Several studies have raised concerns about a potential link between the widely used type 2 diabetes drug metformin and an increased risk of birth defects in pregnancies. However, a new study shows that use of the drug by men who are planning to become pregnant or women in the early stages of pregnancy does not appear to be associated with an increased risk of serious birth defects in their children.
The two studies, published Monday in the Annals of Internal Medicine, contradict a 2022 study that found men’s use of metformin in the three months before pregnancy increased the risk of birth defects in their offspring by 40%.
Dr. Ran Rotem, author of the new study on metformin use by fathers and a researcher at Harvard’s T.H. Chan School of Public Health, said the findings should be “reassuring” for parents.
“Traditionally, the focus has been on mothers when it comes to pregnancy, fetal health and newborn health, but we’re increasingly realizing that fathers are important too,” she said.
He added that any increased risk of birth defects seen in previous studies may be related to diabetes and related complications rather than the drug itself.
“When thinking about medications, we also have to think about the underlying condition for which the medication is typically prescribed,” Rotem says. “We know that diabetes itself can be difficult to manage, both in terms of fertility and potential complications during pregnancy and in the newborn.”
Metformin is the first-choice drug for the treatment of type 2 diabetes and has been widely used to control blood glucose levels since the 1960s.
This drug is currently the most commonly prescribed oral medication to treat type 2 diabetes, and before taking metformin, women are recommended to tell their doctor if they are planning to become pregnant, currently pregnant, or breastfeeding.
“The father’s health is important.”
In the study on metformin use by fathers, researchers from Harvard T.H. Chan School of Public Health and the Khan Sagol Maccabi Research and Innovation Center at Maccabi Healthcare Services in Israel analyzed data from birth and medical records of nearly 400,000 babies born in Israel between 1999 and 2020.
The researchers compared that data with information such as the age of the babies’ fathers, laboratory test results, and medication records, including data on metformin prescriptions.
The researchers didn’t specifically look at how long the men had been taking the drugs, “but there were a lot of people who had been taking the drugs for a long time, and the results were pretty consistent across them,” Rotem said.
The researchers found that the rate of major birth defects was 4.7% in babies whose fathers did not take diabetes medications in the months before pregnancy, compared with 6.2% in babies whose fathers took metformin before pregnancy.
When the researchers adjusted the data to take into account factors such as the father’s other underlying medical conditions and whether the mother also had diabetes or related comorbidities, they found no increased risk of major birth defects in children whose fathers were exposed to metformin.
Men who used antidiabetic medications during sperm development leading up to conception were more likely to be older, have more underlying medical conditions, and have a history of infertility and smoking compared with fathers who did not take antidiabetic medications.
“We found that paternal metformin use during sperm development was not associated with an increased risk of neonatal malformations, providing confidence that fathers planning to start a family can continue to use the drug for diabetes management,” Rotem said. “More broadly, our study also suggests that maintaining a good cardiometabolic health profile is important for both parties.”
Mothers of children whose fathers were using metformin also had a higher prevalence of underlying medical conditions and infertility compared with mothers of children whose fathers were not taking diabetes medication.
“If the father is taking diabetes medication, there’s a very good chance the mother is also taking diabetes medication or has other metabolic complications,” Rotem said.
“We know that diabetes itself is bad if it affects the mother, but we’re starting to find evidence that it’s also troublesome for the father,” he said. “If you can manage your diabetes just by making lifestyle changes, like exercising more and watching what you eat, that’s probably a good thing and will be beneficial either way. But if you have to take medication, metformin seems to be a safe option for both mothers and fathers.”
The data also showed that the risk of birth defects was increased if fathers used metformin in combination with other medications (called polytherapy). When fathers used metformin alone (called monotherapy), it did not appear to increase the risk of birth defects.
“When we looked at specific treatment regimens, we still observed a small excess risk, particularly among children of fathers who used metformin in combination with other diabetes medications,” Rotem said.
“However, we also observed that fathers taking multiple medications had poorer diabetes control,” he said, “which indicates that the slightly elevated risk seen with multiple diabetes treatments is likely due to poorer cardiometabolic health in fathers, rather than due to the medications themselves.”
“Poor glycemic control is a risk factor”
Another study published Monday in the Annals of Internal Medicine came to similar results for mothers: Women who continued to take metformin during early pregnancy and added insulin to their treatment had little increased risk of giving birth to babies with major birth defects compared with women who stopped metformin and switched to insulin.
Researchers at the Harvard TH Chan School of Public Health studied data on more than 12,000 women with type 2 diabetes and their pregnancies, drawn from a database of the US Agency for Medicaid and Health Care Administration from 2000 to 2018.
The analysis found that the risk of giving birth to a baby with a birth defect was about 6% when mothers took insulin plus metformin, compared with 8% when mothers took insulin alone.
“We were not surprised by this finding. Although metformin can cross the placenta and potentially affect the fetus, it may help control blood sugar levels and reduce the risk of birth defects,” Dr. Yuhan Qiu, lead author of the study and a researcher at the Harvard T.H. Chan School of Public Health and Pennsylvania State University College of Medicine, said in an email.
“Poor blood sugar control is a risk factor for birth defects. Using insulin plus metformin may result in better blood sugar control than using insulin alone, which may explain the slightly lower risk of live births with birth defects compared with using insulin alone,” Chiu said. “For women with type 2 diabetes who are currently taking metformin and are planning to become pregnant, our study suggests that continuing metformin may pose little or no increased risk of birth defects compared with switching to insulin.”
‘A complicated situation’
Dr. Melane Chuang, medical director of women’s health at NYU Langone’s Family Health Center, said in an email that the two new studies are “well done.”
“We have no intention of changing the way metformin is prescribed to expectant parents,” said Chuang, who is chief of obstetrics and gynecology at NYU Brooklyn Langone, who was not involved in the study.
“I recommend weight loss, diet, and exercise as part of preconception care for parents,” she added. “Weight loss and reducing modifiable risk factors such as smoking, alcohol, and drug use are part of the strategy to improve health and fertility.”
The possible risks associated with maternal and paternal metformin use remain a “complex picture,” but new research could shed more light on the changing picture, Dr. Sara Martins da Silva of the University of Dundee in the UK said in an editorial published Monday alongside the two studies.
“Clearly, the study lacks information on glycemic control, so individual risks and benefits need to be carefully considered and the results interpreted with caution,” she wrote.
“Nevertheless, recent analyses suggest that metformin is a safe and effective treatment option. [type 2 diabetes] “Given the importance of insulin therapy for women and men who wish to become pregnant, as well as for managing hyperglycemia in pregnant women during the first trimester, it may be time to reconsider current prenatal care guidelines that recommend a switch to insulin therapy,” she added.
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