Safety of glucagon-like peptide-1 receptor agonists and other new-generation glucose-lowering agents for the management of type 2 diabetes in pregnancy: a French nationwide population-based study.

Abstract

Aims/hypothesis: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and other second-line glucose-lowering agents are increasingly used among women of reproductive age. Data on the safety of these medications in pregnancy are limited. We aimed to assess the comparative safety of first-trimester exposure to second-line glucose-lowering agents on the risk of organ-specific congenital malformations among pregnancies affected by type 2 diabetes mellitus that was pharmacologically treated.

Methods: We conducted a population-based cohort study using the French National Health Data System including singleton infants born after pregnancies lasting more than 22 weeks, in women aged 18 to 50 years with pregestational, pharmacologically treated type 2 diabetes from January 2011 to August 2024. We defined first-trimester exposure to glucose-lowering agents as having at least one prescription filled from 30 days before through to 91 days after conception. All glucose-lowering agents were considered: insulin, metformin, GLP-1RA, sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), sulfonylureas and other glucose-lowering agents. The primary reference group was the use of insulin alone, but the use of metformin, with and without insulin, and non-use of glucose-lowering agents were also comparators in additional analyses to facilitate comparison with previous studies. Analysed outcomes were major congenital malformations during the delivery stay and up to 1 year after birth to consider delayed identification, using ICD-10 codes as per EUROCAT (European surveillance of congenital anomalies) guidelines. Adjusted RRs and 95% CIs were estimated using Poisson regressions with generalised estimating equations. Values of BMI and HbA_1c were unavailable in the database; proxies of diabetes severity were used instead for confounding adjustment.

Results: Among 19,092 eligible pregnancies, 17.5% were exposed to insulin alone, 34.7% to at least one second-line glucose-lowering agent and 10.4% were unexposed to any glucose-lowering agent during the first trimester. Compared with insulin-only use, first-trimester exposure to second-line glucose-lowering agents was not associated with an increased risk of overall or organ-specific major congenital malformations. Sensitivity analyses using stricter exposure definitions suggested a possible small increased risk of cardiac malformations following first-trimester exposure to GLP-1 RA and sulfonylureas.

Conclusions/interpretation: In this largest study to date on the use of glucose-lowering agents in pregnancy, first-trimester exposure to second-line glucose-lowering agents was not associated with an increased risk of major congenital malformations when compared with insulin-only use. However, a small increased risk of cardiac defects associated with first-trimester exposure to GLP-1RA and sulfonylureas is possible, and thus teratogenicity cannot be excluded.