Women taking nonprescription 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 used for any duration during the second trimester more than doubled the risk of cryptorchidism, though 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. Though just more than a quarter (26%) of the Danish mothers responding to the written questionnaire said 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: “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 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.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

 

据一项包括大鼠模型(用来解释可能的机制)的研究显示，女性在怀孕期间使用非处方止痛药可增加其儿子发生先天性隐睾症的风险。

 

该研究由Henrik Leffers博士带领完成，是一项对1,463名芬兰女性和834名丹麦女性的独生子所进行的出生队列研究，所有受试者均完成了书面问卷调查或电话访问，或以上两者兼而有之。

 

通过对数据进行分析发现，女性在怀孕期间同时使用阿司匹林(乙酰水杨酸)、对乙酰氨基酚(扑热息痛)或布洛芬这3种非处方止痛药中至少一种时，所生的男孩发生隐睾症的风险会增加7倍。另外，在孕中期使用以上所列的任何一种止痛药(不计使用时间长短)均会使隐睾症风险增加2倍以上，不过该病与对乙酰氨基酚的相关性未达到统计学意义；在孕中期同时使用一种以上的止痛药持续超过2周的女性中风险最高 (调整后的比值比，21.7 [1.83~258])。

 

一项相关研究显示，在大鼠子宫内含有3倍于人类推荐剂量的对乙酰氨基酚时可缩短胎鼠肛门与生殖器之间的距离，同时有半数胎鼠睾丸内的睾酮分泌量减少。在本研究补充的2个大鼠模型中所得的数据支持止痛药与隐睾症之间的关系可能与雄激素分泌减少有关这一观点。

 

本月早期发表的一项对47,000名出生于丹麦的男孩(其中有980例在儿童期被确诊患有隐睾症)所进行的队列研究 (Epidemiology 2010;21:779-85)表明，在孕早期和孕中期均使用对乙酰氨基酚可增加隐睾症的发病率(风险比=1.33)；若在第8个和第14个孕周之间使用对乙酰氨基酚超过4周，则风险比(HR)可达到1.38，但在布洛芬和阿司匹林中未发现有此种相关性。本研究对此研究的结果做了进一步的补充。

 

Leffers博士及其同事所进行的研究获得了欧洲委员会和法国政府、Villum Kann Rasmussen基金会以及诺和诺德公司的资助。作者们均无利益冲突的披露。

 

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