh. 832
14 cinahl.tw,sh. 6204
15 ((hand adj2 search$) or (manual$ adj2 search$)).tw,sh. 5380
(electronic database$ or bibliographic database$ or computer?ed database$ or online
16 7370
database$).tw,sh.
17 (pooling or pooled or mantel haenszel).tw,sh. 40680
18 (peto or dersimonian or der simonian or fixed effect).tw,sh. 2227
19 (retraction of publication or retracted publication).pt. 4112
20 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 108538
21 9 and 20 746
22 meta‐analysis.pt. 31019
23 meta‐analysis.sh. 31019
24 (meta‐analys$ or meta analys$ or metaanalys$).tw,sh. 55704
25 (systematic$ adj5 review$).tw,sh. 36716
26 (systematic$ adj5 overview$).tw,sh. 647
456

27 (quantitativ$ adj5 overview$).tw,sh. 149

28 (quantitativ$ adj5 review$).tw,sh. 3454
29 (quantitativ$ adj5 overview$).tw,sh. 149
30 (methodologic$ adj5 review$).tw,sh. 2599
31 (methodologic$ adj5 overview$).tw,sh. 168
32 (integrative research review$ or research integration).tw. 77
33 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 85244
34 21 or 33 85704
35 9 and 34 991
36 limit 35 to (english language and humans and yr="2007 ‐Current") 372

6. CINAHL (EBSCOhost; searched 19 Jan 2012)
* used CADTH systematic reviews filter
S1 and S2
S4 118
Limiters ‐ English Language; Published Date from: 20070101‐20111231
S3 S1 and S2 153
(MH meta analysis or MH systematic review or MH "Technology, Medical/EV" or PT
systematic review or PT meta analysis or systematic* n3 review* or systematic* n3
overview* or methodologic* n3 review* or methodologic* n3 overview* or quantitative
n3 review* or quantitative n3 overview* or quantitative n3 synthes* or research n3
integrati* or research n3 overview* or integrative n3 review* or integrative n3 overview*
or collaborative n3 review* or collaborative n3 overview* or pool* n3 analy* or ti data
synthes* or ab data synthes* or ti data extraction* or ab data extraction* or ti data
abstraction* or ab data abstraction* or ti handsearch* or ab handsearch* or ti hand
search* or ab hand search* or ti mantel haenszel or ab mantel haenszel or ti peto or ab
S2 peto or ti der simonian or ab der simonian or ti dersimonian or ab dersimonian or ti fixed 56464
effect* or ab fixed effect* or ti latin square* or ab latin square* or ti met analy* or ab met
analy* or mw met analy* or ti metanaly* or ab metanaly* or metanaly* or ti health
technology assessment* or ab health technology assessment* or ti hta or ab hta or ti htas
or ab htas or ti meta regression* or ab meta regression* or ti metaregression* or ab
metaregression* or ti mega regression* or ab mega regression* or mw systematic review*
or mw biomedical technology assessment* or mw bio‐medical technology assessment* or
ti medline or ab medline or ti Cochrane or ab Cochrane or ti pubmed or ab pubmed or ti
medlars or ab medlars or mw medline or mw Cochrane or mw pubmed or mw medlars or
so Cochrane or so health technology assessment or so evidence report or cf y)
MH reproduction techniques OR MH fertilization in vitro OR MH embryo transfer OR MH
S1 4079
infertility/th
457

7. PsycINFO (OvidSP; 2002 to January Week 2, 2012)
1 exp Reproductive Technology/ 712
2 exp Infertility/ 671
3 1 or 2 1213
5 exp "Literature Review"/ or review.mp. 123414
6 meta‐analysis.mp. or exp Meta Analysis/ 7137
7 overview.mp. 25531
8 assessment.mp. or exp Measurement/ 169792
9 systematic.mp. 22951
10 exp Evaluation/ or evaluation.mp. 85381
11 5 or 6 or 7 or 8 or 9 or 10 353575
12 4 and 11 125

8. Web of Science (Thomson Reuters; 20 Jan 2012)
# 4 97 (#3) AND Language=(English)
Databases=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH Timespan=2007‐
2012
Lemmatization=On
# 3 216 #2 AND #1
Databases=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH Timespan=All Years
Lemmatization=On
# 2 1,189,240 Title=(review OR systematic) OR Title=("meta‐analysis" OR "metaanalysis") OR
Title=(assessment OR evaluation OR overview)
Lemmatization=On
# 1 4,296 Title=("assisted reproductive" OR "assistive "reproductive" OR "assisted reproduction" OR
"assistive reproduction") OR Title=(IVF OR "in vitro fertilization" OR "in vitro fertilisation") OR
Title=("embryo transfer" OR intracytoplasmic" OR ICSI) OR Title=("infertility treatment*" OR
"infertility therap*")
Lemmatization=On

9. Scopus (SciVerse; 20 Jan 2012)
(TITLE("assisted reproduct*" OR ivf OR "in vitro fertilization" OR "in vitro fertilisation" OR intracytoplasmic OR icsi
OR "infertility treatment*" OR "infertility therap*") AND TITLE(systematic OR review OR overview OR metaanalysis
OR "meta‐analysis" OR assessment OR evaluation)) AND PUBYEAR > 2006 = 277

Part C – ARTs ‐ ECONOMICS
458

Limits: 10 years (i.e. 2002 – 2012)
English language
1. PubMed (www.pubmed.gov; searched 1 Feb 2012) * used CADTH economics filter with addition of term “budget
impact”
#21 Search #19 OR #20 1240
#20 Search #16 AND #17 Limits: English, Publication Date from 2002 to 2012 1229
#18 Search #16 AND #17 2541
#19 Search (#16 AND #17) AND (in process[sb] OR publisher[sb] OR pubmednotmedline[sb]) 37
#17 Search Cost‐Benefit Analysis[MeSH] OR costs and cost analysis[MeSH] OR Cost Savings[MeSH] 684040

OR "cost‐effective*"[tiab] OR economics[majr] OR EC[sh] OR cost[tiab] OR costs[tiab] OR
costing[tiab] OR economic*[tiab] OR “sensitivity analysis”[tiab] OR pharmacoeconomic*[tiab]
OR "budget impact"[tiab]
#16 Search #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 59226

OR #14 OR #15
#14 Search ICS[ti] 196

#8 Search infertility,male/th 5177
#7 Search infertility,female/th 9657

2. Centre for Reviews & Dissemination (CRD) – DARE, NHS EED, HTA databases
(http://www.crd.york.ac.uk/crdweb/; 27 Feb 2012)
H
459

(IVF):TI OR ("in vitro fertilization"):TI OR ("in vitro fertilisation"):TI OR ("assisted
7 192
reproductive"):TI OR ("assisted reproduction"):TI
8 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 385
9 (economic*):TI OR (cost*):TI OR (budget*):TI 10329
10 #8 AND #9 80
11 * FROM 2002 TO 2012 36501
12 #10 AND #11 48

3. EMBASE (Ovid; 1980 to 2012 Week 08) *used SIGN filter for economic studies
3 exp embryo transfer/ 17276
4 exp intracytoplasmic sperm injection/ 9870
5 exp infertility/th 11214
6 female infertility/th 4685
7 male infertility/th 2524
8 1 or 2 or 3 or 4 or 5 or 6 or 7 68571
9 socioeconomics/ 94052
10 cost benefit analysis/ 57494
11 cost effectiveness analysis/ 78274
12 cost of illness/ 11983
13 cost control/ 40633
14 economic aspect/ 86839
15 financial management/ 94012
16 health care cost/ 105408
17 health care financing/ 10699
460

18 health economics/ 30920

19 hospital cost/ 11452
20 (fiscal or financial or finance or funding).tw. 79044
21 cost minimization analysis/ 2002
22 (cost adj estimate$).mp. 1509
23 (cost adj variable$).mp. 126
24 (unit adj cost$).mp. 1744
25 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 558354
26 8 and 25 2797

4. Web of Science (Thomson Reuters; 27 Feb 2012)
# 4 143 #2 AND #1
Refined by: Publication Years=( 2007 OR 2006 OR 2012 OR 2010 OR 2004 OR 2009 OR 2008 OR 2011
OR 2003 OR 2002 OR 2005 )
Lemmatization=On
# 3 219 #2 AND #1
Lemmatization=On
# 2 387,966 Title=(cost OR costs OR costing OR budget* OR economic*)
Lemmatization=On
# 1 20,148 Title=("assisted reproductive" OR "assistive reproductive" OR "assisted reproduction" OR "assistive
reproduction") OR Title=(IVF OR "in vitro fertilization" OR "in vitro fertilisation" OR "embryo
transfer" OR intracytoplasmic OR ICSI OR "infertility treatment" OR "infertility therap*")
Lemmatization=On

5. EconLit (EbscoHost; 27 Feb 2012)
Limiters ‐ Published Date from:
TX "assisted reproduct*" OR TX "in vitro fertili*" OR TX IVF OR TX
S1 20020101‐20121231 192
"embryo transfer" OR TX intracytoplasmic OR TX icsi

6. Health utilities(MEDLINE, including pre‐MEDLINE and in progress (Ovid); 18 Sep 2012 and 16 Oct 2012)
1 exp Quality‐Adjusted Life Years/ 5895
2 exp "Value of Life"/ 5233
3 disability adjusted life.ti,ab. 988
461

4 daly$.ti,ab. 994
5 (index of wellbeing or quality of wellbeing or qwb).ti,ab. 163
6 (multiattribute$ health or multi attribute$ health).ti,ab. 53
7 (health utilit$ index or health utilit$ indices or HUI).ti,ab. 971
(multiattribute$ theor$ or multi attribute$ theor$ or multiattribute$ analys$ or multi attribute$
8 9
analys$).ti,ab.
9 (multiattribute$ utilit$ or multi attribute$ utilit$).ti,ab. 173
10 (health utilit$ scale$ or classification of illness state$).ti,ab. 9
11 (utilit$ adj3 (valu$ or measur$ or health or life or estimat$ or elicit$ or disease)).ti,ab. 5364
12 (euro qual or euro qol or eq‐5d or eq5d or eq 5d or euroqual or euroqol).ti,ab. 3063
13 (sf36 or sf 36).ti,ab. 11470
(short form 36 or shortform 36 or sf thirtysix or sf thirty six or shortform thirtysix or shortform thirty
14 5326
six or short form thirtysix or short form thirty six).ti,ab.
15 (sf12 or sf 12).ti,ab. 1765
16 (short form 12 or shortform 12 or sf twelve or short form twelve).ti,ab. 708
17 (sf 6d or sf6d or short form 6d or shortform 6d or sf six$ or shortform six$ or short form six$).ti,ab. 328
18 (hrqol or hrql).ti,ab. 7762
19 (timetradeoff or time trade off or time trade off or tto).ti,ab. 903
20 (sg or standard gamble or vas or visual analog$).ti,ab. 43861
21 (willingness to pay or WTP).ti,ab. 2020
22 quality adjusted life.tw. 5095
23 (qaly$ or qald$ or qale$ or qtime$).ti,ab. 4281
24 health* year* equivalent*.tw. 37
25 (hye or hyes).tw. 53
26 (hui1 or hui2 or hui3).tw. 241
27 disutil*.tw. 185
28 (hqol or h qol or hrqol or hr qol).tw. 6182
29 (pqol or qls).tw. 227
462

30 ((utility or utilities) adj5 ("quality of life" or health* or score* or weight*)).tw. 3755
31 (preference* adj5 ("quality of life" or health* or score* or weight*)).tw. 3278
32 ((instrument or instruments) adj5 ("quality of life" or health* or score* or weight*)).tw. 7145
1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20
33 92457
or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32
34 ovulatory dysfunction.ti,ab. 241
35 exp Polycystic Ovary Syndrome/ 9260
36 ovarian failure.ti,ab. 2643
37 exp Fallopian Tube Diseases/ 6314
38 tubal obstruction.ti,ab. 314
39 exp Sterilization, Tubal/ 3766
40 exp Endometriosis/ 15577
41 exp Leiomyoma/ 15956
42 fibroid*.ti,ab. 3630
43 exp Infertility, Female/ or exp Infertility/ or exp Infertility, Male/ 50112
44 exp Vasovasostomy/ or exp Sterilization Reversal/ 1346
45 exp Clomiphene/ 4711
46 exp Aromatase Inhibitors/ 5506
47 exp Gonadotropins/ 114589
48 45 or 46 or 47 121706
49 43 and 48 7047
50 exp Reproductive Techniques, Assisted/ 49053
51 assisted reproduct*.ti,ab. 7835
52 exp Fertilization in Vitro/ 26108
53 (in vitro fertili* or ivf).ti,ab. 22754
54 exp Sperm Injections, Intracytoplasmic/ 4097
55 icsi.ti,ab. 4871
56 exp Ovulation Induction/ 9687
463

57 exp Insemination, Artificial/ 9546
58 ovarian drilling.ti,ab. 159
59 exp Varicocele/ 3513
60 exp Multiple Birth Offspring/ 22851
61 multiple birth*.ti,ab. 1700
62 exp Abortion, Spontaneous/ 27553
63 exp Abortion, Habitual/ 6127
64 miscarriage.ti,ab. 5531
65 exp Cesarean Section/ 32526
66 exp Cerebral Palsy/ 14639
67 exp Intellectual Disability/ 77487
68 exp Disabled Children/ 3708
69 exp Developmental Disabilities/ 13370
34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 49 or 50 or 51 or 52 or 53 or 54 or 55
70 324887
or 56 or 57 or 59 or 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69
71 33 and 70 2561
72 limit 71 to (english language and yr="1990 ‐Current") 1906
73 limit 72 to humans 1804

Health utilities (2nd search; 16 Oct 2012)
1 quality‐adjusted life years/ 5968
2 quality adjusted life.ti,ab. 5166
3 (qaly$ or qald$ or qale$ or qtime$ or qualy$ or adjusted life year$).ti,ab. 6921
4 value of life/ 5250
5 models, economic/ 5326
6 questionnaires/ 265699
7 disability adjusted life.ti,ab. 1003
8 (daly or dalys).ti,ab. 980
9 sickness impact profile/ 5566
464

10 severity of illness index/ 148565
11 (index of wellbeing or quality of wellbeing or quality of wellbeing or qwb).ti,ab. 165
12 (health utilit$ index or health utilit$ indices).ti,ab. 572
13 (euro qual or eruo qol or eq‐5d or eq5d or eq 5d or euroqual or euroqol or euroquol).ti,ab. 3096
14 (sf36 or sf 36).ti,ab. 11588
(short form 36 or shortform 36 or sf thirtysix or sf thirty six or shortform thirtysix or shortform thirty
15 5396
six or short form thirtysix or short form thirty six).ti,ab.
16 (short form 12 or sf twelve or short form twelve or sf12 or sf 12).ti,ab. 2202
17 (sf 6d or sf6d or short form 6d or shortform 6d or sf six$ or shortform six$ or short form six$).ti,ab. 337
18 standard gamble.ti,ab. 613
19 (vas or visual analog$).ti,ab. 39028
20 (timetradeoff or time tradeoff or time trade off or tto).ti,ab. 1044
21 Nottingham health profile$.ti,ab. 960
22 sickness impact profile.ti,ab. 983
23 healthy year equivalent$.ti,ab. 12
24 (hye or hyes).ti,ab. 53
25 Halex.ti,ab. 16
26 activity limitation index.ti,ab. 6
27 (hui or hui1 or hui2 or hui3).ti,ab. 797
1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20
28 462372
or 21 or 22 or 23 or 24 or 25 or 26 or 27
29 (multiattribute$ health or multi attribute$ health).ti,ab. 53
(multiattribute$ theor$ or multi attribute$ theor$ or multiattribute$ analy$ or multi attribute$
30 9
analy$).ti,ab.
31 (multiattribute$ utilit$ or multi attribute$ utilit$).ti,ab. 172
32 (health utilit$ scale$ or classification of illness state$).ti,ab. 9
(utilit$ adj3 (score$ or weight$ or valu$ or measur$ or health or life or estimate$ or elicit$ or
33 5862
disease)).ti,ab.
465

34 health state utility valu$.ti,ab. 45
35 indirect utility measur$.ti,ab. 3
36 generic utility measur$.ti,ab. 4
37 mauf.ti,ab. 16
38 (quality of life and preference based measur$).ti,ab. 124
39 (preference$ adj5 (quality of life or health or score$ or weight$)).ti,ab. 3089
40 (hrqol or hrql or hqol or h qol or hr qol).ti,ab. 8265
41 (pqol or qls).ti,ab. 232
42 disutil$.ti,ab. 185
43 ((instrument or instruments) adj5 (quality of life or health$ or score$ or weight$)).ti,ab. 7196
44 incremental cost$.ti,ab. 5233
45 icer$.ti,ab. 1430
46 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 28048
47 28 and 46 15192
48 limit 47 to (english language and humans and yr="1980 ‐Current") 13798
49 infertility/ 8628
50 infertility.ti. 9921
51 infertile.ti. 3830
52 reproductive techniques, assisted/ 5769
53 assisted reproductive.ti,ab. 4499
54 fertilization in vitro/ 23799
55 ivf.ti,ab. 14779
56 disabled children/ 3739
57 vasovasostomy/ 395
58 vasectomy reversal.ti,ab. 302
59 clomiphene/ 4723
60 aromatase inhibitors/ 4247
61 gonadotropins/ 8189

466

62 cerebral palsy/ 14799
63 cerebral palsy.ti,ab. 13432
64 down syndrome/ 19784
65 miscarriage/ 13508
66 miscarriage.ti,ab. 5592
67 abortion, habitual/ 5149
68 abortion, spontaneous/ 13508
69 childlessness.ti,ab. 479
70 multiple birth offspring/ 384
71 multiple birth$.ti,ab. 1706
72 pregnancy, multiple/ 8308
73 caregiver$.ti,ab. 26698
74 spina bifida/ 5051
75 muscular dystrophy/ 12700
76 muscular dystrophy.ti,ab. 15689
77 sperm injections, intracytoplasmic/ 4132
78 icsi.ti,ab. 4924
79 ovulation induction/ 8341
80 insemination, artificial/ 8076
81 ovarian drilling.ti,ab. 160
82 varicocele/ 3531
83 delivery, obstetric/ 19386
84 cesarean section/ 32299
85 developmental disabilities/ 13477
49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63 or 64 or 65 or 66
86 or 67 or 68 or 69 or 70 or 71 or 72 or 73 or 74 or 75 or 76 or 77 or 78 or 79 or 80 or 81 or 82 or 83 or 254924
84 or 85
87 48 and 86 464

467

Part D – ARTs – Primary studies to update systematic reviews
1. PubMed (www.pubmed.gov; searched 12 Mar 2012; monthly update search set up from April 1, 2012)
#29 Search #26 NOT (mice OR rats OR bovine OR buffalo OR beef OR cow* OR canine OR 3785
animal* OR pig OR pigs OR porcine OR camel OR cat OR cats)
#26 Search #21 OR #24 4015
#24 Search #22 NOT #3 Limits: Humans, English, Publication Date from 2008 to 2012 3521
#23 Search #22 NOT #3 Limits: Publication Date from 2008 to 2012 5203
#22 Search #20 AND (#1 OR #2) Limits: Publication Date from 2008 to 2012 5291
#21 Search #20 AND (publisher[sb] OR in process[sb] OR pubmednotmedline[sb]) Limits: 494

Publication Date from 2008 to 2012
#20 Search #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 10152

OR #16 OR #17 OR #18 Limits: Publication Date from 2008 to 2012
#19 Search #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 59365

OR #16 OR #17 OR #18
#17 Search icsi[ti] 1104

#11 Search infertility, male/th 5198
#10 Search infertility,female/th 9698
#3 Search editorial[pt] OR comment[pt] OR letter[pt] OR newspaper article[pt] 1172887
468

#2 Search Controlled clinical trial[pt] OR controlled clinical trials as topic[mh] OR clinical 5163081

trial[pt] OR clinical trials as topic[mh] OR "clinical trial"[tiab] OR evaluation studies[pt] OR
evaluation studies as Topic[mh] OR control[tiab] OR controlled[tiab] OR volunteer[tiab] OR
volunteers[tiab] OR open label*[tiab] OR nonrandom*[tiab] OR non random*[tiab] OR
quasirandom*[tiab] OR Observational stud*[tiab] OR Cohort studies[Mesh] OR cohort[tiab]
OR Longitudinal studies[Mesh] OR longitudinal[tiab] OR Prospective studies[Mesh] OR
prospective[tiab] OR Follow‐up studies[Mesh] OR follow up stud*[tiab] OR followup
stud*[tiab] OR Retrospective studies[Mesh] OR retrospective[tiab] OR Population based
stud*[tiab] OR Population based analy*[tiab] OR Population study[tiab] OR Population
studies[tiab] OR descriptive stud*[tiab] OR Multidimensional stud*[tiab] OR "Comparative
Study"[Publication Type] OR Comparative study[tiab] OR comparative studies[tiab] OR
Case‐control studies[Mesh] OR case control*[tiab] OR case series[tiab] OR case
comparison*[tiab] OR Case history[tiab] OR Case histories[tiab]
#1 Search randomized controlled trial[pt] OR randomized controlled trials as topic[mh] OR 834047

random allocation [mh] OR double‐blind method[mh] OR single‐blind method[mh] OR
random*[tw] OR "Placebos"[Mesh] OR placebo[tiab] OR ((singl*[tw] OR doubl*[tw] OR
trebl*[tw] OR tripl*[tw]) AND (mask*[tw] OR blind*[tw] OR dumm*[tw]))

Part E – ARTs ‐ Grey literature searches (run between Feb – Mar, 2012)
ARTS‐related association web sites:
Society of Obstetricians and Gynaecologists of Canada (SOGC) http://www.sogc.org/index_e.asp * scanned clinical
practice guidelines, sections for reproductive endocrinology and infertility and SOGC policy and practice
Canadian Fertility and Andrology Society (CFAS) www.cfas.ca/ * scanned Canadian ART Register annual reports,
articles and reports sections
Cochrane Collaboration Menstrual Disorders & Subfertility Group
www.fmhs.auckland.ac.nz/som/obsgynae/research/cochrane/default.aspx *scanned review topics list for female
HU
& male infertility
American Society for Reproductive Medicine (ASRM) www.asrm.org/ * scanned practice guidelines (series is called
Committee Opinions – published in journal Fertility & Sterility)
Resolve: the National Infertility Association www.resolve.org/ *scanned sections of website
International Federation of Fertility Societies (IFFS) www.iffs‐reproduction.org/ *scanned sections of website
US Centers for Disease Control and Prevention (CDC) www.cdc.gov/ART/index.htm *scanned sections of website
UK Human Fertilisation & Embryology Authority (HFEA) www.hfea.gov.uk/ *scanned website section on research &
evidence
European Society for Human Reproduction (ESHRE) www.eshre.eu/ *scanned guidelines & position papers sections
of website (their official journal is Human Reproduction)
Society for Assisted Reproductive Technology (SART) www.sart.org/ *scanned web site (their official journal is
Fertility & Sterility)
Assisted Human Reproduction Canada (AHRC) www.ahrc‐pac.gc.ca *scanned web site & reports & publications
section
American Infertility Association (AFA) www.ivf.net/ivf/the‐american‐infertility‐association‐o542.html *scanned
web site (mainly consumer info.)
International Committee Monitoring Assisted Reproductive Technologies (ICMART) www.icmartivf.org/ *scanned
publications (all from peer reviewed journals), reports, publications & presentations
469

Infertility Network www.infertilitynetwork.org *scanned web site
Guidelines
‐ National Guideline Clearinghouse www.guidelines.gov *reproductive techniques, assisted or fertilization in vitro
or embryo transfer or infertility or ivf or ICSI or intracytoplasmic = 83 references (only 1 relevant)
‐ CMA Infobase www.cma.ca/clinicalresources/practiceguidelines * icsi OR intracytoplasmic = 0 references;
reproduction OR reproductive OR ivf OR infertility = 4 references (1 relevant but already identified)
‐ Toward Optimum Practice (TOP guidelines) www.topalbertadoctors.org/ *scanned guidelines under obstetrics &
gynecology = 0 references
‐ Scottish Intercollegiate Guidelines Network (SIGN) www.sign.ac.uk *scanned guidelines under obstetrics &
gynecology = 0 references
‐ Guidelines Advisory Committee (GAC)
www.gacguidelines.ca/index.cfm?pagepath=GAC_Endorsed_Guidelines&id=21080 *scanned section of web site =
HU
0 references
‐ New Zealand Guidelines Group www.nzgg.org.nz/search?search=IVF *infertility or IVF or assisted reproduction or
ICSI or intracytoplasmic = 0 references
‐ BC Guidelines www.bcguidelines.ca/alphabetical.html *scanned alphabetic list of guidelines
‐ Aetna Clinical Policy Bulletins www.aetna.com/cpb *infertility / IVF = 1 Clinical Policy Bulletin
Clinical Trials
‐ Clinical Trials.gov www.clinicaltrials.gov * reproductive techniques, assisted or fertilization in vitro or embryo
transfer or infertility or ivf or ICSI or intracytoplasmic = 126 hits
HTA agency web sites
Canada
‐ Canadian Agency for Drugs & Technologies in Health (CADTH) www.cadth.ca *"assisted OR assistive OR
reproduction OR reproductive OR ARTS OR infertility OR fertility OR fertilization OR fertilisation OR ivf OR icsi OR
intracytoplasmic" = 20 hits (only 1 relevant, already identified)
‐ Institut national d’excellence en santé et en services sociaux (INESSS) www.inesss.qc.ca *scanned list of
publications back to 2003 & projects in progress = 0 relevant
‐ Institute of Health Economics (IHE) www.ihe.ca *scanned publications back to 2007 = 1 relevant report (already
identified)
‐ McGill University Health Centre. Technology Assessment Unit www.mcgill.ca/tau/ *scanned informal reports,
work in progress and reports back to 2002
‐ Health Quality Ontario (HQO) (i.e., Ontario Medical Advisory Secretariat (MAS) / Ontario Health Technology
Advisory Committee (OHTAC)) www.hqontario.ca/en/mas/mas_ohtas_mn.html *scanned reviews in progress,
preliminary evidence reviews, OHTAC recommendations, & evidence‐based analyses = 1 report &
recommendations (already identified)
‐ University of Calgary. Health Technology Assessment Unit http://wcmprodlb.ucalgary.ca/cipph/HTAUnit*scanned
HTA projects list = 1 report (already identified)
UK
‐ National Institute for Health and Clinical Excellence (NICE) www.nice.org.uk *infertility = 59 hits (1 report (2004),
already identified)
USA
‐ Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov *assisted reproductive = 30 hits (1 relevant,
already identified)
‐ California Technology Assessment Forum (CTAF) www.ctaf.org/ *scanned publications back to 2003 = 0 relevant
Other
470

‐ NHS Evidence www.evidence.nhs.uk/nhs‐evidence‐content * "assisted reproductive" OR infertility OR IVF OR "in
vitro fertili*" OR ICSI OR intracytoplasmic = 2,613 hits *scanned first 100 only
‐ New York Academy of Medicine. Grey literature collection http://greylit.org/ *(limited to 2007 – 2012)
reproductive = 84 hits; infertility = 1 hit (0 relevant); vitro = 0 hits
‐ Open Grey: System for Information on Grey Literature in Europe www.opengrey.eu/ *assisted reproduct* = 16
hits; infertility = 94 hits (all older materials)
‐ Google.ca www.google.ca ("assisted reproductive" OR IVF OR ICSI OR "infertility treatment*") AND (Alberta OR
Canada OR guidelines OR standards) *scanned first 100 hits only
471

References

1. Zegers‐Hochschild F, Adamson GD, De MJ, Ishihara O, Mansour R, Nygren K, et al. International Committee for
Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of
ART terminology, 2009. Fertil Steril 2009;92(5):1520‐4. Available: http://www.icmartivf.org/ivf‐glossary.html.
2. PharmacoEconomics guide chart. [n.s.]: Walter Kluwer Health / Adis; 2005. Available: http://pt.wkhealth.com/pt/pt‐
core/template‐adis/phe/media/PEC_Guide_Chart_WEB.pdf.
3. Single A, Ahearn E, Culyer T, Dahlgren H, Facey K, MacPherson K, et al. HTAi consumer glossary: a beginner's guide to
words used in health technology assessment. v. 27. [Edmonton (AB)]: Health Technology Assessment international
(HTAi); 2009. Available:
http://www.htai.org/fileadmin/HTAi_Files/ISG/PatientInvolvement/Glossary/HTAiPatientAndConsumerGlossaryOcto
ber2009_01.pdf.
4. Lee RC, McIsaac M, Berzins S. Issues associated with assisted reproductive technologies (ARTS) and preimplantation
genetic diagnosis (PGD): a rapid review conducted for the Alberta Health Technologies Decision Process. Calgary (AB):
University of Calgary. Centre for Health and Policy Studies (CHAPS); 2007.
5. Assisted reproductive technologies. Draft final report. Calgary (AB): University of Calgary. Centre for Health and Policy
Studies (CHAPS); 2007.
6. Chuck A, Yan C. Assistive reproductive technologies: a literature review and database analysis [and supplement].
Edmonton (AB): Institute of Health Economics (IHE); 2009. Available:
http://www.ihe.ca/documents/Assistive_Reproductive_Technologies.pdf.
7. Deonandan R. The public health implications of assisted reproductive technologies. Chronic Dis Can 2010;30(4):119‐
24. Available: http://www.phac‐aspc.gc.ca/publicat/cdic‐mcbc/30‐4/ar_01‐eng.php.
8. Ryan GL, Sparks AE, Sipe CS, Syrop CH, Dokras A, van Voorhis BJ. A mandatory single blastocyst transfer policy with
educational campaign in a United States IVF program reduces multiple gestation rates without sacrificing pregnancy
rates. Fertil Steril 2007;88(2):354‐60.
9. American Society for Reproductive Medicine. Multiple gestation associated with infertility therapy: an American
Society for Reproductive Medicine Practice Committee Opinion. Fertil Steril 2012;97(4):825‐34. Available:
http://www.asrm.org/uploadedFiles/ASRM_Content/News_and_Publications/Practice_Guidelines/Committee_Opini
ons/Multiples_nonprintable.pdf.
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Prepared by the University of Alberta for the Government of Alberta, © 2014

Questions & answers for policy makers ..................................................................................................... 21

Executive summary ..................................................................................................................................... 30

Background ................................................................................................................................................. 38

Objectives ............................................................................................................................................... 38

Introduction ................................................................................................................................................ 40

Infertility ................................................................................................................................................. 40

Economic evaluation .......................................................................................................................... 54

Social systems and demographics (S) ......................................................................................................... 55

Burden of illness ..................................................................................................................................... 55

Summary of recent health technology assessments .................................................................................. 78

Environmental scan of ARTs policies .......................................................................................................... 80

Policies in Canada ................................................................................................................................... 80

ICSI, assisted hatching and other forms of micromanipulation ......................................................... 84

Technology effects and effectiveness (T) ................................................................................................... 87

Economic evaluation (E) ........................................................................................................................... 111

Economic studies of ARTs interventions .............................................................................................. 111

Budget impact and cost‐effectiveness analysis ........................................................................................ 123

Conclusions ............................................................................................................................................... 146

Appendix ‐ Additional tables ................................................................................................................ 150

References ................................................................................................................................................ 472

Figure 1. Natural conception ‐ trends in pregnancy & miscarriage according to age ................................ 60

Table 1. Drugs commonly used in ARTs in Canada ..................................................................................... 45

Table 25. Included studies ........................................................................................................................ 162

Drug: generic name(s) Brand name(s) Mode of action [Mode of delivery]

Estrogen agonists & antagonists: Clomid®, Serophene®, Act on pituitary gland to stimulate ovulation or replace

Dopamine agonists: bromocriptine, Parlodel®, Dostinex®, Prolactin inhibitors; used to regulate high levels of

Human menopausal gonadotropin (hMG): Repronex®, Act on ovaries to stimulate ovulation. May also be

Human chorionic gonadotropin (hCG) Ovidrel® Act on ovaries to stimulate ovulation [Injection]

Follicle‐stimulating hormone (FSH): Bravelle®, Gonal‐F®, Act on ovaries to stimulate ovulation [Injection]

Gonadotropinreleasing hormone (GnRH) – Lupron Depot®, Act on pituitary gland to regulate ovulation (either

Antihyperglycemic agent: metformin Glucophage® Used for women with insulin resistance or polycystic

Progesterone Crinone®, Used to thicken the lining of the uterus for egg

Aromatase inhibitors: letrozole, Femara®, Arimidex® Used off‐label for hormone therapy in both male

Parameter Inclusion Criteria Exclusion Criteria

No change / Restrictive policy Permissive policy Quebec policy Funding without Regulation without

Type of Child ECS Grades 1 to 3 Grades 4 to 9 Grades 10‐12

Normal $3,248.35 $6,496.71 $6,496.71 $6,187.33

Mild to moderate $5,686.35 $6,496.71 $6,496.71 $6,187.33

Severe disabilities $27,808.35 $22,961.71 $22,961.71 $22,961.71

Quebec policy outcomes: $75,719,977 $18,580,120 $160,828,416 $255,128,513

Policy Ongoing pregnancy Neonatal and

Policy Ongoing pregnancy Neonatal and

Restrictive policy: $77,790,114 $17,704,387 $334,371,503 $429,866,005

Policy Ongoing pregnancy Neonatal and

Cost per healthy live birth $55,895 $50,553 $53,516 $40,020

Base Case Quebec policy Funding without Regulation

Cost‐effectiveness ratio 6,317 4,565 6,323 4,935 7,344 5,381

Part V: Treatment Outcomes

Details of legislation, guidelines, and Female partner age Number of cycles Assisted hatching or Embryo freezing and PGS/PGD Fetal reduction Oocyte, embryo, or Surrogacy

Details of legislation, guidelines, and Female partner age Number of cycles Assisted hatching or Embryo freezing and PGS/PGD Fetal reduction Oocyte, embryo, or Surrogacy

Details of legislation, guidelines, and Female partner age Number of cycles Assisted hatching or Embryo freezing and PGS/PGD Fetal reduction Oocyte, embryo, or Surrogacy

Details of legislation, guidelines, and Female partner age Number of cycles Assisted hatching or Embryo freezing and PGS/PGD Fetal reduction Oocyte, embryo, or Surrogacy

Details of legislation, guidelines, and Female partner age Number of cycles Assisted hatching or Embryo freezing and PGS/PGD Fetal reduction Oocyte, embryo, or Surrogacy

Details of legislation, guidelines, and Female partner age Number of cycles Assisted hatching or Embryo freezing and PGS/PGD Fetal reduction Oocyte, embryo, or Surrogacy

Details of legislation, guidelines, and Female partner age Number of cycles Assisted hatching or Embryo freezing and PGS/PGD Fetal reduction Oocyte, embryo, or Surrogacy

Details of legislation, guidelines, and Female partner age Number of cycles Assisted hatching or Embryo freezing and PGS/PGD Fetal reduction Oocyte, embryo, or Surrogacy

Details of legislation, guidelines, and Female partner age Number of cycles Assisted hatching or Embryo freezing and PGS/PGD Fetal reduction Oocyte, embryo, or Surrogacy

Details of legislation, guidelines, and Female partner age Number of cycles Assisted hatching or Embryo freezing and PGS/PGD Fetal reduction Oocyte, embryo, or Surrogacy

Review Details of Review Study Selection Characteristics of Included Studies Outcomes

Review Details of Review Study Selection Characteristics of Included Studies Outcomes

Review Details of Review Study Selection Characteristics of Included Studies Outcomes

Review Details of Review Study Selection Characteristics of Included Studies Outcomes

Review Details of Review Study Selection Characteristics of Included Studies Outcomes