Combined Hormonal Contraception
Carolyn L. Westhoff, MD, MSc
Surya Cooper, MD, MPH,
Ian Joseph Bishop, MD, MPH
Types of Combined Hormonal Contraception
Combination hormonal contraceptives (CHCs) include pills, rings, patches, and injections and contain, by definition, an estrogen and a progestin. The mainstay of combined hormonal contraceptives for the first decades was a combination estrogen/progestin oral tablet. A fixed combination of mestranol 150 µg/norethynodrel 9.85 mg was developed as a combination oral contraceptive but first approved in 1957 as a treatment for menstrual disorders and infertility. The combination, marketed as Enovid®, was approved by the U.S. FDA as an oral contraceptive pill (OCP) in 1960 with a regimen of 21 consecutive days of active pills with a 7-day break between cycles. The 7-day break was designed to induce a withdrawal bleed that would mimic menses, resulting in 13 artificial cycles per year. As the original pills contained a substantial hormone dose, the hypothalamic-pituitary axis remained suppressed during the 7-day break, thus maintaining effectiveness. Innovations from this prototype include decreases in dose, changes in specific hormonal constituents, deviations from the fixed combination, and increases in the number of active tablets with concomitant decreases in the number of inert tablets per cycle. In the United States, at least 20 distinct formulations of combined oral contraceptives (COCs) are FDA approved and available, most of which contain ethinyl estradiol (EE) as the estrogen component. COCs are marketed as both branded and therapeutic equivalent (generic) products; the generic versions are also given distinct product names creating a market with an appearance of dozens of different formulations. The U.S. FDA approved a combination estrogen/progestin injection in 2000; such injections are not currently available in the United States but are widely used elsewhere (see Chapter 8). The U.S. FDA approved the first transdermal and transvaginal contraceptive delivery systems in 2001. The first non-EE containing COCs became available in Europe in 2009 and the United States in 2010.
Following their approval in 1960, oral contraceptive use increased rapidly in the United States and Europe. Case reports of pulmonary embolism in oral contraceptive users led to hearings on the cardiovascular safety by the FDA in 1963.1 In 1968, Vessey and Doll2 published a large case-control study of thrombosis risk in U.K. pill users, reporting a 9-fold risk increase. Due to this serious risk and other side effects, lower dose formulations
rapidly emerged and dominated the market worldwide. Today’s oral contraceptives have approximately 90% lower progestin doses than Enovid. However, with so many different progestins in use, each having different affinities for steroid hormone receptors, one cannot make simple dose comparisons between progestins based on their weight alone. Similarly, the estrogen content of COCs has declined. Mestranol is a prodrug of EE, and 150 µg of mestranol is roughly equivalent to 105 µg of EE. Most of today’s oral contraceptives have daily EE doses ranging from 10 to 35 µg; the disadvantage of using lower EE doses (or estradiol at any dose) is more spotting or unpredictable bleeding,3 which may contribute to user dissatisfaction. Importantly, it remains controversial whether COCs with EE doses below 35 µg are actually safer or otherwise more acceptable to users. Such results indicate that improving safety related to the estrogen component of oral contraceptives may require new estrogens or different delivery systems.
rapidly emerged and dominated the market worldwide. Today’s oral contraceptives have approximately 90% lower progestin doses than Enovid. However, with so many different progestins in use, each having different affinities for steroid hormone receptors, one cannot make simple dose comparisons between progestins based on their weight alone. Similarly, the estrogen content of COCs has declined. Mestranol is a prodrug of EE, and 150 µg of mestranol is roughly equivalent to 105 µg of EE. Most of today’s oral contraceptives have daily EE doses ranging from 10 to 35 µg; the disadvantage of using lower EE doses (or estradiol at any dose) is more spotting or unpredictable bleeding,3 which may contribute to user dissatisfaction. Importantly, it remains controversial whether COCs with EE doses below 35 µg are actually safer or otherwise more acceptable to users. Such results indicate that improving safety related to the estrogen component of oral contraceptives may require new estrogens or different delivery systems.
Several combined hormonal contraceptives already in use or under study contain estrogens other than EE. Estradiol 2.5 mg combined with the progestin nomegestrol acetate 1.5 mg (sold under the brand names Naemis and Zoely® among others) has a cycle with 24 active tablets and 4 placebo tablets; this product is available in Europe but not in the United States. A multiphasic oral contraceptive containing estradiol valerate (E2V) 1 to 3 mg per tablet and dienogest (DNG) 2 to 3 mg per tablet (sold as Natazia® and Qlaira®) has a cycle with 26 active tablets and 2 placebo tablets. Estradiol valerate circulates as estradiol. Products under development include pills that contain estetrol (E4), an estrogen with four hydroxyl side chains, and vaginal rings with estradiol (E2) instead of EE.
While the search for a safer pill has driven most dose reductions and other innovations in oral contraceptive regimens, the desire for a more favorable side effect profile has been another key motivator. Other changes in the past few decades have been non-science based; patent expiration and industry competition for marketing advantage has driven a number of minor and generally unimportant OC formulation changes. While many of these factors have led to dramatic decreases in estrogen doses, EE remains the most commonly used estrogen in oral contraceptives (and in the transdermal patch and the vaginal ring) worldwide. EE is a potent estrogen that is easily absorbed orally and that provides excellent cycle control.3
As we move forward in our discussion of CHCs, it is important to remember the concepts of “high-dose” and “low-dose” COC formulations that were introduced in Chapter 2. This “dose” refers to the estrogen content, specifically EE. High-dose COCs contain EE 50 µg or more, whereas low-dose products contain EE doses less than 50 µg.
Variations in Oral Formulations
Throughout the 1960s and still today, monophasic formulations (every tablet contains the same estrogen-progestin dose) dominate the market for combined hormonal products. Although the original 21-day active hormone and 7-day pill-free interval remains the most common COC
regimen, alterations in drug delivery over 4-week or longer time periods have increased the options available to women today.
regimen, alterations in drug delivery over 4-week or longer time periods have increased the options available to women today.
Phasic Regimens
Phased pill products emerged in the late 1970s with both sequential (biphasic) regimens and multiphasic regimens; some only altered the progestin doses and others varied both the estrogen and progestin doses throughout a single cycle. Today, multiphasic products include even more variations. The general aim of this approach is to lessen total dosage and minimize metabolic changes, spotting, breakthrough bleeding, or other annoying side effects (if any) while maintaining efficacy. Some products were developed simply to provide patent protection for a company for their hormonal product line. Overall, metabolic studies of multiphasic preparations indicate no differences or very slight improvements over the metabolic effects of low-dose monophasic products, and no difference in efficacy. Multiphasic products have efficacy similar to monophasic products, but evidence that multiphasic products have less breakthrough bleeding than do their monophasic counterparts is weak.4,5 Thus, starting hormonal contraception with a monophasic product is reasonable.
Extended Regimens
The term “extended regimen” refers to combined hormonal administration for more than 21 days in a 28-day cycle. With a traditional 21/7 regimen, the hypothalamic-pituitary-ovarian (HPO) axis returns to near-normal activity quickly after the last dose. In an evaluation of 15 premenopausal women using 30 to 50 µg EE pills combined with levonorgestrel (LNG) or norgestrel, the investigators found follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations and pulse frequency, fully suppressed on the first day of the hormone-free interval (HFI), increased to levels similar to values obtained on cycle day 2 to 11 from controls with regular cycles not using an OC. Thus, HPO axis activation occurs by the end of a 7-day hormone-free week. Killick et al.6 evaluated extending the HFI to 9 or 11 days in women using 30 to 40 µg EE pills combined with either LNG or gestodene (GSD). They used a crossover design, so each of the 28 subjects had a cycle of observation with a 7-, 9-, and 11-day HFI. Although none of the women ovulated, the investigators found significant variation in follicle growth between subjects with the longer intervals raising concern that reactivation of the HPO axis presents a mechanism for failure.
Given the importance of estrogen feedback on suppression of FSH, lowering the dose of EE below 30 µg may allow more rapid follicle development. van Heusden and Fauser7 compared hormone profiles and follicle growth during the 7-day HFI between users of 20 and 30 µg EE pills with similar (gonane) progestins. Median follicle diameters at the beginning and at the end of the HFI were statistically significantly smaller in the 30 µg EE group, with a dominant follicle (defined as greatest follicle diameter ≥10 mm) observed at the end of the HFI in 22% of women using 20 µg compared to
none among women using 30 µg EE pills. Consistent with greater follicle activity, the area under the curve (AUC) for E2 during the HFI was higher in users of the 20 µg EE pills and correlated with a more rapid rise of FSH than among users of the higher EE dose. Thus, the hormone-free week may allow a dominant follicle to develop, and any delay in beginning, or improper use (e.g., missed pill, ring removal) during the subsequent cycle may increase the risk of ovulation and pregnancy.
none among women using 30 µg EE pills. Consistent with greater follicle activity, the area under the curve (AUC) for E2 during the HFI was higher in users of the 20 µg EE pills and correlated with a more rapid rise of FSH than among users of the higher EE dose. Thus, the hormone-free week may allow a dominant follicle to develop, and any delay in beginning, or improper use (e.g., missed pill, ring removal) during the subsequent cycle may increase the risk of ovulation and pregnancy.
Studies evaluating the pharmacodynamics of a shorter HFI have not consistently shown a reduction in follicle growth or pituitary suppression.8,9 The best data supporting the benefit of a reduced HFI come from a large prospective cohort study involving over 52,000 women conducted in Europe and the United States. This study found significantly lower failure rates associated with using 24-day regimens of EE combined with either drospirenone (DRSP) or norethindrone (NET) compared to 21-day formulation.10
Whether reducing the HFI improves breakthrough bleeding associated with initiation of low EE pills remains controversial, as most studies do not compare results with a common formulation.11,12 However, reducing the HFI does seem to decrease the number of days of withdrawal bleeding.11
Trials comparing 21/7 and 24/4 products with the same hormones provide clarity about the differences with these regimens. A randomized open-label, 6-month study of an EE 20 µg/NET acetate 1 mg pill enrolled 938 women in a 4:1 ratio with 705 women receiving the 24/4 regimen and 181 in the 21/7 regimen in the final analysis.13 The study was not large enough to determine a significant difference in efficacy comparing the two products. The number of days with breakthrough bleeding or spotting was comparable between the groups, but the 24-day group demonstrated a steady decline in breakthrough bleeding/spotting days, so that in cycle 6, the mean number of bleeding days was lower in the 24-day group (0.95 vs. 1.63). Additionally, each cycle with the 24-day product demonstrated a shorter duration of withdrawal bleeding (bleeding beginning after the last day of active drug intake), achieving statistical significance in the second cycle. On average, women using the 24/4 regimen experienced one less day of bleeding per month. Thus, if both products are available, the 24/4 regimen has slightly better cycle control; whether this translates to increased compliance or continuation is unknown.
A 3-cycle treatment study compared ovarian activity with 24/4 and 21/7 regimens of an EE 20 µg/DRSP 3 mg pill.14 In the third cycle, the first 3 tablets were substituted with placebo to identify what would happen with noncompliance when starting a new pill pack (in essence, the 21/7 group had a 10-day pill-free interval and the 24/4 had a 7-day pill-free interval). The 24/4 schedule was associated with greater follicular suppression and only one ovulation in cycle 3 compared with four ovulations in the 21/7 regimen. A study of 12 women using this formulation for either 23 or 24 hormone days documented greater suppression of FSH, LH, inhibin B, and estradiol during the pill-free interval when compared to women using the same product with 21 hormone days.8
This latter study demonstrates the concept of “escape” follicular activity, which is decreased in women using a 24/4-day regimen, even with lower hormone doses. In general, ovarian follicular activity is greater with products containing less EE, and the maximal follicular size reached is larger. In one study, approximately 30% of women using an EE 20 µg product achieved follicular diameters of 15 mm or greater compared to only 15% of women using an EE 35 µg product when the pill-free interval was extended from 7 to 9 days.15 Once follicles achieve a diameter greater than 10 mm, an increasing percentage will ovulate even in the presence of oral contraceptive treatment.16 Lower-dose EE formulations produce less suppression of gonadotropin secretion; users of a 20 µg EE product have higher FSH, LH, and estradiol blood levels.15 Thus, increasing the number of active hormone days to 24 in a 28-day cycle overcomes the risk of escape ovulation. Bear in mind that with correct daily COC use, a pharmacodynamics trial found no differences in follicular development between women assigned to an OC with EE 20 µg versus an OC with EE 30 µg.17
Another approach to reducing reactivation of the HPO axis during the HFI involves the addition of a low EE dose given alone to replace inert pills for several days (e.g., Mircette® has 21 EE/desogestrel [DSG] tablets, two placebo tablets, and 5 EE-only tablets; Lo Loestrin® Fe has 24 EE/NET tablets, two EE-only tablets, and two hormone-free iron tablets). The rationale for this approach is that EE should result in suppression of FSH secretion and prevent follicle growth. A randomized study that compared women using either a 21-day EE 20 µg/LNG 100 µg pill followed by a 7-day HFI or a 24/4 regimen of EE 20 µg/DRSP 3 mg to an experimental regimen of EE 20 µg with DSG 150 µg followed by EE 10 µg for 7 days found no difference in follicle activity between formulations.18 However, the different progestins used make interpretation of results challenging. A study that evaluated the effects of EE during the HFI among women using EE 30 µg/LNG 150 µg did show a beneficial effect on suppression of FSH, E2, and inhibin B.19
Extended Cycles
“Extended cycle” refers to the continuous use of a combined hormonal product beyond 28 days without an HFI. Three approaches are in common use: tricycle extended cycles, continuous cycles, and flexible cycles. The tricycle regimen provides a convenient approach to reduce the number of withdrawal bleeds to four times per year. Each blister pack includes 84 active combined pills followed by 7 days of placebo pills (Seasonale® EE 30 µg/LNG 150 µg) or 7 days of EE 10 µg (Seasonique® EE 30 µg/LNG 150 µg; LoSeasonique® EE 20 µg/LNG 100 µg). For continuous cycles, women use the active combined hormonal product every day without any hormone-free interruption. A formulation of EE 20 µg/LNG 90 µg is approved for 1-year continuous use by the U.S. FDA; however, any low-dose monophasic pill is suitable for continuous doing. A potential disadvantage of continuous use is breakthrough bleeding particularly in early cycles of
use, but this seems to improve over time.20 A small randomized study that compared 21/7 cycles or continuous use of a EE 20 µg/LNG 100 µg pill found more overall bleeding and spotting days in the continuous group but significantly fewer bleeding days that required protection.21 Women randomized to continuous use were also more likely to have amenorrhea and reported significantly fewer days of bloating and menstrual pain.
use, but this seems to improve over time.20 A small randomized study that compared 21/7 cycles or continuous use of a EE 20 µg/LNG 100 µg pill found more overall bleeding and spotting days in the continuous group but significantly fewer bleeding days that required protection.21 Women randomized to continuous use were also more likely to have amenorrhea and reported significantly fewer days of bloating and menstrual pain.
Flexible cycle refers to an extended cycle of variable length. With flexible use, the woman decides when to initiate a 4-day HFI. Typically, this decision is prompted by an episode of breakthrough bleeding. Only one 4-day HFI is permitted every 28 days. The rationale for a flexible 4-day HFI comes from a study that demonstrated that initiation of a 4-day pill break improved bleeding patterns in women using continuous pills.22 A formulation of EE 20 µg/DRSP 3 mg designed for flexible use with a novel electronic tablet dispensing device is approved in Australia but not in the United States.23 A 1-year open-label phase 3 study conducted in the United States randomized women to one of two flexible extended regimens or the conventional 24/4 regimen, and found a bleeding-signal flexible approach was associated with good contraceptive efficacy and fewer bleeding/spotting days than the conventional 24/4 regimen.24
Taking active pills continuously can more fully suppress ovulation and can suppress menses and other cyclic symptoms like dysmenorrhea, mood changes, headaches, and bloating.22 For years, clinicians have prescribed unlimited daily oral contraceptives to treat conditions such as endometriosis, bleeding disorders, menstrual seizures, and menstrual migraine headaches, as well as to avoid bleeding in athletes and busy individuals. Many women do not require the periodic experience of vaginal bleeding to assure themselves that they are not pregnant. Monthly bleeding, periodic bleeding, or no bleeding—this is an individual woman’s choice. Any combination oral contraceptive can be used on a daily basis; even the lowest estrogen dose formulations provide excellent bleeding and side effect profiles in a continuous regimen.20,21,25 As with the extended regimen, continuous dosing provides greater ovarian suppression, reducing the potential for breakthrough and escape ovulations.26 A further benefit of continuous use is simplification of the pill-taking schedule with the potential of better compliance and a lower failure rate. The return of ovulation and achievement of pregnancy are not delayed after discontinuation of continuous dosing.26,27 Extended cycling to suppress menses is increasingly acceptable.28,29
Variations in Oral Contraceptives Unrelated to Hormonal Content
Some products replace the inert tablets with either iron or folate or even add folate to the active hormonal component of each pack. Because reproductive age women may develop iron deficiency secondary to heavy menses, adding some iron may be beneficial, but since any combined hormonal contraceptive use tends to reduce menstrual blood loss, the benefit of adding iron is modest. The goal of adding folate is to help women maintain folate sufficiency, so that if they become pregnant immediately on stopping the
OC, this folate sufficiency may help to prevent a neural tube defect in that pregnancy.30,31 The benefits of adding minerals or vitamins to contraceptive formulations have yet to be proven and mostly serve as a patent modifier related to marketing.
OC, this folate sufficiency may help to prevent a neural tube defect in that pregnancy.30,31 The benefits of adding minerals or vitamins to contraceptive formulations have yet to be proven and mostly serve as a patent modifier related to marketing.
In the United States, pill packs usually contain 28 tablets with 7 inert tablets during the 7-day break; including these inert tablets was intended to help women maintain their pill-taking routine. In many other countries, a 21-day blister pack (without any inert tablets) is routine.
Nonoral Formulations
In addition to pills, CHC is also available in a monthly vaginal ring formulation, weekly transdermal adhesive patch formulation, and monthly combined injections—most of these are provided in 4-week cycles. A vaginal ring (AnnoveraTM) designed for use for 13 consecutive 21/7 cycles was approved in the United States in 2018. The hormones in the rings and patch are also available in oral formulations. While the ring, patch, and injections have been less well studied than pills, the risks and benefits are likely similar. The main benefit of using a ring, patch, or injection (where available) is that less frequent dosing may help to support more consistent use; however, evidence for that benefit is inconsistent.32,33 Using a ring or an injection may also be more discreet, a benefit for some adults and adolescents who do not want partners or parents to know about their contraceptive use.
Transdermal Contraceptives
The U.S. FDA-approved transdermal contraceptives include a 20-cm2 patch that releases EE 20 µg/day and norelgestromin (NLGM, the primary active metabolite of norgestimate [NGM]) 150 µg/day. The product was originally marketed as the branded product Evra®, but now is only available as the generic Xulane®. Three weekly patches are used consecutively (thus for 21 days) after which scheduled withdrawal bleeding will occur during a patch-free week. The overall 1-year Pearl Index from the pivotal trials ranged between 0.7 and 1.24.34,35,36 At that time, most women in clinical trials were required to be at or close to normal weight and thus only 10% of the participants in the pivotal trials had a weight greater than 90 kg; these heavier study participants experienced one third of the on-treatment pregnancies.37 The patch label therefore carries a warning about lesser effectiveness in heavier women, and these results led to extensive evaluation of the possible relation between weight and effectiveness for many other hormonal contraceptives.38 A 4-month U.S. trial randomized 500 COC users who were content with their COC but willing to try a nondaily option to use either the EE/NLGM patch or the 1-month vaginal ring contraceptive; at the end of the study, most patch users preferred to resume the oral contraceptive while ring users preferred the ring.39
A randomized pharmacokinetic study compared this EE/NLGM patch to an EE 30 µg/LNG 150 µg oral contraceptive and the EE/etonogestrel (ENG) contraceptive vaginal ring.40 The 21-day AUC for EE was 50% greater among
the women who used the patch compared to those who used the oral contraceptive, and 300% greater than contraceptive ring users; even with just eight women in each group, these results were highly statistically significant. The higher-than-expected EE AUC may explain side effects (breast tenderness) and greater hepatic globulin induction with patch use compared to use of oral contraceptives of the same dose,41 which could translate to higher venous thromboembolism (VTE) risk.
the women who used the patch compared to those who used the oral contraceptive, and 300% greater than contraceptive ring users; even with just eight women in each group, these results were highly statistically significant. The higher-than-expected EE AUC may explain side effects (breast tenderness) and greater hepatic globulin induction with patch use compared to use of oral contraceptives of the same dose,41 which could translate to higher venous thromboembolism (VTE) risk.
Concerns over EE exposure have led to the development of other patches. Alternatives to the EE/NLGM patch under investigation include a weekly formulation designed to deliver EE 30 µg/day and LNG 120 µg/day and EE 20 µg/day and GSD 60 µg/day.
A large trial that randomized women to either the EE/LNG patch or an EE 20 µg/day LNG 100 µg/day COC showed comparable 6-month Pearl Indexes (4.45 [patch] and 4.02 [COC]),42 bleeding patterns, safety, and acceptability.43,44 The study population included a large proportion of obese women, but an analysis stratified by obesity found minimal difference in Pearl Indices. The U.S. FDA did not approve the EE/LNG patch based upon this Pearl Index despite the comparable result in the COC group. Data from other recent studies of hormonal contraceptives has shown a trend toward rising Pearl Indexes with more recent COC clinical trials of the same products (See Chapter 2 for discussion of the “Creeping Pearl”).38,45
The weekly EE/GSD patch containing EE 0.55 mg and GSD 2.1 mg provides similar daily systemic exposure to EE and GSD as an oral contraceptive containing EE 20 µg/day and GSD 60 µg/day; in contrast, the EE systemic exposure with the EE/NLGM patch was at least 200% greater than an oral comparator.46 An analysis of ovulation inhibition in 173 women using the EE/GSD patch showed no differences by body mass index (BMI), even among women with a BMI greater than 35 kg/m2.47 The bleeding pattern with this patch was comparable to an EE 20 µg/LNG 100 µg oral contraceptive.48 Results from a 13-cycle phase 3 open-label study in Europe yielded an adjusted Pearl Index of 0.81 with favorable bleeding patterns and a low rate of adverse events.49 However, results from a large multicenter U.S. study of this patch that began in 2009 have not been reported (ClinicalTrials.gov NCT00910637), suggesting that the development program has been halted.
Extended use of the existing combined hormonal patch may be associated with some estrogen accumulation; as this patch already yields higher systemic hormone levels than most current CHC, extended use seems unwise.40 A small randomized study comparing a 12-week regimen of continuous use of the EE/NGM patch followed by a 1-week HFI to the standard cycles showed high acceptability of both use patterns. Because the release system for each patch is different, any new patches that enter the market will require evaluation of extended use.
Vaginal Hormonal Contraception
The original CHC vaginal ring, 52 mm in diameter, 4 mm in cross section, and made of ethylene vinyl acetate (EVA), releases EE 15 µg/day and
etonogestrel (ENG, which is the active metabolite of DSG) 120 µg/day (NuvaRing® and bioequivalent rings including MyRingTM and Ornibel®). The hormones are embedded with EVA in a core that has a thin EVA outer release-controlling membrane. These rings are approved for single-cycle use for 21 days, but ovarian suppression continues even with 6 or more weeks of use.50 Four efficacy studies showed pregnancy rates of less than 1%, similar to the pregnancy rates in contemporary studies of COCs.51 In a crossover study, ovarian suppression was substantially greater when using the ring than when using a monophasic EE 20 or 30 µg oral contraceptive with LNG.52 Despite the low EE dose and the consequent low EE systemic exposure,40 bleeding and spotting days are somewhat less with this ring than with an EE 30 µg/day oral contraceptive.53 In a U.S. trial that evaluated 500 COC users interested in switching methods, most of those who were randomly assigned to this vaginal ring were highly satisfied and preferred to continue the ring after the study ended.39
etonogestrel (ENG, which is the active metabolite of DSG) 120 µg/day (NuvaRing® and bioequivalent rings including MyRingTM and Ornibel®). The hormones are embedded with EVA in a core that has a thin EVA outer release-controlling membrane. These rings are approved for single-cycle use for 21 days, but ovarian suppression continues even with 6 or more weeks of use.50 Four efficacy studies showed pregnancy rates of less than 1%, similar to the pregnancy rates in contemporary studies of COCs.51 In a crossover study, ovarian suppression was substantially greater when using the ring than when using a monophasic EE 20 or 30 µg oral contraceptive with LNG.52 Despite the low EE dose and the consequent low EE systemic exposure,40 bleeding and spotting days are somewhat less with this ring than with an EE 30 µg/day oral contraceptive.53 In a U.S. trial that evaluated 500 COC users interested in switching methods, most of those who were randomly assigned to this vaginal ring were highly satisfied and preferred to continue the ring after the study ended.39
A novel CHC ring, FDA designated as a “contraceptive vaginal system,” releases EE 13 µg/day and segesterone acetate (SA) 150 µg/day (Annovera). SA, also known as Nestorone®, is a potent progestin not used in pills as it is not orally active. This ring is also intended for cyclic use (21 days in, 7 days out), but it is unique in that a single ring is reusable for up to 1 year or 13 cycles.54,55 Prolonged use of the same ring does not increase the risk of vaginal infection and does not disrupt the vaginal ecosystem.56
Contraceptive vaginal rings delivering estradiol are under investigation. A dose-finding study evaluated six 21-day rings designed to release E2 300 µg/day along with various doses of ENG or nomegestrol acetate.57 Results demonstrated excellent ovulation suppression and cycle control with most of the six rings. Merck Sharp & Dohme Corp. initiated a U.S. phase 3 clinical trial program with a vaginal ring releasing estradiol 300 µg/day and ENG 125 µg/day in 2015 but terminated the study prematurely for business reasons (ClinicalTrials.gov NCT02524288). Fortunately, development of a combined E2/SA ring continues through the efforts of the Population Council and National Institute of Child Health and Human Development. Dose-finding studies have evaluated rings designed for 90 days of continuous use releasing E2 (in a range of doses) and SA 200 µg/day and found excellent ovulation suppression.58 A phase 2B study currently in progress is evaluating the efficacy, safety, and cycle control of a 3-month E2/SA vaginal ring (ClinicalTrials.govNCT03432416).
Studies support using the EE/ENG contraceptive ring continuously50,59 albeit with a similar spotting profile as that seen with extended-cycle COCs. With continuous use, the ring can be prescribed monthly rather than every 4 weeks. One approach for continuous use of the ring involves changing on a standard day each month (such as the first of the month, or any date significant to the woman), rather than every 28 days as the ring contains sufficient hormone release for this interval.
Injectable Combination Hormonal Contraception
Two monthly CHC injections are widely available around the world. Combined injections are highly effective reversible methods with failure rates less than 1%; in randomized trials, they have higher continuation rates than do progestin-only injections due to more predictable bleeding patterns.3
Cyclofem® contains 5 mg estradiol cypionate and 25 mg medroxyprogesterone acetate (E2-C/MPA); this formulation was studied and FDA approved as Lunelle in the United States in 2000, but was withdrawn due to manufacturing challenges. A large 60-week U.S. clinical trial with a COC comparison group demonstrated high efficacy and safety. Withdrawal bleeding starts about 22 days after the injection, lasts an average of 6 days, and tends to be consistent during the first year of use.60 Amenorrhea incidence is 1% to 4% per cycle. Acceptability and satisfaction were similar between COC and injections.61 Pharmacokinetic-pharmacodynamic studies reported contraceptive concentrations of MPA and found that ovulation remained suppressed for at least 2 months after the third injection. Injection site (arm, hip, or leg) and body weight had no important effects on MPA concentrations.62,63
Another CHC injection is Mesigyna®, which contains 5 mg estradiol valerate and 50 mg norethisterone enanthate (E2-V/NET-EN). Estradiol valerate is rapidly metabolized to yield estradiol (E2) after injection.
The progestin components of these combined injections differ, but both are widely used at higher doses in progestin-only injectables. A large randomized trial with 5,680 women in China compared efficacy, side effects, and bleeding patterns of Mesigyna, Cyclofem, and a third investigational injectable.64,65 Mesigyna and Cyclofem had low (<1%) 1-year failure rates. Discontinuations for bleeding complaints were lower for Mesigyna than for Cyclofem (0.6% vs. 3.7%). Overall discontinuation rates were lower for Mesigyna than for Cyclofem (14% vs. 19%).
Pharmacodynamics
Contraceptive Effects
The primary mechanism of action of CHCs is suppression of the HPO axis, limiting gonadotropin release and thus inhibiting follicular development and ovulation. Progestins alone suppress LH release and thus can be highly effective contraceptives. The estrogen component of CHC contributes to suppressing FSH, thus attenuating follicle development, and the estrogen also potentiates the progestin actions. This estrogen function has allowed reduction of the progestin dose in the pill. The mechanism for this action is probably estrogen’s effect in increasing the concentration of intracellular progestin receptors. Therefore, a minimal level of estrogen enhances CHC efficacy. The estrogen component also balances the progestin effect on the endometrium, reducing breakthrough bleeding as compared to
progestin-only systemic contraception. The effects of estrogens and progestins on ovulation are well documented, and ultrasound assessment of follicle growth and rupture combined with serum hormone evaluation to document progesterone production by the corpus luteum provide reliable surrogates of a contraceptive effect.
progestin-only systemic contraception. The effects of estrogens and progestins on ovulation are well documented, and ultrasound assessment of follicle growth and rupture combined with serum hormone evaluation to document progesterone production by the corpus luteum provide reliable surrogates of a contraceptive effect.
Because the progestin will always take precedence over estrogen (unless the estrogen dose is increased many, many fold), changes in the endometrium, cervical mucus, and perhaps tubal function reflect progestin stimulation. The contribution of contraceptive mechanisms other than ovulation inhibition has not been conclusively demonstrated. Although the progestin in the CHC produces an endometrium considered not receptive to ovum implantation (decidualized bed with exhausted and atrophied glands) and cervical mucus thick and impervious to sperm transport, both of these potential mechanisms become moot when ovulation does not occur. In the setting of ovulation, ovarian steroids may lead to more favorable endometrial and cervical changes. Therefore, while the product labeling for CHCs suggest endometrial or cervical mechanisms, these are largely theoretical. Chapter 2 reviews contraceptive mechanisms of steroid hormones in more detail.
Hepatic Effects
Contraceptive steroids affect numerous organs and systems separate from the reproductive system or from the mechanism of action. These effects vary based on the type of estrogen and progestin; future development of novel agonists and antagonists will likely result in products with differential effects on various organ systems. Today, most products contain EE. Key EE effects include stimulation of hepatic proteins through both first- and second-pass metabolism. Use of a CHC releasing EE increases sex hormone-binding globulin (SHBG), corticotropin-binding globulin (CBG), and thyroid-binding globulin (TBG), with maximal levels by day 7 to 10 of each cycle regardless of the route of administration. These changes are so characteristic that they can reveal, in COC users, whether an individual has been taking the pill (somewhat analogous to measuring HgA1C among people with diabetes to evaluate treatment success).66 The magnitude of binding globulin increases is directly related to the estrogen dose. These EE-induced increases are generally mitigated by the progestin, and this effect varies greatly by progestin type and dose. The more androgenic progestins, such as LNG decrease these changes, while newer progestins, such as DRSP, that do not stimulate the androgen receptor, allow the largest estrogen-induced increases to occur. In essence, these “androgenic” effects are actually “antiestrogenic.” Increases in these binding globulins do not have direct clinical effects, but they do lead to changes in the circulating levels of their ligands. For instance, among pill users, the circulating total thyroid levels will be higher due to the increases in TBG, but these levels do not signify thyroid dysfunction. Estradiol delivered transdermally or vaginally in physiologic doses does not stimulate the liver.
Metabolic Effects
Weight Gain
Many women believe weight gain is a common side effect of CHCs.67,68 COC users who attribute weight gain to their contraceptive are more likely to discontinue use by 6 months.69 However, available data from clinical trials contradict this belief.70,71,72,73,74,75 Results from two multicenter randomized doubleblind placebo-controlled randomized clinical trials designed to evaluate the efficacy of triphasic EE/NGM in the treatment of moderate acne vulgaris provide insight into commonly reported side effects.54,70 Over 500 women took part in these 6-month studies, and only 18 (7.9%) EE/NGM subjects and 9 (3.8%) placebo subjects discontinued because of adverse experiences. Notably, three of the nine discontinuations in the placebo group occurred due to weight gain, compared to only one in the EE/NGM group (the additional discontinuations in the OC group occurred primarily due to nuisance side effects such as nausea), and the incidence of weight gain (2%) did not differ between the groups.
A Swedish longitudinal study from 1986 to 2006, including over 600 women, reported no difference in weight/BMI increase between women who had used COCs at some time and women who had never used COCs. Further, a longitudinal analysis to assess any association between COC use and weight gain, which evaluated age, COC use, children, smoking, and exercise, found the only predictor for weight increase was age (gain of 0.45 kg/year).76 A Cochrane review that included 49 trials did not find evidence supporting a causal relationship between CHC and weight gain.77 The majority of trials that compared pill types and doses found little difference in weight gain between groups, contradicting the myth that weight gain is dose related.
Fewer studies have evaluated the effect of CHCs on weight gain in obese women, as most CHC studies have excluded this population. A study that randomized women to use of either an EE 30 µg/LNG 150 µg or EE 20 µg/LNG 100 µg COC for 3 to 4 months found no difference in the pattern of weight gain between the cohorts of normal weight (n = 96) and obese (n = 54) women with either OC formulation.78 A Swedish randomized, multicenter, open-label trial of 983 women treated with the EE/ENG vaginal ring or a COC for 13 cycles saw relatively small changes in baseline mean body weight and body composition for both groups with no notable between-group differences.79 Although these data support lack of a causal relationship between CHC use and weight gain, clinicians need to approach the discussion of weight gain with sensitivity. Clinicians need to carefully reinforce the lack of association between oral contraceptives and weight gain and focus the patient on the real culprits: diet and level of exercise. Most women gain a moderate amount of weight as they age, whether they use CHCs or not. However, if a woman strongly believes her CHC is causing weight gain, she is at high risk for discontinuation and requires counseling on alternative contraceptive strategies.
Lipoproteins and Oral Contraception
In women who use CHC for at least 3 months, the estrogen component of CHC lowers low-density lipoprotein cholesterol (LDL) and increases highdensity lipoprotein cholesterol (HDL).80 These changes occur due to firstpass hepatic effects with all orally administered estrogens, and as a result of secondary pass of EE. The progestin component antagonizes estrogeninduced beneficial lipid changes, modulated by the progestin’s effect on androgenicity. Oral contraceptives with relatively high doses of progestins (doses not used in today’s low-dose formulations) do produce unfavorable lipoprotein changes.81 Formulas with less androgenic progestins generally show more favorable effects on lipids compared to more androgenic progestins, such as LNG.82 The magnitude of change is related to the EE dose, the progestin type, and the woman’s weight (i.e., normal weight vs. obese).
EE causes a dose-related increase in triglycerides. Oral, but not transdermal, estradiol also increases triglyceride levels. Although COC formulations containing EE 35 µg increase triglyceride-rich very low-density lipoprotein (VLDL) levels by 2.2-fold, these estrogen-induced triglyceride particles are different in size than endogenously produced triglycerides and do not appear to increase a woman’s risk for atherosclerosis.83
Animal studies have indicated a protective action of estrogen against atherosclerosis. Oral administration of combination estrogen/progestin to monkeys being fed a high-cholesterol, atherogenic diet decreased the extent of coronary atherosclerosis.84,85,86 In similar experiments, estrogen treatment markedly prevented arterial lesion development in rabbits.87,88,89 These animal studies help explain why older, higher dose combinations, which had an adverse impact on the lipoprotein profile, did not increase subsequent cardiovascular disease.90,91
Similarly, in a prospective study of normal-weight and obese women randomly assigned to one of two lose-dose 21-day COC formulations (either EE 30 µg/LNG 150 µg or EE 20 µg/LNG 100 µg), no changes in mean total cholesterol or triglycerides were observed in the overall group or in either BMI subgroup. There was a 5.7% reduction in HDL in the overall group; in the BMI subgroups, this reduction was somewhat greater in the normal weight group and in all women assigned to the EE 30 µg/LNG 150 µg pill. These small changes in lipid markers are not clinically significant and are unlikely to impact cardiovascular risk. These findings provide evidence to support that low-dose CHCs do not have an important effect on lipid profiles of women with higher BMIs.92
Unless a patient has a strong family history of cardiovascular disease or preexisting hyperlipidemia, routine screening for lipid levels is not necessary before prescribing CHC. In past decades, considerable marketing hype emphasized the importance of the impact of CHCs on the cholesterol-lipoprotein profile. If indeed certain CHCs had a negative relevant impact on the lipoprotein profile, one would expect to find evidence of atherosclerosis as a cause of an increase in subsequent cardiovascular disease. There is no
such evidence.91,93 Thus, the mechanism of the cardiovascular complications during CHC use is likely a short-term acute mechanism related to thrombosis, an estrogen-related effect.
such evidence.91,93 Thus, the mechanism of the cardiovascular complications during CHC use is likely a short-term acute mechanism related to thrombosis, an estrogen-related effect.
Low androgenic progestins do not adversely affect the cholesterollipoprotein profile. One must be cautious regarding the clinical significance of subtle lipoprotein changes, and as with the older progestins and adverse changes in lipoproteins, it seems unlikely that oral contraceptives will have a clinically meaningful beneficial or adverse effect on the incidence of coronary heart disease.
Carbohydrate Metabolism
Insulin sensitivity is affected mainly by the progestin component of CHCs.94 Progesterone is a competitive inhibitor of the insulin receptor, and estrogen increases the release of insulin from the pancreatic islet cells and decreases insulin sensitivity. The glucose intolerance is dose related, and effects are minimal with the low-dose formulations. With the older high-dose oral contraceptives, many women experienced marked impairment of glucose tolerance and impaired insulin secretion.95 But modern low-dose CHCs currently available in the United States do not have any clinically significant adverse effects on carbohydrate metabolism and do not increase the incidence of diabetes.96 CHC may produce an increase in peripheral resistance to insulin action. Most women can meet this challenge by increasing insulin secretion, and there is no change in the glucose tolerance test. In the CARDIA Study, which included 1,940 women aged 18 to 30 years, use of low-dose COCs was associated with lower glucose levels and with a lower odds ratio (OR) for the development of diabetes.97 Further, obesity has little effect on any CHC-induced changes in carbohydrate metabolism: obese and normal-weight women experience similar changes in glucose and insulin, all too small to be clinically significant.92 Long-term use (up to 7 years) of low-dose COCs did not increase the risk of type 2 diabetes compared with use of nonhormonal contraception in women with a history of prior gestational diabetes mellitus.98 Further, women with polycystic ovarian syndrome and insulin resistance do not report increased insulin resistance.99
Long-term follow-up studies of large populations have failed to detect any increase in the incidence of diabetes mellitus or impaired glucose tolerance (even in past and current users of high-dose pills).100,101,102 Oral contraceptive use does not produce an increase in diabetes mellitus.101,102,103,104 The minor hyperglycemia associated with oral contraception is not deleterious and is completely reversible. Even women who have risk factors for diabetes in their history are not affected. Use of low-dose monophasic and multiphasic oral contraceptives in women with recent gestational diabetes does not significantly impact glucose tolerance over 6 to 13 months does not increase the risk of overt diabetes mellitus during long-term follow-up.98,105 Women with previous gestational diabetes often develop overt diabetes and its associated vascular complications. Until overt diabetes develops, these patients can still appropriately use low-dose CHC. The contraindication to use reflects the cardiovascular risk.
In clinical practice, it may be necessary to prescribe CHC for the overtly diabetic patient. Historically, women with diabetes were denied CHC due to concerns about the effect on carbohydrate and lipid metabolism. Recent data and the CDC MEC emphasize the safety of CHC for women with diabetes without complications (category 2 applies for CHC for any diabetic patient without cardiovascular or microvascular complications associated with diabetes). No effect on insulin requirement is expected with low-dose formulations.106 This effect in women under age 35 who are otherwise healthy and do not smoke is probably very minimal with low-dose CHC. Reliable protection against pregnancy is a benefit for these patients that outweighs the small risk. In a 1-year study of women with insulin-dependent diabetes mellitus who were using a low-dose oral contraceptive, no deterioration could be documented in lipoprotein or hemostatic biochemical markers for cardiovascular risk.107 A case-control study could find no evidence that oral contraceptive use by young women with insulin-dependent diabetes mellitus increased the development of retinopathy or nephropathy.108 Finally, no effect of oral contraceptives on cardiovascular mortality could be detected in a group of women with diabetes mellitus.109 Although the CDC MEC states that the advantages of using CHC in the overt diabetic without complications outweigh the theoretical or proven risks (category 2), there still remains a need for clinical judgment as directly relevant studies are not available.110
Cardiovascular Effects
Venous Thromboembolism
Coagulation Biomarkers
Administration of EE at pharmacologic levels causes an increase in the production of procoagulant factors such as factor V, factor VIII, factor X, and fibrinogen.111 In addition, anticoagulant factors and proteins significantly decrease. The progestin component modulates the EE-induced clotting factor responses.112 The net effects depend upon the estrogen used and route of administration (see Chapter 2). EE-containing contraceptives rapidly cause prothrombotic changes in the coagulation system manifested by immediate downstream effects such as increased prothrombin fragment 1 + 2, increased D-dimer, and changes in endogenous thrombin potential, a global marker of thrombophilia.112,113 Studies that have tried to differentiate the effects of different HC formulations on thrombophilia have had mixed results.112,114,115,116,117,118 The coagulation system changes in a procoagulant direction with CHC use, but the average changes are small and values tend to remain with normal ranges. Which changes are clinically important is not entirely clear.112 Changes in individual factors have weak or unknown relationships to VTE risk, and thus one must be cautious about overinterpreting the clinical importance of the any laboratory changes, as none are validated surrogates or proven predictors for VTE risk.
Pharmacodynamic studies of EE-containing contraceptives are consistent in showing procoagulant effects. E2-containing oral contraceptives are less well studied but have similar or slightly less effect on the coagulation system compared to EE-containing contraceptives.119,120
Whether the various progestins paired with EE modulate the procoagulant effect of estrogen is controversial with studies reporting small differences of uncertain clinical relevance.121,122 Studies that evaluated a specific measure of thrombin generation, the activated protein C sensitivity ratio, have reported that CHCs containing EE and low-androgenic gonanes or DRSP cause more thrombin generation than older CHCs.123 This research test is a global measure of coagulation system activation, and studies show that greater activation is directly related to VTE risk in individuals with hereditary thrombophilias.124,125 However, this test has not been validated as a surrogate for VTE risk associated with different CHC formulations.
Estetrol (E4) is another estrogen being studied as an oral contraceptive. A detailed hematologic study demonstrated that E4 combined with DRSP caused little or no procoagulant changes from baseline, while the comparison oral contraceptive containing EE/DRSP led to substantial changes from baseline.126 Current experience with this agent is limited to clinical trials; we will not be able to learn if the favorable laboratory results will translate into lower VTE risk until this combination comes into widespread clinical use.
Transdermal and transvaginal CHC delivery systems avoid hepatic firstpass effects. As such, initial hopes were that these nonoral contraceptives would have less effect on coagulation and on VTE risk than EE-containing oral contraceptives. However, in actuality, the second-pass metabolism of EE when delivered via a nonoral route is quite extensive. A randomized crossover study found that patch and ring use were associated with greater increases in the activated protein C sensitivity ratio than with an EE/LNG oral contraceptive.127 Another crossover study showed similar adverse changes of multiple coagulation factors when comparing the EE/NLGM patch and an EE/NGM oral contraceptive.128 These results suggested that using the patch or ring would not avoid the VTE risks of EE-containing COCs.
The monthly contraceptive injections are less studied; a WHO randomized trial published in 2003 compared the hemostasis effects among 259 women using two monthly injectables to the effects of an EE/NET oral contraceptive among 119 women.129 In the 9-month study, the injection users had slightly smaller unfavorable changes in their coagulation system than did the oral contraceptive users. While that study measured many individual factors, it did not assess the more global measures of coagulation system activation such as thrombin generation (measured by APCsr) or D-dimer or fragment 1+2.
Epidemiologic Studies of CHC and Thrombosis
Older epidemiologic evaluations of oral contraceptives and vascular disease indicated that venous thrombosis was an effect of estrogen, limited to current users, with a disappearance of the risk by 3 months after
discontinuation.130,131 Thromboembolic disease was believed to be a consequence of EE administration with the level of risk related only to the EE dose.132,133,134 In the first years of oral contraception, the available products, containing high doses of EE or mestranol, were associated with a 4- to 6-fold increased risk of venous thrombosis.135 Smoking was documented to produce an additive increase in the risk of arterial thrombosis136,137,138 but had no effect on the risk of VTE.139,140
discontinuation.130,131 Thromboembolic disease was believed to be a consequence of EE administration with the level of risk related only to the EE dose.132,133,134 In the first years of oral contraception, the available products, containing high doses of EE or mestranol, were associated with a 4- to 6-fold increased risk of venous thrombosis.135 Smoking was documented to produce an additive increase in the risk of arterial thrombosis136,137,138 but had no effect on the risk of VTE.139,140
Because of the increased risks for venous thrombosis, myocardial infarction (MI), and stroke, lower dose formulations (<50 µg estrogen) came to dominate the market, and clinicians became more careful in their screening of patients and prescribing of oral contraception. Two forces, therefore, were at work simultaneously to bring greater safety to women utilizing oral contraception: (1) the use of lower dose formulations and (2) the avoidance of COCs by high-risk patients. Because of these two forces, the Puget Sound study in the United States documented a reduction in venous thrombosis risk to 2-fold greater than nonusers.141
Is there still a risk of VTE with the current low-dose oral contraceptive formulations and nonoral CHC? Epidemiologic studies have included case-control studies, very large multiyear prospective trials, and even larger database evaluations (Table 7.1).
Each study type has its strengths and weaknesses. VTE is fortunately rare, with about 1 event per 1,000 CHC users per year, but this relative rarity makes comparator studies difficult. The very large studies that use data directly from existing databases are often the only quick and cost-efficient way to evaluate the associations between various CHC types and these outcomes. Despite these advantages, database studies usually cannot evaluate important confounding factors (for VTE, these may include family history, obesity, smoking, and other risk factors not captured by insurance claims or registries). Database studies also have only indirect measures of the CHC exposure—that is, they typically know about prescriptions, but do not have direct information about whether and when a woman actually used the CHC. The incidence of VTE in database studies is usually lower than that found in other study types.142,143,144
In contrast, case-control studies may be disadvantaged by recall bias145,146,147 while the smaller number of VTEs available for analysis typically hamper prospective cohort studies, as seen with Dinger et al.148
Dramatic changes in CHC availability and in clinical practice frequently can occur during the time frame of any study, which can create analytical challenges. Thus, the differences in results across studies remain a topic for vigorous methodologic discussion. Keeping these limitations in mind, we present some of the key papers below.
The World Health Organization (WHO) Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception was a hospital-based, case-control study with subjects collected from 21 centers in 17 countries in Africa, Asia, Europe, and Latin America.145 A subevaluation of data from 10 centers in 9 countries assessed the risk of
idiopathic VTE associated with a formulation containing EE 30 µg and LNG (doses ranging from 125 to 250 µg) compared to the risk associated with preparations containing EE 20 or 30 µg and either DSG or GSD.149 The OR for VTE, adjusted for body weight and height, for EE-LNG formulation users compared with nonusers was 3.5. Compared to nonusers, the OR for EE-DSG and EE-GSD products were 9.1. Thus, the risk of VTE with EE-LNG use was 2.6 times lower than with EE-DSG and EE-GSD use.
idiopathic VTE associated with a formulation containing EE 30 µg and LNG (doses ranging from 125 to 250 µg) compared to the risk associated with preparations containing EE 20 or 30 µg and either DSG or GSD.149 The OR for VTE, adjusted for body weight and height, for EE-LNG formulation users compared with nonusers was 3.5. Compared to nonusers, the OR for EE-DSG and EE-GSD products were 9.1. Thus, the risk of VTE with EE-LNG use was 2.6 times lower than with EE-DSG and EE-GSD use.
Table 7.1 Epidemiologic Studies of CHC and VTE Risk | ||||||||||||||||||||||||||||||||||||
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The Transnational Study of Oral Contraceptives and the Health of Young Women analyzed 471 cases of deep vein thrombosis and/or VTE from the United Kingdom and Germany.146 These investigators found an OR of 3.2 for VTE among women using CHC containing EE 35 µg or less and a progestin other than DSG or GSD. They reported that the OR was 1.5-fold greater for women using EE-DSG and EE-GSD products than other products.
In Denmark, Lidegaard et al.150 performed a hospital-based, case-control study of women with confirmed diagnoses of VTE in 1994 and 1995 (in Denmark, all women with this diagnosis are hospitalized, and therefore, very few, if any, cases were missed). They identified a 2-fold increased VTE risk in current oral contraceptive users, across EE doses ranging from 20 to 50 µg. The increased risk was concentrated in the first year of use. Because there were more short-term users of the new progestins and more long-term users of the older progestins, adjustment for duration of use resulted in no significant differences between the progestin types. Factors associated with an increased VTE risk included coagulation disorders, treated hypertension during pregnancy, family history of VTE, and a greater BMI. Notably, conditions not associated with an increased risk of VTE included smoking, migraine, diabetes, hyperlipidemia, parity, or age at first birth. This study could not establish the absence or presence of a dose-response relationship comparing the EE 20 µg dose to higher doses. However, a 5-year update reported that EE 20 µg had a lower risk than did products with EE 30 to 40 µg.151 Additionally, this update found that the risk of venous thrombosis associated with current COC use declined with increasing duration of use, VTE risk was slightly lower with EE/LNG than EE/DSG or EE/GSD oral contraceptives, smoking more than 10 cigarettes per day increased VTE risk, and progestin-only contraceptive products did not increase VTE risk.
Case-control studies using VTE cases derived from the computer records of general practices in the United Kingdom concluded that the increased risk associated with oral contraceptives was the same for all types, and that the pattern of risk with specific oral contraceptives suggested confounding because of “preferential prescribing” (defined later).152,153 In these studies, matching cases and controls by year of birth eliminated differences between different types of oral contraceptives. A similar analysis based on 42 cases from a German database also found no difference between new progestin and older progestin oral contraceptives.154 Thus, in these two studies, more precise adjustments for age eliminated a confounding bias. An assessment of the incidence of VTE in the United Kingdom before and after the decline in EE/DSG and EE/GSD product use could detect no impact on the statistics (neither an increase nor a decrease).155
A reanalysis of the Transnational Case-Control Study considered the duration and patterns of oral contraceptive use, focusing on first-time users of oral contraceptives with EE doses less than 50 µg.156,157 Statistical analysis with adjustment for duration of use in the 105 cases who were firsttime users could find no differences between different progestin products. A similar reanalysis of the United Kingdom General Practice Database could demonstrate no difference between different oral contraceptive formulations.157
A case-control study in Germany assessed the outcome when the cases were restricted to hospitalized patients compared to results when all cases, both in-hospital and out-of-hospital, were considered.158 The conclusion
indicated that hospital-based studies overestimated the risk of VTE, and that there was no difference comparing progestins when all cases were included.
indicated that hospital-based studies overestimated the risk of VTE, and that there was no difference comparing progestins when all cases were included.
Former users discontinue oral contraceptives for a variety of reasons and often are switched to what clinicians perceive to be “safer” products, a practice called “preferential prescribing.”159,160,161 Individuals who do well with a product tend to remain with that product. Thus, at any one point in time, individuals on an older product will be relatively healthy and free of side effects—the “healthy user effect.” This is also called attrition of susceptibles because higher risk individuals with problems are gradually eliminated from the group.162 Comparing users of older and newer CHC products requires careful analysis to adjust for important differences between these individuals.
Because EE/DSG and EE/GSD products were marketed as less androgenic and therefore “better” (a marketing claim not substantiated by epidemiologic studies), clinicians chose to provide these products to higher risk patients and older women.159,160 In addition, clinicians switched patients perceived to be at greater VTE risk from older oral contraceptives to the newer formulations with EE/DSG and EE/GSD. Furthermore, these products were prescribed more often to young women who were starting oral contraception for the first time (these young women will not have experienced the test of pregnancy or previous oral contraceptive use to help identify those who have an inherited predisposition to venous thrombosis). These changing practice patterns exert different effects over the lifetime of a product, and meaningful analytical adjustments are extremely difficult to achieve.
The initial VTE risk epidemiologic studies were impressive in their agreement. All indicated increased relative risks (RRs) or ORs associated with EE/DSG and EE/GSD compared with EE/LNG. Nevertheless, results of the early studies may have been influenced by the same unrecognized biases. Consistent conclusions may be the result of consistent errors.
Shortly after the first oral contraceptive with DRSP (EE 30 µg/DRSP 3 mg) was marketed, 40 VTE cases in DRSP users (2 of which were fatal) were reported in Europe in 2002.163 The Dutch College of General Practitioners issued a statement encouraging clinicians not to prescribe the EE-DRSP product. However, this story is similar to that reported with EE/DSG and EE/GSD (“third-generation” progestins), only to learn that preferential prescribing and the healthy user effect probably biased the early studies. In postmarketing surveillance of EE 30 µg/DRSP 3 mg, only one VTE case occurred in a million cycles compared with five among users of other oral contraceptives.163 In a subsequent monitoring study, the VTE incidence in new DRSP users was comparable to that seen in users of other low-dose oral contraceptives.164 The prospective European Active Surveillance (EURAS) cohort study (see below) enrolled only new OC users containing a variety of progestins, including DRSP and LNG.165 The cardiovascular event incidence
was similar for all progestins. An American cohort study also focused on new OC users and found that VTE occurred at a similar low rate when comparing DRSP users to other oral contraceptives.166
was similar for all progestins. An American cohort study also focused on new OC users and found that VTE occurred at a similar low rate when comparing DRSP users to other oral contraceptives.166
The Danish investigators have continued their interest in hormonal contraception and venous thrombosis and performed a national database study using the reliable Danish national registries of events from 1995 to 2005.143 As in the earlier Danish case-control study,151 the VTE risk in current COC users decreased with duration of use and with EE dose and was slightly higher with EE/DSG, EE/GSD, EE/DRSP, and EE-cyproterone acetate (CPA) products. Did this study escape the problems of preferential prescribing and the healthy user effect (attrition of susceptibles)? The incidence of thrombotic events in the comparator group (EE-LNG users) was lower than that reported in other studies, possibly because this group did demonstrate a healthy user effect, but also because database studies often ascertain fewer cases than studies that use active surveillance. The study was not limited to new users. This study was unable to control for BMI or family history of thrombosis, two important markers for women at high risk of venous thrombosis. Preferential prescribing may be a confounder in the Danish database studies; however, the problem of a healthy user effect is also possible.
A case-control study from the Netherlands also reported higher risks of venous thrombosis in EE/DSG, EE/GSD, EE/DRSP, and EE/CPA users compared with EE-LNG users.147 The authors supported their results by citing findings from their own institution that users of oral contraceptives containing EE/DRSP and EE/CPA had lower levels of free protein S and free tissue factor pathway inhibitor associated with greater resistance to activated protein C compared with EE/LNG users.118 The RRs in that study were surprisingly high, more so than all other reports involving low-dose oral contraceptives. Once again, the healthy user effect is a possible confounder because the study was not limited to new users. The authors claimed to mitigate any attrition of susceptibles by analyzing only short-term users. Even though the validity of this approach can be debated, the results indicated nonsignificant increased risks with EE/DRSP and EE/CPA compared with EE/LNG, and any conclusion was limited by a small number of short-term users. In that study, the risk associated with products containing EE 20 µg was not increased compared to nonusers.
In an effort to better ascertain risk, several true prospective studies have compared the thrombosis effects of various CHC formulations. Strengths of these studies include the ability to adjust for baseline confounding and rigorous adjudication of outcome with published methodology. The European Active Surveillance (EURAS) study enrolled 58,674 European women initiating a new prescription for combined oral contraception and contacted subjects every 6 months to assess safety outcomes and found no significant difference in VTE risk between DRSP and LNG COCs (hazard ratio [HR], 1.0; 95% confidence interval [CI], 0.6 to 1.8) and DRSP with
other oral contraceptives (HR, 0.8; 95% CI, 0.5 to 1.3).165 The subsequent International Surveillance Study of Women Taking Oral Contraceptives (INAS-OC) study followed more than 85,000 women in the United States and Europe and found no increased risk of VTE in DRSP users compared with LNG users (HR, 0.8; 95% CI, 0.4 to 1.3).167 The Transatlantic Active Surveillance on Cardiovascular Safety of NuvaRing study used a similar design and found no significant difference in the risk of VTE between women using the EE/ENG contraceptive vaginal ring compared with combined OCPs users (adjusted HR, 0.8; 95% CI, 0.5 to 1.5).168 Most recently, the International Active Surveillance study “Safety of Contraceptives: Role of Estrogens” (INAS-SCORE) investigated the cardiovascular risks associated with the use of estradiol-containing pills and found an adjusted HR of 0.5 (95% CI, 0.2 to 1.5) for a COC-containing E2V and DNG compared to EE/LNG pills.148
other oral contraceptives (HR, 0.8; 95% CI, 0.5 to 1.3).165 The subsequent International Surveillance Study of Women Taking Oral Contraceptives (INAS-OC) study followed more than 85,000 women in the United States and Europe and found no increased risk of VTE in DRSP users compared with LNG users (HR, 0.8; 95% CI, 0.4 to 1.3).167 The Transatlantic Active Surveillance on Cardiovascular Safety of NuvaRing study used a similar design and found no significant difference in the risk of VTE between women using the EE/ENG contraceptive vaginal ring compared with combined OCPs users (adjusted HR, 0.8; 95% CI, 0.5 to 1.5).168 Most recently, the International Active Surveillance study “Safety of Contraceptives: Role of Estrogens” (INAS-SCORE) investigated the cardiovascular risks associated with the use of estradiol-containing pills and found an adjusted HR of 0.5 (95% CI, 0.2 to 1.5) for a COC-containing E2V and DNG compared to EE/LNG pills.148
Several studies have compared VTE risk between oral and nonoral contraceptive users.169 Six studies assessing the contraceptive patch had mixed results with two studies suggesting a VTE risk among patch users about double the risk in EE/LNG oral contraceptive users, but the other such studies found similar VTE risks among patch and oral contraceptive users. Only three studies assessed VTE risk among vaginal contraceptive users; one of these found a doubling of risk and the others found no increase in risk compared to COC users. While excess VTE risk among patch and ring users (compared to COC users) is uncertain, it is clear that the patch and ring are not safer than oral contraceptives for VTE. A 2017 systematic review did not identify any studies of VTE risk among women using monthly injectable CHC.169
Conclusion: The venous thrombosis risk associated with modern EE-containing hormonal contraceptives is increased about 2-fold and is greatest in the first year of use.165,170,171 VTE risk increases with increasing body weight and age and increases with EE dose. The contribution of different progestins to the VTE risk seems to be small; studies of different design find different progestin effects, which may reflect bias and unmeasured confounding. The important takeaway is that EE increases venous thrombosis risk; the impact of progestins remains controversial. Although progestins may modulate the hepatic effects of estrogens, prospective studies fail to show any significant differential effect on thrombosis risk. Thus far, a single prospective study suggests that estradiol-containing oral contraceptives may have slightly lower VTE risk than EE-containing contraceptives.
The general population incidence of VTE is higher than previously estimated; this may be due to obesity and other lifestyle changes as well as the prevalence of sensitive diagnostic methods. VTE risk associated with low-dose oral and nonoral CHCs is lower than previously reported and concentrated among high-risk individuals (e.g., obesity and inherited or acquired thrombophilias). Because women over 40 and women with a BMI greater than 30 kg/m2 have higher baseline VTE risks, CHC is not a first-choice contraceptive for them.
Venous Thromboembolism and Inherited Thrombophilias
An inherited resistance to activated protein C, the factor V Leiden mutation, is common in European populations with as much as 5% to 7% having this single gene mutation. The mutation is much less prevalent (<1%) in Africans, Asians, and other populations.172 The factor V Leiden mutation is the most common inherited coagulation problem transmitted in an autosomal-dominant fashion.173,174 Heterozygotes have a 6- to 8-fold increased risk of VTE, and homozygotes an 80-fold increased risk. This mutation accounts for a significant portion of VTE in European populations, including among women who experience VTE while taking CHC.
CHC users who have this mutation will thus experience an independent increased VTE risk from both risk factors (i.e., a multiplicative increase in risk). The VTE risk in EE CHC users with this mutation may be 15- to 30-fold greater than women who do not use CHC and do not have the mutation.175,176,177 The risk of VTE is greatest in the initial months of CHC use, and it has been suggested that VTE occurring in the first month of exposure should make the clinician suspect the presence of a clotting disorder.178
The second most prevalent inherited thrombophilia is the prothrombin gene 20210A mutation. A combination of the prothrombin gene mutation and the Leiden mutation is found in about 2% of VTE cases179; the prothrombin gene mutation leads to smaller increases in VTE risk than the factor V Leiden mutation. Although genetic defects in the coagulation inhibitors antithrombin, protein C, and protein S are less frequent, they still carry a substantial increase in risk. Acquired thrombophilias include the presence of antiphospholipid antibodies (lupus anticoagulant and anticardiolipin) usually associated with autoimmune diseases.
Should screening for the factor V Leiden mutation (or for other inherited clotting disorders) be routine prior to prescribing contraceptives? Given the ethnic mix in the United States, of the approximately 12 million women currently using oral contraceptives, about one-half million are likely to carry the factor V Leiden mutation. Most experts believe that screening for inherited disorders should be pursued only in women with a family history (in a parent or sibling) of VTE or, perhaps, in obese women. Calculations of the number needed to screen (NNS) to prevent one VTE and the cost for selective screening using contemporary testing modalities are not available at this time. Women who have an inherited disorder of the coagulation system, whether this is known due to screening or case finding, should not use CHC.
The inherited and acquired thrombophilias predispose to VTE independently from the increased risk associated with estrogen-containing contraceptives. Even among women with a thrombophilia, VTE is uncommon, and identification of a thrombophilia does not predict a clinical event. Table 7.2 synthesizes many risk estimates to give an approximation of the VTE risks in different population subgroups. We know that VTE generally occurs among people who have multiple risk factors; even women experiencing a VTE during CHC use usually have multiple risk factors,113 and
thus clinicians should avoid prescribing CHC to women who have multiple VTE risk factors.
thus clinicians should avoid prescribing CHC to women who have multiple VTE risk factors.
Table 7.2 Relative Risk and Approximate Incidence of Venous Thromboembolism | ||||||||||||||||||||||||||||||
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Hypertension
Hormonal contraceptive-induced hypertension was observed in approximately 5% of users of high-dose pills. More recent evidence indicates that small increases in blood pressure can be observed even with EE 30 µg pills.180,181,182,183 The lack of clinical hypertension in most studies may be due to the rarity of its occurrence. The Nurses’ Health Study reported an increased risk of clinical hypertension in current users of low-dose COCs, with an incidence of 41.5 cases per 10,000 women per year.184 Therefore, an initial and a periodic blood pressure assessment is still an important element of clinical surveillance, even when low-dose oral contraceptives are used. Postmenopausal women in the Rancho Bernardo Study who had previously used oral contraceptives (probably high-dose products) had slightly
higher (2 to 4 mm Hg) diastolic blood pressures.100 Because past users do not demonstrate differences in incidence or risk factors for cardiovascular disease, it is unlikely this blood pressure difference has an important clinical effect.
higher (2 to 4 mm Hg) diastolic blood pressures.100 Because past users do not demonstrate differences in incidence or risk factors for cardiovascular disease, it is unlikely this blood pressure difference has an important clinical effect.
The mechanism for an effect of CHC on blood pressure is thought to be related to the effect of EE on the renin-angiotensin system. The most consistent finding is a marked increase in plasma angiotensinogen, the renin substrate, up to 8-fold normal values (on high-dose EE pills). In nearly all women, excessive vasoconstriction is prevented by a compensatory decrease in plasma renin concentration. If hypertension does develop, the renin-angiotensinogen changes may take 3 to 6 months to disappear after CHC discontinuation. Changes in angiotensinogen are less pronounced with E4-containing COCs.106
One must also consider the effects of CHCs in patients with preexisting hypertension or cardiac disease. Women with uncontrolled hypertension using a CHC have an increased risk of arterial thrombosis.185,186,187 Some women with treated hypertension using CHCs have been reported to have poor control of blood pressure with higher diastolic pressures.188 With successful medical control of blood pressure and close follow-up (e.g., every 3 months), the clinician and the nonsmoking patient who is under age 35 and otherwise healthy may choose low-dose CHC, but with each additional cardiovascular risk factor, other contraceptives become preferred choices. Closer follow-up is also indicated in women with renal disease or a strong family history of hypertension or cardiovascular disease.
Arterial Thrombosis (Myocardial Infarction and Stroke)
Because death and disability can follow stroke and MI, these are the most important potential CHC adverse effects. A relative increase in incidence of stroke or MI in young women carries little increase in absolute risk because the baseline incidence is so low. However, the incidence of stroke and MI increase dramatically with age; thus, CHC use should be avoided among women 35 years and older with any significant cardiovascular disease risk factors including hypertension, diabetes, metabolic syndrome, migraine, smoking, and obesity. Careful patient selection is the key to avoiding MI and stroke.
It has been difficult to establish a dose-response relationship between contraceptive estrogens and arterial thrombosis because these events are so rare. Nevertheless, EE dose appears to be important for the risk of MI and stroke.189,190 Thus, a rationale for advocating low-dose CHCs (i.e., those with EE < 50 µg) continues to be valid.
Myocardial Infarction
Myocardial infarction is a rare event in healthy reproductive age women (Table 7.3). In a WHO multicenter case-control study that included 368 cases of acute MI in COC users, factors associated with an increased risk included smoking, history of hypertension (including hypertension in
pregnancy), diabetes, rheumatic heart disease, abnormal blood lipids, and a family history of stroke or MI.185 Duration of use and past use of CHC did not affect risk. Although there was about a 5-fold overall increased odds of MI in current COC users, essentially all cases occurred in women with cardiovascular risk factors. A population-based, case-control study published in 1996 analyzed 187 cases of MI in low-dose CHC users in the Kaiser Permanente Medical Care Program.192 The MI incidence among CHC users was 5.2 per 100,000 woman-years for an OR of MI among current CHC users of 1.65 (95% CI, 0.45 to 6.06) compared with past or never users. Current CHC users who experienced an MI had more risk factors than the CHC users in the control group. A European case-control study including 182 MI cases found that 77% of the MIs had occurred among women aged 35 or older. That study reported an overall OR of 2.34 for current CHC users with MI risk concentrated among smokers and women with hypertension, diabetes, obesity, and a family history of MI.193,194 These results are consistent with other studies of MI and CHC195,196,197 and emphasize the great importance of carefully assessing CV risk factors before prescribing CHC. The lower odds of MI reported in the more contemporary studies (compared to the earliest studies of this association) reflects both lower CHC dose and the benefits of more careful screening prior to CHC
prescription. Case-control studies of oral low-dose EE oral contraceptives consistently show that MI and stroke in HC users are concentrated among women who have hypertension or are smokers.91,111,198,199,200 The cohort studies are somewhat less helpful because their numbers of cases are too small for definitive analyses of subgroups.
pregnancy), diabetes, rheumatic heart disease, abnormal blood lipids, and a family history of stroke or MI.185 Duration of use and past use of CHC did not affect risk. Although there was about a 5-fold overall increased odds of MI in current COC users, essentially all cases occurred in women with cardiovascular risk factors. A population-based, case-control study published in 1996 analyzed 187 cases of MI in low-dose CHC users in the Kaiser Permanente Medical Care Program.192 The MI incidence among CHC users was 5.2 per 100,000 woman-years for an OR of MI among current CHC users of 1.65 (95% CI, 0.45 to 6.06) compared with past or never users. Current CHC users who experienced an MI had more risk factors than the CHC users in the control group. A European case-control study including 182 MI cases found that 77% of the MIs had occurred among women aged 35 or older. That study reported an overall OR of 2.34 for current CHC users with MI risk concentrated among smokers and women with hypertension, diabetes, obesity, and a family history of MI.193,194 These results are consistent with other studies of MI and CHC195,196,197 and emphasize the great importance of carefully assessing CV risk factors before prescribing CHC. The lower odds of MI reported in the more contemporary studies (compared to the earliest studies of this association) reflects both lower CHC dose and the benefits of more careful screening prior to CHC
prescription. Case-control studies of oral low-dose EE oral contraceptives consistently show that MI and stroke in HC users are concentrated among women who have hypertension or are smokers.91,111,198,199,200 The cohort studies are somewhat less helpful because their numbers of cases are too small for definitive analyses of subgroups.
Table 7.3 Incidence of Myocardial Infarction in Reproductive Age Women | ||||||||||||||||||||||||||||||||||||
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Stroke
Both case-control and cohort studies indicate an increased risk of stroke among current high-dose COC users and a lesser risk (with ORs around 2) among women using lower doses.138,201,202,203 Thrombotic stroke is extremely rare in healthy, nonsmoking, normotensive women with the use of COCs containing EE doses less than 50 µg (Table 7.4). A study of all 408 strokes identified among 1.1 million reproductive age women enrolled in the California Kaiser Permanente Medical Care Program yielded an incidence rate of 11.3 strokes per 100,000 woman-years. In a case-control analysis, the adjusted OR for current CHC use was 1.18 for ischemic stroke and 1.14 for hemorrhagic stroke, both estimates with
wide confidence intervals overlapping 1.0.204 Similar to MI, the risk factors for ischemic stroke included smoking, hypertension, diabetes, and elevated body weight. The risk factors for hemorrhagic stroke were similar. The low risk of stroke among CHC users at Kaiser Permanente may partly result from stringent medical criteria regarding who would be eligible to use CHC. A case-control study from Washington State had similar results.205 A pooled analysis of the data from California and Washington concluded that low-dose oral contraceptives are not associated with an increase in stroke risk.206
wide confidence intervals overlapping 1.0.204 Similar to MI, the risk factors for ischemic stroke included smoking, hypertension, diabetes, and elevated body weight. The risk factors for hemorrhagic stroke were similar. The low risk of stroke among CHC users at Kaiser Permanente may partly result from stringent medical criteria regarding who would be eligible to use CHC. A case-control study from Washington State had similar results.205 A pooled analysis of the data from California and Washington concluded that low-dose oral contraceptives are not associated with an increase in stroke risk.206
Table 7.4 Incidence of Stroke in Reproductive Age Women | |||||||||||||||||||||||||||||||||
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