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Boston Additional data to estimate the teratogenicity of metformin in the male reproductive phase and in the first trimester are provided by two parallel studies published in the journal Annals of Internal MedicineFor example, exposure of women to metformin in the early stages of pregnancy was harmless for the offspring (2024; DOI: 10.7326/M23-1405).

Metformin is a standard medication for treating type 2 diabetes. Continuing treatment with metformin is conceivable during pregnancy, at least for some preparations. It is used off-label for gestational diabetes and polycystic ovary syndrome.

Due to the limited data available, it is still not clear whether women with type 2 diabetes who take metformin in early pregnancy are at risk of malformations. Metformin crosses the placenta and produces similarly high concentrations in the fetus.

A large cohort of 12,489 pregnant women with pre-existing type 2 diabetes who either continued treatment with metformin and received insulin in addition or switched to insulin monotherapy within 90 days of their last menstrual period was examined. 850 women in the insulin monotherapy group and 1,557 in the insulin plus metformin group were evaluated.

The estimated risk for non-live births was 32.7% with insulin monotherapy (reference) and 34.3% with insulin plus metformin (risk ratio 1.02, 95% confidence interval (95% CI) 1.01 to 1.04). The estimated risk for congenital malformations was 8.0% with insulin monotherapy and 5.7% with insulin plus metformin (risk ratio 0.72, 95% CI 0.51 to 1.09).

According to the study authors, there is no evidence of an increased risk of non-live births or malformations in a metformin-containing regimen. The study confirms the assumption that metformin exposure in early pregnancy is harmless, commented Susanne Reger-Tan, senior physician and head of the diabetes center and nutritional medicine at the Clinic for Endocrinology, Diabetology and Metabolism at the University Hospital in Essen. Reger-Tan, however, cites methodological criticisms of this study, namely that metformin prescriptions were evaluated instead of metformin intake and documentation of malformations were evaluated instead of observed malformations.

For Wolfgang Paulus, senior physician and head of the advisory center for reproductive toxicology at the University Women’s Hospital in Ulm, the timing of the randomization was also unfortunate. A large part of the child’s organ development takes place in the first 90 days after the last menstrual period. If the collectives are divided up late, it is not surprising that no differences in the rates of malformations in children can be seen between the two groups, according to Paulus’ assessment.

In the overall view with other studies, for example on the long-term safety of metformin-exposed children (5-11 years) during pregnancy with regard to their weight (Endocrine Practice2024; DOI: 10.1016/j.eprac.2024.05.017), the current data complement and support the safety of metformin with regard to short-term effects on mother and child.

Since the long-term effects on children’s weight were also observed to be opposite to those with higher BMI (PLOSMedicine2019; DOI: 10.1371/journal.pmed.1002848), the long-term effects continue to offer potential for controversial discussions.

Since metformin can cross the placenta, I think it is still necessary to exercise caution in its use until the long-term effects that have been reported are further clarified, says Rachel Lippert, head of the junior research group Neural Circuits at the German Institute of Human Nutrition (DIfE) in Potsdam-Rehbrück.

Experts such as Michael Zitzmann, senior physician and specialist in internal medicine/endocrinology and andrology at the University Hospital in Münster, nevertheless advocate reconsidering the guidelines if necessary.

In light of these findings, the study may indeed provide grounds for a revision of current recommendations for metformin in pregnant women with type 2 diabetes. Such a revision could reconsider the practice of switching to insulin therapy and allow the continuation of metformin, which could bring benefits such as better glycemic control, reduced maternal weight gain, and possibly lower costs and less invasiveness compared to insulin therapy, commented Zitzmann.

So far, the current S2e guideline on diabetes in pregnancy of the German Diabetes Society from 2022 only considers metformin in individual cases of severe insulin resistance.

In the study published in parallel, almost 400,000 children of men with type 2 diabetes who had taken metformin during the sperm production phase were examined. Here, too, no significantly increased incidence of major congenital malformations was observed. However, the study authors point out that men with an increased risk of cardiovascular disease who took metformin could represent a risk factor for malformations in children.

In addition, they found an increased incidence of malformations in the offspring of fathers who received antidiabetic polytherapy. This increase could possibly be attributed to generally poorer metabolic health, the study authors explain.

In summary, the mechanisms by which paternal metformin exposure might affect offspring health are a combination of genetic, epigenetic, metabolic and hormonal mechanisms, said Raffaele Teperino, research leader of the Environmental Epigenetics Group, Institute of Experimental Genetics, Helmholtz Diabetes Center, Munich and German Center for Diabetes Research (DZD).

According to Teperino, further research is needed to fully understand these mechanisms and their long-term effects on offspring health. © cw/aerzteblatt.de