Data Show No Link Between GLP-1 and Hypertensive Disorders of Pregnancy

A systematic review and meta-analysis published in Endocrine examined whether preconception or first-trimester exposure to glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is associated with hypertensive disorder of pregnancy (HDP) risk. Pooling data from 3 retrospective cohort studies conducted in the United States between 2014 and 2025, researchers found no statistically significant association between exposure and HDP (OR, 0.91; 95% CI, 0.57-1.47; P = .70).¹

The findings come amid rising off-label use of GLP-1 RAs for weight management in women of reproductive age, despite the fact that these agents are not approved for use during pregnancy.¹

“These findings are timely, given the emergence of a “new era” in obesity management, which GLP-1 RAs and dual agonists, such as tirzepatide, have a transformative impact on cardiovascular health in non-pregnant patients,” the study authors wrote.¹

Study Design and Included Cohorts

Researchers searched the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, PubMed, Scopus, and Embase from inception through December 15, 2025, using terms related to hypertensive disorders of pregnancy and GLP-1 RAs. The review, registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD420251273858), followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹

Of 75 records identified, 3 retrospective cohort studies met inclusion criteria, representing 10,880 total pregnancies: 4942 exposed to a GLP-1 RA and 5938 unexposed. All 3 studies evaluated semaglutide, liraglutide, dulaglutide, tirzepatide, exenatide, lixisenatide, or albiglutide exposure occurring anywhere from up to 3 years before conception to early gestation.¹

Odds ratios were pooled using a random-effects Mantel-Haenszel model, and risk of bias was assessed with the Cochrane Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool, which rated all 3 included studies as having a moderate overall risk of bias.¹

Pooled Results Show No Significant Association

Individually, the 3 cohorts pointed in different directions. Imbroane et al, the largest cohort with 8534 pregnancies matched 1:1 for maternal age, race, ethnicity, and comorbidities, reported a lower HDP risk among exposed patients (OR, 0.84; 95% CI, 0.76-0.94). Pondugula et al, which analyzed 618 pregnancies with GLP-1 RA exposure up to 1 year before pregnancy, also found a lower risk in the diabetes subgroup (OR, 0.56; 95% CI, 0.40-0.79).¹

By contrast, Maya et al, which followed 1728 singleton pregnancies and examined GLP-1 RA discontinuation before conception, reported an increased risk of HDP among exposed pregnancies (OR, 1.54; 95% CI, 1.24-1.92).¹

When pooled, the confidence interval crossed the line of no effect (OR, 0.91; 95% CI, 0.57-1.47), and heterogeneity across the 3 studies was substantial (I² = 94%; P < .00001 for the Cochran Q test). The study authors concluded that periconceptional or first-trimester GLP-1 RA exposure is not significantly associated with HDP risk, but that available evidence remains limited.¹

Supplemental Data Point to a Possible "Metabolic Legacy" Effect

Two of the studies pooled in the meta-analysis offer additional detail on how exposure timing may modify HDP risk. In the Pondugula et al cohort study, GLP-1 RA exposure up to 1 year before pregnancy was associated with lower adjusted odds of HDP compared with unexposed controls in both the pregestational diabetes mellitus cohort (aOR, 0.52; 95% CI, 0.30-0.90) and the weight management cohort (aOR, 0.51; 95% CI, 0.30-0.87), with associations slightly more robust among patients whose exposure continued into pregnancy.²

GLP-1 RA exposure in the weight management cohort was also associated with decreased odds of gestational weight gain (GWG) below Institute of Medicine recommendations (aOR, 0.38; 95% CI, 0.18-0.80), a pattern the study authors attributed to possible rebound weight gain following medication cessation.²

A separate meta-analysis published in JACC: Advances, which pooled 4 observational studies representing 36,963 pregnancies (including the Imbroane et al cohort also included in the Endocrine analysis), found that GLP-1 RA exposure was associated with lower odds of adverse maternal outcomes—defined to include HDP, gestational diabetes, cesarean delivery, and pregnancy loss—compared with other antidiabetic medications (OR, 0.72; 95% CI, 0.66-0.79; P < .00001), as well as a lower risk of preterm birth (OR, 0.66; 95% CI, 0.53-0.82; P = .0001).³

That analysis found no significant association between GLP-1 RA exposure and major congenital anomalies (OR, 1.08; 95% CI, 0.86-1.37; P = .51) or overall adverse fetal outcomes (OR, 0.91; 95% CI, 0.72-1.16; P = .44).³

Limitations and Clinical Implications for Pharmacists

All 3 studies included in the primary Endocrine meta-analysis were retrospective and observational, limiting any causal interpretation, and relied heavily on International Classification of Diseases, Tenth Revision diagnostic codes, which may be subject to misclassification or underreporting. The study population was also drawn exclusively from the United States, which may limit generalizability.¹

The study authors noted that GLP-1 RAs remain unapproved for use during pregnancy, and current prescribing guidance recommends discontinuation at least 2 months prior to conception based on adverse findings in animal studies.¹

For pharmacists, these findings underscore the importance of counseling patients of reproductive age who are prescribed GLP-1 RAs for type 2 diabetes or weight management about the current uncertainty surrounding periconceptional and early pregnancy exposure. Given the heterogeneity in the pooled data and the possibility that abrupt discontinuation before pregnancy could contribute to weight gain rebound and altered HDP risk, the study authors emphasized the need for large prospective studies to clarify safety and inform clinical strategies for high-risk pregnancy populations.

REFERENCES

1. Pisani D, Lorenza D, Fordellone M, et al. Hypertensive disorders of pregnancy and GLP-1 receptor agonist timing: a systematic review and meta-analysis. Endocrine. 2026;91(1):241. Published 2026 Jul 31. doi:10.1007/s12020-026-04701-9

2. Pondugula N, Culhane JF, Lundsberg LS, Partridge C, Merriam AA. Gestational Weight Gain and Hypertensive Disorders of Pregnancy With Prepregnancy and Early Pregnancy Glucagon-Like Peptide-1 Receptor Agonist Exposure. Obstet Gynecol. 2026;147(3):293-302. doi:10.1097/AOG.0000000000005995

3. Kodali LSM, Metlock FE, Nriagu BN, et al. GLP-1 Receptor Agonist Exposure During Pregnancy: A Systematic Review and Meta-Analysis of Adverse Pregnancy Outcomes. JACC Adv. 2026;5(6 Pt 1):102649. doi:10.1016/j.jacadv.2026.102649