Altitude as a risk factor for the development of hypospadias. Geographical cluster distribution analysis in South America

Objective Hypospadias is the most common congenital anomaly affecting the genitals. It has been established as a multifactorial disease with increasing prevalence. Many risk factors have been identified such as prematurity, birth weight, mother's age, and exposure to endocrine disruptors. In recent decades multiple authors using surveillance systems have described an increase in prevalence of hypospadias, but most of the published literature comes from developed countries in Europe and North America and few of the published studies have involved cluster analysis. Few large-scale studies have been performed addressing the effect of altitude and other geographical aspects on the development of hypospadias. Acknowledging this limitation, we present novel results of a multinational spatial scan statistical analysis over a 30-year period in South America and an altitude analysis of hypospadias distribution on a continent level. Method A retrospective review was performed of the Latin American collaborative study of congenital malformations (ECLAMC). A total of 4,020,384 newborns was surveyed between 1982 and December 2011 in all participating centers. We selected all patients with hypospadias. All degrees of clinical severity were included in the analysis. Each participating center was geographically identified with its coordinates and altitude above sea level. A spatial scan statistical analysis was performed using Kulldorf's methodology and a prevalence trend analysis over time in centers below and above 2000 m. Results During the study period we found 159 hospitals in six different countries (Colombia, Bolivia, Brazil, Argentina, Chile, and Uruguay) with 4,537 cases of hypospadias and a global prevalence rate of 11.3/10,000 newborns. Trend analysis showed that centers below 2000 m had an increasing trend with an average of 10/10,000 newborns as opposed to those centers above 2000 m that showed a reducing trend with an average prevalence of 7.8 (p = 0.1246). We identified clusters with significant increases of prevalence in five centers along the coast at an average altitude of 219.8 m above sea level (p > 0.0000). Reduction in prevalence was found in clusters located in two centers on the Andes mountains. Altitude of 2,000 m was associated with hypospadias (Figure), with an OR 0.59 (0.5–0.69). There are ethnic arguments to support our results supported by protective polymorphism distribution in high lands. Conclusion Altitude above 2,000 m is suggested to have a protective effect for hypospadias. Specific clusters have been identified with increased risk for hypospadias. Environmental risk factors in these areas need to be further studied given the association seen between altitude and the distribution of more severe cases.[Figure