Maternal and perinatal risk factors of hypospadias: A case-control study

Hypospadias is a congenital malformation in males with a multifactorial etiology that remains partially understood. Hypospadias has been linked to endocrine, genetic, epigenetic, environmental, and maternal factors. Its incidence ranges from 0.4 to 8.2 per 1,000 live male births.

This study aimed to investigate maternal, gestational, and neonatal risk and potentially modifiable factors for hypospadias in a Brazilian cohort.

A case-control study was conducted using data of births between 1996 and 2021 available in the Latin American Collaborative Study of Congenital Malformations (ECLAMC) registry. Cases were 46 neonates with hypospadias and controls were 1,241 male neonates without malformations, matched by time and place of birth. Exposure data on maternal health, lifestyle, and neonatal characteristics were collected. Variables with a p-value <0.20 in univariate analysis were entered into a multivariate logistic regression model to identify independent risk factors of hypospadias.

In the multivariate model, independent predictors of hypospadias were: a positive family history of congenital anomalies of the kidney and urinary tract (CAKUT) (Odds ratio (OR), 19.3; 95 % Confidence Interval (CI), 7.7-48.5; p < 0.001), small for gestational age (SGA) status (OR, 4.4; 95%CI, 1.9-10.2; p < 0.001), frequent maternal alcohol consumption (OR, 8.4; 95%CI, 1.3-54.3; p = 0.025), maternal hypertension (OR, 3.6; 95%CI, 1.2-10.9; p = 0.023), and maternal diabetes (OR, 3.3; 95%CI, 1.2-8.8; p = 0.018). In contrast, each additional week of gestation was associated with about 11 % reduction in the odds of hypospadias.

Similar to previous studies, neonatal factors including SGA status and a positive family history of CAKUT substantially increased the odds of hypospadias. In addition, a higher gestational age had a protective effect against the occurrence of hypospadias. The maternal risk factors included chronic hypertension, diabetes, and frequent alcohol consumption during pregnancy, which also significantly increased the odds of hypospadias. The risk factors of hypospadias can be unified through a proposed mechanism of placental dysfunction. We hypothesize that conditions which compromise the placenta can disrupt the production of human chorionic gonadotropin, leading to a relative androgen deficiency in male fetus during urethral closure.

This study confirms SGA, familial CAKUT and lower gestational age as risk factors of hypospadias and identifies maternal hypertension, diabetes, and-most notably-frequent alcohol consumption as significant, potentially modifiable predictors. The significant association with alcohol consumption highlights a critical role of the intrauterine environment and a key area for public health intervention.