Growing Evidence Of Association Between Hypospadias And Certain Drugs, Chemicals

Evidence suggesting an association between certain medications and chemicals and the development of hypospadias is growing in quantity and quality, according to a scoping review that highlights the need for still more research.

For the scoping review, researchers looked at 22,324 studies examining potential association between any medications or chemicals and any form of hypospadias in humans, excluding case reports and animal studies. They then peer-reviewed a subset of papers that found a statistically significant association between exposures to any of these substances in pregnancy and the development of hypospadias in offspring.

"There is mounting evidence for an association between various drugs and chemicals and adverse outcomes, such as increased risk of hypospadias," said Paul Fowler, director of the Institute of Medical Sciences at the University of Aberdeen, in Scotland.

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More research is needed to establish whether these associations reflect causality, what the mechanisms may be, and whether alternative treatments might lower the risk, Fowler, who wasn't involved in the study, said by email.

"Proving causality as opposed to a statistical association is challenging," Fowler said.

Progestins are one potential risk factor for hypospadias identified in the scoping review, which was publised in the Journal of Pediatric Urology. One study in the review, for example, found an almost doubled risk of hypospadias in women who used progestin alone for oral contraception (adjusted odds ratio 1.9).

Dydrogesterone, indicated for prevention of threatened or repeated miscarriages as well as a range of gynecological conditions, was associated with an increased risk of hypospadias (OR 1.28) in a study of women who underwent in vitro fertilization or other forms of artificial reproductive technology.

Utilization of clomiphene citrate (aOR 1.9) alone or in combination with a variety of other fertility agents (aOR 2.2) was also significantly associated with a risk of hypospadias in previous research.

Studies of antidepressants didn't find an association with hypospadias risk, with the exception of venlafaxine (aOR 2.4) in one study.

One antihistamine, loratadine, was also associated with hypospadias (OR 2.39).

Endocrine disruptors have also been tied to hypospadias (OR 3.13), as have polybrominated diphenyl ethers (PBDEs), although an odds ratio wasn't reported in the review.

Study co-author Dr. Gideon Koren of Hebrew University, in Jerusalem, didn't respond to requests for comment.

Many pregnant women may be exposed to these medications or chemicals before realizing they are pregnant, or take certain medicines to promote conception or prevent miscarriage, said Richard Sharpe, of the MRC Centre for Reproductive Health at the University of Edinburgh, in the UK.

Therefore, clinicians should advise women who are trying to conceive to limit exposure to medications, alcohol, and recreational drugs at this time as well as during early pregnancy, Sharpe, who wasn't involved in the study, said by email.

However, it's also possible that underlying medical conditions that lead women to use certain medications might also be the cause of hypospadias, Sharpe added.

"The biggest single risk factor associated with hypospadias is intrauterine growth restriction resulting in low birthweight," Sharpe said. "Considering how common this is, I would always suspect this before anything else."

—Lisa Rapaport

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