Zidovudine Exposure during Pregnancy and Hypospadias in Infants: An Analysis of Data from the Antiretroviral Pregnancy Registry, 1989-2014

Objective: To evaluate a potential increase in the number of hypospadias cases after in utero exposure to zidovudine (ZDV) reported to the Antiretroviral Pregnancy Registry (APR), a prospective cohort study of antiretroviral-exposed pregnancies. Methods: The rate of hypospadias in male infants following first trimester exposure to ZDV-containing regimens was compared to three internal unexposed groups. Results: Of 7,643 prospective pregnancies, 6,504 (85%) were exposed and 1,139 (15%) were unexposed to ZDV during pregnancy. Among the 7,812 male birth outcomes resulting from these pregnancies (including multiple births), the earliest exposure to ZDV was during 1st trimester in 1,969 infants; during 2nd/3rd trimester in 4,662 infants (Group 1), 1,169 infants had no ZDV exposure (Group 2), and 1,424 had exposure to antiretrovirals (ARV) other than ZDV in the 1st trimester (Group 3). In total, 22 hypospadias cases were reported. The odds ratio of 1st trimester ZDV exposed cases compared to the three unexposed groups were 3.74 (95% CI 1.45, 9.66), 1.63 (95% CI 0.52, 5.12), and 2.00 (95%CI 0.63, 3.28). Conclusion: The increased rate of hypospadias in the primary screening analysis for 1st trimester ZDV-exposed infants compared to ZDV exposures in 2nd/3rd trimester did not persist when compared to those without any ZDV exposure and those with 1st trimester exposures to non-ZDV ARVs. The data do not support a causal relationship between zidovudine exposure and hypospadias. The disappearance of the possible signal in more sophisticated analyses suggests that the increase may be related to other factors.