Maternal hypertensive traits and adverse outcome in pregnancy: a Mendelian randomization study.

Abstract

Hypertensive disorders of pregnancy are associated with adverse feto-maternal outcomes. Existing evidence is mostly limited to observational studies, which are liable to confounding and bias. This study investigated the causal relevance of component hypertensive indices on multiple adverse pregnancy outcomes using Mendelian randomization. Uncorrelated (r2 < 0.001) genome-wide significant (P < 5 × 10-8) single-nucleotide polymorphisms associated with SBP, DBP and pulse pressure (PP) were selected as instrumental variables. Genetic association estimates for outcomes of preeclampsia or eclampsia, preterm birth, placental abruption and hemorrhage in early pregnancy were extracted from summary statistics of genome-wide association studies in the FinnGen cohort. Two-sample, inverse-variance weighted Mendelian randomization formed the primary analysis method. Odds ratios (OR) are presented per-10 mmHg higher genetically predicted hypertensive index. Higher genetically predicted SBP were associated with higher odds of preeclampsia or eclampsia [OR 1.81, 95% confidence interval (CI) 1.68-1.96, P = 5.45 × 10-49], preterm birth (OR 1.09, 95% CI 1.03-1.16, P = 0.005) and placental abruption (OR 1.33, 95% CI 1.05-1.68, P = 0.016). Higher genetically-predicted DBP was associated with preeclampsia or eclampsia (OR 2.54, 95% CI 2.21-2.92, P = 5.35 × 10-40). Higher genetically predicted PP was associated with preeclampsia or eclampsia (OR 1.68, 95% CI 1.47-1.92, P = 1.9 × 10-14) and preterm birth (OR 1.18, 95% CI 1.06-1.30, P = 0.002). This study provides genetic evidence to support causal associations of SBP, DBP and PP on multiple adverse outcomes of pregnancy. SBP and PP were associated with the broadest range of adverse outcomes, suggesting that optimized management of blood pressure, particularly SBP, is a key priority to improve feto-maternal health.