VIEWS AND REVIEWS

Congenital anomalies after assisted

reproductive technology
Anja Pinborg, M.D., D.M.Sci., Anna-Karina Aaris Henningsen, M.D., Sara Sofie Malchau, M.D.,
and Anne Loft, M.D.
Fertility Clinic, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Worldwide, more than 5 million children have been born after assisted reproductive technology (ART), and in many developed countries
ART infants represent more than 1% of the birth cohorts. It is well known that ART children are at increased risk of congenital mal-
formations even after adjustment for known confounders such as maternal age. The proportion of ART children is not negligible,
and knowledge about the causes of the higher risk of congenital malformations is crucial to develop prevention strategies to reduce
the future risk in ART children. The aim of this review is to summarize the literature on the association between ART and congenital
anomalies with respect to subfertility, fertility treatment other than ART, and different ART
methods including intracytoplasmic sperm injection, blastocyst culture, and cryotechniques.
Trends over time in ART and congenital anomalies will also be discussed. (Fertil SterilÒ Use your smartphone
2013;-:-–-. Ó2013 by American Society for Reproductive Medicine.) to scan this QR code
Key Words: Assisted reproductive technology, IVF, ICSI, congenital anomalies, malformation and connect to the
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N
ewborns with congenital birth, for example, cardiac septum and the causality of the association of
anomalies are observed at defects and patent ductus arteriosus, ART and congenital anomalies is proba-
a low incidence in all popula- but even after adjusting for bly multifactorial. The major concern is
tions. The incidence varies over time prematurity, ART children are at still whether the ART procedures them-
and by place and is, apart from genetic a slightly increased risk of selves, embryo culture media, culture
causes, influenced by, for example, malformations compared with their time, and advanced procedures such as
medical drugs, with one of the most spontaneously conceived counterparts. intracytoplasmic sperm injection (ICSI)
serious examples being the Thalido- Worldwide, five million children and cryopreservation of embryos, have
mide case. Since the first child have been born after ART (9). In 2005, a possible negative impact on the ART
conceived by assisted reproductive ART infants represented >1% of the to- offspring. Moreover, the ovarian stimu-
technology (ART) was born, concern tal U.S. birth cohort (10), and in 2008 the lation resulting in altered endocrine pro-
has risen as to the safety of the proportion of children born after ART files with several corpora lutea in early
methods. From the literature it is well- ranged from 0.8% to 4.9% of the na- pregnancy may influence implantation
known that ART children are at tional birth cohorts, with more than and early fetal and placental develop-
increased risk of congenital malforma- 1.5% being ART children overall in Eu- ment. Concerns of epigenetic changes
tions even after adjustment for known rope (11). Certainly, the proportion of related to the ART procedures have also
confounders such as maternal age. ART children is not negligible, and been raised with increasing evidence of
This has been shown in larger national knowledge about the causes of the a higher risk of epigenetic diseases such
population-based studies in the United higher risk of congenital malformations as Bechwith-Wiedemann and Angelman
States, Australia, and the Nordic is crucial to develop prevention strate- syndrome (12, 13). Finally, subfertility or
countries (1–3), as well as in several gies to reduce the future risk in ART chil- the parental characteristics per se have
meta-analyses (4–8). Some of the dren. The scientific literature on the been shown to affect the perinatal
malformations are related to preterm possible causal pathways is limited, outcome including the risk of
congenital anomalies (14).
Received November 5, 2012; revised December 1, 2012; accepted December 3, 2012.
A.P. has nothing to disclose. A.-K.A.H. has nothing to disclose. S.S.M. has nothing to disclose. A.L. has
One obstacle in the literature on
nothing to disclose. ART and congenital malformations is
Reprint requests: Anja Pinborg, M.D., D.M.Sci., Fertility Clinic, Section 4071, Rigshospitalet, Copenha- the heterogeneous classification of mal-
gen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark (E-mail: apinborg@rh.
regionh.dk). formations, as some studies include
both major and minor malformations,
Fertility and Sterility® Vol. -, No. -, - 2013 0015-0282/$36.00
Copyright ©2013 American Society for Reproductive Medicine, Published by Elsevier Inc.
whereas others only include major birth
http://dx.doi.org/10.1016/j.fertnstert.2012.12.001 defects. Further, some studies report

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VIEWS AND REVIEWS
singletons and twins together, while others show the results for
the two groups separately. In most of these studies, twins
born after ART show no increased prevalence of congenital
malformation compared with twins born after spontaneous
conception (2–4, 15, 16). Finally, the definition of
a major malformation varies from study to study, and some
include analyses on other subsets of malfor-
mations such as weeded and relatively severe malformations,
thereby excluding predefined less severe conditions (3, 17,
18). Weeded malformations were identified by excluding
some conditions that are relatively common, variable in
registration, and sometimes associated with preterm birth
and low birth weight. The remaining malformations were
classified as ‘‘weeded’’ and will contain mainly major
malformations, but also some less severe conditions (17).
Another obstacle is ascertainment bias, with children con-
ceived by ART being more carefully examined and thus having
higher malformation rates. Even in the large national controlled
register studies this is possible as ART children are hospitalized
more and therefore have more malformations recognized.
This review will focus on birth defects in ART singletons,
and if singleton data are not available, then on the general
ART population. The aim of this review is to summarize the
literature on the association between ART and congenital
anomalies with respect to subfertility, fertility treatment other
than ART, and different ART methods including ICSI, blasto-
cyst culture, and cryotechniques.
Subfertility (Time-to-Pregnancy >1 Year)
Maternal age increases with longer time to pregnancy (TTP),
therefore shortening of the TTP reduces the patient's age at
time of conception. Population-based studies from the United
States have described the impact of maternal age on birth de-
fects with an incidence of 2.7% at 26 years of age and 3.4% at
37 years of age (19). Thus adjustment for maternal age is piv-
otal when analyzing the influence of subfertility on ART
outcomes.
Based on the Danish national birth cohort, Zhu et al.
showed that singletons born of subfertile couples who
conceived spontaneously had a higher risk of congenital
anomalies (hazard ratio [HR], 1.20; 95% confidence interval
[CI], 1.07–1.35) than singletons born of fertile couples with
TTP <1 year (14). Further, the study revealed that the overall
prevalence of congenital malformations increased with in-
creasing TTP. The children born to those women who re-
ceived fertility treatment had an even higher prevalence of
congenital malformations than singletons of fertile couples
with TTP <1 year (HR, 1.39; 95% CI, 1.23–1.57). On the
basis of their findings, the investigators concluded that the
increased malformation rate after ART was partly due to
the underlying infertility or its determinants (14). One weak-
ness of the Zhu et al. study is that TTP was categorized into
0–2, 3–5, 6–12, and >12 months with no categories above
12 months.
Since prolonged TTP is associated with several adverse
outcomes in the offspring, it should be noticed that on the
TTP spectrum, ART patients are well beyond 1 year. In fact,
3–5 years of infertility is generally the norm (20–22). Hence
2 VOL. - NO. - / - 2013
it is assumed that ART couples, as they receive the most
extensive fertility treatment, also are less reproductively
healthy than subfertile couples with shorter TTP who
conceive either spontaneously or by less invasive fertility
treatments (22). In a recent report, Rimm et al. adjusted
their previous finding from a meta-analysis on congenital
malformations and found that the adjusted risk of malforma-
tions after ART was reduced from an HR of 1.29 (95% CI,
1.01–1.67) to an HR of 1.01 (95% CI, 0.82–1.23), when taking
into account that 40% of major malformations were due to
subfertility (4, 22). These results should be interpreted with
caution as the results in the Rimm et al. study were based
on two independent studies: first the study by Zhu et al.
was used to calculate the magnitude of the influence of
subfertility, and then this estimate was applied to the
pooled risk estimate of congenital malformations after ART
from the earlier meta-analysis.
In a national Swedish register study, approximately 5% of
all infants born after ART had a relatively severe malforma-
tion with an increased risk of an adjusted odds ratio (AOR)
of 1.44 (95% CI, 1.32–1.57) after adjustment for year of birth,
maternal age, and parity (17). When additional adjustment
was made for year of birth, maternal age, parity, years of
known childlessness, and smoking, the increased risk disap-
peared (AOR, 1.12; 95% CI, 0.99–1.28). Thus, increased risk
was mainly due to maternal characteristics, with the most im-
portant factor being subfertility, which was estimated as years
of known childlessness (17).
Subfertility or intrinsic parental characteristics play a sig-
nificant role in the association between ART and congenital
anomalies. To separate the effect of intrinsic parental factors
and the effect of the ART methods themselves on the develop-
ment of congenital anomalies, it is necessary to either adjust
for years of unwanted childlessness or to use subfertile popu-
lations conceiving spontaneously as controls to ART popula-
tions. In the vast majority of studies, normal fertile
populations are used as controls and there is no correction
for subfertility. In these studies it is not possible to distinguish
between parental factors and the influence of the ART treat-
ments per se.
Fertility Treatment Other than ART (Ovulation
Induction and IUI)
On most health indicators, children born after ovulation induc-
tion (OI) and/or IUI seem to perform worse compared with
spontaneously conceived children (23). Three smaller studies
reported no significant difference in the occurrence of congen-
ital anomalies in OI/IUI versus control children (24–26), while
recent larger studies have shown an increased risk of
malformations after OI/IUI (27–29). Finnish population-
based data have shown a significantly higher prevalence of
major malformations among 4,467 children born after OI/IUI
(3.52%) than among control children (2.85%) but still lower
than after ART (4.27%) (27). The AOR for OI/IUI versus controls
was 1.21 (95% CI, 1.02–1.44), while for ART versus controls,
the AOR was 1.31 (95% CI 1.10–1.57) (27).
In 790 Canadian infants born after medical assisted re-
production including ART (n ¼ 319), IUI/OI (n ¼ 173), and

OI (n ¼ 298), the overall risk of birth defects was increased
(AOR, 1.55; 95% CI, 1.01–2.38) after adjustments for maternal
age, parity, smoking, and sex of baby (28). The prevalence was
highest in the ART group (3.45%) compared with 2.89% after
IUI/OI, 2.35% after OI, and 1.86% after natural conception;
probably owing to a limited sample size no adjusted analyses
were made for the subgroups. A recent French cohort study
revealed a prevalence of major malformations of 3.6% in
445 IUI versus 4.2% in 903 ART and 2.1% among 4,044 con-
trols (29). Children born after IUI were twice as likely to have
a major birth defect as children from the background popula-
tion (AOR, 2.0; 95% CI, 1.0–3.8), but the risk in IUI children
was similar to the risk in the ART group.
From the available literature is seems as though infants
conceived by fertility treatments other than ART also carry
a higher risk of congenital anomalies and that this risk may
be increasing with increasing intensity of the treatment or
with the severity of the parental reproductive morbidity.
However, future research is needed to confirm this.
Clomiphene Citrate
The use of clomiphene citrate (CC) is widespread, and in the
United States it is estimated that 1.6% of pregnancies are con-
ceived with the use of CC (30). In 1986, Mikkelson et al. found
that an isomer of CC, the more active zuclomiphene, accumu-
lates over consecutive cycles and can still be detected in
plasma 1 month after administration (31). Thus there is a bio-
logical plausibility of the association between CC and birth de-
fects, although CC is taken before conception. Two types of
birth defects have been commonly reported with the use of
CC: neural tube defects and hypospadias (32–35). In a recent
U.S. national case-control study, associations were shown be-
tween the use of CC and birth defects, but there was some in-
consistency between the findings and previous reports (36). A
major limitation of the study was that the effect of CC could
not be distinguished from the effect of subfertility (36).
On the basis of the current literature, no firm conclusions
can be drawn regarding the association between CC and birth
defects.
ART
Meta-analyses have reported an increased prevalence of con-
genital malformations with an excess risk of 30%–40% in sin-
gletons born after ART (4–7). One meta-analysis observed
a 67% increased risk (8).
These results are consistent with the most recent
population-based studies on congenital anomalies in ART
children from Sweden and Australia (2, 3). K€allen et al.
showed in ART children (n ¼ 31,850) that the prevalence of
congenital anomalies after ART declined over time,
although a slightly increased risk of 15% remained in the
youngest ART cohorts (3). In the youngest cohort of
Swedish ART children born from 2001 to 2006 (n ¼ 15,570,
including 9,372 after ICSI), the crude total malformation
rate was 5.3% versus 4.4% in the general population (3),
while in the earlier cohort (born 1982–2000, n ¼ 16,280
ART infants) the crude malformation rate was 5.0% in ART
versus 4.0% in the general population (17). Only
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Fertility and Sterility®
malformations diagnosed in the neonatal period were
included in these figures, while in the first study the
investigators aimed to include diagnoses from the Swedish
Hospital Discharge register as well and found that by
including malformations diagnosed later in life, there was
a total malformation rate of 8.3% in ART children;
unfortunately, no corresponding figure was available for
the background population (17). In the cohort of Swedish
ART infants born from 2001 to 2007, the adjusted risk of
congenital anomalies in ART infants versus the background
population was 1.15 (95% CI, 1.07–1.24). The adjusted risk
was lower in the younger ART generations (born 2001–
2007) compared with in the older ART generations (AOR,
1.33; 95% CI, 1.24–1.43]) (3, 17).
In a large Australian cohort of 6,163 ART infants (n ¼ 4,756
after IVF and n ¼ 1,407 after ICSI) born from 1986 to 2002,
Davies et al. included malformations diagnoses from gesta-
tional week 20 with a 5-year follow-up period (2). The crude
total malformation rate in ART children was 8.3% versus
5.8% in the background population, with an overall increased
AOR of birth defects for ART versus the background population
of 1.28 (95% CI, 1.16–1.41) (2). However, in singleton newborns
from fresh embryo IVF compared with the background popula-
tion, the AOR was 1.06 (95% CI, 0.87–1.30), thus showing no
increased overall risk of birth defects after IVF (2).
IVF Versus ICSI
The incidence of Y-chromosome deletions and other chromo-
somal anomalies is increased in males with poor semen qual-
ity (37). Several studies have shown that children conceived
by ICSI are at increased risk of inherent and de novo chromo-
somal aberrations (38–40). Further, a higher rate of urogenital
malformations, primarily hypospadias, which has been
related to paternal infertility, has been reported (3, 18). Zhu
et al. found that the adjusted risk of genital organ
malformations in ART children was significantly higher
than in singletons born of subfertile couples conceiving
spontaneously (HR, 2.32; 95% CI, 1.24–4.35) (14). In the
large Swedish study, the increased risk of hypospadias
found in the older ICSI cohorts disappeared over time and
was not present in the younger cohorts of ICSI children (3).
One explanation for this declining incidence of hypospadias
in ICSI boys over time may be a dilution effect, that is, the
indications for ICSI nowadays are much wider and therefore
severe male factor infertility in the father is less frequent
in the younger generations of ICSI boys. However,
improvement in the use of the ICSI technique may also have
an influence. Two meta-analyses have raised the question
of whether birth defects are more common in ICSI versus
IVF infants (7, 41). Lie et al. included four studies and
reached a pooled estimate of 1.12 (95% CI, 0.97–1.28) (41).
Wen et al. reported a pooled estimate of 1.05 in IVF versus
ICSI after including 24 studies and a reverse pooled
estimate of 0.95 (95% CI, 0.83–1.10) in ICSI compared with
in IVF infants (7).
The Swedish study demonstrated no apparent risk differ-
ence according to ART method, with an adjusted risk of birth de-
fects in ICSI versus IVF (2001–2007) 0.90 (95% CI, 0.78–1.04) (3).
3
VIEWS AND REVIEWS
In contrast, the Davies et al. group demonstrated a raised
risk (AOR, 1.55; 95% CI, 1.24–1.94) in ICSI but not in IVF sin-
gletons versus a fertile population with no use of assisted re-
production after adjustments for parental factors (2).
Chromosomal anomalies may be one of the explanations
for the higher birth defect risk in ICSI singletons observed
in the Australian data. Moreover the Australian study in-
cluded medical termination of pregnancies due to birth de-
fects after week 20, while the Swedish study only included
births after week 20. Finally, the Australian study included
nonacquired cerebral palsy as a birth defect, but the preva-
lence of cerebral palsy in IVF and ICSI children was not re-
ported separately.
It should be emphasized that the youngest generations of
ART infants seem to have a lower prevalence of congenital
anomalies. This may be due to changes in the subfertile pa-
tient populations previously explained as the ‘‘dilution ef-
fect,’’ with the parents being less reproductively ill than one
or two decades ago. The declining malformation rates may
also be due to improvements in the ART stimulation regimens
and ART laboratory procedures.
Haliday et al. explored the risk of blastogenesis birth de-
fects, which correspond to birth defects occurring in the first
weeks of embryo development before organogenesis and tend
to affect the formation of the midline and mesoderm (42).
These early developed congenital anomalies include neural
tube defects, abdominal wall defects, esophageal and anal
atresia, and monozygotic twinning. In all, 6,946 IVF or ICSI
singleton pregnancies were linked to birth defects occurring
from 1991 to 2004 in Victoria, Australia. Because of the study
period, it is expected that the vast majority of ETs were cleav-
age stage, but this is not clarified in the paper (42).
Haliday et al. found that overall birth defects increased
after IVF or ICSI with an AOR of 1.36 (95% CI, 1.19–1.55)
and with blastogenesis birth defects markedly increased
(AOR, 2.80; 95% CI, 1.63–4.81). The investigators suggested
that a mechanism initiated about the time of implantation af-
fecting early embryo development in ART pregnancies was
responsible. The increase in blastogenesis defects appeared
greater for fresh ET than for thawed ET, with the risk increase
for fresh ET relative to controls being more than threefold. The
authors claimed that cryopreservation/thawing may act as
a ‘‘selection gate’’ for more viable embryos; alternatively,
the ovarian stimulation in the fresh cycles could have a variety
of adverse effects on implantation and very early pregnancy.
An abnormal hormonal milieu was not present before cryo-
preservation as only frozen ET (FET) performed in a natural
cycle was included. It is possible that the endometrial recep-
tivity is compromised in the presence of the high hormone
levels that persist beyond the time of oocyte collection. In
contrast to FET, fresh ET is associated with lower levels of
pregnancy-associated plasma protein A (PAPP-A) (43, 44),
which has also been shown to be associated with
preeclampsia and fetal growth retardation in spontaneously
conceived pregnancies (45, 46). PAPP-A is known to play
a key role in angiogenesis and placental development
throughout pregnancy (47).
ART children are at an increased risk of congenital anom-
alies of 15%–40%; whether ICSI children have an added risk
4 VOL. - NO. - / - 2013
compared with IVF children is still not clear. The younger
generations of ART children seem to have a lower risk of con-
genital anomalies compared with the older ART generations.
Blastogenesis birth defects should be embedded in future
research.
Blastocyst Culture
Only two reports have examined the risk of congenital anom-
alies in singletons after blastocyst versus cleavage-stage em-
bryo culture (48, 49). In 1,311 singletons born after blastocyst
culture, not, however, stratified for fresh or frozen ET, the risk
of congenital malformations was significantly increased to
1.43 (95% CI, 1.14–1.81) for all congenital anomalies and to
1.33 (95% CI, 1.01–1.75) for relatively severe congenital
anomalies in infants born after blastocyst versus cleavage-
stage transfer (48).
In a smaller one-center trial on 103 infants born after vit-
rified blastocyst transfer, 199 after fresh blastocyst transfer,
and 194 after slow freeze, no increased risk of malformations
was seen, however, the study was not powered to look at rare
outcomes (49).
The risk of congenital anomalies after blastocyst culture
should be continuously monitored and incorporated in the
large national ART registers to follow the prevalence of con-
genital malformations in these children.
FET
Slow freezing. On the basis of the existing literature, children
born after slow freeze have the same prevalence of malforma-
tions as children born after the transfer of fresh embryos
(50–52), although some obstetric outcomes seem to be even
better in children after FET (53, 54). One study has found
that ICSI children born after cryopreservation carry a higher
risk of congenital anomalies (55). However, this finding has
not been verified by other investigators (3, 51, 54).
Vitrification. Only one review on children born after vitrifica-
tion is available (56). The investigators constructed a database
including all live-born infants after vitrification (n ¼ 936),
out of which 12 (1.3%) were noted to have birth defects. Com-
pared with spontaneously conceived infants, no difference
was found.
Only one report with sufficient sample size has looked at
birth defects after vitrification of cleavage-stage embryos or
blastocysts (57). The total birth defect rates were 2.4% versus
1.9% after vitrified and fresh ET, respectively, and the AOR
was 1.41 (95% CI, 0.96–2.10) after adjustments for maternal
age, body mass index (BMI), parity, type of stimulation,
ICSI method, blastocyst culture, and infant sex.
In general, it seems that cryopreservation of embryos pro-
tects against some of the adverse obstetric outcomes after
ART but not when it comes to congenital anomalies, where
the prevalence apart from blastogenesis defects seems to be
as high as after fresh ET. It is far too early to give an opinion
about the risk of birth defects after vitrification.
Perspectives
ART children have a slightly increased risk of congenital
anomalies of 15%–40% compared with spontaneously

conceived children after adjustments for relevant con-
founders. From recent Swedish cohort studies, the overall
risk is not increasing over time as there is a tendency for a de-
cline in the prevalence of congenital anomalies in the youn-
gest ART generations. This may be due to a decreased
reproductive morbidity caused by healthier patient popula-
tions, as the accessibility to ART has increased over time.
The increased risk of congenital anomalies in children born
after fertility treatment can partly be explained by the subfer-
tility of the couples. However, longitudinal studies focusing
on the causal factors including parental characteristics, that
is, causes for infertility, endocrine diseases including polycys-
tic ovarian syndrome and semen quality, and lifestyle factors
such as smoking and BMI, are highly warranted.
Further, the risk of congenital anomalies after different
ovarian stimulation exposures, that is, CC versus gonodotro-
pins and new laboratory procedures such as blastocyst culture
and vitrification, needs continuous surveillance. The ongoing
debate regarding the influence of different culture media on
epigenetic changes and birth weight should also be related
to the risk of birth defects in the offspring.
On the basis of the current literature, it is not possible to
distinguish the effect of parental subfertility, the effect of
ovarian stimulation, and the ART laboratory techniques on
the risk of congenital anomalies, but it has clearly been shown
that children conceived without fertility treatment in subfer-
tile couples also carry a higher risk of congenital anomalies
compared with singletons conceived by fertile couples. Future
research should be devoted to finding the mechanisms of the
association between ART and congenital anomalies. This re-
quires continuously updated large national ART registers or
databases, which also include congenital anomalies in fetuses
diagnosed by prenatal screening procedures resulting in mis-
carriages or induced abortions in the first or second trimester.
New ART techniques should rapidly be incorporated into
these registers, making as expeditious as possible continuous
surveillance from the introduction of the procedure. Finally,
detailed information about parental characteristics, ovarian
stimulation, treatment modality, BMI, and smoking should
also be recorded. This is the only way to explore the causal
pathways and hence develop prevention strategies to reduce
congenital malformations in ART children in the future.
Because they represent >1% of the birth cohorts in many
developed countries, much attention is being paid to the
health and well-being of ART children. New research in the
field raises a lot of media attention and may cause severe con-
cerns in the couples achieving a long-awaited ART preg-
nancy. Thus it is pivotal that new results are presented
meticulously and in the context of the existing literature.
However, as a final remark, it is important to emphasize
that the adjusted risk of congenital malformations is signifi-
cantly increased but seems to decline over time and that the
vast majority of ART infants are healthy.
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