ESPE Yearbook of Paediatric Endocrinology

Am J Physiol Endocrinol Metab 2024 Mar 1;326(3):E268-E276. doi: 10.1152/ajpendo.00361.2023

Brief Summary: C57BL/6 mice were used to study the effects of maternal GLP-1 on dams and their fetuses. Circulating levels of GLP-1 (produced by intestinal L-cells) were seen to decline over gestation despite maintenance of L-cell population. Administration of semaglutide (GLP-1RA) in late pregnancy (E13.5 to E17.5) led to a decrease in appetite, insulin levels and glucose but weight of dams was increased normally. Significant and progressive decreases were noted in fetal weights by E18.5 even when maternal blood glucose was restored, and if anything, circulating fetal IGF-1 levels were increased, perhaps as a compensatory mechanism. Placental weight was unchanged but placental histology and vascularisation was altered as was placental expression of important nutrient transporters including glucose transporter 1 and sodium-neutral amino acid transporter 1; these findings may be responsible for the effect on fetal weight. They conclude that modulation of circulating GLP-1 is very important during pregnancy, and that GLP-1RA has inhibitory effects on placental development and growth and thus on fetal weight, perhaps through placental GLP-1 receptors noted by others to be on mouse endothelial cells and human trophoblast cells. Of note, they previously showed the importance of mouse pancreatic α-cells in controlling maternal metabolic adaptation to pregnancy through enhanced insulin secretion using an inducible Cre/loxp ablation to create an α -null mouse before and during pregnancy. Enteroendocrine L-cells and circulating GLP-1 were maintained in the normal range¹, so clearly intra-pancreatic and circulating GLP-1 must be considered separately when teasing out the role of GLP-1 during pregnancy, and ultimately, the impact of GLP-1RA therapy.

As recently stated in an opinion paper², evidence is lacking to support use of GLP-1RA during pregnancy or even to counsel patients about peri-conceptional exposure. It is wise to counsel use of contraception during GLP-1RA therapy. The mouse data in this paper would certainly support this approach.

References: 1. Qiao L et al, The Essential Role of Pancreatic a-Cells in Maternal Metabolic Adaptation to Pregnancy Diabetes 2022;71(5):978-988. doi: 10.2337/db21-0923.2. Varughese SM et al, GLP-1 receptor agonist therapy and pregnancy: Evolving and emerging evidence Clinical Medicine 2025;25(2):100298. doi: 10.1016/j.clinme.2025.100298.