GLP-1 Receptor Agonists Not Linked to Major Congenital Malformations Periconceptionally in Meta-analysis

The widespread use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for metabolic diseases like type 2 diabetes and obesity raises critical questions about their reproductive safety, particularly for women of childbearing age. Despite their efficacy in managing blood glucose and weight, concerns persist regarding potential impacts on fetal development and birth outcomes if exposure occurs around conception or during pregnancy. Current guidelines often recommend discontinuing GLP-1RAs prior to conception, creating a treatment gap for patients who could benefit from continued metabolic control. This systematic review addresses the urgent need to clarify the association between periconceptional GLP-1RA exposure and the risk of major congenital malformations and other adverse pregnancy outcomes.

Researchers conducted a systematic review and meta-analysis, searching PubMed, Embase, and Web of Science through December 2025 for randomized controlled trials (RCTs) and cohort studies. The inclusion criteria focused on studies reporting offspring or pregnancy outcomes in women exposed to GLP-1RAs within three months before conception or during pregnancy. The primary outcome assessed was major congenital malformations (MCMs), comparing neonates with and without maternal GLP-1RA exposure. Secondary outcomes included spontaneous abortion, stillbirth, preterm birth, large for gestational age (LGA), and small for gestational age (SGA). The analysis included one prospective and five retrospective studies, encompassing a total of 286,599 women, with 43,577 exposed to GLP-1RAs and 243,022 unexposed.

The meta-analysis revealed no significant difference in the risk of major congenital malformations (MCMs) between the GLP-1RAs exposure group and the non-exposure group. The relative risk (RR) for MCMs was 1.02 (95% CI 0.96-1.08), indicating no statistically significant increase.

Meta-analysis of 286,599 women revealed no significant difference in major congenital malformations risk among the GLP-1RAs exposure group compared to non-exposure (RR 1.02, 95% CI 0.96-1.08). Furthermore, the risks for several secondary adverse birth outcomes were also not significantly elevated. Preterm birth showed an RR of 1.09 (95% CI 0.80-1.49), LGA an RR of 2.31 (95% CI 0.56-9.44), SGA an RR of 0.71 (95% CI 0.39-1.27), and stillbirth an RR of 1.16 (95% CI 0.24-5.69). The incidence of spontaneous abortion was reported as comparable between the two groups in one of the included studies. These findings suggest that periconceptional GLP-1RAs exposure is not associated with an increased risk of MCMs or other adverse birth outcomes based on the current observational evidence.