Since their introduction in the late 1950s, combination OCs have become one of our most widely prescribed families of drugs. These drugs are both safe and effective, although minor side effects are common.
will be less effective if improperly practiced, the importance of personal preference cannot be overemphasized. Practitioners should take pains to educate patients about the contraceptive methods available so that selection and use can be based on understanding.
Additional factors that bear on selecting a birth control method include family planning goals, age, frequency of sexual intercourse, and the individual’s capacity for adherence. If family planning goals have already been met, sterilization of either the male or female partner may be desirable. For women who engage in coitus frequently, OCs or a long-term method (e.g., Nexplanon, Depo-Provera, IUD) are reasonable choices.
Conversely, when sexual activity is limited, use of a spermicide, condom, or diaphragm may be more appropriate. Since barrier
Birth Control Method
Failure Ratea (%) Actual
Useb
Theoretical Usec
No method 85 85
EXTREMELY EFFECTIVE Etonogestrel subdermal implant
[Nexplanon] 0.05 0.05
Surgical sterilization
Female: tubal ligation 0.5 0.5
Male: vasectomy 0.15 0.1
Intrauterine devices
Copper T 380A [ParaGard] 0.8 0.6
Levonorgestrel T [Mirena] 0.2 0.2
VERY EFFECTIVE Oral contraceptives
Combination pills 8 0.3
Progestin-only pills 8 0.3
Intramuscular medroxyprogesterone
acetate [Depo-Provera] 3 0.3
Vaginal contraceptive ring
[NuvaRing] 8 0.3
Contraceptive patch [Ortho Evra] 8 0.3
EFFECTIVE Condoms
Male 15 2
Female [FC2 Female Condom] 21 5
Diaphragm with spermicide 16 6
LEAST EFFECTIVE
Contraceptive sponge [Today Sponge]
Parous 32 20
Nulliparous 16 9
Spermicide alone 29 18
Periodic abstinence 25 3–5
Withdrawal 27 4
TABLE 62.1 ■ Effectiveness of Birth Control Methods
aFailure rate: percentage of women who have an unplanned pregnancy during first year of use.
bActual use: failure rate usually observed in actual practice.
cTheoretical use: failure rate that would be expected if the birth control method were practiced exactly as it should be.
Prototype Drugs
DRUGS FOR BIRTH CONTROL Combination Oral Contraceptives
Ethinyl estradiol/norethindrone
Progestin-Only Oral Contraceptives Norethindrone
Long-Acting Contraceptives
Subdermal etonogestrel implant [Implanon]
Depot medroxyprogesterone acetate [Depo-Provera]
Drugs for Emergency Contraception Levonorgestrel alone [Plan B One-Step]
Ulipristal acetate [Ella]
Ethinyl estradiol/levonorgestrel (the Yuzpe regimen)
Mechanism of Action
Combination OCs reduce fertility primarily by inhibiting ovulation. The estrogen in combination OCs suppresses release of follicle-stimulating hormone from the pituitary (and thereby inhibits follicular maturation), and progestin in combination OCs acts in the hypothalamus and pituitary to suppress the midcycle luteinizing hormone surge, which normally triggers ovulation. Secondary mechanisms include thickening of the cervical mucus (creating a barrier to the penetration of sperm) and alteration of the endometrium, making it less hospitable for implantation.
CHAPTER 62 Birth Control
However, even though efficacy of OCs is slightly reduced in higher-weight women, these drugs are still more reliable than most of the alternatives.
Overall Safety
Determining the relative safety of combination OCs is complex.
Part of the difficulty lies with the fact that much of our informa-tion on the adverse effects of OCs was gathered when these agents were employed in higher doses than those employed today. Newer data show that today’s OCs, as currently pre-scribed, are considerably safer than indicated by older studies.
An additional complication stems from the fact that the risk of mortality associated with OCs is much smaller than the risk associated with pregnancy and delivery. Keeping the above provisos in mind, we can make the following observations on OC safety. Of the contraceptive methods available, OCs produce the broadest spectrum of adverse effects, ranging from nausea to menstrual irregularity to rare thromboembolic disorders.
However, despite their wide variety of undesired actions, when used by healthy women, OCs produce no greater mortality than any other form of birth control.
Adverse Effects
Combination OCs can cause a variety of adverse effects.
However, although many types of effects may occur, severe effects are rare. Hence, when compared with the serious risks associated with pregnancy and childbirth, the risks of OCs are low. Nonetheless, because OCs are usually taken by women who are healthy and because OCs represent a potential health hazard (albeit small), we must take steps to minimize risk. To this end, a full medical history should be obtained. If the history reveals an absolute contraindication to OC use (Table 62.3), OCs should not be prescribed. In women with relative contraindications, OCs should be used with caution. Candidates for OCs undergo a physical examination before starting these agents.
Thromboembolic Disorders. Combination OCs have been associated with an increased risk of venous thromboembolism (VTE), arterial thromboembolism, pulmonary embolism, myocardial infarction (MI), and thrombotic stroke. Among OC users, the relative risk of a thrombotic event is 2 to 3 times Components
Estrogens. Only three estrogens are employed: ethinyl estradiol, mestranol, and estradiol valerate. Most combination OCs use ethinyl estradiol. A few older products use mestranol, which undergoes conversion to ethinyl estradiol in the body.
And one new product—Natazia—uses estradiol valerate, which undergoes conversion to estradiol in the body.
Progestins. Combination OCs employ eight different progestins, which can be grouped into four generations (Table 62.2). Progestins in all four generations are equally effec-tive. Differences relate to side effects, especially thrombotic events, androgenic effects (acne, hirsutism, dyslipidemia), and hyperkalemia.
Drospirenone, a fourth-generation progestin, has progestational, antian-drogen, and antialdosterone actions. The drug is a structural analog of spi-ronolactone, a potassium-sparing diuretic that blocks receptors for aldosterone.
Drospirenone was developed in an effort to reduce fluid retention caused by the estrogen component in combination OCs. (Estrogens promote fluid retention by activating the renin-angiotensin-aldosterone system. Drospirenone reduces fluid retention by blocking aldosterone receptors, thereby preventing retention of sodium and water. As a result, OCs made with drospirenone may cause less bloating, weight gain, and hypertension than other combination OCs.) The principal concern with drospirenone is venous thromboembolism, which occurs more often than with other progestins. Also, drospirenone can cause hyperkalemia (secondary to renal retention of potassium).
Effectiveness
As shown in Table 62.1, OCs can be very effective. With perfect use, the failure rate is only 0.3%. However, with typical use, the failure rate is significantly higher: about 8%. Among women of higher weight, efficacy is somewhat reduced. Possible reasons include decreased blood levels of the hormones, sequestration in adipose tissue, and altered metabolism.
Progestins Comments
FIRST GENERATION Ethynodiol diacetate
Norethindrone Lower risk of thrombosis than with other progestins
Mildly androgenic SECOND GENERATION
Levonorgestrel
Norgestrel Greater risk of thrombosis than with More androgenic than FGPsFGPs Prolonged half-life THIRD GENERATION
Desogestrel
Norgestimate Greater risk of thrombosis than with FGPs (especially desogestrel) Less androgenic than FGPs FOURTH GENERATION
Dienogest
Drospirenone For drospirenone and dienogest:
• Greater risk of thrombosis than with other progestins
(especially drospirenone)
• Less androgenic than FGPs
• Low risk of acne and hirsutism For drospirenone only:
• Risk of hyperkalemia TABLE 62.2 ■ Progestins Used in Combination
Oral Contraceptives
FGPs, First-generation progestins.
ABSOLUTE
CONTRAINDICATIONS
RELATIVE
CONTRAINDICATIONS Thrombophlebitis,
thromboembolic disorders, cerebral vascular disease, coronary occlusion, or a past history of these conditions, or a condition that predisposes to these disorders
Abnormal liver function Known or suspected breast
cancer
Undiagnosed abnormal vaginal bleeding
Known or suspected pregnancy Smokers over the age of 35
Hypertension Cardiac disease Diabetes
History of cholestatic jaundice of pregnancy Gallbladder disease Uterine leiomyoma Epilepsy
Migraine TABLE 62.3 ■ Absolute and Relative
Contraindications to the Use of Combination OCs
medroxyprogesterone acetate injection [Depo-Provera], the etonogestrel subdermal implant [Nexplanon], and the “mini-pill”—all of which are discussed later.
Cancer. Oral contraceptives present no known risk of cancer—with the important exception of promoting (not causing) breast cancer growth. The effects of OCs on cancers of the ovaries, endometrium, cervix, and breast have been studied extensively. Effects on three of these cancers are clear: OCs protect against ovarian and endometrial cancer, and have no impact (positive or negative) on cervical cancer, which is caused by human papillomaviruses.
What about breast cancer? OCs do not increase the risk of breast cancer for most women. This conclusion is based on data from the Women’s Contraceptive and Reproductive Experience (Women’s CARE) study. This major study, involving over 9000 women, found no association between present or past use of OCs and the development of breast cancer. This conclusion applied not only to study participants as a whole, but also to women in the following subgroups:
• Those who used OCs with high estrogen content
• Those who used OCs for a prolonged time
• Those who began OC use during adolescence
• Those with a first-degree relative with breast cancer These results should reassure women who are OC users.
However, although this study shows that OCs do not increase risk for most women, the results of another large recent study show that OCs do increase risk for some women, specifically, women who have the BRCA1 gene mutation. Even without taking OCs, these women have a very high—50% to 80%—
lifetime risk of breast cancer. OCs increase this risk by one-third.
The same study found that OCs do not increase risk in women with the BRCA2 mutation.
It is important to note that although OCs do not cause breast cancer, estrogens can promote the growth of existing breast carcinoma. Accordingly, women with this disease should not take OCs.
Hypertension. Combination OCs can cause hypertension, but the risk with today’s low-estrogen preparations is very low. OCs raise blood pressure by increasing blood levels of two compounds: angiotensin (a potent vasoconstrictor) and aldosterone (a hormone that promotes salt and water retention).
If hypertension develops, and if OCs are determined to be the cause, two options are open: (1) discontinue the OC or (2) continue the OC and manage the hypertension with drugs.
Abnormal Uterine Bleeding. By altering the endometrium, OCs may decrease or eliminate menstrual flow. In addition, breakthrough bleeding and spotting may occur, especially with the use of extended-cycle OCs (e.g., Seasonique, Seasonale).
Spotting and bleeding can also occur with monthly-cycle OCs, most often during the first 3 months when low-estrogen OCs are used. If a period is missed while taking monthly-cycle OCs, the possibility of pregnancy should be assessed. Following discontinuation of OCs, normal menstruation usually resumes, although the first period may be delayed. Women with a pretreat-ment history of irregular menses will return to their previous pattern when OCs are discontinued.
Use in Pregnancy and Lactation. OCs have no therapeutic role during pregnancy, and hence are contraindicated for use by pregnant women. Pregnancy should be ruled out before starting OC use, and if pregnancy should occur despite OC use, use should stop immediately. Woman should be assured, the risk in nonusers. However, the absolute risk is still very
small: about 8 to 10 events per 10,000 woman-years of OC use. Furthermore, the risk of thrombosis associated with OCs is considerably lower than the risk associated with pregnancy and delivery. OCs promote thrombosis in part by raising levels of clotting factors. Thrombosis is not due to atherosclerosis.
Formerly, we believed that thrombotic events were caused solely by the estrogen in combination OCs. However, it is now clear that the progestin can contribute too. Two newer progestins—drospirenone and desogestrel—appear to carry the greatest risk.
Fortunately, the risk of thrombotic events with OCs used today is much lower than with the OCs used in the past because the amount of estrogen in OCs has been reduced. When combination OCs first became available, they contained high doses of estrogens (e.g., 100 mcg ethinyl estradiol). Today’s OCs contain no more than 50 mcg ethinyl estradiol (and usually less), so the risk of thromboembolism is quite low.
Major factors that increase the risk of thromboembolism are heavy smoking, a history of thromboembolism, and throm-bophilias (genetic disorders that predispose to thrombosis).
Additional risk factors include diabetes, hypertension, cere-brovascular disease, coronary artery disease, and surgery in which immobilization increases the risk of postoperative thrombosis.
In the past, OCs were not recommended for women older than 35 years because earlier studies indicated an increase in the risk of MI for this group. However, reanalysis showed that the risk was limited to older women who smoked. With today’s low-estrogen OCs, nonsmokers may continue usage until menopause, with no greater risk of MI than among younger women.
Several measures can help minimize thromboembolic phenomena. Specifically:
• The estrogen dose in OCs should be no greater than required for contraceptive efficacy.
• OCs containing drospirenone or desogestrel should generally be avoided as they may pose a higher risk for developing VTE.
• OCs should not be prescribed for heavy smokers, women with a history of thromboembolism, or women with other risk factors for thrombosis.
• OCs should be discontinued at least 4 weeks before surgery in which postoperative thrombosis might be expected.
• Women should be informed about the symptoms of thrombosis and thromboembolism (e.g., leg tenderness or pain, sudden chest pain, shortness of breath, severe headache, sudden visual disturbance) and instructed to consult the prescriber if these occur.
What about the cardiovascular risk for former OC users? Data from the Women’s Health Initiative suggest that use of OCs in the past may protect against cardiovascular disease. Among women with a history of OC use, there was an 8% decrease in the overall incidence of cardiovascular disease, including a reduced risk of angina, MI, peripheral vascular disease, transient ischemic attacks, and elevation of cholesterol.
Can women with a history of thrombosis use drugs for birth control? Yes. Although these women should avoid estrogen/
progestin products, they can still use a progestin-only method.
Options include the levonorgestrel intrauterine system [Mirena],
CHAPTER 62 Birth Control
rising to 80 cases per 100,000 women at age 40 years. Because the risk is low, OCs are generally considered safe for women with migraine, provided they are younger than 35 years, don’t smoke, and are healthy, and provided their headaches are not preceded by visual changes known as an aura (migraine with aura has a greater risk of stroke than migraine without aura).
Migraine and its management are discussed in Chapter 30.
Benign Hepatic Adenoma. Hepatic adenoma is a rare complication seen in women who use OCs that contain mes-tranol. These highly vascular, nonmalignant tumors are usually picked up as incidental findings on a computed tomography scan or magnetic resonance imaging. If hepatic adenoma is diagnosed, discontinuing OCs usually results in spontaneous tumor regression.
Effects Related to Estrogen or Progestin Imbalance.
Many of the mild side effects of combination OCs result from an excess or deficiency of estrogen or progestin. Effects that can result from an excess of estrogen include nausea, breast tenderness, and edema. Progestin excess can increase appetite and cause fatigue and depression. A deficiency in either hormone can cause menstrual irregularities. Side effects related to hormonal imbalance are shown in Table 62.4.
Quite often, these effects can be reduced by adjusting the estrogen/progestin balance of an OC regimen. With most women, therapy is initiated with an OC containing 30 to 35 mcg of ethinyl estradiol. If significant nausea occurs, it can be managed by dosing at bedtime or, if needed, switching to an OC with less estrogen. Using less estrogen can also reduce breast discomfort. During the first 3 months of use, spotting and breakthrough bleeding are common, and usually resolve on their own. If they don’t, they can be managed by increasing the estrogen dosage or by using a product that contains a different progestin. For women who experience androgenic effects (e.g., acne, hirsutism), switching to an OC that has drospirenone or dienogest can help. Other side effects can be reduced by making similar adjustments. When substituting one combination OC for another, the change is best made at the beginning of a new cycle.
Hyperkalemia. Drospirenone, a fourth-generation progestin, promotes renal retention of potassium and can thereby cause hyperkalemia. Accordingly, the drug is inappropriate for women with conditions that predispose to hyperkalemia (e.g., renal insufficiency, adrenal insufficiency, liver disease).
however, that inadvertent use of OCs during early pregnancy poses no risk of fetal harm. Because OCs have no role in pregnancy—and not because they are harmful—these drugs are classified in U.S. Food and Drug Administration (FDA) Pregnancy Risk Category X.a
Combination OCs enter breast milk and reduce milk produc-tion, especially in the early stages of lactation. In contrast, progestin-only OCs have little or no effect on milk production, and hence are preferred for contraception during lactation, at least early on. (Later, when the milk supply is well established, and especially with the addition of solids to the infant’s diet, use of combination OCs may resume.)
Nurses of Childbearing Age. In 2016 the National Institute for Occupational Safety and Health (NIOSH) expanded the list of drugs identified as hazardous. (See https://www.cdc.gov/
niosh/docs/2016-161/pdfs/2016-161.pdf.) NIOSH requires special handling of drugs identified as hazardous. See Chapter 3, Table 3.1, for administration and handling guidelines. The hazardous drugs mentioned in this chapter are listed in the following box.
Safety Alert
HAZARDOUS DRUGS REQUIRING SPECIAL HANDLING
Dinoprostone Estradiol
Estrogen/progesterone combinations Estrogens, conjugated Estrogens, esterified
Medroxyprogesterone acetate Mifepristone
Misoprostol Progesterone Ulipristal
Estrogen Progestin
Excess Deficiency Excess Deficiency
Nausea
Breast tenderness Edema
Bloating Hypertension Migraine
Cervical mucorrhea Polyposis
Early or midcycle breakthrough bleeding
Increased spotting Hypomenorrhea
Increased appetite Weight gain Depression Tiredness Fatigue Hypomenorrhea Breast regression Monilial vaginitis Acne, oily scalpa Hair lossa Hirsutisma
Late breakthrough bleeding Amenorrhea
Hypermenorrhea TABLE 62.4 ■ Side Effects Caused by an Excess of or Deficiency in the Estrogen or Progestin
Content of an Oral Contraceptive Regimen
aCaused by progestins that have strong androgenic activity.
aAs of 2020, the FDA will no longer use Pregnancy Risk Categories. Please refer to Chapter 9 for more information.
Stroke in Women With Migraine. When used by women who experience migraine headaches, OCs may increase the risk of thrombotic stroke. However, the absolute increase is low: only 8 cases per 100,000 women at age 20 years, and
in Chapter 81, neural tube defects can result if folic acid is low early in pregnancy.
Natazia. Natazia has two unique components: estradiol valerate and dienogest, a fourth-generation progestin. Estradiol valerate is a prodrug that undergoes rapid conversion to estradiol, the predominant endogenous estrogen.
Dienogest, which is much like drospirenone (see discussion of Components, earlier), has strong progestational activity and antiandrogenic activity. However, in contrast to drospirenone, dienogest does not cause potassium retention, and hence there is no need to monitor potassium levels. Unlike all other combination OCs, Natazia employs a four-phase dosing schedule, in which the amount of estradiol decreases over the monthly cycle and the amount of progestin (dienogest) increases. Because of this schedule, duration of withdrawal bleeding is shorter than with other combination OCs, and the intensity of bleeding is lighter. In women who normally experience heavy or prolonged menstrual bleeding, Natazia can reduce blood loss.
Dosing Schedules
With only one exception, combination OCs are dosed in a cyclic pattern. For most products, each cycle is 28 days long (see Tables 62.5 through 62.7). However, with a few newer products, the cycle is either extended (to 91 days) or continuous [Amethyst].
28-Day-Cycle Schedules. The 28-day regimens are subdivided into four groups: monophasic, biphasic, triphasic, and quadriphasic (four-phasic). In a monophasic regimen, the daily doses of estrogen and progestin remain constant throughout the cycle of use. In the other regimens, either the estrogen or the progestin changes (or both change) as the cycle pro-gresses. The biphasic, triphasic, and quadriphasic schedules reflect efforts to more closely simulate ovarian production of estrogens and progestins. However, these preparations appear to offer little or no advantage over monophasic OCs.
Most 28-day cycle products are taken in a repeating sequence consisting of 21 days of an active pill followed by 7 days on which either (1) no pill is taken, (2) an inert pill is taken, or (3) an iron-containing pill is taken. The sequence is begun on either (1) the first day of the menstrual cycle or (2) the first Sunday after the onset of menses. With the first option, protection is conferred immediately, and hence no backup contraception is needed. With a Sunday start, which is done to have menses occur on weekdays rather than the weekend, protection may not be immediate, and hence an alternate form of birth control should be used during the first cycle. With both options, each dose should be taken at the same time every day (e.g., with a meal or at bedtime). Successive dosing cycles should commence every 28 days, even if there is breakthrough bleeding or spotting.
Extended-Cycle and Continuous Schedules. Many healthcare providers recommend taking combination OCs for an extended time, rather than following the traditional 28-day cycle, because doing so decreases episodes of withdrawal bleeding with its associated menstrual pain, premenstrual symptoms, headaches, and other problems. Prolonged use of OCs is possible because these drugs suppress endometrial thickening, and hence monthly bleeding is not required to slough off hypertrophied tissue. At this time, 14 products—Amethia, Amethia Lo, Ashlyna, Camrese, Camrese Lo, Daysee, Introvale, Jolessa, Quasense, Seasonale, Seasonique, LoSeasonique, Setlakin, and Amethyst
—are packaged and marketed for prolonged use. The following regimens are employed:
• Introvale, Jolessa, Quasense, Seasonale, and Setlakin—
active pills for 84 days, then no pills for 7 days
Furthermore, drospirenone should be used with caution in women taking other drugs that can elevate serum potassium. Important among these are angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, potassium-sparing diuretics, potassium supplements, and nonsteroidal anti-inflammatory drugs (when taken daily). If women taking these drugs are using a drospirenone-containing OC, potassium levels should be checked during the first cycle of use.
Noncontraceptive Benefits of OCs
OCs decrease the risk of several disorders, including ovarian cancer, endometrial cancer, ovarian cysts, pelvic inflammatory disease (PID), benign breast disease, iron deficiency anemia, and acne. In addition, OCs favorably affect menstrual symptoms:
cramps are reduced, menstrual flow is reduced in volume and duration, and menses are more predictable. In women with premenstrual disorder or premenstrual dysphoric disorder, OCs can reduce symptom intensity. In some women with menstrual-associated migraine, OCs can reduce migraine frequency.
Surprisingly, OCs may even benefit women with rheumatoid arthritis.
Drug Interactions
Drugs and Herbs That Reduce the Effects of OCs. Prod-ucts that induce hepatic cytochrome P450 can accelerate OC metabolism and can thereby reduce OC effects. Products that induce P450 include rifampin (used for tuberculosis), ritonavir (used for HIV infection), several antiseizure agents (carbam-azepine, phenobarbital, phenytoin, and primidone), and St.
John’s wort (an herb used for depression). Women taking OCs in combination with any of these agents should be alert for indications of reduced OC blood levels, such as breakthrough bleeding or spotting. If these signs appear, it may be necessary to either (1) increase the estrogen dosage of the OC, (2) combine the OC with a second form of birth control (e.g., condom), or (3) switch to an alternative form of birth control.
Drugs Whose Effects Are Reduced by OCs. OCs can decrease the benefits of warfarin and hypoglycemic agents.
By increasing levels of clotting factors, OCs can decrease the effectiveness of warfarin, an anticoagulant. By increasing levels of glucose, OCs can counteract the benefits of insulin and other hypoglycemic agents used in diabetes. Accordingly, when combined with OCs, warfarin and hypoglycemic agents may require increased dosage.
Drugs Whose Effects Are Increased by OCs. OCs can impair the hepatic metabolism of several agents, including theophylline, tricyclic antidepressants, diazepam, and chlor-diazepoxide. Because of reduced clearance, these drugs may accumulate to toxic levels. If signs of toxicity appear, dosage of these drugs should be reduced.
Preparations
The combination OCs in current use are listed in Tables 62.5 through 62.8. As you can see, nearly all of these products contain the same estrogen: ethinyl estradiol. In contrast, eight different progestins are employed. Products are listed in order of increasing estrogen content. The OCs with low estrogen are safer. As a rule, high-estrogen OCs are reserved for women taking drugs that induce P450. Products with unique properties are discussed next.
Beyaz, Rajani, and Safyral. In addition to an estrogen and a progestin, these combination OCs contain levomefolate, a metabolite of folic acid. The purpose is to reduce the risk of fetal neural tube defects—anencephaly and
spina bifida—if pregnancy should occur despite contraceptive use. As discussed Text continued on p. 762