Hypertensive Disorders of Pregnancy and Genital Anomalies in Boys: A Danish Nationwide Cohort Study

Background: Although congenital abnormalities in the male reproductive tract are common, their causes remain poorly understood. We studied associations between hypertensive disorders of pregnancy (pregestational hypertension, gestational hypertension, and preeclampsia) and the genital anomalies, cryptorchidism (undescended testes), and hypospadias (ventrally displaced urethral meatus). Methods: We established a population of 1,073,026 Danish boys born alive between 1 January 1978 and 31 December 2012. By means of Cox regression analyses, we estimated hazard ratios with 95% confidence intervals for cryptorchidism and hypospadias according to type and severity of hypertensive disorder. Further, we used restricted cubic spline analyses to investigate the association between gestational age at onset of severe and moderate preeclampsia and the two genital anomalies. Results: We found associations between pregestational hypertension and cryptorchidism (HR: 1.3; 95% CI = 1.1, 1.6) and hypospadias (HR: 1.7; 95% CI = 1.3, 2.3), whereas gestational hypertension was only associated with cryptorchidism (HR: 1.2; 95% CI = 1.1, 1.4). Boys of mothers with preeclampsia had the highest occurrence of cryptorchidism and hypospadias, increasing with preeclampsia severity. Women with HELLP syndrome faced the highest risk of having a child with both cryptorchidism (HR: 2.1; 95% CI = 1.4, 3.2) and hypospadias (HR: 3.9; 95% CI = 2.5, 6.1). Further, the occurrence increased with early onset of preeclampsia diagnosis. Conclusions: These findings support the hypotheses that preeclampsia and genital anomalies share common etiologic factors and that placental dysfunction and androgen deficiency in early pregnancy are important in the etiology of male genital anomalies.