Study advances understanding of metformin effects on fetus

A study published in the American Journal of Obstetrics and Gynecology demonstrates that when the diabetes drug metformin is given to the mother during pregnancy, fetus growth is restricted, including a slowed maturing of the kidneys, which has been linked to a higher risk of obesity and insulin resistance in childhood.

Metformin, which is prescribed to 50 million Americans annually, has long been used outside of pregnancy to control blood sugar, but it is now widely prescribed to pregnant women to reduce complications related to prediabetes, Type 2 diabetes, gestational diabetes and obesity. While metformin is effective for controlling a pregnant woman’s blood sugar and decreasing the odds of a large-for-gestational-age baby, little has been known about the drug’s long-term effects on the newborn.

“We know that when a pregnant woman is obese and has a condition like diabetes, her child is much more likely to develop obesity and diabetes. Because of the widespread use of metformin in pregnant mothers, it is important for us to understand whether the drug is beneficial to babies over the long term, or whether it has unintended consequences,” said study co-author Jed Friedman, Ph.D., associate vice provost for diabetes programs at the University of Oklahoma Health Sciences and director of OU Health Harold Hamm Diabetes Center. The study was led by Baylor College of Medicine and funded by the National Institutes of Health.

Study results show that when given to the mother, metformin freely crossed the placenta and accumulated in the fetal kidneys, liver, intestines, placenta, amniotic fluid and urine, the latter of which was nearly equivalent to the amount found in the mother’s urine. That accumulation during pregnancy was associated with growth restriction in the kidneys, liver, skeletal muscle, heart, and fat deposits that support the abdominal organs, all of which served to lower the fetus’s body weight.

Because fetal growth restriction has been linked to an elevated risk of obesity and insulin resistance in childhood, the child could face additional health risks with age, such as cardiovascular problems. The situation represents something of a catch-22: If blood sugar is not controlled during pregnancy, there are risks to both mother and baby, including obesity and diabetes as the child grows. However, metformin itself may be creating the same risks despite its effectiveness in controlling blood sugar and reducing fetal growth.

Historically, studies of medication during pregnancy have focused on potential harm to the baby with less emphasis on the baby’s growth and metabolism. While metformin is not known to cause birth defects, the fetus also doesn’t have a way to clear the drug.

“Many drugs undergo ‘first-pass’ metabolism by becoming absorbed first in the liver, which decreases the concentration before it continues through the body. However, metformin does not experience the first-pass effect; rather, it is transported across the placenta, exposing the fetus to an adult dose of the drug,” Friedman said.

The research team also studied whether metformin levels in the fetus were affected by the mother’s diet. Half of the research models were fed a conventional diet with 15% calories from fat, while the other half received a high-fat diet with 36% calories from fat. Results showed metformin levels did not differ according to diet.

“This study was small, and much more research is warranted to better understand the effects of metformin on the fetus,” Friedman said. “The first 1,000 days – from the point of conception to a child’s second year of life – is a major focus for us in addressing the obesity and diabetes epidemics.”

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About the project

This study was funded by the National Institutes of Health under grant numbers RO1DK128187 and P51 OD011092. The content of this news release is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Read the full study at https://doi.org/10.1016/j.ajog.2024.06.002.