Mendelian randomisation approaches to the study of prenatal exposures: A systematic review

Background: Mendelian randomisation (MR) designs apply instrumental variable techniques using genetic variants to study causal effects. MR is increasingly used to evaluate the role of maternal exposures during pregnancy on offspring health. Objectives: We review the application of MR to prenatal exposures and describe reporting of methodologic challenges in this area. Data sources: We searched PubMed, EMBASE, Medline Ovid, Cochrane Central, Web of Science, and Google Scholar. Study selection and data extraction: Eligible studies met the following criteria: (a) a maternal pregnancy exposure; (b) an outcome assessed in offspring of the pregnancy; and (c) a genetic variant or score proposed as an instrument or proxy for an exposure. Synthesis: We quantified the frequency of reporting of MR conditions stated, techniques used to examine assumption plausibility, and reported limitations. Results: Forty-three eligible studies were identified. When discussing challenges or limitations, the most common issues described were known potential biases in the broader MR literature, including population stratification (n = 29), weak instrument bias (n = 18), and certain types of pleiotropy (n = 30). Of 22 studies presenting point estimates for the effect of exposure, four defined their causal estimand. Twenty-four studies discussed issues unique to prenatal MR, including selection on pregnancy (n = 1) and pleiotropy via postnatal exposure (n = 10) or offspring genotype (n = 20). Conclusions: Prenatal MR studies frequently discuss issues that affect all MR studies, but rarely discuss problems specific to the prenatal context, including selection on pregnancy and effects of postnatal exposure. Future prenatal MR studies should report and attempt to falsify their assumptions, with particular attention to issues specific to prenatal MR. Further research is needed to evaluate the impacts of biases unique to prenatal MR in practice.