Maternal Cigarette Smoking During Pregnancy and Genital Anomalies in Boys: A Register-Based Cohort and Sibling-Matched Design Study

Daniel Lindbo,1 Linn Håkonsen Arendt,1,2 Andreas Ernst,1,3 Lea Lykke Harrits Lunddorf,1 Nis Brix,1,4 Cecilia Høst Ramlau-Hansen1 1Department of Public Health, Research Unit for Epidemiology, Aarhus University, Aarhus, Denmark; 2Department of Obstetrics and Gynecology, Horsens Region Hospital, Horsens, Denmark; 3Department of Urology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Clinical Genetics, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Daniel Lindbo, Department of Public Health, Research Unit for Epidemiology, Aarhus University, Bartholins Allé 2, Aarhus, 8000, Denmark, Tel +45 21950102, Email lindbo0704@hotmail.comPurpose: Cryptorchidism and hypospadias share several prenatal risk factors. However, in published studies, boys exposed to cigarette smoking during pregnancy have a higher risk of cryptorchidism and a lower risk of hypospadias. Using Danish register-based data, we revisited these findings with a cohort and sibling-matched design to investigate the potential effect of shared time-stable factors.Patients and Methods: For the cohort study, we included 823,670 live-born, singleton boys born from 1991 to 2016. Crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression models for each genital anomaly according to maternal cigarette smoking during pregnancy. For the sibling-matched design, we included 399,258 brothers and used a stratified Cox regression model creating family-adjusted results.Results: In the cohort study, we found a higher risk of cryptorchidism (aHR = 1.18, 95% CI: 1.12, 1.24) and a lower risk of hypospadias (aHR = 0.84, 95% CI: 0.76, 0.93) when comparing boys exposed to cigarette smoking with non-exposed, and for increasing numbers of cigarettes smoked. In comparison, the sibling-matched analyses suggested a slightly weaker association for cryptorchidism and an association of similar magnitude for hypospadias, both in the same direction as in the cohort study.Conclusion: Shared, familial confounding does ...