Men taking metformin during sperm development and within a few months of their partner getting pregnant are at a higher risk of having children with birth defects, a new study reveals.
“We can see that while 3.3 percent of Danish Children are generally born with malformations, 5.2 percent of children whose fathers took the preparation metformin, which is the most widely used diabetes preparation, in the months leading up to the mother becoming pregnant, are born with malformations,” Rune Lindal-Jacobsen, professor of epidemiology and biodemography at the University of Southern Denmark (SDU) said in a press release.
The study, “Preconception antidiabetic drugs in men and birth defects in offspring,” was published in Annals of Internal Medicine.
Diabetes reduces sperm quality and is associated with impaired male fertility, so, proper blood sugar control is crucial to preserve fertility. Metformin, the first-line oral diabetes drug, improves blood sugar control but reduces testosterone levels and possibly sperm quality. However, it is unknown if metformin’s effect on testosterone and sperm quality increases children’s risk of birth defects.
Notably, it takes approximately three months for sperm to fully mature to fertilise an egg. So, men taking diabetes medication within three months of their partner getting pregnant may be at a higher risk of having reduced testosterone and, consequently, poor sperm quality. Now, a team of scientists in Denmark investigated whether men taking diabetes medication, including metformin, within three months of their partners conceiving are at a higher risk of having children with birth defects.
The scientists searched the Danish Medical Birth Registry to identify parents and babies born between 1997 and 2016 and their conception date. They also explored the patient registry to identify babies diagnosed with birth defects and the prescription registry to identify men redeeming diabetes prescriptions within the three months leading up to conception between 1995 and 2018. Any child born to mothers taking any type of diabetes medication before giving birth was excluded.
A total of 1, 116779 children were included in the analysis. Of the total cohort, 3.3% had one or more major birth defects, and 51.4% were male. A total of 7029 children were exposed to their father’s diabetes medications, including insulin, metformin and sulfonylureas.
The rate of birth defects in children born to fathers not taking any diabetes medication was 3.2%, which was similar to the rate of birth defects in children exposed to insulin at 3.3%. However, the rate of birth defects in children exposed to metformin was 5.2% and 5.1% in those exposed to sulfonylurea. Notably, 44.2% of fathers taking sulfonylureas also used metformin.
While insulin use was not associated with an increased risk of birth defects, metformin increased the risk of having a child with birth defect by 40%, and sulfonylureas increased the risk by 34%. Children, exclusively boys, exposed to metformin had higher rates of genital birth defects compared to the rest of the cohort. Interestingly, genital birth defects rates were not increased in children exposed to sulfonylureas.
“The current report found elevated birth defect frequencies among metformin-exposed offspring…but not among insulin exposed offspring, unexposed siblings… Metformin-exposed offspring more often had a genital birth defect, all in boys….Sulfonylureas showed a similar association but lacked statistical significance and specificity to a birth defect category,” the researchers wrote.
It is also worth noting that only metformin use during sperm development was associated with birth defects. Birth defect risk declined to normal levels if metformin was taken more than a year before or after sperm development, meaning that metformin use is not generally unsafe.
“Metformin taken before or after sperm production did not make for an increased risk of malformations, meaning we are certainly not arguing against the use of metformin in general,” Lindahl-Jacobsen said.
However, men may want to carefully consider the timing of metformin use and choice of medication before having children.
“Our study suggests that men with diabetes who take metformin might want to consider switching to another preparation before trying to have a baby,” Lindahl-Jacobsen added.
“It has been known for many years that metformin can inhibit levels of the male sex hormone testosterone, and animal studies have raised suspicions that metformin may affect the quality of sperm cells.
Based on these worrying observations in humans, it is recommended to carefully weigh the possible pros and cons before starting metformin treatment in men of childbearing age until metformin’s influence on malformations in future children is confirmed or refuted,” Elisabeth Mathiesen, professor at the University of Copenhagen and Chief Physician at Rigshospitalet said.
Further research is needed to confirm the findings of this study and determine the pathways involved in metformin’s possible effect on genital birth defects in male children.