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 Urrutia9, Laura J. Havrilesky5,7,Patricia G. Moorman4, William J. Lowery5, Michaela Dinan8, Amanda J. McBroom2, Vic Hasselblad6,Gillian D. Sanders2,3, and Evan R. Myers5
AbstractOral contraceptives 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 oral contraceptive 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 oral contraceptives for contraception or ovarian cancer prevention;
includes comparison group with no oral contraceptive use; study reports quantitative associations between
oral contraceptive 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 conducted by estimating pooled ORs with 95%
confidence intervals (CIs). 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 oral contraceptives. Risk of cervical cancer
was increased with duration of oral contraceptive 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 oral contraceptive use. Compared with
never use, ever use of oral contraceptives 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 oral contraceptives may contribute to a substantial
number of cases. Cancer Epidemiol Biomarkers Prev; 22(11); 1931–43. �2013 AACR.
IntroductionOral contraceptives, themost common form of effective
and reversible contraception in the United States (1),significantly decrease the personal and societal burdensassociatedwithunintendedorunwantedpregnancy (2, 3).Oral contraceptives also have significant noncontracep-tive health benefits such as improving acne and regulating
dysmenorrhea (4–7). However, oral contraceptive use isnot without risks. Many studies show serious adverseevents associated with oral contraceptive use includingvenous thromboembolic disease, myocardial infarction,and stroke (8–10).
In addition to the risk of acute harms, the use of oralcontraceptives may influence the risk of certain cancers(11). Oral contraceptive use may promote or initiatetumors of the breast or cervix (12–14). For breast cancer,these risksmay be even greater forwomen at elevated riskdue to family history of cancer or genetic mutation carrierstatus (e.g., BRCA1/2); however, results from studies areinconclusive (15, 16). Oral contraceptive use has also beenassociated with a greater risk of certain clinically chal-lenging types of breast tumors (17). Conversely, oralcontraceptive use is associatedwith significant reductionsin colorectal, endometrial, andovarian cancers (11, 18–20).A recent systematic review and meta-analysis supports asignificant risk reduction for ovarian cancer incidence andmortality associated with the use of oral contraceptives(20).
Assessing the risk of cancer associated with oral con-traceptive use is fraught with difficulties. For example,cancer is a diseasewith a long latency period, and the time
Authors' Affiliations: 1Center for Health Services Research in PrimaryCare, Durham Veterans Affairs Medical Center; 2Duke Evidence-BasedPractice Center, Duke Clinical Research Institute; Departments of 3Med-icine, 4Community and Family Medicine, 5Obstetrics and Gynecology, and6Biostatistics and Bioinformatics, Duke University School of Medicine;7Duke Cancer Institute, Duke University Health System; 8Duke ClinicalResearch Institute, Durham; and 9Department of Obstetrics and Gynecol-ogy, University of North Carolina at Chapel Hill School of Medicine, ChapelHill, North Carolina
Note: Supplementary data for this article are available at Cancer Epide-miology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).
Corresponding Author: Jennifer M. Gierisch, Department of Medicine,DukeUniversityMedical Center, CampusBox 104427DUMC, Durham, NC27701. Phone: 919-668-5519; Fax: 919-668-1300; E-mail:[email protected]
between exposure to oral contraceptives and diagnosis ofcancer may span decades. Also, temporal variations inoral contraceptive formulations available on the marketand used over a woman’s lifetime may influence associa-tions between cancer risk and oral contraceptive use.Furthermore, patterns of oral contraceptive use over alifetime may be influenced by factors that also affectcancer risks (e.g., gravidity, parity, breastfeeding). Dura-tion of oral contraceptive use or length of time sinceceasing use (i.e., recency) may also modify the risk ofcancers associated with oral contraceptives (13, 21).
We conducted a systematic review and meta-analysis,sponsored by the Agency for Healthcare Research andQuality (AHRQ) and the Centers for Disease Control andPrevention (CDC), to inform the use of oral contraceptivesto reduce the risk of ovarian cancer (20). In addition to theprimary question regarding ovarian cancer, we alsoaddressed other harms and benefits of oral contraceptiveuse. In this article, we examine the evidence for associa-tions between oral contraceptive use and the risks ofdeveloping 4 cancers: breast, cervical, colorectal, andendometrial. When possible, we conducted meta-analy-ses of the literature to assess the risk of developing thesecancers following oral contraceptive use; we also exam-ined risk by duration of oral contraceptive use and timesince last oral contraceptive use (20).
Materials and MethodsWe followed the methodology recommended in
AHRQ’s "Methods Guide for Effectiveness and Compar-ative Effectiveness Reviews" (22). Methods are summa-rized here, with complete details provided in the fullAHRQ report (20).
Search strategyIn collaboration with an experienced librarian, we con-
ducted searches of PubMed, Embase, the Cochrane Data-base of Systematic Reviews, and ClinicalTrials.gov toidentify relevant published literature. Our searches weredate-limited to articles published from January 1, 1990 toJune 29, 2012. For the outcomes presented in this article,we restricted the results to 2000 forward for the followingreason. Formulations of oral contraceptives have beenchanged and updated almost continuously since theirintroduction to the U.S. market in 1957; such changeshave not occurred at discrete time points. Also, year-by-year market share, duration of use, and patterns ofuse are not readily available andwould vary based on thecountry in which a given study was conducted. Realizingthe inaccuracy of any discrete cutoff date with regard tocurrent oral contraceptive formulations, we limited thepublication years of included studies to those publishedfrom 2000 forward to try to maximize the proportion ofsubjectswhoused oral contraceptive formulations similarto those currently on the market. We supplemented elec-tronic searches with amanual search of citations from keyreview articles. Exact search strings are provided inAppendix A of the full AHRQ report (20).
Selection criteriaInclusion criteria for studies relevant to this article
were: (i) study includeswomen taking oral contraceptivesfor contraception or primary prevention of ovarian can-cer; (ii) study includes comparison group with no useof combination or progestin-only oral contraceptives(either no contraceptive method at all or contraceptivemethods other than combination or progestin-only oralcontraceptives); (iii) study reports quantitative associa-tions between exposure to oral contraceptives and breast,cervical, colorectal, or endometrial cancer incidence; (iv)controlled study (randomized trials, cohort studies, case–control studies) or pooled patient-level meta-analyses; (v)sample size for nonrandomized studies�100 subjects; (vi)study is peer-reviewed and English-language; and (vii)published on or after January 1, 2000. Exclusion criteriawere: (i) study reports outcomes related to the use of oralcontraceptives only for contraception, or in specializedpopulations such as women immediately post-termina-tion of pregnancy, or women receiving assisted reproduc-tive technologies; (ii) study does not provide a descriptionof the oral contraceptive formulation(s) or length of oralcontraceptive use; or (iii) publication type is editorial,review, or letter to the editor.
Reviewer pairs used prespecified criteria to assess titlesand abstracts. Full-text articles included by either review-er underwent further evaluation. Eligibility decisions anddisagreementswere reconciled throughdiscussion or by athird reviewer. For included studies, we abstracted dataon study populations, interventions, outcomes, quality,andapplicability.Weused criteriadevelopedbyAHRQtoassess study quality, summarized as good, fair, or poor(22). Quality ratings for individual articles within studygroupings could differ based on articles’ reporting qual-ity, evaluated outcomes, and statistical and analyticalmethods used. We screened and abstracted data usingDistillerSR software (Evidence Partners Inc.).
Data synthesisWhen at least 3 studies were available with compa-
rable study designs and outcomes, we conducted ran-dom-effects meta-analyses grouped by study design(case–control or cohort study) and estimated pooledORs with 95% confidence intervals (CI). As there wereno significant differences by design, we used a random-effects model to combine subgroups and estimate theoverall effect. When studies reported multiple models,we used the most adjusted model. We evaluated het-erogeneity visually and with the Cochran Q statisticusing a threshold P < 0.10. We included pooled analysesin our meta-analyses if all these conditions were met bythe pooled analysis: none of the individual articles werealready included in the meta-analysis, at least half of thestudies were published on or after January 1, 2000, anddata were presented such that their inclusion in meta-analysis was feasible.
Not all studies meeting criteria for inclusion in thereview were included in meta-analyses. The reasons for
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exclusion from meta-analysis were (i) study populationsthat represented specialized subgroups (e.g.,BRCAmuta-tion, family history, age at diagnosis � 45 years, cancersubtype); (ii) studies that reported a subset of results fromthe same study as another article already included in theanalysis; and (iii) studies that didnot report anOR for everoral contraceptiveuseversusnever oral contraceptiveuse.When studies gave results only by subgroup (premeno-pausal, postmenopausal), we combined subgroups togenerate an estimate only when the combined grouprepresented a broad population. When possible, we con-ducted sensitivity analyses by including only U.S.-basedstudies. These analyses were conducted using Compre-hensive Meta-Analysis Version 2 (23).
We estimated the increase ordecrease in absolute risk ofcancer from estimates of the lifetime incidence of malig-nant cases for women beginning at age 45 years generatedusing the National Cancer Institute’s DevCan software(24), estimated lifetime ever use of oral contraceptivesfrom the National Survey of Family Growth (25), and theORs (with 95% CIs) produced in our meta-analyses. Wethen calculated the number needed to treat (NNT) ornumber needed to harm (NNH) by taking the inverse ofthe absolute risk. Because we were unable to conductmeta-analysis of the association of oral contraceptive useand cervical cancer among populations that were selectedfor HPV-positive status, we were unable to generateestimates of change in absolute risk.
Figure 1. Literature flow diagram.�Note that a given study mayaddress more than one outcomegroup. MI, myocardial infarction;OC, oral contraceptive; RCT,randomized controlled trial; VTE,venous thromboembolism.
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When we had sufficient studies to assess the effect ofduration of oral contraceptive use, we used a random-effects model to compute ORs. We required that the ORswere given relative to no oral contraceptive use and thatthe population studied was not restricted to a particularsubpopulation. The challenge of conducting a meta-anal-ysis on duration of oral contraceptive use is that individ-ual studies reported ORs for different duration intervals.We assumed that the logarithm of each OR could bedescribed by a linear model. The model included a ran-dom-effects term, s2, as well as terms for time pointintervals. We then used independent variables to createthe time period desired. The model was fitted using SASPROC NLMIXED (SAS Institute Inc.; 2009) with "subject"set to the particular study.
We evaluated strength of evidence using the approachdescribed in AHRQ’s "Methods Guide" (22, 26).
ResultsOf the 6,476 unique citations screened, we identified
44 studies relevant to breast, 12 to cervical, 11 to colo-rectal, and 9 to endometrial cancers (Fig. 1). Severalincluded studies were relevant to more than one out-come of interest. All studies were observational; we didnot identify any eligible randomized controlled trials.We did not identify any qualitative difference between
breast, cervical, colorectal, or endometrial cancers andoral contraceptive use based on probable dates of expo-sure when examined by study recruitment date versuspublication date.
Breast cancer incidenceForty-four studies (19 good quality, 25 fair, and 3 poor)
evaluated the association between oral contraceptive useand breast cancer incidence (16, 17, 27–78). Of these, 29were case–control studies, 14 were cohort studies, and 1was a pooled analysis (Supplementary Table S1). Fifteencase–control studies (38,682 women; refs. 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; refs. 59–61, 63, 65, 67–69) metcriteria for meta-analysis examining ever versus neveroral contraceptive use. Figure 2 shows the results suggest-ing that a history of oral contraceptive use slightly butsignificantly increases breast cancer incidence comparedwith never oral contraceptive use (OR, 1.08; 95% CI, 1.00–1.17), with a Q value of 73.35 for 21 degrees of freedom(DF); P < 0.001. In a sensitivity analysis of only U.S.-basedstudies, effect sizes were smaller and no longer statisti-cally significant (OR, 1.03; CI, 0.93–1.14). On the basis ofthe point estimates of the meta-analyses, the approximateincrease in estimated lifetime absolute risk of breast
Figure 2. Forest plot of ever versusnever oral contraceptive use andbreast cancer incidence.
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cancer from ever use of oral contraceptives 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 exam-ining duration of oral contraceptive use. We found notime-dependent relationship as a function of durationof use: 1–12 months (OR, 0.95; CI, 0.83–1.09); 13–60months (OR, 1.03; CI, 0.92–1.15); 61–120 months (OR,1.01; CI, 0.90–1.13); and >120 months (OR, 1.04; CI,0.93–1.17). Heterogeneity was significant (t ¼ 5.84, 19DF, 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 sincelast oral contraceptive use. Results show a time-depen-dent relationship as a function of time since last oralcontraceptive use, with higher risk associated with morerecent use of oral contraceptives and ORs that approach 1(no effect) by �20 years of use: 0–5 years (OR, 1.21; CI,1.04–1.41); 5–10 years (OR, 1.17; CI, 0.98–1.38); 10–20 years(OR, 1.13;CI, 0.97–1.31);>20years (OR, 1.02;CI, 0.88–1.18).Heterogeneity was significant (s ¼ 0.12; t ¼ 4.95, 11 DF,P ¼ 0.0004).The strength of evidence for the effect of ever oral
contraceptive use on breast cancer incidence was mod-erate. Most studies were of good or fair quality, exhib-ited consistent findings, and confidence interval forsummary estimate were precise. However, all includedstudies were observational; thus there may be some riskof bias due to limitations of the study designs. Thestrength of evidence was low for both duration of useand time since last use for risk of breast cancer inci-dence; results were inconsistent with a high level ofheterogeneity across studies.
the association between oral contraceptive use and cervi-cal cancer incidence (63, 65, 66, 69, 70, 73, 79–87), including2 articles from an International Agency for Research onCancer (IARC) study representing distinct populations(86, 87). Of these, 9 were case–control studies, 3 werecohort studies, and 1was apooled analysis. Only 2 studieswere conducted with U.S.-based populations (Supple-mentary Table S2).Persistent infection with one or more oncogenic HPV
types is required for cervical carcinogenesis; thus, wom-en who are HPV-positive represent the most relevantpopulation to assess the risks for cervical cancer asso-ciated with oral contraceptive use. Only 3 studies(80, 83, 86) assessed the association between oral con-traceptive use and cervical cancer among women whoare HPV-positive. Limited studies across comparisonsprecluded quantitative synthesis; we summarize eachstudy below.One fair-quality study (86) pooled data from 8 case–
control studies of HPV-positive patients with cervicalcancer. Ever use of oral contraceptives was associatedwith a statistically nonsignificant increase in invasive
cervical cancer (OR, 1.29;CI, 0.88–1.91) and cervical cancerin situ (OR, 2.54; CI, 0.95–6.78). However, duration of usewas significantly associated with cancer incidence suchthat HPV-positive women who used oral contraceptivesfor 5 to 9 years (OR, 2.82; CI, 1.46–5.42) and�10 years (OR,4.03; CI, 2.09–8.02) experienced a significant increase inthe risk of cervical cancers compared with never users.This estimatedidnot varyby time sincefirst or last use; thetrend was not observed for women who used oral contra-ceptives for <5 years.
Two case–control studies (80, 83), both rated poorquality, also assessed the risk of cervical cancer associatedwith oral contraceptive use amongHPV-positive women.One study (80) recruited hospital-based HPV-positivecases and controls in Lima, Peru. Results of this studywere included in the pooled analysis above and, thus,could not be combined again. Compared with HPV-pos-itive controls, HPV-positive women who had ever usedoral contraceptiveswere at elevated risk of cervical cancercompared with women who had never used oral contra-ceptives (OR, 2.7; CI, 0.90–8.4), but the contrast was notsignificant. This study did not compute any analysis byduration of use.
The other case–control study (83) assessed the associ-ation between oral contraceptive use and cervical canceramong hospital-based HPV-positive cases and HPV-pos-itive community controls in the United States. This studyassessed duration of oral contraceptive use; ever useversus never use was not calculated. Increasing the dura-tion of oral contraceptive use—categorized as <5, 5–10,and >10 years—was associatedwith a decrease in cervicalcancers. This trendwas significant only inwomenwith <5years of use compared with never users (OR, 0.6; CI, 0.4–0.9).
In populations that were not selected for HPV-positivestatus, 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 themeta-analysis examining ever versus never oral con-traceptive use. Figure 3 shows results indicating increasedodds of cervical cancer forwomenwho had ever used oralcontraceptives compared with women who never usedoral contraceptives (OR, 1.21; CI, 0.91–1.61), but the com-parison was not significant. There was a large amount ofheterogeneity (Q¼ 25.52, 7 DF, P < 0.001), possibly due todifferences inHPV status among studies, whichmade theestimates unstable. We could not conduct sensitivityanalysis by U.S.-based studies because only one studywas conductedwithin the United States. Results from thiscase–control study (79) show a statistically significantincrease in risk with ever use of oral contraceptives (OR,2.7; CI, 1.2–5.8).
Six studies (63, 79, 81, 82, 85, 87) met criteria for themeta-analysis examining duration of oral contraceptiveuse. Results show no time-dependent relationship as afunction of duration: 1–60months (OR, 0.99; CI, 0.58–1.70)and >60 months (OR, 1.47; CI, 0.91–2.38). Heterogeneitywas significant (t ¼ 4.72; 5 DF, P ¼ 0.0033).
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The strength of evidence for the effect of ever oralcontraceptive use on cervical cancer incidence amongHPV-positive women was insufficient. Only 3 studiesassessed risk in HPV-positive women, and most wereof poor quality. Results were inconsistent, sensitivityanalysis yielded qualitatively different estimates ofeffects, and CIs were wide. Studies did not control forfactors that may influence risk such as age at first useby duration or age at sexual debut, which is likelyhighly correlated with age at first use. Future studiescould influence magnitude and, possibly, direction ofeffect.
the association between oral contraceptive use and colo-rectal cancer incidence (63, 65, 66, 68, 88–95). Of these, 3were case–control studies, 7 were cohort studies, and 1was a pooled analysis. Nine studies were conducted inWestern countries and 2 in China (Supplementary TableS3).
Three case–control studies (88–90), 1 pooled analysis(94), and 7 cohort studies (63, 65, 68, 91–93, 95) repre-senting 503,816 women across 8 studies and 2,969,189person-years across 3 studies met criteria for the meta-analysis examining ever versus never oral contracep-tive use. Figure 4 shows the results showing a decreasein the risk of colorectal cancers among women whoever used oral contraceptives compared with womenwho never used oral contraceptives (OR, 0.86; CI, 0.79–0.95; Q ¼ 17.17, P < 0.046). We conducted sensitivityanalyses of studies that included only patients fromthe United States; results were similar to analysescontaining all studies, but the confidence intervaleclipsed 1 (OR, 0.83; CI, 0.69–1.01). On the basis of thepoint 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 themeta-analysis examining duration of oral contraceptiveuse. We categorized duration of use into 2 intervals andfound no time-dependent relationship as a function ofduration: 1–60 months (OR, 0.88; CI, 0.77–1.01) and >60months (OR, 0.88; CI, 0.76–1.01). There was no significantheterogeneity (t ¼ 1.52; 9 DF, P ¼ 0.164).
The strength of evidence for the effect of oral contracep-tive use on colorectal cancer incidence was moderate.Results were consistent across studies, and the summaryestimate showed high precision with a tight CI. Futurestudies will not likely have an impact on the direction ofeffect but may slightly influence the magnitude of theeffect. The strength of evidence for duration was insuffi-cient; the test was underpowered and we found signifi-cant heterogeneity.
the association between oral contraceptive use and endo-metrial cancer incidence (63, 65, 66, 69, 70, 73, 96–100). Ofthese, 4 were case–control studies and 5 were cohortstudies. Only 2 studies were conducted in the UnitedStates (Supplementary Table S4).
Three case–control studies (73, 97, 100) and 4 cohortstudies (63, 65, 69, 98) representing 308,198 women (with-in 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 oral contraceptiveuse. Figure 5 shows results indicating a protective effectfor endometrial cancer associated with ever oral con-traceptive use (OR, 0.57; CI, 0.43–0.77). Heterogeneitywas significant (Q ¼ 26.11, 6 DF, P < 0.001). We alsoexplored how our findings changed when including only
Figure 3. Forest plot of ever versusnever oral contraceptive use andcervical cancer incidence.
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U.S.-based studies. Only one study was conducted withpatients from the United States and reported a somewhatgreater protective effect than summary estimates for allstudies (OR, 0.34; CI, 0.25–0.47). On the basis of the pointestimates of the meta-analyses, the approximate decreasein absolute risk of endometrial cancer is 1.77% (NNT 60).
DiscussionOur results are confirmatory of initial analyses and
reviews, including those which included studies pub-lished before 2000. This evidence synthesis highlightssome of the tradeoffs about nonreproductive outcomesthat patients and providers need to consider with the useof oral contraceptives: increased risk for some cancers
(breast and cervical) but decreased risk for others (colo-rectal and endometrial). Other considerations includedecreased risk of ovarian cancer (101) and increased riskfor thromboembolic events (102). Estimating the overallbalance of benefit and harm is difficult from a technicalsense and because the timing of the outcomes affected byoral contraceptiveuse is variable—some risks andbenefitsare seen only during use, whereas others occur 20 to 30years in the future. Moreover, different patients may wellhave different values for those outcomes.
We found that the risk of breast cancer was slightly—but significantly—elevated for women who have everused oral contraceptives compared with women whohave never used oral contraceptives. Although the
Figure 4. Forest plot of ever versusnever oral contraceptive use andcolorectal cancer incidence.
Figure 5. Forest plot of ever versusnever oral contraceptive use andendometrial cancer incidence.
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relative increase in riskwas small (OR, 1.08), the relativelyhigh incidence of breast cancer diagnosis means that oralcontraceptive use may contribute to a substantial numberof cases. We found no time-dependent relationship as afunction of duration of oral contraceptive use. Durationresults should be interpreted with caution; there wassignificant heterogeneity, and the test was underpow-ered—which is not surprising, given that breast canceris relatively uncommon during the ages whenwomen aremost likely to be using oral contraceptives. We also foundthat women with more recent use had an elevated risk ofbreast cancer, with decreasing risk over time, so that by 10years since last use, the risk among users was equivalentto never users.
Our results are consistent with results of other meta-analyses and pooled analyses that identified a smallincrease in the relative risk of breast cancer associatedwith having ever used oral contraceptives—a risk thatdiminishes over time since last use (12, 103). The Collab-orative Group on Hormonal Factors in Breast Cancer, acollaborative reanalysis of individual data in 153,536women, found a small but significant increase in therelative risk of breast cancer (OR, 1.07 � 0.02; ref. 12).Similar to our results, the Collaborative Group did notidentify an increase in riskwith increasing duration of useor after discontinuation of use for �10 years. Anotherrecent meta-analysis of premenopausal breast canceracross 37 studies found a somewhat larger increase inthe risk (OR, 1.19; CI, 1.09–1.29), with the greatest riskassociated with oral contraceptive use before first full-term pregnancy (OR, 1.44; CI, 1.28–1.62; ref. 104). Theseresults support our finding that recent use (�5 years) isassociatedwith an increased risk of breast cancer.Womenwho delay first full-term pregnancies may also be morelikely to be recent users of oral contraceptives relativeto a breast cancer diagnosis. These results cannot bedirectly compared with ours, as this meta-analysis wasrestricted to premenopausal women or women <50years who may be at elevated risk due to other factors(e.g., genetic mutations) or represent cancer subtypesthat differentially affect younger women. An alternativeexplanation of an association between oral contracep-tive use and increased incidence may be more surveil-lance in women who use oral contraceptives. Womenwho use oral contraceptives must come in contact withthe health care system on a regular basis, thus increas-ing their chances of receiving referrals for preventivescreenings such as mammography.
We found no significant increase in the risk of cervicalcancer among ever oral contraceptive users comparedwith never users across 9 pooled studies. We also foundno time-dependent relationship as a function of durationof oral contraceptive use. It is important to note that thiscontrast was underpoweredwith only 5 included studies.However, women having long-term use of oral contra-ceptives (�5 years)were at an elevated but not statisticallysignificant risk of cervical cancer compared with neverusers.
Three studies (2,592 women) assessed oral contracep-tive use and cervical cancer incidence among HPV-positive women. Results were similar to those of womennot selected for HPV status. Many studies did notcontrol for factors that may influence risk, such as ageat first oral contraceptive use by duration or age atsexual debut, which is likely highly correlated with ageat first use. Future research is needed to assess theadditional cervical cancer risk associated with oral con-traceptive use among HPV-positive women. However,both studies reported statistically significant increasedrisk of death with �8 years of oral contraceptive usecompared with never use.
Our cervical cancer results differ in some ways fromother evidence syntheses published over the last 10years. Smith and colleagues (13) pooled study-level dataacross 28 studies and found an overall significantincrease in the risk of cervical cancer when comparingever versus never users of hormonal contraceptives[relative risk (RR), 1.2; CI, 1.1–1.3). We found a similarincrease in the risk of cervical cancers, but our summaryestimate was not significant. Both our review and theSmith study found the risk of cervical cancer increasedwith prolonged exposure. This effect weakened butremained significant when stratifying duration by timesince use. For our review, this effect was significant onlyfor women who used oral contraceptives for �5 yearscompared with never users; we did not have sufficientstudies to stratify by time since last use. The Interna-tional Collaborative of Epidemiological Studies of Cer-vical Cancer undertook a collaborative patient-levelreanalysis of 24 observational studies (105). Resultsexpand the duration by recency effect. The analysisfound that excess risk of cervical cancers increases withduration of use, but this effect declined after disconti-nuing oral contraceptives and was equivalent to the riskof nonusers after 10 years of nonuse.
Keymethodological differences between our study andthe 2 recent syntheses preclude drawing exact compar-isons. First, we included only studies of invasive cervicalcancers; other studies also included carcinoma in situ andcervical intraepithelial neoplasia grade 3. It is likely thateffects differ between invasive cancers and cancer pre-cursor lesions. In fact, a case–case comparison in thecollaborative reanalysis showed significant differences inthe risks for in situ and invasive cervical cancers for nearlyevery category of time since last use by duration of use.Second, we included studies that assessed only the effectsof oral contraceptives; the 2 other recent syntheses includ-ed all forms of hormonal contraceptives. It is possible thatformulation differences contribute to some of the differ-ences between our results and their findings. However,the collaborative reanalysis reported separate findings forprogestin-only injectable contraceptives and found a sim-ilar pattern to those reported for oral contraceptives.Third, we did not include the 3 studies conducted withwomen selected for HPV infection status. The effects ofthis decision appear to be negligible; both prior reviews
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noted similar patterns of findings when controlling forHPV status as a covariate (13) compared with HPVuncontrolled studies or among the subset of women witha confirmed HPV infection compared with populationsnot selected for HPV status (105). Last, we date-limitedour search from 2000 forward to minimize the effect ofolder formulations; other studies had no such date restric-tions. Despite these differences,we found similar patternsof increased risk by duration of use. There is no directevidence to suggest that cervical cancer screening recom-mendations should be different based on duration of oralcontraceptive use.We found that the risk of colorectal cancer was signif-
icantly decreased for women who have ever used oralcontraceptives compared with women who have neverused oral contraceptives. However,we foundno evidenceof a time-dependent relationship as a function ofduration.Duration results should be interpreted with caution; thetest was underpowered.Our results are similar to 2 other evidence syntheses
that also assessed the risk of colorectal cancers associatedwith oral contraceptive use (11, 106). Thesemeta-analysesboth found a pooled relative risk of approximately 0.82,which is comparable to our pooled findings. Thesereviews also found no increase in the protective effect byduration of use. The similarity between our findings andthose of the other 2 reviews is noteworthy.We limited ourstudies from January 2000 forward so that we had agreaterprobability of capturing a set of studieswithneweroral contraceptive formulations that may confer differen-tial effects. Thus, we shared no studies in common withthe study by Fernandez and colleagues (106), and weexcluded 12 older or non-English studies and included5 newer studies (63, 68, 90, 93, 95) compared with thesystematic review by Bosetti and colleagues (11). Similar-ity in our findings with these earlier evidence synthesessuggests that oral contraceptives confer a significant pro-tective effect for colorectal cancer, and future researchcould investigate oral contraceptives potential as a ben-eficial therapy for chemoprevention.We identified 9 studies that evaluated the association
between oral contraceptive use and the incidence ofendometrial cancers; 7 were included in our meta-anal-ysis to assess ever versus never oral contraceptive use.We found a significant protective effect with ever oralcontraceptive use and a time-dependent relationshipas a function of duration categorized as <60 and �60months of total use.Our study is one of the few systematic reviews and
meta-analyses to summarize the evidence on the effects oforal contraceptives on endometrial cancers. Grimes andcolleagues (107) conducted a systematic review and qual-itative synthesis of studies up to 1993. They identified 13case–control studieswith protectiveORs ranging from 0.1to 0.6,withmost effects clustering around 0.5. Twoof the 3cohort studies identified also found protective effects oforal contraceptive use. Schlesselman and colleagues (108)conducted a meta-analysis of 11 case–control studies. A
significant duration trend was reported such that longerdurations of use conferred greater protection (RR, 0.44 for4 years of use; RR, 0.33 for 8 years of use; RR, 0.28 for 12years of use;P< 0.0001).We founda similar trendbut useda different analytic approach; direct comparisons aredifficult to draw. Thismeta-analysis also reported on timesince last use and found that the protective effect of oralcontraceptives is diminished after they are discontinuedbut still persists even 20 years after cessation. We did nothave sufficient studies to assess the effect of time since lastuse. Protective effects of oral contraceptives may varywith formulation. However, our results are similar toother studies conducted in the 1990s that may haveincluded different formulations based on market avail-ability. Unfortunately, there are limited data on the for-mulations used in the majority of the studies reviewed,and it is likely that the distribution of formulations in thestudies included in this review is different compared tocontemporary oral contraceptive formulation distribu-tion. If the association between oral contraceptive use andcancer varies based on formulation, particularly estrogendosage, and type of progestin, then estimates of reductionor increases in future cancer risk among current pill usersare subject to considerable additional uncertainty. Ourresults—in combination with other evidence reviews—confirm that oral contraceptives confer a significant pro-tective effect on the risk of endometrial cancers.
LimitationsWhile we conducted a comprehensive systematic
review and evidence synthesis of the current researchon oral contraceptive use and the incidence of breast,cervical, colorectal, and endometrial cancers, there arelimitations to our approach and findings. As expected,we identified no randomized trials; such studies arenot likely feasible. Thus, we included only observationalstudies in our meta-analyses. Even the highest qualityobservational studies are susceptible to multiple formsof bias (e.g., confounding). Most included studiesadjusted for multiple likely sources of cofounding;when possible, we used the most adjusted point esti-mates in our meta-analyses. Recall bias is also a com-mon source of diminished quality in observationalstudies. Our findings were remarkably similar acrosscase–control studies and cohort studies, which suggestsa lack of evidence for recall bias of oral contraceptiveuse across study types. Also, we found significant het-erogeneity across many of our comparisons. We includ-ed a diverse group of studies conducted across theworld; differences in study populations and geographicvariability in other risk factors not routinely assessed(e.g., access to health care) likely contributed to thisheterogeneity. This may be particularly true for cancerssuch as breast, cervical, and colorectal, where screeningcan affect both incidence and mortality and where theremay be associations between oral contraceptive use andscreening behaviors. Sensitivity analyses using onlyU.S.-based studies (or with patients from the United
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States) showed similar patterns to unrestricted analyses.Also, studies varied considerably in the type and spec-ification of covariates, which may be a likely source ofheterogeneity. To try to maximize the proportion ofsubjects who used oral contraceptive formulations sim-ilar to those currently on the market, we included onlystudies published in 2000 and later. However, studypublication date is a gross estimate of oral contraceptiveformulation exposure because observational studiespublished since 2000 still represents some cohortsexposed to earlier formulations. It may have been pref-erable to limit studies by year of diagnosis instead ofpublication date. Yet many of our findings are consis-tent with other meta-analyses without date restrictions,which suggest that current oral contraceptive formula-tions may have similar carcinogenic or protective effectscompared with older formulations. Still, given the longlatent period between exposure and tumor develop-ment, it is likely that recent publications may not fullyassess the effect of formulations introduced in the past20 years.
ConclusionThis systematic review of the literature identified
several gaps in the evidence that warrant future inves-tigation. Several subgroups deserve further attention;there are limited data on the effects of oral contracep-tives on cancer risk in women at elevated risk of malig-nancy due to behavioral risk factors such as smoking,heavy alcohol consumption, obesity, or physical inac-tivity. These factors are known to be associated withcancer development, and so behavioral risk factors maymodify the association between oral contraceptives andcancers. We found that duration of use conferred adifferent pattern of risk, but we found limited supportof a time-dependent relationship. Because the benefitsand risks associated with oral contraceptive use differby pattern of use, more research is needed on theinteraction of different patterns of use (e.g., durationby time since last use, age at initiation by duration) onthe risk of breast, cervical, colorectal, and endometrialcancers to optimize the risks and benefits of oral con-traceptive use.
Quantifying the potential impact of changes in oralcontraceptive formulations is difficult.Althoughour anal-
yses were based onmore recently published data, andwedid not identify an obvious association based on probabledates of exposure within these studies, the long lag timebetween "typical" exposure to oral contraceptives andincident cancers means that the distribution of formula-tions among subjects in even the most recent literature islikely to be different than the distribution among currentoral contraceptive users. This uncertainty affects bothestimated harms (increased risk of breast cancer) andbenefits (decreased risk of endometrial and colorectalcancer).
Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.
DisclaimerThe authors of this report are responsible for its content. Statements in
the report should not be construed as endorsement by AHRQ, CDC, theU.S. Department ofHealth andHuman Services, or theU.S. Department ofVeterans Affairs.
Authors' ContributionsConception and design: J.M. Gierisch, R.M. Coeytaux, R.P. Urrutia, L.J.Havrilesky, A.J. McBroom, G.D. Sanders, E.R. MyersDevelopmentofmethodology: J.M.Gierisch, R.M.Coeytaux,R.P.Urrutia,L.J. Havrilesky, A.J. McBroom, G.D. Sanders, E.R. MyersAcquisition of data (provided animals, acquired and managed patients,provided facilities, etc.): J.M. Gierisch, R.M. Coeytaux, R.P. Urrutia, L.J.Havrilesky, P.G. Moorman, W.J. Lowery, A.J. McBroom, G.D. SandersAnalysis and interpretation of data (e.g., statistical analysis, biostatis-tics, computational analysis): J.M. Gierisch, R.M. Coeytaux, R.P. Urrutia,P.G.Moorman,W.J. Lowery,M.Dinan,A.J.McBroom,V.Hasselblad, G.D.Sanders, E.R. MyersWriting, review, and/or revision of the manuscript: J.M. Gierisch, R.M.Coeytaux, R.P. Urrutia, L.J. Havrilesky, P.G. Moorman, W.J. Lowery, M.Dinan, A.J. McBroom, G.D. Sanders, E.R. MyersAdministrative, technical, or material support (i.e., reporting or orga-nizing data, constructing databases): J.M. Gierisch, A.J. McBroomStudy supervision: G.D. Sanders
AcknowledgmentsThe authors thank Liz Wing, for editorial assistance; Kathryn Roth
Lallinger and Michael Musty, for project coordination; and Megan vonIsenburg, for help with the literature search and retrieval.
Grant SupportAll authors received support and this project was funded under
Contract No. 290-2007-10066-I from the Agency for Healthcare Researchand Quality (AHRQ) and the Centers for Disease Control and Prevention(CDC), U.S. Department of Health and Human Services.
Received March 19, 2013; revised August 21, 2013; accepted August 27,2013; published OnlineFirst September 6, 2013.
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Oral Contraceptives and Breast, Cervical, Colorectal, and Endometrial Cancers
www.aacrjournals.org Cancer Epidemiol Biomarkers Prev; 22(11) November 2013 1943
2013;22:1931-1943. 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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