Add on Metformin to insulin in pregnant women with diabetes fails to reduce neonatal complications: JAMA

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

For pregnant women with preexisting type 2 diabetes (T2D) or diabetes diagnosed early in pregnancy, insulin is recommended. Previous studies have shown that metformin addition to insulin improves neonatal outcomes. Kim A. Boggess, University of North Carolina at Chapel Hill School of Medicine, and colleagues aimed 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.

The randomized clinical trial conducted in 17 US centres enrolled pregnant adults (18 to 45 years) with pre-existing T2D or diabetes diagnosed before 23 weeks gestation between 2019 and 2021. Each participant was given insulin treatment and was assigned to either metformin 1000 mg (n=397) or placebo (n=397) orally twice per day from enrollment (11 weeks -<23 weeks) through delivery.

The primary outcome of the study was a composite of neonatal complications including preterm birth, perinatal death, hyperbilirubinemia, and large or small for gestational age requiring phototherapy.

Prespecified secondary outcomes were neonatal fat mass at birth and maternal hypoglycemia, and prespecified subgroup analyses by maternal BMI less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy.

The study revealed the following findings:

• The composite adverse neonatal outcome occurred in 71% of the metformin group and 74% of the placebo group (adjusted odds ratio, 0.86).
• The most commonly occurring events in the primary outcome in both groups were neonatal hypoglycemia, preterm birth, 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 of being large for gestational age (adjusted odds ratio, 0.63) when compared with the placebo group.

"Using insulin plus metformin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy failed to reduce a composite neonatal adverse outcome," the researchers wrote.

"The effect of reduction in odds of a large-for-gestational-age infant seen after metformin addition to insulin warrants further investigation."

Reference:

Boggess KA, Valint A, Refuerzo JS, et al. Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy: The MOMPOD Randomized Clinical Trial. JAMA. 2023;330(22):2182–2190. doi:10.1001/jama.2023.22949