Diabetes and congenital pathologies

Metformin intake before conception was associated with genital abnormalities in offspring

Polina Loseva, N+1

Danish children whose fathers take metformin shortly before conception have an increased risk of being born with developmental abnormalities. This effect is especially noticeable for abnormalities in the development of the genitals in boys. These conclusions were reached by Danish doctors who published their calculations in the journal Annals of Internal Medicine (Wensink et al., Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring A Nationwide Cohort Study). They warn that the number of children with such birth defects may grow — because metformin is often prescribed for diabetes, and the number of diabetic patients is constantly growing.

Metformin is a popular remedy for type 2 diabetes, and it is likely to become more and more popular in the future. There are two reasons for this. Firstly, risk factors for type 2 diabetes are, among others, obesity and age. There are more and more overweight people, and the average life expectancy in many countries is growing — therefore, we can expect that the number of metformin users will also grow.

Secondly, many aging researchers pin their hopes on metformin as a way to increase life expectancy even more. The fact is that metformin blocks one of the intracellular energy sensors, that is, it prevents the cell from feeling that food has entered it. This not only forces the cell to capture more glucose from the outside (that is, it saves from diabetes), but also encourages it to spend less energy. From this, less molecular debris accumulates in the cell, which means that metformin could theoretically prolong life. So far, however, it has not been approved in this capacity, and its clinical trials are just beginning. But if he shows himself well in them, then the number of his consumers will grow at the expense of people who do not suffer from diabetes.

However, metformin, like any other drug, has side effects. For example, doctors have noticed that it reduces the level of testosterone in the blood. Therefore, Maarten J. Wensink from The University of Southern Denmark together with colleagues decided to test whether metformin affects offspring from fathers who take it.

To do this, the researchers collected data from the national medical register on all children who were born in Denmark from 1997 to 2016. Doctors were interested in those children who had a medical history available, the parents were known, and the mother did not have diabetes or hypertension. There were 1,116,779 children in total.

For each father, the researchers took into account whether he had diabetes or not, if so, what type (first or second type), and what drug he received (insulin, metformin, sulfonylurea or others). In addition, they recorded how long before the expected date of conception of the child, the father received the last prescription for his medicine. Assuming that after receiving the prescription, the person started taking his drug, the authors of the work thus took into account whether the drug could affect the formation of sperm. Since the development time of one sperm in the body is about three months, they suggested that in the body of fathers who received a prescription a couple of months before conception, metformin could directly affect the maturing sperm.

After that, doctors calculated the number of congenital anomalies in children from the database. And then we calculated the odds ratio — how many times the chance of developing a particular defect is higher in children from fathers who took medications compared to the control (children whose parents did not take anything).

This odds ratio was highest (1.40) for fathers who took metformin. Sulfonylurea preparations were in second place (1.34), but the authors did not consider this result statistically significant (p=0.107). Taking insulin was not associated with any abnormalities. Moreover, the correlation was observed only in cases when the father took metformin during the maturation of sperm, that is, in the last months before conception. After recalculating the odds ratio for specific anomalies, the researchers found that it was highest (3.39) for metformin and defects in the development of the reproductive system, and only in boys.

The absolute number of children born with specific abnormalities was small — for example, fathers who took metformin had only 13 boys with genital abnormalities. However, the relative chances of this happening turned out to be quite high. And the authors of the work warn that this number may grow as more and more people take metformin.

The exact mechanism of this influence is still unknown. It can only be assumed that metformin affects sperm cells, and not other aspects of the physiology of men — since other children who were born in the same marriages, but not at the moment when the father took metformin, the frequency of anomalies did not differ from the average.

Nevertheless, this correlation fits perfectly into modern ideas about the mechanisms of aging. If metformin inhibits energy consumption in cells, then it should negatively affect reproduction — because it requires cells to actively divide and grow. At least, gerontologists consider other hypothetical methods of prolonging life (such as calorie restriction) incompatible with reproduction, and do not recommend such restrictive diets, for example, to pregnant women.

Earlier we wrote that metformin can probably reduce the risk of developing dementia. And also about how it began to be included in experimental cocktails to prolong life. So, in one study, it, together with other drugs, increased the life span of flies, and in another, also as part of a cocktail, reduced the epigenetic age of patients.

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