Safety of beta-blocker and calcium channel blocker antihypertensive drugs in pregnancy: a Mendelian randomization study

Abstract

Background Beta-blocker (BB) and calcium channel blocker (CCB) antihypertensive drugs are commonly used in pregnancy. However, data on their relative impact on maternal and foetal outcomes are limited. We leveraged genetic variants mimicking BB and CCB antihypertensive drugs to investigate their effects on risk of pre-eclampsia, gestational diabetes and birthweight using the Mendelian randomization paradigm. Methods Genetic association estimates for systolic blood pressure (SBP) were extracted from summary data of a genome-wide association study (GWAS) on 757,601 participants. Uncorrelated single-nucleotide polymorphisms (SNPs) associated with SBP (p < 5 × 10−8) in BB and CCB drug target gene regions were selected as proxies for drug target perturbation. Genetic association estimates for the outcomes were extracted from GWASs on 4743 cases and 136,325 controls (women without a hypertensive disorder in pregnancy) for pre-eclampsia or eclampsia, 7676 cases and 130,424 controls (women without any pregnancy-related morbidity) for gestational diabetes, and 155,202 women (who have given birth at least once) for birthweight of the first child. All studies were in European ancestry populations. Mendelian randomization estimates were generated using the two-sample inverse-variance weighted model. Results Although not reaching the conventional threshold for statistical significance, genetically-proxied BB was associated with reduced risk of pre-eclampsia (OR per 10 mmHg SBP reduction 0.27, 95%CI 0.06–1.19, p = 0.08) and increased risk of gestational diabetes (OR per 10 mmHg SBP reduction 2.01, 95%CI 0.91–4.42, p = 0.08), and significantly associated with lower birthweight of first child (beta per 10 mmHg SBP reduction − 0.27, 95%CI − 0.39 to − 0.15, p = 1.90 × 10−5). Genetically-proxied CCB was associated with reduced risk of pre-eclampsia and eclampsia (OR 0.62, 95%CI 0.43–0.89, p = 9.33 × 10−3), and was not associated with gestational diabetes (OR 1.05, 95% CI 0.76–1.45, p = 0.76) or changes in birthweight of first child (beta per 10 mmHg SBP reduction 0.02, 95%CI − 0.04–0.07, p = 0.54). Conclusions While BB and CCB antihypertensive drugs may both be efficacious for lowering blood pressure in pregnancy, this genetic evidence suggests that BB use may lower birthweight. Conversely, CCB use may reduce risk of pre-eclampsia and eclampsia without impacting gestational diabetes risk or birthweight. These data support further study on the effects of BBs on birthweight.

Effectiveness and safety of drugs in pregnancy: evidence from drug target Mendelian randomization

“…MR has been used to predict maternal-neonatal effects within the literature, however, these typically use summary-level data from unrelated individuals and do not link maternal-exposure-neonatal outcomes or have genetic data from parent-offspring trios. A recent paper implemented MR to investigate the safety of beta-adrenoreceptor-blocking drugs and calcium channel blockers in pregnancy (30). These drug subclasses are typically the most prescribed antihypertensive drugs during pregnancy.…”

“…MR has been implemented in the literature to identify opportunities for drug repurposing, drug targets and predicting adverse drug effects (19,(25)(26)(27)(28)(29)(30). However, few studies have used MR to estimate the intrauterine effects of drugs.…”

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“…For example, a recent cis-mendelian randomisation study investigated genetic evidence for the safety of two major antihypertensive drug classes in pregnancy. 10 …”

The association of genetically proxied sildenafil with fertility, sexual activity, and wellbeing: a Mendelian randomisation study

“…For example, a recent cis-MR study investigated the efficacy and safety of two major antihypertensive drug classes in pregnancy (14).…”

“…Indeed, cis -MR can provide quasi-randomised evidence for outcomes which it might otherwise be infeasible or unethical to investigate using an RCT. For example, a recent cis -MR study investigated the efficacy and safety of two major antihypertensive drug classes in pregnancy (14).…”