Safety of beta-blocker and calcium channel blocker antihypertensive drugs in pregnancy: a Mendelian randomization study
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Published version
Author(s)
Ardissino, Maddalena
Rajasundaram, Skanda
Reddy, rohin
Ng, Fu
Gill, Dipender
Type
Journal Article
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 fetal 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<5x10-8
) 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 4,743 cases and 136,325 controls
(women without a hypertensive disorder in pregnancy) for pre-eclampsia or
eclampsia, 7,676 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 twosample 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
10mmHg SBP reduction 0.27, 95%CI 0.06-1.19, p=0.08) and increased risk of
gestational diabetes (OR per 10mmHg SBP reduction 2.01, 95%CI 0.91-4.42,
p=0.08), and significantly associated with lower birthweight of first child (beta per 10mmHg SBP reduction -0.27, 95%CI -0.39 to -0.15, p=1.90x10-5
). Geneticallyproxied CCB was associated with reduced risk of pre-eclampsia and eclampsia (OR
0.62, 95%CI 0.43-0.89, p=9.33x10-3
), 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 10mmHg 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.
antihypertensive drugs are commonly used in pregnancy. However, data on their
relative impact on maternal and fetal 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<5x10-8
) 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 4,743 cases and 136,325 controls
(women without a hypertensive disorder in pregnancy) for pre-eclampsia or
eclampsia, 7,676 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 twosample 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
10mmHg SBP reduction 0.27, 95%CI 0.06-1.19, p=0.08) and increased risk of
gestational diabetes (OR per 10mmHg SBP reduction 2.01, 95%CI 0.91-4.42,
p=0.08), and significantly associated with lower birthweight of first child (beta per 10mmHg SBP reduction -0.27, 95%CI -0.39 to -0.15, p=1.90x10-5
). Geneticallyproxied CCB was associated with reduced risk of pre-eclampsia and eclampsia (OR
0.62, 95%CI 0.43-0.89, p=9.33x10-3
), 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 10mmHg 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.
Date Issued
2022-09-06
Date Acceptance
2022-07-14
Citation
BMC Medicine, 2022, 20
ISSN
1741-7015
Publisher
BioMed Central
Journal / Book Title
BMC Medicine
Volume
20
Copyright Statement
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License URL
Sponsor
British Heart Foundation
British Heart Foundation
Grant Number
RG/16/3/32175
RE/18/4/34215
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
Blood pressure
Beta-blocker
Calcium channel blocker
Mendelian randomization
Pregnancy
HYPERTENSION
OUTCOMES
Beta-blocker
Blood pressure
Calcium channel blocker
Mendelian randomization
Pregnancy
Adrenergic beta-Antagonists
Antihypertensive Agents
Birth Weight
Calcium Channel Blockers
Child
Diabetes, Gestational
Eclampsia
Female
Genome-Wide Association Study
Humans
Hypertension
Mendelian Randomization Analysis
Pre-Eclampsia
Pregnancy
Pregnancy Complications
Humans
Pregnancy Complications
Diabetes, Gestational
Eclampsia
Pre-Eclampsia
Hypertension
Birth Weight
Adrenergic beta-Antagonists
Antihypertensive Agents
Calcium Channel Blockers
Pregnancy
Child
Female
Genome-Wide Association Study
Mendelian Randomization Analysis
11 Medical and Health Sciences
General & Internal Medicine
Publication Status
Published
Article Number
ARTN 288