Genetically predicted body mass index and maternal outcomes of pregnancy: A two-sample Mendelian randomisation study

ObjectiveObservational studies have described associations between obesity and adverse outcomes of pregnancy but observational results are liable to influence by residual confounding. Mendelian randomisation (MR) leverages the 'natural' genetic randomisation to risk of an exposure occurring at allele assortment and conception. Similar to randomisation in a clinical trial, this limits the potential for the influence of confounding.DesignA two-sample MR study.SettingSummary statistics from published genome wide association studies (GWAS) in European ancestry populations.Population or SampleInstrumental variants for body mass index (BMI) were obtained from a study on 434 794 females.MethodsInverse-variance weighted MR was used to assess the association between BMI and all outcomes. Sensitivity analyses with weighted median and MR-Egger were also performed.Main outcome measuresFemale-specific genetic association estimates for outcomes were extracted from the sixth round of analysis of the FINNGEN cohort data.ResultsHigher genetically predicted BMI was associated with higher risk of pre-eclampsia (odds ratio [OR] per standard deviation 1.68, 95% confidence interval [CI] 1.46-1.94, P = 8.74 x 10-13), gestational diabetes (OR 1.67, 95% CI 1.46-1.92, P = 5.35 x 10-14), polyhydramnios (OR 1.40, 95% CI 1.00-1.96, P = 0.049). There was evidence suggestive of a potential association with higher risk of premature rupture of membranes (OR 1.16, 95% CI 1.00-1.36, P = 0.050) and postpartum depression (OR 1.12, 95% CI 0.99-1.27, P = 0.062).ConclusionsHigher genetically predicted BMI is associated with marked increase in risk of pre-eclampsia, gestational diabetes and polyhydramnios. The relation between genetically predicted BMI and premature rupture of membranes and postpartum depression should be assessed in further studies. Our study supports efforts to target BMI as a cardinal risk factor for maternal morbidity in pregnancy.