Environmental and Genetic Risk Factors of Congenital Anomalies: an Umbrella Review of Systematic Reviews and Meta-Analyses

Abstract

Background: The prevalence of congenital anomalies in newborns in South Korea was 272.9 per 100,000 in 2005, and 314.7 per 100,000 in 2006. In other studies, the prevalence of congenital anomalies in South Korea was equivalent to 286.9 per 10,000 livebirths in 2006, while it was estimated 446.3 per 10,000 births during the period from 2008 to 2014. Several systematic reviews and meta-analyses analyzing the factors contributing to congenital anomalies have been reported, but comprehensive umbrella reviews are lacking.

Methods: We searched PubMed, Google Scholar, Cochrane, and EMBASE databases up to July 1, 2019, for systematic reviews and meta-analyses that investigated the effects of environmental and genetic factors on any type of congenital anomalies. We categorized 8 subgroups of congenital anomalies classified according to the 10th revision of the International Statistical Classification of Diseases (ICD-10). Two researchers independently searched the literature, retrieved the data, and evaluated the quality of each study.

Results: We reviewed 66 systematic reviews and meta-analyses that investigated the association between non-genetic or genetic risk factors and congenital anomalies. Overall, 269 associations and 128 associations were considered for environmental and genetic risk factors, respectively. Congenital anomalies based on congenital heart diseases, cleft lip and palate, and others were associated with environmental risk factors based on maternal exposure to environmental exposures (air pollution, toxic chemicals), parental smoking, maternal history (infectious diseases during pregnancy, pregestational and gestational diabetes mellitus, and gestational diabetes mellitus), maternal obesity, maternal drug intake, pregnancy through artificial reproductive technologies, and socioeconomic factors. The association of maternal alcohol or coffee consumption with congenital anomalies was not significant, and maternal folic acid supplementation had a preventive effect on congenital heart defects. Genes or genetic loci associated with congenital anomalies included MTHFR, MTRR and MTR, GATA4, NKX2-5, SRD5A2, CFTR, and 1p22 and 20q12 anomalies.

Conclusion: This study provides a wide perspective on the distribution of environmental and genetic risk factors of congenital anomalies, thus suggesting future studies and providing health policy implications.

Keywords: Congenital Disease; Genetic; Meta-Analysis; Non-Genetic; Risk Factor.

Fig. 1. Flowchart showing meta-analysis of studies on genetic and non-genetic factors for congenital diseases.

MTHFR = methylene tetrahydrofolate reductase.

Fig. 2. The range of ORs or RRs in the association between non-genetic risk factor and congenital anomalies (significantly association only).

OR = odds ratio, RR = risk ratio, SES = socioeconomic status.

Fig. 3. The range of ORs or RRs in the association between non-environmental risk factor and congenital anomalies (significantly association only).

OR = odds ratio, RR = risk ratio, MTHFR = methylene tetrahydrofolate reductase, MTRR = methionine synthase reductase gene, MTR = methionine synthase, GATA4 = GATA binding protein 4, NKX2-5 = NK2 homeobox 5, SRD5A2 = steroid 5 alpha-reductase type 2 gene, CFTR = cystic fibrosis transmembrane conductance regulator.