Review

Infertility and miscarriage: common

pathways in manifestation and
management

The relationship between miscarriage and fertility is complex. While most healthcare Angena Agenor1
settings treat miscarriage as a problem of subfertility in assisted reproduction units, & Sohinee Bhattacharya*,2
others believe that miscarriage occurs in super-fertile women. Infertile women
1
Department of Obstetrics
& Gynaecology, University of Aberdeen
undergoing assisted reproduction are at a greater risk of having a miscarriage especially
Medical School, Foresterhill, Aberdeen,
at an advanced age compared with women conceiving naturally. Aberrant expression AB25 2ZD, UK
of immunological factors and chromosomal abnormalities underlie both infertility 2
Dugald Baird Centre for Research on
and miscarriage. Common risk factors include increased maternal age, obesity, Women’s Health, Aberdeen Maternity
smoking, alcohol, pre-existing medical conditions and anatomical abnormalities of Hospital, Cornhill Road, Aberdeen,
AB25 2ZL, UK
the reproductive system. Management pathways of both conditions may be similar
*Author for correspondence:
with pre-implantation genetic testing and assisted reproductive technology used Tel.: +44 012 2443 8441
in both conditions. This paper discusses the synergies and differences between the sohinee.bhattacharya@ abdn.ac.uk
two conditions in terms of their epidemiology, etiopathogenesis, risk factors and
management strategies. The two conditions are related as degrees of severity of
reproductive failure with common pathways in manifestation and management.

Keywords: advanced maternal age • assisted reproductive technology • infertility

• miscarriage • recurrent miscarriage • spontaneous abortion • subfertility

Infertility and miscarriage are often treated
in clinical practice as two separate phenom-
ena with distinct etiopathologies and clinical
management [1] . Infertility and miscarriage
are common events of human reproductive
failure, with infertility affecting one in six
couples of reproductive age and miscarriage
occurring in 15–20% [2] of all pregnancies,
but whether there is a causal relationship
between the two conditions remains unclear.
Human reproduction is an inefficient pro-
cess with nearly 30% of embryos being lost at
the implantation stage. At post-implantation,
but before the first missed menses, 30% of
biochemical pregnancies are lost and can
only be diagnosed by falling human cho-
rionic gonadotropin levels. After the first
missed menses, 10% of embryos are lost and
are termed clinical miscarriage [3] .
Research has shown that women who
experience miscarriage are often labeled as
subfertile [4] and infertile women have a
greater risk of miscarriage [5] . On the other
hand, some researchers believe that women
who suffer recurrent miscarriage are actu-
ally superfertile, and the miscarriage is
nature’s way of controlling the number of
pregnancies in these women. Furthermore,
miscarriage is common after undergoing
infertility treatments. These findings sup-
port the theory that infertility and mis-
carriage share common etiopathogenic
pathways and are in fact in a continuum
of human reproductive failure, with total
infertility and live birth at the two extreme
ends of the spectrum [6] .
Human reproductive failure ranges from
an inability to conceive through the incapac-
ity to maintain pregnancy, or pregnancy loss
after successful conception. Figure 1 depicts a
prediction of human reproduction success by
outlining probable reproductive outcomes of
an ovarian cycle in 1000 healthy, young and
part of
fertile females [7] .

10.2217/WHE.15.19 © 2015 Future Medicine Ltd Womens Health (2015) 11(4), 527–541 ISSN 1745-5057 527
Review Agenor & Bhattacharya

Genetic factors
Immunological factors
Gamete development
Genes effecting fertility and
Cytokines gamete development

Fertilization

Antisperm Adhesion factors

antibodies or integrins Embryo cleavage Genes effecting
embryo cleavage

Blastocyst/trophoblast
formation Factors effecting
Leukemia gene expression
HLA expression
inhibitory factor

Antiphospholipid antibodies Implantation

Genes effecting embryo
and fetal development
Mucins
Fetal development and
Endometrial adhesion survival
factors
Uterine NK
cells
Parturition

Figure 1. Follow-up of 1000 reproductive cycles.

HLA: Human leukocyte antigen; NK: Natural killer cell.

If pregnancy is defined as commencing at the time
of implantation, pregnancy wastage can occur at any
time after the blastocyst implants in the uterus. This
paper describes the synergy between the two conditions
of reproductive failure – infertility and miscarriage in
terms of their epidemiology, etiopathogenesis, diagnosis
and management. We also highlight the differences in
these aspects of the two conditions and hypothesize that
these differences are of degree rather than absolute [7] .
Epidemiology of infertility & miscarriage
Definition & classification
The definitions used to classify aspects of human
reproductive failure lack standardization and are com-
plicated by nomenclatures used by some authors and
not by others, making comparability between studies
difficult. The medical literature differentiates between
a clinical/epidemiological versus a demographical
definition of infertility (Table 1) .
The World Health Organization and the Interna-
tional Committee for Monitoring Assisted Reproduc-
tive Technology defines infertility as ‘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’ [8] . This definition
stems from the biological observation that 85–90%
of noncontracepting couples of normal reproductive
health will achieve conception within a year [9,10] . The
epidemiological definition of infertility lengthens the
12-month period to 24 months or more, while the
demographic approach extends this even further to
5 years [11] . Other definitions however shorten this to
6 months [12] . Demographers define infertility as the
inability to remain pregnant or achieve a live birth.
This definition is closer to the public viewpoint as live
birth rather than conception is the desired outcome.
Infertility is further classified as primary or sec-
ondary and by the etiology subtype. According to
WHO, primary infertility occurs when a woman fails
to achieve conception. Secondary infertility, however,
arises after the achievement of a pregnancy and the
failure to subsequently conceive [13] .
Couples who are unable to conceive but have absence
of abnormalities after an evaluation of their fertil-
ity profile are said to have unexplained or idiopathic
infertility [12] .
Miscarriage on the other hand, is defined by WHO
as pregnancy loss due to expulsion or death of the fetus

528 Womens Health (2015) 11(4) future science group

 Infertility & miscarriage: common pathways in manifestation & management Review

Table 1. Published definitions of infertility.

Organization Definitions
NICE guideline 2004 Infertility should be defined as failure to conceive after regular
unprotected sexual intercourse for 2 years in the absence of
known reproductive pathology
American Society for Reproductive Infertility is a disease defined by failure to achieve a successful
Medicine 2008 pregnancy after 12 months or more of regular unprotected
intercourse. Earlier evaluation and treatment may be justified
based on medical history and physical findings and is
warranted after 6 months for women over age 35 years
International Committee for Monitoring Infertility (clinical definition): a disease of the reproductive
Assisted Reproductive Technology and system defined by the failure to achieve a clinical pregnancy
WHO 2009 after 12 months or more of regular unprotected sexual
intercourse
Demographic definition Inability of a noncontracepting, sexually active woman to have
a live birth

or embryo weighing ≤500 g, and before 20–24 weeks’
gestational age [11] . Miscarriage is classified as first
trimester ≥12 weeks’ gestation (early) or late, which
ranges from 12–24 weeks’ gestation. In addition to
these commonly used definitions, there are various
terms in use to classify infertility and miscarriage [12] .
Terms used to describe miscarriage include ‘abor-
tion’ or ‘spontaneous abortion’, however, the social
stigma associated with these terms has made them less
popular, and moreover may be confused with thera-
peutic termination of pregnancy. ‘Early fetal demise’
or ‘early pregnancy loss’ are acceptable terminology
for miscarriage and are further classified depending
on ultrasound or clinical parameters [3] . Depending
on the timing and stage of development of conceptus,
miscarriage may be termed as implantation failure or
embryonic demise.
Recurrent miscarriage is defined as three or more
consecutive pregnancy losses prior to 24 weeks’
gestation and occurs in 1–3% of reproductive age
women [14] . There is a wide debate regarding the defi-
nition of recurrent miscarriage, with some Early Preg-
nancy Units defining the condition as two or more
miscarriages if the losses occur in women above the age
of 35 or in the second trimester. Table 2 summarizes
suitable terms recommended by the European Society
of Human Reproduction and Embryology’s Special
Interest Group in early pregnancy events [15] .
Prevalence
For both infertility and miscarriage, the prevalence
within and between different geographical locations
is difficult to determine, this is due to heterogene-
ity in terms of the definitions, nature of the sampled
population, the denominator used in its calculation,
exposure and outcomes [12] . For instance, according
to Biovin et al., it is estimated that approximately
72.4 million women in a consensual relationship, aged
20–44 years, are infertile [16] . However, this is in con-
trast to the 2004 Demographic and Health Survey
report by WHO on fecundity and infertility which
stated that 186 million married women in develop-
ing countries aged 15–49 years were infertile due to
primary or secondary infertility.
A universally quoted figure for sporadic miscar-
riage is one in five for clinically recognized pregnan-
cies [17] . A miscarriage rate of 31% was found in an
observational study of 200 women within 3 months of
conception. A biochemical pregnancy rather than an
ultrasound recognizable pregnancy was found in 41%
of these women [18] . A similar study reported a mis-
carriage rate of 11% for clinical pregnancy and 26.9%
for biochemical pregnancy. A 12% pregnancy loss was
reported before 8 weeks’ gestation in 630 women [19] .
Thus in terms of definitions, both infertility and
miscarriage are similar in that both conditions result
in childlessness. Both conditions however, are defined
variously in the literature and the population preva-
lence of the conditions are dependent on the definitions
used, making a case for standardization of definitions.
Ethiopathogenesis of infertility
& miscarriage
Immunological factors
The presence of paternally inherited genes in the
implanted blastocyst makes it a foreign graft, which
would consequently be rejected if certain factors in
the maternal–fetal interface did not prevent it. Thus
abnormalities in the maternal immune tolerance to a
semi-allogeneic allograft may cause a miscarriage. Var-
ious immunological factors influence reproduction and
lack of expression of these factors could contribute to

future science group www.futuremedicine.com 529

Review Agenor & Bhattacharya

Table 2. Terms and definitions recommended by the European Society for Human Reproduction and
Endocrinology’s Special Interest Group in early pregnancy events.
Term Definition
Biochemical pregnancy loss Positive pregnancy test history followed by negative test, no
ultrasound assessment performed
Implantation failure Where the pregnancy sac has never been visualized in the uterus
Early pregnancy loss or delayed Intrauterine pregnancy with indication of fetal heart activity lost
miscarriage and/or crown lump length not increasing over 1 week or presence
of an empty sac, at less than 12 weeks’ gestation
Late pregnancy loss After 12 weeks’ gestational age where fetal measurement was
followed by loss of fetal heart activity
Empty sac Gestation sac with absent embryonic structures or gestation sac
with embryonic structures and no heart activity
Fetal/ embryonic loss Previous identification of embryo or fetus and fetal heart activity
followed by loss of heart activity
Heterotopic pregnancy Intrauterine plus ectopic pregnancy (e.g., tubal, cervical, ovarian
and abdominal)
Pregnancy of unknown location No identifiable pregnancy on ultrasound with positive
blood/urine HCG
HCG: Human chorionic gonadotropin.

human reproductive failure. Thus, the achievement of
fertilization and pregnancy maintenance depends on
the interaction between these factors. Current research
implicates the role of HLA expression, integrins, anti-
sperm antibodies (ASA), cytokines, leukemia inhibi-
tory factor (LIF), antiphospholipid antibody (APA),
mucin 1, endometrial adhesion factors and uterine
natural killer cells in reproduction.
Contrastingly, scarce evidence supports association of
T cells, antiendometrial antibodies, antitrophoblast anti-
bodies, anti-HLA antibodies, peripheral natural killer
cells and inadequacy of blocking antibodies and sup-
pressor cells in reproduction [1] . Both organ-specific and
systemic autoimmunity have been reported to be asso-
ciated with an increased risk of recurrent miscarriage.
Prothrombotic mechanisms, as well as direct inhibitory
actions against trophoblastic activity have been demon-
strated in antiphospholipid antibody syndrome associ-
ated with miscarriage. In women with recurrent miscar-
riage a disturbed T-helper cell profile is often seen, where
reduced numbers of Tregs have been reported. These
cells are necessary for regulating excessive activity of the
Th1 and Th17 subsets. These cells, operating through
excessive natural killer cell activity, may have antipreg-
nancy effects and may be crucial in investigating unex-
plained infertility or miscarriage. [20]
Figure 2 summarizes immunological and immunoge-
netic factors and their interactions during primiparous
pregnancy [1] .
HLA may impact various stages of gestation
(Figure 2) , its expression is associated with increased
successful implantation and elevated rates of embryo
cleavage [21,22] . Studies in closely related human popu-
lations showed that sharing of certain maternal–fetal
or paternal HLA antigens may influence fetal devel-
opment and survival. If intact, trophoblast or fetal
cells enter maternal circulation, antibodies produced
by stimulated maternal B cells can be targeted against
fetal HLA proteins [23,24] . Research in the 1980s sug-
gested that normal pregnancy required anti-HLA anti-
bodies as women with recurrent miscarriage (RM)
rarely had anti-HLA. This suggested that lack of HLA
could indicate abnormal maternal immune response
to the fetus [25–27] . However, later studies discovered
that only 5% of women who carried pregnancy to term
during the first trimester had anti-HLA antibodies in
comparison to 10% of anti-HLA antibodies rates in
women who had miscarried [28] .
Presently, anti-HLA antibodies are not regarded as
important factors associated with pregnancy mainte-
nance, instead anti-HLA antibodies may be the result
of later stages of pregnancy. This is reinforced by evi-
dence in which 62% of 226 women with live births
failed to develop anti-HLA antibodies, whereas those
who did develop anti-HLA antibodies did so only after
28th week of gestation [29] .
Antisperm antibodies mainly affect gamete devel-
opment and fertilization, although they might also
influence pregnancy (Figure 2) . Both sexes can produce
ASA and ASA in blood has been linked to reduced
fertility in both sexes and may cause disturbance of
sperm-oocyte fusion and recognition during fertiliza-

530 Womens Health (2015) 11(4) future science group

 Infertility & miscarriage: common pathways in manifestation & management Review

tion [30] . The quality of semen, sperm maturation or
function may be adversely affected by ASA in men [31] .
In women, postcoital survival of sperm in the repro-
ductive tract may be affected and female infertility
at different stages of reproduction can be caused by
ASA [32,33] .
Studies in the 1980s discovered that ASA-positive
women had lower rates of pregnancy than ASA-neg-
ative women. However, in these earlier studies serum
samples were collected only after miscarriage had
occurred suggesting ASA may be a result of pregnancy
loss rather than a cause [34,35] . Later studies found no
association between ASA and recurrent miscarriage or
outcomes of IVF pregnancies. [36–38] .
Integrins are adhesion molecules that facilitate
cell–substratum and cell–cell interactions, which
may play a role in fertilization, implantation and
development of the placenta in humans (Figure 2) [1] .
For instance, obstruction of certain integrin recep-
tors prevents the binding of human spermatozoa to
zona-free hamster oocyte [39] . Unexplained infertility
in women has been associated with non-expression
of certain integrin subunits, whereas infertile women
have a deferred expression of certain integrins [40] .
Nevertheless, the importance of integrins in human
reproduction remains unclear.
Primitive interactions between oocytes and the
female reproductive system, gamete development and
embryonic and blastocyst development and implanta-
tion may be regulated by LIF [41] . LIF expression has
been detected in the fallopian tube and follicular fluid
which influences oocyte transportation and fertiliza-
tion and embryonic development [42] . However, one
study reported that there was no association between
LIF expression in follicular fluid and development
of IVF embryos [43] . Alterations in LIF expression in
human endometrium during implantation has been
linked to human reproductive failure. In vitro endome-
trial cultures from fertile women indicated an increase
in LIF; contrastingly LIF concentrations remained
constant in infertile women whereas women who had
numerous implantation failures had a decrease in LIF
concentrations [44] .
APA possibly affects pregnancy from the blastocyst/
trophoblasts stage through parturition (Figure 2) . Anti-
cardiolipin and lupus anticoagulant are the best charac-
terized APA linked to reproductive failure [45–47] . Fetal
loss and disturbance of pregnancy has been associated
with high APA concentrations. High concentrations
of APA have been found in infertile women compared
with fertile controls [48] . However, in IVF studies, the
significance of APA is controversial. Smaller studies
implicated high concentration of APA in the failure
of IVF [49–52] while other larger studies found no asso-
ciation between APA and reproductive outcome [53,54] .
In this context it should be noted that APA is clearly
associated with fetal death but evidence regarding its
association with infertility and early pregnancy loss is
controversial and inconclusive [55] .
Cytokines are involved in gamete development,
trophoblast invasion, implantation, placental devel-
opment, decidualization and immune tolerance to
pregnancy [56] . Cytotoxic reactions and tissue injury
in disease are produced by Th1 whereas antibody pro-
duction and promotion or eosinophil function is medi-
ated by Th2 [57] . Thus pregnancy maintenance may
depend on whether immune response is pathological
or protective suggesting a possible role of cytokines in
reproductive outcome [58–60] . For instance, some stud-
ies reported that women with higher rates of recurrent
spontaneous abortion (RSA) had a higher concentra-
tion of Th1 cytokines whereas women with successful
pregnancies had higher levels of Th2 cytokines [60–62] .
Natural killer (NK) cells which are found in periph-
eral circulation may play a role during the various
stages of pregnancy (Figure 1) . Elevated peripheral
NK cells (CD56 + and CD56 +/CD16 +) in some RM
women have been reported [63] . It was also found that
high preconceptional NK activity in RM women sig-
nified a higher risk of subsequent miscarriages com-
pared with women who had normal preconceptional
profile [64] . Nevertheless using peripheral NK numbers

No ovum
n = 50 (5%) No fertilization
Reproductive
cycles n = 1000 n = 71 (7.5%)
Ovum in fallopian No implantation
tube 950 (95%) Fertilization n = 103 (12%) Early pregnancy Miscarriage
n = 879 (92.5%) loss n = 103 (13%) n = 67 (10%)
Implantation
n = 776 (88%) Clinical Perinatal deaths
pregnancies n = 6 (1%)
n = 673 (87%)
Live births
n = 600 (89%)

Figure 2. Immunogenetic factors involved in regulation of fertility and miscarriage.

future science group www.futuremedicine.com 531

Review Agenor & Bhattacharya
as a predictor of reproductive failure may not be reli-
able. Concentration of CD56 + predicted 86% of repro-
ductive outcome in RM women, whereas in infertile
women CD56 + was a poor predictor of reproductive
outcome [65–68] . Uterine NK cells, a category of NK-
like cells, present at the fetal–maternal interface may
play a more active role in reproduction than peripheral
NK cells. Elevated concentration of uterine CD57+ NK
cells has been found in women with RM [66,69] .
Hemostatic pathways are intimately involved in ovu-
lation, implantation and development of the tropho-
blast or placenta. Trophoblast function is affected in
women with inherited or acquired thrombophilia, and
consequent abnormal placentation can result in preg-
nancy loss or other complications of pregnancy [70] .
Similar mechanisms could underlie repeat implanta-
tion failure during IVF and recurrent pregnancy loss.
Complement-inhibitory proteins, maternal regulatory
T cells, tryptophan-catabolizing enzymes and immu-
noregulatory cytokines present at the maternal–fetal
interface are thought to maintain maternal tolerance to
fetal antigens and thereby help in preserving the preg-
nancy. Hence protein C, protein S, antithrombin III,
lupus anticoagulant, activated protein C resistance,
immunoglobulin M and G anticardiolipin antibod-
ies, homocysteine, Factor V Leiden, prothrombin
G20210A mutation, methylenetetrahydrofolate reduc-
tase C677T mutation, antithyroglobulin antibodies
have all been implicated in unexplained infertility,
implantation failure and recurrent miscarriage [71,72] .
Thus, depending on the point of action in the fertil-
ity process, immunological disturbances may result in
either miscarriage or infertility. [73,74]
Chromosomal abnormalities
Accurately assessing the genetic contributions to infer-
tility and susceptibility to miscarriage is difficult as
other contributing components such as immunological,
hormonal and advanced age are likely to have a genetic
element. A current theory suggests that occurrence of
most of the chromosomal abnormalities are de novo
and are due to random errors created during embry-
onic development and gametogenesis [75] . Genetic test-
ing of miscarriage samples has enabled miscarriage to
be viewed as a rescue mechanism to impede the contin-
ued growth of an abnormal implanted pregnancy [76] .
Chromosomal abnormalities are the most common
causes (50%) of first trimester pregnancy losses and are
associated with a reduction in fertility [77] . It is suggested
that submicroscopic chromosomal alterations not iden-
tified by conventional cytogenic analysis can provide an
explanation for some unexplained miscarriages [78] .
Maternal advanced age associated with trisomies is
the most common risk factor for infertility and mis-
532 Womens Health (2015) 11(4)
carriage, accounting for approximately 25% of all
first trimester pregnancy losses. Furthermore, other
aneuploid concepts such as trisomies 1 and 19 are lost
before they are clinically detected. Aberrant spermato-
genesis may cause reciprocal Y-autosome transloca-
tion – t(13q14q) is the most frequent Robertsonian
translocation identified in infertile males and arises
from unusual behavior of the rearranged autosomes
during spermatogenesis [79,80] . In a 1990 review based
on 22199 couples who experienced multiple pregnancy
losses, 5% of the couples had chromosomal abnormal-
ities (inversion and reciprocal and Robertsonian trans-
location). This carriership was ten-times more likely to
occur in RM couples than in the normal population.
Factor V Leiden is the most frequently inherited
predisposition to thrombosis [81] . It was discovered
that 9% of 139 abortuses had an elevation of Factor
V Leiden carrier frequency compared with 4% of 403
unselected pregnant females [82,83] . However, some
studies found no association between Factor V Leiden
and RM, especially if the miscarriage occurred early in
pregnancy [84–86] .
Sperm chromosome abnormalities, multifactorial
disorders and skewed X chromosomes inactivation
are some other genetic mechanisms which may influ-
ence the etiology of pregnancy loss [87] . Research of
spermatozoa and RM found no substantial differ-
ence between the spermatozoa of the RM group and
that of the control for the following factors: rate of
aneuploidy, total rate of anomalies, hyperhaploidy and
hypohaploidy and total rate of structural anomalies.
However, the study did demonstrate an important
difference in the incidence of chromosome breaks [88] .
Chromosomal abnormalities, especially maternal
age associated trisomies play a role in the etiopatho-
genesis of both infertility and miscarriage although
the specific abnormalities implicated vary in the two
conditions. While Factor V Leiden is most commonly
implicated genetic predisposition to miscarriage and
recurrent miscarriage, sperm chromosomal abnormal-
ities play a greater role in male factor or unexplained
infertility.
Risk factors common to infertility
& miscarriage
Advanced age
Numerous studies have demonstrated the relationship
between advanced age with a decrease in fertility and
the increasing incidence of miscarriage [89–91] . The pri-
mary causes for the reduction in fertility are due to the
decrease in oocyte number and oocyte quality. The
decline in oocyte quality can be observed in IVF patients
where the embryo viability decreases with age [92,93] .
Aneuploidy is the main cause of miscarriage in these
future science group
 Infertility & miscarriage: common pathways in manifestation & management
groups of women. Over the age of 40 years, only 50%
of women are still capable of conceiving and the risk
of miscarriage is five-times greater than 31–35-year-old
women. Furthermore, within 10 years half of these
women would have reached menopause [93] .
Maternal obesity
Although maternal obesity has not been shown in the
literature to be a risk factor for infertility per se, access
to assisted reproduction techniques (ART) is often
restricted for overweight and obese women until they
have lost weight. The reason for this is that pregnancy
outcomes of ART are often poor in women with a high
BMI [94] . Moreover, in a meta-analysis of observational
studies, Metwally et al. showed that maternal obesity
was strongly associated with both the risk of sporadic
and recurrent miscarriage in spontaneous and assisted
conceptions [95,96] .
Smoking
The harmful effect of tobacco on fertility and reproduc-
tion is under appreciated. Cumulative data supporting
the evidence that cigarette smoke has an adverse effect
on fertility have been summarized by several reviews [97–
102] . A recent large-scale study with a sample of nearly
15,000 pregnancies investigated the time to conception.
Along with smoking other factors such as ethnicity,
alcohol consumption and parental age were assessed to
determine their level of impact. It was discovered that
failure to achieve conception within 6–12 months was
linked to active smoking. This delay in conception was
54% higher in smokers than in nonsmokers [103] .
Increasing risk of miscarriage (natural and assisted
reproduction) has been linked to smoking through
many studies [104,105] . One study using women
14–39 years old [105] found that 34.6% of women who
had a miscarriage smoked, as compared with 21.8%
smokers among those who did not have a miscarriage.
Other studies showed that smokers required twice
as many IVF cycles to conceive compared with non-
smokers. Additionally the damaging effect of smoking
is more distinguishable in older women [105] . Limited
data are available on the possible link between smok-
ing and chromosomal abnormalities in abortus tissue.
Nonetheless, some constituents of cigarettes such as
nicotine, cyanide and carbon monoxide may result in
placental deficiency and restrict embryonic and fetal
growth, leading to their demise. Other effects include
ovarian follicular depletion and loss of reproductive
function [106] .
Alcohol
Alcohol intake has been reported to show a connec-
tion with pregnancy loss. These reports, however,
future science group
Review
fail to determine the direct impact of alcohol and the
influence of secondary changes consequent of alcohol-
ism, like cirrhosis [107] . Moreover, Abel observed that
blood alcohol levels >200 mg/dl could promote mis-
carriage [108] . Nonetheless, the link between moderate
alcohol consumption and spontaneous abortion (SA)
is undecided. For instance, Harlap and Shiono stated
that miscarriage risk is only increased in females with
habitual moderate consumption but not for moder-
ate consumption. Furthermore, they reported a two-
fold increased risk of miscarriage with daily alcohol
consumption compared with nondrinkers [109] . Also,
Anokute has indicated a dose–response association
between miscarriage and alcohol consumption [110] ,
whereas Parazzini, among several studies have disputed
this alcohol miscarriage association [111] .
Currently, knowledge on the effect of alcohol con-
sumption on fertility is limited as these studies gener-
ally depend on timing and levels of alcohol consump-
tion [112] , but in men alcohol can reduce libido and
quality of sperm and cause impotence [113,114] .
A study that looked at alcohol consumption in both
sexes before and during ART treatment found that
alcohol consumption by both partners reduced prob-
ability of a live birth and elevated the risk of a miscar-
riage [115] . Contrastingly, in a similar study no asso-
ciation was found between female fertility and alcohol
consumption [116] .
Pre-existing medical disorders including
gynecological disorders
Polycystic ovarian syndrome (PCOS) is associated
with infertility. Characteristics of PCOS that cause
infertility include ovarian dysfunction and hyper-
insulinemia which may disturb follicular matura-
tion inhibiting a dominant follicle selection [6,117] .
The effect of the condition on pregnancy loss is not
established, but it is speculated that PCOS may indi-
rectly increase the risk of miscarriage. The majority of
PCOS patients are obese and obesity, including high
BMI, increases miscarriage frequency independently of
PCOS. Furthermore, insulin resistance in PCOS has
a two- to four-fold greater risk of the patient develop-
ing diabetes which is associated with increased risk for
SA. Additionally, high levels of luteinizing hormone in
PCOS patients during the follicular is associated with
miscarriage [118] .
Endometriosis, a pelvic inflammatory disease has
a higher prevalence in subfertile populations than
the normal population. Endometriosis is also linked
to reduced pregnancy rate after ART treatment. The
only reliable data supporting this are meta-analysis by
Barnhart et al. which found that fertilization, implan-
tation, oocytes retrieval, estradiol concentration and
www.futuremedicine.com 533
Review Agenor & Bhattacharya
pregnancy rates were lower in endometriosis patients
compared with controls [119] .
Thyroid auto-immunity (TAI) is found in greater
prevalence in infertile women compared with parous
age-matched women. This is particularly in women
with PCOS and endometriosis. Women with TAI are at
a significantly greater risk of pregnancy loss during the
first trimester compared with non-TAI patients [120] .
The use of cancer treatment regimens such as radio-
therapy and aggressive chemotherapy in young cancer
survivors can cause ovarian atrophy and decreased fol-
licular stores resulting in premature menopause and
permanent infertility. Fertility preservation techniques
have included embryo/oocyte preservation, ART and
gynecological surgeries in selected patients. For gyne-
cological cancers such as uterine, cervical and ovar-
ian cancers, obstetric/reproductive outcome is highly
successful, although 8% of cervical cancer survivors
in a large review of the literature experienced second
trimester miscarriage [121,122] . For breast cancer, more
than 8% of fertile survivors conceive, though limited
data are available. However, the available data did not
reveal any association with pregnancy loss.
Anatomical defects
Uterine septum is the congenital anomaly most closely
associated with reproductive failure including infertility,
miscarriage and RM [123,124] . One review found that mis-
carriage occurred in 79% of pregnancies in women diag-
nosed with septate uteri [125] . Intrauterine adhesions have
been found in 7–30% of patients who have had a mis-
carriage. Furthermore, in women who were investigated
for infertility and several of those who had failed IVF
attempts, 13.5% were found with adhesions [126–128] .
Other anatomical abnormalities such as endometrial
polyps have been discovered at higher rates (46.7%) in
infertile women with endometriosis and in lower rates
(0.6–5%) in RM patients [129–131] . Uterine fibroids can
also account for infertility as well as miscarriage [132] .
The management of infertility & miscarriage
Table 3 summarizes the common pathogenic pathways
for infertility and miscarriage and suggests possible
management options for each condition. The manage-
ment of infertility and miscarriage requires a dedicated
multidisciplinary team ideally consisting of doctors,
nurses and support staff and in the case of miscar-
riage, ultrasonagraphers and midwives should also be
included. It is imperative that communication between
staff and patients be clear and concise. Appointment
systems, laboratory facilities and clinic location should
be conveniently accessible [2] .
Follicle stimulating hormone level is normally done
for measuring ovarian reserve irrespective of maternal
534 Womens Health (2015) 11(4)
age and menstrual regularity. CD3 follicle stimulating
hormone level ≤10 mIU/ml is within normal range
of fertility whereas a ≥10 mIU/ml is prognostic of
decreased fertility [133,134] .
In the management of miscarriage, research has
demonstrated the importance of an early pregnancy
assessment unit. The benefits have included an early
confirmation of diagnosis usually on the initial visit,
reduction of prolonged hospital admissions and the
number of National Health Service (NHS) beds being
occupied [135,136] .
For miscarriage diagnosis a biochemical pregnancy
loss does not entail the use of an ultrasound assessment,
it comprises a history of positive pregnancy test fol-
lowed by a negative pregnancy test. On the other hand,
a clinical diagnosis of a miscarriage is determined by
vaginal bleeding history and either vaginally passed
conception substances or the discovery of an open cer-
vical os. However, clinical characteristics should not
be used as the only means to diagnose a miscarriage as
discrepancies can be found within this method. Fur-
thermore, declining levels of serum human chorionic
gonadotropin, can be used to diagnose miscarriage [3] ,
but has no role in the management of infertility.
Common management strategies
Table 3 summarizes the management strategies avail-
able for the different types of miscarriage [137] .
Preimplantation genetic testing includes preim-
plantation genetic diagnosis and screening and is the
process by which embryonic cells produced by in vitro
fertilization are analyzed to diagnose genetic abnor-
malities prior to intrauterine transfer such that only
those embryos with the highest chance of survival
are transferred [138] . This should logically increase the
chances of IVF success, but evidence surrounding this
is controversial [139] . The process can start at the stage
of oocyte retrieval in IVF procedures when maternal
inherited disease is tested in the oocyte nuclei. Alterna-
tively, blastomere or trophectoderm can be used from
the embryo at the six- to eight-cell stage on day 3 after
fertilization.
Preimplantation genetic diagnosis aims to detect a
single gene mutation, while preimplantation genetic
screening screens for aneuploidies using PCR, or FISH
techniques. These techniques can be used for sex deter-
mination of the embryo so that sex linked inherited
disorders can be eliminated. However, misdiagnosis is
relatively common and arises from the small amount
of DNA available for testing, the short time period for
testing and failure of amplification of the specific DNA
segment.
Active and passive immunization using lympho-
cyte immunization and IvIg treatment have been
future science group
 Infertility & miscarriage: common pathways in manifestation & management Review

Table 3. Summary of etiopathogenesis and management options for infertility and miscarriage.
Infertility Miscarriage Management option
PCOS Obesity; increased Metformin, HCG, progesterone, IVF with
testosterone/LH GM-CSF culture of embryos
Endometriosis Inflammatory cytokines TNF-α inhibitors, IVF
Male factor DNA chromatin damage PGD/PGS; allogeneic lymphocyte
immunization; intravenous
immunoglobulin
Unexplained Aneuploidy IVF with PGD/PGS, egg donation
Antiphospholipid antibody Heparin, aspirin
or lupus anticoagulant
Immunological factors Prednisolone, TNF-α inhibitors
GM-CSF: Granulocyte macrophage-colony stimulating factor; HCG: Human chorionic gonadotropin; LH: Luteinizing hormone;
PCOS: Polycystic ovarian syndrome; PGD: Preimplantation genetic diagnosis; PGS: Preimplantation genetic screening.

suggested to improve the immunological recognition differentiation of the endometrium to facilitate

of pregnancies by establishment of microchimerism,
reducing NK cell activity and modifying cytokine
production in unexplained RM or infertility. The
2006 Cochrane review concluded, however, that this
treatment was no better than placebo in prevent-
ing miscarriage [140] . Moreover, [141] Wilczinsci et al.
found that treatment with PLI-induced preconcep-
tionally cytokine changes which neither indicated
Th2 shift nor correlated with subsequent pregnancy
success in RM or unexplained infertility.
Low molecular weight Heparin with or without
aspirin is often used to treat women with recurrent
miscarriage [142] . Both drugs being antithrombotic
agents may be effective in treating RM especially
those with antiphospholipid syndrome but their role
in the management of infertility is controversial.
The Cochrane review on aspirin or anticoagulants
for treating recurrent miscarriage in women with-
out antiphospholipid syndrome, reported similar live
birth rates in the aspirin and placebo groups [143] . It
is biologically plausible that aspirin may be effective
in treating miscarriages occurring in the second tri-
mester through a similar mechanism to preeclamp-
sia prevention by increasing placental perfusion.
Stern et al. reported that heparin and aspirin did
not improve pregnancy or implantation rates for
APA-positive or antinuclear antibodies (ANA)-pos-
itive patients with IVF implantation failure [144] . In
their systematic review, Seshadri et al. found that
while nonrandomized observational studies consis-
tently found increased clinical pregnancy and live
birth rates with adjuvant heparin therapy, pooled
effect measures from randomized trials did not show
any improvement of outcomes [145] .
Similarly, progesterone and prednisolone have
both been suggested as remedies for RM. Proges-
terone is known to induce secretory changes and
implantation. It also reduces myometrial contractil-
ity and maintains the corpus luteum of pregnancy.
However, the Cochrane review including 15 trials on
2118 women found no statistical difference in mis-
carriage rates between the progestogen and placebo
or no treatment groups [146] . Prednisolone, a gluco-
corticoid receptor agonist, has been suggested as a
treatment in RM with high number of NK cells in
the uterus.
Although assisted reproductive technology is
becoming increasingly popular for the management of
infertility, its role in the treatment of recurrent miscar-
riage is controversial. Vissenberg and Goddijn in their
review conclude that currently there is insufficient
evidence to support the use of IVF or intrauterine
insemination (IUI) for the treatment of recurrent
miscarriage [147] . Nevertheless, oocyte donation in
case of age-related infertility and implantation failure
and immunotherapy for endometriosis may have some
beneficial effects on preventing unexplained miscar-
riage and infertility. Moreover, surrogacy, adoption
and fostering are all time-tested methods to prevent
childlessness.
Conclusion & future perspective
The definitions and nomenclature used for describ-
ing conditions of subfertility and miscarriage lack
standardization, making comparison of the litera-
ture difficult. There needs to be a joint effort on
behalf of the learned societies and relevant interna-
tional organizations for global standardized defini-
tions of terminology in infertility and miscarriage.
Advanced maternal age at the time of first concep-
tion can pose a problem for both fertility as well
as pregnancy loss. Raising awareness regarding the
optimum age for motherhood should start early
and be a part of school-based health education.

future science group www.futuremedicine.com 535

Review Agenor & Bhattacharya

Interventions to tackle other lifestyle factors such
as obesity, smoking and alcohol and substance mis-
use should be evaluated in the light of enhancing
fecundity by means of large multicentered random-
ized controlled trials. In fact, lifestyle modification
by reducing weight and the antidiabetic biguanide
drug Metformin has met with some success in the
treatment of infertility and miscarriage associated
with PCOS. Active and passive immunization using
allogenic lymphocyte immunization and IvIg may
be improve immunological recognition of pregnan-
cies and thus improve prognosis in some cases of
infertility and miscarriage [142] .
Hormonal profiling, hysterosalpingographic or ultra-
sound examination of the female reproductive tract,
endometrial biopsy, chromosomal and immunologic
analyses all play their role in the diagnostics of both
infertility and miscarriage, although the extent to which
each investigation adds value varies between the two
conditions. For example, investigations of the anatomy
of the female reproductive tract play an important role
in the investigation of infertility but not miscarriage.
Advances in genetic and bioassay techniques such as
preimplantation genetic testing, have meant better
understanding of the etiopathogenesis and consequently
the management of both infertility and miscarriage.

Executive summary
Epidemiology of infertility & miscarriage
• Definitions and terminology for infertility and miscarriage lack standardization making comparison between
studies difficult.
• The prevalence of infertility and miscarriage are difficult to determine due to heterogeneity of definitions,
terminology and samples used, denominator, exposure and outcomes.
Immunological factors
• Current research implicates the role of HLA expression, integrins, antisperm antibodies, cytokines, leukemia
inhibitory factor, antiphospholipid antibody, mucin 1, endometrial adhesion factors and uterine natural killer
cells in reproduction.
• Contrastingly, scarce evidence supports association of T cells, antiendometrial antibodies, antitrophoblast
antibodies, anti-HLA antibodies, peripheral natural killer cells and inadequacy of blocking antibodies and
suppressor cells in reproduction.
• Lack of expression of these factors could contribute to human reproductive failure.
Chromosomal abnormalities
• Chromosomal abnormalities are the most common causes of first trimester pregnancy losses and are
associated with a reduction in fertility.
• Novel techniques include, FISH, array comparative genomic hybridization, comparative genomic hybridization,
quantitative fluorescence polymerase chain reaction, multiplex ligation-dependent probe amplification.
• Cytogenic research has demonstrated that numerical abnormalities account for the majority of those losses
(86%), structural abnormalities (6%) and other genetic factors including mosaicism (8%) accounts for a small
percentage (6%). Balanced translocations or inversions may contribute to 50% of structural abnormalities.
• Maternal advanced age associated with trisomies is the most common risk factor for infertility and miscarriage
accounting for approximately 25% of all first trimester pregnancy losses.
• Common risk factors associated with infertility and miscarriage include advanced maternal age, obesity,
smoking and alcohol, pre-existing medical conditions such as diabestes, polycystic ovarian syndrome,
endometriosis and thyroid disorders are found in greater prevalence in infertile women and are linked to
pregnancy loss.
The management of infertility & miscarriage
• Preimplantation genetic screening can play a role in preventing miscarriage due to chromosomal
abnormalities in IVF pregnancies.
• Active and passive immunization using allogenic lymphocyte immunization and IvIg may improve
immunological recognition of pregnancies and thus improve prognosis in some cases of infertility and
miscarriage.
• Heparin with or without aspirin improves success in recurrent miscarriage in women with antiphospholipid
antibody or lupus anticoagulant.
• Progesterone and prednisolone are potentially effective in preventing miscarriage in high-risk cases with high
NK cell count.
• Where miscarriage and infertility are associated with polycystic ovarian syndrome, lifestyle modification and
metformin therapy have met with some success.
• Important factors in managing infertility and miscarriage include cost, legal and ethical considerations.
• IVF/intra-cytoplasmic sperm injection although important management strategies for infertility, play a very
small role in managing miscarriage, except where preimplantation genetic diagnosis is useful.

536 Womens Health (2015) 11(4) future science group

 Infertility & miscarriage: common pathways in manifestation & management
Despite this, around 30% of cases of infertility and
almost 60% of first trimester miscarriage remain unex-
plained. Future research should focus on the biological
mechanisms underpinning these unexplained condi-
tions with a view to developing evidence-based diagnos-
tic testing that will inform clinical and cost–effective
management strategies for both conditions. Meanwhile,
adoption, fostering, surrogacy and oocyte donation
remain viable options for childless couples.
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The authors have no relevant affiliations or financial involve-
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als discussed in the manuscript. This includes employment,
consultancies, honoraria, stock ownership or options, expert
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