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Risks and side effects associated with estrogen-progestin contraceptives
Authors: Kathryn A Martin, MD Pamela S Douglas, MD
Section Editors Robert L Barbieri, MD William F Crowley, Jr, MD Deputy Editor
Kathryn A Martin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2013. | This topic last updated: фев 7, 2013.

Overall cancer risk — Oral contraceptive use has been associated with an increased risk of certain types of cancer and a decrease in others. However, it appears that the pill is not associated with an overall increased risk of cancer. This was illustrated in the Royal College of General Practitioners' cohort study, which included nearly 50,000 women followed for a mean of 24 years. In pill users compared with nonusers, risks were significantly lower for colorectal, uterine, and ovarian cancer [85]. The incidence of breast cancer was similar in pill users and never users, but there were significant trends of increasing risk of cervical and central nervous system cancer in pill users. Depending upon the data set used, there was either a nonsignificant or significant reduction in overall cancer risk among users compared with nonusers, with an estimated absolute risk reduction between 10 and 45 per 100,000 woman-years.

Breast cancer — Available data on breast cancer risk with OC use are conflicting.
Epidemiologic studies have generally not demonstrated an association between OC use and the risk of breast cancer later in life [86-91]. This can be illustrated by the results of three of the largest series:

■In the Nurses' Health Study, in women over age 40 years, neither long-term past OC use, nor use prior to a first full-term pregnancy was associated with an increased breast cancer risk [88].
■A population-based, case-control study evaluated women ages 35 to 64 (4574 women with breast cancer and 4682 controls), over 75 percent of whom were using or had used OCs [89]. The relative risks of breast cancer for current or previous oral contraceptive use were 1.0 (95% CI 0.8-1.2) and 0.9 (95% CI 0.8-1.0), respectively. Breast cancer risk was not associated with estrogen dose, duration of use, initiation at a young age (<age 20), or race.
■In the Royal College of General Practitioners' study described above, the risk of breast cancer was similar in users compared with never users of the pill (RR 0.98, 95% CI 0.87-1.10) [85].

In contrast, an increase in risk has been reported in some pooled and meta-analyses. In one pooled analysis published before the observational studies noted above [88,89], there was a small but significant increase in the overall relative risk of breast cancer (RR = 1.07) in forever versus never users [92]. However, because pill users are young, this represented a very small rise in absolute risk. In addition, concerns have been raised about this meta-analysis because a low percentage of women had ever used oral contraceptives (40 percent), and it lacked the follow-up necessary to determine whether there were long-term effects of OC use [90].

Data on breast cancer risk in OC users with a family history of breast cancer are also conflicting. In the above case-control study, the risk was not increased in women with a family history of breast cancer [89]. In contrast, a review of women taking OCs prior to 1975 (high dose formulations) found an increase in breast cancer risk in those who had a first-degree relative with breast cancer (RR = 3.3; 95% CI 1.6-6.7) [93].

Oral contraceptive use may increase breast cancer risk in carriers of BRCA1 mutations, and possibly BRCA2 mutations.

Cervical cancer — There appears to be an increased risk for developing cervical cancer among women who have taken OCs [85,91,94-96]. A systematic review of 28 studies, including over 12,000 women with cervical cancer, found that the risk increased with increasing duration of oral OC use (table 3) [97]. Although there was considerable variation in study designs, the increased risk of cervical cancer was demonstrated after adjusting for the number of sexual partners, previous cervical smears, smoking, histology (adenocarcinoma or squamous cell), HPV status, and use of barrier methods. Adjustment for HPV status may not have been reliable since HPV testing at regular intervals was not routinely performed; thus, some HPV infections could have been missed [97].

The best available evidence comes from The Collaborative Group on Epidemiological Studies of Cervical Cancer, which reanalyzed and pooled individual participant data from 24 epidemiologic studies that included 16,573 women [98]. The risk of invasive cervical cancer increased with increasing duration of use (RR for five or more years of use 1.90, 95% CI 1.69-2.13). The risk decreased after use ceased, returning to that of nonusers after 10 years.

Similar patterns of risk were seen for invasive and in-situ cancer, and for women who tested positive for high-risk HPV. The absolute increase in risk is very low: the authors estimate that 10 years of use between ages 20 and 30 would increase the cumulative incidence of cervical cancer from 7.3 to 8.3 per 1000 and 3.8 to 4.5 per 1000 in less developed and more developed countries, respectively. It is still unclear whether the relationship between oral contraceptive use and cervical cancer is a causal one because their use is also associated with exposure to human papillomavirus, the known cause of cervical cancer.

Some studies indicate HPV-negative OC users do not have an increased risk of cervical cancer [97,99]. The mechanism for an increased cervical cancer risk in HPV-positive OC users noted in some studies may be related to a metabolite of estradiol, 16 alpha-hydroxyestrone, which can act as a cofactor with oncogenic HPV to promote cell proliferation [96,99-101].

Ovarian cancer — Epidemiologic studies have consistently shown that prolonged use of oral contraceptive pills (OCs) reduces the risk of ovarian cancer [91]. An analysis of 45 epidemiological studies from 21 countries found that, compared with women who had never used OCs, any use of OCs was associated with a significant reduction in risk of developing ovarian cancer (RR 0.73, 95% CI 0.70-0.76) [102]. Importantly, the protective effect persisted for 30 years after cessation of OCs. Low dose OCs are as effective as higher dose OCs. This topic is reviewed in detail separately. (See "Epithelial ovarian cancer: Pathology".)

The use of OCs to reduce the risk of ovarian cancer in women at high risk of this disease (BRCA1 or BRCA2 mutations) is reviewed separately.

Endometrial cancer — The use of oral contraceptive pills decreases the risk of endometrial cancer [85,91,103]. In one study, women using combination oral contraceptive pills for at least 12 months had a relative risk of endometrial cancer of 0.6 (95% CI 0.3-0.9) compared with nonusers [103]. The protective effect of oral contraceptives persisted for at least 15 years after cessation of use. This benefit is likely related to the progestin effect of oral contraceptives, which suppress endometrial proliferation. (See "Endometrial carcinoma: Epidemiology and risk factors".)

Melanoma — The impact of oral contraceptives on the risk of melanoma has been unclear. In a prospective cohort study of premenopausal Caucasian women, current oral contraceptive use was associated with a twofold increase in risk, particularly in current users with 10 or more years of use [104]. However, a systematic meta-analysis that included 18 case-control studies showed no evidence for an increased risk of melanoma with the use of OCs [105]. (See "Risk factors for the development of melanoma", section on 'Other factors'.)

OVERALL MORTALITY — As described above, oral contraceptive use in women over age 35 who smoke is associated with an increased risk of death from cardiovascular events. However, overall mortality rates are not increased, and may actually be decreased, among ever users of oral contraceptives compared with never users, as illustrated by the following observations:

■In the Oxford Family Planning cohort study of 17,032 women of reproductive age followed for 32 years, the rate ratio for death from any cause in those who had ever used oral contraceptives was 0.89 compared with never users (after adjusting for smoking, age, parity, social class, and duration of use) [106].
■In the Nurses’ Health Study, there was no adverse effect of oral contraceptive use on overall long-term mortality (relative risk [RR] of mortality 0.93 for ever users versus never users; RR 1.06 for ≥10 years of use) [107].
■A possible mortality benefit was reported in the Royal College of General Practitioners' prospective cohort study of over 46,000 women followed for up to 39 years [108]. Ever users of OCs had a significantly lower rate of death from any cause (RR 0.88). Lower rates of death were also seen for all cancers combined, individual cancers (colorectal, uterine, ovarian), cardiovascular disease, and coronary heart disease. The estimated absolute reduction in all cause mortality for ever users of OCs was 52 per 100,000 woman years.

The majority of women in this study had taken oral contraceptives containing higher doses of estrogen than are typically used today (≥50 mcg versus 20 to 35 mcg ethinyl estradiol). These data should reassure young, nonsmoking women that current use of oral contraceptives is not associated with an increased long-term risk of death, and may actually provide a small benefit.

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