Utilising novel Mendelian randomization approaches to investigate a potential causal effect of fetal growth on maternal cardiometabolic risk in the UK Biobank

Mothers of low birth weight infants are at increased risk of cardiovascular disease in later life. It is hypothesised this reflects a combination of 1) fetal factors influencing maternal vasculature via placental implantation, which also independently affect fetal growth, and 2) confounding by genetics and/or the environment whereby women with a pre-disposed risk of cardiometabolic dysfunction may have an impaired ability to adapt to the physiological stress of pregnancy. However, this does not preclude the possibility that there is a direct causal effect of fetal growth on maternal future cardiovascular health, with limited studies examining this alternative. Here, we applied two novel, complementary Mendelian randomization (MR) approaches to data from the UK Biobank that enabled us to investigate a potential causal effect of fetal growth (using birth weight as an available measure for fetal growth) on maternal cardiometabolic risk, even in the absence of offspring genotype information. A gene-by-environment interaction MR approach that stratified on maternal parity found no large differences in estimates of the causal effect of offspring birth weight on maternal cardiometabolic risk factors in parous and nulliparous females. Given that offspring birth weight cannot be causal for maternal cardiometabolic risk in nulliparous females, our results suggest that offspring birth weight is unlikely to causally affect maternal cardiometabolic risk factors. We also employed an offspring genotype by proxy MR design, which leveraged genotype and phenotype information from 45,546 spousal pairs. As fathers transmit half their alleles to their offspring, it follows that paternal genotype will proxy offspring genotype, which can in turn proxy offspring birth weight for MR analyses. This approach also found no strong evidence for a causal effect of offspring birth weight on maternal cardiometabolic risk factors although confidence intervals were wide. Our study serves as a blueprint for future investigations into the putative causal effects of offspring on their parents using MR.