Periconceptional use of GLP-1 receptor agonists and the risk of major congenital malformations: a systematic review and meta-analysis.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for metabolic diseases, but their reproductive safety remains controversial. We assessed the impact of periconceptional GLP-1RA exposure on birth outcomes to inform their use in reproductive-aged women. PubMed, Embase, Web of Science (through December 2025) were searched for randomized controlled trials (RCTs)/cohorts reporting offspring or pregnancy outcomes in women exposed to GLP-1RAs within three months before conception or during pregnancy. The primary outcome was major congenital malformations (MCMs), compared between neonates with or without maternal GLP-1RA exposure. Secondary outcomes were spontaneous abortion, stillbirth, preterm birth, large for gestational age (LGA), and small for gestational age (SGA). One prospective and five retrospective studies involving 286,599 women (43,577 exposed and 243,022 unexposed to GLP-1RAs) were included. Meta-analysis showed no significant difference in MCM risk in the GLP-1RA exposure group, compared with the non-exposure group (relative risk (RR): 1.02, 95% CI: 0.96-1.08). Risks of preterm birth (RR: 1.09, 95% CI: 0.80-1.49), LGA (RR: 2.31, 95% CI: 0.56-9.44), SGA (RR: 0.71, 95% CI: 0.39-1.27), and stillbirth (RR: 1.16, 95% CI: 0.24-5.69) were not significantly elevated. The incidence of spontaneous abortion was comparable between the two groups in one study. Evidence suggests that periconceptional GLP-1RA exposure in women is not associated with an increased risk of MCMs or other adverse birth outcomes. However, given the observational design and limited exposed pregnancies, these findings should not be interpreted as proof of safety. Large prospective cohorts and RCTs are needed to confirm the safety of GLP-1RA usage before pregnancy.