25282
Congenital Abnormalities of the Male Reproductive System and Risk of ASD
Autism spectrum disorder (ASD) is a developmental disorder with increasing prevalence reported worldwide. While the specific mechanisms driving ASD pathogenesis remain largely unknown, accumulating evidence suggests that androgens have extensive influence on structural and functional brain development in regions that are relevant for ASD, and that atypical in-utero androgens levels or actions is a potential risk factor for ASD. Direct evidence, however, remains scarce, owing in part to the difficulty of obtaining direct measurements of fetal androgens levels during pregnancy. Hypospadias (abnormal positioning of the urethral opening) and cryptorchidism (undescended testis) are two of the most common birth defects in newborn boys, are strongly associated with deficiencies in prenatal androgens, and are readily recognizable at birth. Thus, having cryptorchidism or hypospadias is a proxy indicator of atypical androgen actions during pregnancy, but the association between these two disorders and ASD has not been extensively studied on an individual level.
Objectives:
To evaluate whether male newborns diagnosed with either hypospadias or cryptorchidism at birth were at a higher risk of receiving ASD diagnosis later in life, compared with children born without these conditions.
Methods:
We analyzed all male singleton live births (n=147,324) from January 1, 1999 through December 31, 2008 occurring in a large Israeli healthcare organization. Boys with cryptorchidism (n=3,650) or hypospadias (n=2,343) were identified via ICD-9 codes. ASD cases (n=1,329) were identified by ICD-9 code and verified by review of medical records. Analyses were conducted using logistic mixed effect models with random component accounting for family clusters, and adjusted for covariates.
Results:
In multivariable-adjusted analyses, the odds ratio (OR) for ASD among boys with hypospadias or cryptorchidism was 1.31 (95% confidence interval (CI): 1.03-1.65). For cryptorchidism only the OR was 1.39 (95% CI: 1.04-1.86) and for hypospadias only was 1.16 (95% CI: 0.79-1.71). Restricting to boys who underwent surgical correction strengthened the results for cryptorchidism (OR: 1.63, 95% C.I 1.08-2.45), but not hypospadias.
Conclusions:
Boys with cryptorchidism were at higher risk of ASD, but we did not observe an increased risk among boys with hypospadias. Differences in ASD risk between the disorders may reflect variations in critical windows of exposure to a hypoandrogenic in-utero environment, or effects of other signaling systems involved in the etiology of the disorders. Understanding the links between cryptorchidism and ASD could shed light on mechanisms of ASD pathogenesis.