Differences in risk factors for second and third degree hypospadias in the national birth defects prevention study

Hypospadias is a frequent birth defect with three phenotypic subtypes. With data from the National Birth Defects Prevention Study, a large, multi-state, population-based, case-control study, we compared risk factors for second and third degree hypospadias.

A wide variety of data on maternal and pregnancy-related risk factors for isolated second and third degree hypospadias was collected by means of computer-assisted telephone interviews to identify potential etiological differences between the two phenotypes. Logistic regression was used to calculate odds ratios including a random effect by study center.

In total, 1547 second degree cases, 389 third degree cases, and 5183 male controls were included in our study. Third degree cases were more likely to have a non-Hispanic black or Asian/Pacific Islander mother, be delivered preterm, have a low birth weight, be small for gestational age, and be conceived with fertility treatments than second degree cases and controls. Associations with both second and third degree hypospadias were observed for maternal age, family history, parity, plurality, and hypertension during pregnancy. Risk estimates were generally higher for third degree hypospadias except for family history.

Most risk factors were associated with both or neither phenotype. Therefore, it is likely that the underlying mechanism is at least partly similar for both phenotypes. However, some associations were different between second and third degree hypospadias, and went in opposite directions for second and third degree hypospadias for Asian/Pacific Islander mothers. Effect estimates for subtypes of hypospadias may be over- or underestimated in studies without stratification by phenotype.