Genetic Insights Into Perinatal Outcomes of Maternal Antihypertensive Therapy During Pregnancy

Abstract

Importance: Limited information exists regarding the impact of pharmacotherapy in pregnancy due to ethical concerns of unintended fetal harm. Yet, maternal prescriptive drug use for chronic conditions such as hypertension is common.

Objective: To investigate potential causal relationships between perturbing maternal genetic variants influencing antihypertensive drug targets and perinatal outcomes among offspring using mendelian randomization (MR).

Design, setting, and participants: This 2-sample MR study used individual-level single-nucleotide variation (SNV) outcome data from mother-father-offspring trios with complete genetic and phenotypic information from the Norwegian Mother, Father and Child Cohort Study (MoBa) and summary-level SNV exposure data from UK Biobank participants sourced from the Integrative Epidemiology Unit OpenGWAS project. Pregnant individuals were recruited across Norway during their routine ultrasonography examination at 18 weeks' gestation between June 1999 and December 2008, and mothers, fathers, and offspring were followed up after birth. Novel genetic instruments for maternal antihypertensive drug targets that act via systolic blood pressure (SBP) were derived from individual-level data analyzed in January 2018. Two-sample multivariable MR analysis of these maternal drug targets and offspring outcomes were performed between January 2023 and April 2024.

Exposures: Maternal genetic variants associated with drug targets for treatments of hypertension, as specified in the National Health Service dictionary of medicines and devices.

Main outcomes and measures: Offspring outcomes were Apgar score at 1 minute and 5 minutes, offspring developmental score at 6 months, birth length, birth weight z score, gestational age, head circumference, and congenital malformation. Maternal hypertensive disorders of pregnancy were a positive control.

Results: The MoBa sample contained 29 849 family trios, with a mean (SD) maternal age of 30.2 (18.6) years and a mean (SD) paternal age of 32.8 (13.1) years; 51.1% of offspring were male. Seven independent SNVs were identified as influencing maternal SBP via the antihypertensive drug target instruments. For higher levels of maternal SBP acting through the CACNB2 calcium channel blocker target, the estimated change in gestational age was 3.99 days (95% CI, 0.02-7.96 days) per 10-mm Hg decrease in SBP. There was no evidence of differential risk for measured perinatal outcomes from maternal SBP acting through drug targets for multiple hypertensive subclasses, such as between the ADRB1 β-adrenoceptor-blocking target and risk of congenital malformation (estimated odds ratio, 0.28 [95% CI, 0.02-4.71] per 10-mm Hg decrease in SBP). Maternal and paternal SBP acting through the EDNRA vasodilator antihypertensive target did not have a potential causal effect on birth weight z score, with respective β estimates of 0.71 (95% CI, -0.09 to 1.51) and 0.72 (95% CI, -0.08 to 1.53) per 10-mm Hg decrease in SBP.

Conclusions and relevance: The findings provided little evidence to indicate that perturbation of maternal genetic variants for SBP that influence antihypertensive drug targets had potential causal relationships with measures of perinatal development and health within this study. These findings may be triangulated with existing literature to guide physicians and mothers in decisions about antihypertensive use during pregnancy.

Figure 1.. Directed Acyclic Graph Demonstrating the Intergenerational Within-Family Pharmacologic Mendelian Randomization Framework

Arrows indicate offspring outcomes mediated via phenotypic expression in the offspring or the genetic inheritance of the offspring from the mother. β Represents the estimate of interest. Maternal exposure to a drug target of interest, such as a β-adrenoreceptor blocker, is instrumented by the maternal genotype in a gene (eg, the single-nucleotide variations on the ADRB1 gene targeted by the drug substance). The offspring genotype may directly influence the offspring outcome; thus, an estimate that controls for offspring genotype would be unbiased by direct genetic inheritance as it would close the potential direct causal pathway and ensure the independence assumption holds. SBP indicates systolic blood pressure.

Figure 2.. Forest Plots Demonstrating the Estimated Causal Effect of the Maternal Genetic Drug Targets With Offspring Outcomes per 10-mm Hg Decrease in Systolic Blood Pressure

Results are shown for the inverse variance–weighted estimate where multiple single-nucleotide variations (SNVs) were available and for the Wald ratio otherwise. Odds ratios (ORs) were estimated for the outcome of hypertensive disorders of pregnancy. All other estimates are mean differences.