Metformin could help prevent hypoglycemia in premature infants delivered by nondiabetic women who received steroids to prevent early labor. 

Gestational diabetes is linked to a higher risk for hypoglycemia in newborn infants, but whether temporary increases in blood glucose during pregnancy could have the same effect is unclear. 

When administered to pregnant people, the steroid betamethasone –– which is used to prevent preterm labor in high-risk individuals –– causes a temporary spike in blood sugar. Elevated glucose levels usually resolve on their own within 48 hours. But betamethasone is also linked to higher rates of hypoglycemia in newborns. 

In a randomized clinical trial published in January in JAMA Network Open, Israeli researchers tested whether controlling a pregnant woman’s blood sugar with metformin after betamethasone administration could lower incidents of hypoglycemia in premature newborns. 

“We think that the temporary spike could have an impact on the fetus’ pancreas that could cause hypoglycemia in the fetus once it is born,” said Enav Yefet, MD, PhD, OB/GYN and director of maternal fetal medicine at Tzafon Medical Center in Tiberias, Israel, and the lead author of the study. 

The study included 169 pregnant women (average age, 30 years) who did not have diabetes and who received one course of betamethasone between 24 and 36.5 weeks of pregnancy to prevent preterm labor. Treated at three medical centers in Israel, half the women were given 425 mg of metformin three times daily before meals, and another dose of 850-1700 mg at 10 PM, for the first 48 hours after receiving betamethasone. The other half were control participants and received standard of care, ie, no intervention. 

Women in the metformin vs control group had lower average glucose levels following treatment (121 mg/dL vs 127 mg/dL; P = .01). When their babies were born, those born to mothers who had vs had not been treated with metformin were less likely to have hypoglycemia (21% vs 40%; P = .04; relative risk, 0.53; 95% CI, 0.28-0.99). All babies were born after their mothers had stopped taking metformin. 

Yefet said the correlation will need to be tested in future studies. 

“We need to do animal models to figure it out completely, but there is a point there because it was a success. We were able to prevent hypoglycemia in the neonate,” she said. 

Amy Valent, DO, medical co-director of the Diabetes and Pregnancy Program at Oregon Health & Science University in Portland, Oregon, agreed that more research needs to be done to prove whether a direct relationship exists between a short-lived increase in blood glucose during pregnancy and hypoglycemia in newborns. The study was unique in administering relatively high doses of metformin (up to 2975 mg/dL per day) to pregnant women without diabetes over a short period of time. 

“To my knowledge, we have not looked at this” previously, Valent said. 

Valent said the study should prompt clinicians to pay attention to blood glucose levels in pregnant women who do not have diabetes, especially after they are given a drug that can increase blood sugar. 

“We really don’t have very good protocols for this population,” Valent said. “Every unit I have ever been on has had different protocols for this, if they have a protocol at all.” 

Yefet said the situation is the same in Israel. 

“We don’t have a protocol for monitoring blood glucose when administering corticosteroids if the woman is not diabetic. So we do not have any means to prevent [hyperglycemia] because we don’t monitor it,” she said. 

Yefet and her team chose to test metformin because of its strong safety profile compared to insulin, as well as the ease of administration. Metformin is not FDA-approved for use in pregnant women who do not have diabetes, and its use in this capacity is off-label. Some studies have raised concerns about the long-term effects of metformin use during gestation, including increasing infant risk for obesity later in life and producing smaller-than-average infants. Valent said while the study is thought-provoking, she isn’t quite ready to use the drug in this context. 

“Is that short, temporary spike in blood sugar after being administered a steroid playing any role in infant hypoglycemia? We need to better understand that first,” Valent said. 

Kaitlin Sullivan is a journalist living in Colorado.