Background: Cyclooxygenase (COX) inhibitors—acetaminophen, ibuprofen and acetylsalicylic acid—have endocrine-disruptive properties in the rainbow trout. In humans, aspirin blocks the androgen response to human chorionic gonadotropin (hCG), and, because hCG-stimulated androgen production in utero is crucial for normal testicular descent, exposure to COX inhibitors at vulnerable times during gestation may impair testicular descent. We examined whether prenatal exposure to acetaminophen, ibuprofen, and acetylsalicylic acid was associated with increased occurrence of cryptorchidism.
Methods: Our study used data on 47,400 live-born singleton sons of mothers enrolled in the Danish National Birth Cohort during 1996-2002. Cryptorchidism was identified in 980 boys during childhood, of whom 565 underwent orchiopexy. The use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy was assessed in 3 computer-assisted telephone interviews and 1 self-administered questionnaire. We estimated adjusted hazard ratios (HRs) of cryptorchidism by Cox regression analysis.
Results: Exposure to acetaminophen during both the first and second trimesters was associated with increased occurrence of cryptorchidism (HR = 1.33 [95% confidence interval = 1.00-1.77]). Exposure for more than 4 weeks within the postulated time-window of programming testicular descent (gestational weeks 8-14) was associated with a HR of 1.38 (1.05-1.83) for cryptorchidism. Exposure to ibuprofen and acetylsalicylic acid was not associated with cryptorchidism.
Conclusion: Maternal intake of acetaminophen for more than 4 weeks during pregnancy, especially during the first and second trimesters, may moderately increase the occurrence of cryptorchidism.
From the aPerinatal Epidemiology Research Unit, Departments of Obstetrics and Pediatrics, Aarhus University Hospital, Skejby, Denmark; bDepartment of Occupational Medicine, Aarhus University Hospital, Aarhus, Denmark; cArizona Respiratory Center, University of Arizona, Tucson, AZ; dDepartment of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; eDepartment of Epidemiology, Boston University, Boston, MA; fDepartment of Occupational and Environmental Medicine, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; gThe Institute of Public Health, University of Aarhus, Aarhus, Denmark; and hDepartment of Epidemiology, School of Public Health, UCLA, Los Angeles, CA.
Submitted 20 March 2010; accepted 7 June 2010; posted 30 August 2010.
The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the Danish National Birth Cohort is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Aarhus University, Faculty of Health Sciences, supported Morten Søndergaard Jensen with a PhD scholarship.
Correspondence: Morten Søndergaard Jensen, Perinatal Epidemiology Research Unit, Departments of Obstetrics and Pediatrics, Aarhus University Hospital, Skejby, Brendstrupgaardsvej 100, DK-8200 Aarhus N, Denmark. E-mail: firstname.lastname@example.org.