Metformin, Maternal Glycemic Control, and Neonatal Hypoglycemia After Antenatal Steroids: A Randomized Clinical Trial.

Importance: Although betamethasone reduces complications of prematurity, it can cause maternal hyperglycemia and neonatal hypoglycemia. Metformin effectively treats maternal hyperglycemia and has been shown to decrease neonatal hypoglycemia in women with gestational diabetes. Objective: To evaluate the impact of metformin treatment after betamethasone administration on maternal glycemic control and the incidence of neonatal hypoglycemia in preterm infants. Design, Setting, and Participants: This multicenter, open-label randomized clinical trial was conducted from July 1, 2020, to June 30, 2024, at 3 medical centers in Israel. Pregnant women receiving betamethasone from 24.0 to 36.5 gestational weeks due to increased preterm delivery risk were studied. Women with diabetes were excluded. Interventions: Participants were randomized to metformin (425 mg 3 times daily before meals and 850-1700 mg at 10 pm) or no treatment. The treatment lasted up to 48 hours after the first betamethasone dose. Capillary glucose was measured before meals (preprandial), 90 minutes after starting meals (postprandial), and at 10 pm. Main Outcome and Measure: The primary end points were the mean maternal glucose values up to 48 hours from first betamethasone injection and the rate of neonatal hypoglycemia in preterm deliveries (<37 gestational weeks). Results: A total of 169 women (mean [SD] age, 29.7 [5.4] years), including 84 with 48 preterm infants in the metformin group and 85 with 58 preterm neonates in the control group, were included in the study. Mean (SD) maternal total and postprandial glucose values were significantly lower in the metformin group (121 [15] vs 127 [17] mg/dL; P = .01; and 129 [22] vs 138 [26] mg/dL; P = .009, respectively). Neonatal hypoglycemia rate was lower in the metformin group (10 [21%] vs 23 [40%]; P = .04; relative risk, 0.53; 95% CI, 0.28-0.99). Mild adverse effects, mostly gastrointestinal, were reported by 12 women (14%). Conclusions and Relevance: In this randomized clinical trial, metformin was safe and effective in preventing betamethasone-induced maternal hyperglycemia and neonatal hypoglycemia. Metformin should be considered as a treatment option for women who receive antenatal corticosteroids to prevent their related adverse effects. Trial Registration: ClinicalTrials.gov Identifier: NCT04332393.