1 TNO Prevention and Health, Department of Reproduction and Perinatology, P.O.Box 2215, 2301 CE Leiden and 2 Department of Obstetrics and Gynaecology, University Hospital St Radboud, Nijmegen, The Netherlands
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Abstract |
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Key words: congenital malformations/IVF children/national registry/Netherlands
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Introduction |
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Many studies have concluded that IVF pregnancies carry an increased risk for multiplicity, perinatal mortality, preterm birth and low birth weight in comparison with pregnancies after spontaneous conception (Beral and Doyle, 1990; Rufat et al., 1994
; Koudstaal et al., 2000
). It has also been hypothesized that IVF conceptions may carry an increased risk of congenital malformations. Theoretically, an increase in congenital malformations after IVF may be caused by an increase in chromosomal aberrations due to the relatively advanced age of the infertile couples and an increased rate of fertilization by abnormal sperm. Moreover, the IVF procedure may induce point mutations by the actions of physical and chemical teratogens, thereby enhancing the risk of congenital malformations (Biggers, 1981
).
Several studies have investigated the incidence of congenital malformations in IVF conceptions. Some report a possible increase in the incidence of central nervous system (CNS) defects, specifically neural tube defects (Lancaster, 1987; Beral and Doyle, 1990
; Rizk et al., 1991
; FIVNAT, 1995
; Bergh et al., 1999
; Ericson and Källen, 2001
). Others indicate possible higher risks of chromosomal abnormalities, alimentary tract atresia, urogenital abnormalities and limb malformations (Rizk et al., 1991
; Westergaard et al., 1999
; Ericson and Källen, 2001
; Hansen et al., 2002
). However, other studies have concluded that there is no evidence of an increase in the occurrence of malformations (Wennerholm et al., 1991
; Rufat et al., 1994
; Saunders et al., 1996
; DSouza et al., 1997
; Dhont et al., 1997
; Olivennes et al., 1997
)
Because most of these reports only concern small numbers of IVF pregnancies, without proper control groups, no firm conclusions can be drawn. Most of the studies use general population statistics as reference rates for congenital malformations, which is not appropriate as IVF mothers differ in age, parity and obstetric history from the general population of women. Other methodological problems involve the difference in procedures by which malformations are diagnosed and registered in the compared groups. The malformation rates in the general population are mostly derived from routine registers, whereas the rates within the IVF population often result from detailed examination and follow-up.
In this study we investigated whether a difference existed in overall and specific congenital malformation rates between children born after IVF (n = 4224) and naturally conceived children (n = 314 605), controlling for several confounding maternal factors. Records of the National Database of Obstetrics and Neonatology were used both for the IVF children and for the controls.
By comparing the number of congenital malformations registered for the IVF children in the national database with the number registered in specific questionnaires collected from the same group of children as part of a large survey of IVF pregnancies, the difference in registration practice of congenital malformations between these two data sources was determined.
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Materials and methods |
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In this perinatal database, all birth records of children conceived after spontaneous pregnancies were selected to constitute a control population (n = 314 605) by excluding all pregnancies where the use of any assisted reproduction method such as hormonal ovulation induction, intrauterine insemination or IVF was coded.
The IVF study population consisted partially of a cohort of 1925 IVF children (including 9% ICSI) born in 1995 and 1996. This IVF cohort is part of a larger survey including >50% of all IVF births in The Netherlands from 19941996 (Buitendijk, 2000). Detailed information on the kind of congenital malformations was collected by questionnaires addressed to both the mothers of the IVF children and the obstetricians involved in the pregnancy and delivery care. These questionnaires were completed within ~2 months after birth.
Comparing information resulting from specific questionnaires for this IVF cohort with information recorded on a routine basis for the controls may introduce a large bias. To avoid this ascertainment bias we traced the birth records of the children in the IVF cohort in the National Perinatal Database. Because no unique identification is currently available in The Netherlands, a statistical matching procedure had to be applied using the following maternal and infant variables: birth date (day, month, year) of the child and the mother, gender of the child and birth order for multiple births. Additional checks on birth weight and gestational age were also performed. Using this matching procedure we were able to find the birth records of 89% of the children of this IVF cohort (n = 1716). In 79% of these traced records the conception method was correctly coded as IVF. Furthermore, all other birth records in this National Perinatal Database coding IVF as conception method (n = 2508) were added to the IVF study population. The IVF study population therefore included a total of 4224 IVF children. A small proportion of these were ICSI children. In these birth records, however, no distinction can be made between IVF and ICSI because no separate coding exists for ICSI. The congenital malformations recorded in the birth records of these IVF children were compared with the congenital malformations recorded in the birth records of the control population selected from the same database.
Possible differences in registration practice of congenital malformations were investigated in the children of the IVF cohort for whom information on congenital malformations was available both from the traced standard birth records in the National Perinatal Database and from the specific questionnaires completed by the IVF mothers and obstetricians (n = 1716).
In the National Perinatal Database congenital malformations are classified through a standard coding system. Congenital malformations are coded by organ system in specific categories or in non-specific categories if no details are known. Eight different organ systems are distinguished with 51 specified and 20 unspecified categories of congenital malformations. This classification was also used to code the malformations reported in the specific questionnaires of the IVF cohort. All specific malformations, the total number of malformations per organ system and the overall incidence of all malformations were compared for the IVF study population and the control population. In this study a distinction was also made between major and minor congenital malformations based on the severity of the malformation. The calculated differences in malformation rates were expressed using odds ratios (OR) and 95% confidence intervals (CI). The 2-test was used to test for any significant difference in malformation rate (P < 0.05). The Fischer exact test was used when the numbers were very small. A logistic regression model was used to correct the estimated OR for the overall number of malformations for the distribution of the maternal characteristics age of the mother, parity and ethnicity by introducing them into the model as covariates. The statistical analyses were performed in SPSS, version 10.
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Results |
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Further investigation of congenital malformations occurring in the different organ systems was performed (Figure 1). Except for the categories skin and abdominal wall malformations and chromosomal and syndromal malformations, the ORs for IVF children appeared slightly higher for every specific organ system. The difference only reached statistical significance for cardiovascular malformations (OR = 1.56, 95% CI: 1.102.22). Further exploration of the cardiovascular system abnormalities showed that all specific cardiovascular malformations were more frequently reported in IVF children, the ORs ranging from 1.32 to 4.38 (Figure 2
). However, only the difference in occurrence of single umbilical artery reached statistical significance (OR = 1.93, 95% CI: 1.113.35).
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The congenital malformation prevalence was compared for the 1716 children of our IVF survey for whom both routinely completed national birth records and specific questionnaire information was available to determine the difference in registration practice between these two data sources.
In these 1716 children a total of 95 congenital malformations were coded. The prevalence of congenital malformations recorded in the specific questionnaires appeared almost twice as high as the prevalence based on the birth records of the same children (5.0% versus 2.7% respectively). Of the non-registered cases, 67% concerned congenital malformations not visible at birth and therefore not recorded within the time period between birth and the completion of the birth record or concerned minor malformations that may not have been considered worth recording such as single umbilical artery, hypospadia or skin tags. However, for 16 of the 95 congenital malformations non-recording in the birth records could not be explained, resulting in a true under-registration of congenital malformations in birth records of the national perinatal database of 17%. The list of 16 non-registered malformations is given in Table III.
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Discussion |
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The strength of our study in comparison with earlier studies is that we were able to use the same data source of congenital malformations for both the IVF and the naturally conceived children. Moreover, our sample size was sufficiently large to test for differences in the overall rate of malformations as well as to correct for confounding maternal characteristics. A large number of previous studies are difficult to interpret due to small sample size, different data sources used to ascertain malformations for the IVF and the control group and the fact that no adequate control population was available and controlling for confounding factors was not possible (Morin et al., 1989; Ron-El et al., 1994
; Rufat et al., 1994
; Petersen et al., 1995
; Sutcliffe et al., 1995
; Verlaenen et al., 1995
; Olivennes et al., 1997
)
A limitation of our study is that we were not able to distinguish the small number of ICSI children included in our IVF study population because no separate coding exists for ICSI in the National Perinatal Database. However, other studies showed that ICSI children do not differ from IVF children in the risk of congenital malformations or in the number of neonatal complications (Govaerts et al., 1998; Bonduelle et al., 2002
). Furthermore, the estimated percentage of ICSI children is only 9%.
A small proportion of IVF birth records in the perinatal database is not included in the IVF study population because the conception method is not correctly filled in. Due to this misclassification these records are either wrongly excluded if another artificial conception method is coded or these records are wrongly added to the naturally conceived control group. However, the proportion of IVF birth records wrongly added to the control group is so small compared with the large control group (n = 314 605) that the effect will be negligible
Our study is based on >85% of all Dutch births in 1995 and 1996. Non-participation in the perinatal database is caused by logistic aspects such as the availability of staff and registration software. It is not influenced by whether or not pregnancies have been conceived through assisted reproductive techniques. Therefore, selection bias cannot be an issue in this study.
We determined that the standard birth records in the National Perinatal Database used for the comparison of malformation rates tend to under-report ~17% of the congenital malformations visible at birth. This under-reporting is probably similar for the IVF group and the naturally conceived control group or slightly higher in the control group because IVF children are possibly examined more thoroughly at birth. This would not, however, influence the drawn conclusion of no difference in congenital malformations between IVF and naturally conceived children. The under-registration of congenital malformations in routinely completed birth records is a well-known phenomenon. A longer and more detailed follow-up often results in more accurate registration of congenital malformations (Marazita et al., 2002)
A small excess risk of malformations in IVF children was shown for all organ systems except for the categories skin and abdominal wall malformations and chromosomal and syndromal malformations. Only the incidence of the cardiovascular organ system defects reached statistical significance. The specific malformations within the different organ systems often occurred slightly more frequently in the IVF children and sometimes less frequently. Of all the specific malformations, only the increases in the IVF children of the relatively minor malformations single umbilical artery, inguinal hernia, club foot and other unspecified skeletal and muscular malformations reached statistical significance. Many comparisons were made for all the specific malformations between the IVF and the control group. Therefore, these increases could be chance findings due to multiple testing. Due to relatively small numbers in each specific congenital malformation group, we were not able to correct for possible confounding factors. It is likely that, as was observed for the overall incidence of malformations, maternal factors such as age and parity, rather than the IVF procedure itself, may have an influence on the occurrence of specific malformations. Therefore, the interpretation of the small increases in congenital malformations observed in almost all organ systems is difficult. The increases could indicate a real increase in malformations that becomes more pronounced when using a larger study size. On the other hand we would expect that, if there was a harmful effect of the IVF procedure, malformations of only some specific organ systems or malformations originating from one common cause would be increased. Instead, we observed small increases in malformations of various organ systems. Therefore, it is more likely that special surveillance of children conceived by IVF, such as antenatal surveillance or more thorough paediatric examination after birth, could have resulted in some defects being diagnosed and recorded in the IVF birth records that would not have been noted and recorded for naturally conceived children, despite the use of the same data source. This is particularly likely for minor malformations since minor defects do not always have firm diagnostic criteria.
Ericson and Källen studied the Medical Birth Registry of 19821997 and reported an excess of congenital malformations for IVF children (OR = 1.47) (Ericson and Källen, 2001). In accordance with the present study, the excess risk disappeared when confounders were taken into account. In the study of Dhont the increase in overall risk of congenital malformations was also no longer significant after correcting for maternal age (Dhont, 1999
). Westergaard et al. also concluded that the characteristics of the patients rather than the assisted reproductive technology determine the higher risks of malformations in IVF pregnancies (Westergaard et al., 1999
).
Our study did not reveal any increased risk of neural tube defects or other defects of the CNS for IVF children, contrary to other studies (Lancaster, 1987; Beral and Doyle, 1990
; Rizk et al., 1991
; FIVNAT, 1995
; Bergh et al., 1999
; Ericson and Källen, 2001
). Neither did our study confirm the higher than expected numbers of chromosomal malformations in IVF children reported by others (Rizk et al., 1991
; Macas et al., 2001
; Hansen et al., 2002
). Likewise, our study did not reveal the excess risk for alimentary atresia reported by Ericson et al. (Ericson and Källen, 2001
). In the present study an increase in the number of club foot and other skeletal and muscular malformations was found. Rizk et al. also showed a higher than expected number of limb malformations and Hansen et al. reported more musculoskeletal defects (Rizk et al., 1991
; Hansen et al., 2002
). Animal studies also reported more limb malformations in calves born after in-vitro production (Wagtendonk-de Leeuw van et al., 2000).
Several studies reported an increase in hypospadias for boys born after IVF and especially after ICSI, relating the occurrence of hypospadia to the paternal subfertility (Silver et al., 1999; Wennerholm et al., 2000
; Ericson and Källen, 2001
). Using the standard birth records, we found no overall increase in hypospadias in our IVF children. However, we were unable to distinguish between IVF and ICSI children within the birth records of the National Perinatal Database since no separate coding for ICSI is being used. In the subgroup of IVF children for whom detailed questionnaire information was available, a distinction could be made between IVF and ICSI conception. When comparing the number of diagnosed hypospadias within these two groups a significantly higher number of hypospadias was reported for the ICSI children (OR = 5.48, 95% CI: 1.7017.65) than for the IVF children. This increase in hypospadias should be further investigated by comparing children conceived through ICSI with naturally conceived children, controlling for confounding factors.
In conclusion, in our study the overall risk of congenital malformations was slightly increased for IVF children compared with naturally conceived children. This increase could, however, be totally ascribed to differences in maternal characteristics between the IVF mothers and the mothers conceiving naturally. To make statistically meaningful comparisons of specific malformations with sufficient power, data pooling of malformations reported in several comparable studies and continued follow-up is necessary to achieve large enough numbers of specific malformations.
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Acknowledgements |
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Notes |
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References |
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Submitted on January 31, 2002; accepted on May 3, 2002.