Effects of Genetically-Proxied Antihypertensive Drug Targets on Preeclampsia and Birth Weight

BackgroundPreeclampsia is a leading cause of maternal and perinatal morbidity and mortality, and a major contributor to low birth weight. Beta blockers (BB) and calcium channel blockers (CCB) are the most commonly recommended agents to treat hypertension in pregnancy. Yet it remains unknown whether these agents alter the risk of preeclampsia (PE), and if so, whether effects arise through maternal physiology or through direct fetal mechanisms. ObjectivesTo use drug-target Mendelian randomization (MR) to estimate the effects of genetically-proxied inhibition of beta-adrenergic and L-type calcium-channel targets on PE risk, birth weight, partitioned into maternal and fetal genetic components, and gestational age (GA). MethodsWe constructed instruments from genome-wide significant, LD-independent variants within prespecified windows around systolic blood pressure (SBP) modulating drug targets in addition to a genome-wide SBP instrument (European ancestry). Outcomes comprised of PE (16,349 cases / 595,135 controls), maternal and fetal genetic effects on birth weight (n{approx}210,267 and n{approx}298,142), and GA (n{approx}151,987). Two-sample MR estimated effects per 5mmHg decrease in SBP. Bayesian colocalization assessed shared causal variants. Multiple testing was controlled with Benjamini-Hochberg correction. ResultsGenetically lower SBP was associated with reduced PE risk and modest increases in birth weight and GA. BB (ADRB1) target inhibition showed no convincing reduction in PE risk but was associated with lower birth weight, with associations predominantly through direct fetal genetic effects and strong colocalization at ADRB1 with fetal birth-weight signals. In contrast, CCB targets collectively associated with lower PE risk without consistent evidence of fetal growth impairment; colocalization support for individual CCB loci was limited. Sensitivity analyses (heterogeneity, pleiotropy) did not materially alter these patterns where instrument counts permitted. ConclusionsDrug-target MR suggests that BB pathways are unlikely to meaningfully reduce PE and are linked to reduced fetal growth - chiefly via direct fetal mechanisms. In contrast, CCB pathways are associated with lower PE risk and largely neutral fetal growth effects. These findings support prioritizing CCBs for evaluation in comparative trials of PE prevention.