More data show increase in male genitalia anomalies

In 2002 a Dutch group reported a 21.3-fold increased risk of hypospadias among the offspring of women who had in utero exposure to DES (Lancet 2002; 359:1102-7). However, the results of that study raised questions related to patient selection and the appropriateness of the control group, said Wouter Feitz, MD, PhD, a pediatric urologist at Radboud University Nijmegen Medical Center in Nijmegen, the Netherlands.

The results showed that 3.3% of the patients' mothers had in utero DES exposure, compared with 1.2% of the reference group. The difference translated into an odds ratio of 2.8 for the association between DES exposure and hypospadias. Adjustment for confounding factors resulted in an odds ratio of 2.2. Fathers' exposure to DES did not influence the risk of hypospadias, as the incidence of DES exposure was 1.7% for fathers of patients and 1.4% in the reference group.

"DES exposure may affect reproductive structures and functions, which could be essential for normal genital development," Dr. Feitz said. "Male genital development may be disturbed by external exposures, such as medication and assisted reproductive techniques."

The results raise two questions that remain to be resolved, he added. The first question pertains to whether the findings represent a transient generational effect or one that might be passed on to future generations. Dr. Feitz said the answer will not be known for another 20 or 30 years. Also unresolved is the issue of whether the sisters of the hypospadias patients might be affected by their mothers' in utero exposure to DES.

U.S. data: Linear increase Findings from the second study of incidence of penile anomalies came from a review of the Nationwide Inpatient Sample, a 20% sample of U.S. hospitals containing data on 5 to 7 million inpatient stays per year. The database was queried for all newborn male admissions, and ICD-9 codes were used to identify those newborns with penile anomalies. The analysis covered 4- to 5-year intervals between 1988 and 2000.

"Several studies over the past 10 to 15 years have suggested that hypospadias might be increasing in incidence," said Caleb Nelson, MD, a former urology resident at the University of Michigan, Ann Arbor, working with John Wei, MD. "It's not clear whether those findings are real or just an artifact. We wanted to look at this very large national database to see whether we could gain more insights into the reported increase in penile anomalies."

The analysis identified 4.84 million newborn males, 37,577 of whom had congenital penile anomalies, an overall incidence rate of 7.8 per 1,000 newborns. The incidence increased in a nearly linear fashion from 7.0 per 1,000 newborns presenting between 1988 and 2001 to 8.3 per 1,000 for the period 1997 to 2000 (p<.0001).

The most common diagnosis was hypospadias, which accounted for 68.3% of all the anomalies. Next in order of frequency was chordee (8.6%), followed by hypospadias with chordee (5%).