Preterm birth remains one of the leading causes of neonatal morbidity and mortality worldwide. To reduce the risk of respiratory distress and other complications in premature infants, antenatal corticosteroids—most commonly betamethasone—are routinely administered to pregnant individuals at high risk of early delivery. While this intervention has saved countless lives, emerging evidence suggests it may also carry unintended metabolic consequences for newborns, particularly an increased risk of neonatal hypoglycemia.

New research now raises an important question: could metformin, a widely used and well-studied medication, help protect premature infants from hypoglycemia when their mothers receive antenatal steroids—even in the absence of gestational diabetes?

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Antenatal Steroids and Their Role in Preterm Birth

Betamethasone is a cornerstone of obstetric care for individuals at risk of preterm labor. Administered typically between 24 and 34 weeks of gestation, the steroid accelerates fetal lung maturation and significantly reduces the risk of respiratory distress syndrome, intraventricular hemorrhage, and neonatal death.

However, betamethasone has systemic metabolic effects. One of its well-known side effects is a temporary rise in maternal blood glucose levels. This steroid-induced hyperglycemia usually peaks within 24 hours and resolves spontaneously within 48 hours, even in pregnant individuals without diabetes.

Despite its transient nature, this spike in glucose appears to have downstream effects on the fetus and newborn.

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Neonatal Hypoglycemia: A Serious Early-Life Risk

Neonatal hypoglycemia is one of the most common metabolic complications in newborns, especially those born prematurely. Low blood glucose levels shortly after birth can lead to seizures, brain injury, and long-term neurodevelopmental impairment if not promptly recognized and treated.

Infants born to mothers with gestational diabetes are known to have a higher risk of hypoglycemia due to fetal hyperinsulinemia—an adaptive response to elevated maternal glucose levels during pregnancy. However, whether short-term elevations in maternal glucose, such as those caused by antenatal steroids, can produce a similar effect has been less clear.

Recent studies suggest that even brief episodes of maternal hyperglycemia following betamethasone administration may stimulate excess insulin production in the fetus. After birth, when the maternal glucose supply is suddenly interrupted, this elevated insulin level can drive neonatal blood sugar dangerously low.

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The Potential Role of Metformin

Metformin is a first-line treatment for type 2 diabetes and is increasingly used in pregnancy, particularly for gestational diabetes and polycystic ovary syndrome. It works primarily by reducing hepatic glucose production and improving insulin sensitivity, without causing hypoglycemia.

Researchers are now exploring whether metformin could mitigate the temporary hyperglycemia induced by antenatal steroids, even in pregnant individuals without diabetes. By blunting the glucose surge following betamethasone administration, metformin may reduce fetal exposure to elevated glucose levels and, in turn, lower the risk of neonatal hypoglycemia.

Early data suggest that this approach could be particularly beneficial for premature infants, who already have limited metabolic reserves and immature glucose regulation systems.

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Nondiabetic Pregnancies: An Overlooked Population

Most clinical attention regarding neonatal hypoglycemia has focused on pregnancies complicated by gestational or preexisting diabetes. However, the majority of pregnant individuals receiving antenatal steroids do not have diabetes.

This has raised concerns that the metabolic effects of betamethasone in nondiabetic pregnancies may be underrecognized. While maternal glucose elevations are typically transient and asymptomatic, the fetus may still experience metabolic programming effects that increase vulnerability after birth.

The possibility that metformin could offer protective benefits in this population represents a shift in how clinicians think about risk stratification and prevention strategies in neonatal care.

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Safety Considerations for Metformin Use in Pregnancy

Metformin has a well-established safety profile in pregnancy. Numerous studies have shown no increase in congenital anomalies or adverse pregnancy outcomes, and long-term follow-up studies in children exposed to metformin in utero have been largely reassuring.

However, extending metformin use to pregnant individuals without diabetes solely for neonatal benefit raises important questions. These include optimal dosing, timing relative to steroid administration, and identifying which patients are most likely to benefit.

Experts emphasize that while early findings are promising, more randomized controlled trials are needed before routine use can be recommended.

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Implications for Neonatal and Obstetric Care

If future studies confirm that metformin reduces the risk of neonatal hypoglycemia following antenatal steroid exposure, it could lead to meaningful changes in clinical practice. Such an approach may reduce the need for neonatal intensive care admissions, decrease invasive glucose monitoring, and lower the risk of long-term neurodevelopmental complications.

For healthcare systems, preventing neonatal hypoglycemia could translate into shorter hospital stays and reduced healthcare costs. For families, it could mean fewer interventions during a critical and emotionally vulnerable time.

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Looking Ahead

The balance between maternal treatment and neonatal outcomes is a central challenge in obstetric medicine. Antenatal steroids remain an essential, life-saving therapy for preterm birth, but growing awareness of their metabolic effects underscores the need for complementary strategies to protect newborns.

Metformin’s potential role in preventing neonatal hypoglycemia represents an intriguing and biologically plausible solution. While more research is required, these findings highlight the evolving understanding of how temporary changes during pregnancy can have lasting effects on newborn health.

As science continues to refine prenatal care, the goal remains clear: to ensure that interventions designed to save lives also support the healthiest possible start for the most vulnerable infants.