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- Title
Genetic Insights Into Perinatal Outcomes of Maternal Antihypertensive Therapy During Pregnancy.
- Authors
Barry, Ciarrah-Jane S.; Walker, Venexia M.; Burden, Christy; Havdahl, Alexandra; Davies, Neil M.
- Abstract
This mendelian randomization study uses mendelian randomization to investigate potential causal relationships between perturbing maternal genetic variants influencing antihypertensive drug targets and perinatal outcomes among offspring. Key Points: Question: Is there a potential causal relationship between maternal antihypertensive drug exposure during pregnancy and offspring outcomes? Findings: In this mendelian randomization study including 29 849 mother-father-offspring trios, maternal genetic variants for systolic blood pressure acting through drug targets for treatments of hypertension provided little evidence for potential causal relationships between multiple antihypertensive drug subclass targets and differential risk of measured perinatal outcomes. Paternal and maternal effect estimates were similar. Meaning: This study found little evidence of harm to offspring from the studied antihypertensive subclasses and may establish a framework to assess the risks of the impact of maternal drug target perturbation during pregnancy using family-based genetic data. 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.
- Subjects
NORWAY; RESEARCH funding; INFANT development; HUMAN abnormalities; HYPERTENSION; BODY weight; QUESTIONNAIRES; ANTIHYPERTENSIVE agents; PREGNANCY outcomes; CEPHALOMETRY; DESCRIPTIVE statistics; GENETIC variation; STATURE; ODDS ratio; APGAR score; GESTATIONAL age; PREGNANCY complications; CONFIDENCE intervals; DATA analysis software; CHILDREN; PREGNANCY
- Publication
JAMA Network Open, 2024, Vol 7, Issue 8, pe2426234
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2024.26234