Elsevier

The Lancet

Volume 370, Issue 9599, 10–16 November 2007, Pages 1609-1621
The Lancet

Articles
Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16 573 women with cervical cancer and 35 509 women without cervical cancer from 24 epidemiological studies

https://doi.org/10.1016/S0140-6736(07)61684-5Get rights and content

Summary

Background

Combined oral contraceptives are classified by the International Agency for Research on Cancer as a cause of cervical cancer. As the incidence of cervical cancer increases with age, the public-health implications of this association depend largely on the persistence of effects long after use of oral contraceptives has ceased. Information from 24 studies worldwide is pooled here to investigate the association between cervical carcinoma and pattern of oral contraceptive use.

Methods

Individual data for 16 573 women with cervical cancer and 35 509 without cervical cancer were reanalysed centrally. Relative risks of cervical cancer were estimated by conditional logistic regression, stratifying by study, age, number of sexual partners, age at first intercourse, parity, smoking, and screening.

Findings

Among current users of oral contraceptives the risk of invasive cervical cancer increased with increasing duration of use (relative risk for 5 or more years' use versus never use, 1·90 [95% CI 1·69–2·13]). The risk declined after use ceased, and by 10 or more years had returned to that of never users. A similar pattern of risk was seen both for invasive and in-situ cancer, and in women who tested positive for high-risk human papillomavirus. Relative risk did not vary substantially between women with different characteristics.

Interpretation

The relative risk of cervical cancer is increased in current users of oral contraceptives and declines after use ceases. 10 years' use of oral contraceptives from around age 20 to 30 years is estimated to increase the cumulative incidence of invasive cervical cancer by age 50 from 7·3 to 8·3 per 1000 in less developed countries and from 3·8 to 4·5 per 1000 in more developed countries.

Introduction

The International Agency for Research on Cancer (IARC) has classified combined oral contraceptives as carcinogenic to humans; this assessment was made partly on the basis of increased risk for cancer of the cervix.1 The incidence of cervical cancer increases with age and so the contribution of hormonal contraceptives to the lifetime incidence of cervical cancer will depend largely on the effects at older ages, when most women are past users.2 The Collaborative Group on Epidemiological Studies of Cervical Cancer has brought together and reanalysed individual participant data from relevant epidemiological studies worldwide, to examine the relation between cervical cancer and the pattern of use of hormonal contraceptives.3, 4, 5

Section snippets

Identification of studies and data collection

Epidemiological studies with an outcome of invasive cervical cancer, or cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ, with information on duration of use of hormonal contraceptives, were eligible for inclusion. Cases were defined as women with invasive cancer or CIN3/carcinoma in situ, and controls defined as women without cervical cancer. Case-control studies with at least 100 cases of invasive cancer or at least 200 cases of CIN3/carcinoma in situ, and cohort

Results

In all, 35 eligible studies were identified: data from 24 studies,7, 8, 10, 12, 13, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 were available for this analysis, including three international multicentre studies (IARC,7, 8, 27, 39, 40, 41, 42, 43, 44, 45, 46 Brinton Latin America,37, 38 and WHO50, 51, 52, 53, 54, 55). Data could not be retrieved for ten studies,56, 57, 58, 59, 60,

Discussion

This collaborative reanalysis confirms that current and recent use of combined oral contraceptives is associated with an increase in the risk of invasive cancer of the uterine cervix.1 The relative risk in current users increases with increasing duration of oral contraceptive use: use for 5 or more years (mean 11·1 years) is associated with about a doubling in risk. The increased risk of cervical cancer associated with use of combined oral contraceptives diminishes with time since last use

References (70)

  • JG Boyce et al.

    Oral contraceptives and cervical carcinoma

    Am J Obstet Gynecol

    (1977)
  • Carcinoma of the cervix and tobacco smoking: Collaborative reanalysis of individual data on 13 541 women with carcinoma of the cervix and 23 017 women without carcinoma of the cervix from 23 epidemiological studies

    Int J Cancer

    (2006)
  • Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16 563 women with cervical cancer and 33 542 women without cervical cancer from 25 epidemiological studies

    Int J Cancer

    (2006)
  • Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8097 women with squamous cell carcinoma and 1374 women with adenocarcinoma from 12 epidemiological studies

    Int J Cancer

    (2007)
  • C Ngelangel et al.

    Causes of cervical cancer in the Philippines: a case-control study

    J Natl Cancer Inst

    (1998)
  • S Chichareon et al.

    Risk factors for cervical cancer in Thailand: a case-control study

    J Natl Cancer Inst

    (1998)
  • F Sitas et al.

    The spectrum of HIV-1 related cancers in South Africa

    Int J Cancer

    (2000)
  • N Munoz et al.

    Epidemiologic classification of human papillomavirus types associated with cervical cancer

    N Engl J Med

    (2003)
  • Breast cancer and hormone-replacement therapy in the Million Women Study

    Lancet

    (2003)
  • KT Zondervan et al.

    Oral contraceptives and cervical cancer—further findings from the Oxford Family Planning Association contraceptive study

    Br J Cancer

    (1996)
  • M Plummer

    Improved estimates of floating absolute risk

    Stat Med

    (2004)
  • SK Kjaer et al.

    Human papillomavirus-the most significant risk determinant of cervical intraepithelial neoplasia

    Int J Cancer

    (1996)
  • A Hildesheim et al.

    HPV co-factors related to the development of cervical cancer: results from a population-based study in Costa Rica

    Br J Cancer

    (2001)
  • J Deacon 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)
  • MH Schiffman et al.

    Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia

    J Natl Cancer Inst

    (1993)
  • N Ylitalo et al.

    Smoking and oral contraceptives as risk factors for cervical carcinoma in situ

    Int J Cancer

    (1999)
  • LA Brinton et al.

    Long-term use of oral contraceptives and risk of invasive cervical cancer

    Int J Cancer

    (1986)
  • CJ Jones et al.

    Risk factors for in situ cervical cancer: results from a case-control study

    Cancer Res

    (1990)
  • JR Daling et al.

    The relationship of human papillomavirus-related cervical tumors to cigarette smoking, oral contraceptive use, and prior herpes simplex virus type 2 infection

    Cancer Epidemiol Biomarkers Prev

    (1996)
  • MM Madeleine et al.

    Human papillomavirus and long-term oral contraceptive use increase the risk of adenocarcinoma in situ of the cervix

    Cancer Epidemiol Biomarkers Prev

    (2001)
  • FX Bosch et al.

    Risk factors for cervical cancer in Colombia and Spain

    Int J Cancer

    (1992)
  • G Ursin et al.

    Sexual, reproductive, and other risk factors for adenocarcinoma of the cervix: results from a population-based case-control study (California, United States)

    Cancer Causes Control

    (1996)
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