Effect of paternal age on outcomes in

assisted reproductive technology

cycles: systematic review and
meta-analysis
Guy Morris, M.B.Ch.B. (Honours), M.R.C.O.G.,a,b Dimitrios Mavrelos, M.D., M.R.C.O.G.,a,b
Efstathios Theodorou, M.R.C.O.G.,a Mia Campbell-Forde, B.Sc., M.Sc.,a David Cansfield, B.Sc. (Hons), M.Res.,a
Ephia Yasmin, M.D., M.R.C.O.G.,a,b Philippa Sangster, M.Sc., F.R.C.S. (Urol),a,b Wael Saab, M.D., M.R.C.O.G.,a
Paul Serhal, F.R.C.O.G.,a and Srividya Seshadri, M.D., M.Sc., M.R.C.O.G.a
a
Centre for Reproductive and Genetic Health, London, United Kingdom; and b Reproductive Medicine Unit, University
College London Hospitals National Health Service Foundation Trust, London, United Kingdom

Objective: To investigate whether paternal age exerts an independent effect on the clinical outcomes of assisted reproductive technol-
ogy (ART) cycles.
Evidence Review: Observational studies were identified through a systematic search of MEDLINE, EMBASE, Cochrane Central Register
of Controlled Trials, and National Health Service evidence. Data for women aged %39 years were extracted and analyzed. We included
all studies, both autologous and donor oocyte, into separate analyses of the effect of paternal age on ART outcome. We excluded studies
in azoospermic men, women aged R40 years, ART including preimplantation genetic testing, and involving donor sperm. The included
studies scored well on the Newcastle-Ottawa Quality Assessment Scale for observational studies. The primary outcome was live birth
rate and secondary outcome measures were clinical pregnancy rate and miscarriage rate. When pooling data, the random-effects model
was used to counter the effect of heterogeneity in the studies.
Result(s): Live birth rate was reported in three autologous oocyte studies (2,926 cycles) and five donor oocyte studies (7,648 cycles).
Live birth rate was found to be increased significantly when male age was <40 years in autologous oocyte studies but no difference in
live birth rate was found in donor oocyte studies. Clinical pregnancy rates were found to be statistically higher when the paternal age
was under 40 years in autologous oocyte studies, however, there was no difference in clinical pregnancy in the same age category when
donor oocyte studies were analyzed. Miscarriage rate was reported in two autologous oocyte studies (970 cycles) and four donor oocyte
studies (3,741 cycles). Miscarriage was found to be more likely with male age >40 years in autologous studies. In donor oocyte studies,
the miscarriage rate was not increased when male age was >50 years. All of the autologous oocyte studies reported a statistically sig-
nificant association between male age and female age.
Conclusion(s): The findings of this review and meta-analysis, based on the donor oocyte model, suggest that advanced paternal age
does not exert an independent effect on the outcome of ART cycles. Miscarriage rates do not appear to be increased even for men >50
years of age after treatment with donor oocytes. The meta-analysis of autologous oocyte studies suggests that increasing male age may
have a deleterious effect on the outcome of ART, however, this may be confounded by the strong association with increasing maternal
age. (Fertil Steril RevÒ 2020;1:16–34. Ó2020 by American Society for Reproductive Medicine.)
Key Words: Paternal age, in vitro fertilization, miscarriage, donor oocytes, assisted reproductive outcomes
Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-
and-sterility/posts/xfnr00006

Received February 24, 2020; revised April 6, 2020; accepted April 23, 2020.
G.M. has nothing to disclose. D.M. has nothing to disclose. E.T. has nothing to disclose. M.C.-F. has nothing to disclose. D.C. has nothing to disclose. E.Y. has
nothing to disclose. P.S. has nothing to disclose. W.S. has nothing to disclose. P.S. has nothing to disclose. S.S. has nothing to disclose.
Funding: No funding required.
Reprint requests: Guy Morris, M.B.Ch.B. (Honours), M.R.C.O.G., Centre for Reproductive and Genetic Health, 230 - 232 Great Portland Street, Fitzrovia, Lon-
don, United Kingdom, W1W 5QS (E-mail: guy.morris1@nhs.net).

Fertil Steril Rev® Vol. 1, No. 1, October 2020 2666-5719/$36.00

© 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.xfnr.2020.04.001

16 VOL. 1 NO. 1 / OCTOBER 2020


ESSENTIAL POINTS

Male age does not affect live birth rate, clinical pregnancy
rate, or miscarriage when using donor oocytes.

Live birth rate appears to decrease when using a woman’s
own oocytes if the male partner is >40 years, but this is
likely to reflect the effect of maternal age.

Miscarriage rate appears to increase when using a woman’s
own oocytes if the male partner is >40 years, but this is
likely to reflect the effect of maternal age.
D
elayed parenthood is becoming more common in
both men and women across the globe (1). The age
of first-time mothers has increased steadily during
the last few decades (2) and the age of fathers has matched
this increase (3). Of babies born in the United Kingdom in
2016, 15% had a father aged >40 years (4).
Increasing paternal age has been associated with an in-
crease in the risk of adverse pregnancy outcome and may
impact child health (1). Earlier studies suggested higher
paternal age was associated with increased rates of miscar-
riage, pre-eclampsia, and low birth weight (5–7). A recent
population-based retrospective study of 40,529,905 births
in the United States found that advanced paternal age,
R45 years, increased the odds of premature birth and sei-
zures in the neonate and of gestational diabetes in the
mother (8).
The impact of maternal age on the chance of success with
assisted reproductive technology (ART) is well documented;
women >40 years of age have a significantly lower chance
of success with ART compared with younger patients (9).
This likely is due to higher rates of chromosomal abnormality
within oocytes, embryo aneuploidy, and decreased ovarian
reserve (10–12). In contrast, there is significantly less
evidence for the impact of male age on the outcome of an
ART cycle.
It has been shown that increasing male age results in a
deterioration across all parameters of the semen analysis:
decrease in total sperm numbers >34 years of age; decrease
in normal sperm concentration >40 years; and decrease in
motility >43 years (13). Studies evaluating the effect of
increasing male age on in vitro fertilization (IVF)/intracy-
toplasmic sperm injection (ICSI) outcomes have been con-
flicting. Where some studies have found an association
between increased male age and reduced pregnancy rate
(14) other studies have not found it to be an independent
factor (15). Systematic reviews of both autologous and
donor oocyte studies into the effect of paternal age have
not found strong evidence for a detrimental effect but
have acknowledged that the level of evidence available
was weak (16, 17). Since the most recent donor oocyte sys-
tematic review, there has been a further retrospective study
including 949 cycles that did not find an effect of paternal
age. In contrast, more recent and larger autologous cohort
studies have suggested that advanced paternal age has a
deleterious effect on ART outcome (18–21). In view of the
inconclusive evidence regarding the effect of paternal age
on the outcomes of ART, we addressed this important
VOL. 1 NO. 1 / OCTOBER 2020
Fertil Steril Rev®
clinical question by performing a systematic review and
the first meta-analysis.
MATERIAL AND METHODS
Inclusion Criteria
The study included primary articles that studied all cycles of
ART (IVF and ICSI) that resulted in fresh embryo transfer.
The primary outcome measure was live birth rate (LBR;
defined as the number of live births per cycle of ART) and
the secondary outcome measures were clinical pregnancy
rate (CPR; clinical pregnancy defined as the observation of
a pregnancy sac on ultrasound at least 4 weeks after embryo
transfer) and miscarriage rate (MR; miscarriage defined as any
pregnancy loss, including biochemical pregnancies, occur-
ring before 20 weeks of gestation). The outcomes were defined
according to the terminology recommended in the Interna-
tional Committee Monitoring Assisted Reproductive Technol-
ogies glossary (22) and the updated and revised nomenclature
for the description of early pregnancy events (23).
Literature Search
The Cochrane Central Citation Index Register of Controlled
Trials, MEDLINE, EMBASE, National Health Service evidence,
and conference abstracts were searched for randomized
controlled trials and observational studies that addressed
the impact of paternal age on ART published up to December
2018. The search strategy used the following keywords and/or
medical subject heading terms: paternal age, father age, IVF,
ICSI, ART, pregnancy outcome, and miscarriage. The full elec-
tronic search is provided in Table 1. We restricted the results
to those in English. The results were separated into donor
oocyte studies and autologous oocyte studies.
Study Selection
Criteria for inclusion in the study were established prior to the
literature search. One reviewer (G.M.) carried out study selec-
tion. First, the titles and abstracts of the electronic searches
were scrutinized. Each title was included or excluded accord-
ing to predefined inclusion criteria. The full manuscripts of
the titles and abstracts considered to be relevant for inclusion
were obtained. Where duplicates were identified the most
recent and complete version was selected and included. No
randomized controlled trials were identified that addressed
the role of paternal age. Data were extracted by three authors
(G.M., M.C.F., and D.C.) from the included studies. Data were
extracted according to paternal and maternal age groups as
reported in the manuscript. Where data were not reported au-
thors were contacted to provide the required information.
Study Quality Assessment
Two reviewers (G.M. and E.T.) used the Newcastle-Ottawa
Quality Assessment Scales for observational studies to com-
plete a quality assessment of the included articles (24). The
Newcastle-Ottawa scale ranges from 0 to 9, awarding one
star for all categories (representativeness of cohort, selection
of nonexposed, ascertainment of exposure, demonstration
17

TABLE 1
Full electronic search for paternal age and outcome of assisted
reproductive technology.
1. Paternal age.mp. or Paternal Age/
2. Fathers/ or father age.mp.
3. 1 or 2
4. Infertility, Male/ or Pregnancy Rate/ or Ovulation Induction/ or
Fertilization in Vitro/ or Embryo Transfer/ or Infertility, Female/ or
ivf.mp. or Oocytes/ or Infertility/
5. ICSI.mp. or Sperm Injections, Intracytoplasmic/
6. assisted reproductive technology.mp. or Reproductive Tech-
niques, Assisted/
7. Pregnancy Complications/ or Infertility, Female/ or Reproductive
Techniques, Assisted/ or Spermatozoa/ or Semen/ or assisted
reproductive therapy.mp. or Fertilization in Vitro/ or Infertility,
Male/
8. Embryo Implantation/ or Oocytes/ or Fertilization in Vitro/ or
Infertility, Male/ or Semen Analysis/ or Sperm Injections, Intracy-
toplasmic/ or Pregnancy Rate/ or Spermatozoa/ or IMSI.mp. or
Pregnancy Outcome/
9. 4 or 5 or 6 or 7 or 8
10. Miscarriage.mp. or Abortion, Spontaneous/
11. Recurrent miscarriage.mp. or Abortion, Habitual/
12. Live Birth/ or Embryo Transfer/ or Pregnancy Outcome/ or Birth
Rate/ or Pregnancy Rate/
13. low birth weight.mp. or Infant, Low Birth Weight/
14. intrauterine growth restriction.mp. or Fetal Growth Retardation/
15. Prenatal Exposure Delayed Effects/ or Pregnancy Complications/
or Placenta/ or Gestational Age/ or Fetal Growth Retardation/ or
IUGR.mp. or Infant, Newborn/ or Pre-Eclampsia/
16. Preterm birth.mp. or Premature Birth/
17. Pregnancy Outcome/ or Obstetric Labor, Premature/ or Preg-
nancy Complications/ or Pregnancy Complications, Infectious/ or
Premature Birth/ or Fetal Membranes, Premature Rupture/
18. Gestational age.mp. or Gestational Age/
19. 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18
20. 3 and 9 and 19
Note: ICSI ¼ intracytoplasmic sperm injection; IUGR ¼ intrauterine growth restriction.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.
that outcome not present at start of study, assessment of
outcome, duration of follow-up, and adequacy of follow-
up) except comparability by design or analysis for which
two stars can be assigned. This was used to give a quantitative
appraisal of the overall quality of the included studies. Each
study was scored by the two reviewers independently and
any discrepancies were settled by a third reviewer (S.S.)
(Table 2).
Publication Bias
Assessment for publication bias in the included studies for the
outcome of clinical pregnancy was performed. The funnel plot
for publication bias is shown in Figure 1 (RevMan, version
5.3, Cochrane Community).
Statistical Analysis
Clinical pregnancy, LBR, and MR were extracted from each
included study according to maternal and paternal ages. For
each study, the effect was measured using odds ratio (OR)
for dichotomous outcomes, which are presented with their
corresponding 95% confidence intervals (CIs). We considered
P< .05 to be statistically significant. Whenever possible,
outcome data from each study were pooled using a Mantel-
18
Haenszel model, applying the random-effects model to
counter the effect of heterogeneity in the studies.
Statistical heterogeneity was quantified using I2 statistic,
which described the percentage of total variation across the
studies that is due to heterogeneity rather than sampling error
(25). The analysis was conducted using RevMan (version 5.3
software, The Cochrane Collaboration).
RESULTS
The search strategy of this systematic review is reported in
line with the Preferred Reporting Items for Systematic Review
and Meta-Analyse statement (26) attached as Figure 2. The
search strategy resulted in 325 citations, of which 259 were
excluded because it was clear from scrutinizing the title and
abstract that they did not fulfil the inclusion criteria. Eighteen
donor oocyte abstracts and 13 autologous oocyte abstracts
were excluded because they were duplicates. Full manuscripts
of 19 articles addressing autologous oocyte studies and 16 ar-
ticles addressing donor oocyte studies were obtained. A total
of nine of the autologous studies were excluded from the
autologous studies; eight articles were conference abstracts
or studies where there was no extractable data. Of the studies
of donor oocyte cycles, five studies were excluded because
they were conference abstracts or studies where there was
no extractable data. The total number of observational studies
included in the autologous oocyte review was ten and the to-
tal number of studies included in the donor oocyte review
was 11.
Study Characteristics
Study characteristics of the included studies are presented in
Table 3. None of the authors of the included studies declared
any conflicts of interest. The included studies varied in publi-
cation date from 1998–2018 for autologous oocyte studies
and 1996–2018 for donor oocyte studies. There were no ran-
domized studies for inclusion in the review due to the nature
of the study question. All included studies were observational
cohort studies. Of the autologous oocyte studies, five were
retrospective and three were prospective. All the donor oocyte
studies were retrospective. Sample size varied between 136
and 2,627 ART cycles for autologous oocyte studies and 255
and 4,887 cycles for donor oocyte studies. All studies reported
the maternal age within the cohort studied. Of the eight autol-
ogous oocyte studies included, one study included cycles of
IVF and gamete intrafallopian transfer (27), four
included only ICSI (28–31), two included a mixture of IVF/
ICSI (19, 20), and one included only IVF cycles (15). Three
studies explicitly excluded cycles including preimplantation
genetic testing (19, 20, 32) and one study excluded sperm
obtained by surgical extraction (19). One study excluded
cycles of ART involving double-embryo transfer (20). One
study limited the female age to <35 years (28), two studies
limited female age to <39 years (15, 30), and three studies
included women >40 years of age (27, 29, 32). Three studies
reported median maternal age (standard deviation) by
paternal age group (19, 29, 30). Where possible, to control
for maternal age, we excluded the results reported for women
R40 years (27).
VOL. 1 NO. 1 / OCTOBER 2020
VOL. 1 NO. 1 / OCTOBER 2020

TABLE 2

Newcastle–Ottawa Scale appraisal of included studies.

Demonstration Data for clinical
that outcome Comparability pregnancy Was
Representativeness Selection Ascertainment not present at by design or /live birth/ follow-up Adequacy of Included in
Study Autologous/donor of cohort of nonexposed of exposure start of study analysis miscarriage long enough follow up Score meta-analysis?
Kumtepe et al. (2003) Auto * * * * */* */-/- * * 9 Yes
Klonoff-Cohen et al. (2004) Auto - * * * */* */*/- * * 9 Yes
McPherson et al. (2017) Auto * * * * */* -/-/- * * 8 Yes
Spandofer et al. (1998) Auto * * * * */* */-/- * * 9 Yes
Wu et al. (2016) Auto * * * * -/- */*/- * * 7 Yes
Bellver et al. (2008) Auto * * * * */* */-/- * * 9 Yes
Aboulghar et al. (2007) Auto * * * * */x */-/- * * 8 Yes. Only for
age >50 y
Kaarouch et al. (2018) Auto * * * * */- */-/- * * 8 Yes
Nijs et al. (2009) Auto * * * * */- -/-/- * * 7 Yes
Chapuis et al. (2017) Auto * * * * -/- */-/- * * 7 Yes
Whitcomb et al. (2010) Donor * * * * */* */*/* * * 9 Yes
Gallardo et al. (1996) Donor * * * * */* */-/* * * 9 Yes
Gu et al. (2012) Donor * * * * */* */*/* * * 9 Yes
Frattarelli et al. (2007) Donor * * * * */* */*/* * * 9 Yes. Only for age
>50 y
Luna et al. (2009) Donor * * * * */* */*/* * * 9 Yes
Medina et al. (2012) Abstract Donor * * * * */- */-/* * * 8 Yes
Ho et al. (2015) Abstract Donor * * * * */- */*/* * * 8 Yes
Robertshaw et al. (2014) Donor * * * * */* -/*/* * * 9 Yes
Meyer et al. (2012) Abstract Donor * * * * */- */*/- * * 8 Yes
Capelouto et al. (2018) Donor * * * * */* */*/- * * 9 Yes
Begueria et al. (2014) Donor * * * * */* */*/* * * 9 Yes
Note: * ¼ star awarded; - ¼ star not awarded.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.

Fertil Steril Rev®

19
 Of the donor oocyte studies, four studies reported the
FIGURE 1
oocyte age as being %31 years (33–36), whereas the
remaining studies reported oocyte age as being <35
years. Four studies reported that donors had a normal
ovarian reserve either based on antral follicle count >8
(37–39) or based on assessment of baseline gonadotropins
(33, 34, 37, 38). Recipient endometrial development for
the transfer cycle was described in three of the studies,
with a minimum development of either R7 mm (34) or
R8 mm (33, 38). Two studies excluded surgically
retrieved sperm and donor sperm (37, 39). One study
included semen samples surgically obtained, as a frozen
specimen or by electroejaculation (36). Three studies were
conference abstracts from which it was possible to extract
Autologous oocyte publication bias.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.
data (35, 40, 41). We performed a subgroup analysis of
the impact of paternal age >50 years, where maternal
age was %39 years, in both autologous and donor oocyte
studies where outcomes were reported. All included

FIGURE 2
Iden fica on

Records iden fied through Addi onal records iden fied

database searching through other sources
(n = 325) (n = 0)

Records excluded as did

not meet inclusion criteria
Screening

Possible eligible ar cles a er screening of (n = 259)

abstracts (n=35)
Duplicates results
excluded
(n = 31)

Full-text ar cles excluded

Full-text ar cles assessed for eligibility Autologous studies:

Eligibility

(n = 35)
Autologous studies (n = 19) Abstract with no data (n = 2)
No data to extract from
Donor studies (n = 16)
manuscript (n= 6)
Difference in sperm used
between groups (n = 1)

Donor studies:

Abstract with no data to

Studies included in quan ta ve synthesis
Included

extract (n = 3)
(meta-analysis) No data to extract from
Autologous studies (n = 10) manuscript (n = 2)
Donor studies (n = 11)

Observational studies’ identification and selection process.

Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.

20 VOL. 1 NO. 1 / OCTOBER 2020

 TABLE 3
VOL. 1 NO. 1 / OCTOBER 2020

Characteristics of included studies.

Autologous or Confounders
Author (y) Study design donated oocyte Study population Age groups studied Summary of results adjustment Conclusions
Kumtepe et al. Retrospective Autologous Male factor infertility Men <40 y (678 cycles) Male age correlated with Regression analysis to The effect of
(2003) (919 cycles) Men >40 y (241 cycles) pregnancy rate. Regression account for increasing male
Median female age 30.7 y analysis showed this effect female age age is not a
and 36.2 y, respectively dependent on female age. direct effect but
(P< .001) reflects
increasing
female partner
age.
Klonoff-Cohen Prospective Autologous 221 IVF/GIFT couples – Men %35 y (46 men) Each additional year of Regression analysis to Advancing paternal
et al. (2004) 166 men 36–40 y (63 men) paternal age associated account for (and maternal)
>40 y (46 men) with 11% increased odds female age age had a
Maternal age <35; 35–39; of not achieving a live Confounders: no. of deleterious
R40 y birth. previous IVF/GIFT effect on IVF
attempts, parity, and GIFT
type of outcomes.
procedure, no. of
embryos
transferred,
paternal
education,
ethnicity,
smoking and
alcohol history,
type of infertility.
McPherson et al. Retrospective Autologous 4,057 first cycles IVF/ Male age <40 y; R40 y Logistic regression analysis Logistic regression Evidence of an
(2017) ICSI (2,215 cycles showed a strong effect of analysis to interaction
with embryo maternal age and live birth account for between
transfer) (P< .001) and negative maternal age, maternal and
association between maternal and paternal age on
paternal age and live births paternal BMI, log term births.
(P¼ .04) transformed FSH Advanced
concentration, paternal age’s
no. of eggs effect on the
collected. probability of a
term birth was
only evident in
couples where
the maternal
age range was
27–35 y.
Spandofer et al. Retrospective Autologous 821 ICSI cycles %39 y (527 men) Clinical pregnancies. Men Only analyzed cycles No effect of

Fertil Steril Rev®

(1998) 40–49 y (257 men) %40 y (205/389 cycles) when female paternal age on
R50 y (37 men) Men R40 y (4/9 cycles) partner %35 y to ICSI pregnancy
Female age %35 exclude effect of outcome.
female age.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.
21
 TABLE 3
22

Continued.
Autologous or Confounders
Author (y) Study design donated oocyte Study population Age groups studied Summary of results adjustment Conclusions
Wu et al. (2016) Retrospective Autologous 2,627 ICSI cycles Male age <30 y; 30–34; After adjusting for female age, Multiple linear Increased paternal
35–39; 40–44; 45–49; paternal age had no effect regression to age negatively
>50 y on pregnancy outcomes adjust for influences no.
Median maternal age per (OR for a 5-year interval), maternal age, no. of high-quality
male age: 26.67; including the rates of of transferred embryos but
30.08; 32.77; 33.99; clinical pregnancy (OR embryos, and day has no effect on
33.43; 33.26 y 0.919; 95% CI 0.839– of embryo pregnancy
1.006; P¼ .067), ongoing transfer. outcomes in
pregnancy (OR 0.914; ICSI cycles.
95% CI 0.833–1.003;
P¼ .058), early pregnancy
loss (OR 1.019; 95% CI
0.823–1.263; P¼ .861),
live births (OR 0.916; 95%
CI 0.833–1.007; P¼ .070),
and preterm births (OR
1.061; 95% CI 0.898–
1.254; P¼ .485).
Bellver et al. Retrospective Autologous 1,286 IVF cycles Male age %30; R31; The predictive value of Maternal age and No effect of
(2008) R33; R35; R36; paternal age maternal BMI paternal age on
R37; R38; R39; (incorporating the effect of included in IVF/ICSI
R41 y maternal age and their logistic regression outcomes.
Female age <30; 31–35; BMI) were estimated using analysis.
36–38 y a ROC curve analysis,
AUC ¼ 0.541 (95% CI
0.479–0.603). A logistic
regression analysis was
performed to quantify the
effect of male age on IVF/
ICSI outcome. No
significant association was
observed.
Aboulghar et al. Retrospective Autologous 227 cycles in men >50 Male age <50 y and R50 y No significant difference For each case in the Paternal age has no
(2007) y and 227 cycles in Median female age 33.2 y between 2 groups in study group, a effect on the
men <50 y and 32.7 y, respectively clinical pregnancy rate (OR control was pregnancy rate
1.06; 95% CI ¼ 0.72– selected as the after ICSI.
1.55). Subgroup analysis of first next ICSI
men 50–59 y vs. >60 y cycle with a man
VOL. 1 NO. 1 / OCTOBER 2020

showed no difference in <50 y and a

clinical pregnancy rate spouse with an
age ranging from
1 y above or
below the index
case.
Only 1 control was
selected for each
patient.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.
 TABLE 3
VOL. 1 NO. 1 / OCTOBER 2020

Continued.
Autologous or Confounders
Author (y) Study design donated oocyte Study population Age groups studied Summary of results adjustment Conclusions
Kaarouch et al. Prospective Autologous 83 couples undergoing Male age <40 y (n ¼ 41) Clinical pregnancy rate 32% Women <40 y; Advanced paternal
(2018) IVF for male factor and R40 y (n ¼ 42) vs. 17% and miscarriage exclusion criteria: age cut-off for
infertility Median female age 33  rate 42% vs. 60%. consumption of ART should be
4.28 y and 35  3 y alcohol and/or set at 40 y.
(P¼ .06) tobacco,
azoospermia,
cryptospermia,
retrograde
ejaculation, and
collection
problems (partial
ejaculate),
varicocele,
patients with
history of
exposure to
gonadotoxins,
such as
chemotherapy,
radiotherapy, or
pesticides, and
history of
infection or fever
in 3 previous
months,
antioxidant
treatment,
infertile couples
with female
factor.
Nijs et al. (2009) Prospective Autologous 278 first IVF/ICSI cycles Male age %34 y; 35–39 y; Logistic regression analysis of Logistic regression Advanced paternal
R40 y male age and PR could not analysis to age not
Female age %34; 35–39; identify any correlation in account for associated with
R40 y the overall patient maternal age. a decreased live
Mean female age 31.9 y population (45.5% PR; B ¼ Cycles with testicular birth rate. DNA
(4.2 y, range 20–46 y) 0.202; P¼ .81) or in each spermatozoa and fragmentation
male age class (%34 y: preimplantation index was not
51.1% PR; B ¼ 0.24; genetic diagnosis affected
P¼ .77; 35–39 y: 41% PR; cycles were not significantly by
B ¼ 0.004; P¼ .98; 40 y: included in the increased male
38.3% PR; B ¼ 0.065;

Fertil Steril Rev®

study. Mode of age.
P¼ .45). When correcting fertilization not
for female age (by splitting considered to be
into 3 female age groups, a confounder.
see above), male age did
not influence any of the
PR (all P>.05).
23

Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.
 TABLE 3
24

Continued.
Autologous or Confounders
Author (y) Study design donated oocyte Study population Age groups studied Summary of results adjustment Conclusions
Chapuis et al. Retrospective Autologous 859 IVF and 1,632 ICSI Male age 20–29 y; 30–39 Clinical pregnancy rate Maternal age Increasing paternal
(2017) cycles y; 40– 50 y; >51 y used decreased >51 y in both reported as being age (>51 y)
for both IVF and ICSI IVF and ICSI treatment. equal between negatively
Median female age: 29.39; groups of men influences the
34.22; 37.08; 37.00 y, aged 40–50 and rate of clinical
respectively (P< .0001) R51 y. pregnancy
when the
woman is
>37 y.
Whitcomb et al. Retrospective Donor 1,392 cycles Male age <30; 30–34; 35– Increasing male age associated Adjusted for Male age not
(2010) 39; 40–44; 45–49; 50– with increased ICSI maternal age in associated with
54; R55 y (P< .01) and number of regression live birth rate in
Female donor embryos transferred analysis. donor oocyte
aged 21–33 y (P¼ .02). cycles when
adjusted for
maternal age.
Gallardo et al. Retrospective Donor 345 cycles Male age: <30; 31–40; Pregnancy rates: 64.5%; Age (up to 64 y)
(1996) 41–50; >51 y 45.6%; 51.0%; 71.4%, does not affect
Female donor age <35 y respectively. sperm
characteristics
or its ability to
fertilize human
eggs. Similarly,
embryo
development
in vitro as well
as implantation
in recipient uteri
are not affected
by age of the
male.
Frattarelli et al. Retrospective Donor 1,023 cycles Male age: %35; 36–40; Men aged %45 y had After controlling for
(2007) 41–45; 46–50; 51–55; significantly more motile female age with
>55 y sperm than men >45 y use of the donor
Female donor age %35 y (P< .05). A significant oocyte model,
decrease in the number of male age >50 y
blastocyst embryos on day significantly
5 was noted in men >55 y affected
VOL. 1 NO. 1 / OCTOBER 2020

(P< .05). A significant pregnancy

increase in pregnancy loss outcomes and
rate (P< .05) and decrease blastocyst
in live birth rate (P< .01) formation rates.
were noted. Semen volume
and total
motility
decreased with
increasing male
age.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.
 TABLE 3
VOL. 1 NO. 1 / OCTOBER 2020

Continued.
Autologous or Confounders
Author (y) Study design donated oocyte Study population Age groups studied Summary of results adjustment Conclusions
Luna et al. (2009) Retrospective Donor 672 cycles Male age <40; 40–49 and Clinical PR, implantation, and A significant
>50 y loss rates were maintained decrease in
Female age (oocyte age in in the 3 age groups. When implantation
manuscript) men in group C were rate was noted
26.2  3.2; subdivided by age (50–59 y only in
25.9  3.1; 26.6  3.4 and >60 y), a significant pregnancies of
y decrease in implantation male partner’s
rates (P¼ .022) was noted >60 y.
in the latter. A trend
toward a lower clinical PR
(72% [72/100] vs. 50%
[8/16]; P¼ .14) and a
higher loss rate (13% [9/
72] vs. 38% [3/8]; P¼ .17)
was also noted for men
>60 y.
Medina et al. Retrospective Donor 260 cycles Male age: %34; 35–38; Pregnancy rates: 63%, 69%, There were no
(2012) R39 y and 66%, respectively. significant
Abstract Female donor age not Miscarriage rate: 10.0%, differences
stated 9.8%, and 21.0%, between
respectively. groups in their
fertilization,
clinical
pregnancy, or
implantation
rates. The
abortion rate
was
significantly
higher in male
age >39 y,
compared with
the other 2
groups, as deter
mined using
chi-square
(P< .05).
Ho et al. (2015) Retrospective Donor 255 cycles Male age <40; 40–45; Pregnancy rate: 77.6%, Individual semen
Abstract 45–50; >50 y 73.6%, 72.5%, and parameters and
Female donor age not 78.85%, respectively. paternal age did

Fertil Steril Rev®

stated not have
significant
effects on
fertilization rate
or pregnancy
outcomes in
oocyte recipient
25

cycles.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.
 TABLE 3
26

Continued.
Autologous or Confounders
Author (y) Study design donated oocyte Study population Age groups studied Summary of results adjustment Conclusions
Robertshaw et al. Retrospective Donor 237 cycles Male age: 25-29; 30–34; There was 26% lower odds of Advanced PA has
(2014) 35–39; 40–44; 45–49; a live birth with each 5-year an adverse
50–54; >54 y increase in PA (odds ratio impact on ART
Female donor age 21–31 y 0.73; 95% CI 0.6–0.91; outcome. After
P< .01), after controlling adjusting for
for embryo grade, no. no. and embryo
transferred, and donor grades
age. transferred, a
younger PA has
a more
favorable ART
outcome.
Meyer et al. Retrospective Donor 332 pairs of couples Male age: <40; 40–49; Paired analysis of 146 recipient In shared OD cycles,
(2012) resulting in 664 R50 y couples (in which a single increased male
Abstract cycles Female age not stated donor’s oocytes were age is
fertilized by 1 male partner associated with
R50 and another <50) impaired semen
revealed no statistically parameters.
significant difference in However, this
day 3 IR, day 5 IR, total unique study
pregnancy rate, or live birth design, which
rate. used a paired
analysis of
younger and
older men that
shared the same
oocyte donor,
demonstrated
that paternal
age did not
appear to affect
significantly
pregnancy
outcomes.
Capelouto et al. Retrospective Donor 949 cycles Male age: %30; 31–35; A small effect of male age on Female recipient age Neither advancing
(2018) 36–40; 41–45; 46–50; CPR for men 46– 50 y (RR and BMI, prior male age,
R51 y 0.84; 95% CI 0.70–0.99), parity of the elevated BMI,
Female donor age 21–30 y but again this effect was female recipient, nor poor sperm
VOL. 1 NO. 1 / OCTOBER 2020

no longer apparent after no. of oocytes quality were

adjusting for female thawed, and no. associated with
recipient age and BMI, no. of embryos outcomes in
of prior births, no. of transferred. We frozen donor
embryos transferred, and also controlled for oocyte IVF
male BMI (aRR 0.91; 95% male age in the cycles.
CI 0.73–1.14). BMI analysis and
male
BMI in the age
analysis.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.
 Fertil Steril Rev®

studies scored >7 using the Newcastle-Ottawa Quality

outcomes when

Note: aRR ¼ adjusted relative risk; ART ¼ assisted reproductive technology; AUC ¼ area under the curve; BMI ¼ body mass index; CI ¼ confidence interval; CPR ¼ clinical pregnancy rate; FSH ¼ follicle stimulating hormone; GIFT ¼ gamete intrafollopian transfer;
donor is <36 y
Paternal age does
Assessment scale (Table 1).

not affect the

reproductive
Conclusions

the oocyte

of age.
Autologous Oocyte Studies
Clinical pregnancy in autologous oocyte studies. Eight
studies (11,004 cycles) showed CPRs according to paternal
age; semen origin
analysis including
covariates: donor

(fresh vs. frozen);

ICSI ¼ intracytoplasmic sperm injection; IVF ¼ in vitro fertilization; IR ¼ implantation rate; OD ¼ oocyte donation; OR ¼ odds ratio; PA ¼ paternal age; PR ¼ pregnancy rate; ROC ¼ receiver operating characteristic; RR ¼ relative risk.
age. The age ranges studied and the corresponding female
no. of embryos
Logistic regression

age; recipient
Confounders

ages are shown in Table 2. Meta-analysis of the data showed

adjustment

transferred. that CPR is higher when the man is aged <40 years (OR 1.65;
95% CI 1.24–2.19; P¼ .0005). The meta-analysis had high
heterogeneity with an I2 value of 79% (P< .00001;
Figure 3). One study reported CPR but used male age >50
years as the independent variable (42). This study was
95% CI 0.94–1.03; P¼ .52);

95% CI 0.94–1.03; P¼ .52).

biochemical pregnancy rate

excluded from the primary meta-analysis because data could

outcomes analyzed (OR for

P¼ .91); miscarriage (1.06;

(1.0; 95% CI 0.96 –1.05;

CI 0.94 –1.033; P¼ .52),

ongoing pregnancy rate

and live birth rate (0.98;

not be extracted for men aged 40–50 years. However, the data
Summary of results

were included in the subgroup analysis of the effect of male

Any of the reproductive

age >50 years.

a 5-year interval):

Live birth in autologous oocyte studies. Three studies (2,926

(0.98; 95%

cycles) reported live births according to paternal age. Meta-

analysis of the data from these studies showed that achieving
a live birth was more likely if the man was aged <40 years (OR
2.37; 95% CI 1.15–4.85; P¼ .02). The meta-analysis had high
heterogeneity with an I2 value of 62% (P¼ .07; Figure 4)
Female donor age 18–35 y
30–34; 35–39; 40–44;
45–49; 50–54; 55–59;

Miscarriage rate in autologous oocyte studies. Two studies

Male age %25; 25–29;
Age groups studied

(970 cycles) reported MR according to paternal age. It was

possible to calculate a MR from the data provided in two
further studies (20, 32). Meta-analysis of these four studies
showed that the chance of miscarriage was increased if the
>60 y

man was aged >40 years (OR 1.77; 95% CI 1.30–2.40;

P¼ .0003). The meta-analysis had low heterogeneity with an
I2 value of 0% (P¼ .51; Figure 5). The majority of the cycles
in the analysis were contributed by a single study (19).
Study population

Donor Oocyte Studies

4,887 cycles

Clinical pregnancy in donor oocyte studies. Seven studies

(8,241 cycles) reported clinical pregnancy rate according to
paternal age. Meta-analysis of these seven studies did not
find a significant difference in the chance of achieving a clin-
donated oocyte

ical pregnancy whether the male age was >40 years or <40
Autologous or

years (OR 0.95; 95% CI 0.84–1.07; P¼ .41). The included

Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.

studies had a low level of heterogeneity with an I2 value of

Donor

15% (P¼ .32; Figure 6).

Live birth in donor oocyte studies. Five studies (7,648 cycles)
reported LBR according to male age. Meta-analysis of these
five studies did not find a significant difference in the chance
Study design
Retrospective

of having a live birth whether the male age was >40 or <40
years (OR 1.03; 95% CI 0.80–1.32; P¼ .84). There was a high
statistical heterogeneity with an I2 value of 77% (P¼ .002;
Figure 7).
Miscarriage rate in donor oocytes studies. Four studies (3741
cycles) reported MR according to male age. Meta-analysis of
Begueria et al.

these four studies did not find a significantly increased risk

TABLE 3

Continued.

(2014)
Author (y)

of miscarriage if the male age was >40 years (OR 1.08; 95%
CI 0.70–1.65; P¼ .73). The studies had a high level of heteroge-
neity with an I2 value of 70% (P¼ .02; Figure 8).

VOL. 1 NO. 1 / OCTOBER 2020 27

FIGURE 3
Effect of paternal age on clinical pregnancy rate (CPR). Autologous oocytes. CI ¼ confidence interval; M-H ¼ Mantel-Haenszel.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.
Male Age >50 Years Subanalysis
We performed a subgroup analysis of clinical outcomes when
data for male age >50 years was reported. Data were extracted
from all studies that provided information for a treatment
group with the male age >50 years. Of the autologous oocyte
studies only three studies provided a male age grouping >50
years (19, 30, 42). These studies (5,572 cycles) using autolo-
gous oocytes reported CPR when the male age was >50 years.
Meta-analysis of these three studies showed no difference in
CPR if the male age was >50 years (OR 1.28; 95% CI 0.81–
2.03; P¼ .29). There was moderate heterogeneity between
the two studies with an I2 value of 49% (P¼ .14; Figure 9).
Six studies (8,227 cycles) of donor oocyte ART reported
CPR with male age >50 years. Meta-analysis of these studies
FIGURE 4
Effect of paternal age on live birth rate (LBR). Autologous oocytes. CI ¼ confidence interval; M-H ¼ Mantel-Haenszel.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.
28
did not find a difference in clinical pregnancy using donor
oocytes if the male age was >50 years (OR 0.92; 95% CI
0.72–1.19; P¼ .53); and there was a moderate level of hetero-
geneity between the studies with an I2 value of 46% (P¼ .10;
Figure 10).
Six studies (8,748 cycles) using donor oocytes reported
LBR with male age >50 years. Meta-analysis of the studies
found no difference in the LBR when the male age was >50
years (OR 1.16; 95% CI 0.95–1.40; P¼ .14). There was low-
level heterogeneity between the studies with an I2 value of
29% (P¼ .21; Figure 11). Five studies (4,611 cycles) of donor
oocyte ART reported MR with male age >50 years. Meta-
analysis of the studies showed a trend toward increased risk
of miscarriage if the male age was >50 years, but this did
VOL. 1 NO. 1 / OCTOBER 2020
 Fertil Steril Rev®

FIGURE 5

Effect of paternal age on miscarriage rate (MR). Autologous oocytes. CI ¼ confidence interval; M-H ¼ Mantel-Haenszel.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.

not reach statistical significance (OR 1.41; 95% CI 0.96–2.08;
P¼ .08). There was a low degree of heterogeneity between the
studies with an I2 value of 35% (P¼ .18; Figure 12).
DISCUSSION
This systematic review, including ten autologous oocyte
observational studies and 11 donor oocyte observational
studies, provides evidence for the impact of male age on the
outcome of ART. The meta-analysis of the donor oocyte
studies suggests that increased male age, >40 years old or
even >50 years, does not have a negative impact on the clin-
ical outcome of ART. The MR with treatment with donor oo-
cytes does not appear to be increased for older men. This
contrasts with the analysis of the autologous oocyte studies
that suggest male age >40 years reduces the chances of clin-
ical pregnancy and live birth while also increasing the chance
of having a miscarriage.
There have been two methods used to assess the effect of
increasing male age: retrospective/prospective cohort studies

FIGURE 6

Effect of paternal age on clinical pregnancy rate (CPR). Donor oocytes. CI ¼ confidence interval; M-H ¼ Mantel-Haenszel.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.

VOL. 1 NO. 1 / OCTOBER 2020 29

FIGURE 7

Effect of paternal age on live birth rate (LBR). Donor oocytes. CI ¼ confidence interval; M-H ¼ Mantel-Haenszel.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.

in couples attending fertility services and retrospective/pro-
spective cohort studies using donor egg treatments to attempt
to account for the effect of increasing female age. A system-
atic review of studies assessing the effect of paternal age on
ART outcome found there to be insufficient evidence to
demonstrate an unfavorable effect of paternal age on ART
outcomes (16). Since that review, a number of larger cohort
studies have been performed, however, the results of these
studies have been contradictory. Some studies have
found that paternal age has a detrimental effect on outcome
(19–21, 43) and others have not found evidence of a
detrimental effect (21, 30, 44, 45). A systematic review of
studies performed using the donor egg model suggested that
advancing paternal age is not associated with adverse
oocyte donation outcomes (17). Many studies used an upper
age range of >40 years for male age when assessing
outcome and the numbers of men aged >50 years were
often very low or not described. One study that

FIGURE 8

Effect of paternal age on miscarriage rate (MR). Donor oocytes. CI ¼ confidence interval; M-H ¼ Mantel-Haenszel.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.

30 VOL. 1 NO. 1 / OCTOBER 2020

 Fertil Steril Rev®

FIGURE 9

Effect of paternal age >50 years on clinical pregnancy rate (CPR). Autologous oocytes. CI ¼ confidence interval; M-H ¼ Mantel-Haenszel.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.

demonstrated an effect of increasing paternal age found that
this was evident when male age was >50 years (19).
Our analysis has a number of strengths. A comprehensive
search strategy, interrogating relevant databases, was used. A
valid method of data synthesis was used, and the included
studies were assessed using the validated Newcastle-Ottawa
Quality Assessment Scale. The included studies scored well,
which suggests a low risk of bias.
There were weaknesses in our analysis, which originate in
the clinical heterogeneity of the included studies. One source
of clinical heterogeneity for the autologous oocyte studies
was the maternal age of the couples. Three of the studies
included women >40 years (27, 29, 32) and three of the
studies only reported median maternal age per paternal age
group. To attempt to control for maternal age we excluded re-
sults for women aged >40 years, however, for Nijs et al. (32)

FIGURE 10

Effect of paternal age on clinical pregnancy rate (CPR). Donor oocytes. CI ¼ confidence interval; M-H ¼ Mantel-Haenszel.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.

VOL. 1 NO. 1 / OCTOBER 2020 31

FIGURE 11

Effect of paternal age >50 years on live birth rate (LBR). Donor oocytes. CI ¼ confidence interval; M-H ¼ Mantel-Haenszel.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.

and Kumtepe et al. (29), a small number of women >40 years
of age were included. Some heterogeneity is to be expected
because the included studies spanned two decades and
different geographical locations, and, therefore, include
differing populations as well as different clinical protocols.
It also could be affected by the shifting nature of the popula-
tion that seeks fertility treatment. Although this may be a
weakness of the analysis, it also may make our findings
more generalizable. In the included studies there were insuf-
ficient details of the adjusted analysis for known confounders
such as maternal body mass index. We did not include a
meta-analysis of the adjusted ORs. The populations examined
in the studies were different, two studies included couples
with defined male factor infertility, and two studies (20, 30)
explicitly only included first cycles of ART whereas others
may have included multiple cycles from the same couple.

FIGURE 12

Effect of paternal age >50 years on miscarriage rate (MR). Donor oocytes. CI ¼ confidence interval; M-H ¼ Mantel-Haenszel.
Morris. Paternal age and ART: is there an effect? Fertil Steril Rev 2020.

32 VOL. 1 NO. 1 / OCTOBER 2020


The conflicting findings of the autologous studies and
donor oocyte studies may represent the difficulty in control-
ling for female age across the included studies. All of the
autologous oocyte studies reported a statically significant as-
sociation between male age and female age. Female age was
controlled using different methods in the studies included.
One study included only cycles of ART when female age
was %35 years (28); one study limited maternal age to <39
years and performed linear regression analysis including
female age (30); one study included only women aged <40
years and reported that maternal age was not significantly
different between the two groups analysed (31); one study
matched couples according to maternal age into the two
male age cohorts with mean age of both groups of 33.2 years
and 32.7 years, respectively; four of the studies used
regression analysis to account for the effect of maternal age
(15, 27, 29, 32). Increasing female age could be a confounder
that may explain the observed effect of paternal age in the
autologous studies in our meta-analysis. The strength of the
donor oocyte model is that maternal age is controlled for
much more robustly. That the analysis of the donor oocyte
studies did not find a statistically significant effect of
increased male age lends weight to the argument that the
observed effect in the autologous studies is a result of statis-
tical heterogeneity or confounding. That no effect on live
birth or clinical pregnancy was seen in the donor oocyte
model even when male age >50 years was considered sug-
gests that paternal age does not exert an independent effect.
Similarly, the fact that we did not find an association between
male age >50 years and CPR in autologous oocytes may
reflect that these men have younger partners. Thus, reinforc-
ing that it is maternal age that is the most important determi-
nant of outcome.
Increasing male age is associated with increasing sperm
DNA fragmentation (46–48) with increased DNA damage
being evident at >45 years of age (47). DNA damage may
be attributable to both intra-gonadal and extra-gonadal fac-
tors such as oxidative stress producing reactive oxygen spe-
cies and ineffective apoptosis prior to ejaculation (49, 50).
DNA fragmentation has been associated with reduced success
of ART (51, 52). There are numerous repair pathways by which
the oocyte can repair damaged sperm DNA (53, 54). The abil-
ity of the oocyte to resist DNA damage appears to decrease
with increasing female age (54); because there is a consistent
correlation with increasing male and increasing female age
one would expect the impact of increasing male age to be syn-
ergistic with that of female age. Indeed, that is what one of the
included studies demonstrated through their analysis (20).
Our analysis of the autologous oocyte studies showed that
MR increases with male age >40 years. This may be explained
by the mechanisms that link DNA fragmentation with recur-
rent miscarriage (55). If DNA damage is the mechanism
through which the observed decrease in clinical pregnancy
and LBR occurs, then the importance of effective sperm selec-
tion techniques that could be used to mitigate this effect is
clear (56). A number of studies have observed that the use
of ICSI mitigated the effect of increased sperm DNA fragmen-
tation (51, 52). The recent large hyaluronan-selected intracy-
toplasmic sperm injection for infertility treatment
VOL. 1 NO. 1 / OCTOBER 2020
Fertil Steril Rev®
randomized controlled trial found no improvement in live
birth but noted a significant reduction in miscarriage when
using physiological ICSI rather than conventional ICSI (57).
Our review and meta-analysis, based on the donor oocyte
model, suggests that advanced male age is not associated with
poorer outcomes from ART and is unlikely to affect negatively
the chance of success. The association between increased
male age >40 years and poorer outcome from ART for studies
with autologous oocytes is likely to be related to the strong
association with increasing maternal age and inadequate
controlling for that in these studies.
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