Employing widely-used diabetes medication before conception or in early pregnancy might not correlate with an increased risk of birth defects, based on studies.
Two studies, released on Monday in the Annals of Internal Medicine, debunk a 2022 study that claimed a 40% rise in birth defects among babies born to men who used metformin in the three months preceding conception.
These findings offer "comfort" to parents, according to Dr. Ran Rotem, an author of the metformin and paternal usage study and a researcher at the Harvard T.H. Chan School of Public Health.
"Traditionally, the mother has been the focus when it comes to pregnancy and the health of the newborn," he stated. "However, we're uncovering evidence that the father is also significant."
The increased risk of birth defects observed in previous research might be attributable to diabetes or related conditions, rather than the medication itself, according to Rotem.
"When we talk about a medication, we must also consider the underlying conditions in which it's typically prescribed," he remarked. "We know that diabetes itself can pose challenges regarding fertility and potential complications in pregnancy and newborns."
Metformin, a primary medication for managing type 2 diabetes, has been extensively used since the 1960s to manage blood sugar levels. It's now the most frequently prescribed oral medication for type 2 diabetes. Those planning to take metformin are recommended to inform their doctor if they're pregnant, planning to become pregnant, or breastfeeding.
For the study on paternal metformin usage, researchers from the Harvard T.H. Chan School of Public Health and the Kahn-Sagol-Maccabi Research and Innovation Center of Maccabi Healthcare Services in Israel examined data from Israeli birth records and medical records for nearly 400,000 babies born between 1999 and 2020.
They compared this data with information on the babies' fathers, including their ages, lab test results, and medication records, including data on metformin prescriptions.
Although the researchers didn't specifically look at how long the men had been using the medication, "we did have many individuals who had been on the medication for a long time, and the results were consistent for those individuals as well," Rotem remarked.
The researchers found that the prevalence of major birth defects was 4.7% in babies of fathers not exposed to diabetes medications before conception, compared to 6.2% in babies of fathers exposed to metformin before conception.
After adjusting for factors such as the fathers' other underlying health conditions and whether the mother also had diabetes or related medical conditions, the researchers found no increased risk of major birth defects in babies exposed to paternal metformin.
Men who used diabetes medications during the sperm developmental period, leading up to conception, were older, had a higher prevalence of underlying health conditions, and were more likely to have fertility problems and a history of smoking compared to fathers not exposed to diabetes medications.
"Our study shows that paternal use of metformin in the sperm development period is not associated with an increased risk of birth defects in newborns, providing assurance to fathers planning to start a family that they can continue using the drug to manage their diabetes," Rotem stated. "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 and fertility problems was also seen among the mothers of babies whose fathers used metformin, compared to the mothers of babies with no paternal diabetes medication exposures.
"If the father is on diabetes medication, the mother is much more likely to be on diabetes medication or have other metabolic conditions," Rotem stated. "We know that diabetes is harmful when it affects the mother, and we're finding evidence that it's also problematic for the father. If you can manage diabetes through lifestyle changes – exercising more, eating healthily – that's probably beneficial anyway. But if medication is necessary, it seems like metformin is a safe choice for both."
The data also indicated that the risk of a birth defect was higher when the father used metformin in combination with other medications, known as a polytherapy. Paternal metformin monotherapy, or using metformin alone, did not appear to increase the risk of birth defects.
"When we examined specific treatment regimens, modestly elevated excess risks were still observed, particularly among babies of fathers who used metformin in conjunction with other diabetes medications," Rotem said. "However, we also observed that fathers who took multiple medications had poorer diabetes control. This suggests that the modestly elevated risk observed for diabetes polytherapies was likely not caused by the medications themselves, but rather by the poorer cardiometabolic health profile of the fathers."
Here's a rephrased version of the text:
The findings suggest that the chances of giving birth to a baby with birth defects are approximately 6% when the mother uses a combination of insulin and metformin, as opposed to 8% when the mother uses insulin alone. This outcome was anticipated, considering metformin might transit through the placenta, affecting the fetus, but it can aid in managing blood sugar levels which could potentially lower the risk of birth defects.
Dr. Yu-Han Chiu, the main researcher, mentioned this observation in an email, explaining that poor blood sugar control can increase the likelihood of birth defects. Combining insulin with metformin might result in better blood sugar control than using insulin alone, which could explain the lower risk of birth defects found in the study. Chiu added that for women with type 2 diabetes who currently use metformin and are planning to conceive, the research suggests that continuing to use metformin may not lead to an increased risk of birth defects as compared to switching to insulin.
A 'complicated picture' surrounds the potential risks associated with the use of metformin by both parents, but the new studies provide more clarity to this evolving scenario. Dr. Meleen Chuang, medical director of women's health at the Family Health Centers at NYU Langone, supported this view, stating that metformin prescription should not be altered for parents planning to conceive.
Chuang stressed the importance of weight loss, diet, and exercise as part of preconception care for both parents, as well as reducing modifiable risk factors such as decreasing weight, quitting smoking, and limiting alcohol and substance use to improve health and fertility.
In a related article published alongside the studies, Dr. Sarah Martins da Silva of the University of Dundee in the United Kingdom noted that the possible risks associated with the paternal and maternal use of metformin continue to present a 'complex picture.' However, the new studies contribute to making this evolving picture clearer.
Martins da Silva concluded that while individual risks and benefits should be carefully evaluated, these recent analyses suggest that metformin is a safe and efficient treatment option for managing type 2 diabetes in people trying to conceive and managing hyperglycemia in pregnant women during the first trimester. She proposed that it might be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy.
Read also:
The most frequently prescribed oral medication for managing type 2 diabetes is metformin, which is widely used to manage blood sugar levels.
Parents planning to take metformin are advised to inform their doctors about their pregnancy plans due to its extensive use in managing diabetes.
