OTC Painkillers Tied To Undescended Testes


From Human Reproduction

Women who take over-the-counter painkillers during pregnancy have an increased risk of having sons born with undescended testes, according to a study that also incorporates rat models to show why this might be.

Using data from a birth cohort study of singleton sons born to 1,463 women in Finland and 834 in Denmark, all of whom either completed written questionnaires or telephone interviews or both, the researchers, led by Henrik Leffers, Ph.D., of Rigshospitalet in Copenhagen, found the risk of cryptorchidism to increase sevenfold in boys born to women who used more then one of three over-the-counter painkillers – aspirin (acetylsalicylic acid), acetaminophen (paracetamol), or ibuprofen – simultaneously during their pregnancies.

Exact doses of the painkillers were not recorded.

The findings, published online Nov. 8 in the journal Human Reproduction (doi:10.1093/humrep/deq323), also showed that any of these painkillers that were used for any duration during the second trimester more than doubled the risk of cryptorchidism, although the association for acetaminophen did not reach statistical significance.

The highest risk was observed, Dr. Leffers and his colleagues reported, among women who used more than one compound simultaneously for more than 2 weeks in the second trimester (adjusted odds ratio, 21.7 [1.83-258]).

A possible mechanism for this effect, Dr. Leffers and his colleagues hypothesized, was demonstrated by some of the study's coauthors, who found in a linked investigation that intrauterine exposure to acetaminophen, at three times the recommended dose for humans, led to a reduction in anogenital distance among fetal rats, and also reduced testosterone production by about half in fetal rat testes.

Aspirin was also tested in rats, but the results were not conclusive.

“A particular strength of this study is the use of two complementary rat models to support the contention that the association between analgesic use and cryptorchidism seen in our cohort study may result from a reduction in androgen production,” Dr. Leffers and his colleagues wrote.

Their study adds to findings published earlier this month (Epidemiology 2010;21:779-85) from a cohort of 47,000 boys born in Denmark, 980 of whom were identified in childhood as having cryptorchidism. That study, which also looked at acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy through telephone interviews and questionnaires with mothers, saw exposure to acetaminophen during both the first and second trimesters associated with increased cryptorchidism (hazard ratio, 1.33).

Acetaminophen exposure of more than 4 weeks between the 8th and 14th gestational weeks was associated with an HR of 1.38. However no association was found for either ibuprofen or aspirin.

Dr. Leffers and his colleagues' study found all but one of their statistically significant associations in the Danish part of their cohort, and speculated that differences in design of the Finnish and Danish cohort studies may have been partly responsible.

Although the Finnish questionnaire asked respondents to list only which medications were taken and when, the Danish telephone interviews asked the most pointed questions about over-the-counter and prescription pain medications, including which products were used in which weeks of pregnancy.

Although just more than a quarter (26%) of the Danish mothers who responded to the written questionnaire said that they had used mild analgesics, more than half (56%) of those interviewed by telephone said the same.

“These findings indicated that many mothers did not consider mild analgesics as medication and hence strongly underreported their use unless specifically asked. We therefore only included the data from the computer-assisted telephone interview from the Danish part of the study,” the investigators wrote.

In a press release accompanying the study, Dr. Leffers said that a “single paracetamol tablet (500 mg) contains more endocrine disruptor potency than the combined exposure to the 10 most prevalent of the currently known environmental endocrine disruptors during the whole pregnancy.”

Men who are born with cryptorchidism, the researchers noted, see an increased risk of having poor semen quality and testicular germ cell cancer.

Dr. Leffers and his colleagues' study was funded by European Commission and French government grants, the Villum Kann Rasmussen Foundation, and Novo Nordisk.

None of its authors declared conflicts of interest.

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