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Chapter
Congenital anomalies and assisted
34
reproductive technologies
Mona Aboulghar
Introduction
The population of children born after assisted reproductive
technologies (ART) has increased dramatically around the
world. An explicit example is Denmark, where 4% of infants
are born after in-vitro fertilization (IVF) and intracytoplasmic
sperm injection (ICSI) techniques, and 40% of these are
twins [1]. There is naturally interest now in studying those
children born regarding obstetric complications, congenital malformations, and long-term effects.
Risks associated with pregnancies following ART techniques
IVF pregnancies are associated with increased perinatal risks, of
which multiple pregnancies are the most serious due to higher
levels of obstetric complications [2,3,4].
Multiple pregnancies
Probably the highest risk result of IVF pregnancies is multiple
pregnancy, which has been reported 27 times more frequently
than in the general population [5].
The risks of multiple pregnancies include: perinatal mortality, preterm birth, low birth weight, gestational hypertension,
placental abruption, and placenta previa [1,2]. The incidence of
monozygotic twins is higher in ART pregnancies [6], and these
are known to carry higher risks than dizygotic twins. Even when
pregnancy starts with higher-order multiple pregnancy, the
ongoing twins are still associated with a mild increased risk of
premature delivery and low birth weight when compared with
nonreduced twin pregnancies [7].
Increased perinatal morbidity is known to be higher in
singleton ART pregnancies as well, which could be attributed
to the underlying reproductive pathology [4].
Congenital malformations following IVF
Rizk and co-workers evaluated the congenital malformations in
961 babies conceived by IVF from Bourn Hall Clinic and the
Hallam Medical Center between 1978 and 1987 [8]. The overall
prevalence of congenital malformation was 3%, and 2.5% of the
babies had at least one major malformation diagnosed during
the first week of life (Table 34.1). The difference between the
two proportions is due to multiple malformations in some
babies: five babies had more than one malformation diagnosed
under one week and two babies had more than one malformation diagnosed at any time. Although the malformation rates
were higher in multiple births than with singleton births, the
differences were not statistically significant (Table 34.1). Rizk
et al. [8] compared the congenital malformations in IVF babies
born and conceived in the United Kingdom with three sources
of control data. Congenital malformations diagnosed during
the first week of life were compared with the expected values
from (1) the Office of Population Censuses and Surveys
(OPCS), which is a voluntary scheme of reporting malformations diagnosed in the first week of life in England and Wales h
(adjusted for maternal age and multiplicity); and (2) the Scottish
Information Statistics Division, which routinely abstracts data
on the prevalence of malformations in the live-born in Scotland
diagnosed before one week of life (adjusted for maternal age)
(Table 34.2). Congenital abnormalities diagnosed at any time
(including terminations) were compared with the expected
maternal age-adjusted values from the Liverpool Congenital
Malformations Register, which contains data from many sources
on malformations diagnosed at any age in the five health districts
of the Liverpool region (UK) (Table 34.3). The information was
presented system by system (Tables 34.2, 34.3). No specific
malformations were significantly increased, but higher than
expected numbers of central nervous system, chromosomal,
urogenital, and limb malformations were observed (Table 34.3).
However, more recently published reports have suggested
an increased risk of birth defects in both IVF and ICSI pregnancies (Tables 34.4, 34.5)[9](Figures 34.1, 34.2, 34.3, 34.4,
34.5, 34.6, 34.7, 34.8, 34.9, 34.10). Buckett et al. reported on all
ART procedure s, as compared with naturally conceived children; IVF, IVM (in-vitro maturation), and ICSI were found to
have slightly higher risks of congenital malformations. Odds
ratios for any congenital abnormality were 1.42 (95% confidence interval [CI] 0.52–3.91) for IVM, 1.21 (95% CI 0.63– 2.62)
for IVF, and 1.69 (95% CI 0.88–
3.26) for ICSI [3]. Olson et
al.
Ultrasonography in Reproductive Medicine and Infertility, ed. Botros R. M. B. Rizk. Published by Cambridge University Press. © Cambridge
University Press 2010.
Section 4: Early pregnancy after infertility treatment
Table 34.1. Major malformations diagnosed within the first week of life
of IVF babies
Singleton Multiple Total
Total major malformations (%) 2.9 3.3 3.0
Babies with at least one
major malformation (%)
Reproduced with permission from Rizk B, et al. [8].
Table 34.2. Observed and expected malformations diagnosed under one
week of age in IVF babies
Central nervous system 3 2.2/2.2
Chromosomal 5 1.8/2.5
Urogenital system 13 3.2/12.4
Limb 16 6.8/53.0
Alimentary system 2 2.5/3.4
Respiratory system 1 0.1/1.0
Cardiovascular system 7 1.8/10.1
Eye and ear 4 1.0/2.4
Other musculoskeletal 7 1.8/6.5
Skin and integument 4 1.9/30.7
Other 2 _
Total major malformations 29 15.0/30.8
Total babies with at least one major
malformation
Reproduced with permission from Rizk B, et al. [8].
2.4 2.7 2.5
Observed Expected
24 12.4/25.8
Table 34.3. Observed and expected malformations diagnosed at any time
(including termination) in IVF babies
Observed Expected
Central nervous system 5 2.8
Chromosomal 5 3.7
Urogenital system 3 1.9
Limb 8 5.4
Alimentary system 2 2.5
Respiratory system 1 0.4
Cardiovascular system 5 8.4
Eye and ear 1 1.4
Other musculoskeletal 2 2.0
Other 2 _
Total major malformations 34 29.0
Total babies with at least one major
malformation
Reproduced with permission from Rizk B, et al. [8].
32 25.3
Reasons for concern after ICSI procedures
Concerns about ICSI are related to technical, biological, and
genetic hazards. The link to increased incidence of chromosomal anomalies, congenital abnormalities, and perinatal hazards
has been attributed to abnormal semen, to abnormal karyotyping, and to the technique of ICSI in which the oocyte membrane
is pierced, bypassing the natural genetic selection that occurs in
IVF [15].
reported a 1.3-fold higher risk in IVF and one of 1.1 for IUI
(intrauterine insemination) pregnancies for birth defects when
compared with naturally conceived babies [10].
An Australian study found the odds ratio (OR) for multiple
major defects to be 2.0 in IVF and ICSI, which was higher than
that in the general population of naturally conceived infants
[11]. This agrees with an Israeli study [12], in which the increase
in congenital malformations was 2.3 and 1.75 times higher than
in the spontaneously conceived group.
A Danish study included a large number of IVF/ICSI
births (8602) between 1995 and 2000, of which 3438 were
twins (40%) and 5164 were singletons (60%). The incidence
of malformations was similar in ICSI compared with IVF
babies; however, the total malformation rate was significantly
higher in twins compared with singletons. A significant
increase in hypospadias was observed in ICSI babies [1].
This has been reported in several other studies, when testicular sperm were used [13].
A study on cryopreserved ICSI embryos found a 2-fold
increased incidence of congenital malformations [14].
Comparison of risks following IVF and ICSI
Because of the difference in technique used between ICSI and
IVF where non-natural selection of the fertilizing sperm, and
possible damage to the oocyte, occurs, there has been concern
that ICSI could increase the risk of birth defects.
A follow-up study of 2059 neonates resulting from ICSI
treatment [16], found 38 (1.8%) cases presenting with congenital abnormalities (22 major and 16 minor). Comparing the
outcome of miscarriages and congenital malformations in
terms of semen origin, ICSI and IVF were found not to differ.
A large prospective multicenter study including 59 centers
in Germany compared the major malformation rate in ICSI
pregnancies with that of naturally conceived controls [17].
A slight increase in malformations was reported, 8.6% versus
6.9%, resulting in a crude relative risk of 1.25 (95% CI
1.11–1.40). In their study they found no influence of sperm
origin on major malformation rate in children born after ICSI.
Bonduelle et al. [18,19], in two large published studies,
reported on major malformations (defined as those causing functional impairment or requiring surgical correction). The risk was
similar in both ICSI and live-bornIVF children:3.4% versus 3.8%
(P = 0.538). The malformation rate in ICSI was not found to be
related to sperm origin or sperm quality. The number of
284
Table 34.4. A summary of recent studies of IVF children and the risk of congenital anomalies
Chapter 34: Congenital anomalies
Number of
Author (year)
Zhu (2006) 1483 Population-based study Denmark 6.6% (hazard ratio 1.20)
Bonduelle (2005) 540 Population-based study Belgium OR 1.80
Kallen (2005) 16 280 Population-based registry Sweden 5% vs 4% (relative risk 1.26)
Klemetti (2005) 4559 Population-based registry Finland OR 1.3
Merlob (2005) 278 Population-based registry Israel 9.35% vs 4.05%
Olson (2005) 1462 Population-based registry USA 6.2% vs 4.4%
Anthony (2002) 4224 Population-based registry The Netherlands OR 1.20
Hansen (2002) 837 Population-based registry Australia 9% vs 4.2% (OR 2.0)
Isaksson (2002) 92 Case–control study Finland 7.2% vs 3.5% in singletons.
Koivurova (2002) 304 Population-based registry Finland 6.6% vs 4.4% (OR 1.53)
Ericson (2001) 9111 (estimated) Population-based study Sweden OR 0.89
Koudstaal (2000) 307 Clinic The Netherlands 2.3% (OR 1.0)
Bergh (1999) 5856 Population-based study Sweden 5.4% vs 3.9%
Bowen (1998) 84 Case–control study Australia 3.6% vs 5% (no significant difference)
D’souza (1997) 278 Case–control study USA 2.5% vs 0%
Sutcliffe (1995) 91 Clinic UK OR 1.4
Reproduced with permission from Anpananthar A, SutcliffeA.[9].
Table 34.5. A summary of recent studies of ICSI children and the risk of congenital anomalies
IVF children Type Country
Risk of congenital anomaly in IVF vs. naturally
conceived children ± odds ratio (OR)
Number of ICSI
Author (year)
Zhu (2006) 398 Population-based study Denmark 8.8% (hazard ratio 1.39)
Bonduelle (2005) 540 Population-based study Belgium 4.6% (OR 2.7)
Katalinic (2004) 3372 Tertiary infertility center Germany 8.7% vs 6.1% (OR 1.24%)
Hansen (2002) 301 Population-based study Australia 8.6% vs 4.2% (OR 2)
Ludwig (2002) 3372 Population-based study Germany 8.6% vs 6.9% (RR 1.25)
Sutcliffe (2001) 208 Case-control-study UK 4.8% vs 4.5% (OR 1.06)
Wennerholm (2000) 1139 Population-based study Sweden 7.6% (OR 1.75)
Bowen (1998) 89 Case-control study Australia 4.5% vs 5% (no significant difference)
Bonduelle (1996) 877 Population-based study Belgium 2.6% (within normal range)
Sutcliffe (1995) 56 Fertility center Australia OR 0.67
Reproduced with permission from Anpananthar A, SutcliffeA.[9].
stillbirths was similar in both groups (1.69% in the ICSI group
versus 1.31% in the IVF). The total malformation rate taking
into account major malformations in stillbirths, in terminations, and in live-born children was again similar (4.2% versus
children Type Country
excluding preterm deliveries. ICSI pregnancies were comparable
to those from IVF, and both had worse perinatal outcomes than
naturally conceived pregnancies. No long-term effects were
observed in children up to the age of 5–8years.
Risk of congenital anomaly in ICSI vs. naturally
conceived children ± odds ratio (OR)
4.6%, P = 0.482).
A meta-analysis of 19 studies reported an OR of 1.29 for
congenital malformations, being similar in children born from
IVF and ICSI [20].
Knoester et al. [21] compared singleton ICSI, IVF, and nat-
urally conceived children as regards congenital malformations
and fetal growth, general health, and medical consumption,
Chromosomal abnormalities
Chromosomal study of abortuses following ART techniques
showed no increase in the incidence of anomalies when compared with naturally conceived pregnancies, or between IVF
(54.5%) and ICSI (61.5%), but there was an increase in ICSI
285
Section 4: Early pregnancy after infertility treatment
Figure 34.1. 2D image of acrania.
Figure 34.3. 3D image of median facial cleft.
Figure 34.2. 3D image of acrania.
TESE (testicular sperm extraction), and in cryo-oocytes and IUI
pregnancies [22]. However, in another study [23], ICSI pregnancies had a significantly higher rate of chromosomal aberrations than IVF.
First-trimester screening using nuchal translucency
(NT) thickness, biochemical marker assessment, pregnancyassociated plasma protein A (PAPP-A), and free beta human
chorionic gonadotropin (β-hCG) is now routine practice in
many countries. Since the numbers of pregnancies following
ART procedures are increasing around the world, it became
necessary to determine whether any difference could be
detected in the first-trimester screening among the naturally
conceived population compared with the assisted-conception
population. A Danish study [24] compared 1000 pregnancies
achieved after ART with a control group of 2543 pregnancies
conceived spontaneously, as regards NT thickness, PAPP-A,
and free β-hC G. In chromosomally normal pregnancies conceived after IVF and ICSI, the P APP-A MOMs (multiples of
the median) values were significantly decreased when compared with those of pregnancies conceived spontaneously
(0.78 and 0.79 vs. 0.98), while there was no difference in the
group treated by frozen embryo replacement. There was no
difference in the level of free β-hCG between groups. The
median nuchal translucency thickness was smaller in the overall ART group than in controls. The false-positive rate of firsttrimester combined screening in the overall ART group,
adjusted for maternal age, was significantly higher than in
controls (9.0% vs. 6.0%). This stresses the importance of
including data of mode of conception while calculating the
risk for Down syndrome in patients following ART procedures.
Reported anomalies following ART procedures
Specific anomalies reported with IVF include the extrophy epispadius complex, which showed a 7.3-fold relative increase in
incidence in IVF infants (P = 0.0021) [25]. Reported anomalies
having higher prevalence in ART techniques include gastrointestinal (GI) (OR 9.85; 95% CI 3.44–28.44), cardiovascular (OR 2.30;
95% CI 1.11–4.77), and skeletal (OR 1.54; 95% CI 0.48–4.94) [9].
A review of our own data based on mid-trimester ultrasound
examination of 1690 ICSI pregnancies showed 1018 singletons,
621 twins, 10 triplets, and 41 cases of anomalies representing
2.4%, of which 90.2% (37) were major and 9.7% minor [4]. This
was compared with a control group of 3396 spontaneously
pregnant patients: 3200 singletons, 99 twins, and 11 triplets,
and 86 cases of anomalies (2.5%). Of those, 87.2% (75) were
286
Chapter 34: Congenital anomalies
a
Figure 34.4. (a) Septated cystic hygroma, 2D image. (b) Cystic hygroma.
b
Figure 34.5. Encephalocele.
major and 12.7% minor [11]. The odds ratio for incidence of
anomalies in ICSI pregnancies was 1.04 (CI 0.71–1.52). These
results were similar in twin ICSI and spontaneous groups: 2.5%
and 3.5%, respectively (P = 0.50). (MMA Aboulghar, unpublished data). The most common anomalies were CNS –31% of
the ICSI group compared with 37% in the spontaneous group;
similarly, 31% renal anomalies compared with 18.6%, GI
anomalies 31.7% and 12.7%, followed by skeletal 12.9% and
12.7%, heart anomalies 7.3% and 5.8%; no difference was found
in the type of anomalies. The incidence of anomalies agrees with
several Egyptian studies. The incidence of congenital malformations in live-born infants ranged from 1.16% to 3.17% [26].
Examples of detected anomalies are shown in Figures 34.1,
34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, and 34.10.
Intrauterine insemination (IUI) pregnancies
The rate of congenital malformations is not increased and no
effect of frozen semen or donated semen has been confirmed
Figure 34.6. Kyphosoliosis.
from the literature. Reported incidence of malformations is
1.4% in singletons and 1.7% in twins; there was a slightly higher
incidence of trisomy 21, possibly related to higher maternal age.
The commonest malformations were cardiovascular, similar to
the general population [27].
In the French registry, a higher rate of congenital malforma-
tions was found among IVF pregnancies compared with IUI,
2.7% compared with 1.9% (P = 0.009). However, this rate did not
differ using husband semen or donor semen. The rate of trisomy
21 increased with maternal age as well as donor age [28]. Other
reports agreed with these results and, in addition, assessment of
the psychosocial development of such infants up to the age of
8–10 years appeared to be reassuring [29].
Anomalies after testicular sperm extraction (TESE)
The incidence of hypospadias was significantly higher in the
male offspring using epididymal or testicular sperm [13]. These
findings are supported by another study including IVF pregnancies and was attributed to the high incidence of maternal
progesterone administration [30]. Other malformations were
287
Section 4: Early pregnancy after infertility treatment
Figure 34.9. Holoprosencephaly.
Figure 34.7. Skeletal dysplasia, marked micromelia.
a
b
Figure 34.10. Facial cleft.
not found to be increased in ICSI children conceived with
epididymal or testicular sperm when compared with malformation rates for IVF or spontaneously conceived children [13].
The data published did not show any differences between nonobstructive azoospermia (NOA) and obstructive azoospermia
pregnancies, except for a strong tendency toward a lower gestational age in singletons and a higher percentage of premature
twins in the NOA group [31].
288
Congenital malformations in infertile patients conceiving naturally
Compared with singletons born of fertile couples, singletons
born of infertile couples who had conceived naturally or after
treatment had a higher prevalence of congenital malformation:
hazard ratios – 1.20 (95% CI 1.07–1.35) and 1.39 (1.23–1.57).
The overall prevalence of congenital malformations increased
with increasing time to pregnancy [32]. It is suggested that the
hormonal treatment used for infertility management may
explain the occurrence of genital org an malformations.
Figure 34.8a, b. Ventriculomegaly.
Chapter 34: Congenital anomalies
However, the increased prevalence of congenital malformations seen in singletons born after ART is partly due to underlying infertility or its determinants [32].
Conclusion
ThepopulationofchildrenbornafterARThasincreased
dramatically worldwide, and a literature search has shown
increased perinatal risks with IVF pregnancies. Multiple
pregnancies are the most serious due to higher obstetric
complications. These include perinatal mortality, preterm
birth, low birth weight, gestational hypertension, placental
abruption, and placenta previa. The risks are higher with
singleton pregnancies as well. Congenital malformations are
reported to be higher in IVF and ICSI pregnancies, reaching an OR of 2.0 in some studies. These were significantly
higher in twins. Concern exists with the ICSI procedure, as
it produces a non-natural selection of sperm and piercing
of oocyte cytoplasm; however, studies comparing congenital
malformations in ICSI with those in IVF showed no difference in incidence.
First-trimester screening for chromosomal anomalies using
PAPP-A and β-hCG, as well as NT thickness measurement,
showed differences between spontaneous and IVF pregnancies
as well as a higher false-positive rate.
Some congenitalmalformations are more common following
ART pregnancies, including hypospadias, especially after testicular sperm extraction, and the extrophy–epispadius complex.
In our own data of ultrasound-detected anomalies, the
incidence of congenital malformations was similar between
ICSI and spontaneous pregnancies.
Anomalies are not increased in IUI pregnancies.
The incidence of congenital malformations is higher in
spontaneous pregnancies of infertile couples.
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Chapter
Multiple pregnancy following IVF
35
James Hole, Kathy B. Porter, Sherri K. Taylor, Vicki Arguello, Robin Brown, Tiffany Driver and Willie Cotten
Introduction
The diagnosis of multiple gestation is frequently met with joy
and excitement by families who have undergone assisted reproduction; however, the happiness is tempered when the realization occurs that this diagnosis places the mother and the
gestation at significantly increased risk for morbidity and mortality. The incidence of twin pregnancies in the United States
has been increasing at an alarming rate from both delay of
childbearing until later in life and, more importantly, the use
of assisted reproductive techniques. The classically reported
rate for spontaneous twinning is 1:80 and for triplets 1:6000
to 1:8000 [1,2 ]. When compared with natural ovulation, assisted reproduction signi ficantly increases the chance of multiple
gestation: 20-fold for twin gestation and 40-fold for triplets or
quadruplets [3].
Twinning can be classified as either monozygotic (when a
single fertilized ovum divides into two embry os) or dizygotic
(when two separate ova are fertilized and implant in the same
cycle). Monozygosity occurs in 31% of spontaneous twins,
whereas dizygosity accounts for 69%. Most monozygotic
twins are dichorionic/diamniotic (when division occurs within
3 days post fertilization) or monochorionic/diamniotic (division on days 4–8); however, when division occurs on days 8–12,
the result will be a monochorionic/monoamniotic twin
(approximately 1:10 000 pregnancies). If division is delayed
until 13 days, the result is a conjoined twin. The incidence of
monozygotic twinning has consistently reported to be stable at
4–5 per 1000 births. The incidence of dizygotic twinning continues to vary depending on race and ethnicity, ranging from
1.3 per 1000 in Japan to 49 per 1000 in certain Nigerian tribes.
The increase in twins has typically been from dizygotic gestations, with no consistent increase in the rate of monozygosity.
Higher-order multiple gestations (triplets or above) are usually
combinations of multiple (di-, tri-, and higher) zygosity and
monozygotic divisions within these (Figures 35.1, 35.2, 35.3,
35.4, 35.5).
Diagnosis
The diagnosis of spontaneous multiple gestation is often
made when the clinical examina tion suggests size greater
than dates or during routine first- or second-trimester dating
or anatomical ultrasound evaluation. Multiple gestation in
assisted reproduction is generally diagnosed very early during the post-therapy ultrasound evaluation. Ultrasound can
usually delineate chorionicity, which should always be ascertained as early as possible in gestation. Monochorionicity has
been shown to be a more important predictor of adverse
outcome than zygosity [4]. The “ twin peak” (also called
lambda) sign is a very reliable marker for dichorionicity.
The lack of this finding and the presence of the so-called
“T” sign strongly suggest monochorionicity ( Figures 35.6,
35.7). Other useful sonographic tools include the number
of yolk sacs, placental locations and apparent number, and
fetal sex.
Complications
There is significant increase in both maternal and fetal morbidity and mortality with multifetal pregnancies. Congenital
anomalies, preterm birth, low birth weight, cerebral palsy,
intracranial hemorrhage, blindness, and chronic pulmonary
disease are among the more common known complications of
twin gestations that occur either directly from the twinning or
from prematurity [5]. From 1978 to 1987 at the Bourn Hall
clinic and the Hallam Medical Center, Rizk et al. reported a
23% multiple pregnancy rate in 961 babies conceived by
in-vitro fertilization [6]. Twins were present in 19% and triplets
in 4% with no quadruplet or high-order multiple pregnancy.
Overall, 32% were categorized as low birth weight and 6% as
very low birth weight (Tables 35.1, 35.2). The perinatal mortality rate was 2- to 3-fold higher than that of infants born in
England and Wales; this is attributed to multiple pregnancy
(Tables 35.3 , 35.4, 35.5). The congenital malformations were
within expected range (2.5%), as discussed in Chapter 34.Tan
et al. reported the obstetric outcome from the same series and
highlighted the increased incidence of preeclampsia, placenta
previa, and cesarean section [7]. Increased maternal morbidities included hypertension, gestational diabetes, anemia, preeclampsia, antepartum and postpartum hemorrhage, abnormal
placentation, polyhydramnios and cesarean section [8,9]. Less
frequently considered, but of significant consequence, is the
Ultrasonography in Reproductive Medicine and Infertility, ed. Botros R. M. B. Rizk. Published by Cambridge University Press. © Cambridge
University Press 2010.
Section 4: Early pregnancy after infertility treatment
Figure 35.1. First-trimester dichorionic twins.
Figure 35.2. First-trimester monochorionic twins.
Figure 35.4. Monochorionic/monoamniotic cord knot.
NOSE/LIPS
NOSE/LIPS
Figure 35.5. Conjoined twins.
292
Figure 35.3. Quadruplet gestation.
parenting stress sustained by the mothers and families of multiple gestations. A study of scores evaluating “severe parental
stress” in IVF pregnancies gave results of 22% for multiples as
compared with 5% for singletons [10].
Figure 35.6. Dichorionic twins, “lambda” sign.
Aneuploidy screening
Assessment for aneuploidy is an important aspect in the evaluation of abnormalities in any pregnancy, singleton or multiple. As