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Preconception paternal metformin use linked to major birth defects

7th April 2022

Metformin use by fathers approximately three months prior to conception appears to increase the risk of developing genital birth defects

Metformin use by fathers with diabetes, three months before conception, is linked to an increased risk of birth defects among their offspring. This was the main finding of a study by Danish researchers from the Department of Epidemiology, Biostatistics and Bio-demography, and Interdisciplinary Center on Population Dynamics, University of Southern Denmark, Denmark.

It is already known that diabetic men have a significantly higher percentage of sperm with nuclear DNA damage and which is a factor associated with compromised fertility and increased miscarriage rates.

Furthermore, other research suggests that there is a relationship between male and female diabetes and fecundity (i.e. their ability to produce live offspring) and that early evaluation and treatment may be warranted for diabetics prior to attempting to conceive.

However, as well as men, data also shows that among pregnant women with type 1 diabetes, increasingly worse glycaemic control in the three months before or after estimated conception was associated with a progressively increased risk of major cardiac defects in their offspring.

In men, the entire spermatogenic process is thought to require approximately 74 days and for the present study, the Danish team looked at fathers who had a prescription for any diabetic medication, including insulin, metformin and sulfonylureas, during the three months before conception, which they termed the sperm development period (sDev).

Since diabetes is known to affect sperm, their primary interest was to examine if the use of diabetic medicines might prevent damage to paternal sperm. They used a national patient registry to extract individual-level data and excluded mothers who were diabetic and using diabetic medication at any time prior to birth.

The primary outcome of interest was the diagnosis of 1 or more major birth defects in the first year of life. The authors calculated odds ratios and adjusted for several factors birth year, paternal age, income, education, maternal age and smoking status.

Metformin use and birth defects

A total of 1,116,779 offspring were included in the analysis, of whom, 3.3% had one or more birth defects. A total of 7,029 offspring were exposed to paternal diabetic medication including insulins (5,298), metformin (1,451) and sulfonylureas (647). The main birth defects observed among metformin-exposed offspring were genital defects, all of which occurred in boys.

In regression analysis, the adjusted odds ratio (aOR) for birth defects during the sDev period for insulins was 0.98 (95% CI 0.85 – 1.14), 1.40 (95% CI 1.08 – 1.82, p = 0.012) for metformin and 1.34 (95% CI 0.94 – 1.92) for sulfonylureas.

Interestingly, the frequency of birth defects varied among paternal metformin users at different time points in comparison to the sDev period. For example, longer than 1 year before the sDev, the frequency was 4% but this increased to 4.4% one year before sDev before peaking at 5.2% during sDev.

Moreover, the frequency declined thereafter to 3.3% more than one year after sDev. However, the birth defect frequency was non-significant and no higher than non-metformin users, at all time points other than during sDev.

The authors concluded that preconception use of metformin is associated with major birth defects, particularly genital birth defects in boys, although added that further work was required to confirm these findings.

Wensink MJ et al. Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring. A Nationwide Cohort Study Ann Intern Med 2022.