Abstract
OBJECTIVE: Primary prevention strategies are critical to reduce the global burden of congenital heart defects (CHDs); this requires robust knowledge of causal agents. We aimed to review associations between CHDs and maternal advanced age, obesity, diabetes, hypertension, smoking and alcohol consumption and assess the causal nature of the associations. DESIGN: Systematic review of reviews with application of a Bradford Hill criteria score-based causal assessment system. DATA SOURCES: We searched PubMed, Embase and Episteminokos (January 1990-April 2023). ELIGIBILITY CRITERIA: Systematic reviews of original epidemiological studies reporting association (relative risk) between one or more of the above maternal factors and CHDs overall (any type) in subsequent offspring. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers selected eligible reviews, assessed the risk of bias and assigned the strength of evidence for causality. RESULTS: There was strong evidence of a causal relationship between CHDs and maternal obesity (prepregnancy and early pregnancy) and pre-existing diabetes (six of seven Bradford Hill criteria met). For pre-existing hypertension (strength and biological gradient not met), and advanced age (strength, consistency and biological gradient not met), causal evidence was moderate. Evidence for the causal contribution of gestational diabetes, gestational hypertension, smoking and alcohol consumption was weak (strength, consistency, temporality and biological gradient not met). CONCLUSIONS: CHDs can be reduced with stronger action to reduce maternal obesity and pre-existing diabetes prevalence. Investigating environmental exposures that have received limited attention, such as air pollutants and chemical exposures, is important to further inform prevention.