Lifestyle in Pregnancy and Hypospadias in Sons: A Study of 85,923 Mother-Son Pairs from Two Danish Pregnancy Cohorts

Camilla Lomholt Kjersgaard,1 Linn Håkonsen Arendt,1,2 Andreas Ernst,1,3 Morten Søndergaard Lindhard,4,5 Jørn Olsen,1,6 Tine Brink Henriksen,5 Katrine Strandberg-Larsen,7 Cecilia Høst Ramlau-Hansen1 1Department of Public Health, Research Unit for Epidemiology, Aarhus University, Aarhus, Denmark; 2Department of Obstetrics and Gynecology, Horsens Regional Hospital, Horsens, Denmark; 3Department of Urology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Pediatrics, Randers Regional Hospital, Randers, Denmark; 5Perinatal Epidemiology Research Unit, Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark; 6Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 7Department of Public Health, Section of Epidemiology, Copenhagen University, Copenhagen, DenmarkCorrespondence: Camilla Lomholt KjersgaardDepartment of Public Health, Research Unit for Epidemiology, Aarhus University, Bartholins Allé 2, Aarhus, 8000, DenmarkTel +45 40 19 44 38Email ck@ph.au.dkPurpose: Hypospadias is one of the most frequent male congenital malformations. It remains controversial whether maternal lifestyle during pregnancy may affects the risk of having a son with hypospadias, especially for smoking with many suggesting lower risk. We assessed the individual and joint associations between maternal cigarette smoking, pre-pregnancy body mass index (BMI), alcohol consumption, binge drinking, and caffeine consumption and occurrence of hypospadias in sons.Patients and Methods: This cohort study utilized the Danish National Birth Cohort and the Aarhus Birth Cohort, holding detailed information on lifestyle factors in early pregnancy between 1989 and 2012. The Danish health registers were used to identify boys with hypospadias, according to International Classification of Diseases. Potential confounders and covariates were identified by literature search and use of directed acyclic graphs. Missing data were handled by multiple imputation and Cox proportional hazards models were applied to analyse data.Results: In total, 85,923 live-born singleton boys were included in the study of whom 502 (0.6%) were diagnosed with hypospadias. Maternal smoking in early pregnancy was associated with lower occurrence of hypospadias. An increase of one cigarette smoked per day was associated with lower risk of having a son with hypospadias (adjusted hazard ratio (HR) 0.97 (95% confidence interval (CI) 0.94, 1.00)). However, sub-analyses suggested that the results may be prone to unadjusted confounding. We found no association between pre-pregnancy BMI, alcohol consumption, binge drinking, or caffeine consumption and hypospadias.Conclusion: Maternal smoking during pregnancy was associated with lower occurrence of hypospadias but we cannot exclude uncontrolled confounding. The other investigated maternal lifestyle factors were not associated with hypospadias in sons.Keywords: smoking, prenatal exposures, alcohol, caffeine, BMI, birth defects