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Maternal Diabetes Mellitus and Genital Anomalies in Male Offspring: A Nationwide Cohort Study in 2 Nordic Countries

Arendt, Linn, Håkonsena,b; Lindhard, Morten, Søndergaardb; Henriksen, Tine, Brinkb; Olsen, Jørnc; Cnattingius, Svend; Petersson, Gunnard; Parner, Erik, Thorlunde; Ramlau-Hansen, Cecilia, Høsta

doi: 10.1097/EDE.0000000000000781
Perinatal and Pediatric Epidemiology

Background: Pre-existing diabetes has been associated with an increased risk of congenital malformations overall, but studies on genital anomalies in boys are conflicting and possible causal mechanisms are not well understood. Previous studies have mainly assessed pregestational and gestational diabetes in combination. Yet considering the vulnerable time windows for the genital anomalies, associations could well differ between types of diabetes and between the 2 genital anomalies and we therefore aimed to study this further.

Methods: A population-based cohort study of 2,416,246 singleton live-born boys from Denmark (1978–2012) and Sweden (1987–2012) was carried out using Danish and Swedish register-based data. Using Cox regression models, we estimated hazard ratios for hypospadias and cryptorchidism according to maternal diabetes. We considered type and severity of diabetes, as well as timing of diagnosis in relation to birth.

Results: Pregestational type 1 diabetes was associated with a higher risk of both genital anomalies. The highest risks were seen for boys of mothers with diabetic complications (hazard ratio for hypospadias = 2.33 [95% confidence interval, 1.48, 3.66] and hazard ratio for cryptorchidism = 1.92 [95% confidence interval, 1.39, 2.65]). Gestational diabetes was associated with slightly increased risks of both genital anomalies.

Conclusions: These results are consistent with the hypothesis that poor glycemic control may interfere with fetal genital development in the critical early period of organogenesis. Given the widespread and increasing occurrence of diabetes, these results are of public health importance.

From the aDepartment of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark; bPerinatal Epidemiology Research Unit, Department of Paediatric and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark; cDepartment of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; dClinical Epidemiology Unit, Department of Medicine, Solna, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden; and eDepartment of Public Health, Section for Biostatistics, Aarhus University, Aarhus, Denmark.

Submitted February 20, 2017; accepted November 2, 2017.

Supported by Aarhus University, Faculty of Health Sciences, who provided Linn Håkonsen Arendt with a PhD scholarship. Additional financial support for this study was provided by the Karen Elise Jensen Foundation, the Aarhus University Research Foundation, Carl and Ellen Hertz’ Scholarship and The A.P. Møller Foundation for the Advancement of Medical Science. The sponsors played no role in the design and conduct of the study, collection, management, analysis, and interpretation of data; and preparation, review, or approval of the manuscript.

The authors report no conflicts of interest.

Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com).

Correspondence: Linn Håkonsen Arendt, Department of Public Health, Section for Epidemiology, Aarhus University, Bartholins Allé 2, 8000 Aarhus C, Denmark. E-mail: lha@ph.au.dk.

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