Original Investigation 

December 12, 2023

Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy: The MOMPOD Randomized Clinical Trial

Kim A. Boggess, Arielle Valint, Jerrie S. Refuerzo, et al

JAMA. 2023;330(22):2182-2190. doi:10.1001/jama.2023.22949

Key Points

Question  Does metformin added to insulin for the treatment of preexisting type 2 diabetes or diabetes identified early in pregnancy reduce the risk of adverse neonatal outcomes?

Findings  In a randomized clinical trial of 794 pregnant adults (18-45 years), compared with placebo, metformin added to insulin for treatment of preexisting diabetes or diabetes identified in early pregnancy did not reduce a composite adverse neonatal outcome (71% vs 74%) but resulted in fewer large-for-gestational-age infants.

Meaning  Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation.

Abstract

Importance  Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes.

Objective  To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on a composite adverse neonatal outcome.

Design, Setting, and Participants  This randomized clinical trial in 17 US centers enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks’ gestation between April 2019 and November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was completed in May 2022.

Intervention  Metformin 1000 mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery.

Main Outcome and Measures  The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. Prespecified secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy.

Results  Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants’ mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group.

Conclusions and Relevance  Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation.

Trial Registration  ClinicalTrials.gov Identifier: NCT02932475