To the Editor:
The prevalence of hypospadias at birth appears to be increasing in many countries, although the data are not completely consistent.1 Unpublished data from the Centers for Disease Control and Prevention indicate that maternal asthma may be a risk factor.1 This hypothesis is supported by ecologic data, because the prevalence of asthma has also increased in many countries, including Denmark, in recent years.2 Glucocorticoid is the cornerstone in treatment of asthma, and a recent experimental study has shown that supraphysiological doses of prednisone treatment has an inhibitory effect on urethral fold fusion, leading to hypospadias in male mouse fetuses, whereas low doses accentuate urethra formation.3 There may be a similar effect of prednisone in human fetuses. We therefore examined the association of hypospadias in boys born to Danish women in relation to use of asthma drugs during pregnancy.
We performed a case–control analysis in the 4 Danish counties of North Jutland, Aarhus, Viborg, and Ringkjoebing (total population of 1.6 m, with 65,383 male births in the study period, which was 1989–2002 in North Jutland [n = 34,859], 1996–2002 in Aarhus [n = 20,382], and 1998–2002 in Viborg [n = 4148] and Ringkjoebing [n= 5994]).4 From the nationwide Danish Hospital Discharge Registry, we identified all cases of hypospadias from 1989 to 2003, including their full maternal prescription history. The registry comprises data of all hospital discharges in Denmark since 1977 and includes 10-digit personal identifiers. Up to 20 discharge diagnoses were classified until the end of 1993 according to International Classification of Diseases, 8th Revision (ICD-8) (hypospadia codes 752.20, 752.21, 752.22, 752.28, and 752.29) and thereafter using ICD-10 (Q54.0, Q54.1, Q54.2, Q54.3, Q54.4, Q54.8, and Q54.9).
We found 319 cases of hypospadias (diagnosed at any time after birth). We also collected data on preeclampsia, because it has been associated with hypospadias. The Danish Birth Registry contains information on all births in Denmark since 1 January 1973. From this registry, we selected a control group of male births without a recorded diagnosis of hypospadias for whom there was a full prescription history during the same period. We matched 10 controls to each case for birth month, birth year, and county of residence of the child.
The National Health Service reimburses part of patients’ expenditure on many prescribed drugs, including asthma drugs. The 4 counties have pharmacies equipped with electronic systems that record information on the drug, dose, personal identification number, and date of dispensing of the drug. All data are transferred to a research database at Aarhus University. The data from the 4 counties are electronically available from 1 January 1989 for North Jutland, 1 January 1996 for Aarhus, and 1 January 1998 for Ringkjoebing and Viborg. We extracted data on all prescriptions for asthma drugs (ATC group R03) and for systemic glucocorticoids (ATC group H02A) during the first trimester and 90 days before conception. To control potential confounding, we also extracted data about prescriptions for antidiabetics and antiepileptics and about a discharge diagnosis of preeclampsia. We used conditional logistic regression to estimate the relative risk for hypospadias after exposure to asthma drugs while adjusting for available variables.
Use of any asthma drug was thus not associated with any increased risk of hypospadias (odds ratio [OR] = 0.9; 95% confidence interval [CI] = 0.5–1.7) (Table 1). The OR associated with use of glucocorticoids (inhalation and systemic) was 1.1 (CI = 0.4–2.7). We also observed an association between preeclampsia and an increased risk of hypospadia (2.6; 1.5–4.3) that is consistent with earlier reports.5,6 Because this study was based on registry data on births, birth outcome, and prescriptions that are routinely recorded independently of the diagnosis, selection bias and many types of information bias were prevented. Nonetheless, any noncompliance or nonuse of prescribed asthma drugs might have biased the estimation of a real effect of these drugs toward the null, if there were such an effect.
Henrik Toft Sørensen
Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark, Department of Epidemiology, Boston University School of Public Health, Boston, MA, firstname.lastname@example.org
Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
Department of Clinical Epidemiology, Department of Community Oral Health and Pediatric Dentistry, Aarhus University Hospital, Aarhus, Denmark
Kenneth J. Rothman
Department of Epidemiology, Boston University School of Public Health, Boston, MA
1. Erickson JD. Epidemiology of hypospadias. In: Baskin L, ed. Hypospadias and Genital Development
. Philadelphia: Kluwer Academic/Plenum Publishers; 2004:25–29.
2. Thomsen SF, Ulrik CS, Larsen K, et al. Change in prevalence of asthma in Danish children and adolescents. Ann Allergy Asthma Immunol
3. Yucel S, Desouza A, Baskin LS. In utero prednisone exposure affects genital development. J Urol
4. Sørensen HT, Pedersen L, Skriver MV, et al. Use of clomifene during early pregnancy and risk of hypospadias: population based case–control study. BMJ
5. Akre O, Lipworth L, Cnattingius S, et al. Risk factor patterns for cryptorchidism and hypospadias. Epidemiology
6. Aschim EL, Haugen TB, Tretli S, et al. Risk factors for hypospadias in Norwegian boys—association with testicular dysgenesis syndrome? Int J Androl