Using human genetics to understand the effect of modulating targets of antihypertensive drugs in pregnancy

Background and Aims Hypertension during pregnancy is a major cause of maternal and neonatal morbidity and mortality, yet the efficacy and safety of antihypertensive treatments in this setting remain uncertain. We evaluated the effects of antihypertensive drug targets on adverse pregnancy-related outcomes using genetic variants to instrument target perturbation. Methods We performed drug target Mendelian randomization to mimic pharmacological perturbation of targets from six commonly used antihypertensive drug classes, using data from up to 671,922 pregnant women. Genetic variants near drug target genes associated with systolic or diastolic blood pressure were selected as instruments. We estimated effects of target modulation on six primary and eight secondary pregnancy outcomes. Results Genetically instrumented downregulation of blood pressure through beta-blocker (BB) and calcium-channel blocker (CCB) targets, particularly ADRB1 and CACNB2, was associated with a reduced risk of hypertensive disorders of pregnancy, including preeclampsia. For example, CACNB2-instrumented lowering corresponded to a 7% (95% CI: 5-9%) reduction in preeclampsia risk per 1 mmHg decrease in blood pressure. For most other targets, estimates were directionally consistent but imprecise. Across additional outcomes, effects varied by target, with suggestive evidence for reduced risks of miscarriage, preterm birth, small-for-gestational-age birth, and labour induction, although these estimates were accompanied by substantial uncertainty. Conclusions These findings support a protective effect of BB and CCB targets on hypertensive disorders of pregnancy and highlight potential target-specific differences in safety. This work illustrates the value of Mendelian randomization in addressing clinical uncertainties where robust trial evidence is limited.