Parental risk factors and anorectal malformations: systematic review and meta-analysis

In recent years, a number of studies have shown that prenatal exposures of the parents are associated with an increased risk for having a malformed child. However, only few studies exist regarding the association with anorectal malformations (ARM).

ARM are rare birth defects concerning anus and rectum. Approximately 1 in 2,500 to 1 in 5,000 new born babies are affected [1‐3]. Different degrees of severity are distinguished, ranging from mild anal stenosis over anal atresia with or without fistula to persistent cloaca or even cloacal exstrophy [4]. Furthermore, ARM frequently manifest with other malformations. Approximately 64% of all ARM patients are affected and have one or more additional extra-anal anomalies [5]. Previous studies have shown that associated malformations are more frequent in "high" defects that are complex and difficult to manage with a poor functional prognosis than in "low" defects that are less complex and easily treated with an excellent functional prognosis. Associated malformations mainly include the genitourinary system (21-61% and more), spine and spinal cord (5-40%), the rest of the gastrointestinal tract (10-25%) and the heart (9-20%) [6]. Anorectal malformations affect several socioeconomic and ethnic groups [7‐11]. Boys seem to be at a slightly higher risk than girls (1.3:1) [12]. It is assumed that the defects occur during the 4th to 8th week of fetal development [13‐18]. Current knowledge about the causes, however, is still sparse. In addition to genetic factors, prenatal exposures of the parents to tobacco, alcohol, caffeine, illicit drugs, overweight/obesity, diabetes mellitus and occupational hazards are subject to ongoing debate as potential environmental risk factors, in particular because the few existing studies are based on retrospectively collected data from individual centers only.

We conducted a systematic review and meta-analysis of epidemiological studies to summarize current evidence on the relationship between parental risk factors and anorectal malformations and to identify knowledge deficits that need to be addressed in future research.

This systematic review and meta-analysis summarized the results of 22 studies on the association between prenatal environmental risk factors and infants born with an anorectal malformation reported between 1981 and June 2010. The majority of the studies were conducted in the United States. Case numbers ranged from 14 ARM cases in the study by Shiono et al. [33] to 564 ARM cases in the study by Honein et al. [31]. Studies were also heterogeneous with respect to control selection and adjustment for covariates. Meta-analysis was done for risk factors reported on in at least two studies, i.e. maternal and paternal smoking, maternal alcohol consumption, underweight, overweight, obesity, any maternal diabetes mellitus, pre-gestational and gestational diabetes. Consistently increased risks were observed for paternal smoking, maternal overweight, obesity and diabetes, but not for maternal smoking and alcohol consumption.

There is a great discrepancy in the reported results on the associations between maternal illicit drug use and ARM which impede comparability. Closer examination of the studies suggests that different data collection could lead to these different results. In the study by van Gelder et al. [41], mothers were interviewed by telephone by trained interviewers using a standardized questionnaire. Forrester and Merz [1] used register-based data from the Hawaii Birth Defects Program where trained staff collected information on cases through review of medical records. Thus, only consumption that had to be severe enough to be recorded in routine medical records was ascertained. It appears conceivable that illicit drug use might have been asked for and recorded more often among mothers of children with malformations than among other mothers. The discrepancy found on the associations between maternal exposures to X-rays may likewise be partly resulting from different exposure definitions. Van Rooij et al. [39] examined the maternal occupational hazard to X-rays during pregnancy whereas Stoll et al. [38] assessed women's own X-ray examinations during pregnancy.

When available, data on ARM infants with isolated anomalies (no additional major defects) were preferred in this review to data on ARM infants with multiple defects. Only six of the 22 reviewed studies looked at both groups [7, 30, 34, 37, 38, 40]. Analyses, however, showed nearly the same results. Furthermore, two studies by Martínez-Frías et al. [44] and Sharpe et al. [45] were excluded because they grouped ARM with other congenital malformations (among others intestinal and tracheo-esophageal atresias) which might mix or dilute potential effects in case of diverse etiologies. The excluded studies did not find an association with the examined risk factors. In contrast, although Honein et al. [31] reported on the examination of "rectal atresia", a very rare subgroup of ARM, we included this study because it appears that the term of "rectal atresia" was used synonymously for ARM, given that the reported sample size, collected within one year, appear too high for rectal atresia and Honein et al. [31] compared their results with other studies reported on ARM. In general, there is no unique terminology for ARM that is used in the literature. Besides anorectal malformation, terms of anal atresia, anorectal atresia and imperforate anus can be found for this anomaly. Even ARM itself is a mixed group with isolated and associated malformations ranging from lower to higher forms with different genetic background [46].

Looking at some other gastro-intestinal malformations, maternal diabetes also seems to be a risk factor for esophageal atresia [25, 32, 34]. However, no clear association was found with gastroschisis, omphalocele, small-intestinal atresia and duodenal atresia [32, 34, 36, 43]. There is a suggestive association between maternal overweight and omphalocele [40], but not for the other defects. Maternal obesity also seems to be a risk factor for omphalocele, whereas an inverse association was found for gastroschisis [47, 48]. The use of illicit drugs including cocaine, methamphetamines and marijuana during pregnancy was found to be associated with increased risk of gastroschisis [47] and the use of cocaine, amphetamines, decongestants and pseudoephedrine was associated with intestinal atresia [49‐51]. Consistently increased risks for maternal smoking were only observed for pyloric stenosis [52]. For omphalocele and gastroschisis, no consistently increased risks were found regarding alcohol consumption [47].

The significant associations with ARM and some other gastro-intestinal malformations show that the rise in maternal overweight and obesity, as well as diabetes during the last decades are of relevance for these birth defects. For example, the prevalence of overweight (obesity) in adult females from the Netherlands increased from 30% (6%) in 1981 to 42% (12%) in 2004 [53]. In girls, overweight (obesity) prevalence doubled or even tripled from 1980 to 1997 and again from 1997 to 2002-2004. The same trend was observed in the United States where 17.9% of all school-age girls were overweighed (11.7% obese) in 1999-2000 and 22.3% were overweighed (13.6% obese) in 2003-2004 [54]. During the same time, the number of women with diabetes was also increasing. The worldwide prevalence of type 1 and type 2 diabetes in women has doubled since the 1980s [55, 56]. The overall prevalence was estimated to be 2.2% worldwide in 1995 and is expected to be 2.8% in 2025 with a higher proportion in the developed countries than in the developing countries (3.6% vs. 1.7% in 1995; 4.5% vs. 2.5% in 2025) [57]. Previous studies underline the need of substantial efforts to limit the obesity epidemic, which is also the main cause of the growing prevalence of diabetes among women in child-bearing age [58, 59]. Besides many other beneficial health effects, such efforts could substantially reduce the risk of ARM and other birth defects in the offspring. Although associations of maternal smoking and alcohol consumption with ARM do not seem to be established based on existing evidence, the adverse health effects of these habits on the embryonic development underline the importance of avoiding them throughout pregnancies and beyond.

Our review has a number of limitations mostly resulting from the overall scarcity of published evidence. First, our meta-analysis was limited by the data provided in the individual studies. Not all studies provided risk estimates adjusted for potentially influential confounders, such as maternal age, ethnicity, education, parity, periconceptional smoking and folic acid intake [40] or maternal age, race/ethnicity, education, smoking, binge drinking, pregnancy BMI and periconceptional folic acid use [41]. Analyses of diabetes were only adjusted for BMI in the study by Correa et al. [34], known as potential influential confounder. Due to the small number of studies, we decided to pool adjusted and crude values for meta-analyses. Second, some studies used affected (malformed) control groups. Other studies used mixed controls of live-born malformed and healthy babies. A potential advantage of using malformed controls is potential reduction of response bias or recall bias that may occur when a non-malformed control group is used. On the other hand, observed associations may be biased if the risk factors of interest are also associated with the malformations of controls. Third, most sample sizes were small, so the power to detect associations was low. Fourth, despite the lack of indication of major publication bias, it is impossible to be ruled out completely, especially in the light of the low number of studies. Finally, although we searched in four databases (PubMed, EMBASE, ISI Web of Knowledge and the Cochrane library) and completed our search by reviewing related and cross-referencing literature, existence of relevant missing studies cannot be excluded.

To our knowledge, our article is the first systematic review and meta-analysis that provides an overview of the few available studies that reported on the association between prenatal environmental risk factors of the parents and ARM. Adequate evidence is still very limited. Therefore, further multicenter or register-based studies are needed to clarify the role of key risk factors for the development of ARM. One example is the recent establishment of the German Network for Congenital Uro-REctal Malformations (CURE-Net). The aim of this consortium is to collect data of affected newborns as well as of older patients with an anorectal malformation (ARM) or an exstrophy-epispadias complex (EEC) that allow to investigate molecular causes, clinical implications and psychosocial outcomes. For a standardized description of diagnostic subgroups, international classifications are used (Krickenbeck for ARM [60] and Gearhart & Jeffs for EEC [61]). Associated malformations are collected with means of the London Dysmorphology Database [62] and environmental risk factors according to the core dataset of surveillance of congenital anomalies in Europe (EUROCAT) [63]. Nationwide data acquisition should enable to achieve a sample size that is large enough to clarify the role of key risk factors for the development for ARM and EEC in general but also for each subgroup separately. Furthermore, activities are ongoing aiming to expand such a register on an international level. The recently established International Consortium on Anorectal Malformations (ARM-Net), a European collaboration between France, Italy, Germany and the Netherlands, aims to identify genetic and environmental risk factors by data sharing and combined research activities [64]. Both consortia offer the unique opportunity to establish a basis for future research to overcome current scarcity of evidence in the field of ARM, especially from populations outside the United States.