Maternal drug use and the risk of anorectal malformations: systematic review and meta-analysis

Nadine Zwink,Ekkehart Jenetzky

doi:10.1186/s13023-018-0789-3

Abstract

BackgroundOrigin of anorectal malformations (ARM) are considered multifactorial. Several genetic and non-genetic risk factors are discussed in literature. Maternal periconceptional medical drug use as possible risk factor, however, has not been reviewed systematically.MethodsStudies published between 1977 and April 2017 were reviewed through systematic search in PubMed, ISI Web of Knowledge and Scopus databases. Furthermore, related and cross-referencing publications were reviewed. Pooled odds ratios (95% confidence intervals) were determined to quantify associations of maternal periconceptional use of folic acid, multivitamins, anti-asthma medication (separated in any anti-asthma medication, inhaled corticosteroids and salbutamol), thyroid hormone supplements, psychiatric drugs (separated in antidepressants, any selective serotonin reuptake inhibitors [SSRI], sertraline, citalopram, fluoxetine, paroxetine, hypnotics and benzodiazepine) and aspirin with ARM using meta-analyses.ResultsThirty-seven studies that reported on the association between maternal periconceptional drug intake and infants born with ARM were included in this review. These were conducted in the United States of America (n = 14), Sweden (n = 6), Hungary (n = 5), Germany (n = 3), the Netherlands (n = 3), Denmark (n = 2), France (n = 2), Norway (n = 1) and the UK (n = 1). However, only few of these studies reported on the same risk factors. Studies were heterogeneous with respect to case numbers, period ingestion of medical drug use, control selection and adjustment for covariates. Consistently increased risks were observed for any anti-asthma medication, and hypnotics and benzodiazepine, but not for folic acid, multivitamins, inhaled corticosteroids, salbutamol, thyroid hormone supplements, antidepressants, any SSRI, sertraline, citalopram, fluoxetine, paroxetine and aspirin. In meta-analyses, pooled odds ratios (95% confidence intervals) for any anti-asthma medication, and hypnotics and benzodiazepine were 1.64 (1.22–2.21), and 2.43 (1.03–5.73), respectively.ConclusionEvidence on maternal drug use before conception and during pregnancy as risk factor for ARM from epidemiological studies is still very limited. Nevertheless, the few available studies indicate any anti-asthma medication, and hypnotics and benzodiazepine to be associated with increased risks. Further, ideally large-scale multicenter and register-based studies are needed to clarify the role of maternal drug intake for the development of ARM.

Highlights

Origin of anorectal malformations (ARM) are considered multifactorial
Two articles were excluded because they were published in Spanish or French, seven articles because they described the use of medical drugs in animal models, five articles because of too low case numbers (n < 2), nine articles because they referred to results of already selected articles and further three articles because they reported on ARM cases analyzed in a group with other anomalies
To our knowledge, our article is the first systematic review and meta-analysis that provides an overview of the available epidemiological studies that reported on the association between maternal medical drug use before and during pregnancy and ARM

Summary

Introduction

Origin of anorectal malformations (ARM) are considered multifactorial. Several genetic and nongenetic risk factors are discussed in literature. Assisted reproductive techniques pose a strongly increased risk for ARM [32,33,34,35,36,37,38], but it remains unclear whether the procedure itself or underlying parental infertility cause the defects Besides these non-genetic factors, the influence of maternal drug intake before and during pregnancy, such as vitamin A overdose [39] or deficiency [40], multivitamin [27], folic acid [27, 41], anti-asthmatic drugs [42] or benzodiazepine lorazepam [43], is subject to ongoing debate

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