Key takeaways:
- Metformin significantly reduced maternal hyperglycemia following antenatal betamethasone administration.
- Use of metformin was associated with a lower risk of neonatal hypoglycemia in preterm infants.
- No cases of maternal hypoglycemia were reported in either the metformin or control group.
- The randomized trial included pregnant women without pregestational or gestational diabetes at risk for preterm birth.
- Metformin was generally well tolerated, with mostly mild adverse events reported.
Findings from a study published in JAMA Network Open have highlighted safety and efficacy from metformin administration toward preventing betamethasone-induced maternal hyperglycemia and neonatal hypoglycemia.1
Pregnant women at risk of preterm birth are often given antenatal corticosteroids (ACSs) such as betamethasone, which have proven benefits that include reduced odds of respiratory distress syndrome, intraventricular hemorrhage, and more. However, ACSs have been linked to maternal hyperglycemia and associated neonatal hypoglycemia.2
“Neonatal hypoglycemia, especially in preterm infants, is a major concern due to its association with serious short- and long-term complications,” wrote investigators.1
Assessing the effects of metformin
The intention-to-treat randomized clinical trial was conducted to determine whether metformin can reduce neonatal hypoglycemia linked to maternal betamethasone use. Three university-teaching medical centers conducted the study from July 1, 2020, to June 30, 2024.
Participants included pregnant women older than 18 years receiving betamethasone to manage increased preterm delivery risk. The medication was given to these individuals between 24 and 36.5 weeks’ gestation.
Exclusion criteria included pregestational and gestational diabetes, chronic heart failure, chronic kidney failure, and allergic sensitivity to metformin. Participants were randomly assigned 1:1 to a research group receiving metformin after betamethasone use or a control group with no metformin administration.
Betamethasone administration and following treatment
Betamethasone was administered as a 12-mg dose through intramuscular injection, with an additional 12 mg offered if the delivery did not occur within 24 hours of administration. In the research group, participants took metformin tablets 425 mg before meals, alongside 850 to 1700 mg at approximately 10 PM.
Patients could receive treatment for up to 48 hours after the first dose of betamethasone. Blood glucose level was measured before meals, 90 minutes after starting meals, and at 10 PM. Mean maternal glucose measures up to 48 hours after the first betamethasone injection were reported as the primary outcome.
Mean maternal preprandial glucose values, postprandial glucose values, and the rate of abnormal glucose values were reported as secondary outcomes. Covariates included demographic, background, and obstetric characteristics. Investigators also obtained data about potential treatment-related adverse events.
Participant characteristics and glucose values
There were 169 women with a mean age of 29.7 years included in the study, 91 of whom were randomly assigned to the metformin group and 96 of whom were randomly assigned to the control group. Of these, 84 and 85, respectively, were evaluated. Forty-eight neonates in the metformin group and 58 in the control group were born preterm, and metformin treatment was halted by 5 participants.
Patient and pregnancy characteristics did not significantly differ between groups, except for a greater body mass index and rate of prior preterm delivery in the metformin group. The metformin group presented with significantly reduced mean maternal total glucose values vs the control group, at 121 vs 127 mg/dL, respectively.
Patients receiving metformin also had significantly reduced postprandial glucose values, with a mean of 129 mg/dL vs 138 mg/dL among controls. Maternal hypoglycemia, defined as glucose level at or below 60 mg/dL, was not reported in either group.
Neonatal outcomes and safety
Twenty-one percent of the metformin group presented with preterm neonatal hypoglycemia vs 40% in the control group. This indicated a relative risk of 0.53 for neonatal hypoglycemia among patients receiving metformin. Other maternal and neonatal outcomes did not significantly differ between groups.
Fourteen percent of the metformin group reported mild adverse events, with 10% discontinuing treatment because of these effects. Overall, metformin was indicated as safe and effective for preventing maternal hyperglycemia and neonatal hypoglycemia caused by ACSs.
“Metformin should be considered as a treatment option for women who receive antenatal corticosteroids to prevent their related adverse effects,” wrote investigators.
References
- Yefet E, Massalha M, Talmon G, et al. Metformin, maternal glycemic control, and neonatal hypoglycemia after antenatal steroids: a randomized clinical trial. JAMA Netw Open. 2026;9(1):e2552807. doi:10.1001/jamanetworkopen.2025.52807
- Gyamfi-Bannerman C, Thom EA, Blackwell SC, et al; NICHD Maternal–Fetal Medicine Units Network. Antenatal betamethasone for women at risk for late preterm delivery. N Engl J Med. 2016;374(14):1311-1320. doi:10.1056/NEJMoa1516783
