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These currently are available in forms that contain both estrogen and progestin or contain only progestin. Progestin-only injectables and pills are considered very effective, yet second-tier agents, due to the need for increased patient compliance. Similarly, products containing both estrogen and progestin, often termed combination hormonal contraception (CHC), are considered in this tier. These may be supplied as pills, transvaginal rings, or transdermal patches.
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Combination Hormonal Contraceptives Mechanism of Action
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The contraceptive actions of CHCs are multiple, but the most important effect is suppression of hypothalamic gonadotropin-releasing factors. This in turn blocks pituitary secretion of follicle-stimulating hormone (FSH) and LH to inhibit ovulation. The progestin component provides ovulation prevention by suppressing LH; they thicken cervical mucus and thereby retard sperm passage; and they render the endometrium unfavorable for implantation. Estrogen blocks ovulation by suppressing FSH release. It also stabilizes the endometrium, which prevents intermenstrual bleeding—also known as breakthrough bleeding. The net effect is an extremely effective yet highly reversible method (Mansour, 2011).
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Combination Oral Contraceptive Pills
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Combination oral contraceptive pills are the most frequently used birth control method in the United States. In a 2006 to 2010 survey, 17 percent of US women were using these (Jones, 2012). COCs are marketed in an almost bewildering variety (Table 38-4). Most are also available as generics, and the FDA (2013) confirms the bioequivalence of COC generics. The American College of Obstetricians and Gynecologists (2013b) supports the use of either branded or generic preparations.
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Pharmacologically, ethinyl estradiol is the most common estrogen present in COC formulations in the United States. Less frequently, mestranol or estradiol valerate is used. Unwanted effects most often attributed to the estrogen component include breast tenderness, fluid retention, weight gain, nausea, and headache.
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COCs also contain one of several progestins that are structurally related to progesterone, testosterone, or spironolactone. Thus, these progestins bind variably to progesterone, androgen, estrogen, glucocorticoid, and mineralocorticoid receptors. These affinities explain many pill-related side effects and are often used to compare one progestin with another.
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Most progestins used in COCs are related to testosterone and may impart androgenic side affects such as acne and adverse HDL and LDL levels. To avoid these effects, progestins more structurally similar to the progestone molecule have been developed. Medroxyprogesterone acetate is one example, but it is mainly used in a progestin-only injectable form. Another, nomegestrol acetate, is used in a COC approved outside the United States. Despite these pharmacological differences, the true advantage of one progestin over another is less apparent clinically (Lawrie, 2011; Moreau, 2007).
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Another progestin, drospirenone, is structurally similar to spironolactone. The doses used in currently marketed COCs have effects similar to 25 mg of this diuretic hormone (Seeger, 2007). Drospirenone displays antiandrogenic activity, provides an antialdosterone action to minimize water retention, and has antimineralocorticoid properties that may, in theory, cause potassium retention and hyperkalemia (Krattenmacher, 2000). Thus, it is avoided in women with renal or adrenal insufficiency or with hepatic dysfunction. Moreover, serum potassium level monitoring is recommended in the first month for patients chronically treated concomitantly with any drug associated with potassium retention. These include NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists, heparin, aldosterone antagonists, and potassium-sparing diuretics (Bayer HealthCare Pharmaceuticals, 2012).
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Since the development of COCs, their estrogen and progestin content has dropped remarkably to minimize adverse effects. Currently, the lowest acceptable dose is limited by the ability to prevent pregnancy and to avoid unacceptable breakthrough bleeding. Thus, the daily estrogen content varies from 10 to 50 μg of ethinyl estradiol, and most contain 35 μg or less.
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With COCs termed monophasic pills, the progestin dose remains constant throughout the cycle. In others, the dose frequently is varied, and terms biphasic, triphasic, or quadriphasic pill are used depending on the number of dose changes within the cycle. In some formulations, the estrogen dose also varies. In general, phasic pills were developed to reduce the total progestin content per cycle without sacrificing contraceptive efficacy or cycle control. The theoretical advantage of a lower total progesterone dose per cycle has not been borne out clinically (Moreau, 2007). Cycle control also appears to be comparable among mono- through triphasic pills (van Vliet, 2006, 2011a,b).
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Hormones are taken daily for a specified time (21 to 81 days) and then replaced by placebo for a specified time (4 to 7 days), which is called the “pill-free interval.” During these pill-free days, withdrawal bleeding is expected.
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With the trend to lower estrogen doses to minimize side effects, there is concern for follicular development and ovulation. To counter this, the active-pill duration in some formulations is extended to 24 days. And, these 24/4 regimens do appear to reduce ovulation and breakthrough bleeding rates (Fels, 2013).
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Alternatively, longer durations of active hormone, designed to minimize the number of withdrawal episodes, have been introduced (Edelman, 2006). These extended-cycle products produce a 13-week cycle, that is, 12 weeks of hormone use, followed by a week for withdrawal menses. The product Amethyst provides continuous active hormone pills for 365 days each year. Such extended or continuous regimens may be especially suited for women with significant menstrual symptoms.
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For general initiation, women should ideally begin COCs on the first day of a menstrual cycle. In such cases, a supplementary contraceptive method is unnecessary. With the more traditional “Sunday start,” women begin pills on the first Sunday that follows menses onset, and an additional method is needed for 1 week to prevent conception. If menses begin on a Sunday, then pills are begun that day and no supplementary method is required. Alternatively, with the “Quick Start” method, COCs are started on any day, commonly the day prescribed, regardless of cycle timing. An additional method is used during the first week. This latter approach improves short-term compliance (Westhoff, 2002, 2007b). If the woman is already pregnant during Quick Start initiation, COCs are not teratogenic (Lammer, 1986; Rothman, 1978; Savolainen, 1981). Similarly, same-day initiation can be implemented with the contraceptive vaginal ring or patch (Murthy, 2005; Schafer, 2006).
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For maximum efficiency, pills should be taken at the same time each day. If one dose is missed, contraception is likely not diminished with higher-dose monophasic COCs. Doubling the next dose will minimize breakthrough bleeding and maintain the pill schedule. If several doses are missed or if lower-dose pills are used, the pill may be stopped, and an effective barrier technique used until menses. The pill may then be restarted. Alternatively, a new pack can be started immediately following identification of missed pills, and a barrier method used for 1 week. If there is no withdrawal bleeding, the woman should continue her pills but seek attention to exclude pregnancy.
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With initiation of COCs, spotting or bleeding is common. It does not reflect contraceptive failure and typically resolves within one to three cycles. If unscheduled bleeding persists, those with bleeding during the first part of a pill pack may benefit from an increase in the pill’s estrogen dose, whereas those with bleeding during the second part may improve with a higher progestin dose (Nelson, 2011).
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Method-Specific Effects
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Altered Drug Efficacy
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Combination oral contraceptives interfere with the actions of some drugs. In such cases, doses can be adjusted as shown in Table 38-5. Conversely, some drugs decrease the COC effectiveness. Three groups are notable: the antitubercular drugs rifampin and rifabutin; efavirenz and ritonavir-boosted protease inhibitors, which are used to treat HIV infection; and enzyme-inducing anticonvulsants, which include phenytoin (Dilantin), carbamazepine (Tegretol), oxcarbazepine (Trileptal), barbiturates, primidone (Mysoline), and topiramate (Topamax) (Gaffield, 2011; Panel on Antiretroviral Guidelines for Adults and Adolescents, 2013). With these, a method other than COCs is preferable. However, if a COC is selected for concurrent use with an agent from these three groups, then a preparation containing a minimum of 30 μg ethinyl estradiol should be chosen.
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In obese women, COCs are highly effective (Lopez, 2010). That said, some but not all studies point to a potential increased pregnancy risk with COC use due to lowered hormone bioavailability (Brunner, 2005; Holt, 2002, 2005; Westhoff, 2010). With the transdermal patch method, however, there is stronger evidence that obesity may alter pharmacokinetics and lower efficacy (Insertion of the Mirena intrauterine system. Initially, threads from behind the slider are first released to hang freely. The slider found on the handle should be positioned at the top of the handle nearest the device. The IUD arms are oriented horizontally. A flange on the outside of the inserter tube is positioned from the IUD tip to reflect the depth found with uterine sounding).
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Although their effects on carbohydrate metabolism are considered clinically insignificant, COCs do have notable effects on lipid and protein synthesis. In general, COCs increase serum levels of triglycerides and total cholesterol. Estrogen decreases LDL cholesterol concentrations but increases HDL and very-low density (VLDL) cholesterol levels. Some progestins cause the reverse. Despite this, the clinical consequences of these perturbations have almost certainly been overstated. Oral contraceptives are not atherogenic, and their impact on lipids is inconsequential for most women (Wallach, 2000). But in women with dyslipidemias, the American College of Obstetricians and Gynecologists (2013e) recommends assessment of lipid levels following COC initiation. Moreover, for women with LDL cholesterol levels > 160 mg/dL or for those with multiple additional risk factors for cardiovascular disease, alternative contraceptive methods are recommended.
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With COCs, protein metabolism is affected, and estrogens prompt increased hepatic production of various globulins. First, fibrinogen and many of the clotting factor levels are increased in direct proportion to estrogen dose and may lead to thrombosis (Comp, 1996). Angiotensinogen production is also augmented by COCs, and its conversion by renin to angiotensin I may be associated with “pill-induced hypertension” discussed subsequently. Last, COCs increase sex-hormone binding globulin (SHBG) levels, which decrease bioavailable testosterone concentrations and improve androgenic side effects.
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Regarding carbohydrate metabolism, there are fortunately limited effects with current low-dose formulations in women who do not have diabetes (Lopez, 2012a). And, the risk of developing diabetes is not increased (Kim, 2002). Moreover, COCs may be used in nonsmoking, diabetic women younger than 35 years who have no associated vascular disease (American College of Obstetricians and Gynecologists, 2013e). Last, studies have not supported a connection between COCs and weight gain (Gallo, 2011).
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Other metabolic changes, often qualitatively similar to those of pregnancy, have been identified in women taking oral contraceptives. For example, total plasma thyroxine (T4) and thyroid-binding proteins are elevated. These pregnancy-like effects should be considered when evaluating laboratory tests in women using COCs.
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Cardiovascular Effects
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Despite increased plasma angiotensinogen (renin substrate) levels, most women using low-dose COCs formulations rarely develop clinically significant hypertension (Chasan-Taber, 1996). However, it is common practice for patients to return 8 to 12 weeks after COC initiation for evaluation of blood pressure and other symptoms.
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During initial contraception selection, a history of gestational hypertension does not preclude subsequent COC use. Also, COCs are permissible in women with well-controlled uncomplicated hypertension who are nonsmokers, otherwise healthy, and younger than 35 (American College of Obstetricians and Gynecologists, 2013e). In contrast, severe forms of hypertension, especially those with end-organ involvement, usually preclude COC use.
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For women with prior stroke, COCs should not be considered due to risks for repeat events. The risk for a first stroke is substantially increased in women who have hypertension, who smoke, or who have migraine headaches with visual aura or other focal neurological changes and use oral contraceptives (MacClellan, 2007). However, for nonsmoking women younger than 35, the risk of ischemic and hemorrhagic strokes is extremely low, and method benefits considerably outweigh risks (World Health Organization, 1996, 1998). Moreover, because of this low risk, the American College of Obstetricians and Gynecologists (2013e) notes that COCs may be considered for women with migraines that lack focal neurological signs if they are otherwise healthy, normotensive nonsmokers younger than 35 years.
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For women with prior myocardial infarction, COCs should not be considered. Also, in women with multiple cardiovascular risk factors, which include smoking, hypertension, older age, and diabetes, the risk for myocardial infarction outweighs the benefits of this method. However, for those without these risks, low-dose oral contraceptives are not associated with an increased risk of myocardial infarction (Margolis, 2007; World Health Organization, 1997).
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It has long been known that the risk of deep-vein thrombosis and pulmonary embolism is increased in women who use COCs (Stadel, 1981). These clearly are estrogen-dose related, and rates have substantively decreased with lower-dose formulations containing 10 to 35 μg of ethinyl estradiol. The incidence of venous thromboembolism (VTE) with COC use is only 3 to 4 per 10,000 woman-years and is lower than the incidence of 5 to 6 per 10,000 woman-years estimated for pregnancy (Chap. 52, Pathophysiology) (Mishell, 2000). The enhanced risk of VTE appears to decrease rapidly once COCs are stopped. And because these complications are increased in women smokers older than 35 years, COCs are not recommended for this population (Croft, 1989).
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Those most at risk for VTE include women with thrombophilias (Comp, 1996). Other clinical factors that increase the risk of VTE with COC use are hypertension, obesity, diabetes, smoking, and a sedentary lifestyle (Pomp, 2007, 2008). Moreover, COC use during the month before a major operative procedure appears to double the risk for postoperative VTE (Robinson, 1991). Thus, the American College of Obstetricians and Gynecologists (2013d) recommends balancing the risks of VTE with those of unintended pregnancy during the 4 to 6 weeks required to reverse the thrombogenic effects of COCs before surgery. In the early puerperium, VTE risks are also increased, and COCs are not recommended for women within the first 4 weeks after delivery. For all women, an increased VTE risk with drospirenone-containing COCs has been shown in two studies. Accordingly, the FDA has encouraged an assessment of benefits and VTE risks in users of these pills (Food and Drug Administration, 2011; Jick, 2011; Parkin, 2011).
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Fortunately, most studies indicate that overall, COCs are not associated with an increased risk of cancer (Hannaford, 2007). In fact, a protective effect against ovarian and endometrial cancer has been shown (Collaborative Group on Epidemiological Studies of Ovarian Cancer, 2008; Tsilidis, 2011). Protection from these cancers decreases, however, as time from pill use lengthens (Tworoger, 2007). In contrast, the relative risk of cervical dysplasia and cervical cancer is increased in current COC users, but this declines after use is discontinued. Following 10 or more years, risk returns to that of never users (International Collaboration of Epidemiological Studies of Cervical Cancer, 2007).
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Although COC use in the past was linked to development of hepatic focal nodular hyperplasia and benign hepatic adenoma, large studies do not support this (Heinemann, 1998). Moreover, there is also no evidence for increased risk of hepatocellular cancer (Maheshwari, 2007). For women with known tumors, COCs may be used in those with focal nodular hyperplasia, but avoided in those with benign hepatic adenoma and hepatocellular carcinoma (Kapp, 2009b). Rates of colorectal cancer appear to be reduced in ever users (Bosetti, 2009; Kabat, 2008).
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It is unclear whether COCs contribute to the development of breast cancer, and major studies show no risk or a small risk among current users, which drops with time following cessation (Collaborative Group on Hormonal Factors in Breast Cancer, 1996; Marchbanks, 2002). In women who are carriers of the BRCA1 or BRCA2 gene mutation, risks for breast cancer are not increased by COC use (Brohet, 2007; Iodice, 2010). With regard to benign breast disease, COCs appear to lower rates (Vessey, 2007).
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As summarized in Table 38-6, many noncontraceptive benefits are associated with COC use (American College of Obstetricians and Gynecologists, 2012c). And indeed, COCs may be used for these effects, even in those without contraceptive needs.
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Low-dose estrogen formulations are not associated with depression or premenstrual mood changes and may actually improve the latter (Joffe, 2007). This is especially true with the drospirenone-containing COCs. Several studies have shown symptom improvement in women with premenstrual dysphoric disorder (PMDD) who use the drospirenone-containing COC Yaz (Lopez, 2012b; Pearlstein, 2005; Yonkers, 2005). And, the FDA has approved indications for this pill to include treatment of PMDD and moderate acne vulgaris for women requesting oral contraception.
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Cholestasis and cholestatic jaundice are uncommon, but they resolve when COCs are discontinued. For women who have active hepatitis, COCs should not be initiated, but these may be continued in women who experience a flare of their liver disease while already taking COCs. Use of progestin-only contraception in these women is not restricted. Moreover, there is no reason to withhold COCs from women who have recovered. With cirrhosis, mild compensated disease does not limit the use of COCs or progestin-only methods. However, in those with severe decompensated disease, all hormonal methods should be avoided (Kapp, 2009a).
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The progestin component of COCs reduces serum free testosterone levels and inhibits 5α-reductase to limit conversion of testosterone to its active metabolite, dihydrotestosterone. The estrogen component increases SHBG production and also lowers circulating androgen levels. The expected results of these actions are to improve androgenic conditions such as acne and hirsutism.
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Hyperpigmentation of the face and forehead—chloasma—is more likely in women who demonstrated such a change during pregnancy. This is less common with low-dose estrogen formulations. Cervical mucorrhea, likely due to cervical ectopy, is common in response to the estrogen component of COCs (Critchlow, 1995). Although previously used for treating functional ovarian cysts, low-dose COC formulations have no effects related to cyst resolution or prevention (European Society of Human Reproduction and Embryology, 2001; Grimes, 2011).
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The Ortho Evra patch is another combination hormonal contraceptive formulation. It has an inner layer containing an adhesive and hormone matrix, and a water-resistant outer layer. Thus, women can wear the patch in bathtubs, showers, swimming pools, saunas, and whirlpools without decreased efficacy. The patch may be applied to buttocks, upper outer arm, lower abdomen, or upper torso, but the breasts are avoided. Because the hormones are combined with the adhesive, improper skin adherence will lower hormone absorption and efficacy. Therefore, if a patch is so poorly adhered that it requires reinforcement with tape, it should be replaced.
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Initiation of the patch is the same as for COCs, and a new patch is applied weekly for 3 weeks, followed by a patch-free week to allow withdrawal bleeding. Although a patch is ideally worn no longer than 7 days, hormone levels remain in an effective range for up to 9 days. This affords a 2-day window for patch change delays (Abrams, 2001).
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In general, the transdermal patch and vaginal ring produce metabolic changes, side effects, and efficacy rates comparable to those with COC pills. However, the patch has been associated with a higher VTE risk in some but not other studies (Cole, 2007; Jick, 2010; Lidegaard, 2012). And despite this lack of convincing association, the FDA (2008) ordered labeling for the patch to state that users may be at increased risk for developing VTE. Obesity—90 kg or greater—may be associated with an increased risk for patch contraceptive failure (Zieman, 2002). Last, application-site reaction and breast tenderness are more frequent during initial cycles in patch wearers (Urdl, 2005).
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The NuvaRing is yet another form of combination hormonal contraception and is a flexible intravaginal ring. Constructed of ethinyl vinyl acetate, the ring measures 54 mm in diameter and 4 mm in cross section (Fig. 38-5). During insertion, the ring is compressed and threaded into the vagina, but no specific final intravaginal position is required. Its core releases ethinyl estradiol and the progestin etonogestrel, which are absorbed across the vaginal epithelium. Before being dispensed, the rings are refrigerated, and once dispensed, their shelf life is 4 months. The ring is placed within 5 days of menses onset and after 3 weeks of use, is removed for 1 week to allow withdrawal bleeding. Contraception will still be afforded if a ring is left in place for a fourth week (Merck, 2012b).
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Patient satisfaction is high with this method, although vaginitis, ring-related events, and leukorrhea are more common (Oddsson, 2005). Despite this, no deleterious affect on vaginal flora or on lower reproductive-tract or endometrial epithelia has been found (Bulten, 2005; Veres, 2004). Approximately 70 percent of partners feel the ring during intercourse (Dieben, 2002). If this is bothersome, the ring may be removed for intercourse but should be replaced within 3 hours to maintain efficacy.
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Injectable Progestin Contraceptives
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Both intramuscular depot medroxyprogesterone acetate (Depo-Provera), 150 mg every 3 months, and norethisterone enanthate, 200 mg every 2 months, are injectable progestin contraceptives that have been effectively used worldwide for years. Available in the United States, DMPA is injected into the deltoid or gluteus muscle, but massage is avoided to ensure that the drug is released slowly. Alternatively, a subcutaneous version, depo-subQ provera 104, is also available and is injected into the subcutaneous tissue of the anterior thigh or abdomen every 3 months.
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DMPA is an effective method, and as with other progestin-only methods, contraception is provided by ovulation inhibition, increased cervical mucus viscosity, and creation of an endometrium unfavorable for ovum implantation. Initial injection is given within the first 5 days following menses onset. Therapeutic serum levels sufficient to exert a consistent contraceptive effect are observed by 24 hours. Thus, no additional contraceptive method is required with initiation within this window. Alternatively, limited data support a “Quick Start” or initiation of DMPA regardless of cycle day. If so implemented, investigators recommend an initial negative pregnancy test result before injection, a supplemental contraceptive method during the 7 days following injection, and a second pregnancy test after 3 to 6 weeks to identify an early pregnancy (Rickert, 2007; Sneed, 2005). Fortunately, pregnancies conceived during DMPA use are not associated with an increased risk of fetal malformation (Katz, 1985). For women who present for intramuscular DMPA reinjection more than 13 weeks or subcutaneous DMPA reinjection more than 14 weeks after the prior dose, the manufacturer recommends exclusion of pregnancy before reinjection (Pfizer, 2010, 2012).
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Actions and Side Effects
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Injected progestins offer the convenience of a 3-month dosing schedule, contraceptive effectiveness comparable with or better than COCs, and minimal to no lactation impairment. Iron deficiency anemia is less likely in long-term users because of amenorrhea, which develops in up to 50 percent after 1 year and in 80 percent after 5 years.
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Similar to other progestin-only contraceptive, irregular menstrual bleeding is common, and a fourth of women discontinued DMPA in the first year because of this (Cromer, 1994). Unique to DMPA, prolonged anovulation can follow discontinuation, which results in delayed fertility resumption. After injections are stopped, one fourth of patients do not resume regular menses for up to 1 year (Gardner, 1970). Accordingly, DMPA may not be ideal for women who plan to use birth control only briefly before attempting conception.
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As with other progestins, DMPA has not been associated with cardiovascular events or stroke in otherwise healthy women. However, in those with severe hypertension, an increased risk of stroke has been found in DMPA users (World Health Organization, 1998). Moreover, the US MEC expresses concerns regarding hypoestrogenic effects and reduced HDL levels from DMPA in women with vascular disease or multiple risks for cardiovascular disease.
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Weight gain is generally attributed to DMPA, and these increases are comparable between the two depot forms (Bahamondes, 2001; Nault, 2013; Westhoff, 2007c). In long-term users, loss of bone mineral density is also a potential problem (Petitti, 2000; Scholes, 1999). In 2004, the FDA added a black box warning to DMPA labeling, which notes that this concern is probably most relevant for adolescents, who are building bone mass, and perimenopausal women, who will soon have increased bone loss during menopause. That said, it is the opinion of the World Health Organization (1998) and American College of Obstetricians and Gynecologists (2008) that DMPA should not be restricted in those high-risk groups. And, it seems prudent to reevaluate overall risks and benefits during extended use (d’Arcangues, 2006).
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It is somewhat reassuring that bone loss appears to be reversible after discontinuation of therapy but is still not complete after 18 to 24 months (Clark, 2006; Gai, 2011; Scholes, 2002).
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So-called mini-pills are progestin-only contraceptives that are taken daily. These contraceptives have not achieved widespread popularity and are used by only 0.4 percent of American women (Hall, 2012). Unlike COCs, they do not reliably inhibit ovulation. Rather, their effectiveness depends more on cervical mucus thickening and endometrial atrophy. Because mucus changes are not sustained longer than 24 hours, mini-pills should be taken at the same time every day to be maximally effective. If a progestin-only pill is taken even 4 hours late, a supplemental form of contraception must be used for the next 48 hours. Progestin-only pills are contraindicated in women with known breast cancer or pregnancy. Other cautions are listed in Table 38-3.