Association Of Oral Contraceptive Use Research Articles

Abstract WMP108: Genomic Risk Scores And Oral Contraceptive-associated Ischemic Stroke Risk

Objective: To evaluate whether a genomic risk score for ischemic stroke (IS) modifies oral contraceptive (OC)-associated IS risk. Background: OCs are generally safe but vascular risk factors are known to increase OC-associated IS risk. If a genomic risk score could identify a subset of women with substantially increased risk of OC-associated IS, this could influence prescribing guidelines and reduce stroke events. Methods: In the Genetics of Early-Onset Stroke (GEOS) study, there were 340 premenopausal women (143 IS cases and 197 controls) with data on OC use within 30 days prior to index event for cases or prior to interview for controls. Using a previously validated genomic risk score (metaGRS) for IS based on 19 polygenic risk scores of vascular events and risk factors, we stratified our sample into tertiles of genomic risk and calculated the association between OC use and IS within each tertile. We tested if the association between OC use and IS depended on genomic risk of stroke using logistic regression with an OC use*metaGRS interaction term. Results: Among all women, OC use was significantly associated with IS (odds ratio = 2.4, p = 0.002). The odds ratio for IS associated with OC use decreased from 3.9 in the tertile with highest genomic risk of IS to 1.5 in the tertile with lowest genomic risk (see Table). The formal test of interaction was consistent with our hypothesis (p = 0.07) that the genomic risk score modifies the association of OC use with IS. Conclusions: The results of our exploratory analysis support the need for international collaboration to generate sufficient sample sizes to determine whether a genomic risk score could be clinically useful in reducing OC-associated IS.

Association of oral contraceptives and tubal ligation with antimüllerian hormone.

Oral contraceptives (OCs) and tubal ligation are commonly used methods of contraception that may impact ovarian function. Few studies have examined the association of these factors with antimüllerian hormone (AMH), a marker of ovarian aging. We examined the association of OC use and tubal ligation with AMH in the Nurses' Health Study II prospective cohort among a subset of 1,420 premenopausal participants who provided a blood sample in 1996-1999. History of OC use and tubal ligation were reported in 1989 and updated every 2 years until blood collection. We utilized generalized linear models to assess whether mean AMH levels varied by duration of and age at first use of OCs and history, age, and type of tubal ligation. In multivariable models adjusted for smoking, reproductive events, and other lifestyle factors, we observed a significant, inverse association between duration of OC use and mean AMH levels (P for trend = 0.036). Compared to women without a tubal ligation, AMH levels were significantly lower when the procedure included a clip, ring, or band (1.04 ng/ml vs 1.72 ng/ml, P < 0.01). AMH levels were not associated with age at first use of OCs or age at tubal ligation. Our analysis found an association between duration of OC use and certain types of tubal ligation with mean AMH levels. Further research is warranted to confirm the long-term association of these widely used contraceptive methods with AMH.

The use of oral contraceptive is inversely associated with the risk of type 2 diabetes mellitus among middle-aged women

Objective To assess the cross-sectional association between oral contraceptive (OC) use and type 2 diabetes mellitus (T2DM) risk among US women. Methods The data was obtained from the National Health and Nutrition Examination Survey (NHANES 2007–2018). OC use was assessed by questionnaires and the diagnosis of T2DM was confirmed by the glycosylated hemoglobin, fasting blood glucose, and self-report. Binary logistic regression models and the restricted cubic spline model were adopted to evaluate whether OC use was associated with T2DM. Results Compared with non-users, the odds ratio (OR) with 95% confidence interval (CI) of T2DM risk for the OC users was 0.71 (0.57–0.89) in unadjusted Model. The association remained significant in fully adjusted models, and the OR with 95%CI was 0.78 (0.62–0.99). In the stratified analyses, there was an inverse association of OC use with T2DM risk when women were overweight. Dose-response analysis also revealed an inversely nonlinear relationship between the duration of OC use and T2DM (p-value for linearity = .589). Conclusions Our findings suggested that OC use may be inversely associated with T2DM risk.

Association of oral contraceptives and tubal ligation with risk of early natural menopause.

What is the association of oral contraceptives (OCs) and tubal ligation (TL) with early natural menopause? We did not observe an association of OC use with risk of early natural menopause; however, TL was associated with a modestly higher risk. OCs manipulate hormone levels, prevent ovulation, and may modify the rate of follicular atresia, while TL may disrupt the blood supply to the ovaries. These mechanisms may be associated with risk of early menopause, a condition associated with increased risk of cardiovascular disease and other adverse health outcomes. We examined the association of OC use and TL with natural menopause before the age of 45 years in a population-based study within the prospective Nurses' Health Study II (NHSII) cohort. Participants were followed from 1989 to 2017 and response rates were 85-90% for each cycle. Participants included 106 633 NHSII members who were premenopausal and aged 25-42 years at baseline. Use, duration and type of OC, and TL were measured at baseline and every 2 years. Menopause status and age were assessed every 2 years. Follow-up continued until early menopause, age 45 years, hysterectomy, oophorectomy, death, cancer diagnosis, or loss to follow-up. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs adjusted for lifestyle, dietary, and reproductive factors. Over 1.6 million person-years, 2579 members of the analytic cohort experienced early natural menopause. In multivariable models, the duration, timing, and type of OC use were not associated with risk of early menopause. For example, compared with women who never used OCs, those reporting 120+ months of OC use had an HR for early menopause of 1.01 (95% CI, 0.87-1.17; P for trend=0.71). TL was associated with increased risk of early menopause (HR = 1.17, 95% CI, 1.06-1.28). Our study population is homogenous with respect to race and ethnicity. Additional evaluation of these relations in more diverse populations is important. To our knowledge, this is the largest study examining the association of OC use and TL with early natural menopause to date. While TL was associated with a modest higher risk of early menopause, our findings do not support any material hazard or benefit for the use of OCs. The study was sponsored by UO1CA176726 and R01HD078517 from the National Institutes of Health and Department of Health and Human Services. The work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors have no competing interests to report. N/A.

Oral contraceptive use by formulation and endometrial cancer risk among women born in 1947\u20131964: The Nurses\u2019 Health Study II, a prospective cohort study

Oral contraceptives (OCs) have been associated with long-term lower endometrial cancer risk; relatively little is known about associations with more recent OC formulations and associations with longer-term risk. A total of 107,069 women from the Nurses’ Health Study II recalled OC use from age 13 to baseline (1989); biennial questionnaires updated data on OC use until 2009. OCs were classified by estrogen and progestin type, dose, and potency based on reported brand. 864 incident endometrial cancer cases were identified through 2017. Multivariable Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals [95% CI] for the association of OC use with endometrial cancer risk. OC use was associated with lower endometrial cancer risk (ever use, HR 0.77 [95% CI 0.65–0.91]; >10 years of use, 0.43 [0.32–0.58] vs. never OC use). Inverse associations for duration were evident regardless of time since last use. Longer durations (> 5 years) of ethinyl estradiol (0.52 [0.41–0.67]) and second-generation progestins (0.43 [0.30–0.61]), both versus never use, were more strongly associated with lower risk than mestranol (0.66 [0.50–0.88], p-het = 0.01) and first-generation progestins (0.62 [0.49–0.78], p-het = 0.03). Inverse associations were generally observed for cross-classified cumulative average estrogen and progestin dose and potency (< vs. ≥ median; ever use vs. never OC use), with the exception of high estrogen and low progestin dose. OCs were associated with lower endometrial cancer risk, independent of time since last use. Use of ethinyl estradiol and second-generation progestins were more strongly inversely associated with risk compared with older formulations.

Association of Oral Contraceptives use with Breast Cancer and Hormone Receptor Status in Iraqi Women

BACKGROUND: Worldwide, there is a significant concern regarding the association of breast cancer risk and oral contraceptives use. Differences in demographical and pathological breast cancer characteristics in Iraqi patients have been reported compared to other western countries; however, studies addressing the risk of breast cancer among oral contraceptive users in Iraq and subsequent correlation with hormonal receptor status are lacking.&#x0D; AIM: The aim of the study was to evaluate association of breast cancer risk and oral contraceptives use in patients visiting tertiary oncology center and to correlate hormone receptor status with history of oral contraception use in breast cancer patients.&#x0D; PATIENTS AND METHODS: Two hundred women with breast cancer were compared regarding patterns of oral contraceptives use with 300 age-matched healthy female controls by personal interview and questionnaire. Patient’s records were reviewed for hormone receptor status.&#x0D; RESULTS: A significantly higher proportion (49%) of women with breast cancer reported a positive history of combined oral contraceptives use as compared with (35.7%) healthy controls. Ever oral contraceptives users had a significantly increased risk of breast cancer (odds ratio [OR] = 1.73; 95%, confidence interval = 1.2–2.5, p = 0.003), with the highest risk was seen in early use before the age of 20 (OR = 6.62, p = 0.02); whereas increased duration of use did not significantly increase the risk of breast cancer. There was no significant association between estrogen and progesterone receptors expression profile in breast cancer patients and combined oral contraceptive use.&#x0D; CONCLUSION: In Iraqi women, the risk of breast cancer increases with oral contraceptives intake particularly when starts early before the age of 20 years. The hormonal receptor status of breast cancer patients is not significantly affected by combined oral contraceptives use.

Association of Use of Oral Contraceptives With Depressive Symptoms Among Adolescents and Young Women

Oral contraceptives have been associated with an increased risk of subsequent clinical depression in adolescents. However, the association of oral contraceptive use with concurrent depressive symptoms remains unclear. To investigate the association between oral contraceptive use and depressive symptoms and to examine whether this association is affected by age and which specific symptoms are associated with oral contraceptive use. Data from the third to sixth wave of the prospective cohort study Tracking Adolescents' Individual Lives Survey (TRAILS), conducted from September 1, 2005, to December 31, 2016, among females aged 16 to 25 years who had filled out at least 1 and up to 4 assessments of oral contraceptive use, were used. Data analysis was performed from March 1, 2017, to May 31, 2019. Oral contraceptive use at 16, 19, 22, and 25 years of age. Depressive symptoms were assessed by the DSM-IV-oriented affective problems scale of the Youth (aged 16 years) and Adult Self-Report (aged 19, 22, and 25 years). Data from a total of 1010 girls (743-903 girls, depending on the wave) were analyzed (mean [SD] age at the first assessment of oral contraceptive use, 16.3 [0.7]; (mean [SD] age at the final assessment of oral contraceptive use, 25.6 [0.6] years). Oral contraceptive users particularly differed from nonusers at age 16 years, with nonusers having a higher mean (SD) socioeconomic status (0.17 [0.78] vs -0.15 [0.71]) and more often being virgins (424 of 533 [79.5%] vs 74 of 303 [24.4%]). Although all users combined (mean [SD] ages, 16.3 [0.7] to 25.6 [0.6] years) did not show higher depressive symptom scores compared with nonusers, adolescent users (mean [SD] age, 16.5 [0.7] years) reported higher depressive symptom scores compared with their nonusing counterparts (mean [SD] age, 16.1 [0.6] years) (mean [SD] score, 0.40 [0.30] vs 0.33 [0.30]), which persisted after adjustment for age, socioeconomic status and ethnicity (β coefficient for interaction with age, -0.021; 95% CI, -0.038 to -0.005; P = .0096). Adolescent contraceptive users particularly reported more crying (odds ratio, 1.89; 95% CI, 1.38-2.58; P < .001), hypersomnia (odds ratio, 1.68; 95% CI, 1.14-2.48; P = .006), and more eating problems (odds ratio, 1.54; 95% CI, 1.13-2.10; P = .009) than nonusers. Although oral contraceptive use showed no association with depressive symptoms when all age groups were combined, 16-year-old girls reported higher depressive symptom scores when using oral contraceptives. Monitoring depressive symptoms in adolescents who are using oral contraceptives is important, as the use of oral contraceptives may affect their quality of life and put them at risk for nonadherence.

Association of oral contraceptive use with suicidal behavior among representative Korean population: Results from Korea National Health and Nutrition Examination Survey (2007–2016)

IntroductionThe association of suicide with the use of oral contraceptives (OC) is unknown in the Asian population. We aimed to evaluate the association of OC use and suicidal behavior in a nationally representative population of Korean women. MethodOf the 44,501 women who participated in the Korea National Health and Nutrition Examination Survey (KNHANES) (2007–2016), 27,067 women aged 20 years or older who had completed information on OC use and suicidal behavior were included. Women with a history of cancer were excluded. Compared to non-users of OC, odds ratios (ORs) for suicide attempt/ideation were calculated using a multivariable logistic regression among OC users, with testing of the interaction term of OC use and history of depression. We also conducted a stratified analysis by history of depression. ResultsA total of 4,067 women (14.0%) reported they had suicide ideations or had attempted suicide, respectively. OC use was associated with an increased prevalence of suicidality (OR = 1.13, 95% CI 1.00–1.24) after adjustments for age, demographic factors, age of menarche, and lifestyle behaviors. When stratified by history of depression diagnosis, ORs linearly increased as the total duration of OC use lengthened among women with a history of depression; however, women without a history of depression showed peaked OR at 4- to 12-month use. ConclusionThere is an increased association between OC use and suicidality and the pattern of the relationship differs depending on whether there is a history of depression.

The Association of Oral Contraceptive Use and Bone Mineral Density in Korean Premenopausal Women: A Cross Sectional Study from the Korea National Health and Nutrition Examination Survey 2008–2010

The Association of Oral Contraceptive Use and Bone Mineral Density in Korean Premenopausal Women: A Cross Sectional Study from the Korea National Health and Nutrition Examination Survey 2008–2010

Is the Use of Oral Contraceptives Associated With Operatively Treated Anterior Cruciate Ligament Injury?

Background: The incidence of anterior cruciate ligament (ACL) injuries is 2 to 9 times higher in women than in men. In addition, in vitro studies have demonstrated that ACL is an estrogen target tissue, and some studies have therefore suggested a protective association between oral contraceptives (OC) and the likelihood of sustaining ACL injury. Hypothesis: There is a protective association between OC use and the likelihood of operatively treated ACL injury. Study Design: Case-control study; Level of evidence, 3. Methods: The study population included 4497 women with an operatively treated ACL injury registered in the Danish Knee Ligament Reconstruction Registry for the 2005 to 2011 period and 8858 age-matched controls with no ACL injury. The study evaluated exposure to OC use at the time of ACL injury (index date) and in the 5 previous years (“ever user”) or no OC use (“never user”). Ever users were further classified as either new users (patients who redeemed their first prescription within the first year before the index date), long-term users (redeemed additional prescriptions 1 to 5 years before the index date), or recent users (redeemed their most recent prescription >1 year before the index date). Finally, a dose-response analysis of OC use was performed. Conditional logistic regression was used to calculate the relative risk (RR) with a 95% CI of sustaining an operatively treated ACL injury according to OC use. Results: The adjusted RR associating OC with ACL injury was 0.82 (95% CI, 0.75-0.90) between ever users and never users. Furthermore, there was a decreased RR of sustaining ACL injury of 0.80 (95% CI, 0.74-0.91) in long-term users and 0.81 (95% CI, 0.72-0.89) in recent users. Using OC for more than 4 years did not seem to alter the likelihood of sustaining an operatively treated ACL injury. Conclusion: This population-based pharmacoepidemiological study including 13,355 women indicates that a protective association exists between OC use and the likelihood of sustaining an operatively treated ACL injury. Although this study does indicate a protective association of OC use, OC should not be used as a prophylactic measure before additional clinical studies have further clarified the biological and causal association between OC use and the likelihood of sustaining operatively treated ACL injury.

Abstract 2166: A prospective study on oral contraceptive use and risk of colorectal adenomas

Abstract Background: Most colorectal cancers (CRC) arise from colorectal adenomas. The influence of reproductive factors on CRC, including oral contraceptive (OC) use, has been examined for a number of years, but less research is available on the role of OC use on adenomas. A better understanding of this association will provide insight into the mechanism through which hormones impact colorectal carcinogenesis. Objective: To examine the association of OC use and colorectal adenomas using detailed data from a large prospective cohort study with 32 yrs of follow-up data. Design: The Nurses' Health Study was established in 1976 when 121,701 female registered nurses 30-55 yrs of age completed a mailed questionnaire on medical history and lifestyle factors. We assessed OC use every 2 yrs between 1976-1982 and categorized this use according to ever (≥2 mo) and never use (reference), duration of use (never, ≤1, &amp;gt;1-&amp;lt;2, ≥2-&amp;lt;5, ≥5-&amp;lt;10, 10+ yrs), and time since last use (never, ≤4, &amp;gt;4-&amp;lt;10, ≥10-&amp;lt;15, 15+ yrs). Participants had to undergo a lower bowel endoscopy during the study period to be eligible for the current analyses. All colorectal adenoma cases identified at endoscopy were included from 1986 (when endoscopies were first accessed) through 2010; cases were stratified by subsite (proximal, distal, rectal), stage/size (small/early, large/advanced), and number of adenomas (1, 2+). Methods: Multivariable logistic regression models for clustered data were used to estimate odds ratios [OR (95% CIs)]. Models were adjusted for age, body mass index, height, physical activity, smoking, processed and red meat, folate, calcium, total energy, alcohol, aspirin use, age at first birth, parity, hormone therapy use/duration, family history of CRC, time period, as well as endoscopy information including reason, number, and yr since most recent. Results: Among 70,164 participants who had a lower bowel endoscopy, 49% (N=34,329) reported never using OCs and 51% (N=35,835) reported ≥2 mo of use. We recorded 2,950 never-users with an adenoma compared to 3,075 ever-users. Ever OC use was associated with a slight increase of small/early stage adenomas [OR=1.12 95% CI (1.03-1.22)] but not with large/advanced stage adenomas or any other category (e.g., number of adenomas). Duration of OC use was not associated with adenomas but longer times since last OC use were associated with increased odds for all of the adenoma outcomes [e.g., compared to never use, 15+ yrs since last use for all adenomas: OR=1.18 (1.08, 1.29)]. Shorter times since last OC use were inversely associated [e.g., ≤4 yrs since last use for all adenomas: OR=0.76 (0.67, 0.86)]. Conclusions: The null association between OC use and colorectal adenomas may be more nuanced than initially described in the literature. We found that OC use was associated with certain stages/sizes of colorectal adenomas (e.g., small/early) and further exploration of the time since last OC use associations are warranted. Support: P01CA87969, T32CA09001, T32HD060454 Citation Format: Brittany M. Charlton, Ed Giovannucci, Charles S. Fuchs, Stacey A. Missmer, Bernard A. Rosner, Kana Wu, Karin B. Michels. A prospective study on oral contraceptive use and risk of colorectal adenomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2166. doi:10.1158/1538-7445.AM2014-2166

Association of Oral Contraceptives Use and Lung Cancer Risk among Women: an Updated Meta-analysis Based on Cohort and Case-control Studies

Previous studies on the association of oral contraceptives (OC) use and lung cancer generated inconsistent findings. The aim of this study was to confirm any definite correlation between OC use and lung cancer risk. Publications were reviewed and obtained through PubMed and EMBASE databases literature search up to November, 2013. Reference lists from retrieved articles were also reviewed. The language of publication was restricted to English. A meta-analysis was performed to evaluate the association by calculating pooled odds ratios (ORs) and 95% confidence intervals (CIs). A total of 14 studies consisting of 9 case- control studies and 5 cohort studies were finally included in this meta-analysis. There was no significant association observed between OC use and lung cancer risk in the overall analysis (OR=0.91; 95% CI=0.81-1.03). There was a significant protective effect in Europe (OR=0.74; 95% CI=0.60-0.91) and a borderline significant protective effect with an adenocarcinoma histology (OR=0.90; 95% CI=0.80-1.01) in subgroup analyses. No association was observed for methodological quality of study, study design, smoking status and case number of study. This meta-analysis suggests that OC use is not likely to be associated with the risk of lung cancer at all. While a significant protective effect of OC use on lung cancer was observed in Europe, interpretation should be cautious because of the potential biases of low-quality studies. At the same time, more attention should be paid to the possible association of OC use with adenocarcinoma of lung. Our findings require further research, with well-conducted and large-scale epidemiological studies to confirm effects of OC use on lung cancer.

Low-Grade, Systemic Inflammation in Adolescents: Association With Early-Life Factors, Gender, and Lifestyle

Low-grade, systemic inflammation is related to increased risk of cardiovascular disease in adults. The proinflammatory state tracks from adolescence to adulthood. Identifying correlates of inflammation in adolescents could provide opportunities to prevent cardiovascular disease in adulthood. However, population-based data on correlates of inflammation in adolescence are limited. Therefore, the authors studied the associations of early-life factors, gender, and lifestyle with inflammation (measured by high-sensitivity C-reactive protein and leukocyte count) at age 16 years (2001-2002) in the prospective, population-based Northern Finland Birth Cohort 1986 Study (n = 5,240). In females, being born small for gestational age and current use of oral contraceptives were associated with the proinflammatory state. The association of birth size with inflammation was not observed in males. In logistic regression analyses, oral contraceptive use (odds ratio (OR) = 2.83), abdominal obesity (OR = 5.17), and smoking (OR = 2.72) were associated with elevation of both inflammation markers in females; abdominal obesity (OR = 5.72) and smoking (OR = 2.02) were associated in males. Thus, females appear more susceptible to the adverse effects of being born small for gestational age than males. Given the widespread use of oral contraceptives and the potential pathophysiologic consequences of the proinflammatory state, the association of oral contraceptive use with inflammation in adolescence may have public health implications.

Reproductive History, Oral Contraceptive Use, and the Risk of Ischemic and Hemorrhagic Stoke in a Cohort Study of Middle-Aged Swedish Women

Controversy persists as to whether oral contraceptive (OC) use and reproductive history play a role in the etiology of stroke, particularly ischemic stroke. Our aim was to investigate this question in a cohort of middle-aged Swedish women. The Women's Lifestyle and Health Cohort Study included 49259 Swedish women, aged 30 to 49 years at baseline (1991 to 1992). Participants completed an extensive questionnaire and were traced through linkages to national registries until the end of 2004. Among the 45699 women included in these analyses, there were 285 cases of incident stroke during follow-up (193 ischemic stroke, 72 hemorrhagic stroke, and 20 of unknown origin). Neither ischemic nor hemorrhagic stroke risk was related to OC use, duration, or type of OC use, even among women who were smokers or hypertensive. Though not statistically significant, risk of hemorrhagic stroke was elevated in women who started using OCs after the age of 30 (Hazard Ratio [HR] 2.3, 95% CI=0.8 to 6.8) and women recommended by a doctor to stop using OC for medical reasons (2.1, 0.9 to 5.0) compared with never users. Compared with nulliparous women, parous women had a statistically significant lower risk of hemorrhagic stroke (0.5, 0.2 to 0.8), but similar association was not found for ischemic stroke (0.9, 0.5 to 1.4). There was no significant association of OC use with ischemic or hemorrhagic stroke, and the parity was associated with reduced risk of hemorrhagic stroke but not with ischemic stroke.

A Case-Control Study of Oral Contraceptive Use and Incident Breast Cancer

Oral contraceptive (OC) use has been linked to increased risk of breast cancer, largely on the basis of studies conducted before 1990. In the Case-Control Surveillance Study, a US hospital-based case-control study of medication use and cancer, the authors assessed the relation of OC use to breast cancer risk among 907 case women with incident invasive breast cancer (731 white, 176 black) and 1,711 controls (1,152 white, 559 black) interviewed from 1993 to 2007. They evaluated whether the association differed by ethnicity or tumor hormone receptor status. After control for breast cancer risk factors, the multivariable odds ratio for 1 year or more of OC use, relative to less than 1 year of use, was 1.5 (95% confidence interval: 1.2, 1.8). The estimates were similar within age strata (<50 years and >or= 50 years). The odds ratios were larger for use within the previous 10 years, long-duration use, and black ethnicity, but these differences were not statistically significant. The association of OC use with breast cancer risk did not differ according to the estrogen or progestogen receptor status of the tumor. These results suggest that OC use is associated with an increased risk of breast cancer diagnosed in recent years.

The Risk of Venous Thrombosis among Women with Thrombophilia and Oral Contraceptive Use: A Meta-Analysis

Introduction: Several small studies have reported an increased risk of venous thrombosis (VT) with thrombophilic disorders that is compounded by the use of oral contraceptives (OCP). The objective of this meta-analysis was to summarize the risk of VT among women with thrombophilia and OCP use, and to assess the interaction between OCP use and thrombophilia.Methods: Data sources used included MEDLINE, EMBASE, CINAHL, and COCHRANE REVIEW databases (1950–2008), and reference lists of retrieved articles. We selected studies that assessed among reproductive-aged women with and without VT the prevalence of OCP use and thrombophilic disorders, including factor V Leiden (FVL), prothrombin (PT) G20210A, elevated procoagulant factor VIII, hyperhomocysteinemia, lupus anticoagulant, and deficiencies of proteins C, S and antithrombin III. VT was defined as objectively confirmed deep vein thrombosis, pulmonary embolism or cerebral vein thrombosis. Fifteen studies were included. Two independent reviewers extracted data on study characteristics, quality, risk factors, and outcomes. Odds ratios (ORs) were calculated for each study and pooled using the random effects model.Results: There was an increased risk of VT in women with OCP use (pooled OR 3.0, 95% confidence interval (CI) 2.0–4.5), women with any thrombophilic disorder (pooled OR 4.8, 95% CI 3.6–6.5), women with FVL (pooled OR 4.7, 95% CI 3.1–7.5), and women with PT G20210A (pooled OR 3.3, 95% CI 0.8, 13.1). OCP users with FVL had a 18-fold increased risk of VT compared to healthy OCP non-users (pooled OR 17.8, 95% CI 5.6–56.8) and OCP-using women with PT G20210A had a 12-fold increased risk (pooled OR 12.4, 96% CI 0.9– 166) compared to healthy OCP non-users. The association of OCP use and VT was of similar magnitude among women with FVL (pooled OR 3.2, 95% CI 1.3–7.7) and women without FVL (pooled OR 3.9, 95% CI 1.8 to 8.6). Significant heterogeneity (I2 >80%) was present among models for OCP use, PT G20210A, and OCP use among FVL-negative women.Conclusions: We have shown that OCP use, thrombophilia, and in particular FVL and PT G20210A are associated with an elevated risk of VT of similar magnitude. However, the combination of OCP use and thrombophilia further amplifies the risk of VT compared to when either of the risk factors are considered alone. Though heterogeneity was observed, our study suggests, and confirms previous reports of an interaction between OCP use and thrombophilia.

Abstract CN02-03: Prospects for targeted reduction of ovarian cancer risk

Abstract CN02-03 The 5 year survival for patients diagnosed with Stage 3 and 4 epithelial ovarian cancer (EOC) is less than 40% in spite of overall benefit from primary treatment with debulking surgery and chemotherapy. For advanced EOC, even clinical complete responses are usually time-limited, a situation that supports a strategy for earlier intervention. Efforts to establish a screening program with ultrasound and CA-125 have been encumbered by false positive results. The absence of demonstrated benefit in a definitive trial precludes the implementation of widespread screening in the general population. For high risk women like those with BRCA or HNPCC mutations, prophylactic salpingo-oophorectomy is available for risk reduction. Otherwise, the identification of specific risk markers and precursor lesions in the general population remains a challenging goal for EOC prevention research. Because access to human tissues of interest is limited, many questions about the natural history of EOC remain to be answered, and translational efforts have focused on preclinical models and animal studies. In spite of the difficulties, there are promising leads and methodology that can be pursued to make ovarian cancer risk reduction a broader reality. From epidemiologic studies, a major result in risk modification is the association of oral contraceptive use with EOC risk reduction. The literature is replete with studies that also link EOC with a variety of other hormonal and reproductive factors. These results have been used to support a number of etiologic hypotheses including risk related to 1) incessant ovulation, 2) gonadotropins, 3) hormones (estrogen/androgen/progesterone, and 4) inflammation. These hypotheses are interrelated and support a systems biology approach that integrates changes in the tumor microenvironment along with changes in the epithelium to identify targeted opportunities for preventive modulation. At this point, the translational research process may be well served by small clinical trials that are carefully designed to reconcile inconsistencies in existing data and to test mechanistic leads from preclinical studies as well as from investigations with therapeutics like bevacizumab and anti-Mullerian hormone. Pathways of interest include those related to aromatase and prostaglandins. With specific targets in mind, biomarker comparison in controls using placebo versus subjects using chemopreventive agents as mechanistic probes should allow an improved definition of risk and response. Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN02-03.

The Risk of Oral Contraceptives in the Etiology of Inflammatory Bowel Disease: A Meta-Analysis

Several environmental and genetic factors have been implicated to date in the development of Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to provide a quantification of the risk of oral contraceptive pill (OCP) use in the etiology of inflammatory bowel disease. A literature search was performed to identify comparative studies reporting on the association of oral contraceptive use in the etiology of UC and CD between 1983 and 2007. A random-effect meta-analysis was used to compare the incidence of UC or CD between the patients exposed to the OCP and nonexposed patients. The results were adjusted for smoking. A total of 75,815 patients were reported on by 14 studies, with 36,797 exposed to OCP and 39,018 nonexposed women. The pooled relative risk (RR) for CD for women currently taking the OCP was 1.51 (95% confidence interval [CI] 1.17-1.96, P= 0.002), and 1.46 (95% CI 1.26-1.70, P < 0.001), adjusted for smoking. The RR for UC in women currently taking the OCP was 1.53 (95% CI 1.21-1.94, P= 0.001), and 1.28 (95% CI 1.06-1.54, P= 0.011), adjusted for smoking. The RR for CD increased with the length of exposure to OCP. Moreover, although the RR did not reduce once the OCP was stopped, it was no longer significant once the OCP was stopped (CI contains 1), both for CD and for UC. This study provides evidence of an association between the use of oral contraceptive agents and development of IBD, in particular CD. The study also suggests that the risk for patients who stop using the OCP reverts to that of the nonexposed population.

Oral contraceptive use, hormone replacement therapy, reproductive history and risk of colorectal cancer in women

Evidence from epidemiologic studies suggests a possible role of exogenous and endogenous hormones in colorectal carcinogenesis in women. However, with respect to exogenous hormones, in contrast to hormone replacement therapy, few cohort studies have examined oral contraceptive use in relation to colorectal cancer risk. We used data from a large cohort study of Canadian women enrolled in a randomized controlled trial of breast cancer screening to assess the association of oral contraceptive use, hormone replacement therapy and reproductive factors with risk of colorectal cancer, overall and by subsite within the colorectum. Cancer incidence and mortality were ascertained by linkage to national databases. Among 89,835 women aged 40-59 at enrollment and followed for an average of 16.4 years, we identified 1,142 incident colorectal cancer cases. Proportional hazards models were used to estimate the associations between the exposures of interest and risk of colorectal cancer. Ever use of oral contraceptives at baseline was associated with a modest reduction in the risk of colorectal cancer (hazard ratio 0.83, 95% confidence interval 0.73-0.94), with similar effects for different subsites within the colorectum. No trend was seen in the hazard ratios with increasing duration of oral contraceptive use. No associations were seen with use of hormone replacement therapy (ever use or duration of use) or reproductive factors. Our results are suggestive of an inverse association between oral contraceptive use and colorectal carcinogenesis. However, given the lack of a dose-response relationship and the potential for confounding, studies with more complete assessment of exogenous hormone use throughout the life course are needed to clarify this association.

Association of Oral Contraceptive Use, Other Contraceptive Methods, and Infertility with Ovarian Cancer Risk

Although oral contraceptives are protective for ovarian cancer, it is unclear how long this protection persists. The authors prospectively assessed this question as well as associations of other, less studied contraceptive methods (tubal ligation, rhythm method, diaphragm, condoms, intrauterine device, foam, spousal vasectomy) and infertility with ovarian cancer risk among 107,900 participants in the US Nurses' Health Study. During 28 years of follow-up (1976-2004), 612 cases of invasive epithelial ovarian cancer were confirmed. Duration of oral contraceptive use was inversely associated with risk (p-trend = 0.02), but no clear trend was observed for years since last use. However, for women using oral contraceptives for >5 years, the rate ratio for ovarian cancer for <or=20 years since last use was 0.58 (95% confidence interval (CI): 0.39, 0.87), with no association found for >20 years since last use (rate ratio (RR) = 0.92, 95% CI: 0.61, 1.39). Tubal ligation (RR = 0.66, 95% CI: 0.50, 0.87) was associated with decreased ovarian cancer risk, whereas intrauterine device use (RR = 1.76, 95% CI: 1.08, 2.85) and infertility (RR = 1.36, 95% CI: 1.07, 1.75) were associated with an increased risk. Results suggest that the beneficial effect of oral contraceptives on ovarian cancer risk attenuates after 20 years since last use. Furthermore, tubal ligation, intrauterine device use, and infertility were associated with ovarian cancer risk.