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Men’s use of diabetes medicine may cause malformations in children

The diabetic preparation metformin may be associated with a risk of malformations if consumed while the sperm for a pregnancy is produced.

By Marianne Lie Becker, , 3/29/2022

A large Danish study shows that children of fathers who take the diabetic preparation metformin during the period when sperm is produced are at increased risk of malformations; in particular, malformations of boys’ genitals.

- Our study suggests that men with diabetes who take metformin might want to consider switching to another preparation before trying to have a baby, says Rune Lindahl-Jacobsen, Professor of Epidemiology and Biodemography at the University of Southern Denmark (SDU).

He and his research group at SDU, along with researchers from Rigshospitalet and Stanford University, USA, have studied data in national registers for the entire Danish population to examine whether the risk of malformations differed in children with fathers treated with the diabetic preparations insulin, metformin or sulfonylurea before conception.

Focus on the role of men in fertility

The results of the study focus on the role of men in fertility.

- 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 Lindahl-Jacobsen says.

Overall, the study puts future fathers’ exposure to environmental pollutants and medication when producing sperm on the agenda in relation to pregnancy planning.

- Traditionally, there has been a focus on women’s exposure during pregnancy and thus children’s risk of malformations, while looking at the men to a lesser extent, he says.

- Therefore, this study is important not just in relation to the large public health perspective, but also as an illustration of the importance of also including the male factor in understanding malformations.

Registers show more malformations

The children, whom the researchers looked more closely at in the study, were identified based on if the fathers had filled at least one prescription during the three months, leading up to the pregnancy, in which the sperm was produced.

The researchers examined risk of malformations in children in connection with the use of the various diabetic preparations using available data in the National Patient Register and the Pharmaceutical Statistics Register.

Among all of the 1,116,779 children in the study (all children born in Denmark between 1996 and 2016 by mothers who did not have diabetes), 3.3 percent had a malformation. By contrast, 5.2 percent had malformations if the fathers took metformin.

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

Rune Lindahl-Jacobsen, professor

Children whose fathers took insulin did not have a higher rate of malformations than the control group. There were too few children whose fathers took sulfonylurea to assess the risk to these children.

- 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, Rune Lindahl-Jacobsen emphasises.

Need for thorough consideration

According to the authors, the extent of the diabetes pandemic suggests that the treatment of possibly future fathers with diabetes should be subject to further study in terms of both pharmacological treatment and the importance of diet, physical exercise and weight loss.

- 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, says Elisabeth R Mathiesen, Professor at the University of Copenhagen and Chief Physician at Rigshospitalet, where she researches diabetes and pregnancy.

- 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, she says.

The Danish Medicines Agency and the Danish Health Authority have been briefed on the study.

Key figures from the study

The number of children with malformations whose fathers took metformin was 5.2 percent, while the number of children with malformations whose fathers did not take metformin was 3.3 percent. This corresponds to an increased risk of 40 percent or a risk factor of about 1.5.

Between 1996 and 2016, 1,451 fathers who took metformin in the months leading up to conception had 75 children with birth defects. Most of the malformations are in the genitals of male children, who have three times the risk of malformations.

In 2020, 5,800 men aged 25-44 in Denmark were taking metformin for diabetes.
Overall, the study shows no increased risk of malformations in children of fathers taking metformin. Only during the three-month period leading up to conception, when the sperm are formed.

Meet the researcher

Rune Lindahl-Jacobsen is a Professor at the Department of Public Health.


Editing was completed: 29.03.2022