Incidence of congenital malformations in children born after ICSI.
ABSTRACT The aim of this study was to determine the incidence of congenital malformations in a complete cohort of children born after intracytoplasmic sperm injection (ICSI). The medical records were retrieved for 1139 infants, 736 singletons, 200 sets of twins and one set of triplets. The total number of infants with an identified anomaly was 87 (7.6%), 40 of which were minor. The incidence of malformations in children born after ICSI was also compared with all births in Sweden using data from the Swedish Medical Birth Registry and the Registry of Congenital Malformations. For ICSI children, the odds ratio (OR) for having any major or minor malformation was 1.75 [95% confidence interval (CI) 1.19-2.58] after stratification for delivery hospital, year of birth and maternal age. If stratification for singletons/twins was also done, the OR was reduced to 1.19 (95% CI 0.79-1.81). The increased rate of congenital malformations is thus mainly a result of a high rate of multiple births. The only specific malformation which was found to occur in excess in children born after ICSI was hypospadias (relative risk 3.0, exact 95% CI 1. 09-6.50) which may be related to paternal subfertility.
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ABSTRACT: In-vitro fertilisation is an effective treatment for infertility, but there is concern about the health of children. We investigated, in a retrospective registry study, malformations, cancers, and deaths in the complete Swedish in-vitro-fertilisation birth cohort compared with the general population. We collected data from all in-vitro-fertilisation clinics in Sweden and compared the obstetric outcomes of babies (n=5856) born between 1982 and 1995 with all babies born in the general population (n=1,505,724) during the same period, according to data from the Swedish Medical Birth Registry and the Registry of Congenital Malformations. We investigated the incidence of childhood cancer through the Swedish Cancer Registry. Data were stratified for maternal age, parity, previous subfertility, year of birth, and multiple of pregnancies. Multiple births occurred in 27% of pregnancies compared with 1% in the control group. In the in-vitro-fertilisation group, more babies were born preterm (<37 weeks) than controls (30.3 vs 6.3%) and more had low birthweights (<2500 g, 27.4 vs 4.6%). The perinatal mortality was 1.9% in the in-vitro fertilisation group and 1.1% in the controls. For in-vitro-fertilisation singletons, the risk ratios, adjusted for year of birth, for very preterm birth (<32 weeks) and very low birthweight (<1500 g) were 3.54 (95% CI 2.90-4.32) and 4.39 (3.62-5.32), respectively. Malformations occurred in 5.4% of all babies in the in-vitro-fertilisation group (1.39 [1.25-1.54]), and the rates of neural-tube defects and oesophageal atresia were higher than those in the controls. There was no increase in childhood cancer in the in-vitro-fertilisation group. A high frequency of multiple births and maternal characteristics were the main factors that led to adverse outcomes, and not the in-vitro-fertilisation technique itself. The clinical practice of in-vitro-fertilisation needs to be changed to lower the rate of multiple pregnancy.The Lancet 11/1999; 354(9190):1579-85. · 39.06 Impact Factor
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ABSTRACT: In order to evaluate the safety of the intracytoplasmic sperm injection (ICSI) procedure, a prospective follow-up study of 423 children born after ICSI was carried out. The aim of this study was to compile data on karyotypes, congenital malformations, growth parameters and developmental milestones. Before starting the infertility treatment, couples were asked to participate in a follow-up study including genetic counselling and prenatal diagnosis. The follow-up study of the child was based on a visit to the paediatrician-geneticist at birth or at 2 months of age, at 1 year and at 2 years of age when a physical examination for major and minor malformations and a psychomotoric evaluation were done. Between April 1991 and September 1994, 320 pregnancies obtained after ICSI led to the birth of 423 children (222 singletons, 186 twins and 15 triplets). Prenatal diagnosis determined a total of 293 karyotypes, one of which was abnormal (0.3%), and four were benign familial structural aberrations, all inherited from the paternal side. A total of 14 (3.3%) major malformations were observed, defined as those causing functional impairment or requiring surgical correlation. Neurological or developmental problems at the age of 2 months were found in 14 children, four of whom were multiples. Compared to most registers of children born after assisted reproduction and to registers of malformations in the general population, the figure of 3.3% major malformations is within the expected range. Before drawing any firm conclusion, further careful evaluations of the available data are necessary.Human Reproduction 08/1996; 11(7):1558-64. · 4.67 Impact Factor
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ABSTRACT: The safety of intracytoplasmic sperm injection (ICSI) as a novel procedure of assisted fertilization may be assessed by the health of the children born. In a prospective follow-up study of children born after assisted procreation, 130 children born consecutively after ICSI were compared with 130 control children born after in-vitro fertilization (IVF). In both groups, mothers were matched for age and had the same standard treatment protocol. There were 74 singleton, 50 twin and six triplet children in each group. Prenatal karyotyping and ultrasound screening, physical examination at birth and developmental milestones, with a follow-up at 2 months and 1 year, were recorded. Prenatal karyotypes were obtained in 100 of the 130 children in the ICSI group compared with 22 of the 130 children in the matched IVF group. All karyotypes were normal except for one prenatally detected mosaicism, which was not confirmed at birth. Four major malformations were detected in the ICSI group (holoprosecencephaly, femur fibula ulna syndrome and palatoschisis in two children), compared with six in the matched IVF group (coarctation of the aorta, palatoschisis, hypospadias, unilateral cryptorchidism, soft tissue syndactily and 11-beta-hydroxylase deficiency). In the ICSI and IVF groups, mean +/- SD birth weights were 2.94 +/- 0.67 and 2.80 +/- 0.73 kg, lengths were 48.46 +/- 3.56) and 47.47 +/- 5.78 cm, and head circumferences were 33.79 +/- 2.20 and 31.19 +/- 8.88 cm respectively. Among the ICSI singletons, the mean +/- SD birth weight was 3.28 +/- 0.58 kg and among the twins it was 2.60 +/- 0.43 kg; for the IVF singletons and matched twins the mean +/- SD birth weights were 3.19 +/- 0.56 and 2.36 +/- 0.61 kg respectively. In conclusion, there was no difference in the paediatric follow-up of 130 children born after ICSI and 130 children born after conventional IVF in age-matched control patients.Human Reproduction 01/1996; 10(12):3327-31. · 4.67 Impact Factor
Human Reproduction vol.15 no.4 pp.944–948, 2000
Incidence of congenital malformations in children born
U.-B.Wennerholm1,4, C.Bergh1, L.Hamberger1,
K.Lundin1, L.Nilsson1, M.Wikland3and B.Ka ¨lle ´n2
Previous reports have been reassuring regarding the outcome
of children born after ICSI, showing no increase in major
malformations (Bonduelle et al., 1994, 1995, 1996a,b, 1998a;
Liebaers et al., 1995; Palermo et al., 1996; Wennerholm et al.,
1996). The incidence of major malformations detected at birth
or during the perinatal period in these studies was reported to
range between 0.95% and 3.6%, not significantly different
in the general population. A re-evaluation of some of these
results has provided a less reassuring interpretation (Kurinczuk
and Bower, 1997): their re-analysis compared birth defects in
the Belgian ICSI children cohort (n ? 420) to 100 454 infants
born in Western Australia and concluded that the odds ratio
(OR) for major birth defects was higher after ICSI [OR 2.0;
95% confidence interval (CI) 1.4–2.9]. However, the authors
cautioned about confounders, e.g. a lower maternal age, a lower
multifetal pregnancy rate and a possible lower surveillance in
the reference population. Recently, a statistically significant
increase in sex chromosomal aberrations (0.83%) was reported
in a total of 1082 prenatal tests in pregnancies after ICSI
(Bonduelle et al., 1998b). Methodological shortcomings in the
previous studies such as small numbers and lack of proper
controls also emphasize the need to collect data from other
centres and proper control groups.
We have studied the rate of congenital malformations in a
cohort of children born after ICSI using data from the medical
records, the Swedish Medical Birth Registry (MBR) and the
Registry of Congenital Malformations (RCM). A comparison
has been made with all births in Sweden and also with births
after conventional IVF during corresponding time periods.
1Department of Obstetrics and Gynaecology, Sahlgrenska
University Hospital, Go ¨teborg,2Tornblad Institute, University of
Lund and3Fertility Center Scandinavia, Carlanderska Hospital,
Go ¨teborg, Sweden
4To whom correspondence should be addressed at: Institute for
Women’s and Children’s Health, Department of Obstetrics and
Gynaecology, Sahlgrenska University Hospital, O¨stra,
416 85 Go ¨teborg, Sweden
The aim of this study was to determine the incidence of
congenital malformations in a complete cohort of children
born after intracytoplasmic sperm injection (ICSI). The
medical records were retrieved for 1139 infants, 736 single-
tons, 200 sets of twins and one set of triplets. The total
40 of which were minor. The incidence of malformations in
children born after ICSI was also compared with all births
in Sweden using data from the Swedish Medical Birth
Registry and the Registry of Congenital Malformations.
For ICSI children, the odds ratio (OR) for having any
major or minor malformation was 1.75 [95% confidence
interval (CI) 1.19–2.58] after stratification for delivery
hospital, year of birth and maternal age. If stratification
for singletons/twins was also done, the OR was reduced to
1.19 (95% CI 0.79–1.81). The increased rate of congenital
malformations is thus mainly a result of a high rate of
multiple births. The only specific malformation which was
found to occur in excess in children born after ICSI was
hypospadias (relative risk 3.0, exact 95% CI 1.09–6.50)
which may be related to paternal subfertility.
Key words: intracytoplasmic sperm injection/malformations
Materials and methods
The study group included all infants born in Sweden after ICSI
performed at the two IVF clinics in Go ¨teborg, Sahlgrenska University
Hospital and Fertility Center Scandinavia. The Swedish definition of
birth comprises all liveborn and stillborn babies delivered after 28
weeks of gestation. The study population included all children born
as a result of ICSI from the first child born in 1993 to the last one
born as a result of ICSI performed before January 1998. Altogether,
1139 infants were born in Sweden, 736 singletons, 200 sets of twins
(400 infants) and one set of triplets. Infants delivered abroad (n ?
53) were excluded from this study. Since there is no registry of
therapeutic abortions in Sweden, terminated pregnancies were
excluded from comparisons with conventional IVF and population
data, but are discussed separately.
The number of children born after ICSI as a function of sperm
origin (ejaculated, epididymal or testicular spermatozoa) and the
replacement of fresh or frozen–thawed pre-embryos respectively is
shown in Table I. Medical records were retrieved for all infants.
Intracytoplasmic sperm injection (ICSI) has been in clinical
use since 1991 (Palermo et al., 1992) and has revolutionized
the treatment of severe male infertility. More than 20 000
children have been born worldwide with the use of this
technique (de Mouzon and Lancaster, 1997). The primary
question regarding ICSI is if the technique per se carries an
increased risk of genetic aberrations and malformations in the
children. This has been a special concern since spermatozoa
with impaired motility and morphology are often utilized
and, furthermore, immature spermatozoa derived from the
epididymis and the testis are also used in combination with
this technique and it may rather be the selection of patients
that constitutes a risk.
© European Society of Human Reproduction and Embryology
Congenital malformations in ICSI children
Table I. Number of children (singletons, twins and triplets) born after ICSI as a function of sperm origin and the replacement of fresh or frozen–thawed pre-
Transfer of fresh pre-embryosTransfer of frozen–thawed pre-embryosTotal no.
These were also identified in the Swedish MBR and the RCM (Ka ¨llen,
1987) in order to find any diagnoses which were missing in the
medical record. The MBR also allowed the calculation of the expected
numbers of malformed infants from all births.
The MBR has been in existence since 1973 (Cnattingius et al.,
1990) and covers nearly all births in the country (1–2% missing). It
is based on standardized medical documents used at all delivery units
and at the paediatric examination of newborn infants. When using
the registry in this study, stratification for year of birth, delivery
hospital and maternal age was done. Using the Mantel–Haenszel
technique, ICSI infants were compared with all infants born after
the above-mentioned stratifications and an OR with 95% CI was
determined for having a diagnosis of congenital malformation accord-
ing to the International Classification of Diseases (ICD) (ICD-9,
1977; ICD-10, 1992).
A possible excess of genito-urinary defects, major cardiovascular
defects and gastrointestinal defects in children conceived by ICSI
was shown in the Australian study (Kurinczuk and Bower, 1997).
Previous studies have shown an association between hypospadias and
reduced paternal fertility, notably with paternal problems (Sweet
et al., 1974) and between oesophageal atresia and maternal infertility
(Robert et al., 1993).
A similar procedure was therefore performed for three specific
conditions: hypospadias, congenital heart defects (excluding persistent
ductus arteriosus [PDA]), and intestinal atresia. For these specific
conditions, the expected number of cases was determined from the
population and compared with the observed numbers using exact
tests based on Poisson distributions. The observed/expected ratio
represents an estimate of the risk ratio (RR).
MBR and those which were only identified from the medical
records and/or RCM. The total number of infants with an
identified anomaly was thus 87 (7.6%), 40 of which were mild
or uncertain conditions. Only eight of the malformations not
recorded in the MBR were severe enough to be reportable to
the RCM, four of which had actually been reported. Tables II
and III also specify which infants were born in twin births.
Relatively serious malformations were more common in
twins than in singletons (OR 2.24, 95% CI 1.47–3.19). In
malformations, only infants registered in the MBR could be
used as there was no reference information based on medical
record screening. A total of 57 infants with any malformation
diagnosis was identified in the MBR among the 1008 infants.
The OR for having any congenital malformation registered in
the MBR among ICSI children versus the total population
was 1.75 (95% CI 1.19–2.58) after stratification for delivery
hospital, year of birth and maternal age. Of these 57 malformed
infants, 10 (18%) had malformations directly related to preterm
birth (PDA and undescended testicles) and twins were especi-
ally over-represented. If stratification for singletons/twins was
also done, the OR was reduced to 1.19 (95% CI 0.79–1.81).
In singletons, the OR was 1.39 (95% CI 0.82–2.38) and in
twins 0.86 (95% CI 0.45–1.63). None of the latter OR differed
significantly from 1.0. The low OR in twins may be partly
due to the fact that after ICSI the majority of twin pairs are
dizygotic but in the general population a substantial proportion
is monozygotic and the malformation risk is slightly increased
among the latter. In two sets of twins in our study group, the
twins had the same malformation (hypospadias occurred in
both infants in one twin pair and PDA occurred in both infants
in one twin pair delivered preterm).
A few specific malformations appeared to exist in excess.
There were seven infants with hypospadias but only six were
identifiable in the MBR (one was mis-coded). The expected
number of infants with hypospadias, stratifying for year of
birth, delivery hospital, maternal age and parity, was 2.01. The
relative risk (RR) was 3.0 (exact 95% CI 1.09–6.50).
Two infants with an intestinal atresia were identified in the
MBR and two additional infants had intestinal atresia but were
not identified in the MBR. The expected number of infants
with intestinal atresia recorded in the MBR was 0.33.
There were eight infants with a cardiac diagnosis (disreg-
arding PDA) registered in the MBR. The expected number of
infants with such a diagnosis in the MBR was 9.6, stratified
Of 1139 infants born in Sweden after 937 ICSI procedures
performed at the two IVF clinics in Go ¨teborg, 1008 infants
(830 deliveries among 780 women) were identified in the
MBR. Of the missing 107 deliveries, 101 occurred during
1998 when the MBR was not yet finalized. The other six
deliveries had thus not been reported to the MBR or could not
be identified because of errors in the identification numbers:
in four of these instances the women were foreign citizens
and no complete identification number had been given. Fifty-
three infants delivered abroad were excluded from this study,
since they were not part of the MBR. None of these infants
had any registered malformation according to the medical
records which were scrutinized.
Tables II (relatively serious malformations) and III (minor
or variable anomalies) present the identified malformations,
divided into those which had a malformation diagnosis in the
U.-B.Wennerholm et al.
Table II. Relatively serious congenital malformations in 1139 infants (400 twins) born after ICSI
Diagnosis No. of infants
Total no. of
No. of twins
Corpus callosum agenesi
VSD ? ASD
VSD ? pulmonary stenosis
Valvular aortic stenosis
Aortic and mitral stenosis
Hypoplastic left heart syndrome
Complex cardiac defect
Cleft palate ? microphthalmia
? foot deformity
Oesophageal atresia ? absent
Small bowel atresia
Duodenal atresia ? tricuspidal
malformation ? lung malf.
Anal atresia ? sacrum
Omphalocele ? cystic kidney
? Fallot’s tetrad
Hypospadias (1 mis-coded in
Hypospadias ? preauricular
Hypospadias ? valgus
Pes equinovarus adductus
Pes equinovarus ? unstable hip
Absent hand ? ASD
46,XX, t (12q;?)c
aIdentified from medical records and/or the RCM.
bStillborn infant, trisomy 13 discussed but not verified.
cUnbalanced translocation with partial monosomi of chromosome 12q and partial trisomy of another
MBR ? Medical Birth Registry; RCM ? Registry of Congenital Malformations; VSD ? ventricular septum
defect; ASD ? atrial septum defect.
for year of birth, maternal age, parity and delivery hospital.
When all sources were used, 15 infants with cardiac defects
were identified (the expected number was seven or eight).
Amongthem, fivewereserious (expectednumbertwoor three).
There were three infants with chromosome aberrations and
one with a genetic syndrome (Nager syndrome). One further
infant had a possible but unverified trisomy 13.
There were two further multi-malformed infants, one of
which was diagnosed with Goldenhar syndrome.
Table IV compares the presence of major malformations
among the 1008 ICSI infants and the 5446 infants born after
conventional IVF (Bergh et al., 1999). Among the latter, only
infants reported to the MBR or RCM were included and a
similar restriction was therefore made for the ICSI material.
Some differences appeared to exist. Most notable perhaps was
the complete absence of neural tube defects or hydrocephaly
in the ICSI material. The difference in rates (14/5446 and 0/
1008), however, may be random. The lower exact confidence
limit of the OR was 0.85 (not significant). The rate of neural
tube defects registered in Sweden was 5.5 per 10 000 and of
hydrocephaly 1.6 per 10 000. The expected number of such
defects among infants born after conventional IVF was thus
Congenital malformations in ICSI children
Table III. Minor or variable anomalies in 1139 infants (400 twins) born after ICSI
Diagnosis No. of infants with
Total no. of
Unspecified cardiac defect
PDA ? valgus foot deform.
Tooth in lower jaw
Unilateral kidney agenesis
Valgus foot deformity
aIdentified from medical records and/or the RCM.
bThe infant was regarded as without any cardiac defect at the age of 7 months.
MBR ? Medical Birth Registry; RCM ? Registry of Congenital Malformations; PDA ? persistent ductus
which were detected by second trimester ultrasound scanning.
These abnormalities included trisomy 18, polycystic kidney
disease and acrania (two cases).
As a routine, all patients with singleton pregnancies were
offered an early amniocentesis for karyotyping, but it was not
compulsory. Prenatal karyotyping was performed on 149
fetuses (13.1%). Abnormal results were found in four cases
(2.7%). One singleton was a trisomy 18 and the parents chose
to terminate the pregnancy in this case. Two were familial
structural anomalies inherited from the father. One twin had
an unbalanced translocation (see Table II).
Table IV. Presence in the Registry of Congenital Malformations (RCM) or
the Medical Birth Registry (MBR) of some severe congenital malformation
diagnoses among infants born after conventional IVF (n ? 5446) and after
ICSI (n ? 1008)
Cleft lip and/or palate
Small bowel atresia
Limb reduction defect
Other chromosome anomaly
Even though the medical records could be identified for all
infants born after ICSI, they could not all be identified in the
MBR. This is mainly due to the fact that the registry is not
yet complete for 1998, but even for previous years some cases
are missing. There are generally 1–2% of births missing in
the MBR and in this study of infants born after ICSI before
1998 there are six missing births among 836 deliveries (0.7%).
The present study illustrates the problems in evaluating data
obtained by screening of medical records for selected patients,
e.g. infants born after IVF or ICSI. Rates of malformations
obtained in this manner are difficult to compare with rates
determined, for instance, from population registers (Lancaster,
1987). We found that a substantial number of congenital
malformations were not included in the MBR and if data from
medical record screening had been compared with rates from
the MBR, the malformation risk associated with ICSI would
have been exaggerated. Even after restriction to conditions
identified in the registry, however, an excess risk was seen in
children born after ICSI, amounting to 75% [i.e. OR 1.75
(95% CI 1.19–2.58)]. This excess risk can to a large extent be
explained byconditions associated withmultiple and premature
birth, notably PDA and undescended testicle. It is also plausible
that paediatric examination and recording of data concerning
3.9 and after ICSI was 0.8. There thus seemed to be an
increased risk of such defects after conventional IVF but this
was not demonstrated after ICSI.
Hypospadias seemed to occur more frequently after ICSI
than after conventional IVF but the difference (7/1008 and 13/
5446) was not statistically significant: OR ? 2.92 (exact
95% CI 0.98–7.90, not significant). The population rate of
hypospadias was about two per 1000 and the expected number
of hypospadias was therefore ~11 after conventional IVF and
two after ICSI.
The only other malformation with a reasonably high fre-
quency was oro-facial clefts — the rates were similar in ICSI
and IVF and the OR was 0.73 (95% CI 0.19–4.26), thus not
During the study period, four pregnancies after ICSI were
interrupted because of the presence of fetal abnormalities,
U.-B.Wennerholm et al.
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infants born after IVF and ICSI may be more detailed than
for the average baby.
There is one condition which seems clearly over-represented
among infants born after ICSI, namely hypospadias. This
condition has been associated with reduced parental fertility
(Ka ¨llen et al., 1991) and notably with paternal problems
(Sweet et al., 1974). An association with ICSI is therefore
plausible. Hypospadias has also been associated with progestin
exposure during organogenesis (Harris, 1990). Progesterone
or progestins are often given after IVF treatment as luteal
phase support. This association is probably due to confounding
from the major reason for progestin therapy, bleeding in
early pregnancy, an association seen irrespective of whether
progestins have been used or not (Ka ¨lle ´n et al., 1992). The
apparently higher frequency of hypospadias after ICSI than
after conventional IVF supports the explanation that the
association between hypospadias and ICSI is due to con-
founding by paternal subfertility.
When specific malformations were compared between
infants born after ICSI and after conventional IVF, there was
an apparent lack of neural tube defects and hydrocephaly
observed among the former but an over-representation among
the latter, even though this difference may be random. These
conditions are associated with twinning, and the rate of twin
pregnancies in the conventional IVF material is higher (27%)
than in the ICSI material (20%). It is, however, also possible
that neural tube defects are specifically related to female
infertility, as has been repeatedly suggested although never
proven (cf. review by Elwood et al., 1992).
The crude increased rate of malformation in ICSI depends
mainly on the presence of conditions related to prematurity
and multiple births (e.g. PDA, undescended testicle). The only
specific effect is seen on hypospadias which may be due to
an association between paternal subfertility and hypospadias.
This study was supported by grants from the Go ¨teborg Medical
Society and the Regional Authority of West Sweden. We would like
to thank the midwives and technicians of the IVF clinics at the
Fertility Center Scandinavia and Sahlgrenska University Hospital (in
alphabetical order)for theirhelp
A.-S.Forsberg, H.Holter, E.Nilsson, E.Reismer and E.Samuelsson.
We also want to thank Anders Ericson, Medical Birth Registry,
National Board of Health, Stockholm, for giving us access to the
Received on September 6, 1999; accepted on December 13, 1999
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