New Studies Find No Clear Link Between Metformin Use Before or Early in Pregnancy and Major Birth Defects

Two studies published Monday in the Annals of Internal Medicine take on a question that has worried parents managing type 2 diabetes: does metformin, the drug so many of them take, raise the chance of a baby being born with a major birth defect? Both papers, from researchers at the Harvard T.H. Chan School of Public Health, conclude that it does not appear to, whether the drug is taken by fathers before conception or by mothers in early pregnancy.

The findings cut against a 2022 study that tied metformin use by men in the three months before conception to a 40% higher risk of birth defects in their children. Metformin has been used to control blood sugar since the 1960s. It is a first-line treatment for type 2 diabetes and the most commonly prescribed oral drug for the condition. People are advised to tell their doctor before starting it if they plan to become pregnant, are pregnant or are breastfeeding.

The paternal study was done with the Kahn-Sagol-Maccabi Research and Innovation Center of Maccabi Healthcare Services in Israel. It analyzed birth and medical records for nearly 400,000 babies born in Israel from 1999 to 2020, and matched them with information on the fathers: age, laboratory results and medication records, including metformin prescriptions. Major birth defects appeared in 4.7% of children whose fathers had taken no diabetes medication in the months before conception, and in 6.2% of children whose fathers had taken metformin. But once the researchers adjusted for the fathers' other health conditions and for whether the mothers also had diabetes or related problems, the extra risk disappeared.

The groups were not alike to begin with. Men on diabetes medication during the sperm development period were older, had more underlying health conditions, were more likely to have fertility problems and were more likely to have a history of smoking. Their partners also had more health conditions and fertility problems. As Dr. Ran Rotem, an author of the study, put it, when a father is on diabetes medication the mother is much more likely to be on it too, or to have other metabolic problems. He argued that earlier risk signals may reflect the disease and its comorbidities rather than the drug. The study did not specifically examine how long the men had taken metformin, though Rotem said many had been on it for a long time and their results were consistent.

There was one wrinkle. Risk was modestly elevated among children of fathers who took metformin together with another diabetes drug, though metformin alone showed no such increase. Rotem noted that fathers on multiple medications had more poorly controlled diabetes, which suggests to him that their worse cardiometabolic health, not the drugs, drove the difference. His message for fathers planning a family is that they can continue metformin. If lifestyle changes alone can manage diabetes, he said, that is helpful, but if medication is needed, metformin looks like a safe choice.

The second study looked at mothers. Researchers drew on US Medicaid data from 2000 to 2018, covering more than 12,000 women with type 2 diabetes. Women who kept taking metformin and added insulin in the first trimester showed little to no added risk of a baby with major birth defects compared with women who stopped metformin and switched to insulin. The estimated risk was about 6% with insulin plus metformin and 8% with insulin alone. Lead author Dr. Yu-Han Chiu said the team was not surprised: metformin may cross the placenta, but it can help blood sugar control, and poor control is itself a risk factor for birth defects.

Outside experts were receptive. Dr. Meleen Chuang of NYU Langone, who was not involved, called the studies well done and said she would not change how metformin is prescribed to parents trying to conceive. She would still urge both parents to work on weight, diet, exercise, and on cutting smoking, alcohol and substance use. In an accompanying editorial, Dr. Sarah Martins da Silva of the University of Dundee called the picture complex but clearer, and cautioned that the studies lack data on glycemic control. She nonetheless wrote that metformin appears safe and effective for men and women trying to conceive and for pregnant women in the first trimester, and that it may be time to reconsider guidelines advising a switch to insulin.