Current Combined Oral Contraceptives Research Articles

Venous Thromboembolic Risk of Estradiol Valerate-Dienogest Compared with Ethinyl Estradiol-Levonorgestrel Combined Oral Contraceptives.

This pooled analysis compared the risk of venous thromboembolism (VTE) associated with combined oral contraceptives (COCs) containing estradiol (E2) valerate-dienogest with those containing ethinyl E2-levonorgestrel. Data were retrieved from two large, prospective, observational cohort studies. Propensity score subclassification was applied to balance baseline parameters between the COC user cohorts. Crude and adjusted hazard ratios (HRs) were calculated based on the extended Cox model. The pooled data set included 11,616 E2 valerate-dienogest users and 18,681 ethinyl E2-levonorgestrel users, contributing 17,932 and 29,140 women-years of observation, respectively. A significantly decreased VTE risk in E2 valerate-dienogest COCs compared with ethinyl E2-levonorgestrel COCs was observed (propensity score-stratified HR 0.46, 95% CI, 0.22-0.98). This pooled analysis expands data from a previous postauthorization safety study and provides valuable real-world safety information on the relative safety of current COCs.

Review of the literature on combined oral contraceptives and cancer.

Millions of women have given preference to the use of combined oral contraceptives (COCs) since its introduction in the 1960s. Both oestrogens and progestogens can regulate proliferation and it is plausible these effects may contribute to carcinogenesis. We aimed to review the accumulated knowledge to date to appreciate the modifying effects combined oral contraceptives may have on carcinogenesis. Our methodology involved a review of the current published literature, paying attention to studies published in the last 20 years. It has been noted that the overall cancer odds do not change with the use of COCs. Increased risk for breast cancer with COC use is not consistently backed in the literature; the results range from no increase in risk to a 20%–30% elevation in risk, and the risk seems to be temporary, limited to recent or current regular COC use. Also, diagnosed breast cancer cases seem to be clinically advanced in ever-users compared to never-users. Data show that the ongoing and prolonged use of COCs may provide diminished risk for endometrial, colorectal and ovarian cancers. Although studies do not clearly support increased risk with COC use in high-risk groups, such as women with family history of cancer or BRCA carriers, local and international guidelines are available for clinical decision-making. For cervical cancer, COCs seem to enhance the risk with more than 5 years of use, and in many studies, this enhanced risk diminishes after discontinuation and restores to those of never-users within 10 years. The relationship between COC use and liver malignancy risk assessments has provided conflicting findings. Some studies have suggested that hormonal contraceptives may increase the risk of not only hepatocellular carcinoma but also intrahepatic cholangiocarcinoma. Combined oral contraceptives are safe and effective and the effects are reversible. Patients who pursue family planning should be warned of possible carcinogenic outcomes, but it should also be explained that—in addition to sexual health advantages—preferring COCs may also decrease the risks of endometrial, colorectal and ovarian cancers.

Etonogestrel implant use in women primarily choosing a combined oral contraceptive pill: A proof-of-concept trial

ObjectiveWe evaluated a novel concept of initiating the etonogestrel implant as a “back-up” method in women who desire using combined oral contraceptives (COC) but want to decrease their risk of unintended pregnancy with a more effective method. Study DesignIn this prospective cohort study, we planned to include 20 women as a proof-of-concept. We enrolled both new COC starters and continuing COC users and placed an etonogestrel implant. Participants completed daily bleeding diaries and attended follow-up visits at 1, 3, and 6 months. We assessed implant continuation through six months of study participation and side effects with dual hormonal contraceptive use. ResultsBetween September and December 2016, we enrolled 10 new starters and 10 current COC users. All participants completed 1-month follow-up, and 18 (90%) subjects completed the 3- and 6-month follow-up assessments. Two current COC users had the implant removed for mood changes before 6 months. At the 6-month follow-up visit, 10 women were using both pills and implant, seven relied on the implant only, and one was using a COC only. Three new starters chose implant removal at end of study participation; one for weight gain and acne, another for mood changes, and one for decreased libido. No subjects discontinued the implant for bleeding complaints. ConclusionIn this proof-of-concept study, women using COCs were willing to initiate the implant as a “back-up” method to improve pregnancy prevention. Most women continued the implant through 6 months and after completing study participation. ImplicationsInitiating the etonogestrel implant as a “back-up” method may be an option for women who desire more effective pregnancy prevention while using combined oral contraceptive pills for its bleeding profile or non-contraceptive benefits.

Progestin-only and combined oral contraceptives and receptor-defined premenopausal breast cancer risk: The Norwegian Women and Cancer Study.

Receptor-defined subtypes of breast cancer represent distinct cancer types and have differences in risk factors. Whether the two main hormonal forms of oral contraceptives (OCs); i.e. progestin-only (POC) and combined oral contraceptives (COC), are differentially associated with these subtypes are not well known. The aim of our study was to assess the effect of POC and COC use on hormone receptor-defined breast cancer risk in premenopausal women in a prospective population-based cohort - The Norwegian Women and Cancer Study (NOWAC). Information on OC use was collected from 74,862 premenopausal women at baseline. Updated information was applied when follow-up information became available. Multiple imputation was performed to handle missing data, and multivariable Cox regression models were used to calculate hazard ratios (HR) for breast cancer. 1,245 incident invasive breast cancer cases occurred. POC use ≥5 years was associated with ER+ (HR = 1.59, 95% CI 1.09- 2.32, ptrend = 0.03) and ER+/PR+ cancer (HR = 1.63, 95% CI 1.07-2.48, ptrend = 0.05), and was not associated with ER- (pheterogeneity = 0.36) or ER-/PR- (pheterogeneity = 0.49) cancer. COC use was associated with ER- and ER-/PR- cancer, but did not increase risk of ER+ and ER+/PR+ cancer. Current COC use gave different estimates for ER/PR-defined subtypes (pheterogeneity = 0.04). This is the first study to show significant associations between POC use and hormone receptor-positive breast cancer. The lack of power to distinguish effects of POC use on subtype development calls for the need of larger studies to confirm our finding.

Thromboembolism as the adverse event of combined oral contraceptives in Japan

BackgroundThe risk of thromboembolism associated with combined oral contraceptives (COCs) in Japanese women is not clear yet. The aim of this study is to estimate the current risk of thromboembolism among COC users in Japan. MethodsWe used the Pharmaceuticals and Medical Devices Agency (PMDA) database disclosed by PMDA from April 2004 to December 2013, and extracted thromboembolic events among adverse events from the adverse event information of COC products. ResultsOf the 581 thromboembolic events, venous thromboembolism (VTE) accounted for 394 events, arterial embolism and thrombosis (ATE) were 154, and thrombosis of unspecified sites was 33. In VTE, deep vein thrombosis and pulmonary embolism were the most frequent (78.4%), followed by cerebral vein thrombosis (11.4%). In ATE, cerebral infarction was the most frequent (76.0%) and approximately 6.9-fold higher than coronary heart diseases. The annual estimated incidence per 10,000 person-years of VTE, ATE and all thromboembolisms in current users of all COCs were 1.11 (95% confidence interval: 1.00–1.24), 0.37 (0.30–0.44), and 1.56 (1.42–1.71), respectively. The frequency of all thromboembolic events that developed within 90days from the start of COCs was 45.5%, and that within 360days was 81.2%. Sixteen deceased cases were suspected to be associated with thromboembolism, and the estimated mortality rate between 2009 and 2013 was 0.50 (0.30–0.84) per 100,000 person-years. ConclusionsIncidence rates of thromboembolism, particularly VTE, in Japanese current COC users became clear for the first time, being slightly lower than people in Western countries.

Hormone withdrawal-associated symptoms with ethinylestradiol 20 μg/drospirenone 3 mg (24/4 regimen) versus ethinylestradiol 20 μg/desogestrel 150 μg (21/7 regimen).

ObjectiveTo assess whether the combined oral contraceptive (COC) ethinylestradiol (EE) 20 μg/drospirenone 3 mg taken in a 24/4-day regimen (ie, 4-day hormone-free interval) is more effective than an EE 20 μg/desogestrel (DSG) 150 μg COC taken in a 21/7-day regimen (ie, 7-day hormone-free interval) in reducing hormone withdrawal-associated symptoms (HWAS).MethodsThis double-blind, randomized study (NLM identifier: NCT01076582) was conducted at 34 centers in 12 countries. Otherwise healthy women who experienced ≥2 HWAS of headache, pelvic pain, and/or bloating when using their current COCs in a 21/7-day regimen were recruited. Subjects rated the severity of their HWAS daily on a seven-point Likert scale during a baseline cycle and during four 28-day cycles with EE/drospirenone 24/4 (n=290) or EE/DSG 21/7 (n=304). The primary variable was the mean change from baseline to cycle 4 in the composite HWAS score (sum of scores for all three symptoms) during cycle days 22–28.ResultsIn the EE/drospirenone 24/4 group, the mean (standard deviation) composite HWAS score during cycle days 22–28 was reduced from 42.2 (24.8) at baseline to 12.8 (13.4) at cycle 4 (change from baseline: −30.3 [22.9]). In the EE/DSG 21/7 group, the corresponding value was reduced from 41.9 (25.8) to 14.3 (13.2) (change from baseline: −27.7 [24.8]), not significantly different versus EE/drospirenone 24/4. Bleeding pattern, treatment response, rescue medication use, compliance, quality of life, and tolerability were similar between treatments.ConclusionBoth EE/drospirenone 24/4 and EE/DSG 21/7 reduced the composite HWAS score from baseline to cycle 4 in otherwise healthy women. The differences between treatments were too small to be statistically significant.

Types of combined oral contraceptives used by US women

BackgroundWe sought to estimate the prevalence of types of combined oral contraceptives (COCs) used among US women. Study DesignWe analyzed interview-collected data from 12,279 women aged 15–44 years participating in the National Survey of Family Growth, 2006–2010. Analyses focused on COC use overall, by pill type, across sociodemographics and health factors. ResultsThe prevalence of current COC use (88 different brands) was 17%. The majority of COC users used earlier-formulation COCs: ≥30 mcg (67%) versus <30 mcg estrogen (33%), monophasic (67%) versus multiphasic (33%) dosages and traditional 21/7 (88%) versus extended/other cycle regimens (12%) regimens. Norgestimate (32%) and norethindrone (20%) were the most commonly used progestins. Sociodemographic, gynecological and health risk factors were associated with type of COC use. ConclusionFurther investigation of specific COC use and of the factors associated with types of pills used among US women at the population level is needed.

Combined Oral Contraceptive Use Increases HPV Persistence but Not New HPV Detection in a Cohort of Women From Thailand

Women diagnosed with cervical cancer report longer duration and more recent use of combined oral contraceptives (COCs). It is unclear how COC use impacts risk of cervical carcinogenesis. We estimated the risk of new human papillomavirus (HPV) DNA detection and persistence among 1135 human immunodeficiency virus (HIV)-negative women aged 20-37 years from Thailand who were followed for 18 months at 6-month intervals. Type-specific HPV DNA, demographic information, hormonal contraceptive use, sexual behavior, genital tract coinfection, and Papanicolaou test results were assessed at baseline and each follow-up. Women who reported current COC use during follow-up were less likely to clear HPV infection compared with nonusers, independent of sexual behavior, and Papanicolaou test diagnosis (AHR: 0.67 [95% CI: .49-.93]). Similar associations were not observed among women reporting current use of depomedroxyprogesterone acetate (DMPA). Neither COC nor DMPA use was significantly associated with new HPV DNA detection. These data do not support the hypothesis that contraceptive use is associated with cervical cancer risk via increased risk of HPV acquisition. The increased risk of HPV persistence observed among current COC users suggests a possible influence of female sex hormones on host response to HPV infection.

Risk of venous thromboembolism and the use of dienogest- and drospirenone-containing oral contraceptives: results from a German case-control study

ObjectiveThe primary objective of the study was to clarify whether the use of the oral contraceptive 2 mg dienogest/30 μg ethinylestradiol (DNG/EE) is associated with a higher risk of venous...

Adverse mood effects of combined oral contraceptives in relation to personality traits

Objective Mood symptoms, such as depressed mood, anxiety and increased irritability, remain one of the major reasons for discontinuation of combined oral contraceptive (COC) pills. The aim of this study was to compare personality traits in women with ongoing or previous use of COCs and different experiences from these compounds with respect to adverse mood symptoms. Study design Thirty women currently on COCs with no reports of adverse mood symptoms, 28 women currently on COCs and experiencing mood-related side effects, 27 women who had discontinued COC use for reasons other than adverse mood symptoms and 33 women who had discontinued COC use due to adverse mood effects were included. All participants were asked to fill out the Swedish universities Scales of Personality (SSP) to assess different personality traits. Results The women who were experiencing mood-related side effects on their current COC use exhibited higher scores on the somatic anxiety and stress susceptibility traits as compared to the women who did not experience any mood-related side effects from their current COCs. Women who had discontinued COC treatment because of adverse mood effects had higher scores of detachment and mistrust compared to women who had discontinued COC for reasons unrelated to mood effects. Conclusion Higher scores on specific personality traits such as somatic anxiety and stress susceptibility are found in women with ongoing experience of adverse mood symptoms from COC. Higher scores of mistrust and detachment are more common among women who have discontinued COC treatment due to adverse mood effects.

Mortality from venous thromboembolism in young Swedish women and its relation to pregnancy and use of oral contraceptives – an approach to specifying rates

Pregnancy and use of combined oral contraceptives (COCs) are major risk factors for venous thromboembolism (VTE) in young women and we wanted to obtain accurate VTE mortality data overall, by age, associated with the use of COCs and pregnancy. From the Swedish Cause of Death Register (CDR) we identified women aged 15-44 with VTE as underlying or contributory cause of death during the period 1990-1999. We scrutinized medical records and included verified VTE cases without active cancer or terminal disease. Pregnancy statistics and COC utilization data were obtained from national databases. Of the 120 cases included, 9 (8%) were associated with pregnancy and 28 (23%) with current COC use. The overall refined VTE mortality rate in current COC users was 7.5[4.7; 10.3] per million user-years and the corresponding pregnancy-related rate was 8.9[4.1;17.0] per million pregnancy years, rates increasing with age. For ages 15-24, the rate was significantly higher in current COC users than in non-pregnant women not using COCs: 6.0[3.1; 10.5] per million user-years vs. 0.3[0.0; 1.2] per million woman years. Underlying cause mortality data included 82% of VTE deaths associated with COCs, and 56% of maternal deaths had a pregnancy-related code. Mortality figures from VTE associated with the use of COCs and pregnancy were similar. COC use had an important impact on the total VTE mortality in the youngest age group. Standard mortality statistics do not allow accurate monitoring of VTE mortality in young women due to missing data, misdiagnoses and coding rules.

Forty years of combined oral contraception: the evolution of a revolution

The combined oral contraceptive (COC) pill has become an integral part of fertility choice in almost every country since its introduction in 1960 in the United States. It was the first contraceptive method to provide sexual freedom of choice for women through reliable personal, private control of fertility. Modern, very low-dose pills have maintained a high degree of contraceptive efficacy, but the margin for error in pill-taking appears much smaller. These COCs have a much lower incidence of side effects and serious complications than early high-dose COCs. Serious health risks from venous thromboembolism are rare, and not measurably higher for pills containing third-generation compared with earlier progestogens. Most women feel very well taking modern COCs, but myths about these drugs still abound. Most non-contraceptive health benefits of COCs are still not widely appreciated in spite of much evidence. Controversy still persists over the association between COC use and breast cancer. Although slightly more breast cancers are detected in current COC users (relative risk 1.24; 95% CI, 1.15-1.33), they are less advanced and less aggressive. Some women have pre-existing medical risk factors for COC use, and a detailed history for cardiovascular risk factors is one of the most important precautions.

Cardiovascular Events Associated With Different Combined Oral Contraceptives

Studies of combined oral contraceptive (COC) use and cardiovascular disease have been conducted against a background of low cardiovascular risk in young women, changing COC composition and changing user selection and monitoring. Studies of myocardial infarction have found inconsistent results, possibly because of differences in the prevalence of risk factors (particularly smoking and raised blood pressure) in the populations studied. In the absence of a history of smoking and other conventional risk factors, current users of modern COCs probably do not have an increased risk of myocardial infarction. Neither are former users at risk. Evidence for important differences in the risk of myocardial infarction between formulations is weak and contradictory. Current users of low estrogen dose COCs have a small increased risk of ischaemic stroke although most of the risk occurs in women with other risk factors (notably smoking, hypertension and probably a history of migraine). Former users of COCs do not have an increased risk of ischaemic stroke. There is insufficient information to determine whether major differences in the risk of ischaemic stroke exist between products. Current users appear to have a modestly elevated risk of haemorrhagic stroke, mainly in women older than 35 years; former users do not. Data examining the risk of haemorrhagic stroke in current COC users with other risk factors are very sparse, as are those relating to the haemorrhagic stroke risk associated with particular COCs. Numerous studies have found, with remarkable consistency, an elevated risk of venous thromboembolism among current users of low estrogen dose COCs. The risk is substantially elevated among women with various inherited clotting factor defects. The effects in COC users with other risk factors for venous thrombosis tend to be less pronounced and more inconsistent. A number of studies have found higher relative risks among current users of low estrogen dose COCs containing desogestrel or gestodene, than among users of similar products containing levonorgestrel. A number of explanations, in terms of bias or confounding, have been proposed for these clinically small differences. At best, empirical evidence for these explanations, is weak. The risk of cardiovascular disease of any description is low in COC users. Women can minimise, and possibly eliminate entirely, their arterial risks by not smoking and by having their blood pressure checked before using a COC (in order to avoid its use if raised blood pressure is discovered). Users may decrease their venous thromboembolic risk by their choice of COC preparation although the effects will be modest.

Pill Use Makes Minimal Contribution to the Risk Of Myocardial Infarction

A case-control study conducted by the World Health Organization in 21 centers in 17 countries in Africa Asia Europe and Latin America and the Caribbean confirmed that acute myocardial infarction is a rare event in users of combined oral contraceptives (OCs) with no other risk factors for cardiovascular disease. A total of 368 women who had survived an acute myocardial infarction were compared with 941 age-matched controls. In Europe 87% of cases and 48% of controls had at least 1 risk factor for cardiovascular disease (i.e. family history of myocardial infarction or stroke smoking hypertension diabetes rheumatic heart disease or abnormal blood lipids); in developing countries these rates were 72% and 35% respectively. 31% of European women with myocardial infarction and 16% of controls were current combined OC users; in developing countries these rates were 23% and 9% respectively. Compared with past users and never users of combined OCs current OC users had approximately 5 times the risk of acute myocardial infarction (odds ratios of 5.0 in Europe and 4.8 in developing countries). Women who reported that their blood pressure had not been checked before initiating OC use had a higher risk of acute myocardial infarction (9.5 in Europe and 6.0 in developing countries) than those whose pressure had been checked (2.6 and 3.5 respectively). For women with blood pressure problems independent of pregnancy the odds ratios of myocardial infarction were 68.1 in Europe and 15.3 in developing countries. The elevated risk of acute myocardial infarction in OC users recorded in this study appears due to the influence of other risk factors for cardiovascular disease and a lack of screening for hypertension. A high body mass index and a history of hypertension were the largest contributors to the risk among OC users in Europe while smoking and a history of hypertension were most salient in developing countries.