New research from Europe found that women who took a combination of more than one type of mild painkiller like paracetamol, aspirin and ibuprofen, during pregnancy, or who took at least one of these during the second trimester, were more likely to have sons with cryptorchidism, commonly known as undescended testicles, a condition associated with poor sperm quality, and a type of testicular cancer later in life.

The researchers said this might partly explain the rise in male reproductive disorders we have seen in the last few decades.

You can read about the study by researchers from Denmark, Finland and France, and led by Dr Henrik Leffers, senior scientist at the Rigshospitalet in Copenhagen, in the 8 November issue of the journal Human Reproduction.

Cryptorchidism is where a testicle fails to descend from within the abdomen into the scrotum before a baby boy is born. Usually only one testicle is affected, but sometimes it can happen to both. The problem usually corrects itself in the first few months of life.

Baby boys can be born with a mild form of the condition, where the testicle is located high in the scrotum, or a severe form, where it sits high in the abdomen and can't be felt from the outside at all, and there are also forms in between.

The researchers noted there has been a marked increase in cases of cryptorchidism in the last few decades: for example in Denmark it has gone up from 1.8 per cent in 1959-1961 to 8.5 per cent in 1997-2001.

They said the increase is too big to be explained by random fluctuations and differences in public health surveillance.

"Moreover, this finding is in accordance with the reported decline in reproductive health in the adult male population over the past five decades," they wrote.

Leffers and colleagues found that women who used more than one painkiller at the same time, for example paracetamol (also known as acetaminophen) and ibuprofen, were seven times more likely to give birth to boys with some form of cryptorchidism compared to women who took no painkillers.

They also found that the second trimester, that is during weeks 13 to 28 of the pregnancy, appeared to be a particularly sensitive time. While the size of the risk varied with individual painkillers, their analysis showed that taking analgesic during these weeks was linked to more than double the risk of cryptorchidism.

Of the individual painkillers, the researchers found that taking ibuprofen or aspirin during the second trimester approximately quadrupled the risk of cryptorchidism, while paracetamol doubled it, although this was not statistically significant.

However, using more than one painkiller at the same time during the second trimester was linked to a 16-fold higher risk of cryptorchidism.

For the study, Leffers and colleagues used data taken from two groups of women: 834 in Denmark, and 1,463 in Finland, who enrolled after they became pregnant. When their baby boys were born, they were examined for presence and severity of cryptorchidism.

The women in Finland completed written questionnaires that asked them about their use of medication during pregnancy, while the women in Denmark did the same, or were interviewed over the phone, or both.

The researchers found no statistically significant link between reported use of painkillers in pregnancy and risk of cryptorchidism in the Finnish cohort, but they did in the Danish one. They suggested this was because of two things: the Finnish women under-reported use of painkillers, and the prevalence of cryptorchidism in Finland is lower than in Denmark (2.4% vs 9.3%), so you need a larger group to find the same number of cases.

The under-reporting of painkiller use among the Finnish women was put down to the fact they only filled in written questionnaires, and this may have led them to not class mild painkillers as "medication". The telephone interviews asked detailed questions about use of painkillers.

For example, of the 298 Danish women who completed both the written questionnaire and the telephone interview, only 30.9 per cent reported using painkillers in their written responses, while 57.2 per cent reported doing so in the telephone interview responses.

The findings were supported by another piece of work that some of the researchers did on rats.

Dr Ulla Hass at the Technical University of Denmark in Søborg, and Dr Bernard Jégou from INSERM (Institut National de la Santé at de la Recherche Médicale) at the University of Rennes in France, found that the painkillers disrupted the production of male hormones, reducing levels of testosterone during the crucial period when the male organs are formed in the fetus.

They said the effect was similar to that caused by known endocrine hormone disrupters such as phthalates, a group of chemicals unsed in the manufacture of PVC and other plastics.

Leffers said if this same mechanism is the cause of increasing reproductive problems among young men in the industrialized world, then we need to look at the use of mild painkillers in pregnancy, as "this could be a major reason for the problems".

The researchers found that exposure to the mild painkillers while in the womb reduced the distance between the anus and the genitals (AGD: anogenital distance) in the male rat offspring. AGD in newborns is a recognized marker for levels of male hormone in the womb environment, and changes in this measure predict increased risk of a range of reproductive problems in adult males.

The researchers found that exposure to mild analgesics while in the womb reduced the levels of testosterone in the unborn rats by about 50 per cent.

Jégou said we don't know much about the underlying mechanism, which could be related to inhibition of prostaglandins, a group of messenger molecules. He said in another study, some of the same researchers found that phthalate endocrine disruptors are almost as strong at inhibiting production of prostaglandins as drugs like mild painkillers:

"However, currently we do not know how a reduction of prostaglandin synthesis can reduce testosterone production," he added.

The researchers said the risk from mild painkillers appears to be much higher than that from known endocrine disrupters like phthalates, and as most women in industrialized nations are inevitably exposed to low levels of endocrine disrupters, add to that the effect from mild painkiller use, and the combination might explain the increased rate of cryptorchidism and later life male reproductive problems we have been seeing in recent decades.

Leffers said that a single 500 mg paracetamol tablet had a stronger effect as an endocrine disrupter as being exposed for the whole of a pregnancy to ten of the most common known endocrine disrupters.

"In fact, a single tablet will, for most women, be at least a doubling of the exposure to the known endocrine disruptors during the pregnancy and that dose comes on a single day, not spread out over nine months as with the environmental endocrine disruptors," said Leffers.

"Thus, for women using mild analgesics during the pregnancy, the mild analgesics will be by far the largest exposure to endocrine disruptors," he added.

The researchers said more studies are needed and that the advice currently given to pregnant women should be revised.

In the meantime, Leffers said they "recommend that pregnant women seek advice from their physician before using mild analgesics and in general follow the advice to use as little medicine during pregnancy as possible".

"Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat."
David Møbjerg Kristensen, Ulla Hass, Laurianne Lesné, Grete Lottrup, Pernille Rosenskjold Jacobsen, Christele Desdoits- Lethimonier, Julie Boberg, Jørgen Holm Petersen, Jorma Toppari, Tina Kold Jensen, Søren Brunak, Niels E. Skakkebæk, Christine Nellemann, Katharina M. Main, Bernard Jégou, and Henrik Leffers.
Hum. Reprod. deq323, first published online 8 November 2010
DOI:10.1093/humrep/deq323

Additional sources: European Society of Human Reproduction and Embryology, Mayo Clinic.

Written by: Catharine Paddock, PhD