The diabetes drug metformin has been linked to a higher risk of birth defects in children of men who took it, but men shouldn’t stop taking the medication abruptly, experts warn. The drug, also commonly used to treat polycystic ovary syndrome (PCOS), is deemed safe in women, but still shouldn’t be taken during pregnancy.
Baby boys whose fathers took metformin were more than three times as likely to have a genital birth defect compared to babies whose fathers never took it. The risk was only in men who took metformin within three months of conceiving—that’s when sperm develops. The study was published in Annals of Internal Medicine.
“Three months is important as it takes two to three months to make a sperm,” says Michael L. Eisenberg, MD, a urologist at Stanford Health Care and one of the researchers. “That would be the window of exposure which could impact the sperm which lead to a pregnancy.”
Dr. Eisenberg tells Motherly more studies have to confirm their findings. The correlation found does not mean that we know for sure if metformin in men causes the defects.
Metformin is approved to treat type 2 diabetes. But it’s also used off-label (not officially approved) for weight loss, gestational diabetes and diabetes prevention. Additionally, it’s used to help women with PCOS, as it can treat the insulin resistance commonly seen in the condition and improve fertility. Several studies have linked metformin with positive outcomes in terms of treating PCOS and subsequently conceiving.
The drug is pretty popular, as about 86 million prescriptions were written for it in 2019. It’s commonly used by men without diabetes to help with weight loss, so the men impacted by it may not only be those with type 2 diabetes.
About the study
The scientists evaluated over 1.1 million babies born in Denmark from 1996 to 2017 whose mothers didn’t have hypertension or diabetes. They looked at men under 40 on diabetes treatments including insulin (most often used to treat type 1 diabetes), metformin, and sulfonylureas (another group of medicines used to treat diabetes).
The researchers didn’t find an increased risk for birth defects in babies whose fathers took insulin; there were too few babies born to fathers who took sulfonylureas to pinpoint any risks with certainty. But babies born to dads who took metformin showed a stark increase in defects.
Of all the babies, 51.4% were boys and 3.3% had at least one major birth defect. Among the 1,451 babies exposed to metformin, 49.4% were boys and 5.2% of them had a birth defect. For comparison, of the 5,298 babies exposed to insulin, 51.3% were male and 3.3% had major defects. There were 647 babies born to fathers who took sulfonylureas; 49.3% were male and 5.1% of them had a major birth defect. In those exposed to metformin, there were 1.4 times higher odds of the child having at least one major birth defect, even after researchers adjusted for other factors.
Detected birth defects were those affecting genitals, the digestive and urinary systems, as well as heart issues. Scientists noted genital birth defects were only in boys.
The genital defects reported in the study include hypospadias, which happens when the urethra does not exit from the tip of the penis.
Researchers didn’t see effects in babies conceived by men who took metformin earlier in life, or before the three-month period of time leading up to conception. So the main timeline of concern seems to be taking it within three months of conceiving.
Unpacking the findings
The American College of Physicians say men with diabetes who take metformin should talk to their doctors about possibly switching to another treatment when trying to conceive.
Serena H. Chen, MD, a reproductive endocrinologist at IRMS Reproductive Medicine in New Jersey who was not involved in the research, tells Motherly that a “huge weakness” of the study was that there was no data on glycemic control.
“If your hemoglobin A1c [HbA1c; a marker of blood sugar levels over time] is elevated, we know that increases the risks for birth defects,” Dr. Chen explains. “All they did was correlate pharmacy data.”
Dr. Eisenberg says earlier mouse studies have suggested that fetal metformin exposure can impair normal testicular development.
Men, women and metformin
Wondering if females taking metformin for PCOS could put their infants at risk? This research didn’t show that, but it also didn’t study that question.
There is some research on pregnant women taking it. Researchers didn’t find a link within the first trimester, and another study found it can decrease the risk of congenital anomaly because it helped women achieve better glycemic control.
Metformin can make women with PCOS more responsive to other fertility modulating medications like clomiphene citrate (Clomid). Metformin can lower insulin resistance, which may underlie many of the issues caused by PCOS, Dr. Chen says.
“I would not say [metformin] is a fertility treatment for women. This is a common misperception, even amongst physicians,” Chen adds.
As for metformin in women: “It appears to be safe, but right now it should not be given in pregnancy for PCOS alone and it does not appear to reduce the chance for miscarriage so I would recommend that decisions about continuing once pregnant should be reviewed with a medical or reproductive endocrinologist,” Dr. Chen says. “This is something that has to be individualized. Benefits of continuing should outweigh potential risks.”
As for men, it may be a good idea to talk to your doc if you’re on metformin and TTC.
“Men who are trying to conceive should discuss this with their physicians before making any changes,” Dr. Chen notes.
More research is needed
Dr. Maarten Jan Wensink, an associate professor at the University of Southern Denmark, who led the study, says the results should be confirmed with more research. He says parental contributions to their children’s health should be taken seriously.
“The best treatment for type 2 diabetes remains lifestyle intervention: Diet, physical exercise,” he tells Motherly via email. Relying on that alone to treat diabetes can be difficult, but it can take away any potential harm done by medication, he notes.
“Men aspiring to fatherhood could consider switching to a different drug, but that is a decision that they should make together with their physician,” Dr. Wensink says. “Metformin is the first choice drug for type 2 diabetes because it is generally safe for the father and effective against diabetes. Yet alternatives are available.”
Dr. Michael L. Eisenberg, a urologist at Stanford Health Care.
Dr. Serena H. Chen, a reproductive endocrinologist at IRMS Reproductive Medicine in New Jersey.
Dr. Maarten Jan Wensink, an associate professor at the University of Southern Denmark.
Bartak, V. Sperm quality in adult diabetic men. International Journal of Fertility. 1979;24(4):226-32.
Corcoran C, et al. Metformin. 2021. Stat Pearls Publishing.
Given J E, et al. Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study. BMJ. 2018; 361 :k2477 doi:10.1136/bmj.k2477
Langer, O, et al. Level of glycemia and perinatal outcome in pregestational diabetes. Journal of Maternal Fetal Medicine. 2000; 9: 35-41. doi:10.1002/(SICI)1520-6661(200001/02)9:1<35::AID-MFM8>3.0.CO;2-6
Paternal metformin use associated with major birth defects if used during period of sperm development. American College of Physicians (press release). March 28, 2022.
Wensink, M, et al. Preconception antidiabetic drugs in men and birth defects in offspring. Annals of Internal Medicine. 2022 Mar. doi:10.7326/M21-4389