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EPI-13-0298R Oral Contraceptive Use and Risk of Cancer
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Oral Contraceptive Use and Risk of Breast, Cervical, Colorectal, and Endometrial
Cancers: A Systematic Review
Jennifer M. Gierisch1,2,3, Remy R. Coeytaux2,4, Rachel Peragallo Urrutia5, Laura J. Havrilesky6,7,
Patricia G. Moorman4, William J. Lowery6, Michaela Dinan8, Amanda J. McBroom2, Vic
Hasselblad9, Gillian D. Sanders2,3, Evan R. Myers6
1 Center for Health Services Research in Primary Care, Durham Veterans Affairs Medical
Center, Durham, NC
2 Duke Evidence-based Practice Center, Duke Clinical Research Institute, Durham, NC
3 Department of Medicine, Duke University School of Medicine, Durham, NC
4 Department of Community and Family Medicine, Duke University School of Medicine,
Durham, NC
5 Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill School
of Medicine, Chapel Hill, NC
6 Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC
7 Duke Cancer Institute, Duke University Health System, Durham, NC
8 Duke Clinical Research Institute, Durham, NC
9 Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham,
NC
Running Title: Oral Contraceptives and Breast, Cervical, Colorectal, and Endometrial Cancers
Keywords: Breast, Cervical, Endometrial, Colorectal, Oral Contraceptives
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Financial Support: All authors received support and this project was funded under Contract No.
290-2007-10066-I from the Agency for Healthcare Research and Quality (AHRQ) and the
Centers for Disease Control and Prevention (CDC), U.S. Department of Health and Human
Services.
Corresponding Author: Jennifer M. Gierisch, Department of Medicine, Duke University
Medical Center, Campus Box 104427 DUMC, Durham, NC, 27701; phone, 919-688-5519; fax,
919-688-1300; [email protected]
Disclosure of Potential Conflicts of Interest: None of the authors have any relationships they
believe could be construed as resulting in an actual, potential, or perceived conflict of interest
with regard to the manuscript submitted for review.
Acknowledgments: The authors thank Liz Wing, MA, for editorial assistance; Kathryn Roth
Lallinger, MSLS, and Michael Musty, BA, for project coordination; and Megan von Isenburg,
MSLS, for help with the literature search and retrieval.
Disclaimer: The authors of this report are responsible for its content. Statements in the report
should not be construed as endorsement by AHRQ, CDC, the U.S. Department of Health and
Human Services, or the U.S. Department of Veterans Affairs.
Word Count: 5652 (body text only); Tables: 4 (Supplementary Data); Figures: 5
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EPI-13-0298R Oral Contraceptive Use and Risk of Cancer
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ABSTRACT
Oral contraceptives (OC) may influence the risk of certain cancers. As part of the AHRQ
Evidence Report, Oral Contraceptive Use for the Primary Prevention of Ovarian Cancer, we
conducted a systematic review to estimate associations between OC use and breast, cervical,
colorectal, and endometrial cancer incidence. We searched PubMed®, Embase®, and Cochrane
Database of Systematic Reviews. Study inclusion criteria were women taking OCs for
contraception or ovarian cancer prevention; includes comparison group with no OC use; study
reports quantitative associations between OC exposure and relevant cancers; controlled study or
pooled patient-level meta-analyses; sample size for nonrandomized studies >100; peer-reviewed,
English-language; published from January 1, 2000 forward. Random-effects meta-analyses were
performed by estimating pooled odds ratios with 95% confidence intervals.
We included 44 breast, 12 cervical, 11 colorectal, and 9 endometrial cancers studies.
Breast cancer incidence was slightly but significantly increased in users (OR=1.08, CI 1.00–
1.17); results show a higher risk associated with more recent use of OCs. Risk of cervical cancer
was increased with duration of OC use in women with human papillomavirus infection;
heterogeneity prevented meta-analysis. Colorectal cancer (OR=0.86, CI 0.79–0.95) and
endometrial cancer incidences (OR=0.57, CI 0.43–0.77) were significantly reduced by OC use.
Compared with never use, ever use of OCs is significantly associated with decreases in
colorectal and endometrial cancers and increases in breast cancers. Although elevated breast
cancer risk was small, relatively high incidence of breast cancers means that OCs may contribute
to a substantial number of cases.
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INTRODUCTION
Oral contraceptives (OCs), the most common form of effective and reversible contraception
in the United States (1), significantly decrease the personal and societal burdens associated with
unintended or unwanted pregnancy (2,3). OCs also have significant noncontraceptive health
benefits, such as improving acne and regulating dysmenorrhea (4-7). However, OC use is not
without risks. Many studies demonstrate serious adverse events associated with OC use,
including venous thromboembolic disease, myocardial infarction, and stroke (8-10).
In addition to the risk of acute harms, the use of OCs may influence the risk of certain
cancers (11). OC use may promote or initiate tumors of the breast or cervix (12-14). For breast
cancer, these risks may be even greater for women at elevated risk due to family history of
cancer or genetic mutation carrier status (e.g., BRCA1/2); however, results from studies are
inconclusive (15,16). OC use has also been associated with a greater risk of certain clinically
challenging types of breast tumors (17). Conversely, OC use is associated with significant
reductions in colorectal, endometrial, and ovarian cancers (11,18-20). A recent systematic review
and meta-analysis supports a significant risk reduction for ovarian cancer incidence and mortality
associated with the use of OCs (20).
Assessing the risk of cancer associated with OC use is fraught with difficulties. For example,
cancer is a disease with a long latency period, and the time between exposure to OCs and
diagnosis of cancer may span decades. Also, temporal variations in OC formulations available on
the market and used over a woman’s lifetime may influence associations between cancer risk and
OC use. Further, patterns of OC use over a lifetime may be influenced by factors that also affect
cancer risks (e.g., gravidity, parity, breastfeeding). Duration of OC use or length of time since
ceasing use (i.e., recency) may also modify the risk of cancers associated with OCs (13,21).
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We performed a systematic review and meta-analysis, sponsored by the Agency for
Healthcare Research and Quality (AHRQ) and the Centers for Disease Control and Prevention
(CDC), to inform the use of OCs to reduce the risk of ovarian cancer (20). In addition to the
primary question regarding ovarian cancer, we also addressed other harms and benefits of OC
use. In this paper, we examine the evidence for associations between OC use and the risks of
developing four cancers: breast, cervical, colorectal, and endometrial. When possible, we
conducted meta-analyses of the literature to assess the risk of developing these cancers following
OC use; we also examined risk by duration of OC use and time since last OC use (20).
MATERIALS AND METHODS
We followed the methodology recommended in AHRQ’s “Methods Guide for Effectiveness
and Comparative Effectiveness Reviews” (22). Methods are summarized here, with complete
details provided in the full AHRQ report (20).
Search strategy
In collaboration with an experienced librarian, we conducted searches of PubMed, EMBASE,
the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov to identify relevant
published literature. Our searches were date-limited to articles published from January 1, 1990,
to June 29, 2012. For the outcomes presented in this paper, we restricted the results to 2000
forward for the following reason. Formulations of OCs have been changed and updated almost
continuously since their introduction to the U.S. market in 1957; such changes have not occurred
at discrete time points. Also, year-by-year market share, duration of use, and patterns of use are
not readily available and would vary based on the country in which a given study was conducted.
Realizing the inaccuracy of any discrete cutoff date with regard to current OC formulations, we
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limited the publication years of included studies to those published from 2000 forward to try to
maximize the proportion of subjects who used OC formulations similar to those currently on the
market. We supplemented electronic searches with a manual search of citations from key review
articles. Exact search strings are provided in Appendix A of the full AHRQ report (20).
Selection criteria
Inclusion criteria for studies relevant to this paper were (1) study includes women taking OCs
for contraception or primary prevention of ovarian cancer; (2) study includes comparison group
with no use of combination or progestin-only OCs (either no contraceptive method at all or
contraceptive methods other than combination or progestin-only OCs); (3) study reports
quantitative associations between exposure to OCs and breast, cervical, colorectal, or
endometrial cancer incidence; (4) controlled study (randomized trials, cohort studies, case-
control studies) or pooled patient-level meta-analyses; (5) sample size for nonrandomized studies
>100 subjects; (6) study is peer-reviewed and English-language; and (7) published on or after
January 1, 2000. Exclusion criteria were (1) study reports outcomes related to the use of OCs
only for contraception, or in specialized populations such as women immediately post-
termination of pregnancy, or women receiving assisted reproductive technologies; (2) study does
not provide a description of the OC formulation(s) or length of OC use; or (3) publication type is
editorial, review, or letter to the editor.
Reviewer pairs used prespecified criteria to assess titles and abstracts. Full-text articles
included by either reviewer underwent further evaluation. Eligibility decisions and
disagreements were reconciled through discussion or by a third reviewer. For included studies,
we abstracted data on study populations, interventions, outcomes, quality, and applicability. We
used criteria developed by AHRQ to assess study quality, summarized as good, fair, or poor (22).
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Quality ratings for individual articles within study groupings could differ based on articles’
reporting quality, evaluated outcomes, and statistical and analytical methods used. We screened
and abstracted data using DistillerSR software (Evidence Partners Inc, Manotick, ON, Canada).
Data synthesis
When at least three studies were available with comparable study designs and outcomes, we
performed random-effects meta-analyses grouped by study design (case-control or cohort study)
and estimated pooled ORs with 95% confidence intervals (CIs). As there were no significant
differences by design, we used a random-effects model to combine subgroups and estimate the
overall effect. When studies reported multiple models, we used the most adjusted model. We
evaluated heterogeneity visually and with the Cochran Q statistic using a threshold P value of
less than 0.10. We included pooled analyses in our meta-analyses if all these conditions were met
by the pooled analysis: none of the individual papers were already included in the meta-analysis,
at least half of the studies were published on or after January 1, 2000, and data were presented
such that their inclusion in meta-analysis was feasible.
Not all studies meeting criteria for inclusion in the review were included in meta-analyses.
The reasons for exclusion from meta-analysis were (1) study populations that represented
specialized subgroups (e.g., BRCA mutation, family history, age at diagnosis ≤45 years, cancer
subtype); (2) studies that reported a subset of results from the same study as another article
already included in the analysis; and (3) studies that did not report an OR for ever OC use versus
never OC use. When studies gave results only by subgroup (premenopausal, postmenopausal),
we combined subgroups to generate an estimate only when the combined group represented a
broad population. When possible, we conducted sensitivity analyses by including only U.S.-
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based studies. These analyses were performed using Comprehensive Meta-Analysis Version 2
(Biostat; Englewood, NJ; 2005) (23).
We estimated the increase or decrease in absolute risk of cancer from estimates of the
lifetime incidence of malignant cases for women beginning at age 45 years generated using the
National Cancer Institute’s DevCan software (24), estimated lifetime ever use of OCs from the
National Survey of Family Growth (25), and the ORs (with 95% CIs) produced in our meta-
analyses. We then calculated the number needed to treat (NNT) or number needed to harm
(NNH) by taking the inverse of the absolute risk. Because we were unable to perform meta-
analysis of the association of OC use and cervical cancer among populations that were selected
for HPV-positive status, we were unable to generate estimates of change in absolute risk.
When we had sufficient studies to assess the effect of duration of OC use, we used a random-
effects model to compute ORs. We required that the ORs were given relative to no OC use and
that the population studied was not restricted to a particular subpopulation. The challenge of
performing a meta-analysis on duration of OC use is that individual studies reported ORs for
different duration intervals. We assumed that the logarithm of each OR could be described by a
linear model. The model included a random-effects term, σ2, as well as terms for time point
intervals. We then used independent variables to create the time period desired. The model was
fitted using SAS PROC NLMIXED (SAS Institute Inc.; Cary, NC; 2009) with “subject” set to
the particular study.
We evaluated strength of evidence using the approach described in AHRQ’s “Methods
Guide” (22,26).
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RESULTS
Of the 6,476 unique citations screened, we identified 44 studies relevant to breast, 12 to
cervical, 11 to colorectal, and 9 to endometrial cancers (Figure 1). Several included studies were
relevant to more than one outcome of interest. All studies were observational; we did not identify
any eligible randomized controlled trials. We did not identify any qualitative difference between
breast, cervical, colorectal or endometrial cancers and OC use based on probable dates of
exposure when examined by study recruitment date versus publication date.
Breast cancer incidence
Forty-four studies (19 good quality, 25 fair, and 3 poor) evaluated the association between
OC use and breast cancer incidence (16,17,27-78). Of these, 29 were case-control studies, 14
were cohort studies, and 1 was a pooled analysis (Supplementary Table 1). Fifteen case-control
studies (38,682 women) (16,27-30,33,37,48,49,51,54,56,73,74,78) and 8 cohort studies (317,341
women across 5 studies and 3,981,072 person-years across 3 studies) (59-61,63,65,67-69) met
criteria for meta-analysis examining ever versus never OC use. Figure 2 shows the results
suggesting that a history of OC use slightly but significantly increases breast cancer incidence
compared with never OC use (OR=1.08; 95% CI, 1.00 to 1.17), with a Q value of 73.35 for 21
degrees of freedom (DF); P < 0.001. In a sensitivity analysis of only U.S.-based studies, effect
sizes were smaller and no longer statistically significant (OR 1.03; CI, 0.93 to 1.14). Based on
the point estimates of the meta-analyses, the approximate increase in estimated lifetime absolute
risk of breast cancer from ever use of OCs is 0.89% (NNH 113).
Fourteen studies (16,27,30,36,37,44,48,49,54,59-61,63,69,78) met criteria for the meta-
analysis examining duration of OC use. We found no time-dependent relationship as a function
of duration of use: 1–12 months (OR = 0.95; CI, 0.83 to 1.09); 13–60 months (OR = 1.03; CI,
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0.92 to 1.15); 61–120 months (OR = 1.01; CI, 0.90 to 1.13); and >120 months (OR = 1.04; CI,
0.93 to 1.17). Heterogeneity was significant (t = 5.84, 19 DF, P < 0.0001).
Eleven studies (16,27,30,33,37,38,46,49,51,53,59,61) met criteria for the meta-analysis
examining time since last OC use. Results show a time-dependent relationship as a function of
time since last OC use, with higher risk associated with more recent use of OCs and ORs that
approach 1 (no effect) by ≥20 years of use: 0–5 years (OR = 1.21; CI, 1.04 to 1.41); 5–10 years
(OR = 1.17; CI, 0.98 to 1.38); 10–20 years (OR = 1.13; CI, 0.97 to 1.31); >20 years (OR = 1.02;
CI, 0.88 to 1.18). Heterogeneity was significant (σ = 0.12; t value = 4.95 for 11 DF, P = 0.0004).
The strength of evidence for the effect of ever OC use on breast cancer incidence was
moderate. Most studies were of good or fair quality, exhibited consistent findings, and
confidence interval for summary estimate were precise. However, all included studies were
observational; thus there may be some risk of bias due to limitations of the study designs. The
strength of evidence was low for both duration of use and time since last use for risk of breast
cancer incidence; results were inconsistent with a high level of heterogeneity across studies.
Cervical cancer incidence
Twelve studies (five good, four fair, four poor quality) evaluated the association between OC
use and cervical cancer incidence (63,65,66,69,70,73,79-87), including two articles from an
International Agency for Research on Cancer (IARC) study representing distinct populations
(86,87). Of these, nine were case-control studies, three were cohort studies, and one was a pooled
analysis. Only two studies were conducted with U.S.-based populations (Supplementary Table
2).
Persistent infection with one or more oncogenic HPV types is required for cervical
carcinogenesis; thus, women who are HPV-positive represent the most relevant population to
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assess the risks for cervical cancer associated with OC use. Only three studies (80,83,86)
assessed the association between OC use and cervical cancer among women who are HPV-
positive. Limited studies across comparisons precluded quantitative synthesis; we summarize
each study below.
One fair-quality study (86) pooled data from eight case-control studies of HPV-positive
patients with cervical cancer. Ever use of OCs was associated with a statistically nonsignificant
increase in invasive cervical cancer (OR = 1.29; CI, 0.88 to 1.91) and cervical cancer in situ (OR
= 2.54; CI, 0.95 to 6.78). However, duration of use was significantly associated with cancer
incidence such that HPV-positive women who used OCs for 5–9 years (OR = 2.82; CI, 1.46 to
5.42) and ≥10 years (OR = 4.03; CI, 2.09 to 8.02) experienced a significant increase in the risk of
cervical cancers compared with never users. This estimate did not vary by time since first or last
use; the trend was not observed for women who used OCs for <5 years.
Two case-control studies (80,83), both rated poor quality, also assessed the risk of cervical
cancer associated with OC use among HPV-positive women. One study (80) recruited hospital-
based HPV-positive cases and controls in Lima, Peru. Results of this study were included in the
pooled analysis above and, thus, could not be combined again. Compared with HPV-positive
controls, HPV-positive women who had ever used OCs were at elevated risk of cervical cancer
compared with women who had never used OCs (OR = 2.7; CI, 0.90 to 8.4), but the contrast was
not significant. This study did not compute any analysis by duration of use.
The other case-control study (83) assessed the association between OC use and cervical
cancer among hospital-based HPV-positive cases and HPV-positive community controls in the
United States. This study assessed duration of OC use; ever use versus never use was not
calculated. Increasing the duration of OC use—categorized as <5 years, 5–10 years, and >10
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years—was associated with a decrease in cervical cancers. This trend was significant only in
women with <5 years of use compared with never users (OR = 0.6; CI, 0.4 to 0.9).
In populations that were not selected for HPV-positive status, 6 case-control studies
representing 5,436 women (73,79,81,82,84,85) and 3 cohort studies (63,65,69) representing
3,981,072 person-years met criteria for the meta-analysis examining ever versus never OC use.
Figure 3 shows results indicating increased odds of cervical cancer for women who had ever
used OCs compared with women who never used OCs (OR = 1.21; CI, 0.91 to 1.61), but the
comparison was not significant. There was a large amount of heterogeneity (Q = 25.52, 7 DF, P
< 0.001), possibly due to differences in HPV status among studies, which made the estimates
unstable. We could not conduct sensitivity analysis by U.S.-based studies because only one study
was conducted within the U.S. Results from this case-control study (79) show a statistically
significant increase in risk with ever use of OCs (OR = 2.7; CI, 1.2 to 5.8).
Six studies (63,79,81,82,85,87) met criteria for the meta-analysis examining duration of OC
use. Results show no time-dependent relationship as a function of duration: 1–60 months (OR =
0.99; CI, 0.58 to 1.70) and >60 months (OR = 1.47; CI, 0.91 to 2.38). Heterogeneity was
significant (t = 4.72; 5 DF, P = 0.0033).
The strength of evidence for the effect of ever OC use on cervical cancer incidence among
HPV-positive women was insufficient. Only three studies assessed risk in HPV-positive women,
and most were of poor quality. Results were inconsistent, sensitivity analysis yielded
qualitatively different estimates of effects, and confidence intervals were wide. Studies did not
control for factors that may influence risk such as age at first use by duration or age at sexual
debut, which is likely highly correlated with age at first use. Future studies could influence
magnitude and, possibly, direction of effect.
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Colorectal cancer incidence
Eleven studies (4 good, 6 fair, 1 poor quality) evaluated the association between OC use and
colorectal cancer incidence (63,65,66,68,88-95). Of these, 3 were case-control studies, 7 were
cohort studies, and 1 was a pooled analysis. Nine studies were conducted in Western countries
and two in China (Supplementary Table 3).
Three case-control studies (88-90), one pooled analysis (94), and seven cohort studies
(63,65,68,91-93,95) representing 503,816 women across 8 studies and 2,969,189 person-years
across 3 studies met criteria for the meta-analysis examining ever versus never OC use. Figure 4
shows the results demonstrating a decrease in the risk of colorectal cancers among women who
ever used OCs compared with women who never used OCs (OR = 0.86; CI, 0.79 to 0.95; Q =
17.17, P < 0.046). We conducted sensitivity analyses of studies that included only patients from
the U.S; results were similar to analyses containing all studies, but the confidence interval
eclipsed 1 (OR = 0.83; CI, 0.69 to 1.01). Based on the point estimates of the meta-analyses, the
approximate decrease in absolute risk of colorectal cancer is 0.76% (NNT 132).
Ten studies (63,65,68,88-92,94,95) met criteria for the meta-analysis examining duration of
OC use. We categorized duration of use into 2 intervals and found no time-dependent
relationship as a function of duration: 1–60 months (OR = 0.88; CI, 0.77 to 1.01) and >60
months (OR = 0.88; CI, 0.76 to 1.01). There was no significant heterogeneity (t = 1.52; 9 DF, P
= 0.164).
The strength of evidence for the effect of OC use on colorectal cancer incidence was
moderate. Results were consistent across studies, and the summary estimate demonstrated high
precision with a tight confidence interval. Future studies will not likely have an impact on the
direction of effect but may slightly influence the magnitude of the effect. The strength of
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evidence for duration was insufficient; the test was underpowered and we found significant
heterogeneity.
Endometrial cancer incidence
Nine studies (six good, two fair, one poor quality) evaluated the association between OC use
and endometrial cancer incidence (63,65,66,69,70,73,96-100). Of these, four were case-control
studies and five were cohort studies. Only two studies were conducted in the U.S.
(Supplementary Table 4).
Three case-control studies (73,97,100) and 4 cohort studies (63,65,69,98) representing
308,198 women (within 4 studies) and an additional 3,981,072 person-years (within the other 3
studies) were included in this meta-analysis examining ever versus never OC use. Figure 5
shows results indicating a protective effect for endometrial cancer associated with ever OC use
(OR = 0.57; CI, 0.43 to 0.77). Heterogeneity was significant (Q = 26.11, 6 DF, P < 0.001). We
also explored how our findings changed when including only U.S.-based studies. Only one study
was conducted with patients from the U.S. and reported a somewhat greater protective effect
than summary estimates for all studies (OR = 0.34; CI, 0.25 to 0.47). Based on the point
estimates of the meta-analyses, the approximate decrease in absolute risk of endometrial cancer
is 1.77% (NNT 60).
DISCUSSION
Our results are confirmatory of initial analyses and reviews, including those which included
studies published prior to 2000.. This evidence synthesis highlights some of the tradeoffs about
nonreproductive outcomes that patients and providers need to consider with the use of OCs:
increased risk for some cancers (breast and cervical) but decreased risk for others (colorectal and
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endometrial). Other considerations include decreased risk of ovarian cancer (101) and increased
risk for thromboembolic events (102). Estimating the overall balance of benefit and harm is
difficult from a technical sense and because the timing of the outcomes affected by OC use is
variable—some risks and benefits are seen only during use, while others occur 20 to 30 years in
the future. Moreover, different patients may well have different values for those outcomes.
We found that the risk of breast cancer was slightly—but significantly—elevated for women
who have ever used OCs compared with women who have never used OCs. Although the
relative increase in risk was small (OR = 1.08), the relatively high incidence of breast cancer
diagnosis means that OC use may contribute to a substantial number of cases. We found no time-
dependent relationship as a function of duration of OC use. Duration results should be
interpreted with caution; there was significant heterogeneity, and the test was underpowered—
which is not surprising, given that breast cancer is relatively uncommon during the ages when
women are most likely to be using OCs. We also found that women with more recent use had an
elevated risk of breast cancer, with decreasing risk over time, so that by 10 years since last use,
the risk among users was equivalent to never users.
Our results are consistent with results of other meta-analyses and pooled analyses that
identified a small increase in the relative risk of breast cancer associated with having ever used
OCs—a risk that diminishes over time since last use (12,103). The Collaborative Group on
Hormonal Factors in Breast Cancer, a collaborative reanalysis of individual data in 153,536
women, found a small but significant increase in the relative risk of breast cancer (OR = 1.07 ±
0.02) (12). Similar to our results, the Collaborative Group did not identify an increase in risk
with increasing duration of use or after discontinuation of use for ≥10 years. Another recent
meta-analysis of premenopausal breast cancer across 37 studies found a somewhat larger
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increase in the risk (OR = 1.19; CI, 1.09 to 1.29), with the greatest risk associated with OC use
prior to first full-term pregnancy (OR = 1.44; CI, 1.28 to 1.62) (104). These results support our
finding that recent use (≤5 years) is associated with an increased risk of breast cancer. Women
who delay first full-term pregnancies may also be more likely to be recent users of OCs relative
to a breast cancer diagnosis. These results cannot be directly compared with ours, as this meta-
analysis was restricted to premenopausal women or women <50 years who may be at elevated
risk due to other factors (e.g., genetic mutations), or represent cancer subtypes that differentially
affect younger women. An alternative explanation of an association between OC use and
increased incidence may be more surveillance in women who use OCs. Women who use OCs
must come in contact with the health care system on a regular basis, thus increasing their chances
of receiving referrals for preventive screenings such as mammography.
We found no significant increase in the risk of cervical cancer among ever OC users
compared with never users across nine pooled studies. We also found no time-dependent
relationship as a function of duration of OC use. It is important to note that this contrast was
underpowered with only five included studies. However, women having long-term use of OCs
(≥5 years) were at an elevated but not statistically significant risk of cervical cancer compared
with never users.
Three studies (2,592 women) assessed OC use and cervical cancer incidence among HPV-
positive women. Results were similar to those of women not selected for HPV status. Many
studies did not control for factors that may influence risk, such as age at first OC use by duration
or age at sexual debut, which is likely highly correlated with age at first use. Future research is
needed to assess the additional cervical cancer risk associated with OC use among HPV-positive
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women. However, both studies reported statistically significant increased risk of death with ≥8
years of OC use compared with never use.
Our cervical cancer results differ in some ways from other evidence syntheses published over
the last 10 years. Smith and colleagues (13) pooled study-level data across 28 studies and found
an overall significant increase in the risk of cervical cancer when comparing ever versus never
users of hormonal contraceptives (RR = 1.2; CI, 1.1 to 1.3). We found a similar increase in the
risk of cervical cancers, but our summary estimate was not significant. Both our review and the
Smith study found the risk of cervical cancer increased with prolonged exposure. This effect
weakened but remained significant when stratifying duration by time since use. For our review,
this effect was significant only for women who used OCs for ≥5 years compared with never
users; we did not have sufficient studies to stratify by time since last use. The International
Collaborative of Epidemiological Studies of Cervical Cancer undertook a collaborative patient-
level reanalysis of 24 observational studies (105). Results expand the duration by recency effect.
The analysis found that excess risk of cervical cancers increases with duration of use, but this
effect declined after discontinuing OCs and was equivalent to the risk of nonusers after 10 years
of nonuse.
Key methodological differences between our study and the two recent syntheses preclude
drawing exact comparisons. First, we included only studies of invasive cervical cancers; other
studies also included carcinoma in situ and cervical intraepithelial neoplasia grade 3. It is likely
that effects differ between invasive cancers and cancer-precursor lesions. In fact, a case-case
comparison in the collaborative reanalysis showed significant differences in the risks for in situ
and invasive cervical cancers for nearly every category of time since last use by duration of use.
Second, we included studies that assessed only the effects of oral contraceptives; the two other
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recent syntheses included all forms of hormonal contraceptives. It is possible that formulation
differences contribute to some of the differences between our results and their findings.
However, the collaborative reanalysis reported separate findings for progestin-only injectable
contraceptives and found a similar pattern to those reported for OCs. Third, we did not include
the three studies conducted with women selected for HPV infection status. The effects of this
decision appear to be negligible; both prior reviews noted similar patterns of findings when
controlling for HPV status as a covariate (13) compared with HPV uncontrolled studies or
among the subset of women with a confirmed HPV infection compared with populations not
selected for HPV status (105). Last, we date-limited our search from 2000 forward in order to
minimize the effect of older formulations; other studies had no such date restrictions. Despite
these differences, we found similar patterns of increased risk by duration of use. There is no
direct evidence to suggest that cervical cancer screening recommendations should be different
based on duration of OC use.
We found that the risk of colorectal cancer was significantly decreased for women who have
ever used OCs compared with women who have never used OCs. However, we found no
evidence of a time-dependent relationship as a function of duration. Duration results should be
interpreted with caution; the test was underpowered.
Our results are similar to two other evidence syntheses that also assessed the risk of
colorectal cancers associated with OC use (11,106). These meta-analyses both found a pooled
relative risk of approximately 0.82, which is comparable to our pooled findings. These reviews
also found no increase in the protective effect by duration of use. The similarity between our
findings and those of the other two reviews is noteworthy. We limited our studies from January
2000 forward so that we had a greater probability of capturing a set of studies with newer OC
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formulations that may confer differential effects. Thus, we shared no studies in common with the
study by Fernandez and colleagues (106), and we excluded 12 older or non-English studies and
included five newer studies (63,68,90,93,95) compared with the systematic review by Bosetti
and colleagues (11). Similarity in our findings with these earlier evidence syntheses suggests that
OCs confer a significant protective effect for colorectal cancer, and future research could
investigate OCs potential as a beneficial therapy for chemoprevention.
We identified nine studies that evaluated the association between OC use and the incidence
of endometrial cancers; seven were included in our meta-analysis to assess ever versus never OC
use. We found a significant protective effect with ever OC use and a time-dependent relationship
as a function of duration categorized as <60 months and ≥60 months of total use.
Our study is one of the few systematic reviews and meta-analyses to summarize the evidence
on the effects of OCs on endometrial cancers. Grimes and colleagues (107) conducted a
systematic review and qualitative synthesis of studies up to 1993. They identified 13 case-control
studies with protective ORs ranging from 0.1 to 0.6, with most effects clustering around 0.5.
Two of the three cohort studies identified also found protective effects of OC use. Schlesselman
and colleagues (108) conducted a meta-analysis of 11 case-control studies. A significant duration
trend was reported such that longer durations of use conferred greater protection (RR = 0.44 for
4 years of use; RR = 0.33 for 8 years of use; RR = 0.28 for 12 years of use; P < 0.0001). We
found a similar trend but used a different analytic approach; direct comparisons are difficult to
draw. This meta-analysis also reported on time since last use and found that the protective effect
of OCs is diminished after they are discontinued but still persists even 20 years after cessation.
We did not have sufficient studies to assess the effect of time since last use. Protective effects of
OCs may vary with formulation. However, our results are similar to other studies conducted in
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the 1990s that may have included different formulations based on market availability.
Unfortunately, there is limited data on the formulations used in the majority of the studies
reviewed, and it is likely that the distribution of formulations in the studies included in this
review are different compared to contemporary OC formulation distribution. If the association
between OC use and cancer varies based on formulation, particularly estrogen dosage and type
of progestin, then estimates of reduction or increases in future cancer risk among current pill
users are subject to considerable additional uncertainty. Our results—in combination with other
evidence reviews—confirm that OCs confer a significant protective effect on the risk of
endometrial cancers.
Limitations
While we performed a comprehensive systematic review and evidence synthesis of the
current research on OC use and the incidence of breast, cervical, colorectal, and endometrial
cancers, there are limitations to our approach and findings. As expected, we identified no
randomized trials; such studies are not likely feasible. Thus, we included only observational
studies in our meta-analyses. Even the highest quality observational studies are susceptible to
multiple forms of bias (e.g., confounding). Most included studies adjusted for multiple likely
sources of cofounding; when possible, we used the most adjusted point estimates in our meta-
analyses. Recall bias is also a common source of diminished quality in observational studies. Our
findings were remarkably similar across case-control studies and cohort studies, which suggests
a lack of evidence for recall bias of OC use across study types. Also, we found significant
heterogeneity across many of our comparisons. We included a diverse group of studies
conducted across the world; differences in study populations and geographic variability in other
risk factors not routinely assessed (e.g., access to health care) likely contributed to this
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heterogeneity. This may be particularly true for cancers such as breast, cervical, and colorectal,
where screening can affect both incidence and mortality and where there may be associations
between OC use and screening behaviors. Sensitivity analyses using only U.S.-based studies (or
with patients from the U.S.) showed similar patterns to unrestricted analyses. Also, studies varied
considerably in the type and specification of covariates, which may be a likely source of
heterogeneity. To try to maximize the proportion of subjects who used OC formulations similar
to those currently on the market, we included only studies published in 2000 and later However,
study publication date is a gross estimate of OC formulation exposure because observational
studies published since 2000 still represents some cohorts exposed to earlier formulations. It may
have been preferable to limit studies by year of diagnosis instead of publication date. Yet, many
of our findings are consistent with other meta-analyses without date restrictions, which suggests
that current OC formulations may have similar carcinogenic or protective effects compared with
older formulations. Still, given the long latent period between exposure and tumor development,
it is likely that recent publications may not fully assess the effect of formulations introduced in
the past 20 years.
Conclusion
This systematic review of the literature identified several gaps in the evidence that warrant
future investigation. Several subgroups deserve further attention; there are limited data on the
effects of OCs on cancer risk in women at elevated risk of malignancy due to behavioral risk
factors such as smoking, heavy alcohol consumption, obesity, or physical inactivity. These
factors are known to be associated with cancer development, and so behavioral risk factors may
modify the association between OCs and cancers. We found that duration of use conferred a
different pattern of risk, but we found limited support of a time-dependent relationship. Because
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EPI-13-0298R Oral Contraceptive Use and Risk of Cancer
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the benefits and risks associated with OC use differ by pattern of use, more research is needed on
the interaction of different patterns of use (e.g., duration by time since last use, age at initiation
by duration) on the risk of breast, cervical, colorectal, and endometrial cancers in order to
optimize the risks and benefits of OC use.
Quantifying the potential impact of changes in OC formulations is difficult. Although our
analyses were based on more recently published data, and we did not identify an obvious
association based on probable dates of exposure within these studies, the long lag time between
"typical" exposure to OCs and incident cancers means that the distribution of formulations
among subjects in even the most recent literature is likely to be different than the distribution
among current OC users. This uncertainty affects both estimated harms (increased risk of breast
cancer) and benefits (decreased risk of endometrial and colorectal cancer).
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FIGURE LEGENDS
Figure 1. Literature flow diagram
*Note that a given study may address more than one outcome group.
MI, myocardial infarction; OC, oral contraceptive; RCT, randomized controlled trial; VTE,
venous thromboembolism
Figure 2. Forest plot of ever versus never oral contraceptive use and breast cancer
incidence
CI, confidence interval; OC, oral contraceptive
Figure 3. Forest plot of ever versus never oral contraceptive use and cervical cancer
incidence
CI, confidence interval; OC, oral contraceptive
Figure 4. Forest plot of ever versus never oral contraceptive use and colorectal cancer
incidence
CI, confidence interval; OC, oral contraceptive
Figure 5. Forest plot of ever versus never oral contraceptive use and endometrial cancer
incidence
CI, confidence interval; OC, oral contraceptive
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Published OnlineFirst September 6, 2013.Cancer Epidemiol Biomarkers Prev Jennifer M. Gierisch, Remy R. Coeytaux, Rachel Peragallo Urrutia, et al. and Endometrial Cancers: A Systematic ReviewOral Contraceptive Use and Risk of Breast, Cervical, Colorectal,
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