Using Mendelian randomization to determine causal effects of maternal pregnancy (intrauterine) exposures on offspring outcomes: Sources of bias and methods for assessing them

Mendelian randomization (MR), the use of genetic variants as instrumental variables (IVs) to test causal effects, is increasingly used in aetiological epidemiology. Few of the methodological developments in MR have considered the specific situation of using genetic IVs to test the causal effect of exposures in pregnant women on postnatal offspring outcomes. In this paper we describe specific ways in which the IV assumptions might be violated when MR is used to test such intrauterine effects. We highlight the importance of considering the extent to which there is overlap between genetic variants in offspring that influence the offspring outcome of interest overlap with genetic variants used as IVs in their mothers. Where there is such overlap, and particularly if it generates a strong association of maternal genetic IVs with offspring outcome via the offspring genotype, the exclusion restriction assumption of instrumental variable analyses will be violated and the causal effect estimate biased. Simple adjustment for offspring genotype might suffice in some circumstances but might also introduce further bias via the father’s genotype. We recommend a set of analyses that ought to be considered when MR is used to address research questions concerned with intrauterine effects on post-natal offspring outcomes, and provide details of how these can be undertaken and interpreted. These additional analyses include the use of genetic data from offspring and fathers, examining associations using maternal non-transmitted alleles, and using simulated data in sensitivity analyses (for which we provide code). We explore the extent to which new methods that have been developed for exploring violation of the exclusion restriction assumption in the two-sample setting (MR-Egger and median based methods) might be used when exploring intrauterine effects in one-sample MR. We provide a list of recommendations that researchers should use when applying MR to test the effects of intrauterine exposures on postnatal offspring outcomes and use an illustrative example with real data to demonstrate how our recommended analysis steps and approaches can be applied and appropriately interpreted.