Use of oral contraceptives for five years or more appears to raise the risk of cervical cancer among women infected with human papillomavirus (HPV). The odds of developing cervical cancer are nearly tripled among women who use the pill for 5-9 years and quadrupled among those who rely on the pill for 10 years or more, compared with the odds among never-users.¹ An HPV-positive woman's likelihood of developing cervical cancer is also associated with the number of times she has given birth. Compared with those who have never borne a child, HPV-infected women who have had 1-2 births have twice the odds of developing cervical cancer, and those who have given birth seven or more times have four times the odds.²

Oral contraceptive use and high parity long have been thought to be tied to the development of cervical cancer, yet past research into these associations has been hindered by a lack of information about whether women were infected with HPV, one of the main immediate causes of cervical cancer. A series of studies by the International Agency for Research on Cancer (IARC) included assessments of women's HPV status and thus provide an opportunity to investigate the independent role of reproductive factors in the development of cervical cancer.

Data and Analyses

IARC sponsored case-control studies of invasive cervical cancer between 1985 and 1997 in eight countries (Brazil, Colombia, Morocco, Paraguay, Peru, the Philippines, Spain and Thailand). In addition, in two countries (Colombia and Spain), research was conducted on the occurrence of carcinoma in situ. All of the studies followed similar protocols. Cases (women with cervical cancer) and controls (women recruited either from the same hospital or from the same region as the cases) were interviewed in person. Interviewers collected detailed information on participants' background characteristics, sexual and reproductive behavior, contraceptive history, smoking habits, history of sexually transmitted diseases, Pap smear history and hygienic practices. HPV infection was diagnosed through analysis of cervical cells collected from participants.

Data from these studies were pooled, yielding a total of 1,853 women with cervical carcinoma (either invasive or in situ) and 1,916 controls. HPV was detected in tissue samples from 1,676 cases and 255 controls; all subsequent analyses were focused on these women. The investigators used logistic regression to control for the effects of study center, age, education, smoking, lifetime number of sexual partners, age at first intercourse, Pap smear history, and pill use or parity (depending on the factor being studied).

Pill Use and Cervical Cancer

Roughly one-third of both cases and controls who were HPV-positive had ever used oral contraceptives; the average duration of use was 6.1 years. The data suggest that ever-users of oral contraceptives were slightly more likely than never-users to have developed cervical carcinoma (odds ratio, 1.4), although this increase was not statistically significant.

Among women who had used oral contraceptives for no more than four years, the odds of cervical cancer were no different from those among never-users. However, women who had taken the pill for 5-9 years had a significantly elevated risk of cervical cancer (odds ratio, 2.8), and those who had done so for 10 or more years had even further increased odds (4.0).

Compared with never-users, women who began taking oral contraceptives before age 20 or in their early 20s had elevated odds of cervical neoplasia (odds ratios, 2.9 and 1.7, respectively), while those who did so later had no increased risk. When the investigators examined duration of use and age at first use together, they found that women who had used the pill for five or more years were at similarly elevated risk regardless of whether they began using oral contraceptives before or after age 25. This finding leads them to comment that cancer risk is "more likely to be determined by duration of oral contraceptive use than by age at first use."

Current pill users and women who had used the pill in the preceding 1-5 years had increased risks of cervical carcinoma (odds ratios, 2.6 and 4.7, respectively), but use in the more distant past was not associated with the risk of disease. The effect of recency of use, however, depended on duration of use. For women who had used the pill for less than five years, the only effect was a marginal increase in risk among those who had used it within the previous five years. By contrast, longer-term users had an elevated risk of cancer that persisted for up to 14 years after they discontinued use.

Parity and Cervical Cancer

More than nine in 10 women with cancer and controls had given birth. Regardless of their cancer status, study participants had had about five births each, and the median age at first birth was 20-21 years. Cervical cancer risk rose steadily as a woman's number of births increased. Compared with nulliparous women, those who had borne one or two children had 1.8 times the odds of developing cancer; odds ratios were 2.6-2.8 for those who had had 3-6 births and 3.8 for those with seven or more births. Likewise, cervical cancer risk was closely linked to age at first birth; the odds ratio was highest among women who gave birth at age 16 or younger (4.4), and then ranged from 2.5 among those who initially delivered at ages 17-19 to about 2.2 among those who did so at age 20 or older.

Type of delivery also appears related to cervical cancer: The few women who had given birth only by cesarean section had a risk of cervical cancer no different from that among women with no lifetime births. However, the odds of cervical neoplasia were elevated among women who had delivered only vaginally (2.6) or both vaginally and via cesarean section (2.2). In contrast, the only association seen between a history of abortion (either induced or spontaneous) and cervical cancer was a significantly reduced likelihood of cancer among women who had had two or more abortions (odds ratio, 0.6).

When the researchers restricted their analysis to women with at least one birth and controlled for the effects of age at first full-term pregnancy, the overall number of full-term pregnancies still predicted cervical cancer risk: Compared with women who had had 1-2 births, those who had borne three or four children had 1.5 times the odds of disease; the odds ratio climbed to 2.3 among women with seven or more lifetime births. Thi s relationship was more pronounced among women whose cancer was diagnosed before age 45 than among those who found out later that they had cancer.

Women whose first full-term pregnancy occurred 5-14 years previously had elevated odds of cervical cancer (1.7), while those who had first given birth 15 or more years before had no increase in their cancer odds. By contrast, in analyses controlling for the effects of number of full-term pregnancies, age at first full-term pregnancy was no longer associated with cervical cancer risk.

Finally, the investigators examined the combined effects of parity and oral contraceptive use; for all comparisons, nulliparous women who had never used the pill were the reference group. Regardless of women's history of pill use, increasing parity was associated with increased cancer risk. For never-users of oral contraceptives, odds ratios rose from 1.8 for those who had had 1-2 births to 3.4 among those who had borne five or more children. Results were similar for women who had used the pill for less than five years, with odds ratios increasing from 1.9 to 2.6. Among those who had taken oral contraceptives for longer durations, however, the differentials were much sharper; the odds ratio was 4.9 for those with 1-2 lifetime births, 6.0 for those with 3-4 births and 11.8 for those who had given birth five or more times.

Conclusions

The researchers who analyzed pill use and cervical carcinoma comment that the relationship they found between the two suggests that oral contraceptives promote "some step in the process of HPV-related cervical carcinogenesis." However, they find no evidence that pill use promotes HPV infection: An examination of all controls in the pooled data showed no association between oral contraceptive use and HPV infection.

As for the findings on parity and cervical cancer, the researchers responsible for those analyses observe that the lack of association between abortion and cancer "provides some hint that events related to the second and third trimesters of pregnancy or to delivery might be relevant" to cervical cancer development. They cite changes in hormonal levels late in pregnancy that might increase the likelihood of cervical carcinoma.

The author of a commentary published along with the studies observes that they had several shortcomings, including wide confidence intervals in some of the analyses and reliance on just one assessment of HPV status (making it difficult to know how recently infection had occurred). Nevertheless, he notes that the most important aspect of the studies is that because they were restricted to women infected with HPV, they suggest that observed associations between cervical cancer and parity or pill use are not related to differences in levels of HPV infection. Confirmation of these results, the author argues, will bring about "wider acceptance that high parity and long-term use of oral contraceptives can act as cofactors in the genesis of cervical cancer."³--M. Klitsch

REFERENCES

1. Moreno V et al., Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study, Lancet, 2002, 359(9312):1085-1092.

2. Muñoz N et al., Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case-control study, Lancet, 2002, 359(9312):1093-1101.

3. Skegg DCG, Oral contraceptives, parity, and cervical cancer, commentary, Lancet, 2002, 359(9312):1080- 1081.