Reactions 896 - 6 Apr 2002

Maternal in utero diethylstilbestrolincreases hypospadias in offspring

Women who were exposed to diethylstilbestrol inutero are marginally, but significantly, more likely toproduce sons with hypospadias, according toresearchers from The Netherlands.1

In their study, 16 284 women, who had beendiagnosed with fertility disorders, returned aquestionnaire designed to identify offspring withhypospadias. Cumulatively, these women reportedgiving birth to 8934 sons. In utero exposure todiethylstilbestrol was reported in the mothers of 205boys, 4 of whom had hypospadias. In contrast, only 8 ofthe remaining 8729 boys had hypospadias, giving aprevalence ratio of hypospadias following maternal inutero exposure to diethylstilbestrol of 21.3 (95% CI6.5–70.1).

The researchers note that the cases of hypospadias inboys with mothers exposed to diethylstilbestrol in uterowere more severe than for the other 8 cases, and thathydrocephalus was also present in one of the boys. Therisk of hypospadias was unaffected by potentialconfounding factors, including maternal age at birth andfertility treatment.

The researchers point out that their conclusions arebased on a small number of cases, and that the absoluterisk of hypospadias associated with maternal in uteroexposure to diethylstilbestrol is low. They acknowledgethe limitations inherent in questionnaire-basedretrospective studies, and advise that their findings needconfirmation with further epidemiological research.

Transgenerational factors not consideredIn an accompanying commentary, Sonia Hernandez-

Dıaz, from the Boston University School of PublicHealth in the US, says that potential transgenerationalconfounding factors affecting both prenatal maternalexposure to diethylstilbestrol and the risk ofhypospadias in the index child were not considered inthe study.2 She comments that there is evidence thathypospadias are more common in sons born tosubfertile woman and points out that ‘results from aselected cohort of subfertile women might not begeneralisable to all diethylstilbestrol-exposed women’.She does, however, say that the findings are ‘intriguing’,and that further research on exposure todiethylstilbestrol may provide insight into currentconcerns regarding exposure to weaker estrogens.1. Klip H, et al. Hypospadias in sons of women exposed to diethylstilbestrol in

utero: a cohort study. Lancet 359: 1102-1107, 30 Mar 2002.2. Hernandez-Dıaz S. Iatrogenic legacy from diethylstilbestrol exposure. Lancet

359: 1081-1082, 30 Mar 2002.800888238

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Reactions 6 Apr 2002 No. 8960114-9954/10/0896-0001/$14.95 Adis © 2010 Springer International Publishing AG. All rights reserved