Risk factors for hypospadias

The associations found in this study support the hypothesis that genetic predisposition, placental insufficiency, and substances that interfere with natural hormones play a role in the etiology of hypospadias

2007 Study Abstract

Despite being one of the most common congenital defects in boys, the etiology of hypospadias remains largely unknown. In this case-referent study, we evaluated a wide spectrum of potential risk factors for hypospadias. Cases were identified from the hospital information system, and referents were recruited through the parents of the cases. Both parents of cases and referents completed written questionnaires that they received through the mail. Logistic regression analyses were used to assess the independent contribution of different factors to the risk of hypospadias. The final database included 583 cases and 251 referents.

Hypospadias more often occurred in children whose father had hypospadias (OR=9.7; 95%CI: 1.3-74.0) and in children with a low birth weight (OR=2.3; 95%CI: 1.2-4.2). Indications for elevated risks were found when mothers were DES-daughters (OR=3.5; 95%CI: 0.8-15.6), fathers were subfertile (OR=1.8; 95%CI: 0.7-4.5), the parents had undergone fertility treatment (OR=2.3; 95%CI: 0.9-5.8), and in twin or triplet pregnancies (OR=2.0; 95%CI: 0.8-5.1). Maternal use of iron supplements (OR=2.2; 95%CI: 0.8-6.0), maternal smoking (OR=1.5; 95%CI: 1.0-2.4), paternal prescriptive drug use (OR=2.6; 95%CI: 1.1-6.6), and paternal exposure to pesticides (OR=2.1; 95%CI: 0.6-7.1) during the 3 months immediately prior to conception or in the first trimester of pregnancy also appeared to increase the risk of hypospadias.

A strong indication for an increased risk of hypospadias was found among boys whose mothers were exposed to DES in utero – ‘DES-daughters’ – an association reported in a previous article by our group. In 2002, Klip et al. reported the prevalence ratio for hypospadias in sons of DES-daughters to be 21.3 (95%CI: 6.5–70.1), which was the first suggestion of a transgenerational effect of DES in humans. However, the association between intrauterine DES exposure and hypospadias was assessed in a cohort of women with fertility problems, who do not reflect DES-daughters in general. According to our findings, the excess risk of hypospadias appears to be of a much smaller magnitude. This may be explained by the differences in study design, and in the study population in particular, and probably results in a more valid risk estimate that is concordant with findings from a recent study in France. It is possible that DES-related pathology of reproductive structures in DES-daughters interferes with normal fetal development during pregnancy, but other explanations have been suggested as well.

We found no indication that DES-sons ‘transmit’ a predisposition to hypospadias to their sons. Our results also point towards an association between paternal subfertility and hypospadias.



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