Neonatal outcome and congenital malformations in children born after in-vitro fertilization

Sari Koivurova1,2,5, Anna-Liisa Hartikainen2, Mika Gissler3, Elina Hemminki3, Ulla Sovio4 and Marjo-Riitta Järvelin1,4

1 Department of Public Health Science and General Practice, 2 Department of Obstetrics and Gynecology, University Hospital of Oulu, Oulu, 3 National Research and Development Center for Welfare and Health, Helsinki, Finland and 4 Department of Epidemiology and Public Health, Imperial College School of Medicine, London, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: To evaluate the neonatal outcome and the prevalence of congenital malformations in children born after IVF in northern Finland we carried out a population-based study with matched controls. METHODS: Firstly, 304 IVF children born in 1990–1995 were compared with 569 controls, representing the general population in proportion of multiple births, randomly chosen from the Finnish Medical Birth Register (FMBR) and matched for sex, year of birth, area of residence, parity, maternal age and social class. Secondly, plurality matched controls (n = 103) for IVF twins (n =103) were randomly chosen from the FMBR and analysed separately. Additionally, IVF singletons (n = 153) were compared with singleton controls (n = 287). Mortality rates were compared with national figures from FMBR. RESULTS: Most mortality rates were twice as high as national figures in the general population. When compared with the control group representing the general population, the incidences of preterm birth [odds ratio (OR) 5.6, 95% confidence interval (CI) 3.7–8.6], very low birth weight (OR 6.2, 95% CI 2.0–19.0), low birth weight (OR 9.8, 95% CI 5.6–17.3), neonatal morbidity (OR 2.4, 95% CI 1.7–3.4) and hospitalization (OR 3.2, 95% CI 2.2–4.6) were significantly higher in the IVF group. The prevalence of heart malformations was four-fold in the IVF population than in the controls representing the general population (OR 4.0, 95% CI 1.4–11.7). CONCLUSIONS: Neonatal outcome after IVF is worse than in the general population with similar maternal age, parity and social standing, mainly due to the large proportion of multifetal births after IVF. The higher prevalence of heart malformations does not solely arise from multiplicity but from other causes. In order to improve neonatal outcome after IVF, the number of embryos transferred should be limited to a minimum.

Key words: congenital malformations/hospitalization/in-vitro fertilization/neonatal outcome


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Since IVF has become an efficient and widely used treatment for infertile couples over the last 20 years there has been concern about the health of children born after this treatment. Because of the relative novelty of IVF, the follow-up of children born after IVF is still quite limited. IVF is responsible for the increasing number of multifetal pregnancies, multiplicity being an important risk factor for adverse neonatal outcomes due to preterm birth, low birth weight and small for gestational age (SGA) (Friedler et al., 1992Go; Balen et al., 1993Go; Gissler et al., 1995Go; Bergh et al., 1999Go; Buitendijk, 1999Go). A number of studies have shown that children born after IVF have more neonatal problems (Yeh et al., 1990Go; D'Souza et al., 1997Go) and need longer hospitalization and intensive care than spontaneously conceived ones (Gissler et al., 1995Go; Addor et al., 1998Go; Koudstaal et al., 2000Go). In spite of the strong effect of multiplicity on neonatal outcomes, children from singleton IVF pregnancies also seem to be more predisposed to adverse neonatal outcomes such as preterm birth, low birth weight and longer hospitalization than other children (Gissler et al., 1995Go).

Infertile women are frequently of advanced age at the time of conception and they may have a variety of underlying causes for infertility. Furthermore, during the IVF process the embryo is exposed to mechanical, thermal and chemical alterations. Theoretically, these factors can increase the risk of congenital malformations. Lancaster's study from the late 1980s was the first to report a higher prevalence of neural tube defects and transposition of the great vessels among IVF children (Lancaster, 1987Go). The majority of later studies have been negative as far as congenital malformations are concerned. However, a few very recent studies have reported an increase in the prevalence of neural tube defects, oesophageal atresias (Bergh et al., 1999Go; Ericson and Källén, 2001Go), omphalocele and hypospadias (after ICSI) among IVF children compared with spontaneously conceived controls (Ericson and Källén, 2001Go).

The objective of this population-based cohort study is to compare neonatal outcomes, the need for hospitalization after birth and the prevalence of congenital malformations between IVF children and spontaneously conceived controls matched for maternal age, parity, social class, sex, year of birth, area of residence and fetal plurality. The aim of having a unique study design with two separate control groups, firstly representing general population and secondly controls matched for plurality, was to evaluate the effect of IVF and multiplicity separately from each other on the neonatal outcome. Our a priori hypothesis was that there are more neonatal complications leading to longer hospitalization as well as a higher incidence of congenital malformations in children born after IVF, which was based on a few observations in previous literature and on a pilot study we conducted in 1997.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
A cohort study with a group of IVF exposed children born in 1990–1995 and two groups of unexposed naturally conceived controls was set up. The exposed children were recruited from the register at the IVF outpatient clinic in the University Hospital of Oulu and the Infertility Clinic of the Family Federation of Finland in Oulu. These two clinics, the latter being a private clinic, cover all IVF treatments in northern Finland, i.e. the provinces of Oulu and Lapland.

Pre-study sample size calculations—primary for the subsequent long-term follow-up—were based on the approximation of a frequency of 15% for developmental disorders including neurological signs (gross and fine motor, speech and other handicaps) among the unexposed population. For 80% power, 0.05 alpha-error, ratio of 2:1 (unexposed:exposed) and a risk ratio of 1.6 for the outcome between the groups, a sample size of at least 238 exposed and 476 unexposed children was required.

There were 306 liveborn (154 singletons and 152 children from multiple pregnancies; 123 twins, 25 triplets and four quadruplets) and three stillborn (one twin and two triplets) IVF exposed children born in 1990–1995 in the study group. One singleton was conceived by ICSI, the rest of the children were born after conventional IVF and only fresh embryos were used. To examine neonatal outcome two separate unexposed liveborn control groups from the Finnish Medical Birth Register (FMBR; includes all births after completion of the 22nd gestational week or with birth weight of 500 g or more) were to be chosen: (i) 618 live controls (i.e. 2:1, 2x309, at this point we were unaware of the three stillborn cases among the IVF population) were to be chosen at random for all exposed children and matched in the following order: sex, year of birth, area of residence (i.e. the provinces of Oulu and Lapland), parity, maternal age and social class defined by occupation of the mother [upper white collar, lower white collar, blue collar, entrepreneurs (small business) and farmers, students, housewives and unknown]. This control group (control I) represents the general population in the proportion of multiple births with similar maternal age, parity and social class. (ii) A second control group for multiples was randomly chosen (1:1, 152:152), and matched for plurality in addition to the matching criteria listed above. Consequently, we were able to do the stratified analyses by plurality, i.e. exposed singletons had their own singleton controls derived from control I group (hereafter control SII), and multiple births their own controls (control TII, T refers to twin). However, in the final study population the numbers differ because data on some unexposed children (missing controls) were not found (i.e. an exposed child may have only one control instead of the planned two) (Figure 1Go).



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Figure 1. Study design, final study population and the geographical catchment area of the study.

 
Data were collected from hospital records by a resident physician (S.K.) regarding neonatal parameters, length of neonatal hospitalization at neonatal wards and intensive care units, and congenital malformations. Neonatal diagnoses in hospital records were set by resident or specialized paediatricians and were based on the International Classification of Diseases (ICD-10) codes. For the subsequent long-term follow-up study we used the hospital records for the previous 3 years, enabling us to get information of congenital malformations detected at any stage between birth and 3 years of age.

Neonatal morbidity was defined as having one or more of the following diagnoses based on ICD-10 codes: neonatal infections, hypoglycaemia, hyperbilirubinaemia needing blue light therapy, respiratory distress syndrome, bronchopulmonary dysplasia, patent ductus arteriosus, apnoea or intracranial haemorrhage. Ponderal index (kg/m3) is a neonatal measure of thinness reflecting intrauterine growth. Congenital malformations were defined according to the definition of the Finnish Register of Congenital Malformations and Birth Defects, which follows ICD-9.

The perinatal mortality rate (PNMR) includes stillbirths from the completed 22nd gestational week onwards or with birth weight of at least 500 g with early neonatal deaths. The early neonatal mortality rate includes neonatal deaths <7 days from birth, and the late neonatal mortality rate includes neonatal deaths during 7–27 days. Mortality rates were compared with national figures from FMBR regarding northern Finland, but stillbirths were excluded from further statistical analyses related to comparisons between the exposed children and their controls in terms of neonatal outcomes or congenital malformations.

Conditional logistic regression for matched sets was used to calculate odds ratios with 95% confidence intervals (CI) for categorical and categorized variables. The percentages were also calculated using matched sets, the denominator varies slightly due to some missing values, variable by variable. The aim of having a control cohort drawn from the general population was to compare the whole group of IVF children with the average population and to be able to estimate the consequences of the increased number of multiple pregnancies together with IVF treatment on the outcome of the child. The second set of controls matched for plurality was chosen to control the confounding caused by multiple birth on the outcome of the child. Success in matching was explored and it turned out that we were unable to follow only the matching criteria of the area of residence, because there were not enough eligible naturally conceived children from multiple pregnancies to be included in the control group. For the same reason, for triplets and quadruplets the matching criteria were not fulfilled at all and hence they were excluded from analyses stratified for plurality, but included in population-based analyses.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The final study population for population-based matched neonatal analyses and matched analyses stratified for plurality is presented in Figure 1Go. The male:female ratio was about 1:1 in both IVF and control populations.

Mortality
Mortality rates in the IVF group and in the general population in Northern Finland in 1990–1995 are presented in Table IGo. There were three stillbirths in the IVF group: one stillbirth occurred in a twin pregnancy and two stillbirths in a triplet pregnancy. Two infants in the IVF group and three infants in the control group died during the neonatal period. The causes of neonatal death in the IVF group were preterm birth in one of the cases and multiple anomalies (amniotic band sequence) in one case. In the control group the cause of death was preterm birth in all three cases.


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Table I. The mortality rates in the IVF group and in the general population from the Finnish Medical Birth Register in northern Finland in 1990–1995
 
Neonatal outcome
The risk of preterm birth (<37th gestational week) was nearly six-fold higher in the IVF group when compared with controls representing the general population. The incidence of birth before the completion of the 32nd gestational week was over seven-fold and the incidence of birth between the 32nd and the 36th gestational weeks was over four-fold higher in the IVF group compared with control I group. No statistically significant differences in the proportion of children born preterm were found in analyses stratified for plurality (Table IIGo).


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Table II. Neonatal parameters and congenital malformations in matched IVF and control groups (The odds ratios and percentages were calculated using matched sets. The denominator varies slightly variable by variable due to some missing values.)
 
The mean birth weight in the whole IVF group was 2917 g (SD 746.5) and in the control I group 3453 g (SD 585.7). In the comparisons stratified for plurality the mean birth weights were 3364 g (SD 595.5) among the IVF singletons and 3483 g (SD 569.5) among the control singletons. For twins the figures were 2594 g (SD 528.1) versus 2547 g (SD 602.0) respectively. The risk of very low birth weight (<1500 g) was six-fold higher and the risk of low birth weight (1500–2499 g) was almost ten-fold higher in the whole IVF group when compared with control I group. Furthermore, a low Ponderal index (<25 kg/m3, which was the lower quartile in our study population) was significantly, almost three times, more common in the IVF population than in control I group. The analyses stratified for plurality showed no statistically significant differences for either very low/low birth weight or low Ponderal index (Table IIGo).

The incidence of neonatal morbidity was significantly, over two-fold, higher in the IVF group when compared with the control I group. When stratified for plurality, no significant differences occurred. As a consequence of increased morbidity IVF children were significantly more often hospitalized and intubated during the neonatal period at neonatal intensive care units and/or neonatal wards than their controls representing group I. In analyses stratified for plurality no significant differences were found. No significant differences were found in the incidence of low Apgar score (<=7) at 5 min in any of the comparisons (Table IIGo).

Congenital malformations
There were in total 20 children with minor or major congenital malformations/syndromes in the IVF group, giving a malformation rate of 6.6%. No malformations occurred in stillborn children. Six cases of malformation were found in the IVF singletons, eight in twins and six in triplets. Fourteen cases of malformation were found in children born preterm (<37 gestational weeks) and six in children born at term. There were no major differences in the sex distribution of malformations in the IVF group (males, 11 versus females, 9). One case of trisomy 21 occurred in the IVF group. In the group of controls representing general population (control I) 25 children with minor or major congenital malformations/syndromes were found; 24 malformations in singletons and one in twins, giving a malformation rate of 4.4%. The majority of the malformations (n = 23) were found in infants born at term. The prevalence of congenital malformations in the control group was strongly associated with the male sex (males, 21 versus females, four), even if urogenital malformations were excluded. Specific congenital malformations are listed in Table IIIGo. In addition to the listed congenital malformations, a number of inguinal (IVF versus controls, nine versus eight) and umbilical hernias (10 versus three), unstable hips (two versus seven), undescended testes (two versus five) and hydroceles (one versus two) occurred in both groups, but were not considered to be malformations.


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Table III. Population-based comparison of the prevalence of children with congenital malformations/syndromes in the liveborn IVF (n = 304) and control I groups (n = 569a, represents general population in proportion of plurality)
 
When all heart anomalies listed in Table IIIGo were analysed together, there was a four-fold increase in their prevalence in the IVF group compared with control I group [odds ration (OR) 4.0, 95% confidence interval (CI) 1.4–11.7]. The difference was not so prominent among singletons (OR 3.0, 95% CI 0.5–18.0) and was not found at all among twins (OR 0.8, 95% CI 0.2–3.4). For other malformations (including CNS, limb and visceral malformations) no significant differences were found among the groups (Table IIGo).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The present study is a population-based cohort study consisting of all children born after IVF in northern Finland between 1990 and 1995, with carefully matched controls representing firstly the average population in the proportion of multiple births and secondly infants from multiple births in proportion to that in the IVF exposed group, to examine the effect of IVF on neonatal outcome independently of multiplicity. The unique study design with different control groups allows us to estimate the effect of IVF and multiplicity separately on the outcome of the infant born after infertility treatments. Furthermore, due to matching, the control population in this study represents children of old primiparous women minimizing the confounding effect of maternal age and parity. Another strength of this study is that we could trace nearly all children originally chosen for the study.

In our study, most mortality rates during the neonatal period were twice as high in the IVF group as in the general population from the same area and in the same time period. The power of the study in this respect was too small to make statistical inferences. Previous publications report stillbirth rates in IVF populations ranging between 4.3–19.7/1000 (MRC Working Party, 1990; Rizk et al., 1991Go; Friedler et al., 1992Go; FIVNAT, 1995Go; Tanbo et al., 1995Go; Westergaard et al., 1999Go), which is in accordance with our stillbirth rate. It should be noted that the definitions of birth differ by country and this may cause some variation in the stillbirth rates. The perinatal mortality rate for IVF children in this study (16.2/1000) was on average lower than most previously reported figures (17.0–39.7/1000) (MRC Working Party, 1990; Rizk et al., 1991Go; Friedler et al., 1992Go; Balen et al., 1993Go; Olivennes et al., 1993Go; FIVNAT, 1995Go; Gissler et al., 1995Go; Westergaard et al., 1999Go; Koudstaal et al., 2000Go). Generally, the perinatal mortality rates in IVF populations are reported to be substantially higher than in the general population (MRC Working Party, 1990; Rizk et al., 1991Go; Friedler et al., 1992Go; FIVNAT, 1995Go). In previous reports, the total neonatal mortality rates range between 15.5–19.2/1000 (MRC Working Party, 1990; Rizk et al., 1991Go; FIVNAT, 1995Go), being higher than our corresponding figure, 6.5/1000. The elevated mortality rates among IVF children are mainly due to the increased proportion of multifetal pregnancies following infertility treatments. Also, the characteristics of infertile women, especially advanced age, which may affect the course of IVF pregnancy, may, in turn, have an effect on the increased mortality rates.

There were significantly more preterm births and cases of very low or low birth weight in the IVF group than in the control I group in our study, which is in accordance with numerous previous reports (MRC Working Party, 1990; Friedler et al., 1992Go; Tan et al., 1992Go; Gissler et al., 1995Go; Tallo et al., 1995Go; D'Souza et al., 1997Go; Bergh et al., 1999Go). No differences were found in the analysis stratified for plurality, thus not confirming the previous information of an elevated risk of preterm birth in IVF singletons (Gissler et al., 1995Go; Tanbo et al., 1995Go; Verlaenen et al., 1995Go; Westergaard et al., 1999Go; Koudstaal et al., 2000Go). According to these results, multiplicity seems to be the most important factor behind the increased incidence of preterm birth and very low/low birth weight in IVF children.

As a whole, the IVF group survived the neonatal period worse than the general population-based control I group. Neonatal morbidity, including all the most common neonatal complications, was over twice as high in the IVF group as in the control I group. Consequently, the IVF children required admission to the neonatal intensive care unit or neonatal ward three times more often than controls. Similar results have been reported previously (FIVNAT, 1995Go; Gissler et al., 1995Go; Tallo et al., 1995Go; Tanbo et al., 1995Go; D`Souza et al., 1997; Koudstaal et al., 2000Go). Since only small and statistically non-significant differences occurred among singletons in our study, it can be concluded that multiplicity, along with preterm birth and low birth weight, are the most important determinants of neonatal outcome.

All children in the area are screened at birth for congenital malformations by paediatricians in specialized obstetric units or, occasionally, by general practitioners at local delivery units. Also later IVF and spontaneously conceived children go through the same medical examination protocol conducted by general practitioners and public health nurses in the public child welfare clinics. Therefore, we believe that no ascertainment bias was present regarding congenital malformations. The malformation rate in the population-based control group (4.4%) is similar to that of general Finnish population (The Finnish Register of Congenital Malformations and Birth Defects, unpublished data). The malformation rate in the IVF group (6.6%) in this study was higher than most previously reported rates after IVF or ICSI, which range between 2.2–6.1% (MRC Working Party, 1990; Rizk et al., 1991Go; Friedler et al., 1992Go; FIVNAT, 1995Go; Bonduelle et al., 1996Go; Palermo et al., 1996Go; D'Souza et al., 1997Go; Addor et al., 1998Go; Westergaard et al., 1999Go) and are similar to the rates of congenital malformations in the general populations. Some of these studies have taken therapeutic abortions due to prenatal diagnosis of congenital malformations into account with no notable increase in the malformation rates. The diagnoses of congenital malformations in these studies were mostly set at the neonatal period, unlike in our study, where we had information up to 3 years of age (for the subsequent follow-up study) enabling us to include also cases with malformations detected at any stage during the first 3 years of age. This might explain the higher malformation rate in our study. Still, it is difficult to make comparisons of international malformation rates, because the classifications of malformations are highly variable from one country to another. A recent Swedish study has reported an increased malformation rate of 7.6% (therapeutic abortions excluded) with an excess of hypospadias among ICSI children. They concluded this was mainly a result of a high rate of multiple births following ICSI and the excess of hypospadias was connected to paternal subfertility (Wennerholm et al., 2000Go). Recent studies, also Swedish, with large study populations (no data on therapeutic abortions) reported an increase in the prevalence of neural tube defects, oesophageal atresias (Bergh et al., 1999Go; Ericson and Källén, 2001Go), omphalocele and hypospadias (after ICSI) (Ericson and Källén, 2001Go) among IVF children compared with population-based control groups. Our numbers on these malformations are too small to confirm this. Furthermore, we have no complete knowledge about possible therapeutic abortions or miscarriages in IVF pregnancies that did not lead to birth during the whole study period (no therapeutic abortions during 1992–1995; no knowledge during 1990–1991), which is a deficiency in this study. The starting point of our study was to choose IVF pregnancies ending in a birth, and thus all abortions were excluded. This may cause bias if the probability for a malformed fetus to be aborted varies between IVF and spontaneous pregnancies. Furthermore, our control groups were taken among live births, which was the reason why the group comparisons were made between liveborn children. However, no malformations were found among stillbirths in our study, and we believe that no major bias was caused, and if that was the case, it dilutes the differences between the groups.

Interestingly, there was a four-fold increase in the incidence of heart malformations, specifically septal defects, in the IVF group when compared with control I group, though this was not so prominent in the analysis stratified for plurality. To our knowledge, no previous reports of this kind have been published. An Australian re-analysis of a Belgian study on birth defects in ICSI children also found a four-fold excess of major cardiovascular defects after ICSI (Kurinczuk and Bower, 1997Go), but this re-analysis was quite controversial and was criticised by the original authors. Congenital heart malformations are due to complex multifactorial genetic and environmental causes, and fewer than 10% of all cardiac malformations arise from recognized chromosomal aberrations and mutations of single genes (Friedman and Child, 1998Go). Some investigators have noted that the mothers of children with VSD had a worse reproductive history than mothers without a child with VSD. They concluded that reproductive ability with differing levels of maternal hormones may be inversely related to the risk of VSD (Sands et al., 1999Go), which might be supported by our results.

Although there were no statistically significant differences in the incidence of heart malformations in the analyses stratified for plurality, the excess of ASD and VSD in the IVF group cannot be solely explained by multiplicity. Heart defects do not arise directly from preterm birth, but from other background factors, and there was an increase, though non-significant, among singletons also. In most previous studies the sample sizes are too small to detect any differences in the prevalence of congenital malformations among IVF children compared with the general population. Larger population-based studies including data on therapeutic abortions are needed to investigate this further.

In conclusion, our results showed a poorer neonatal outcome for the IVF children when compared with controls representing general population in terms of preterm birth, lower birth weight and related problems arising mainly from multiplicity, since no statistically significant differences occurred in the analyses stratified for plurality. An excess of cardiac septal defects, but not of other congenital malformations, was found in the IVF children. This phenomenon probably results from a complex mechanism. Our control population represents children of old and primiparous women, so the differences would probably be even greater compared with children from the population at common reproductive age. Due to a high rate of multiple pregnancies and births, IVF technology leads to increasing financial expenses to societies in the form of increased use of health services during pregnancy and the neonatal period. To date, the most important procedure, which could improve neonatal outcome and reduce financial costs, is to limit the number of embryos transferred, hence reducing the number of multiple pregnancies.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
We wish to thank Annukka Ritvanen, MD for her important advice and comments on the manuscript. We also gratefully acknowledge the financial support from The Alma and K.A. Snellman Foundation, Oulu, Finland and from the National Social Insurance Institute, Finland.


    Notes
 
5 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, University Hospital of Oulu, PO BOX 24, 90029 Oulu, Finland. E-mail: sari.koivurova{at}oulu.fi Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Addor, V., Santos-Eggiman, B., Fawer, C.L., Paccaud, F. and Calame, A. (1998) Impact of infertility treatments on the health of newborns. Fertil. Steril., 69, 210–215.[ISI][Medline]

Balen, A.H., MacDougall, J. and Tan, S.L. (1993) The influence of the number of embryos transferred in 1060 in-vitro fertilization pregnancies on miscarriage rates and pregnancy outcome. Hum. Reprod., 8, 1324–1328.[Abstract]

Bergh, T., Ericson, A., Hillensjö, T., Nygren, K-G. and Wennerholm, U-B. (1999) Deliveries and children born after in-vitro fertilization in Sweden 1982–95: a retrospective cohort study. Lancet, 354, 1579–1585.[ISI][Medline]

Bonduelle, M., Legein, J., Buysse, A., Van Assche, E., Wisanto, A., Devroey, P., Van Steirteghem, A.C. and Liebaers, I. (1996) Prospective follow-up study of 423 children born after intracytoplasmic sperm injection. Hum. Reprod., 11, 1558–1564.[Abstract/Free Full Text]

Buitendijk, S.E. (1999) Children after in vitro fertilization. An overview of the literature. Int. J. Technol. Assess. Health Care, 15, 52–65.[ISI][Medline]

D'Souza, S.W., Rivlin, E., Cadman, J., Richards, B., Buck, P. and Lieberman, A. (1997) Children conceived by in vitro fertilization after fresh embryo transfer. Arch. Dis. Child., 76, F70–F74.[ISI]

Ericson, A. and Källén, B. (2001) Congenital malformations in infants born after IVF: a population-based study. Hum. Reprod., 16, 504–509.[Abstract/Free Full Text]

FIVNAT (French In vitro National) (1995) Pregnancies and births resulting from in vitro fertilization: French national registry, analysis of data 1986 to 1990. Fertil. Steril., 64, 746–756.[ISI][Medline]

Friedler, S., Mashiach, S. and Laufer, N. (1992) Births in Israel resulting from in-vitro fertilization/embryo transfer, 1982–1989: National Registry of the Israeli Association for Fertility Research. Hum. Reprod., 7, 1159–1163.[Abstract]

Friedman, W.F. and Child, J.S. (1998) Congenital heart disease in the adult. In Fauci, A.S., Braunwald, E., Isselbacher, K.J. et al. (eds) Harrison's principles of internal medicine. McGraw-Hill, Singapore, vol. 1, pp. 1300–1309.

Gissler, M., Malin Silverio, M. and Hemminki, E. (1995) In-vitro fertilization pregnancies and perinatal health in Finland 1991–1993. Hum. Reprod., 10, 1856–1861.[Abstract]

Koudstaal, J., Braat, D.D.M., Bruinse, H.W., Naaktgeboren, N., Vermeiden, J.P.W. and Visser, G.H.A. (2000) Obstetric outcome of singleton pregnancies after IVF: a matched control study in four Dutch university hospitals. Hum. Reprod., 15, 1819–1825.[Abstract/Free Full Text]

Kurinczuk, J.J. and Bower, C. (1997) Birth defects in infants conceived by intracytoplasmic sperm injection: an alternative interpretation. Br. Med. J., 315, 1260–1266.[Abstract/Free Full Text]

Lancaster, P.A.L. (1987) Congenital malformations after in-vitro fertilization. Lancet, ii, 1392–1393.

MRC Working Party on children conceived by in vitro fertilisation (1990) Births in Great Britain resulting from assisted conception, 1978–87. Br. Med. J., 300, 1229–1233.[ISI][Medline]

Olivennes, F., Rufat, P., André, B., Pourade, A., Quiros, M.C. and Frydman, R. (1993) The increased risk of complication observed in singleton pregnancies resulting from in-vitro fertilization (IVF) does not seem to be related to the IVF method itself. Hum. Reprod., 8, 1297–1300.[Abstract]

Palermo, G.D., Colombero, L.T., Schattman, G.L., Davis, O.K. and Rosenwaks, Z. (1996) Evolution of pregnancies and initial follow-up of newborns delivered after intracytoplasmic sperm injection. J. Am. Med. Assoc., 276, 1893–1897.[Abstract]

Rizk, B., Doyle, P., Tan, S.L., Rainsbury, P., Betts, J., Brinsden, P. and Edwards, R. (1991) Perinatal outcome and congenital malformations in in-vitro fertilization babies from the Bourn–Hallam group. Hum. Reprod., 6, 1259–1264.[Abstract]

Sands, A.J., Casey, F.A., Craig, B.G., Dornan, J.C., Rogers, J. and Mulholland, H.C. (1999) Incidence and risk factors for ventricular septal defect in `low risk' neonates. Arch. Dis. Child. Fetal Neonatal Ed., 81, F61–F63.[Abstract/Free Full Text]

Tallo, C.P., Vohr, B., Oh, W., Rubin, L.P., Seifer, D.B. and Haning, R.V. Jr (1995) Maternal and neonatal morbidity associated with in vitro fertilization. J. Pediatr., 127, 794–800.[ISI][Medline]

Tan, S.L., Doyle, P., Campbell, S., Beral, V., Rizk, B., Brinsden, P., Mason, B. and Edwards, R.G. (1992) Obstetric outcome of in vitro fertilization pregnancies compared with normally conceived pregnancies. Am. J. Obstet. Gynecol., 167, 778–784.[ISI][Medline]

Tanbo, T., Dale, P.O., Lunde, O., Moe, N. and Åbyholm, T. (1995) Obstetric outcome in singleton pregnancies after assisted reproduction. Obstet. Gynecol., 86, 188–192.[Abstract/Free Full Text]

Verlaenen, H., Cammu, H., Derde, M.P. and Amy, J.J. (1995) Singleton pregnancy after in vitro fertilization: expectations and outcome. Obstet. Gynecol., 86, 906–910.[Abstract/Free Full Text]

Wennerholm, U.B., Bergh, C., Hamberger, L., Lundin, K., Nilsson, L., Wikland, M. and Källén, B. (2000) Incidence of congenital malformations in children born after ICSI. Hum. Reprod., 15, 944–948.[Abstract/Free Full Text]

Westergaard, H.B., Tranberg Johansen, A.M., Erb, K. and Nyboe Andersen, A. (1999) Danish National In-Vitro Registry 1994 and 1995: a controlled study of births, malformations and cytogenetic findings. Hum. Reprod., 14, 1896–1902.[Abstract/Free Full Text]

Yeh, J., Leipzig, S., Friedman, E.A. and Seibel, M.M. (1990) Results of in vitro fertilization pregnancies: experience at Boston's Beth Israel Hospital. Int. J. Fertil., 35, 116–119.[ISI][Medline]

Submitted on September 20, 2001; accepted on December 17, 2001.