Clomiphene and hypospadias on a detailed level: signal or chance?

Background: Clomiphene, a drug used to induce ovulation, is chemically related to diethylstilbestrol (DES). DES is associated with vaginal cancer and infertility among daughters and with hypospadias among second-generation male offspring. Because clomiphene has a long half-life and metabolites have been found in feces up to 6 weeks after administration, fetal exposure is possible if the mother took this drug prior to becoming pregnant.

Methods: Case-control analyses were performed to investigate the association between clomiphene exposure and hypospadias. Cases were all male subjects registered in the European Concerted Action on Congenital Anomalies and Twins (EUROCAT) Northern Netherlands registry for congenital anomalies with nonsyndromal hypospadias. Controls were all male children born without hypospadias, including those with chromosomal and monogenic defects. Logistic regression analyses were performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Of 392 cases, 7 (1.8%) were exposed to clomiphene compared with 64 of 4538 controls (1.4%). For penoscrotal hypospadias, we found that the OR was significantly increased (6.08; 95% CI, 1.40-26.33); for the mild and moderate forms of hypospadias, the ORs were not increased.

Conclusions: Because penoscrotal hypospadias is rare, the effect is diluted when all forms of hypospadias are studied as a group. Therefore, our study stresses the importance of studying birth defects on as detailed a level as possible. Other studies should be conducted to confirm our findings.