Glucagon-Like Peptide-1 Receptor Agonists among Pregnancies with Pregestational Diabetes and Its Relationship with Congenital Malformations

Abstract Pregestational diabetes is a common complication seen in pregnancy, with significant increase seen in the use of glucagon-like peptide-1 receptor agonists (GLP-1 RA) for diabetes management in reproductive-age individuals. The objective of this study was to describe the perinatal outcomes and prevalence of congenital malformations associated with the use of GLP-1 RA in individuals with pregestational diabetes using a national dataset. This study was a retrospective cohort study of patients with pregestational diabetes and pregnancies using data obtained from the Epic Cosmos database between May 1, 2022 and April 30, 2025. Demographics, perinatal outcomes, and prevalence of congenital malformations were compared by GLP-1 RA exposure in pregnancy. Categorical variables were compared with Chi-square and continuous variables were compared using student t-tests for two comparisons. No individual level data were available, so covariate adjustment was not performed. The total sample population was 143,593 patients with pregestational diabetes, with 24.4% (n = 35,083) of patients using a GLP-1 RA at some time point in pregnancy. Patients with GLP-1 RA usage were more likely to develop pre-eclampsia (13.1 versus 11.9%, p < 0.00001), have a cesarean delivery (44.4 vs. 38.9%, p < 0.0001), have a first trimester pregnancy loss/termination (9.8 vs. 7.5%, p < 0.00001), and a preterm delivery (23.1 vs. 20.8%, p < 0.0001) when compared with patients without GLP-1 RA use. There was no statistically significant difference in the overall rate of any congenial malformation by GLP-1 RA use (3.3% in both groups, p = 0.63). However, patients with GLP-1 RA usage were more likely to have fetuses with genital malformations (0.7 vs. 0.6%, p = 0.02) and urinary malformations (0.5 vs. 0.4%, p = 0.01) compared with patients without GLP-1 RA use. GLP-1 RA therapy in a large cohort of pregnant patients with pregestational diabetes was associated with an overall low rate of malformations but found to have a possible increase in genital and urinary malformations. Counseling of patients prior to use of this medication in the preconception period is required.