Anita L. Nelson
Lawrence S. Neinstein
Combination hormonal contraceptives are agents that include both estrogen and progestin. In general, the progestin component provides contraception (primarily by thickening cervical mucus and suppressing ovulation) and the estrogen component provides cycle control. Currently, several forms of combination hormonal contraception are available in the United States—oral contraceptive (OC) pills, contraceptive transdermal patches, and contraceptive vaginal rings. Progestin-only pills are also discussed in this chapter.
OCs are the most widely used method of reversible birth control in the United States. With>45 years of successful use, considerable professional confidence has developed in the safety and efficacy of OCs, and a growing appreciation is building among health care providers for the extensive noncontraceptive benefits that pills offer. However, public understanding of these issues lags considerably. Until recently, most Americans could not name a single noncontraceptive benefit of the pill. Today, many women are at least aware of the acne treatment and cycle control benefits, but many women remain concerned about the safety of the pill. These public (mis)perceptions directly influence patient compliance and continuation rates.
The first-year failure rate in typical use for combined OCs has been calculated to be 8%, which is virtually the same as the progestin-only OCs (Trussell, 2004). Because the failure rates observed in clinical trials are generally observed to be<1%, much of the real world failure has been attributed to incorrect pill-taking habits. The lack of daily use of pills has been substantiated by a telephone survey by Oakley et al. (1991), who found that among new start OC users, only 13% reported having taken the pill correctly for 9 months. Often, women are not even aware of their incorrect pill-taking habits. Potter et al. (1996) compared patients' diaries with records generated by computer chips built into the pill packaging, which recorded the time and date the pill was removed from its pack. In the first cycle, nearly 60% of patients' diaries reported that the patient had missed no pills at all, whereas the electronic device reported that only one third of women had reported perfect use. By the third cycle, the electronic device reported that>50% of women had missed more than two pills during that cycle.
Body Weight and Efficacy
Recent studies have suggested a connection between heavier body weight and increased failure rates with OCs. Comparing women in the highest quartile of weight (>70.5 kg) with the lower-weight women, Holt et al. (2002) found that the failure rates in heavier women were 1.2 to 4.5 times higher. In Holt's initial analysis, there was evidence that this increased pregnancy rate was even higher with lower-dose formulations. However, the author's later analysis did not report any dose-related pregnancy risk, although the second article confirmed the higher failure rates with greater body weight (Holt et al., 2005). It is not clear what the underlying cause of such a trend might be. Is it that taller women have a larger volume of distribution? Could it be that heavier women have more adipose tissue, which produces more estrogen to keep the cervical mucus favorable? Finally, are there other nonbiologic features that may explain the higher failure rates? A retrospective analysis of the 1997 National Health Interview Survey and the 1995 National Survey of Family Growth found that the increase in pregnancy rates seen in women with body mass indexes (BMIs)>30 was no longer statistically significant after adjustments were made for age, marital status, education, poverty, ethnic/race parity, and dual method use (Brunner and Hogue, 2005). More research is needed to answer this question. In the interim, clinicians may need to put this issue into perspective. Heavier women have a demonstrated increased risk for thrombotic complications with higher-dose pills. Their known risk for thrombosis outweighs the evidence currently available, suggesting the need for higher-dose pills to prevent pregnancy. However, it is appropriate to counsel heavier women that they may be at higher risk for pregnancy than are slender women to encourage more careful taking of pills and weight loss.
Changes in pill packets and new delivery systems have been designed to enhance successful use of hormonal contraception.
The doses of the sex steroids in OCs have been dramatically reduced since the 1960 introduction of norethynodrel (Enovid), which contained 9.85 mg of progestin and 150 µg of estrogen. All pills with>50 µg of estrogen have been removed from the U.S. market. The hormones used in combination birth control pills include an estrogen component and a progestin component:
An extensive array of formulations has evolved over the years in an attempt to meet the needs of women with individual sensitivities to particular sex hormone combinations and strengths. Table 43.1 lists the names, components, and doses of the branded pills currently available. Generic formulations of most of the branded pills are also used frequently to reduce contraceptive costs and are listed in Table 43.1.
Most packs are for a single cycle. Some include only the active pills (generally 21), whereas others add additional (generally nonactive) pills to make a total of 28 pills in the pack. Active pills are packaged in one of three patterns:
The placebo pills have been the focus of much recent innovation in pills. Some formulations add iron supplements to the placebo pills. The 7-day pill-free interval has been recognized to be excessively long with modern low-dose formulations (Mishell, 2005). The early, higher-dose pills required 5 days for serum hormone levels to drop low enough to permit the endometrium to start sloughing; with modern formulations endometrial support is lost within 2 days of taking the last active pill. Ovarian follicular recruitment with the low-dose formulations also begins much earlier during the pill-free week. As a result, breakthrough ovulation may be more likely with low-dose pills, especially if a woman misses any of the first pills in her next pill packet. In addition, patients have more time to develop estrogen-deficiency symptoms during the 7 days of placebo pills. To reduce the 7-day hormone-free interval, one formulation (Mircette) replaced the last five placebo pills with five pills containing 10 µg of EE. Two newer formulations (Yaz and Loestrin 24 Fe) include 24 active low-dose pills and either four placebo pills (Yaz) or four pills with ferrous sulfate (Loestrin 24 Fe) in their 28-day pill packet.
The most profound change in pill packaging and in pill-utilization patterns is the elimination or at least minimization of the number of withdrawal bleeding episodes a pill user experiences each year. Monthly withdrawal bleeding was critical to the acceptance of Enovid in 1960. Women wanted monthly reassurances that they were not pregnant. This was important because OCs were new and because the high-dose pills often caused symptoms that were suggestive of pregnancy, such as nausea, vomiting, and breast tenderness. In 1960, there were no rapid, early pregnancy tests, so the monthly withdrawal bleeding functioned as a home pregnancy test. The withdrawal bleed also signaled that “everything was still working” to women who might have been skeptical about how the pills might adversely impact their reproductive systems. When menstruation-like monthly withdrawal bleeding was built into the pill, it improved women's menses in two ways: OC withdrawal bleeding was generally shorter and lighter than the woman's usual spontaneous menstrual flow, and it was entirely predictable. For the first time, women could plan their lives and activities around their menses rather than having the menses interrupt their lives.
Extended Cycle Pills
Currently, we recognize that the placebo pill–induced withdrawal bleeding is not medically necessary and that it causes measurable suffering. Elimination of the pill-free interval also reduces breakthrough ovulation (Archer et al., 2005; Pierson et al., 2005). Extended cycle use of hormonal contraceptives is clearly the wave of the future for most women. Although extended cycle use of any monophasic formulation is possible, the available FDA-approved extended cycle OCs (EE and levonorgestrel [Seasonale and Seasonique]) allow easier patient education and utilization, which is very important for young women. Many insurance plans allow women only one pack of pills/month; extended cycle packages require fewer return trips for refills and less negotiation with pharmacists in months that last>28 days. Seasonale has 84 pills containing 30 µg EE with 0.15 mg levonorgestrel followed by 7 placebo pills. To reduce second cycle spotting, the seven placebo pills are replaced with 10 µg EE tablets in Seasonique. Lybrel was approved in May 2007 and includes 365 active pills per year. Other formulations with lower-dose pills (20 µg EE) in 84/7 configurations.
Drugs that induce hepatic enzymes can decrease serum concentrations of the estrogen or progestin components of
combination hormonal contraceptives and increase failure rates (see Table 43.2).
Anticonvulsants are the most common class of drugs known to have this effect. These drugs are of particular concern because they are also teratogens. The anticonvulsants that increase hepatic clearance include barbiturates (phenobarbitol and primidone), phenytoin, carbamazepine, felbamate, topiramate, and vigabatrin and are all known to decrease serum steroid levels in women taking OCs. Instead, women using these agents may be better served by using progestin injections or intrauterine contraceptives. If OCs are desired, low-dose formulations (<35 µg EE) or progestin-only pills should not be prescribed for women using these anticonvulsants. The 35-µgEE formulations should be used with caution. If a 3-month trial of 35-µg EE pills coupled with condoms yields continued breakthrough bleeding, a 50-µg EE formulation may be necessary. It should be recognized that no published data support the enhanced contraceptive efficacy of higher-dose (50 µg EE) pills (ACOG Committee on Practice Bulletins-Gynecology, 2006). Clinicians should avoid the use of 50-µg mestranol-containing pills in this situation, as 50 µg of mestranol converts to substantially lower levels (35–40 µg) of EE. There are also no data about the effectiveness of nonoral delivery systems of combination hormonal contraceptives used with these drugs. The transdermal method may be attractive, as the total estrogen delivery is higher than with 35 µg pills, but no specific studies of efficacy have been published. It is advisable to shorten or eliminate the hormone-free interval when any of the combination hormonal contraceptives are used in women taking any of these anticonvulsants. Not all anticonvulsants impact liver metabolism; valproic acid, gabapentin, lamotrigine, and tiagabim do not affect sex steroid levels.
Contrary to popular belief and, in some cases, product labeling, there are only two anti-infective agents that decrease steroid levels in women taking combination OCs. These drugs are rifampin and griseofulvin. Isoniazid increases hepatic transaminase levels and may mask markers of an estrogen-induced hepatoma. Other more common anti-infective agents that do NOT decrease steroid levels in women taking combination OCs include tetracycline (Murphy et al., 1991), doxycycline (Neely et al., 1991), ampicillin (Joshi et al., 1980; Friedman et al., 1980), metronidazole (Joshi et al., 1980), and quinalones (Maggiolo et al., 1991; Back et al., 1991; Csemiczky et al., 1996). Routine use of backup methods with these antibiotics is not warranted (World Health Organization, Department of Reproductive Health and Research, 2005).
St. John's Wort
Studies have suggested that St. John's wort, which is sold over-the-counter to treat mild-to-moderate depression, may halve the circulating levels of sex steroids. One placebo-controlled study found that unscheduled bleeding was significantly higher in OC users who took St. John's wort; large follicles (≥30 mm) were seen at higher rates in St. John's wort users (40% versus 6%); and ovulation was detected in up to five times as many women if they used St. John's wort (Murphy et al., 2005).
Some antiretroviral drugs induce hepatic enzymes and lower circulating steroid levels, whereas others decrease such activity and raise the steroid levels. Tobacco use also increases metabolism of sex steroids.
Mechanisms of Action
Work-up Needed for Pill Initiation
A complete medical history is needed to identify any contraindications requiring further evaluation (see subsequent text). Blood pressure measurement is prudent before starting estrogen-containing contraceptives. Breast examination may also be needed. No other examinations are needed before initiating OCs (Stewart et al., 2001; World Health Organization, Department of Reproductive Health and Research, 2005). Having determined that the young woman wants to use birth control pills and is a good candidate, the next questions that arise are how to initiate the pills, how many packs to dispense, and when to schedule a return visit.
Quick Start/Same-Day Start
The quick start or same-day start of birth control pills is the most attractive protocol to use with adolescent women. Teens are often in acute need for immediate contraception. Studies have shown that up to 25% of teens given prescriptions to start their pills with their next menses never start them (Westhoff et al., 2003). The most common reasons for not starting pills include interval pregnancy, change in method, confusion about pill instructions, and fear about possible side effects. Virtually all of these barriers can be overcome by immediate initiation of the pills. If the clinician is reasonably certain that a woman is not pregnant, she should be told to
start taking her pills the same day (starting with the first one in the pack) and to abstain from intercourse or to use condoms for the next 7 days. If she has had unprotected sexual intercourse within the previous 5 days, administer two levonorgestrel emergency contraceptive pills immediately and have her start the first pill in her pack the next day. Sensitive urine pregnancy testing may be performed if there is anything in her history that raises suspicion of an ongoing pregnancy. The patient should be advised that her next menses will be delayed and will start with the placebo pills. If she fails to have a withdrawal bleed or has any symptoms of pregnancy, she should have pregnancy testing done as soon as possible. There is no concern that birth control pills are teratogenic, but early diagnosis of pregnancy is always important (Ahn, 2005).
Reassuringly, clinical studies that compared women who used quick start with those who used conventional start of OCs found no increase in the number of days of unscheduled spotting, or bleeding. In fact, the only significant difference between the two groups was that many more of the quick start users (72%) were on the pill 3 months later than were the conventional start users (56%) (Lara-Torre and Schroeder, 2002; Westhoff et al., 2003).
Quick Start in Women with Irregular Menses
For women who do not have regular menses, the same quick start initiation rules apply. For example, if a woman is amenorrheic, she can start OCs at any time if it is reasonably certain that she is not pregnant. She will need to abstain or to use the backup method for 7 days. If a patient has just had an abortion (spontaneous or elective), she can start using OCs immediately; no backup method is necessary. If a woman is switching from another method, she can start pills immediately. There is no need to wait for menses. She will need to use a backup method for 7 days if there has been any interruption in her prior protection (e.g., >13 weeks since her last depot medroxyprogesterone acetate [DMPA] injection, late for restart of patches, etc.). In each of these circumstances, the need for emergency contraception (EC) should be evaluated.
First Day Start
If quick start of OCs is not possible, then the first day start is acceptable. With this protocol, the patient is given an interval method (condoms) to use until the first day of her next menses, when she should start her pills. No backup method is needed after a first day start. The patient may need to align the pills in her pack to correspond to her pill-taking day.
The least attractive pill initiation protocol is the Sunday start. The most significant drawback for the Sunday start is that if a patient needs last-minute refills, she may have difficulty getting in touch with her provider during the weekend. Furthermore, as a Sunday start represents a start on cycle day 1 to 6, instructions for backup methods can be unduly complex, confusing, and are often ignored. However, sometimes the pill packets require a Sunday start.
All teens should be given condoms and taught how to use them, even if they select OCs. This is important because teens need dual methods to help reduce the risk of sexually transmitted diseases. In addition, many will decide to discontinue the pill before they return for their scheduled follow-up visit (Rosenberg et al., 1995). If those young women are knowledgeable about condom use and have a supply of condoms available, they may be less likely to have unprotected intercourse. Because many women will forget to take all their pills, providing a prescription for EC in advance of need is an important part of OC initiation. At the time of pill initiation, be sure to review with the patient when she is to take her pills, where she plans to store them, what she should do about missed pills, and how she plans to remember to take her pills.
When OCs are initiated, two other practical and somewhat interrelated issues arise: How many cycles to dispense/prescribe, and how soon to see the patient in follow-up.
Prescription Length and Follow-up Appointments
For adult women, the World Health Organization (WHO) recommends that a year's requirement of OCs be given to reduce barriers to access (World Health Organization, Department of Reproductive Health and Research, 2005). However, adolescent women have relatively high rates of brand switching and method switching. Pills that are generously dispensed to a woman cannot be recalled and used by other patients if she changes methods or formulations. For that reason, clinics often limit initial users to three packs. Insurance companies may limit dispensing even more stringently for other reasons: To guarantee that a woman is still under their plan at the time she uses her pills, that she will not switch brands or methods, and that she pays a full co-pay for each pack of pills. In adolescents, the OC discontinuation rate is high and teenaged girls often think of new questions as they use their pills. For these reasons, the traditional 3-month follow-up visit is still important for new-start adolescents. In some situations, it may be advisable to see the teen in 1 month and again at 3 months after pill initiation.
Noncontraceptive Benefits Important to Adolescent Women
Decreased Menstrual Discomfort
Cyclically administered combination OCs significantly reduce monthly menstrual blood loss, the number of days of bleeding, and dysmenorrhea. Mittelschmerz is eliminated in most women because ovulation is inhibited in all but a very small percentage of cycles. Women with anovulatory cycles or dysfunctional uterine bleeding—common problems in adolescents—achieve predictable, controlled cycles with the use of OCs. Women who are taking medications that increase menstrual blood loss (e.g., anticonvulsants, anticoagulants) benefit from these impacts of OC use. Women who have bleeding disorders also benefit from suppression of ovulation, which reduces their risk of internal hemorrhage each month.
Dysmenorrhea is a particularly important problem faced by adolescent girls (see Chapter 50). Dysmenorrhea inflicts considerable suffering and compromises the young woman's productive potential. Painful menses is the single greatest reason why women younger than 25 years miss days at school and work (Davis et al., 2000). OCs significantly reduce dysmenorrhea, even when given in traditional cyclic manner. In a placebo-controlled study of teenaged girls with moderate-to-severe menorrhea, the mean overall pain scores decreased significantly in OC users by 3 months (Davis et al., 2005).
Premenstrual tension syndrome may be reduced by the cyclic use of combination OCs. One formulation (Yaz) has been proved to be an effective treatment for premenstrual dysphoric disorder (Yonkers et al., 2005).
More creative applications of birth control pills, such as extended use of monophasic active pills (“bicycling,” “tricycling,” or continuous use), can provide even more benefits to women who have dysmenorrhea or exacerbations of their medical problems during menses. For example, women who have menstrual-related migraine headaches, catamenial seizures, or asthma exacerbations with menses can eliminate those problems by eliminating the placebo pills and avoiding hormone withdrawal. The first FDA-approved product for this was Seasonale. Other variations are expected soon. Flexibility in pill use can allow women to control more routinely when they have their menses. Health care providers frequently use OCs to avoid onset of menses while a patient is on her honeymoon; these same techniques can prevent menses from interfering with other important events in young women's lives.
Improvement in Acne, Hirsutism, and Other Androgen Excess Problems
The FDA has approved 3 brands of oral contraceptives for the treatment of mild-to-moderate cystic acne in women desiring to use oral contraceptives (Ortho Tri-Cyclen, Estrostep and Yaz). By reducing ovarian production of androgens and reducing circulating levels of free testosterone (through increased hepatic production of sex hormone–binding globulin [SHBG]), these OCs reduce the number of lesions and their intensity. Maximal beneficial effects in the clinical trials were seen at 6 months, which might encourage longer-term use. Hair shaft diameter is smaller in OC users, although this beneficial impact of OCs on hirsutism may take 12 months to become clinically apparent.
Treatment of Hypothalamic Hypoestrogenism
Many adolescents have eating disorders (e.g., anorexia nervosa, bulimia), excessive exercise programs, and/or stresses that suppress gonadotrophin production and create a hypoestrogenic state (see Chapters 33 and 52). The lack of estrogen in a teen can compromise bone mineral density accumulation and put her at risk for osteoporosis and fracture at an early age (Gordon and Nelson, 2003). Although it is important to deal with the underlying problems that cause hypoestrogenism, it may also be important to supply adequate estrogen to promote bone health. In most circumstances, the physiological doses of estrogen used to prevent bone loss in postmenopausal women are not adequate to build bone density in adolescent girls. Birth control pills have been the mainstay of therapy in treating women with the athletic triad (Hergenroeder et al., 1997). However, the skeletal benefits of estrogen continue to be debated among different patient groups (Liu and Lebrun, 2006). In addition, because menses may compromise athletic performance, many coaches oppose OC use unless the pills can be used in extended cyclic manner to maintain amenorrhea.
Reduce the Risk of Ovarian and Endometrial Carcinoma
OCs are the only medical intervention with strong evidence that they reduce the risk of developing ovarian cancer later in life. Women who have used OCs for at least 1 year reduce their risk of developing epithelial ovarian cancer by 40%. Long-term users (>10 years) enjoy an 80% reduction in risk. This effect endures for>15 years after the last pill. Ovarian cancer protection is most clearly demonstrated when the pill is taken by young women, just as childbearing and breast-feeding reduce ovarian cancer risk only if they occur before 30 years of age. A case–control study suggested that carriers of the BRCA1 genetic mutation also experience a reduction in ovarian cancer with OC use (Narod et al., 1998). Two mechanisms have been postulated to explain this risk reduction—the inhibition of “incessant ovulation” and increased follicular cell apoptosis.
OC use at any time during the reproductive years significantly reduces a woman's risk of developing any of the three major histological forms of endometrial carcinoma by providing progestin. This protection increases with longer duration of use; women who use OCs for 12 years reduce their risk of endometrial carcinoma by 72%. This protection endures 19 years beyond the last pill use (Schlesselman, 1995). Women with anovulatory cycles achieve the greatest risk reduction.
Other Health Benefits
Anemia is reduced because menstrual blood loss is diminished by OC use. This can benefit women with sickle cell disease and those with iron deficiency anemia. The thickened cervical mucus induced by OCs can block migration of bacteria into the upper genital tract, which reduces a woman's risk of acquiring gonococcal-related pelvic inflammatory disease. Long-term OC use has also been associated with a reduction in benign breast changes.
Both estrogen and progestin have important metabolic effects, with which clinicians should be familiar (Fig. 43.1). In many formulations, the estrogen-induced metabolic impacts may be partially cancelled by the androgenicity of the progestin acting as an antiestrogen. This is why different pills with the same dose of estrogen, but with different progestins or different doses of the same progestin, may have different estrogenic impacts. In general, the second-generation progestins (norgestrel and levonorgestrel) have greater androgenicity than do the first-generation progestins (norethindrone compounds) or the third-generation progestins (norgestimate and desogestrel). The newest progestin, drosperinone, hasantiandrogenic activity itself, and it allows full expression of the estrogen's impact. By the same logic, the androgen-induced metabolic impacts are partially canceled by the estrogen component of the pill. The net metabolic impact of each formulation differs. These differences may be helpful in selecting formulations for women with different medical problems or side effects.
Factors associated with the extrinsic clotting pathway (fibrinogen and factors I, V, VII, VIII, and X) are uniformly increased by estrogen-containing birth control pills in proportion to their estrogen dose. The percutaneous delivery system may have different dose-dependent impacts on coagulation factors than seen with OCs. Most women balance their increases in clotting factors by inducing compensatory increases in their fibrinolytic and anticoagulation factors. However, some women are genetically unable to compensate. The clinical
significance of these changes is discussed later in the section Thromboembolism.
FIGURE 43.1 Metabolic effects of oral contraceptives. HDL, high-density lipoprotein; LDL, low-density lipoprotein; Na, sodium.
Estrogen increases hepatic synthesis of carrier proteins such as albumin, SHBG, thyroxine-binding globulin (TBG), and corticosteroid-binding globulin (CBG). These increases can affect the interpretation of some laboratory tests (such as total thyroxine), but do not affect measures of unbound hormones (such as FT4). Increased levels of SHBG bind free testosterone and reduce androgen-induced changes such as hirsutism and acne (see earlier discussion).
The estrogen component of the combination birth control pill increases angiotensin by increasing hepatic production of its precursor. Angiotensin can cause reversible hypertension in vulnerable patients. However, angiotensin sensitivity is difficult to predict. The pill also activates adrenal production of aldosterone, which causes fluid retention and contributes to higher blood pressure. A history of pregnancy-induced hypertension is not predictive nor is an increased risk for the development of increased blood pressure with OC use. However, women who have experienced hypertension with OC use in the past face at least a 10% risk of recurrence if rechallenged with estrogen-containing contraceptives.
Triglyceride levels are increased by approximately 20% to 30% with exogenous estrogen use. However, estrogen-induced triglycerides are composed of remnants that are not generally conducive to plaque formation. Triglycerides may pose a problem if a patient has baseline elevated triglyceride concentrations near a range predisposing to pancreatitis (>500). Estrogen also increases total cholesterol, high-density lipoprotein (HDL) cholesterol, while decreasing low-density lipoprotein (LDL) cholesterol. The androgenic component of the progestin has the opposite effect. The net impact on lipids, therefore, varies with different formulations. The third-generation progestins, designed to have greater selectivity for progestin receptors, have less androgenic impacts. In combination with estrogen they cause no significant changes in LDL. The drosperinone-containing pills have antiandrogenic effects and have the most notable impacts on reducing LDL and raising HDL. First-generation progestins at lower doses also have minimal impacts on lipid metabolism. The second-generation progestins and higher doses of the first-generation progestins have a slightly adverse impact on HDL/LDL ratio. The clinical significance of this impact has been questioned by experiments showing that OC usage in female monkeys was accompanied by a decrease in coronary artery plaque formation despite adverse lipid impacts (Clarkson et al., 1990). However, until human data are more firmly established, patients with dyslipidemia should be closely monitored when they use combination hormonal methods.
Both estrogen and progesterone have been implicated in influencing glucose metabolism—estrogen may suppress insulin production and progesterone can increase peripheral insulin resistance. With higher hormonal doses, older formulations of birth control pills were noted to cause deterioration in glucose tolerance. Most studies have found that modern pill formulations with lower hormonal doses cause no impairment in glucose tolerance in euglycemic women, but some minor impact of insulin resistance remains (Godsland and Crook, 1994). Even in high-risk patients, however, this is not clinically significant. In a prospective study of women with a history of gestational diabetes who used low-dose OC pills, Kjos et al. (1998) reported no acceleration in the development of glucose intolerance or overt diabetes compared with similar women using nonhormonal contraceptives. OC use in women with overt diabetes rarely changes insulin requirements and has been shown not to increase the risk of diabetic nephropathy or retinopathy.
Medical complications that are considered to be contraindications for estrogen-containing contraceptive use on the basis of current scientific evidence are listed in Table 43.3
as WHO category 4. The contraindications from product labeling are also listed in that table. Apart from the different categories used for the major problems, there are some profound differences between the two lists. For example, endometrial cancer is listed as an absolute contraindication to OC use on product labeling, but is rated by WHO as category 1 (no restriction on use). Similarly, a history of cholestatic jaundice is a contraindication on the labeling, but has been found to be only a relative contraindication by recent scientific evidence (WHO category 2). These differences underscore the need to be familiar with more than product labeling when addressing an individual woman's contraceptive needs. The full WHO list is in Table 42.3.
Health Issues and Risks with Combination Hormonal Contraceptive Use
A summary of the serious side effects traditionally associated with combination hormonal contraceptive use is provided in Table 43.4, with estimates of both relative risk (RR) and absolute risk. These estimates are based on a mixture of newer and older formulations, as well as different age-groups. More specific information about selected issues is provided in the following paragraphs.
Estrogen-containing combination hormonal contraceptives increase hepatic production of extrinsic clotting factors. Some women, such as those with anticardiolipin antibodies or factor V Leiden mutation, are unable to compensate for this increase in clotting factors and may be subject to a substantially increased risk for thromboembolic events. The overall RR of thrombosis is between 2.6 and 4.0; the absolute incidence of venous thrombosis is 15 to 30 per 100,000 women-years for most of the low-dose OC formulations. The first-year RRs of venous thromboembolism are even higher, but these rates are still lower than the incidence of venous thromboembolism in healthy pregnant women (approximately 60 per 100,000).
Reports in the mid-1990s that third-generation progestins (desogestrel and gestodene) may have had more profound thrombotic impacts (three 1995 articles from the WHO [World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception, 1995a, b, c]) were questioned by later analysis, which controlled for selection bias (Lewis, 1999). The fact that the rates of thromboembolism in the United Kingdom increased after the market share of the third-generation OC formulations decreased from 40% to 5%, suggests the lack of increased risk with third-generation progestins. Labeling reflects the uncertainty of the data.
However, the controversy highlighted the need to identify women at risk of venous thromboembolism when taking OCs, not only on the basis of a personal history of prior thromboembolic events but also by inquiring about family history. Suspect histories are those with multiple family members who experienced multiple unexplained clots, generally at an early age. Routine laboratory screening of all potential OC candidates for coagulopathies is inappropriate because it is clearly not cost effective and because
current testing cannot identify all at-risk women. Screening of high-risk women should be considered. The recommendation to stop estrogen-containing contraceptives 1 month before scheduled surgery has been tempered to reflect modern surgical practices. OC use may not need to be interrupted if a low-risk patient is not expected to require prolonged postoperative bed rest; higher-risk women and low-risk women undergoing high-risk procedures should respect the 30-day rule before elective surgery.
Studies with low-dose formulations have detected no overall increased risk of hemorrhagic or ischemic stroke in healthy young women using OC, but one study did find that women who reported a history of migraine headaches doubled their risk of stroke with OC use (Schwartz et al., 1998). Analysis of the Transnational Research Group study concluded that the attributable risk of occlusive stroke for healthy OC users is very small and is overwhelmed by other risk factors, such as hypertension and smoking (Heinemann et al., 1998).
Low-dose OCs (<50 µg EE) do not increase the risk of myocardial infarction (MI) in healthy, nonsmoking women. OCs do not increase plaque formation in adolescents; researchers reported a decrease in intima-media thickness in new-start OC users (Kapella et al., 2005). There are clearly identified groups of at-risk women. Smokers at all ages have increased risks for cardiovascular disease when they use OCs. In the study by Dunn et al. (1999), the adjusted odds ratio for MI in OC users who smoked 20 or more cigarettes/day was 12.5 (95% confidence interval [CI], 7.3 to 21.5). Schwingl et al. (1999) estimated that the attributable risk of death from cardiovascular disease resulting from OC use is 0.06 per 100,000 nonsmokers aged 15 to 34 years. In smokers, this risk rises to 1.73 per 100,000. However, the absolute risk of death with OC use in smokers is less than the risk of death during pregnancy until women are 35 to 40 years old. Smoking cessation should always be promoted in teens, but they do not need to avoid pill use if they continue to smoke. Selection of a low-androgenic formulation may be prudent for smokers (Straneva et al., 2000), as would shortening the pill-free interval, as smokers metabolize estrogen more rapidly.
Up to 3% of OC users experience increased blood pressure while using birth control pills. Estrogen is responsible for much of this risk. OCs also stimulate adrenal production of aldosterone, which can lead to rise in blood pressure induced by fluid retention. The increases in both diastolic and systolic measures are usually reversible within 3 months of pill cessation. If the hypertension does not spontaneously resolve, then other etiologies must be considered. The need for initial therapy depends on the severity of the hypertension.
Liver and Gallbladder Effects
A doubling of the risk of gallstones has been suggested by several prospective and retrospective studies. Although the increase in risk was more impressive with higher-dose pills, it may still be seen with the lower-dose formulations. Cholelithiasis is due to increased cholesterol saturation and biliary stasis. The risk appears to be concentrated in a few short-term users who may be prone to gallbladder disease.
Cholestatic jaundice is very rare, but it has been reported as a result of using estrogen-containing contraceptives.
Pruritus similar to that seen in pregnancy may develop with usage of estrogen-containing contraceptives.
Impact of Combination Hormonal Contraceptive Use on Neoplasia
The single largest concern women voice about OC use is the risk of cancer. Almost one third of all women believe that OCs cause cancer, but only a small minority is aware that OC use decreases the incidence of ovarian and endometrial cancer. A few of the more pertinent neoplasms in adolescents are discussed here.
Historically, there has been concern that OC use might stimulate growth of leiomyomas (fibroids), because they are known to be estrogen-sensitive tumors. Chiaffarino et al. (1999)found in a case–control study of 843 women with fibroids that the risk for current users of OCs was lower than for those who had never used OCs (RR, 0.3; 95% CI, 0.2 to 0.6). The risk of uterine fibroids decreases with duration of OC use. Marshall et al. (1998) also reported a reduction in risk of fibroids in current OC users; however, he noted a higher risk (RR, 1.26; 95% CI, 1.05 to 1.51) for development of clinically diagnosed fibroids in nurses who started using OCs at age 13 to 16 years, compared with never-users. This modest risk should not deter OC use by adolescents, because this association may reflect an earlier age of menarche, which is itself a risk factor for fibroids.
Women who have existing fibroids are often successfully prescribed OCs to reduce their menorrhagia.
OC use for>5 years causes a slight increase in the risk of cervical dysplasia. However, the risk for squamous cell carcinoma does not appear to be affected by OC use. The risk of adenocarcinoma of the cervix may be increased, although this has not yet been conclusively demonstrated. OC users do not require any more intensive or more frequent Pap smears than their relevant risk factors (e.g., age, number of sexual partners, exposure to human papillomavirus, smoking) would routinely dictate.
In contrast to the obvious benefits OCs have in reducing the risks of endometrial and ovarian cancer, the impact of OCs on breast cancer has been more controversial. In humans, there is no evidence that either estrogen or progestin can initiate the development of abnormal mitotic figures in normal breast cells. However, breast cancer cells do divide more rapidly in the presence of estrogen.
Epidemiological studies of present and past OC users have presented conflicting results, but virtually all the risk ratios for breast cancer calculated in these studies show either no increased risk or a small and temporary increased risk, especially with low-dose formulations.
The Cancer and Steroid Hormone (CASH) study of the Centers for Disease Control and Prevention (CDC) found no overall increase in breast cancer with OC use (Centers for Disease Control and Prevention, 1983), but in young women who used the pill, the risk of development of breast cancer by the age 35 years was raised by 2 to 3 cases per 100,000 women (Centers for Disease Control and Prevention, 1984). Importantly, these researchers investigated several high-risk groups and found that OC use was not associated with an increased incidence of breast cancer in the following important subgroups (a) women with a family history of breast cancer, (b) women with and without benign breast disease, and (c) women who started using OCs before their first pregnancy.
The Collaborative Group on Hormonal Factors in Breast Cancer (1996) meta-analysis of 54 studies from 23 countries reported that current users and women who had used OCs within the previous 10 years had a slightly increased risk of developing breast cancer (RR, 1.24; 95% CI, 1.15 to 1.33). Women who started OC use before 20 years of age had an even higher increase in risk when they were current or recent users. However, the magnitude of this increased risk was minimal; the estimated excess numbers of cancers diagnosed up to 10 years after stopping use was 0.5 per 10,000 women. The risk was reversible; no group displayed any increased risk 10 years after stopping OCs. No duration of usage effect was seen. More importantly, the increase in breast cancer was concentrated in the development of localized disease; in fact, the meta-analysis demonstrated that the risk of metastatic breast cancer with lower-dose pills was not increased among current or recent OC users.
Marchbanks et al. (2002) studied women aged 35 to 64 years and found no increased risk of breast cancer in current or past OC users. No increased risk was seen in women with family history of breast cancer or in women who used pills early in their reproductive lives. Norman et al. (2003) reported the results of a population-based case–control study of 1,847 postmenopausal women with invasive breast cancer and 1,932 normal controls and found that OC users were not at increased risk for invasive breast cancer. The risk of breast cancer was highest in women using postmenopausal hormone therapies, who had never used OCs.
On the basis of all these studies, it is not appropriate to deny any adolescent girl hormonal contraceptives even if she has fibrocystic breast changes or a family history of breast cancer. A strong family history of breast cancer, including (at a minimum) one affected first-degree relative is at most, a relative contraindication for the use of modern, low-dose pills. Only a personal history of breast cancer is a contraindication.
As described earlier, the sex hormones in OCs have various degrees of progestogenic, estrogenic, antiestrogenic, and androgenic activities. These differences are important to understand, especially when responding to a patient's concerns about side effects. The impacts of the relative potencies of different formulations vary from individual to individual.
Prospective, double-blind, placebo-controlled studies that were conducted to evaluate the role of the triphasic, norgestimate-containing birth control pills in treating acne provided a unique opportunity to evaluate the incidence of side effects with modern low-dose pills (Redmond et al., 1999). In the 6-month study period, the placebo group had the same incidence of headache, nausea, mastalgia, and other side effects, generally attributed to OCs, as the OC group did. Even the incidence of excessive weight gain was identical. The lack of attributable weight gain with OC use had earlier been demonstrated by Reubinoff et al. (1995), who also reported that users of low-dose OCs did not change body composition or fat distribution.
Some women have particular sensitivity to sex steroids. They may experience side effects either as a result of the pharmacological doses of hormone or because of hormonal imbalances. Many side effects are temporally self-limited and resolve spontaneously in the first few cycles, but sometimes women require a change of pill formulation. When these side effects arise, it is important to analyze them by their constituent hormonal effects (see Table 43.5) to select pills that meet the patient's needs.
Management of Common Side Effects
Typically, 20% to 25% of women experience unscheduled spotting or bleeding at some time during the first three cycles. The incidence of breakthrough bleeding with the more recent ultra–low-dose (20 µg) formulations containing levonorgestrel or desogestrel is roughly comparable to that of 30- to 35-µg pills, although an earlier 20-µg formulation containing low-dose norethindrone did have higher rates of unscheduled bleeding (DelConte et al., 1999; Rosenberg et al., 1999; Sulak et al., 1999). Other causes of vaginal spotting or bleeding must be considered in adolescent girls. Chlamydial cervicitis is a common cause of postcoital bleeding in teens. Inconsistent pill use also commonly causes breakthrough bleeding or spotting. Smokers have notably more challenges with breakthrough bleeding, especially with low-dose pills.
Treatment for persistent spotting or bleeding due to OCs in the face of appropriate pill use depends on the timing of those events within the woman's cycle. For women who have unscheduled spotting and/or bleeding at the
end of their active pills, use a formulation with higher progesterone activity to support the endometrium during those days. Triphasic formulations, which progressively increase progestin dose, are particularly helpful in this situation. If the unscheduled spotting and/or bleeding occurs with the early pills, consider using formulations with higher doses of estrogen in the early pills, or those with lower progestin levels. This will allow the estrogen in the pills to induce endometrial proliferation and cover the denuded, bleeding areas left by menstrual shedding. Spotting and bleeding that occurs sporadically throughout the cycle is highly suspicious for inconsistent pill use, smoking, or drug–drug interactions. However, for women who do not have those problems but are still spotting, shortening the pill-free interval can reduce the frequency of that bleeding, especially if lower-dose formulations are being used.
Acne and Hirsutism
These symptoms are caused by free androgens. In order to cope, switch to a formulation with a higher estrogen content, which will increase SHBG and reduce the level of unbound testosterone, and/or switch to a formulation with a less androgenic progestin.
Chloasma or Melasma
These symptoms are caused by estrogen stimulation of melanocytes. In this situation, it would be prudent to decrease (or eliminate) estrogen content and advise the use of sunscreen and hats.
Explore other causes of weight gain before attributing it to pill use. If the weight gain is concentrated in a woman's breast, hips, and thighs, decrease the estrogen content of her pills. If the gain is accompanied by bloating and fluid retention, switch to a lower dose pill or to a drosperinone-containing formulation. If the weight gain is slowly progressive (and not due to other factors), change to a less androgenic formulation.
Rule out serious problems, such as hypertension and new-onset or worsening migraines, which would require OC cessation. Reduce the dose of estrogen or change to a progestin-only method. If the headache occurs only before or during menses (menstrual or migraine), shorten or eliminate the pill-free interval.
Have the patient take her pill at night. Reduce the estrogen dose if the first maneuver is not successful or if it will interfere with successful pill taking.
Breast tenderness is usually self-limited, but if the problem persists, reduce the estrogen dose of the pill.
Coping with Missed Pills
The WHO has developed advice to be given to women when they miss OCs. The advice differs depending upon how many pills are missed, the strength of her formulation, and when in the cycle the pills are missed. The recommendations are summarized in Figure 43.2.
Because this may be somewhat complicated for a patient to remember, it may be prudent to simplify the instructions to cover two situations: One missed pill versus more than one missed pill. If one pill is missed, have her take it as soon as possible and take the current day's pill within 12 hours. If more than one pill is missed, then have her take two pills today, resume daily pill taking tomorrow, and use condoms for 7 days. If she has had intercourse in the 5 days before the missed pills, she should use EC in place of her two pills today (seeChapter 46).
Increasing Adolescent Compliance
Adolescent compliance with contraceptive methods is often suboptimal; however, adult compliance is also far from perfect. Studies of high-risk teenaged mothers found a 50% discontinuation rate by 12 months (Berenson and Wiemann, 1995). Many factors contribute to noncompliance. The desire of teens for independence and seeming invincibility decreases their motivation to use contraception. The unpredictability and frequent disruptions in their
relationships often cause them to stop using contraception. Many adolescents receive incorrect information from sex education teachers in American schools (Davis, 1994); this misinformation about OCs affects the effectiveness of the method and also reduces compliance.
FIGURE 43.2 Handling missed oral contraceptive pills. (Adapted from Family Planning Association. How many Pills have you missed? Contraception and Sexual Health Guide. London: Family Planning Association.)
To enhance compliance, experts have suggested several measures:
Special considerations in adolescents:
Progestin-only pills have traditionally been reserved for use by breast-feeding women. However, their potential is much greater than that niche. Virtually every woman may be a candidate from a medical standpoint for use of progestin-only pills. The only condition that the WHO rates as category 4 (do not use) for progestin-only pills is current breast cancer. Because the dose of progestin is significantly lower in progestin-only pills than it is in combination OCs, success requires consistent use. The progestin-only pill must be taken at the same time each day. The progestin-only pill works primarily by thickening cervical mucus to prevent sperm entry into the upper reproductive tract. Ovulation is suppressed in 40% to 60% of cycles. There are no placebo pills; a woman takes one active pill a day, even if she is menstruating. The most common side effect from progestin-only pills is unscheduled spotting and bleeding or amenorrhea, just as is seen with other progestin-only methods. Whenever estrogen is contraindicated or undesired (e.g., with melasma), the progestin-only pill is an excellent option. Table 43.1 lists the progestin-only pills available in the United States.
Transdermal Contraceptive Patch
The Ortho Evra transdermal contraceptive system is composed of a 20 cm2 tan-colored thin patch containing EE and 17-diacetyl norgestimate. This patch was very popular with adolescent girls because its once-a-week use is more convenient compared with the daily dosing requirement of OCs. The patch can be worn anywhere on the woman's trunk (except the breasts) or on her upper arms. Women should be cautioned to avoid placing it on areas subjected to friction from undergarments or waistbands. With current fashions, many women have abandoned the attempt to hide the patch and wear it as a fashion statement.
The efficacy of the patch is at least equivalent to that of standard birth control pills for women weighing<90 kg. For women weighing>90 kg, the risk of pregnancy is higher. In the clinical trials,>30% of the pregnancies occurred in the 3% of the study population who weighed>198 pounds (Zieman et al., 2002).
In clinical studies, it was shown that at every age-group, more patch users reported correct and consistent use of their method than did pill users. This difference was greatest among the adolescent girls in the study; 87.7% of 18- and 19-year-old girls in the patch arm used their patches correctly and consistently during the 1-year trial compared with 67.7% of the 18- and 19-year olds who used OCs (Creasy et al., 2000).
The first patch should be applied during the first 5 days of a woman's cycle. Each patch is to remain in place for 7 days, at which time another patch is applied at a different site. The third patch replaces the second patch at a different site 7 days later. After the last patch has been in
place for 7 days, product labeling instructs the patient to remove it and use no patch for the following week, during which time she should start her withdrawal bleeding. It is important to give guidance to patients about what to do if things go wrong.
Patch initiation guidelines should also be flexible. Women switching from pills to patches should place their first patch on the first day of their withdrawal bleeding; they should not wait until they complete their pill pack. The patch should be started immediately after a first trimester pregnancy loss or after intrauterine contraception is removed or 13 weeks after the last DMPA injection. Remember, it takes 2 days to achieve therapeutic hormonal levels, so a backup method should be recommended if the patient is at risk.
The safety and efficacy of quick start of the contraceptive patch has been demonstrated. However, compared with quick start with OCs, quick start with the patch did not increase short-term continuation rates (Murthy et al., 2005). Extended cycle use of the patch has also been reported (Stewart et al., 2005 OBGYN 1389–96). Women using extended cycles had less frequent, but more prolonged, scheduled bleeding episodes than did women using the patch cyclically. There is a slight increase over time of serum levels of estrogen with extended cycle use of the contraceptive patch.
The patch has virtually the same contraindications, precautions, and side effects as combination OCs. One exception is that transdermal administration does not require gastrointestinal (GI) absorption, so that conditions which limit GI absorption, such as diarrhea associated with irritable bowel syndrome (IBS), do not present any problems with patch use. It is not known what the efficacy of the patch is when used by women taking anticonvulsants or other liver enzyme–inducing drugs. Patches cannot be applied to irritated skin surfaces. Women with sunburn, psoriasis, or rashes should not apply the contraceptive patch over affected areas. The patch will not attach or may detach if oils or moisturizers, sun tan lotions, or other skin products coat the area. However, baby oil is very helpful in removing the remnants of adhesive that may stick to the skin after the patch has been removed. Women using the patch are more likely to report first-cycle mastalgia than OC users, but by the second month the frequency of the problem drops to<10%, which is comparable to pill users.
The progestin in the patch is a derivative of norgestimate, which is the low androgen progestin in Ortho Tri-Cyclen. The peak levels of serum estrogen achieved with the patch are only two thirds as high as the daily peak of estrogen from 35-µg EE pills. However, because the patch maintains the same level of hormones in the bloodstream 24 hours/day, the total daily estrogen exposure is 60% higher than with a 35-µg EE pill and 3.4 times higher than the vaginal ring. Product labeling acknowledges the higher estrogen exposure, but it also states that the clinical significance of this higher dose is not known. The reason that higher doses of estrogen from the patch may not have the same thrombotic and other metabolic impacts as higher dose pills is that the percutaneous route of administration bypasses the pill's first pass effect. With the patch, the liver is not exposed to estrogen that does not appear in the bloodstream. With oral drugs, serum levels reflect only a fraction of the drug exposure of the liver, because much of the initial drug that is absorbed is conjugated in the liver and excreted back into the intestine by way of the gall-bladder. More than 5 million women in the United States have used the patch; to date, there has been no convincing evidence of any increased risk of thrombosis, but the U.S. Food and Drug Administration (FDA) now requires that Ortho Evra packaging contain a warning about this potential serious complication. Epidemiological studies focusing on the question of thrombosis have provided conflicting answers about the risk of thromboembolism with patch use.
Vaginal Contraceptive Rings
Pelvic support is needed for the ring. The greatest barrier to acceptance of the vaginal ring is its placement and removal. Placement can be facilitated by loading the ring into an emptied tampon inserter with blunt opening. Have the woman place the tampon inserter into the vault and press the ring out. Once the ring is inside the vagina, it can rest against the vaginal wall in any location, and its movement within the vault causes no problems. In the clinical trials, the vast majority of male partners did not notice any adverse effects from the ring on their sexual satisfaction. If a woman's partner does complain, she can remove the ring and place it in its foil pouch until coitus is over. She must not leave the ring out of her vagina for>3 hours in any 24-hour period. Removal of the ring only requires that the woman introduce a finger into her vagina, locate the ring with her fingertip, and withdraw it from her vagina. If the ring is located high in the vault, it may help to have the woman squat slightly to remove it.
For Teenagers and Parents
http://www.advocatesforyouth.org/youth/health/contraceptives/pill.htm. Advocates for Youth information on OCs with links to other contraceptive choices.
http://www.sex-ed101.com/oral.html. Sex Education 101 Web site on OCs and other contraceptives.
http://www.teenwire.com/index.asp. Teenwire from Planned Parenthood with information about reproductive health including contraception.
http://www.fhi.org/en/RH/FAQs/COC_faq.htm. Frequently Asked Questions sheet on combined OCs from Family Health International.
http://www.orthowomenshealth.com/birthcontrol/options/pills.html. Information from the Ortho Women's Health Web site.
For Health Professionals
http://www.arhp.org/healthcareproviders/resources/contraceptionresources/. Association of Reproductive Health Professionals.
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