Metformin Does Not Improve Neonatal Outcomes for Pregnant Patients With Diabetes

When using insulin to treat patients with preexisting type 2 diabetes (T2D) or gestational diabetes diagnosed early in pregnancy, adding metformin to the regimen did not reduce a composite neonatal adverse outcome, according to new research just published in JAMA.

“The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation,” the authors said.

Metformin | Image credit: Sherry Young – stock.adobe.com

To come to this finding, they enrolled 794 pregnant adults aged 18 to 45 years who had preexisting T2D or gestational diabetes diagnosed prior to 23 weeks’ gestation. The randomized clinical trial spanned across 17 US health centers and was conducted between April 2019 and November 2021, and it’s worth noting that enrollment was paused for up to 9 months due to the impact of the COVID-19 pandemic, and the study was stopped at 75% for futility. Both of these factors limited how much the authors could measure the impact of metformin on less frequent outcomes.

The group was randomized with half receiving 1000 mg metformin (n = 397) and half receiving placebo (n = 397), both taken orally twice a day from enrollment—with patients ranging from 11 to 23 weeks pregnant at enrollment—up until delivery. The mean (SD) age was 32.9 (5.6) years, and the study had a diverse patient cohort with 52% being Hispanic, 29% being Black, and 14% being White. However, a quarter of patients did not disclose their race, and Asian, American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander patients were underrepresented, each making up less than 3% of the total population.

The main measure was a combination of neonatal complications, encompassing perinatal death, preterm birth, being large or small for gestational age, and requiring phototherapy for hyperbilirubinemia. Secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth. Additionally, subgroup analyses were predetermined based on maternal body mass index (BMI; less than 30 kg/m² vs 30 kg/m² or greater) and the presence of preexisting T2D compared with diabetes early in pregnancy.

The combined adverse neonatal outcome occurred in 280 (71%) patients in the metformin group and 292 (74%) in the placebo group (adjusted OR [aOR], 0.86; 95% CI, 0.63-1.19). Across both groups, the primary outcome events predominantly included preterm birth, neonatal hypoglycemia, and the delivery of a large-for-gestational-age infant. Notably, among the individual components of the composite adverse neonatal outcome, metformin-exposed neonates exhibited lower odds of being large for gestational age compared with the placebo group (aOR, 0.63; 95% CI, 0.46-0.86).

The study was stopped at 75% accrual due to futility in detecting a significant difference in the primary outcome, and prespecified secondary outcomes and subgroup analyses showed similar results between the groups. The authors noted that further research is needed to explore the observed reduction in the likelihood of a large-for-gestational-age infant when metformin is added to insulin.

According to the authors, these results differ from those of the MiTy trial, and this may be explained by differences in study populations.

“More than 50% of the current study’s participants were Hispanic, compared with 2% to 3% in the MiTy trial, and Hispanic persons tend to have greater insulin resistance compared with non-Hispanic African American and non-Hispanic White persons,” the authors explained. “In the current trial, approximately 20% were enrolled with diabetes diagnosed early in pregnancy, compared to approximately 10% in the MiTy trial, which may also reflect differences in insulin resistance.”

Additionally, while this trial noted a slight decrease in the occurrence of large-for-gestational-age infants in the metformin group, there were no discernible distinctions in neonatal outcomes or the mode of delivery via cesarean.

“The cesarean delivery rate in this trial was higher than the national rate and the rate among states where the study was conducted, but it was comparable to the rate in the MiTy study, which reflects the complexity of intrapartum care for patients with type 2 diabetes and diabetes identified early in pregnancy,” the authors said.

Aside from the enrollment gap due to COVID-19 and stopping at 75% accrual, the study had other limitations that should be noted. Although maternal BMI was similar between the groups, the metformin group had more participants with obesity compared with the placebo group, which may bias the findings toward the null due to increased insulin resistance. Also, adherence was solely assessed through self-reporting, which could potentially lead to underreporting of poor adherence, though this approach mirrors real-world clinical practice more closely than pill counts. Finally, HbA1c data were only collected for a small percentage (approximately 39%) of participants and only if obtained as part of routine clinical care, preventing definitive conclusions about the impact of metformin on glycemic control due to the proportion of untested participants.

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