Obstetrics & Gynecology · Medical Literature
Hypertensive disorders of pregnancy and GLP-1 receptor agonist timing: a systematic review and meta-analysis.
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), used to treat type 2 diabetes and obesity, may improve metabolic health before conception. However, their association to hypertensive disorders of pregnancy (HDP) after periconceptional or early pregnancy exposure remains unknown. We performed a meta-analysis to investigating association between GLP-1 RAs preconception or first trimester of gestation exposure and HDP risk. Cochrane Central Register of Controlled Trials databases, ClinicalTrials.gov, PubMed, Scopus, and EMBASE databases were searched from inception through December 15, 2025. All eligible studies were observational cohorts. Case reports, reviews, editorials, and studies that lacked HDP data were excluded. We pooled odds ratios with 95% confidence intervals using a random-effects Mantel-Haenszel model. ROBINS-I tool was used to evaluate risk of bias. Of 75 records identified, 3 retrospective cohort studies met inclusion criteria with 10,880 pregnancies (4942 exposed to GLP-1 RAs and 5938 unexposed). All the studies were conducted in the United States between 2014-2025 and evaluated the semaglutide, liraglutide, dulaglutide, tirzepatide, exenatide, lixisenatide, and albiglutide exposure. Two studies showed a lower HDP risks among exposed pregnant, whereas one study found a higher risk. In the pooled analysis, GLP-1 RA exposure showed a HDP risk with an OR 0.91 (OR 0.91, CI 0.57-1.47) with no statistical significance. Periconceptional or first-trimester exposure to GLP-1 RAs are not significantly associated with HDP risk. This available evidence is limited and indicating the need for large prospective studies to establish a possible association between GLP-1 RAs are not significantly associated with HDP risk.
Clinical relevance
GLP-1 receptor agonists are increasingly used in women of reproductive age for type 2 diabetes and obesity management, raising urgent clinical questions about periconceptional and first-trimester safety, particularly regarding hypertensive disorders of pregnancy (HDP), a leading cause of maternal and fetal morbidity. This systematic review and meta-analysis addresses a critical evidence gap by synthesizing all available observational data on GLP-1 RA exposure timing and HDP risk. Given the rapidly expanding prescription rates of agents such as semaglutide and tirzepatide in reproductive-age women, clinicians in obstetrics, endocrinology, and maternal-fetal medicine need this data to guide preconception and early pregnancy counseling.
Key findings
1. Of 75 records screened, only 3 retrospective cohort studies met inclusion criteria, encompassing 10,880 pregnancies (4,942 GLP-1 RA–exposed vs. 5,938 unexposed), highlighting the marked scarcity of high-quality evidence in this domain. 2. Pooled analysis using a random-effects Mantel-Haenszel model yielded an OR of 0.91 (95% CI: 0.57–1.47) for HDP among GLP-1 RA–exposed pregnancies compared to unexposed, which was not statistically significant. 3. The wide 95% CI (0.57–1.47) reflects substantial statistical uncertainty and precludes any definitive conclusion regarding a protective or harmful effect. 4. Directional heterogeneity was present across studies: two of three cohorts reported a lower HDP risk with GLP-1 RA exposure, while one reported a higher risk, indicating inconsistency in the available literature. 5. The GLP-1 RA agents evaluated included semaglutide, liraglutide, dulaglutide, tirzepatide, exenatide, lixisenatide, and albiglutide — all studied within U.S. cohorts from 2014–2025 — limiting generalizability across agents and global populations. 6. Risk of bias was assessed using the ROBINS-I tool; all included studies were retrospective observational cohorts, carrying inherent susceptibility to confounding by indication, selection bias, and residual unmeasured confounders.
Practice implications
Clinicians should counsel reproductive-age women that current pooled evidence does not demonstrate a statistically significant association between periconceptional or first-trimester GLP-1 RA exposure and HDP risk (OR 0.91, 95% CI 0.57–1.47), but the evidence base is insufficient to confirm safety, and established guideline recommendations to discontinue GLP-1 RAs upon confirmed pregnancy should be maintained pending higher-quality data. Patient selection for continuation versus discontinuation decisions should be individualized, weighing the metabolic benefits of GLP-1 RAs in women with obesity or type 2 diabetes against unresolved fetal and obstetric safety signals, with close HDP surveillance throughout gestation for those with periconceptional exposure. Large, prospective, adequately powered studies — ideally stratified by specific GLP-1 RA agent, dose, gestational timing of exposure, and baseline metabolic risk — are urgently needed before practice-changing recommendations can be made.