Perinatal Outcomes Associated With Metformin Use During Pregnancy in Women With Pregestational Type 2 Diabetes

This study attempted to emulate a randomized trial—the Metformin in Women with Type 2 Diabetes in Pregnancy (MiTy) trial—by using two healthcare claims databases to compare perinatal outcomes in women with type 2 diabetes who were on metformin and insulin at conception, and who either continued or discontinued using metformin during pregnancy. One database represented claims from a publicly funded program (individuals enrolled in Medicaid), whereas the other represented claims from a private insurer. By choosing women already on both medications, the authors hoped to reduce indication bias. The primary outcome was a composite of preterm birth, birth injury, neonatal respiratory distress, neonatal hypoglycemia, and NICU admission. Secondary outcomes included components of the composite and other maternal and neonatal outcomes.

Among the 2983 eligible participants, 72% discontinued metformin use during pregnancy. Interestingly, there were significant differences in baseline characteristics between participants who continued using metformin and those who stopped it. Participants who continued using metformin were older and had a higher prevalence of obesity, thyroid disease, anxiety, bipolar disorder, and hyperglycemia than those who discontinued its use. When comparing the two groups, the authors found no difference in the composite perinatal outcome, even after adjusting for several potential confounders, including baseline differences. Similarly, there were no differences in other perinatal outcomes, except for an increase in small for gestational age (SGA) infants among those exposed to metformin, but only in the privately insured group. The authors imply that continuing the use of metformin is not harmful, as it did not increase the composite outcome; however, the increased risk of SGA warrants further investigation.

These findings can be interpreted differently. Participants who continued using metformin had a higher baseline risk for adverse perinatal outcomes; however, they did not experience worse outcomes when continuing metformin, suggesting a potential benefit. Despite adjustments for baseline differences, residual confounding may still be present. The increase in SGA incidence is interesting, as the MiTy trial also showed a higher incidence of SGA.¹ It is unexplained why SGA incidence was (non-significantly) reduced in the publicly funded database but increased in the privately insured database. This article addresses an important question that clinicians and patients with type 2 diabetes face when becoming pregnant and highlights the need for further study.

Reference

1. Feig DS, Donovan LE, Zinman B, et al. Metformin in Women With Type 2 Diabetes in Pregnancy (Mity): A Multicentre, International, Randomised, Placebo-Controlled Trial. Lancet Diabetes Endocrinol. 2020;8(10):834-844. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30310-7/abstract