Preconception Glucagon-like Peptide-1 Receptor Agonist Use Associated With Decreased Risk of Adverse Obstetrical Outcomes

In 2005, the US Food and Drug Administration approved the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) to treat type 2 diabetes mellitus (T2DM) and obesity. GLP-1RAs stimulate insulin secretion by interlocking the GLP-1 receptor on pancreatic beta cells. They also provide delayed gastric emptying and appetite suppression. Between 2020 and 2023, prescriptions for GLP-1RAs rose by 594% in patients between 12 and 25 years of age. Because of the unknown risks to the fetus, the FDA recommends that GLP-1RAs be discontinued at least two months before trying to conceive. Yet, limited data are available on the effects of GLP-1RAs on reproduction and pregnancy. The aim of this study is to assess the association between GLP-1RA use and adverse obstetrical outcomes. This was a retrospective cohort study comparing individuals 18 years of age or older, who were prescribed a GLP-1RA within the 24 months before pregnancy, and an unexposed cohort. The GLP-1RA cohort was matched with the unexposed cohort for similarities. A post hoc comparison included an additional cohort of individuals who took tirzepatide, a dual agonist of GLP-1R and the glucose-dependent insulinotropic peptide receptor within the 24 months before a pregnancy. The primary outcomes were gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDPs), preterm delivery, and cesarean delivery. Secondary outcomes included subtypes of GDM (diet-controlled or medication-controlled), gestational hypertension, and preeclampsia. A total of 4267 individuals were included in each of the 2 cohorts for analysis. Those in the GLP-1RA cohort were less likely than the unexposed cohort to develop GDM 15.2% vs 18.2%; odds ratio (OR), 0.81; 95% CI, 0.72-0.91, have a preterm delivery (3.0% vs 4.4%; OR, 0.68; 95% CI, 0.54-0.85), or undergo cesarean delivery (17.6% vs 19.7%; OR, 0.89; 95% CI, 0.87-0.97). They were also less likely to develop HDP (19.9% vs 22.8%, OR, 0.84; 95% CI, 0.76-0.94) – specifically gestational hypertension (OR, 0.81; 95% CI, 0.71-0.93) and preeclampsia (OR, 0.87; 95% CI, 0.77-1.00). Similar trends were observed within a specific time point: Within 6 months of pregnancy, no difference was observed in the risk of preeclampsia or cesarean delivery in the GLP-1RA and unexposed cohorts (n = 2170). Within 3 months of pregnancy, no difference was observed in the risk of preeclampsia or preterm delivery, but the risk of cesarean delivery was reduced. Significant decreases were observed in the risk of GDM, HDP, and gestational hypertension composites when GLP-1RA was prescribed within 6 or 3 months preceding pregnancy. In post hoc analysis, the risk of cesarean delivery was lower in the tirzepatide cohort (9.6% of 426) than in those prescribed GLP-1RA within 24 months preceding pregnancy (16.2% of 426) (OR, 0.55; 95% CI, 0.37-0.83). No other differences in adverse obstetrical outcomes were observed. In conclusion, prescribing GLP-1RAs within the 24 months preceding pregnancy was associated with decreased risk of several adverse outcomes, including GDM, HDPs, preterm delivery, and cesarean delivery. Compared with tirzepatide, GLP-1RAs do not confer a substantial decreased risk in adverse outcomes. (Abstracted from Am J Obstet Gynecol. 2025;233:116.e1-7)