To the Editor:
The prevalence of hypospadias at birth appears to be increasing in many countries, although the data are not completely consistent.1 Likewise, the incidence of breast cancer has increased over the last decades.1 It has been hypothesized that the effects of environmental synthetic chemicals with intrinsic hormonal activity may play a role in the etiology of both conditions.1 If one or more specific agents cause both conditions, or if etiologic environmental exposures for the 2 conditions are highly correlated, then women who give birth to boys with hypospadias should themselves be at greater risk for breast cancer. We compared the incidence of breast cancer among mothers of boys with hypospadias with the incidence in a matched cohort of mothers of boys without hypospadias.2
Using the Danish Birth Registry3 and Hospital Discharge Registry, we identified a cohort of 4420 women who gave birth to a boy with hypospadia in Denmark from 1977 through 2002. We used the Danish Hospital Discharge Registry to identify cases of hypospadias. This registry contains data on all discharges from hospitals in Denmark since 1977 and includes 10-digit personal identifiers (the Central Personal Registry number), surgical procedures, and up to 20 discharge diagnoses classified according to International Disease Classification, 8th Revision (ICD-8) until the end of 1993 and ICD-10 after 1993. The codes for hypospadias in ICD-8 are 752.20, 752.21, 752.22, 752.28, and 752.29; in ICD-10, the codes are Q54.0, Q54.1, Q54.2, Q54.3, Q54.4, Q54.8, and Q54.9. Once cases of hypospadia were identified, we linked the boy's Central Personal Registry number to the Danish Birth Registry to identify the boy's mother and to extract her Central Personal Registry number for linkage to the Danish Cancer Registry.
After enrolling the cohort of mothers of boys with hypospadias, we identified a cohort of 22,085 women who gave birth to a boy without hypospadias matched to the cohort of mothers of boys with hypospadias on maternal age and birth year of the child. We linked the Central Personal Registry number of mothers in both cohorts to the Danish Cancer Registry to identify all incident breast cancers that occurred within each of the cohorts over almost 350,000 years of follow up. The parity of all women in both cohorts was obtained from the Danish Birth Registry, which contains information on all births in Denmark since 1973.
We compared the incidence rate of breast cancer for mothers in both cohorts and obtained rate ratio estimates and 95% confidence intervals (CIs) computed from Cox regression analysis. The regression model controlled for maternal age at birth, birth year of the child, and number of births before the woman reached age 25.
As shown in Table 1, we identified 26 cases of breast cancer among the 4420 women whose offspring had hypospadias and 173 cases of breast cancer among the 22,085 comparison women (rate ratio = 0.75; 95% CI = 0.49–1.13).
The increase in the occurrence of the 2 hormone-dependent disorders, breast cancer and testicular dysgenesis syndrome (low sperm count, testicular cancer, cryptorchidism, and hypospadias), has caused a debate on the ability of endocrine disruptors to disrupt human hormone action and their responsibility for the common increasing incidence through time.4,5 In this large nationwide prospective cohort study with complete enrollment and follow up, we did not find that giving birth to a child with hypospadias was associated with any increased risk of breast cancer. This result offers some evidence against the theory that the 2 conditions share risk factors.
The strength of our study is that we had a complete and independent registration of births and prospective record-based ascertainment of cancer diagnosis, which reduced the potential for selection and information bias by design.
Henrik Toft Sørensen
Department of Clinical Epidemiology
Aarhus University Hospital
Kenneth J. Rothman
Timothy L. Lash
Department of Epidemiology
School of Public Health
1. Sharpe RM, Irvine DS. How strong is the evidence of a link between environmental chemicals and adverse effects on human reproductive health? BMJ
2. Sørensen HT, Pedersen L, Skriver MV, et al. Use of clomifene during early pregnancy and risk of hypospadias: population based case-control study. BMJ
3. Kristensen J, Langhoff-Roos J, Skovgaard LT, et al. Validation of the Danish Birth Registration. J Clin Epidemiol
4. Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod.
5. Calle EE, Frumkin H, Henley SJ, et al. Organochlorines and breast cancer risk. CA Cancer J Clin