Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 825e834

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The combined oral contraceptive pill- recent developments, risks and benefits Monica V. Dragoman, MD, MPH, Assistant Professor Einstein College of Medicine, Montefiore Medical Center, Department of Obstetrics and Gynecology & Women's Health, 1695 Eastchester Road, Bronx, NY 10461, USA

Keywords: oral contraception hormonal contraception non-contraceptive benefits gynaecology

The introduction of the birth control pill as an effective, coitallyindependent method of contraception was a public health milestone of the last century. Over time, combined oral contraception (COC) formulations and pill-taking regimens have evolved with improved safety and tolerability while maintaining contraceptive efficacy. In addition to protection against pregnancy, use of combined oral contraception confers a number of significant noncontraceptive benefits to users. COC use is also associated with well-studied risks. Common side effects are generally self-limiting and improve with increasing duration of use while serious adverse events, including venous thromboembolism, are rare among healthy COC users. Contraceptive decision-making should include consideration of both the risks and benefits of a given method versus the real consequences of unintended pregnancy. © 2014 Elsevier Ltd. All rights reserved.

Introduction The development of combined hormonal oral contraception has been hailed as one of the most important public health achievements of the twentieth century [1]. Since 1960, “the pill” has been used by hundreds of millions of women worldwide to prevent unintended pregnancy and its accompanying downstream consequences such as unsafe abortion and maternal morbidity and mortality. In 2013, the UNDP reported that 9% of women between the ages of 15 to 49 years who are married or in union use combined oral contraception (COC) [2]. Globally, COC is the second most commonly used form of reversible contraception and has the widest geographic distribution of all modern methods.

E-mail address: mdragoma@montefiore.org.

http://dx.doi.org/10.1016/j.bpobgyn.2014.06.003 1521-6934/© 2014 Elsevier Ltd. All rights reserved.

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Combined oral contraception confers a number of significant benefits to users. Not only do COCs offer safe, effective and reversible protection against pregnancy, but women also derive additional noncontraceptive health benefits from their use. COC use is also associated with well-studied risks. Common side effects are generally self-limiting and improve with increasing duration of use while serious adverse events, notably venous thromboembolism, are rare among healthy COC users. Contraceptive decision-making should include consideration of both the risks and benefits of a given method versus the consequences of unintended pregnancy. Combined oral contraception: past, present and future Correct, consistent use of COC interrupts the usual functioning of the hypothalamic-pituitarygonadal axis by suppressing secretion of luteinizing hormone (progestogen) and follicle stimulating hormone (estrogen) to primarily prevent ovulation [3]. Additional contraceptive effects attributable to progestogen exposure include endometrial atrophy, cervical mucus thickening and decreased tubal motility. Although progestogens provide the dominant contraceptive benefit, estrogen importantly stabilizes the endometrium to minimize breakthrough bleeding and potentiates the action of progestogens, allowing lower doses for contraceptive protection [4]. While the early birth control pills provided effective protection against pregnancy, they were far from perfect. The first combined hormonal oral contraceptive pill contained high doses of both synthetic estrogen (mestranol 150 mcg) and progestogen (norethynodrel 10 mg) and use was associated with significant side effects and unacceptable cardiovascular health risks [5,6]. Subsequent modifications have maintained COC effectiveness while improving safety and tolerability. Additionally, the diverse formulations and variations in pill-taking regimens currently on offer provide expanded choices to women considering COC use. Once the dose-dependent association between estrogens in COC and thromboembolism became apparent, COC with progressively lower doses were developed, resulting in significant decreases in venous thrombosis and cardiovascular risk [7,8]. Most available pills today are manufactured with 20 to 35 mcg of ethinyl estradiol (EE), but some containing EE doses as low as 10 mcg are available [9,10]. While there are no differences in contraceptive effectiveness among COC containing  20 mcg EE and higher dose (up to 50 mcg) pills, women using the former may discontinue more frequently and earlier as well as experience more bleeding disturbances [11]. Theoretically, the lower estrogen content might translate to further reductions in the rare risk of arterial and venous thromboembolism associated with modern COC use but this trend has not been consistently observed in large, population-based studies [12,13]. Contemporary COC typically contain EE paired with one of a number of progestational agents that vary in potency, affinity for steroid receptors, interaction with estrogens, and physiological effects [4]. Older progestins derived from testosterone (e.g. norethindrone, levonorgestrel) are typically associated with more androgenic side effects including acne, excess hair growth and altered carbohydrate and lipid metabolism. Newer progestins derived from progesterone and spironolactone (e.g. chlormadinone acetate, drospirenone) have been designed to bind more selectively to progesterone receptors and minimize androgenic, estrogenic and glucocorticoid side effects. In addition, some progestins, like drospirenone, have a partial antiandrogenic effect [14]. COCs containing 35 mcg EE or less in combination with any one of the existing progestins do not demonstrate obvious differences in contraceptive effectiveness, side effects, cycle control or continuation rates, but further studies are needed [15]. Whether or not there are differences in risk for venous thromboembolism (VTE) across COC formulations with various progestogens remains a point of debate [16,17]. Monophasic COC regimens provide a uniform dose of estrogen and progestin in all active pills during a cycle. In contrast, multiphasic COC vary the dose of either or both steroid hormones. The intention behind this innovation, initiated in the 1980s, was to reduce both total hormone exposure as well as side effects by producing cycles that more closely mimic normal physiology. Several systematic reviews have concluded, however, that multiphasic regimens do not offer superior contraceptive protection or clearly demonstrate any clinical advantage over monophasic formulations [18,19]. Rather, in the absence of greater benefits, use of monophasic regimens over multiphasic regimens may be preferred. Multiphasic COC require stricter adherence to a specific sequential pill-taking order given

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the variation in steroid hormones, potentially increasing the likelihood of incorrect use and subsequent unintended pregnancy. Another strategy to improve safety and tolerability and possibly promote COC adherence has focused on manipulation of the interval between active pill cycles. Traditional pill packs provide active pills for twenty-one consecutive days followed by seven days of placebo to induce cyclic withdrawal bleeding, similar to a natural menstrual cycle. To reduce the duration of withdrawal bleeding and side effects like migraines and dysmenorrhea associated with the hormone free interval, monthly regimens with a shortened placebo period and/or low doses of estrogen were developed [20,21]. Various studies note that use of 24/4 regimens either resulted in lighter scheduled bleeding of lesser duration or no difference and more frequent or no different incidents of unscheduled bleeding while maintaining contraceptive efficacy compared with 21/7 regimens [20e22]. Extended or continuous COC regimens allow women to plan withdrawal bleeding quarterly, on a flexible schedule, or eliminate them entirely [23e26]. Existing clinical trials suggest similar contraceptive efficacy, safety, satisfaction and either equivalent or somewhat improved bleeding patterns with extended regimens compared to cyclic use. Additionally, women randomized to extended use report greater relief from menstrual symptoms such as headaches, bloating, and menstrual pain [27]. Generally, extended and continuous COC users experience fewer scheduled bleeding events, but may have more unpredictable spotting and bleeding episodes to navigate. The newest COC formulations replace synthetic hormones with steroid components that more closely resemble endogenous molecules. In theory, natural estrogens and progestogens may have fewer metabolic and decreased thrombotic effects, further improving on safety [14]. A four-phasic COC containing estradiol valerate (E2V), a compound metabolized to the natural estrogen, estradiol, paired with dienogest, a selective synthetic progestin derived from nortestosterone, effectively suppresses ovulation, maintains cycle control and exhibits favorable metabolic and hemostatic effects [28,29]. Another monophasic COC formulated with the natural estrogen, estradiol (E2), and nomegestrel acetate (NOMAC), a potent synthetic progestin structurally similar to naturally occurring progesterone, has recently been approved in Europe and appears similarly safe and performs well in protecting against unintended pregnancy [30e33]. Further surveillance is necessary to determine whether the promising characteristics of these formulations translate to greater efficacy and safety (e.g. decreases in VTE) over prior products. Despite decades of pioneering research that have produced a diverse array of effective hormonal methods, including COC, contraceptive development continues to evolve. For example, new molecules (e.g. progesterone antagonists, progesterone receptor modulators), pill-taking regimens (e.g. pericoital administration), targets (e.g. multi-purpose technologies, contraceptive vaccines, male contraception, genetic/proteomic molecules) and alternative delivery systems (e.g. intrauterine devices, implants, patches, rings, gels) are under investigation with the potential for even greater contraceptive protection, tolerability, non-contraceptive benefits and safer choices [34].

Non-contraceptive benefits associated with COC use Improved cycle control and relief from menstrual symptoms Taken consistently, cyclic COC use results in predictable, less painful bleeding episodes of decreased volume and duration, compared to normally menstruating women. Extended or continuous COC use is typically associated with even milder symptoms. Women suffering from excessive menstrual bleeding experience significant reductions in both menstrual blood loss (more than 50%) and duration of bleeding with use of various COC formulations [35,36]. Anovulatory bleeding, common at the extremes of reproductive age or in association with obesity as well as polycystic ovary syndrome (PCOS), can improve with exposure to COC, too [37]. Combined oral contraceptive use also offers relief to women suffering from dysmenorrhea. Strikingly, women with the worst symptoms can derive the greatest benefits. One study showed that severe dysmenorrhea can be reduced almost 90% with COC use [38]. Among women with endometriosis, current or recent COC use is associated with less pain throughout the cycle [39].

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Reductions in other challenging menstrual symptoms may accompany COC use. Women with premenstrual syndrome (PMS) or more severe premenstrual dysphoric disorder (PMDD) may experience a decrease in physical (e.g. mastalgia, nausea), mental health (e.g. irritability, depression) and behavioral symptoms (e.g. insomnia, appetite changes) with COC use, perhaps to greater effect than other treatments such as selective-serotonin receptor inhibitors (SSRIs) [40,41]. In contrast, menstrual migraines, sensitive to estrogen withdrawal, may actually worsen with cyclic COC use during hormone free intervals. These migraines can, however, be prevented for many months with use of extended or continuous COC regimens [42]. Improved acne and hirsutism Because combined oral contraception decreases androgen levels and increases sex hormone binding globulin, they can be useful in preventing or reducing unwanted effects of excess androgen exposure such as acne and hirsutism [43]. A recently updated Cochrane systematic review synthesized results from thirty-one randomized controlled trials with a total of over 12,000 participants [44]. All of the COC formulations studied significantly reduced the appearance of both inflammatory and non-inflammatory facial acne lesions compared to placebo. Comparisons between COC formulations were limited and demonstrated mixed results, precluding determination of any superior formulation for this indication. Androgen-sensitive hair growth is also altered with COC use; hair shaft diameter is reduced, with maximal benefits being observed after one to two years of use [45]. Improved bone health Perimenopausal and postmenopausal women (over the age of forty) using COC tend to gain or preserve bone mineral density (BMD) while non-users experience typical age-related bone losses [46e54]. Other women with hypoestrogenic conditions (e.g. hypothalamic amenorrhea) treated with COC also demonstrate increases in BMD [55e57]. COC use among adolescents may result in a net decrease in bone mineral density while premenopausal users experience no difference when compared to non-users of similar age [58]. Although changes in BMD have been observed during hormonal contraceptive use, the clinical relevance of these changes and their impact on risk for subsequent bone fracture remain unclear. Most studies report no differences in risk among past COC users compared to never users, but several suggest mild protective effects [58]. Prevention of ovarian, endometrial and colorectal cancer There is a substantial amount of epidemiological evidence demonstrating that COC use decreases a woman's lifetime risk for ovarian, endometrial and colorectal cancer [59]. A recent re-analysis of data from 45 studies across twenty-one countries found that COC use was associated with a reduction in lifetime mortality from ovarian cancers (both epithelial and non-epithelial) by over 50%. It also reported greater benefit with longer duration of use (1-4 years: RR 0.78 (95% CI, 0.73-0.83); 15 years or more: RR 0.42 (95% CI, 0.36-0.49). Protective effects persist for up to 30 years following COC discontinuation [60]. Risk for endometrial cancer is also reduced by upwards of 50% among COC users compared to never users. Data supporting this claim are derived from well-conducted large, population-based cohort studies [61e63]. A systematic review and meta-analysis evaluating colorectal cancer and combined oral contraception noted nearly a 20% decrease in risk among ever use versus never use [64]. No difference in effect was demonstrated according to duration of use; however, it appeared that protection was stronger relative to recent use (< 10 years since last use: OR 0.51, 95% CI 0.35-0.74) compared to more distant use (> 10 years since last use: OR 0.77, 95% CI, 0.60-0.99). Reductions in mortality Prevention of unintended pregnancy with use of effective, modern methods of contraception, including COC, can be a life-saving strategy during a woman's reproductive years, particularly in

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regions with high rates of maternal mortality. Even after childbearing, large population-based studies suggest that a history of COC use may have an impact on reducing lifetime mortality from all causes compared to never users, supporting a strong overall health benefit associated with COC use [61,65]. Risks associated with COC use Minor side effects Some women using COC may report undesirable side effects resulting from hormonal exposure. Fortunately, these symptoms occur significantly less with currently available low dose COC compared to older preparations, and while side effects can be intense in the first months of use, they frequently resolve with time. Commonly reported side effects such as headaches, nausea, dizziness, and breast tenderness have actually been reported at the same rate in both treatment groups of placebocontrolled clinical trials [66]. Many of these side effects can arise during the hormone free interval rather than during active pill use and COCs with shortened placebo weeks or extended COC regimens may be helpful [67]. Irregular, unpredictable bleeding can also be troubling. Differences in patterns of bleeding and spotting can vary by COC formulation and regimen, but generally, breakthrough bleeding most frequently occurs soon after initiation, ranging from 10-30% in the first month and decreasing to about 10% by the third [68e70]. Breakthrough bleeding occurring months after use commonly results from progestin-induced endometrial decidualization, but is also associated with smoking and inconsistent pill-taking. Weight gain is often perceived to be associated with COC use and frequently cited as a reason for discontinuation even though no causal association has been found. Existing evidence demonstrates that weight change is the same for both COC and placebo users in clinical trials investigating various low dose products [71]. It is unclear whether COC use has an effect on libido. Studies show mixed results. A well-designed prospective cohort study demonstrated that women using a low dose drospirenone-containing COC experienced increased sexual satisfaction, improvement in sexual enjoyment, and no change in libido [72,73]. COC use is not associated with long term impairments in future fertility, regardless of duration of use. Upon discontinuation, women can expect no more than a two week delay in the return of menses, and twelve-month conception rates following COC use range from 72% to 94%, comparable to other contraceptive methods [74]. The experience of minor side effects, in addition to consideration of more serious complications, can influence both a woman's desire to initiate COC as well as her willingness to continue. Each woman should be provided with appropriate information and offered counselling on the full range of contraceptive options available to her to ensure an informed choice. Once a woman has chosen to use COC, supportive reassurance, education and time may be sufficient to manage most problems that arise. Pregnancy Perfect use of COC is associated with a failure rate as low as 0.3%while typical use failure rates better describe COC performance in practice and are as high as 9% [75]. While oral contraception is very effective, the experience of unintended pregnancy as a result of incorrect or inconsistent COC use or from a rare method failure carries significant public health consequences. Women should be advised of the real risks of unintended pregnancy when choosing COC, particularly when other reversible contraceptive methods offering greater protection are available. The daily schedule for medication administration can pose challenges for many women. Most people with chronic medical conditions only comply with their medical treatment 50-60% of the time even when presented with evidence for improved quality of life and longevity [76]. While 80% adherence rates to daily medications are considered acceptable in clinical trials of other medications for chronic use, such a standard would inevitably lead to unintended pregnancy among COC users [77]. Given trends in adherence to daily medications broadly, it may not be surprising that missed pills and

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consecutive days of missed pills during COC use are common [78]. Unfortunately, pill-taking behavior does not necessarily improve over time [79]. Additionally, many women stop COC soon after starting in spite of the method's popularity. Large, population-based studies on contraceptive use patterns report high rates of COC discontinuation within three months to one year of use [80e82]. Smaller retrospective and prospective studies demonstrate similarly high rates of discontinuation. More than 10% of women stop COC within the first month and the proportion of women who discontinue steadily increases over time and by six months to one year, 30e60% of COC users have stopped the method [83e85]. Following discontinuation of COC, a majority of women transition to less effective or no contraception, increasing the risk for unintended pregnancy [81]. In contrast, women who choose long-acting reversible forms of contraception such as the intrauterine device or implant benefit from more effective contraceptive protection, higher rates of adherence, continuation and satisfaction at one year compared with COC users [86]. Thromboembolism The incidence of VTE (8-10/10,000 women-years exposure) and arterial thrombotic events, including both myocardial infarction and stroke(1-4/10,000 woman-years exposure), are very rare among healthy, reproductive age users of modern COC. In addition these incidences are significantly lower than those reported with pregnancy [87]. While the relative risk for VTE is increased approximately three-fold and the relative risk for thrombotic stroke is increased two-fold compared to nonusers, the absolute risk for these serious adverse events among women using COC remains low. Risk for VTE appears to be highest in the first year of COC exposure, but decreases with greater duration of use. No differences in the relative risk of myocardial infarction (MI) or hemorrhagic stroke have been reported with COC use versus non-use [88]. In the mid-1990s, concerns emerged regarding an association between the progestogen content in COC and risk for venous thromboembolism (VTE) [89]. Recently published meta-analyses of observational studies evaluating these associations have concluded that risk for VTE may be between 50 to 80% higher among users of COC containing newer generation progestogens, including gestodene, desogestrel, cyproterone acetate and drospirenone compared with levonorgestrel [90,91]. These estimates of risk rely heavily on large retrospective cohort studies which are criticized for relying on databases to link exposures and outcomes without adequately evaluating potential confounding or effect modification by known risk factors such as smoking, body mass index (BMI), or history of VTE [92]. A recently published prospective multi-national cohort study with over 85,000 participants and up to six years of follow up with high retention offers some of the strongest evidence to date regarding cardiovascular thromboembolism risk among users of various progestogen-containing COC [87]. This study reported that the incidences of VTE, arterial thrombotic events, fatal outcomes, cancer, serious depression and other serious adverse events were similar among users of drospirenone-containing, levonorgestrel-containing and other progestogen-containing COCs. COC use in the setting of co-existing medical conditions Contraceptive decision-making for women with medical conditions can be complex and requires an individualized approach. Recognizing that unintended pregnancy may contribute to a worsening of a woman's medical status as well as pose a risk to fetal growth and development in the setting of maternal disease, women should be offered the most effective form of contraception available after thoughtful consideration of the relative risks and benefits of each method, including COC. While certain conditions such as heavy menstrual bleeding, endometriosis, and severe dysmenorrhea can improve with COC use, combined hormonal contraceptive use by women with other medical conditions such as uncontrolled hypertension, migraines with aura, and history of stroke can pose unacceptable health risks. Evidence-based guidelines regarding the safety of COC for use by women with various characteristics and physiological or medical conditions are available to ensure that women's options for effective contraception are not unnecessarily limited due to overestimations of risk [93].

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Summary Even after fifty years of use, combined hormonal contraception remains a relevant contemporary method of contraception. Newer formulations and pill-taking regimens offer improved safety, tolerability and greater flexibility. The latest COC formulations and ongoing research in contraceptive development offer the potential for still greater improvement. In addition to prevention of unintended pregnancy, women who use COCs garner a number of non-contraceptive benefits, and risks of serious adverse events with use are rare among healthy users.

Practice points  Monophasic COC formulations may be preferred over multiphasic preparations given no clinical advantage and potential for incorrect use.  Extended and continuous COC regimens offer women fewer scheduled bleeding episodes and associated symptoms while maintaining safety and contraceptive effectiveness. Reducing the frequency of the hormone free interval or eliminating it entirely can be helpful in managing a number of menstrual-related complaints and disorders.  Women who choose to use COC receive a number of significant non-contraceptive benefits, including, but not limited to, reductions in lifetime risk for ovarian, endometrial and colorectal cancer as well as all-cause mortality.  Cardiovascular thromboembolism is rare among COC users, lower than risks associated with pregnancy. While the best evidence to date suggests no association between various progestogen-containing COCs and risk for VTE and ATE, even if risks associated with newer generation progestogens are real, the absolute risks for these serious adverse events remain low.  Contraceptive decision-making should be guided by evidence-based assessments of medical eligibility and reflect a woman's personal preferences and choice; there is no one best’ COC, or other contraceptive method, for all women.

Research agenda  New molecules and administration regimens for oral contraception.  Long term effects of COC containing natural estrogens and progestogens on risk for cardiovascular thromboembolism.  Evaluate new strategies and/or technologies to increase COC adherence and continuation.

Conflict of interest None.

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