2015;26:169-176
36. Czeizel A, Ludányi I. An aetiological study of the VACTERL-association. Eur J Pediatr 1985;144:331-337.
37. Falcone Jr RA, Levitt MA, Peña A, et al. Increased heritability of certain types of anorectal malformations. J Pediatr Surg 2007;42:124-128.
Chapter 8
Parental subfertility, fertility treatment
and the risk of congenital anorectal
malformations
Charlotte HW Wijers, Iris ALM van Rooij, Roxana Rassouli,
Marc H Wijnen, Paul MA Broens, Cornelius EJ Sloots, Han G Brunner,
Ivo de Blaauw, Nel Roeleveld
Epidemiology
2015;26:169-176
Abstract
Background Fertility treatment seems to play a role in the etiology of congenital anorectal
malformations, but it is unclear whether the underlying parental subfertility, ovulation induction, or the treatment itself is involved. Therefore, we investigated the odds of anorectal malformations among children of subfertile parents who conceived with or without treatment compared with fertile parents.
Methods We performed a case-control study among 380 cases with anorectal
malformations treated at three departments of Pediatric Surgery in The Netherlands and 1,973 population-based controls, born between August 1988 and August 2012. Parental questionnaires were used to obtain information on fertility-related issues and potential confounders.
Results In singletons, increased risks of anorectal malformations were observed for parents
who underwent intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF) treatment compared with fertile parents (odds ratio = 2.4 [95% confidence interval = 1.0-5.9] and odds ratio = 4.2 [1.9-8.9], respectively). For subfertile parents who conceived after IVF treatment, an elevated risk was also found when they were compared with subfertile parents who conceived without treatment (3.2 [1.4-7.2]). Among children of the latter category of parents, only the risk of anorectal malformations with other major congenital malformations was increased compared with fertile parents (2.0 [1.3-3.3]). No associations were found with intrauterine insemination or use of hormones for ovulation induction.
Conclusions We found evidence of a role of ICSI and IVF treatments in the etiology of
anorectal malformations. However, subfertility without treatment increased only the risk of anorectal malformations with additional congenital malformations.
Introduction
Congenital anorectal malformations are major anomalies of the gastrointestinal system, with a prevalence of approximately 1 in 3000 births worldwide.1 Anorectal malformations are
characterized by disrupted embryonic development of the anus and rectum in the 4th to 8th
week after conception, often also involving other organs, such as the bladder or vagina. Although the physical and psychosocial impact is large for patients with anorectal malformations and their parents,2 knowledge about the potential risk factors is still limited.
In the past decade, the risks of congenital malformations following assisted reproductive techniques (ART), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), received large amounts of scientific attention. Most studies showed an increased prevalence of congenital malformations after ART, but they investigated only heterogeneous patient groups consisting of broad categories of congenital malformations, such as all gastrointestinal malformations.3,4 Four studies, specifically focused on anorectal
malformations, found ART to increase the risk of anorectal malformations more than 3 times compared with spontaneous conceptions,5-8 whereas two studies did not.9,10 Clearly
increased risks of anorectal malformations were not found when all fertility treatments, also including intrauterine insemination (IUI) and ovulation induction, were analyzed together.10,11 However, two studies showed an association between anorectal
malformations and ovulation induction without ICSI or IVF,10,12 whereas one study did not.13
The role of parental subfertility was investigated in only one study, which suggested an association between anorectal malformations and paternal but not maternal subfertility.11
Limitations of the previous studies, however, were low case numbers, moderately to poorly characterized cases, nonspecific or pooled exposure groups, lack of information on potential confounders, and/or different methods of data collection among cases and controls. Furthermore, none of these studies combined the effects of parental subfertility, prolonged time to pregnancy, and types of fertility treatment within one study. Therefore, we aimed to elucidate whether the excess risk of anorectal malformations is attributable to the underlying parental subfertility, the hormones used for ovulation induction, or the ART procedure itself. We performed a case-control study to investigate the role of parental subfertility and prolonged time to pregnancy without fertility treatment or with a range of fertility treatments in the etiology of nonsyndromic anorectal malformations. We also assessed these effects in subgroups of isolated anorectal malformations and anorectal malformations with one or more other major congenital malformations as etiologic heterogeneity was suggested previously.10,14
8
Abstract
Background Fertility treatment seems to play a role in the etiology of congenital anorectal
malformations, but it is unclear whether the underlying parental subfertility, ovulation induction, or the treatment itself is involved. Therefore, we investigated the odds of anorectal malformations among children of subfertile parents who conceived with or without treatment compared with fertile parents.
Methods We performed a case-control study among 380 cases with anorectal
malformations treated at three departments of Pediatric Surgery in The Netherlands and 1,973 population-based controls, born between August 1988 and August 2012. Parental questionnaires were used to obtain information on fertility-related issues and potential confounders.
Results In singletons, increased risks of anorectal malformations were observed for parents
who underwent intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF) treatment compared with fertile parents (odds ratio = 2.4 [95% confidence interval = 1.0-5.9] and odds ratio = 4.2 [1.9-8.9], respectively). For subfertile parents who conceived after IVF treatment, an elevated risk was also found when they were compared with subfertile parents who conceived without treatment (3.2 [1.4-7.2]). Among children of the latter category of parents, only the risk of anorectal malformations with other major congenital malformations was increased compared with fertile parents (2.0 [1.3-3.3]). No associations were found with intrauterine insemination or use of hormones for ovulation induction.
Conclusions We found evidence of a role of ICSI and IVF treatments in the etiology of
anorectal malformations. However, subfertility without treatment increased only the risk of anorectal malformations with additional congenital malformations.
Introduction
Congenital anorectal malformations are major anomalies of the gastrointestinal system, with a prevalence of approximately 1 in 3000 births worldwide.1 Anorectal malformations are
characterized by disrupted embryonic development of the anus and rectum in the 4th to 8th
week after conception, often also involving other organs, such as the bladder or vagina. Although the physical and psychosocial impact is large for patients with anorectal malformations and their parents,2 knowledge about the potential risk factors is still limited.
In the past decade, the risks of congenital malformations following assisted reproductive techniques (ART), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), received large amounts of scientific attention. Most studies showed an increased prevalence of congenital malformations after ART, but they investigated only heterogeneous patient groups consisting of broad categories of congenital malformations, such as all gastrointestinal malformations.3,4 Four studies, specifically focused on anorectal
malformations, found ART to increase the risk of anorectal malformations more than 3 times compared with spontaneous conceptions,5-8 whereas two studies did not.9,10 Clearly
increased risks of anorectal malformations were not found when all fertility treatments, also including intrauterine insemination (IUI) and ovulation induction, were analyzed together.10,11 However, two studies showed an association between anorectal
malformations and ovulation induction without ICSI or IVF,10,12 whereas one study did not.13
The role of parental subfertility was investigated in only one study, which suggested an association between anorectal malformations and paternal but not maternal subfertility.11
Limitations of the previous studies, however, were low case numbers, moderately to poorly characterized cases, nonspecific or pooled exposure groups, lack of information on potential confounders, and/or different methods of data collection among cases and controls. Furthermore, none of these studies combined the effects of parental subfertility, prolonged time to pregnancy, and types of fertility treatment within one study. Therefore, we aimed to elucidate whether the excess risk of anorectal malformations is attributable to the underlying parental subfertility, the hormones used for ovulation induction, or the ART procedure itself. We performed a case-control study to investigate the role of parental subfertility and prolonged time to pregnancy without fertility treatment or with a range of fertility treatments in the etiology of nonsyndromic anorectal malformations. We also assessed these effects in subgroups of isolated anorectal malformations and anorectal malformations with one or more other major congenital malformations as etiologic heterogeneity was suggested previously.10,14