Elsevier

The Lancet

Volume 361, Issue 9364, 5 April 2003, Pages 1159-1167
The Lancet

Articles
Cervical cancer and use of hormonal contraceptives: a systematic review

https://doi.org/10.1016/S0140-6736(03)12949-2Get rights and content

Summary

Background

Human papillomavirus (HPV) is believed to be the most important cause of cervical cancer. Recent studies suggest that long duration use of oral contraceptives increases the risk of cervical cancer in HPV positive women.

Methods

Results from published studies were combined to examine the relationship between invasive and in situ cervical cancer and duration and recency of use of hormonal contraceptives, with particular attention to HPV infection.

Findings

28 eligible studies were identified, together including 12 531 women with cervical cancer. Compared with never users of oral contraceptives, the relative risks of cervical cancer increased with increasing duration of use: for durations of approximately less than 5 years, 5–9 years, and 10 or more years, respectively, the summary relative risks were 1·1 (95% CI 1·1–1·2), 1·6 (1·4–1·7), and 2·2 (1·9–2·4) for all women; and 0·9 (0·7–1·2), 1·3 (1·0–1·9), and 2·5 (1·6–3·9) for HPV positive women. The results were broadly similar for invasive and in situ cervical cancers, for squamous cell and adenocarcinoma, and in studies that adjusted for HPV status, number of sexual partners, cervical screening, smoking, or use of barrier contraceptives. The limited available data suggest that the relative risk of cervical cancer may decrease after use of oral contraceptives ceases. However, study designs varied and there was some heterogeneity between study results.

Interpretation

Although long duration use of hormonal contraceptives is associated with an increased risk of cervical cancer, the public health implications of these findings depend largely on the extent to which the observed associations remain long after use of hormonal contraceptives has ceased, and this cannot be evaluated properly from published data.

Introduction

Cancer of the uterine cervix is the second most common cancer among women in less-developed countries.1 Persistent infection of cervical epithelial cells with certain high-risk types of the human papillomavirus (HPV) is believed to be the most important cause of cervical cancer.2, 3 The types of HPV associated with cervical cancer are transmitted sexually and it seems that a high proportion of sexually active women are infected by one or more of these viruses at some time during their lives.2 Whether women who have been infected by HPV develop a persistent infection or cervical cancer may be affected by other factors, including the use of hormonal contraceptives. Recent studies have suggested that there is an increased risk of cervical cancer in HPV-DNA positive women if they use oral contraceptives for longer than 5 years.4 Due to the potential public health importance of any effects of oral contraceptives on cervical cancer WHO commissioned a systematic review of published evidence.5 Here, we present the results of this review with particular attention to the role of HPV infection, and to the pattern of risk according to duration of use and time since last use of hormonal contraceptives.

Section snippets

Definitions and identification of eligible studies

Epidemiological studies were identified through a Medline search (January, 1966, to July, 2002) and from references cited in identified papers. Key search words included the terms: cervical intraepithelial neoplasia, cervix dysplasia, cervix neoplasms, risk factors, contraceptive agents, papillomavirus human, and (pre-1994) papillomavirus. The search was limited to human studies and restricted to peer-reviewed articles. No language or date limitations were imposed. Studies were potentially

Results

Overall 28 studies were eligible for this systematic review; these studies are described in the table.4, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 The details of the eight studies32, 33, 34, 35, 36, 37, 38, 39, 40, 41 included in the pooled analysis of squamous cell carcinoma by Moreno and colleagues are combined in the table, since not all of the eight contributing studies have published relevant data separately. Results from the WHO

Taking HPV status into account

One approach to taking HPV status into account when looking at the effect of hormonal contraceptives on cervical cancer is to restrict analyses to women who tested positive for HPV. Figure 5 summarises the results from the 12 studies that included 3000 cases (24% of the total) that have done so: the relative risks for short, medium, and long duration use of oral contraceptives of approximately less than 5 years, 5–9 years, and 10 years or longer, were, respectively, 0·9 (0·7–1·2), 1·3

Potential confounding by other factors and subgroup analyses

The studies listed in table 1 had adjusted their main results on the relative risk of cervical cancer in relation to use of oral contraceptives by various potential confounding factors, although the precise adjustment factors varied from study to study. To assess whether adjustment for number of sexual partners, previous cervical screening, smoking, or use of barrier methods of contraceptives might have affected the results with respect to the use of oral contraceptives, published results were

Discussion

The results of this systematic review of published data show that the relative risk of cervical cancer increases with increasing duration of oral contraceptive use, in virtually every way that data were examined. When the results from all studies are combined, the findings are broadly similar for all women, for HPV positive women, for studies that adjusted for HPV status, sexual partners, previous cervical smears, smoking, and use of barrier methods of contraception, and for invasive, in-situ,

References (48)

  • WalboomersJM et al.

    Human papillomavirus is a necessary cause of invasive cervical cancer worldwide

    J Pathol

    (1999)
  • Human Papillomaviruses

    IARC Monogr Eval Carcinog Risks Hum

    (1995)
  • Hormonal contraception and post-menopausal hormonal therapy. Lyon, International Agency for Research on Cancer

    IARC Monogr Eval Carcinog Risks Hum

    (1999)
  • HildesheimA 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)
  • Berrington A, Cox DR. Generalised least squares for the synthesis of correlated information. Biostatistics (in...
  • CoxDR et al.
  • BrintonLA et al.

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

    Int J Cancer

    (1986)
  • JonesCJ et al.

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

    Cancer Res

    (1990)
  • PetersRK et al.

    Risk factors for invasive cervical cancer among Latinas and non-Latinas in Los Angeles County

    J Natl Cancer Inst

    (1986)
  • EbelingK et al.

    Use of oral contraceptives and risk of invasive cervical cancer in previously screened women

    Int J Cancer

    (1987)
  • IrwinKL et al.

    Oral contraceptives and cervical cancer risk in Costa Rica: detection bias or causal association?

    JAMA

    (1988)
  • OberleMW et al.

    Cervical cancer risk and use of DMPA in Costa Rica

    Int J Epidemiol

    (1988)
  • BrintonLA et al.

    Oral contraceptive use and risk of invasive cervical cancer

    Int J Epidemiol

    (1990)
  • HerreroR et al.

    Injectable contraceptives and risk of invasive cervical cancer: evidence of an association

    Int J Cancer

    (1990)
  • Cited by (379)

    • The effects of dietary supplements in patients with cervical cancer: a comprehensive systematic review

      2023, European Journal of Obstetrics and Gynecology and Reproductive Biology: X
    • Cervical cancer in Morocco: A systematic review

      2022, Revue d'Epidemiologie et de Sante Publique
    • A micro-Raman spectroscopy study of inflammatory condition of human cervix: Probing of tissues and blood plasma samples

      2022, Photodiagnosis and Photodynamic Therapy
      Citation Excerpt :

      It is estimated that early diagnosis and timely medical attention can prevent approximately 90% of cancer mortality [6]. A variety of factors can cause cervical cancer, including human papillomavirus (HPV) infections, tobacco use, poor genital hygiene, prolonged use of oral contraceptives pills, and multiple sexual partners [7–10]. When it comes to cervical cancer, it is a relatively slow process before becoming an invasive disease.

    • Molecular Patho-mechanisms of cervical cancer (MMP1)

      2022, Annals of Medicine and Surgery
    View all citing articles on Scopus
    View full text