The Link between Male Genital Anomalies and Adult Male Reproductive Disorders: A Population-Based Data Linkage Study Spanning over 40 Years

Background: Male genital anomalies, hypospadias and undescended testis (UDT) have been linked to adult male reproductive disorders, testicular cancer (TC) and decreased fertility. Few population-based studies have evaluated effects on adult fertility outcomes and, in the case of UDT, the importance of early corrective surgery (orchidopexy). Methods: We conducted a population-based cohort study of all liveborn males in Western Australia, 1970-1999 and followed them up until 2016 via data linkage to hospital admission, congenital anomaly, cancer and assisted reproductive technology (ART) registries. Study factors were hypospadias or UDT and study outcomes as TC, paternity and use of ART for male infertility. Cox regression was used to estimate the association (Hazards Ratio, HR) between genital anomalies and paternity; and Log-Binomial regression (Relative Risk, RR) for ART. Findings: The cohort comprised 350,835 males, 2,484 (0*7%) had hypospadias and 7,499 (2*1%) UDT. There were 530 (0*1%) TC cases, 109,544 (31%) men fathered children (paternity) and 2,680 (0*8%) men had ART. UDT was associated with a 2*4-fold increase in TC (HR 2*43; 95% CI 1*65-3*58) and hypospadias with a small but imprecise increase in TC (HR 1*37; 95%CI 0*51-3*67). Both hypospadias and UDT were associated with a 21% reduction in paternity (adjusted HR (aHR): 0*79; 95%CI 0*71-0*89 and aHR 0*79; 95%CI 0*74-0*85, respectively). UDT was associated with a 2-fold increased use of ART (aRR 2*26; 95% CI 1*58-3*25). For every six-months of delayed orchidopexy, there was a 6% increase in risk of TC (HR 1*06; 95%CI: 1*03-1*08), 5% increase in future ART use (HR 1*05; 95%CI 1*03-1*08); and 1% reduction in paternity (RR 0*99; 95%CI: 0*98-0*99). Interpretation: UDT is associated with an increased risk of TC, male infertility and decreased paternity. We provide new evidence to support current guidelines for orchidopexy before 18 months, to decrease the risk of future TC and infertility. Funding Information: National Health and Medical Research Council Competing Interest Declaration: The authors have no conflicts of interest relevant to this article to disclose. Ethical Approval Statement: Ethics approval was obtained from the Human Research Ethics Committee of the Department of Health WA (#2015/36) and the WA Reproductive Technology Council.