Use of popular diabetes drug in preconception or early pregnancy may not be tied to higher birth defect risk, studies suggest

(CNN) — Some studies have raised concerns about a potential link between the widely used type 2 diabetes drug metformin and an increased risk of conceiving a baby with birth defects. But new research now suggests that the use of the medication among men planning to conceive or women in early pregnancy does not appear to be linked with an increased risk of major birth defects for their children.

The two studies, published Monday in the Annals of Internal Medicine, contradict a 2022 study that linked metformin use by men in the three months before they conceived a baby to a 40% increased risk of birth defects in their offspring.

The findings provide “assurance” for parents, said Dr. Ran Rotem, an author of the new study on the paternal use of metformin and a researcher at the Harvard T.H. Chan School of Public Health.

“Conventionally and traditionally, the mother has been the focus when it comes to pregnancy and when it comes to fetal health and the health of the newborn. What we are increasingly finding is that the father is also important,” he said.

He added that the increased risk of birth defects seen in previous research could be associated with the disease of diabetes or with related comorbidities, and not so much the medication itself.

“When we think about a medication, we also have to think about the underlying conditions in which the medication is usually prescribed,” Rotem said. “We know that diabetes itself is tricky when it comes to both fertility and potential complications in pregnancy and in newborns.”

Metformin is a first-line medication in the treatment of type 2 diabetes and has been widely used to help control blood sugar levels since the 1960s.

The medication is now the most commonly prescribed oral drug for type 2 diabetes, and, before taking metformin, people are recommended to tell their doctor if they plan to become pregnant, are pregnant or are breastfeeding.

‘Health of the father seems to be important’

For the study on paternal use of metformin, researchers at the Harvard T.H. Chan School of Public Health and the Kahn-Sagol-Maccabi Research and Innovation Center of Maccabi Healthcare Services in Israel analyzed data from birth records and medical records on nearly 400,000 babies born in Israel between 1999 and 2020.

They compared that data with information on the babies’ fathers, such as their ages, laboratory test results and medication records, including data on metformin prescriptions.

Although the researchers didn’t specifically look at how long the men had been on the medication, “we did have many people who have been on the medication for a long time, and the results were pretty consistent for those individuals, too,” Rotem said.

The researchers found that the prevalence of major birth defects was 4.7% in children of fathers not exposed to diabetes medications in the months leading up to conception, compared with 6.2% in children of fathers exposed to metformin before conceiving.

When the researchers adjusted their data for factors such as the fathers’ other underlying health conditions and whether the mother also had diabetes or related comorbidities, they found no increased risk of major birth defects in children exposed to paternal metformin.

Men who used diabetes medications during the sperm developmental period, leading up to conceiving, tended to be older in age, had a higher prevalence of underlying health conditions and were more likely to have fertility problems and a history of smoking compared with fathers not exposed to diabetes medications.

“We find that paternal use of metformin in the sperm development period is not associated with excess risk of malformation in newborns, proving assurance that fathers planning to start a family can continue using the drug to control their diabetes,” Rotem said. “More broadly, our study also suggests that maintaining a good cardiometabolic health profile is important for both partners.”

A higher prevalence of underlying health conditions as well as fertility problems was also seen among the mothers of children whose fathers used metformin, compared with the mothers of children with no paternal diabetes medication exposures.

“If the father is on diabetes medication, the mother is much more likely to be on diabetes medication too or have other metabolic comorbidities,” Rotem said.

“We know that diabetes itself is not good when it is in the mother, and we are finding evidence that it’s also tricky for the fathers,” he said. “If you can manage diabetes with just changing your lifestyle – doing more exercise, watching your diet – that’s probably good, and that’s helpful anyways. But if you have to be medicated, it seems like metformin is a safe choice for both.”

The data also showed that risk of a birth defect was higher when the father used metformin along with other medications, described as a polytherapy. Paternal use of metformin alone, known as monotherapy, did not appear to increase the risk for birth defects.

“When we examined specific treatment regimens, modestly elevated excess risks were still observed, specifically among children of fathers who used metformin in tandem with some other diabetes medication,” Rotem said.

“But we also observed that fathers who took multiple medications had more poorly controlled diabetes,” he said. “This again indicates that the modestly elevated risk seen for diabetes polytherapies was likely not caused by the medications themselves, but rather by the worse cardiometabolic health profile of the fathers.”

‘Poor blood sugar control is a risk factor’

The other study that was published Monday in the Annals of Internal Medicine had somewhat similar findings for mothers. Women who continued using metformin and added insulin as a treatment in their first trimester of pregnancy showed little to no increased risk of giving birth to a baby with major birth defects compared with women who discontinued metformin and switched to insulin, according to the study.

The researchers, also from Harvard T.H. Chan School of Public Health, studied data on more than 12,000 women with type 2 diabetes and their pregnancies. The data came from the US Medicaid health care administration’s database from 2000 to 2018.

The analysis showed that the estimated risk for giving birth to a baby with birth defects was about 6% when the mother received insulin plus metformin, versus 8% when the mother received insulin alone.

“We were not surprised by our findings. Although metformin may cross the placenta, potentially affecting the fetus, metformin can help with blood sugar control which may lower the risk of birth defects,” Dr. Yu-Han Chiu, the lead author of the study and a researcher at the Harvard T.H. Chan School of Public Health and Penn State College of Medicine, said in an email.

“Poor blood sugar control is a risk factor for birth defects. Insulin in combination with metformin may result in better blood sugar control than using insulin alone. This may explain why we observed a slightly lower risk of live birth with congenital malformations when comparing with using insulin alone,” Chiu said. “For women with type 2 diabetes and currently taking metformin and planning to conceive, our study suggests continuing metformin had no or little increased risk for birth defects compared to switching to insulin.”

A ‘complex picture’

The two new studies are “well done,” Dr. Meleen Chuang, medical director of women’s health at the Family Health Centers at NYU Langone, said in an email.

“I would not change the way metformin is prescribed for parents trying to conceive,” said Chuang, who was not involved in the new studies and serves as ob-gyn chief of service for NYU Langone Brooklyn.

“I would encourage weight loss, diet, exercise as a part of their preconception care for both parents,” she added. “Reducing modifiable risk factors such as decreasing weight, smoking, alcohol, substance use are some ways to improve health and fertility.”

The possible risks that may come with the paternal and maternal use of metformin remain a “complex picture,” but the new studies help make that evolving picture clearer, Dr. Sarah Martins da Silva, of the University of Dundee in the United Kingdom, wrote in an editorial published alongside the two studies Monday.

“Clearly, individual risks and benefits should be carefully considered and results should be interpreted with caution since studies lack information on glycemic control,” she wrote.

“Nonetheless, these recent analyses suggest that metformin is a safe and effective treatment option for [type 2 diabetes] for men and women trying to conceive as well as managing hyperglycemia in pregnant women in the first trimester,” she added, “and it may be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy.”

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