Fertility, Metformin, and Danish Birth Defects

Results from a long-term study conducted in Denmark show that the popular diabetes drug — metformin — is linked to an increased rate of severe birth defects. Using nearly 20 years of health registry data, researchers found that the underlying rate of birth defects was lower than the rate of birth defects in babies born to fathers who had used metformin.

The study analyzed the health records of 1,116,779 babies, finding that 3.3% had at least one birth defect. However, when looking at 1,451 babies exposed to metformin, the rate of birth defects was 5.2%. Researchers concluded that babies born to men who used metformin up to 90 days before conception were 1.4 times more likely to have one or more major congenital disabilities.

“It wasn’t just taking metformin at any time in a man’s life; it has to do with taking it in that window when the sperm that is going to become the child is being developed,” said Michael Eisenberg MD, who authored the study. Eisenberg called the study’s results “sobering” and compared the rate of congenital disabilities to those associated with pregnancy after the age of 45.

Babies included in the study exposed to insulin did not show an increased rate of birth defects. However, babies exposed to sulfonylureas showed a similar increase in birth defects compared to those exposed to metformin.

Historically, metformin has been used to counter insulin resistance in the United States since 1995, but the medication was introduced much earlier in Europe, around 1957. Prescription data from 2019 recorded 86 million US metformin prescriptions, which is more than double the number of prescriptions issued in 2004. And as the growing proportion of young men that suffer from diabetes and obesity are prescribed metformin, it’s possible that the rate of birth defects will rise.

Some birth defects have increased in prevalence over time, like gastroschisis, which was 30% more prevalent between 2006 and 2012 compared to 1995 through 2005. It is not yet clear what causes gastroschisis, and it may be related to a combination of genes and other factors.

Certain medications like thalidomide, ACE inhibitors, Accutane, and others have been shown to cause congenital disabilities in the past, and drugs remain one of the primary causes of birth defects. Hereditary genetics is another one of these primary causes, producing roughly 20% of congenital defects.

Down syndrome — a mutation of the chromosomes — is an example of a genetic birth defect, and between 1979 and 2003, the rate of this congenital disability increased by 30%.

Genetic disorders are also the most frequent cause of male infertility, contributing to 10–15% of all infertility cases.

Worldwide, male fertility rates have decreased by 15% in men younger than 30. And according to the National Center for Health Statistics, impaired fecundity has affected a growing number of women. Overall, the US general fertility rate was the lowest on record in 2020, and it amounted to half of the observed fertility rate in 1960.

Recently, infertility has been cited as a growing issue for couples trying to conceive, and around 10% of US couples are defined as infertile because of their inability to do so. In vitro fertilization (IVF) is one assistive reproduction technology that has helped couples conceive who may otherwise have fertility challenges. Still, one study from UCLA has shown that babies born using IVF have an increased risk of congenital disabilities.

The background rate of birth defects has not noticeably increased over time, with 1 in every 33 babies being born with one or more birth defects. And rates of infants dying due to congenital disabilities have decreased by 10% from 2003 to 2017.