Elsevier

The Lancet

Volume 359, Issue 9312, 30 March 2002, Pages 1085-1092
The Lancet

Articles
Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study*

https://doi.org/10.1016/S0140-6736(02)08150-3Get rights and content

Summary

Background

Use of oral contraceptives could increase risk of cervical cancer; however the effect of human papillomavirus (HPV), the main cause of cervical cancer, is not usually taken into account. We aimed to assess how use of oral contraceptives affected risk of cervical cancer in women who tested positive for HPV DNA.

Methods

We pooled data from eight case-control studies of patients with histologically confirmed invasive cervical carcinoma (ICC) and from two studies of patients with carcinoma in situ (ISC). Information about use of oral contraceptives was obtained from personal interviews. Effects were estimated as odds ratios, with logistic-regression models adjusted for possible confounders.

Findings

1465 of 1561 (94%) patients with ICC, 211 of 292 (72%) with ISC, and 255 of 1916 (13%) controls were positive for HPV DNA. Compared with never-users, patients who had used oral contraceptives for fewer than 5 years did not have increased risk of cervical cancer (odds ratio 0·73; 95% Cl 0·52–1·03). The odds ratio for use of oral contraceptives was 2·82 (95% Cl 1·46–5·42) for 5–9 years, and 4·03 (2·09–8·02) for use for 10 years or longer, and these risks did not vary by time since first or last use.

Interpretation

Long-term use of oral contraceptives could be a cofactor that increases risk of cervical carcinoma by up to four-fold in women who are positive for cervical HPV DNA. In the absence of worldwide information about HPV status, extra effort should be made to include long-term users of oral contraceptives in cervical screening programmes.

Published online March 27, 2002. http://image.thelancet.com/extras/01art3030web.pdf

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

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    **

    Jan M M Walboomers died on Feb 2, 2000

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