Highlights
Short-term metformin treatment following betamethasone administration significantly lowered mean maternal total and postprandial glucose levels compared to no treatment.
The incidence of neonatal hypoglycemia was reduced from 40% in the control group to 21% in the metformin group, representing a 47% relative risk reduction.
The intervention was well-tolerated, with adverse effects limited to mild gastrointestinal symptoms in a small subset of participants.
These findings suggest metformin is a viable prophylactic strategy to manage the metabolic side effects of antenatal corticosteroids in women at risk for preterm delivery.
The Double-Edged Sword of Antenatal Corticosteroids
Antenatal corticosteroids, such as betamethasone, are a cornerstone of modern perinatology. For women at risk of preterm birth between 24 and 37 weeks of gestation, these steroids significantly accelerate fetal lung maturation and reduce the risk of respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis. However, this life-saving intervention comes with a predictable metabolic cost: transient but severe maternal hyperglycemia.
Glucocorticoids induce peripheral insulin resistance and increase hepatic gluconeogenesis. In the context of pregnancy, where insulin sensitivity is already physiologicaly decreased, betamethasone can cause glucose levels to spike. This maternal hyperglycemia leads to fetal hyperglycemia, which in turn triggers fetal hyperinsulinemia. Once the infant is born and the placental supply of glucose is severed, the neonate’s high insulin levels can cause profound and dangerous hypoglycemia.
The Rational for Metformin Intervention
Metformin, a biguanide commonly used for type 2 diabetes and increasingly for gestational diabetes, functions primarily by inhibiting hepatic glucose production and improving insulin sensitivity. Unlike insulin, which requires intensive monitoring and carries its own risk of hypoglycemia, metformin offers a more stable and easily administered oral alternative. Given its established safety profile in pregnancy, researchers sought to determine if short-term metformin use could counteract the acute glycemic surge following betamethasone administration.
Study Design and Methodology
This multicenter, open-label randomized clinical trial was conducted across three medical centers in Israel between July 2020 and June 2024. The study enrolled 169 pregnant women between 24.0 and 36.5 weeks of gestation who were receiving betamethasone due to an increased risk of preterm delivery. Crucially, women with pre-existing or gestational diabetes were excluded to isolate the effect of steroids on previously normoglycemic individuals.
Participants were randomized into two groups:
1. Metformin Group: Received 425 mg three times daily before meals and a larger dose of 850-1700 mg at 10 pm. The treatment continued for up to 48 hours following the first betamethasone dose.
2. Control Group: Received the standard of care with no specific glycemic intervention.
The primary endpoints were twofold: the mean maternal glucose levels during the 48 hours following the first steroid injection and the rate of neonatal hypoglycemia among infants delivered before 37 weeks. Maternal glucose was monitored via capillary sticks at preprandial, 90-minute postprandial, and late-evening intervals.
Key Findings: Maternal Glycemic Control
The study results revealed a significant improvement in maternal metabolic parameters. The metformin group demonstrated lower mean total glucose values (121 mg/dL vs. 127 mg/dL; P = .01) and significantly lower postprandial glucose levels (129 mg/dL vs. 138 mg/dL; P = .009) compared to the control group. While these numerical differences may appear modest, they represent a consistent dampening of the glycemic peaks typically seen after steroid administration.
Impact on Neonatal Outcomes: Reducing Hypoglycemia
The most clinically striking finding was the impact on the neonates. Among the 106 infants born preterm during the study, the rate of neonatal hypoglycemia was significantly lower in the metformin-exposed group. Specifically, only 21% (10 of 48) of neonates in the metformin group experienced hypoglycemia, compared to 40% (23 of 58) in the control group. This resulted in a relative risk (RR) of 0.53 (95% CI, 0.28-0.99), suggesting that metformin nearly halved the risk of this neonatal complication.
Safety and Tolerability
Safety is a paramount concern when introducing pharmacological interventions during pregnancy. In this trial, metformin was found to be safe for both the mother and the fetus. No serious adverse events were linked to the medication. Approximately 14% of women in the metformin group reported mild adverse effects, which were primarily gastrointestinal in nature (e.g., nausea or diarrhea), consistent with the known side-effect profile of the drug. No maternal hypoglycemic episodes were reported, highlighting the self-limiting nature of metformin’s glucose-lowering mechanism compared to insulin.
Mechanistic Insights and Clinical Implications
The biological plausibility of these findings is robust. By mitigating the maternal glucose excursion, metformin likely reduces the stimulus for fetal pancreatic beta-cell hyperplasia and hyperinsulinism. This “metabolic buffering” ensures that the neonate enters the extrauterine environment with a more balanced endocrine profile, easing the transition to independent glucose regulation.
For clinicians, these results offer a potential shift in practice. Current guidelines often involve reactive monitoring of glucose levels after steroids, with insulin sliding scales reserved for the most severe cases of hyperglycemia. The proactive use of metformin provides a simpler, oral, and preventative strategy that directly addresses the neonatal outcome of concern.
Expert Commentary and Limitations
While the results are promising, expert commentators note that the open-label design is a limitation, though the objective nature of glucose measurements and neonatal blood sugar tests mitigates some bias. Additionally, while the trial showed a reduction in neonatal hypoglycemia, further research is needed to determine if this translates into long-term neurodevelopmental benefits or reductions in Neonatal Intensive Care Unit (NICU) length of stay.
It is also important to consider the dosage. The study utilized a relatively high nocturnal dose (up to 1700 mg) to combat the dawn phenomenon and the specific timing of steroid-induced insulin resistance. Replicating these specific dosing schedules in clinical practice will be essential for achieving similar results.
Conclusion
This randomized clinical trial provides strong evidence that metformin is an effective and safe pharmacological tool for preventing betamethasone-induced maternal hyperglycemia and subsequent neonatal hypoglycemia. By nearly halving the risk of low blood sugar in preterm infants, metformin addresses a significant clinical challenge in obstetric care. Clinicians should consider metformin as a targeted treatment option for women receiving antenatal corticosteroids to improve both maternal metabolic health and neonatal transitions.
Funding and ClinicalTrials.gov
This study was registered at ClinicalTrials.gov (Identifier: NCT04332393). The researchers report no relevant financial disclosures or conflicts of interest that influenced the study outcomes.
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 R, et al. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet. 2006;367(9526):1913-1919.
3. Rowan JA, Hague WM, Gao W, et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358(20):2003-2015.
