Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

62. Contraception

Sarah P. Shrader and Kelly R. Ragucci


KEY CONCEPTS

 Images The attitude of the patient and sexual partner toward contraceptive methods, efficacy rate, the reliability of the patient in using the method correctly (which may affect the effectiveness of the method), noncontraceptive benefits, and the patient’s ability to pay must be considered when selecting a contraceptive method.

 Images Patient-specific factors (e.g., frequency of intercourse, age, smoking status, and concomitant diseases or medications) must be evaluated when selecting a contraceptive method.

 Images Adverse effects or difficulties using the chosen method should be monitored carefully and managed in consideration of patient-specific factors.

 Images Accurate and timely counseling on the optimal use of the contraceptive method and strategies for minimizing sexually transmitted diseases must be provided to all patients when contraceptives are initiated and on an ongoing basis.

 Images Emergency contraception may prevent pregnancy after unprotected intercourse or when regular contraceptive methods have failed.


Unintended pregnancy is a significant public health problem. In the United States, approximately 6 million females become pregnant each year.1 The most recent data reveal that 37% of pregnancies are unintended, with the highest rates occurring in women aged 20 to 34 years.1 However, teen pregnancy rates are still an issue and slow to decline; teen births account for 11% of all the births in the United States.1 About half of all unintended pregnancies end in abortion, and 40% occur in sexually active couples who claim they used some method of contraception.1 If the goal of contraception—for pregnancies to be planned and desired—is to be realized, education on the use and efficacy of contraceptive methods must be improved.

ETIOLOGY AND PATHOPHYSIOLOGY

Comprehension of the hormonal regulation of the normal menstrual cycle is essential to understanding contraception in women (Fig. 62-1). The cycle of menstruation begins with menarche, usually around age 12 years, and continues to occur in nonpregnant women until menopause, usually around age 50 years. Factors such as race, body weight, medical conditions, and family history can affect the menstrual cycle.2 The cycle includes the vaginal discharge of sloughed endometrium called menses. The menstrual cycle comprises three phases: follicular (or preovulatory), ovulatory, and luteal (or postovulatory).

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FIGURE 62-1 Menstrual cycle events, idealized 28-day cycle. (FSH, follicle-stimulating hormone; HCG, human chorionic gonadotropin, LH, luteinizing hormone.) LH: 15 milli-international units/mL = 15 international units/L; 50 to 100 international units/mL = 50 to 100 international units/L. FSH: 10 to 12 milli-international units/mL = 10 to 12 international units/L; 25 milli-international units/mL = 25 international units/L. Estrogen: 40 pg/mL = ∼150 pmol/L; 250 to 400 pg/mL = ∼920 to 1470 pmol/L; 125 to 250 pg/mL = ∼460 to 920 pmol/L. Progesterone: 1 ng/mL = 3 nmol/L; 10 to 15 ng/mL = ∼30 to 50 nmol/L. Temperatures: 99° F = 37.2° C; 98° F = 36.7° C; 97° F = 36.1° C.

(From Hatcher et al.2 This figure may be reproduced at no cost to the reader.)

The Menstrual Cycle

The first day of menses is referred to as day 1 of the menstrual cycle and marks the beginning of the follicular phase.2 The follicular phase continues until ovulation, which typically occurs on day 14. The time after ovulation is referred to as the luteal phase, which lasts until the beginning of the next menstrual cycle. The median menstrual cycle length is 28 days, but it can range from 21 to 40 days. Generally, variation in length is greatest in the follicular phase, particularly in the years immediately after menarche and before menopause.2

The menstrual cycle is influenced by the hormonal relationships among the hypothalamus, anterior pituitary, and ovaries.2 The hypothalamus secretes gonadotropin-releasing hormone (GnRH) in a pulsatile fashion.2 These GnRH bursts stimulate the anterior pituitary to secrete bursts of gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). FSH and LH direct events in the ovarian follicles that result in the production of a fertile ovum.

Follicular Phase

In the first 4 days of the menstrual cycle, FSH levels rise and allow the recruitment of a small group of follicles for continued growth and development (Fig. 62-1).2 Between days 5 and 7, one follicle becomes dominant and later ruptures, releasing the oocyte. The dominant follicle develops increasing amounts of estradiol and inhibin, which cause a negative feedback on the hypothalamic secretion of GnRH and pituitary secretion of FSH, causing atresia of the remaining follicles recruited during the cycle.

Once the follicle has received FSH stimulation, it must receive continued FSH stimulation or it will die.2 FSH allows the follicle to enlarge and synthesize estradiol, progesterone, and androgen. Estradiol stops the menstrual flow from the previous cycle, thickening the endometrial lining of the uterus to prepare it for embryonic implantation. Estrogen is responsible for increased production of thin, watery cervical mucus, which will enhance sperm transport during fertilization. FSH regulates the aromatase enzymes that convert androgens to estrogens in the follicle. If a follicle has insufficient aromatase, the follicle will not survive.

Ovulation

When estradiol levels remain elevated for a sustained period of time, the pituitary releases a midcycle LH surge (Fig. 62-1).2 This LH surge stimulates the final stages of follicular maturation and ovulation (follicular rupture and release of the oocyte). On average, ovulation occurs 24 to 36 hours after the estradiol peak and 10 to 16 hours after the LH peak. The LH surge, which occurs 28 to 32 hours before a follicle ruptures, is the most clinically useful predictor of approaching ovulation. After ovulation, the oocyte is released and travels to the fallopian tube, where it can be fertilized and transported to the uterus for embryonic implantation. Conception is most successful when intercourse takes place from 2 days before ovulation to the day of ovulation.

Luteal Phase

After rupture of the follicle and release of the ovum, the remaining luteinized follicles become the corpus luteum, which synthesizes androgen, estrogen, and progesterone (Fig. 62-1).2 Progesterone helps to maintain the endometrial lining, which sustains the implanted embryo and maintains the pregnancy. It also inhibits GnRH and gonadotropin release, preventing the development of new follicles. If pregnancy occurs, human chorionic gonadotropin prevents regression of the corpus luteum and stimulates continued production of estrogen and progesterone secretion to maintain the pregnancy until the placenta is able to fulfill this role.

If fertilization or implantation does not occur, the corpus luteum degenerates, and progesterone production declines.2 The life span of the corpus luteum depends on the continuous presence of small amounts of LH, and its average duration of function is 9 to 11 days. As progesterone levels decline, endometrial shedding (menstruation) occurs, and a new menstrual cycle begins. At the end of the luteal phase, when estrogen and progesterone levels are low, FSH levels start to rise, and follicular recruitment for the next cycle begins.

EPIDEMIOLOGY

Contraception implies the prevention of pregnancy following sexual intercourse by inhibiting viable sperm from coming into contact with a mature ovum (i.e., methods that act as barriers or prevent ovulation) or by preventing a fertilized ovum from implanting successfully in the endometrium (i.e., mechanisms that create an unfavorable uterine environment). These methods differ in their relative effectiveness, safety, and patient acceptability (Tables 62-1and 62-2).2,3

TABLE 62-1 Comparison of Unintended Pregnancy and Continuation Rates for Pharmacologic Contraceptive Methods

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TABLE 62-2 Comparison of Methods of Nonhormonal Contraception

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The actual effectiveness of any contraceptive method is difficult to determine because many factors affect contraceptive failure. A failure in patients who use the contraceptive agent properly is considered a method failure or perfect-use failure. It is also important to consider user failure or typical-use failure rates, which are usually higher because they take into account the user’s ability to follow directions correctly and consistently.2,3

CLINICAL PRESENTATION

Most health maintenance annual visits should include assessment of and counseling about reproductive health. Clinicians may use this opportunity to provide contraception and educate patients on prevention of sexually transmitted diseases (STDs). Traditionally, hormonal contraception is provided subsequent to breast and pelvic examinations. However, the need for the physical examination may delay access to contraception and reinforces the incorrect perception that these methods of contraceptives are harmful. Therefore, the American Congress of Obstetrics and Gynecology (ACOG) allow provision of hormonal contraception after a simple medical history and blood pressure measurement.4 Other preventive measures, such as pelvic and breast examinations, provision of the human papillomavirus vaccine, and screening for cervical neoplasia, can be accomplished during routine annual office visits.4,5

TREATMENT

Desired Outcomes

The obvious goal of treatment with all methods of contraception is to prevent pregnancy. However, many health benefits are associated with contraceptive methods, including prevention of STDs (with condoms), improvements in menstrual cycle regularity (with hormonal contraceptives), improvements in certain health conditions (with hormonal contraceptives), and management of perimenopause.2,6

Nonpharmacologic Therapy

Periodic Abstinence

ImagesImages Motivated couples may use the abstinence (rhythm) method of contraception, avoiding sexual intercourse during the days of the menstrual cycle when conception is likely to occur. Physiologic changes, such as basal body temperature and cervical mucus, are used during each cycle to determine the fertile period. The major drawbacks are the relatively high pregnancy rates and avoidance of intercourse for several days during each menstrual cycle.2

Barrier Techniques

ImagesImages The effectiveness of barrier methods depends almost exclusively on motivation to use them consistently and correctly.2 These methods include condoms, diaphragms, cervical caps, and sponges (Table 62-2). A major disadvantage is higher failure rates than most hormonal contraceptives; thus, provision of counseling and an advanced prescription for emergency contraception (EC) are recommended for all patients using barrier methods as their primary means of contraception.

Male condoms create a mechanical barrier, preventing direct contact of the vagina with semen, genital lesions, and infectious secretions.2 Most condoms in the United States are made of latex, which is impermeable to viruses. A small proportion are made from lamb intestine, which is not impermeable to viruses. Synthetic condoms manufactured from polyurethane are another option; these condoms are latex-free and do protect against viruses. Condoms are used worldwide as protection from STDs including human immunodeficiency virus (HIV). When condoms are used in conjunction with any other barrier method, their effectiveness theoretically approaches 98%. Spillage of semen or perforation and tearing of the condom can occur, but proper use minimizes these problems. Mineral oil-based vaginal drug formulations (e.g., Cleocin, Premarin, and Monistat), lotions, or lubricants can decrease the barrier strength of latex, thus making water-soluble lubricants (e.g., Astroglide, K-Y Jelly) preferable. Condoms with spermicides are no longer recommended because they provide no additional protection against pregnancy or STDs and may increase vulnerability to HIV.

The female condom is a prelubricated, loose-fitting polyurethane sheath, closed at one end, with flexible rings at both ends.2 Properly positioned, the ring at the closed end covers the cervix, and the sheath lines the walls of the vagina. The outer ring remains outside the vagina, covering the labia. The pregnancy rate is reported to be higher when compared to male condoms. Male and female condoms should not be used together, as slippage and device displacement may occur.

The diaphragm, a reusable dome-shaped rubber cap with a flexible rim that is inserted vaginally, fits over the cervix in order to decrease access of sperm to the ovum. The diaphragm requires a prescription from a clinician who has fitted the patient for the correct size.2 Its efficacy is increased when it is used in conjunction with spermicidal cream or jelly. The diaphragm may be inserted up to 6 hours before intercourse and must be left in place for at least 6 hours afterward. However, leaving it in place for more than 24 hours is not recommended due to the potential for toxic shock syndrome (TSS). With subsequent acts of intercourse, the diaphragm should be left in place, and a condom should be used for additional protection.

The cervical cap (FemCap) is a soft, deep cup with a firm round rim that is smaller than a diaphragm and fits over the cervix like a thimble.2 The cervical cap is available in three sizes and requires a prescription from a clinician who has fitted the patient for the correct size. It should be filled with spermicide prior to insertion. The cervical cap can be inserted 6 hours prior to intercourse and should not be removed for at least 6 hours after intercourse. It can remain in place for multiple episodes of intercourse without adding more spermicide but should not be worn for more than 48 hours at a time to reduce the risk of TSS. Failure rates are higher than with other methods. Diaphragms and cervical caps do not protect against some STDs including HIV, thus condoms should also be used.

Pharmacologic Therapy

Spermicides

Images Images Spermicides, most of which contain nonoxynol-9, are chemical surfactants that destroy sperm cell walls and act as barriers that prevent sperm from entering the cervical os.2 They are available as creams, films, foams, gels, suppositories, sponges, and tablets. Spermicides offer no protection against STDs. In fact, when used frequently (more than two times per day), nonoxynol-9 may increase the risk of transmission of HIV by causing small disruptions in the vaginal epithelium.2,7,8 The World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) do not promote products containing nonoxynol-9 for protection against STDs.

Spermicide-Implanted Barrier Techniques

ImagesImages The vaginal contraceptive sponge (Today) contains 1 g of the spermicide nonoxynol-9.2 It has a concave dimple on one side to fit over the cervix and a loop on the other side to facilitate removal. After being moistened with water, the sponge is inserted into the vagina up to 6 hours before intercourse. The sponge provides protection for 24 hours, regardless of the frequency of intercourse during this time. After intercourse, the sponge must be left in place for at least 6 hours before removal and should not be left in place for more than 24 to 30 hours to reduce the risk of TSS. Sponges should not be reused; after removal, they should be discarded. The sponge comes in one size and is available over the counter (OTC).

Hormonal Contraception

Hormonal contraceptives contain a combination of estrogen and progestin or a progestin alone. Oral contraceptive (OC) preparations first became available in the 1960s, but options have expanded to include a transdermal patch, a vaginal contraceptive ring, and long-acting injectable, implantable, and intrauterine contraceptives.

Combined hormonal contraceptives (CHCs) contain both estrogen and progestin and work primarily before fertilization to prevent conception. Progestins provide most of the contraceptive effect by thickening cervical mucus to prevent sperm penetration, slowing tubal motility, delaying sperm transport, and inducing endometrial atrophy. Progestins block the LH surge, therefore inhibiting ovulation. Estrogens suppress FSH release from the pituitary, which may contribute to blocking the LH surge and preventing ovulation. However, the primary role of estrogen in hormonal contraceptives is to stabilize the endometrial lining and provide cycle control.2,3

Estrogens Two synthetic estrogens found in hormonal contraceptives available in the United States are ethinyl estradiol (EE) and mestranol. Mestranol must be converted by the liver to EE before it is pharmacologically active and is 50% less potent than EE.2,3 Most combined OCs, transdermal patch, and vaginal ring contain estrogen at doses of 20 to 50 mcg of EE.3

Progestins A variety of progestins are available in the United States, and they vary in their progestational activity and differ with respect to inherent estrogenic, antiestrogenic, and androgenic effects.2,3Estrogenic and antiestrogenic properties are secondary to the extent of progestins’ metabolism to estrogenic substances. Androgenic activity depends on two variables: the presence of sex hormone (testosterone) binding globulin (SHBG-TBG) and the androgen-to-progesterone activity ratio. If the amount of SHBG-TBG is decreased, free testosterone levels increase, and androgenic side effects are more prominent.3

Considerations with Combined Hormonal Contraceptive Use Images When selecting a CHC, clinicians are challenged by weighing the benefits and risks associated with the many formulations available. The clinician must determine if the form of contraception is appropriate based upon the patient’s lifestyle and potential adherence. A complete medical examination and papanicolaou (Pap) smear are not necessary before a CHC is prescribed. A medical history and blood pressure measurement should be obtained before prescribing a CHC, along with a discussion of the benefits, risks, and adverse effects with each patient.2,3,9 For example, OCs are associated with noncontraceptive benefits, including relief from menstruation-related problems (e.g., decreased menstrual cramps, decreased ovulatory pain [mittelschmerz], and decreased menstrual blood loss), improvement in menstrual regularity, and decreased iron deficiency anemia.6 Women who take combination OCs have a reduced risk of ovarian and endometrial cancer. There is a 50% reduction in risk in women who have used OCs for 5 years or more, and protection may persist for more than 10 years post-use. Combination OCs may also reduce the risk of ovarian cysts, ectopic pregnancy, pelvic inflammatory disease, endometriosis, uterine fibroids, and benign breast disease. The CHC transdermal patch and vaginal ring are other combined hormonal options that may be more convenient for women than taking a tablet each day.

ImagesImages Adverse effects may hinder adherence and therefore efficacy, so they should be discussed prior to initiating a hormonal contraceptive agent.10 Excessive or deficient amounts of estrogen and progestin are related to the most common adverse effects.2,3,10 The CHC vaginal ring may be uncomfortable for some women and cause vaginal discharge. The CHC patch may cause irritation and now has information added to product labeling regarding the increased potential for thromboembolism.

An important concern regarding the use of CHCs is the lack of protection against STDs. Because of their high efficacy in preventing pregnancy, patients may choose not to use condoms. In addition to public health awareness, clinicians must encourage patients to use condoms for prevention of STDs. OCs have an extensive history of safety concerns, which traditionally were related to high dose estrogen tablets. To replace the traditional absolute and relative contraindications to the use of OCs, the CDC developed a graded list of precautions for clinicians to consider when initiating CHCs (Table 62-3).2,9

TABLE 62-3 U.S. Medical Eligibility Criteria for Contraceptive Use: Classifications for Combined Hormonal Contraceptives

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In addition to the CDC, the ACOG provides information for clinicians to use when selecting CHCs for women with coexisting medical conditions.11 Overall, the health risks associated with pregnancy, the specific health risks associated with CHCs, and the noncontraceptive benefits of CHCs should be factored into risk-to-benefit considerations.

Women Older Than 35 Years Use of CHC in women older than 35 is controversial. Older women, especially women in their 40s, retain a level of fertility even in the perimenopausal state and should use contraception to prevent pregnancy. Formulations with lower doses of estrogen (less than 30 mcg) have increased the use of CHCs in these women. In addition to the benefit of pregnancy prevention, they may improve or decrease the chance of developing perimenopausal and menopausal symptoms and increase bone mineral density (BMD). However, the benefits of using CHCs must be weighed against the risks in women older than 35. The increased risk of cardiovascular disease and venous thromboembolism (VTE) should be considered especially in perimenopausal women greater than 40. Older data suggest an increased risk of myocardial infarction (MI) in older women using CHCs, although many women in these studies were current smokers and used older formulations containing higher doses (greater than 50 mcg) of estrogen. More recent data do not support the increased risk of cardiovascular disease when low-dose formulations of CHCs are used in healthy, non-obese women. Other concerns include the increased risk of ischemic stroke in women with migraines and the increased risk of breast cancer in older women.9,11,12

The risks and benefits of using CHCs in women greater than 35 must be considered on an individual basis. It is recommended that use of CHCs (with less than 50 mcg of estrogen) may be considered in healthy nonsmoking women. CHCs should not be recommended in women older than 35 years with migraine (with or without aura), uncontrolled hypertension, smoking, or diabetes with vascular disease.9,11

Smoking In early studies, OCs with 50 mcg EE or more were associated with MI in women who smoked cigarettes.2,3,9,11 The United States case–control studies have found that both nonsmoking and smoking women, regardless of age, taking OCs with less than 50 mcg EE did not have an increased risk of MI or stroke. However, these studies included few women older than 35 years who were smokers. European studies, with a higher population of older smoking women, demonstrated an increased risk of MI in this population. Therefore, practitioners should prescribe CHC with caution, if at all, to women older than 35 years who smoke. Smoking 15 or more cigarettes per day by women in this age group is a contraindication to CHC, and the risks generally outweigh the benefits of CHC in those who smoke fewer than 15 cigarettes per day.9 Progestin-only contraceptive methods should be considered for women in this group.

Hypertension CHCs can cause small increases (i.e., 6 to 8 mm Hg) in blood pressure, regardless of estrogen dosage.3,9,11 This has been documented in both normotensive and mildly hypertensive women given a 30 mcg EE OC. In case–control studies of women with hypertension, OCs have been associated with an increased risk of MI and stroke. Use of low-dose CHC is acceptable in women younger than 35 years with well-controlled and frequently monitored hypertension. If a CHC-related increase in blood pressure occurs, discontinuing the CHC usually restores blood pressure to pretreatment values within 3 to 6 months.3 Systolic blood pressure greater than or equal to 160 mm Hg or diastolic blood pressure greater than or equal to 100 mm Hg is considered a contraindication to the use of CHCs. Hypertensive women who have end-organ vascular disease or who smoke should not use CHCs. Women with hypertension who are taking potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, or aldosterone antagonists may have increased serum potassium concentrations if they are also using an OC-containing drospirenone, which has antialdosterone properties.3

Dyslipidemia Generally, synthetic progestins adversely affect lipid metabolism by decreasing high-density lipoprotein (HDL) and increasing low-density lipoprotein (LDL).3,11 Estrogens tend to have more beneficial effects by enhancing removal of LDL and increasing HDL levels. Estrogens may moderately increase triglycerides. As a net result, most low-dose CHCs have no significant impact on HDL, LDL, triglycerides, or total cholesterol. CHCs containing more androgenic progestins (e.g., levonorgestrel) may result in lower HDL levels in some patients. Although the lipid effects of CHCs theoretically can influence cardiovascular risk, the mechanism of increased cardiovascular disease in CHC users is believed to be due to thromboembolic and thrombotic changes, not atherosclerosis. Women with controlled dyslipidemia can use low-dose CHCs, although periodic fasting lipid profiles are recommended. Women with uncontrolled dyslipidemia (LDL greater than 160 mg/dL [4.14 mmol/L], HDL less than 35 mg/dL [0.91 mmol/L], triglycerides greater than 250 mg/dL [2.83 mmol/L]) and additional risk factors (e.g., coronary artery disease, diabetes, hypertension, smoking, or positive family history) should consider an alternative method of contraception.

Diabetes Any effect of CHCs on carbohydrate metabolism is thought to be due to the progestin component.3,11 However, with the exception of some levonorgestrel-containing products, formulations containing low doses of progestins do not significantly alter insulin, glucose, or glucagon release after a glucose load in healthy women or in those with a history of gestational diabetes. The new progestins are believed to have little, if any, effect on carbohydrate metabolism. CHCs do not appear to alter the hemoglobin A1c values or accelerate the development of microvascular complications in women with diabetes. Therefore, nonsmoking women younger than 35 years with diabetes but no associated vascular disease can safely use CHCs. Diabetic women with vascular disease (e.g., nephropathy, retinopathy, neuropathy, or other vascular disease) or diabetes of more than 20 years’ duration should not use CHCs.9

Migraine Headaches Women with migraine headaches may experience a decreased or an increased frequency of migraine headaches when using CHCs.3,9,11,13 Studies have demonstrated a higher risk of stroke in women experiencing migraine with aura compared to women with simple migraine. In population-based studies, the risk of stroke in women with migraines has been elevated twofold to threefold. However, given the low absolute risk of stroke in young women (age less than 35 years), the ACOG recommends considering CHCs in healthy, nonsmoking women with migraine headaches without aura.11 Women of any age who have migraine with aura and women over the age of 35 with any type of migraine should not use CHC. Women who develop migraines (with or without aura) while receiving CHC should discontinue use and consider a progestin-only option.

Breast Cancer Worldwide epidemiologic data from 54 studies in 25 countries (many of which studied high dose OCs) were collected to assess the relationship between OCs and breast cancer.11 Overall, investigators noted a small increased risk of breast cancer associated with current or recent use, but OCs did not further increase risk in women with a history of benign breast disease or a family history of breast cancer. A more recent U.S.-based case–control study found no association between overall breast cancer and current or past OC use.11 This study also found no association between depo-medroxyprogesterone acetate (DMPA) and breast cancer. Although some studies have found differences in risk of breast cancer based on the presence of BRCA1 and BRCA2 mutations, the most recent cohort study found no association with low-dose OCs and the presence of either mutation. The choice to use CHCs should not be affected by the presence of benign breast disease or a family history of breast cancer with either mutation. Women with current or past history of breast cancer should not use CHCs.2,9

Thromboembolism Estrogens increase hepatic production of factor VII, factor X, and fibrinogen in the coagulation cascade, therefore increasing the risk of thromboembolic events (deep vein thrombosis, pulmonary embolism). These risks are increased in women who have underlying hypercoagulable states (e.g., deficiencies in antithrombin III, protein C, and protein S; factor V Leiden mutations, prothrombin G2010 A mutations) or who have acquired conditions (e.g., obesity, pregnancy, immobility, trauma, surgery, and certain malignancies) that predispose them to coagulation abnormalities.3,9,11 In the U.S. case–control studies, the risk of VTE in women currently using low-dose OCs (less than 50 mcg EE) was four times the risk in nonusers.3,11 However, this risk is less than the risk of VTE incurred during pregnancy. OCs containing newer progestins such as drosperinone, desogestrel, and norgestimate are associated with a slightly increased risk of thrombosis.2 Although the mechanism for this increased risk is unclear, it is thought that third- and fourth-generation progestins have a greater effect on the procoagulant, anticoagulant, and fibrinolytic pathways.2,14.15 These progestins may also be associated with increased resistance to protein C and may increase levels of sex hormone-binding globulin.2,14 It is thought that continuous, higher exposure to estrogen seen with the transdermal patch or vaginal ring is the reason for an increased thromboembolic risk with these agents as well. An advisory committee to the FDA decided to change the product labeling of the transdermal patch as well as products containing drosperinone to include additional information about the increased risk of thromboembolism.16,17 Therefore, for women who are at an increased risk of thromboembolism (e.g., older than 35 years, obesity, smoking, personal or family history of venous thrombosis, prolonged immobilization), it would be prudent to first consider low-dose oral estrogen contraceptives containing older progestins or progestin-only contraceptive methods. It is important to note that EC has not been associated with an increased risk of thromboembolic events.


Clinical Controversy…

Weighing the risk versus benefit of using CHCs containing third- and fourth-generation progestins, and determining their place in therapy is controversial. Third-generation progestins (desogestrel, norgestimate) and a fourth-generation progestin (drosperinone) have been associated with a higher risk of thromboembolism. Mechanisms underlying this increased risk may include: (a) a greater effect on the procoagulant, anticoagulant, and fibrinolytic pathways than earlier generation progestins; (b) increased resistance to the anticoagulant effect of activated protein C; (c) increased levels of sex hormone-binding globulin; and (d) antiandrogenic effects of drosperinone make the CHC more estrogenic. The overall risk of VTE with older low-dose agents is 6 per 10,000 women per year (compared with 2 to 3 per 10,000 in nonusers). The risk increases to 10 to 15 per 10,000 women per year with drosperinone-containing OCs. Risk of VTE is also higher with the transdermal patch (10 to 15 per 10,000 women per year) and possibly with the vaginal ring (8 per 10,000 women per year). It is thought that continuous, higher exposure to estrogen seen with these formulations may be the cause of this increased risk. It is important to remember that regardless of contraceptive product, the risk is still lower than the risk of thromboembolism during pregnancy (17 per 10,000 women per year).

Obesity The prevalence of obesity continues to rise each year among all age groups including women of childbearing age. It has been hypothesized that women with increased body weight have increased basal metabolic rates and induction of hepatic enzymes, leading to increased hormonal clearance and decreased serum concentrations of hormonal contraceptives. In addition, women who are obese have more adipose tissue, increasing hormonal sequestration, and decreased free hormone serum concentrations resulting in lower efficacy.2,3,11 It is estimated that there is an additional two to four pregnancies per 100 woman-years of use in overweight or obese users.18 This decreased efficacy may be a particular issue with the low-dose OCs. Along these same lines, ACOG recommends that the transdermal contraceptive patch should not be used as a first-line option in women weighing greater than 90 kg.11,17 Increased pregnancy rates have not been demonstrated in obese women using DMPA or the levonorgestrel intrauterine device (IUD). It is important to note that the CDC recommends that the benefit outweighs the potential risk of decreased efficacy in obese women.9

Obese women are also at risk of VTE, although studies evaluating the incidence of thromboembolism in obese women taking hormonal contraceptives have produced conflicting results. ACOG suggests that progestin-only hormonal contraception may be more appropriate for obese women over the age of 35 years, and women should be counseled on the risk and consider alternative contraceptive methods on an individual basis.11 Again, it should be noted that the risk of thromboembolism during pregnancy and in the peripartum period is significantly greater than the risk with any hormonal contraceptive agent.

Systemic Lupus Erythematosus Contraception is important in women with systemic lupus erythematosus (SLE) because the risks associated with pregnancy are high in this population. Historically, clinicians have thought that CHCs exacerbated the symptoms of SLE.3,11 However, trials have shown that OCs do not increase the risk of flare among women with stable SLE and without antiphospholipid/anticardiolipin antibodies. Because 25% of women with SLE who become pregnant choose to terminate the pregnancy, effective contraception is essential for these patients. CHCs should be avoided in women with SLE and antiphospholipid antibodies or vascular complications; progestin-only contraceptives can be used in this situation.9

Sickle-Cell Disease Advantages of CHC generally outweigh the theoretical or proven risks in those with sickle-cell disease.9 Theoretical concerns about the effects of CHCs on platelet activation and red cell deformity, for example, led clinicians to avoid their use in women with sickle-cell disease. However, this concern has been largely disproven. In addition, two-controlled trials have actually demonstrated a reduction in risk of vasoocclusive crises in women with sickle-cell disease using DMPA as the method of contraception.11 Therefore, many clinicians prefer to use DMPA in this patient population.

Oral Contraceptives ImagesImages With perfect-use OCs have a 99% efficacy rate, but with typical-use up to 8% of users may become pregnant (Table 62-1).2,3 The OCs currently available are modifications of the original products introduced in the 1960s and contain significantly less estrogen and progestin. High-dose formulations were associated with vascular and embolic events, cancers, and significant side effects, but reductions in hormone doses have been associated with fewer complications.

Monophasic OCs contain the same amounts of estrogen and progestin for 21 days, followed by 7-day placebo phase. Multiphasic pills contain variable amounts of estrogen and progestin for 21 days, also followed by a 7-day placebo phase. There are no published data demonstrating increased safety or efficacy with the multiphasic tablets compared to monophasic tablets.2,19,20 Extended-cycle tablets and continuous combination regimens may offer some benefits for patients in terms of side effects and convenience. One particular extended-cycle OC increases the number of hormone-containing pills from 21 to 84 days, followed by a 7-day placebo phase, resulting in four menstrual cycles per year.21 Another product provides hormone-containing tablets daily throughout the year.22 Women taking extended-cycle and continuous-cycle tablets tend to have a decreased amount of bleeding over time, often leading to amenorrhea. Continuous combination regimens provide OCs for 21 days, then very low dose estrogen and progestin for an additional 4 to 7 days (during the traditional placebo phase).16,23

Table 62-4 lists available OC products by brand name and specifies hormonal composition. Progestin-only “minipills” (28 days of active hormone per cycle) are also available options.2,3 Progestin-only OCs are less effective than combination OCs and are associated with irregular and unpredictable menstrual bleeding.2,3 Minipills must be taken every day of the menstrual cycle at approximately the same time to maintain contraceptive efficacy. If a progestin-only OC is taken more than 3 hours late, patients should use a backup method of contraception for 48 hours.3 Minipills may not block ovulation (nearly 40% of women continue to ovulate normally), so the risk of ectopic pregnancy is higher with their use than with other hormonal contraceptives.

TABLE 62-4 Composition of Commonly Prescribed Oral Contraceptivesa

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Initiating an Oral Contraceptive Images OCs may be initiated by several different methods, including on the first day of bleeding during the menstrual cycle, on the first Sunday after the menstrual cycle begins or on the fifth day after the menstrual cycle begins. The most popular “Sunday start” method is to begin pills on the first Sunday after the menstrual cycle begins, as this may provide for weekends free of menstrual periods.2,3,24 Women should be instructed to use a second method of contraception for at least 7 days after initiation for maximum effectiveness. It may be preferable to have women use additional contraception for the entire first cycle, due to user failure in the first month. In the “quick start” method for initiating OCs, the patient takes the first tablet on the day of her office visit. Women should be instructed to use a second method of contraception for at least 7 days and informed that the menstrual period will be delayed until completion of the active tablets in the current OC pack. This method has been shown to be more successful in getting women to start OCs and to continue using OCs through the third cycle of use.

Postpartum Use of CHCs In the postpartum phase, there is concern about use of CHCs because of the mother’s hypercoagulability and the effects on lactation. In the first 21 days postpartum (when the risk of thrombosis is higher), estrogen-containing hormonal contraceptives should be avoided (Table 62-3).9,25 If contraception is required during this period, progestin-only contraceptive methods may be acceptable alternatives. It is recommended that women who are breast-feeding avoid CHCs for the first 42 days postpartum in those with risk factors for VTE and for 30 days in those without risk factors. In those women who are not breast-feeding, CHCs should be avoided for up to 42 days postpartum in those with risk factors for VTE.25 After 42 days postpartum, there is no restriction to the use of CHCs.

Choice of Oral Contraceptive ImagesImages Because all combined OCs are similarly effective in preventing pregnancy (Table 62-1), the initial choice is based on the hormonal content and dose, preferred formulation, and coexisting medical conditions (Table 62-3).9 In women without coexisting medical conditions, an OC containing 35 mcg or less of EE and less than 0.5 mg of norethindrone is recommended (Table 62-4).3 This strategy is based on evidence that complications and side effects from CHC (i.e., VTE, stroke, or MI) result from excessive hormonal content. Adolescents, underweight women (less than 50 kg [110 lb]), women older than 35 years, and those who are perimenopausal may have fewer side effects with OCs containing 20 to 25 mcg of EE. With nonadherence to OCs, the risk of pregnancy may be greater in women taking OCs containing less than 35 mcg of EE. Overweight and obese women may have higher contraceptive failure rates with low-dose OCs and may benefit from pills containing at least 35 mcg of EE. Women with oily skin, acne, or hirsutism should be given low androgenic OCs.3 Choice of agent based upon coexisting medical conditions have been previously addressed (Table 62-3).9,11

Conventional regimens (21 days of active pills, 7 days of placebo) provide predictable menses. Because monophasic OCs may be easier to take, easier to identify/manage side effects, and easier to manipulate to alter the timing of the menstrual cycle, they are preferred over multiphasic OCs.2,3 Extended-cycle OCs either eliminate or reduce the number of menstrual cycles per year, leading to less premenstrual symptoms and dysmenorrhea. Commercially available extended-cycle OCs are available, or monophasic 28 day OCs can be cycled by skipping the 7-day placebo phase. With continued use of extended-cycle OCs for 1 year, no significant changes in adverse effects have been noted. However, long-term studies have not been performed to assess the risk of cancer, VTE, or changes in fertility. Continuous combination regimens provide a shortened pill-free interval, from the traditional 7 days to 2 to 4 days. These regimens may be beneficial for women with symptoms such as dysmenorrhea or menstrual migraines.

Managing Oral Contraceptive Side Effects Images Many symptoms occurring with early OC use (e.g., nausea, bloating, breakthrough bleeding) improve spontaneously by the third cycle of use after adjusting to the altered hormone levels.2,3 Women should be counseled to continue their OC for 2 to 3 months before a change is made to adjust the hormonal content. However, a large majority of women who discontinue OCs do so because of the side effects. Patient education and early reevaluation within 3 to 6 months are necessary to identify and manage adverse effects, in an effort to improve adherence. Serious adverse effects that may occur with the use of CHCs are listed in Table 62-5, and common side effects and recommended monitoring are reviewed in Table 62-6.2,3,10 Patients should be instructed to immediately discontinue CHCs if they experience warning signs, described as ACHES (abdominal pain, chest pain, headaches, eye problems, and severe leg pain).3

TABLE 62-5 Serious Symptoms That May Be Associated with Combined Hormonal Contraception

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TABLE 62-6 Drug Monitoring Table for Hormonal Contraception

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Managing Oral Contraceptive Drug Interactions ImagesThe effectiveness of an OC is sometimes limited by drug interactions that interfere with GI absorption, increase intestinal motility by altering gut bacteriologic flora, and alter the metabolism, excretion, or binding of the OC.2,11 The lower the dose of hormone in the OC, the greater the risk that a drug interaction will compromise its efficacy. Women should be instructed to use an additional method of contraception if there is a possibility of a drug interaction altering the efficacy of the OC.3 Although less well documented, these recommendations generally apply to patients receiving transdermal and vaginal CHC products.

Of all antibiotics, rifampin is the one with a true documented pharmacokinetic interaction. Pharmacokinetic studies of other antibiotics have not shown any consistent interaction, but case reports of individual patients have shown a reduction in EE levels when OCs are taken with tetracyclines and penicillin derivatives. The ACOG states that ampicillin, doxycycline, fluconazole, metronidazole, miconazole, fluoroquinolones, and tetracyclines do not decrease steroid levels in women taking OCs.11 The Council on Scientific Affairs at the American Medical Association recommends that women taking rifampin should be counseled about the risk of OC failure and advised to use an additional nonhormonal contraceptive agent during the course of rifampin therapy (Table 62-3). The council also recommends that women be informed about the small risk of interactions with other antibiotics, and, if desired, appropriate additional nonhormonal contraceptive agents should be considered. In addition, women who develop breakthrough bleeding during concomitant use of antibiotics and OCs (and other CHCs) should be advised to use an alternate method of contraception during the period of concomitant use.

Women receiving certain anticonvulsants for a seizure disorder should be offered another form of contraception such as DMPA or IUDs (Table 62-3).9 Some anticonvulsants (mainly phenobarbital, carbamazepine, phenytoin) induce the metabolism of estrogen and progestin, inducing breakthrough bleeding and potentially reducing contraceptive efficacy. In addition, some anticonvulsants (e.g., phenytoin) are known teratogens.

Patient Instructions with Oral Contraceptives Images Many women who take OCs are not educated properly on the appropriate use of these medications. Women should be given the package insert that accompanies all estrogen products and instructed to read it. The written patient information should be supplemented with verbal information describing the mechanism of the medication, both common and serious side effects, and management of these side effects. Although several transient self-limiting side effects often occur, the patient should be aware of the danger signals that require immediate medical attention (Table 62-5). The benefits and risks should be discussed, including the fact that OCs provide no physical barrier to the transmission of STDs, including HIV. Detailed instructions on when to start taking the OC should be provided. Patients should be told the importance of routine daily administration to ensure consistent plasma concentrations and improve adherence and specific instructions should be given regarding what to do if a tablet is missed. The WHO Selected Practice Recommendations for Contraceptive Use have guidelines for managing missed oral contraceptives.26 In addition to when the tablet(s) is missed and how many are missed, the guidelines take into consideration whether the OC contains less than 30 mcg of EE. Limited evidence suggests that the risk of pregnancy is greater when 20 mcg tablets are missed than when 30 to 35 mcg tablets are missed. For instance, if a woman is taking a tablet containing 20 mcg EE and misses one dose or starts a pack 1 day late, she should take a tablet as soon as possible (two tablets on the same day) and then continue taking the rest of the tablets daily. No additional contraceptive protection is necessary. If, however, two or more tablets are missed or the pack is started two or more days late, the woman should follow the same instructions, but condoms should be used or she should abstain from sexual intercourse until she has taken active tablets for 7 days in a row. If missed tablets occur in the third week, she should finish the active tablets in the current pack and start a new pack the next day. She should not take the seven inactive tablets. If the missed doses occur in the first week and unprotected intercourse has occurred, she should consider the use of EC. Instructions are similar for the 30 to 35 mcg tablets; however, no additional contraceptive protection is necessary unless three or more active tablets are missed or the woman starts a pack 3 or more days late. It should be noted that the Society of Obstetricians and Gynecologists of Canada also published guidelines in 2008 for missed doses.26These guidelines differ slightly and do not account for the estrogen content of the tablet. Instructions also may vary in package inserts, which can make for increased confusion with patients and clinicians. It may be prudent, when differing instructions exist, to recommend the more conservative of approaches when dealing with individual patient situations.

Discontinuing Oral Contraceptives and Return of Fertility The ACOG states that there is no evidence that OC use decreases subsequent fertility. The transdermal patch and vaginal ring CHCs also have similar effects on fertility. The average delay in ovulation after discontinuing OCs is 1 to 2 weeks; however, delayed ovulation is more common in women with a history of irregular menses. If amenorrhea does continue beyond 6 months, women should be counseled to see a gynecologist for further fertility work-up.2,3,11 In the past, women were counseled to allow two to three normal menstrual periods before becoming pregnant to permit the reestablishment of menses and ovulation. However, in several large cohort and case–control studies, infants conceived in the first month after discontinuation of an OC had no greater chance of miscarriage or being born with a birth defect than those born in the general population.

Transdermal Contraceptives Images Images A CHC is available as a transdermal patch (Ortho Evra), which includes 0.75 mg of EE and 6 mg of norelgestromin, the active metabolite of norgestimate.2,3 Comparative trials have shown the transdermal patch to be as effective as combined OCs in patients weighing less than 90 kg. Of the 15 pregnancies reported in the clinical trials, five were among women weighing more than 90 kg; therefore, this product is not recommended as a first-line option for these women.2,3,17 Images Some patients experience application-site reactions, but other side effects are similar to those experienced with OCs (e.g., breast discomfort, headache, and nausea).3 A warning from the manufacturer states that women using the patch are exposed to approximately 60% more estrogen than from a typical OC containing 35 mcg of EE. Evidence suggests that higher exposure to estrogen may lead to increased thromboembolic risk, and the labeling for the contraceptive patch now contains a warning of this risk.17 The patch should be applied to the abdomen, buttocks, upper torso, or upper arm at the beginning of the menstrual cycle and replaced every week for 3 weeks (the fourth week is patch-free).2,3 The patch releases estrogen and progestin for 9 days. If the woman forgets to change her patch or restarts the active patches after the ninth day, a backup method should be used for 7 days. Approximately 5% of patches will need to be replaced because they become partly detached or fall off altogether, so single replacements are available. If the patch is detached for more than 24 hours, a new 4-week cycle should be restarted and a backup method used for 7 days.2,3 Users have demonstrated greater adherence with the patch than with an OC, but whether this results in reduced pregnancy rates remains to be seen. The benefits of adherence must be weighed against of the risk of increased estrogen exposure and possibility of VTE.

Vaginal Rings ImagesImages The vaginal contraceptive ring contains EE and etonogestrel (NuvaRing).27 It is a 54 mm flexible ring, 4 mm in thickness. Over a 3-week period, the ring releases approximately 15 mcg/day of EE and 120 mcg/day of etonogestrel. Comparative trials have shown the vaginal ring to be as effective as combined OCs. On the first cycle of use, the ring should be inserted on or before the fifth day of the menstrual cycle, remain in place for 3 weeks, then removed for 1 week to allow for withdrawal bleeding. The new ring should be inserted on the same day of the week as it was during the last cycle, similar to starting a new OC pack on the same day of the week. A second method of contraception should be used if the ring has been expelled accidentally for more than 3 hours; if less than 3 hours, it should be washed and reinserted.2,3,27

Images Side effects, precautions, and contraindications for use of the hormonal ring are similar to those for all CHCs. The most commonly reported reasons for discontinuation of use were device-related issues, such as foreign-body sensation, device expulsion, and vaginal symptoms.27 Cycle control with the vaginal ring appears to be equal or better than with combined OCs, with a low incidence of breakthrough bleeding and spotting after the second cycle of use. Patient acceptability of the delivery system has been studied, and the majority of women do not complain of discomfort in general or during intercourse.3 A potential concern is the possibility of increased VTE (eight cases per 10,000 per year vs. six cases with most CHCs) since etonogestrel is a metabolite of desogestrel which may be associated with increased risk.28 The ring should be inserted vaginally. In contrast to diaphragms and cervical caps, precise placement is not an issue because the hormones are absorbed anywhere in the vagina. Women should be in a comfortable position, and compress the ring between the thumb and index finger and push it into the vagina. There is no danger of inserting the ring too far because the cervix will prevent it from traveling up the genital tract. Removal of the ring is performed in a similar manner; pulling it out and discarding into the foil patch (the ring should not be flushed down the toilet).27 Patients should be discouraged from douching, but other vaginal products, including antifungal creams and spermicides, can be used.3,27

Injectable Progestins Steroid hormones provide longer-term contraception when injected into the skin. Sustained progestin exposure blocks the LH surge, thus inhibiting ovulation. Should ovulation occur, progestins reduce ovum motility in the fallopian tubes. Even if fertilization occurs, progestins thin the endometrium, reducing the chance of implantation. Progestins also thicken the cervical mucus, producing a barrier to sperm penetration. This method of contraception does not provide any protection from STDs.2,9

ImagesImages Women who may benefit from injectable progestins are those who are breast-feeding, those who are intolerant to estrogens (i.e., have a history of estrogen-related headache, breast tenderness, or nausea) or those with concomitant medical conditions in which estrogen is not recommended (Table 62-3). Additionally, injectable progestins are beneficial for women with adherence issues; they have lower failure rates than combined hormonal contraceptive methods (Table 62-1).2,9

Depo-Medroxyprogesterone Acetate Images Images Medroxyprogesterone acetate is similar in structure to naturally occurring progesterone. DMPA (Depo-Provera) is administered every 3 months either by deep intramuscular injection in the gluteal or deltoid muscle or subcutaneously in the abdomen or thigh within 5 days of onset of menstrual bleeding.29,30 With perfect use, the efficacy of DMPA is more than 99%; however, with typical use, 3% of women experience unintended pregnancy.2 Although these injections may inhibit ovulation for up to 14 weeks, the dose should be repeated every 3 months (12 weeks) to ensure continuous contraception. The manufacturer recommends excluding pregnancy in women with a lapse of 13 or more weeks between injections for the intramuscular formulation or 14 or more weeks between injections for the subcutaneous formulation. Depo-Provera is available as a 150 mg/mL injection vial or prefilled syringe for IM injection and Depo-SubQ Provera 104 is available as a prefilled syringe.29,30 Administration of both formulations of DMPA requires a medical office visit; however, pilot studies of patient self-administration of subcutaneous DMPA have demonstrated positive results.31

Although no adverse effects have been documented in infants exposed to DMPA through breast milk, the manufacturer recommends not initiating DMPA until 6 weeks postpartum in breast-feeding women.29,30 However, the CDC cites a lack of evidence supporting this claim and classifies DMPA use during this timeframe as a category 2 suggesting that the benefit may outweigh the theoretical risk.9Women who are not breast-feeding but require contraception can receive DMPA immediately postpartum.9,29,30 Women with sickle-cell disease are good candidates for DMPA, as studies have demonstrated a reduction in sickle cell pain crises in women using DMPA.9 In addition, women with seizure disorders may experience fewer seizures when taking DMPA for contraception, and there is not a concern with anticonvulsants reducing the contraceptive efficacy of DMPA.2,9 Because return of fertility may be delayed after discontinuation of DMPA, it should not be recommended to women desiring pregnancy in the near future. The median time to conception from the first omitted dose is 10 months. Sixty-eight percent of women will be able to conceive within 12 months, 83% within 15 months, and 93% within 18 months of the last injection.2,29,30

Images Menstrual irregularities are the most frequent adverse effects of both formulations of DMPA. Women who cannot tolerate prolonged bleeding may benefit from a short course of estrogen (e.g., 7 days of 2 mg estradiol or 1.25-mg conjugated estrogen given orally), but this will not help reduce the incidence in the long-term.2,10 The incidence of irregular bleeding decreases from 30% in the first year to 10% thereafter. After 12 months of therapy, 55% of women report amenorrhea, with the incidence increasing to 68% after 2 years.10,29,30

Other adverse effects, including breast tenderness and depression, occur less commonly. Weight gain is a concern for many women using DMPA, and the incidence and amount gained vary widely. It has been reported that weight gain averages 1 kg annually and may not resolve until 6 to 8 months after the last injection or patients gain 12 kg on average after using DMPA for 3 years.10,29,30

DMPA has been associated with short-term bone loss in younger women of reproductive age. This potential side effect may be due to lower ovarian estrogen production that occurs when gonadotropin secretion is suppressed.29,30,32 Because longitudinal studies demonstrated effects on BMD, the FDA issued a black box warning for DMPA in 2004.29,30 It states that DMPA should be continued for more than 2 years only if other contraceptive methods are inadequate. It also states that the loss of BMD seems to be greater with increasing duration of use and may not be completely reversible. However, the majority of clinicians view the effects of DMPA on BMD (which in the majority of cases is reversible) as a surrogate marker and there are no clear data that demonstrate the effects of DMPA on fracture risk.32,33 The ACOG and CDC continue to recommend that for most patients the benefits of DMPA outweigh the risks even when used beyond 2 years of use.9,32 ACOG does not recommend the routine screening of BMD in most patients.32 A discussion regarding the risks and benefits of this contraceptive option is recommended prior to initiation and with prolonged use.

Long-acting Reversible Contraception Long-acting reversible contraception (LARC) refers to a category of hormonal and non-hormonal contraceptives that include IUDs and implants. This type of contraception is highly efficacious in preventing pregnancy, but the effects are quickly reversible upon removal.34 LARC does not require effort or adherence by the patient once they are inserted. Therefore, both perfect-use and typical-use efficacy rates do not differ, and they are similar to surgical options such as tubal ligation (Table 62-1).2,34 When compared to other methods of hormonal contraception, especially OCs, LARC methods are not used as frequently in the United States.35All women should be considered potential candidates for this method. In the past, many clinicians offered LARC only when adherence was an issue or in women with contraindications to estrogen. However, with increasing education and ongoing studies, their use is slowly increasing, and many women are choosing them as their first-line contraceptive method.36 Due to the high efficacy rates of LARC methods, many advocates propose that increased use may decrease unintended pregnancy rates.1,34

Subdermal Progestin Implants ImagesImages Nexplanon (formerly called Implanon in the United States) is a single 4-cm-long implant, containing 68 mg of etonogestrel that is placed under the skin of the upper arm using a preloaded inserter.2,37 Clinicians must receive training from the manufacturer prior to insertion or removal of the device. Implanon releases etonogestrel at a rate of 60 mcg daily for the first month, then decreases to an average of 30 mcg daily at the end of the 3 years of recommended use. The primary mechanism of action is suppression of ovulation. When ovulation is not suppressed, etonogestrel still is effective as the progestin thickens the cervical mucus and produces an atrophic endometrium. With both perfect and typical use, the efficacy rate is over 99%.34,37 However, in overweight and obese women weighing more than 130% of their ideal body weight, there is a precaution from the manufacturer of the possibility of decreased efficacy especially over time.37

Images The etonogestrel implant should be inserted between days 1 and 5 of the menstrual cycle in women who have not previously used hormonal contraception.37 If it is inserted at any other time of the menstrual cycle, then it is recommended to use a barrier back-up method for 7 days. Women currently taking OCs can have the implant inserted within 7 days after taking the last active OC tablet. Women currently taking progestin-only OCs should have the implant inserted without skipping any days, on the same day that the progestin-only IUD is removed, or on the day that the DMPA injection is due. After removal, fertility returns within 30 days.

Images The major adverse effect associated with Nexplanon is irregular menstrual bleeding, which led to discontinuation of the implant in 11% of patients in clinical trials.34,37 Women should be counseled about the risk of irregular bleeding patterns so that patients will not request early removal of Nexplanon. Some women (22%) became amenorrheic with continued use, but many continued to have prolonged bleeding and spotting (18% and 34%, respectively) and frequent bleeding (7%). Insertion and removal complications are rare (less than 2%).34,37 Information from the manufacturer suggests using precaution when there is potential for drug interactions in the presence of potent CYP450 inducers (e.g., rifampin, phenytoin, carbamazepine).37 This information conflicts with CDC recommendations; those recommendations classify combining those medications with Implanon as a category 2, suggesting that the benefits typically outweigh the theoretical risks.9 Clinicians should counsel their patients about the benefits and risks if the there is a possibility of a drug interaction.

Intrauterine Devices ImagesImages There are currently three IUDs available, all are T-shaped and are medicated, one with copper (ParaGard) and two with levonorgestrel (Mirena and Skyla). Clinicians must receive training from the manufacturer prior to insertion or removal of the IUDs. These IUDs have several possible mechanisms of action including inhibition of sperm migration, damaging ovum or disrupting transport, and possibly damaging the fertilized ovum. Due to the presence of local progestin, the Mirena and Skyla IUDs have additional mechanisms of endometrial suppression and thickening cervical mucus. The most recent evidence regarding the mechanisms of action demonstrate that the contraceptive activity of IUDs occurs before implanatation.2,34 Efficacy rates with IUDs are greater than 99% with both perfect and typical use.2,34,38,39 IUDs should not be used in the presence of current pregnancy, current pelvic inflammatory disease, current STD, puerperal or postabortion sepsis, purulent cervicitis, undiagnosed abnormal vaginal bleeding, malignancy of genital tract, uterine anomalies or fibroids distorting uterine cavity, allergy to IUD component, or Wilson’s disease (for copper IUD).38,39 The risk of pelvic inflammatory disease among IUD users is low and ranges from 1% to 2.5%. Because the increased risk of infection appears to be related to introduction of bacteria into the genital tract during IUD insertion, the risk is highest during the first 20 days after the procedure.34,40

Images ParaGard is a highly effective IUD that can be left in place for 10 years.2,38 A disadvantage of ParaGard is increased menstrual blood flow and dysmenorrhea; average monthly blood loss among users increased by 35% in clinical trials. Mirena is the more recently approved IUD in the United States, and its use is increasing.35 It is also a highly effective IUD, and it can be left in place for 5 years.34,39 Mirena releases 20 mcg of levonorgestrel daily, but release decreases to 10 mcg daily over the 5 years of use.2,34 Skyla is the most recent IUD to be approved. It releases 14 mcg of levonorgestrel daily and can be left in place for 3 years.41 Systemically absorbed levonorgestrel is minimal and considerably less than with OCs. The levonorgestrel IUD produces its effects locally via suppression of the endometrium, causing a reduction in menstrual blood loss. In contrast to the copper IUD, menstrual flow in users of the levonorgestrel IUD is decreased, and development of amenorrhea has been observed in 20% of users in the first year and 60% in the fifth year. A disadvantage of the levonorgestrel IUD is increased spotting in the first 6 months of use; women should be counseled that the spotting will decline gradually over time.2,39

Due to the local effects on the endometrium and decrease in blood loss, Mirena has an additional indication for treatment of heavy menstrual bleeding (menorrhagia).34,42,43 Return to fertility is rapid and typically occurs within 30 days after removal of the IUD.34,39 Historically, use in nulliparous and adolescent women was considered a precaution to use of an IUD. However, recent evidence, clinical experience, and expert opinion do not preclude use in these populations. Risk versus benefits should be considered, and the woman must be counseled on the IUD.34,44 Strong consideration of an IUD is appropriate in this population due to high efficacy rates.44 In addition, Skyla does not include nulliparous women as a precaution and included about 40% of patients in this population in the clinical trials.41The influence of drug interactions on the efficacy of IUDs is not a primary concern based on manufacturer recommendations.39,43 In addition, the CDC classifies the potential drug interactions with potent CYP450 inducers as a category 2, determining that the benefits typically outweigh any of the theoretical risks.9


Clinical Controversy…

Ulipristal is a selective receptor modulator with mixed progesterone agonist and antagonist activities, and limited data on its mechanism of action are available in humans. Controversy exists because the chemical structure of ulipristal is similar to mifepristone, which given in higher doses is used for medical termination of pregnancy. Limited, small animal study models have demonstrated that ulipristal may inhibit implantation, but it does not terminate pregnancy. It is important to note that pregnancy is defined as the period from implantation to delivery, so prevention of implantation would be an additional contraceptive mechanism. Despite the controversy, there is no clear evidence in humans that ulipristal inhibits implantation or terminates a pregnancy, but clear evidence exist that it is a highly effective formulation of EC.

Emergency Contraception

Images EC is used to prevent unwanted pregnancy after unprotected or inadequately protected sexual intercourse (e.g., no contraception, condom breakage, OC nonadherence, sexual assault). Pregnancy occurs when the fertilized egg is implanted into the endometrial lining. After intercourse, implantation of the fertilized egg typically takes approximately 5 days.45 Progestin-only and progesterone receptor modulator products are approved by the FDA and recommended as first-line EC options.2,3,45 Insertion of the copper IUD or prescribing higher doses of combined OCs (containing estrogen and progestin) are other options but are not widely used.

Currently, the progestin-only formulation containing levonorgestrel (currently marketed as Plan B One-Step and Next Choice) is approved specifically for EC in the United States.46,47 Recent studies support that the primary mechanism of action of progestin-only EC is inhibiting or delaying ovulation. Additional evidence suggests it may impair sperm transport and corpus luteum function, therefore inhibiting fertilization. The most recent data do not support that it may prevent the fertilized egg from implanting into the endometrium.45,48,49 Oral EC will not disrupt the fertilized egg after implantation has occurred.45,48 The levonorgestrel-containing EC formulation is the regimen of choice due to availability, improved tolerability, and potentially increased efficacy rates. Next choice, a two-dose formulation, contains two tablets each containing 0.75 mg of levonorgestrel. The first dose is taken within 72 hours of unprotected intercourse (although the sooner, the more effective); the second dose is taken 12 hours later (the second dose taken 24 hours after the first dose is also efficacious).45,47 A one-dose formulation, Plan B One-Step, containing one tablet of 1.5 mg of levonorgestrel taken within 72 hours of unprotected intercourse is equally effective as the older two-dose formulation.45,46 Evidence does support that the levonorgestrel-containing EC products can be moderately effective in preventing pregnancy up to 120 hours after unprotected intercourse.45 Levonorgestrel-containing EC is now available without a prescription to women and girls of all ages in the United States.45

Images Ulipristal (Ella) is the newest EC product and was approved for use by the FDA in 2010.50 Ulipristal is a selective progesterone receptor modulator with mixed progesterone agonist and antagonist properties.5052 Its mechanism of action depends on the timing of administration relative to the woman’s menstrual cycle. The primary mechanism of action appears to delay ovulation. Ulipristal is available by prescription only and is available as a single dose of 30 mg taken within 120 hours after unprotected intercourse. Evidence supports that it maintains efficacy for the full 120-hour window.51,53 Data exist to support noninferiority of ulipristal compared to levonorgestrel-containing EC; additionally a meta-analysis concluded that pregnancy rates were significantly lower in women taking ulipristal compared to levonorgestrel-containing EC methods.54,55

Images Despite the availability of progestin-only and progesterone receptor modulator EC formulations, use of higher doses of regular combined OCs for EC (Yuzpe method) still is permissible, although studies suggest that they may not be as effective and may be associated with more adverse effects (especially nausea and vomiting).2,3,45 Patients should be counseled to take the appropriate number of tablets within 72 hours and as soon as possible after unprotected sexual intercourse and to repeat the dose in 12 hours. Taking all the tablets at once as a single dose is not recommended when using combination OCs.

Determining the exact effectiveness rate of EC is difficult; however, the range has been reported to be between 59% and 94%.45 Evidence reported that EC may prevent an average of 75% of expected pregnancies when taken appropriately. It is recommended that women have an advanced prescription on hand or access to an OTC formulation to maximize the effectiveness of EC.

Images Common adverse effects include nausea, vomiting, and irregular bleeding.45 Nausea and vomiting occur significantly less when progestin-only and progesterone receptor modulator EC is administered. If the Yuzpe method is prescribed, antiemetics given 1 hour before the dose is taken may be warranted to prevent the increased amount of estrogen-induced GI adverse effects. Many women will experience irregular bleeding regardless of which EC method is used, with the menstrual period usually occurring 1 week before or after the expected time. Routine screening prior to or after receiving progestin-only and progesterone receptor modulator EC is not recommended. If a pregnancy already exists, the EC will not disrupt or harm the embryo. Additionally, there are no contraindications to the use of these methods of EC (for the Yuzpe and copper IUD methods clinicians must adhere to their contraindications and precautions). No current data regarding the safety of repeated use EC are available, but current consensus suggests that the risks are low, and women can receive multiple regimens if warranted. Appropriate counseling should be provided regarding timing of the dose, common adverse effects, and use of a regular contraceptive method (backup barrier methods should be used after EC for at least 7 days).

Personalized Pharmacotherapy

Selecting a contraceptive method should involve the patient and clinician using a shared-decision making model. Contraceptive pharmacotherapy should be personalized for each patient, taking into account desired outcomes from a contraceptive and noncontraceptive perspective. Factors to consider include efficacy, presence of coexisting medical conditions or medications, safety, adverse effects, cost, and patient preference of the contraceptive method (e.g., long-acting, short-acting, hormonal, oral, nonoral, barrier).

EVALUATION OF THERAPEUTIC OUTCOMES

Images Patients should receive both verbal and written instructions on the chosen method of contraception. Followup appointments can increase adherence and provide opportunities to address other health maintenance issues. The contraceptive outcome of pregnancy prevention can be assessed when needed by obtaining a serum or urine pregnancy test.

Monitoring of the Pharmaceutical Care Plan

Contraceptive users should receive cytologic screening as well as annual pelvic and breast examination and a well-woman consultation for routine health maintenance screening and to assess for clinical problems or adverse effects related to contraception (Table 62-6). It is important to note that these annual screenings do not have to occur prior to prescribing hormonal contraception.

Annual blood pressure monitoring is recommended for all users of CHC. When a patient with a history of glucose intolerance or diabetes mellitus begins or discontinues the use of hormonal contraception, glucose levels must be monitored. Monitoring for the presence of adverse effects related to hormonal content or the presence of coexisting medical conditions is recommended for women using CHCs. Women using Implanon should be monitored annually for menstrual cycle disturbances, weight gain, local inflammation, or infection at the implant site, acne, breast tenderness, headaches, and hair loss. Women using DMPA should be asked at 3-month followup visits about weight gain, menstrual cycle disturbances, and fractures. Women using IUDs should be asked at 1- to 3-month follow-up visits about IUD placement (checking for IUD strings to assure the IUD is still in the proper position), changes in menstrual bleeding patterns, and symptoms and protection against STDs. Clinicians should check for proper IUD positioning and symptoms of upper genital tract infection.

Finally, clinicians should monitor and when indicated screen for HIV and STDs. All women should receive counseling about healthy sexual practices including the use of condoms to prevent the transmission of STDs when necessary.

ABBREVIATIONS

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REFERENCES

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