Introduction: The Clinical Dilemma of Antenatal Corticosteroids
The administration of antenatal corticosteroids, specifically betamethasone, is a cornerstone of modern perinatology. For decades, these agents have been indispensable in accelerating fetal lung maturity and reducing the incidence of respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis in infants born preterm. However, this life-saving intervention comes with a metabolic cost. Glucocorticoids are potent antagonists of insulin action, frequently inducing transient but significant maternal hyperglycemia. This surge in maternal glucose levels crosses the placenta, stimulating fetal insulin secretion. When the maternal glucose supply is abruptly severed at birth, the neonate is often left with hyperinsulinism, leading to a high risk of neonatal hypoglycemia—a condition associated with neurological morbidity and prolonged stays in the neonatal intensive care unit (NICU). Efforts to mitigate these side effects without compromising the benefits of steroids have remained a priority for obstetricians and endocrinologists alike.
The Rationale for Metformin Intervention
Metformin, a biguanide commonly used for type 2 diabetes and increasingly for gestational diabetes mellitus (GDM), offers a unique mechanism of action. By increasing insulin sensitivity and inhibiting hepatic gluconeogenesis, metformin manages glucose levels without the risk of maternal hypoglycemia. Previous observational data and trials in women with GDM suggested that metformin might reduce the incidence of neonatal hypoglycemia. A recent multicenter randomized clinical trial conducted in Israel, published in JAMA Network Open, sought to determine if metformin could prophylactically address the glycemic dysregulation triggered by betamethasone in women without pre-existing diabetes.
Study Design and Methodology
The study was a multicenter, open-label randomized clinical trial conducted at three medical centers in Israel between July 2020 and June 2024. The trial enrolled 169 pregnant women between 24.0 and 36.5 gestational weeks who were at increased risk for preterm delivery and required betamethasone administration. Notably, women with pre-existing or gestational diabetes were excluded to isolate the effect of metformin on steroid-induced hyperglycemia specifically.
Intervention Protocol
Participants were randomized into two groups: the metformin group (n = 84) and the control group (n = 85). The metformin group received a structured dosing regimen: 425 mg three times daily before meals and a larger dose of 850-1700 mg at 10 PM. This treatment was initiated immediately after the first betamethasone dose and continued for up to 48 hours. The control group received standard care without prophylactic glycemic intervention.
Monitoring and Endpoints
Maternal capillary glucose was monitored rigorously, with measurements taken before meals, 90 minutes postprandially, and at 10 PM. The primary endpoints were the mean maternal glucose values during the 48-hour window following the first steroid injection and the incidence of neonatal hypoglycemia (defined as blood glucose <40 mg/dL in the first 48 hours of life) among infants born before 37 weeks.
Key Findings: Maternal Glycemic Control
The trial demonstrated a statistically significant improvement in maternal glycemic parameters within the metformin cohort. The mean total maternal glucose value was 121 mg/dL in the metformin group compared to 127 mg/dL in the control group (P = .01). The difference was even more pronounced in postprandial measurements, where the metformin group averaged 129 mg/dL versus 138 mg/dL in the control group (P = .009). While these absolute differences may seem modest, they represent a systemic reduction in the glucose excursion caused by betamethasone, potentially stabilizing the fetal metabolic environment.
Neonatal Outcomes: A Significant Reduction in Hypoglycemia
The most clinically impactful result of the trial was the effect on neonatal health. Among the 106 preterm neonates included in the analysis (48 in the metformin group and 58 in the control group), the rate of neonatal hypoglycemia was nearly halved in the metformin group. Specifically, 21% (10 of 48) of infants in the metformin group experienced hypoglycemia compared to 40% (23 of 58) in the control group. This yielded a relative risk (RR) of 0.53 (95% CI, 0.28-0.99; P = .04). The reduction in hypoglycemia suggests that by dampening the maternal hyperglycemic peak, metformin effectively prevents the secondary fetal hyperinsulinemia that leads to postnatal glucose crashes.
Safety and Tolerability
Safety is a paramount concern when introducing a pharmacological agent during pregnancy. In this trial, metformin was well-tolerated. Twelve women (14%) in the metformin group reported mild adverse effects, predominantly gastrointestinal symptoms such as nausea or diarrhea, which are common with metformin initiation. No serious adverse maternal or neonatal events were attributed to the medication. These findings align with the established safety profile of metformin in pregnancy, which has been documented in numerous GDM trials.
Expert Commentary and Clinical Implications
The results of this trial provide high-quality evidence for a simple, low-cost intervention to improve outcomes for preterm infants. By addressing the ‘iatrogenic’ hyperglycemia caused by betamethasone, clinicians can potentially reduce the need for NICU admissions and invasive glucose monitoring in neonates.
Biological Plausibility
The biological mechanism is robust. Betamethasone induces insulin resistance within hours of administration. Metformin’s ability to enhance peripheral insulin sensitivity and reduce hepatic glucose output directly counteracts this steroid-induced resistance. Importantly, metformin crosses the placenta, and while its primary effect in this study is likely mediated through maternal glucose control, its direct presence in the fetal circulation might also play a role in metabolic stabilization, though this requires further investigation.
Limitations and Generalizability
While the results are compelling, the open-label nature of the trial is a limitation, though the objective nature of glucose measurements (maternal and neonatal) mitigates the risk of observer bias. Furthermore, the study was conducted in a specific geographic population; validation in larger, more diverse cohorts would strengthen the case for universal implementation. The exclusion of women with diabetes also leaves a question regarding whether even more aggressive management is needed for that high-risk subgroup.
Conclusion: Moving Toward a New Standard of Care
The trial by Yefet et al. underscores that the metabolic side effects of antenatal corticosteroids are not merely physiological curiosities but are actionable targets for clinical improvement. Metformin demonstrated a clear benefit in reducing neonatal hypoglycemia, a condition that remains a significant burden in neonatal care. Given its safety profile, low cost, and efficacy, metformin should be strongly considered as a prophylactic treatment for women receiving antenatal steroids for preterm birth risk. This study marks a significant step toward refining the management of preterm labor, ensuring that the benefits of steroids for the lungs do not come at the expense of the infant’s metabolic stability.
Funding and Clinical Trial Information
This study was conducted across three medical centers in Israel. The trial is registered at ClinicalTrials.gov with the identifier NCT04332393.
References
1. 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.
2. Crowther CA, Haslam RR, Anne-Marie S, et al. Neonatal Respiratory Distress Syndrome after Repeat Exposure to Antenatal Corticosteroids. N Engl J Med. 2006;354:1287-1297.
3. Rowan JA, Hague WM, Gao W, et al. Metformin versus Insulin for the Treatment of Gestational Diabetes. N Engl J Med. 2008;358:2003-2015.
