Hypospadias induced by medications and environmental exposures- A scoping review

Objectives: Hypospadias is a congenital birth defect affecting around one in every 300 male infants, characterized by incomplete fusion of the urethralfold.Our objective was to identify drug and chemical exposure in pregnancy associated with increased risk for hypospadias. Methods: We conducted a scoping review of studies of drugs and chemicals associated with hypospadias by searching Medline, EMBASE, Cochrane, Google and Google Scholar from inception to October 9, 2020 in any language. We searched for the terms; drugs, medications, chemicals, environmental agents, hypospadias, humans, In these papers we evaluated the existence of statistical evidence for an association between exposure to drugs and chemicals, and the occurrence of hypospadias. In examining the statistical evidence, we noted whether an association was made between a drug or chemical and hypospadias at p < 0.05, or Odds Ratio or Relative risk above 1, where the lower 95% confidence interval is also above 1. We also noted whether the study's statistical method adjusted for co-variates or confounders. Results: Significant statistical evidence for association between hypospadias and the following drugs and chemicals has been verified: Progestins, dydrogesterone, clomiphene, ibuprofen, venlafaxine, endocrine disruptors, valproic acid and polybrominated diphenyl esters flame retardants. Conclusions: There is increasing accumulation and quality of evidence of drugs and chemicals associated with hypospadias in humans. These may partially explain the rise in the prevalence of male reproductive health disorders in the last fifty years. Advising women of reproductive age about these risks should be an important component of prenatal counseling.