ArticlesEffect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study*
Introduction
Since use of exogenous steroid hormones became more widespread in the 1960s, concern has been raised about the safety of such treatment in patients with neoplastic diseases. Suspicions that use of oral contraceptives is associated with cervical cancer have been raised in many epidemiological studies.1 Human papillomavirus (HPV) has an important role in causation of cervical cancer,2, 3 and is probably a prerequisite for development of the disease, among other factors. Exogenous female hormones such as those used in combined oral contraceptives have been proposed as cofactors.4
Most investigations in case-control studies of the relation between cervical cancer risk and use of oral contraceptives have been of either population or hospital-based control women, without accurate information about the women's HPV status. 80–95% of controls did not have HPV DNA and thus, were probably not susceptible to cervical cancer, irrespective of their exposure to oral contraceptives. Absence of information on HPV could thus have biased estimates of the association to unity. Statistical analyses restricted to women who are positive for HPV DNA should help to assess the role of suspected cofactors in the presence of a strong cause such as HPV.4, 5, 6, 7, 8
Between 1985 and 1997, the International Agency for Research on Cancer (IARC) used similar protocols in case-control studies of invasive cervical cancer in eight countries and of carcinoma in situ in two. Because assessment of HPV DNA in cervical cells was reliable, these studies have provided a unique opportunity to investigate the role of HPV cofactors. Here, we present a pooled analysis of these studies, restricted to patients and controls who were positive for HPV DNA.
Section snippets
Data collection
We analysed the results of studies done in Thailand,9 the Philippines,10 Morocco,11 Brazil,12 Peru13 (unpublished), Paraguay,14 Colombia,2, 15 and Spain.2, 15 Incidence of cervical cancer varied greatly between countries. In Spain and Colombia, two further studies of cervical carcinoma in situ (ISC) were done simultaneously with those of invasive cervical cancer (ICC).16, 17 Because ISC is accepted as an immediate precursor of ICC, we have included these studies in our analysis. A previous
Results
1853 patients with squamous cell carcinoma and 1916 controls were included in the original studies (table), of whom 1676 and 255, respectively were positive for HPV DNA, and were thus included in our analysis. The proportion of controls who were positive for HPV DNA ranged from 5% in Spain to 22% in Morocco. The proportion of patients who were positive for HPV DNA ranged from 70% in Colombia to 97% in Paraguay.
Women participating in these studies had high parity (median of five [IQR 3–7] births
Discussion
Our analysis suggests that risk of invasive squamous cervical cancer and ISC for women who tested positive for HPV DNA is increased three-fold if they have used oral contraceptives for 5 years or longer. Because the prevalence of oral contraceptive use and other risk correlates varied between countries, that odds ratios among ever users of oral contraceptives showed some heterogeneity between studies was not surprising. The increase in risk for women who had used oral contraceptives for 5 years
References (30)
- et al.
Oral contraceptives and cancer of the cervix uteri: a meta-analysis
Acta Obstetr Gynecol Scand
(1992) - et al.
The causal link between human papillomavirus and invasive cervical cancer: a population-based case-control study in Colombia and Spain
Int J Cancer
(1992) - et al.
Human papillomavirus is a necessary cause of invasive cervical cancer worldwide
J Pathol
(1999) IARC monographs on the evaluation of the carcinogenic risk to humans, Vol 72
Hormonal contraception and post-menopausal hormonal therapy
(1999)- et al.
Oral contraceptive use, human papillomavirus infection, and risk of early cytological abnormalities of the cervix
Cancer Res
(1994) - et al.
Oral contraceptives as risk factors for cervical adenocarcinomas and squamous cell carcinomas
Cancer EpidemiolBiomarkers Prev
(1999) - et al.
Different risk factor patterns for high-grade and low-grade intraepithelial lesions on the cervix among HPV-positive and HPV-negative young women
Int J Cancer
(1998) - et al.
Sexual behaviour and smoking as determinants of cervical HPV infection and of CIN3 among those infected: a case-control study nested within the Manchester cohort
Br J Cancer
(2000) - et al.
Risk factors for cervical cancer in Thailand: a case-control study
J Natl Cancer Inst
(1998) - et al.
Causes of cervical cancer in the Philippines: a case-control study
J Natl Cancer Inst
(1998)