CLINICAL OPINION Beyond the pill: New data and options in hormonal and intrauterine contraception Andrew M. Kaunitz, MD Department of Obstetrics and Gynecology, University of Florida Health Science Center/Jacksonville, Jacksonville, Fla Received for publication September 23, 2004; revised December 2, 2004; accepted December 28, 2004 KEY WORDS Contraceptives Intrauterine device With the goal of helping clinicians facilitate contraceptive success for their patients, this Clinical Opinion provides an update regarding older hormonal and intrauterine contraceptives and details newer methods that include the progestin-releasing intrauterine system, the contraceptive patch and ring, and extended and emergency oral contraception. Last, I will look over the horizon and briefly describe potential future methods that include the single rod progestin-releasing implant, folic acid–supplemented oral contraceptives, and hormonal contraception for men. 2005 Elsevier Inc. All rights reserved. Each year, nearly 2% of women of reproductive age in the United States have an induced abortion. 1 This sobering statistic reminds obstetrician-gynecologists that too often, our patients at risk for unintended pregnancy either fail to use effective birth control, or use effective methods incorrectly. Developed over 4 decades ago and represented among the best-studied medications we prescribe, oral contraceptives (OCs), as of 2003, continue to be the reversible contraceptive most used by US women. 2 OC use is safe for most potential users, and its use is associated with numerous noncontraceptive benefits (Table I). Although OCs represent a highly effective birth control method for correct consistent users, 3 inconsistent or incorrect use accounts for the surprisingly high annual failure rate of 8% in typical users. 4 This high failure rate underscores the clinical value of hormonal and intrauterine contraceptives that do not require the user’s daily attention. Although the ‘‘pill’’ is not new, new approaches to starting and taking OC tablets are being developed. When we give patients the first OC prescription, some of the patients will not start their first pack of pills after the onset of their next menses. Investigators have assessed a ‘‘quick start’’ approach to OC initiation that involves immediate in-office ingestion of the first OC tablet after a negative pregnancy test, regardless of the status of the patient’s menstrual cycle. A pilot study suggests that this unconventional approach to OC initiation is safe and results in higher ultimate rates of OC use than conventional ‘‘wait until your next period’’ pill initiation strategies. 5 Approved in 2003, monophasic ethinyl estradiol/ levonorgestrel (Seasonale, Barr Laboratories, Pomona, NY) represents a formulation that extends conventional OC use from 3 weeks (21 tablets) of hormonally active tablets followed by 1 placebo week to 12 weeks (84 tablets) followed by 1 week off. 6 Women who are interested in this ‘‘4 periods a year’’ approach to OCs must be aware that initial breakthrough spotting is considerably more common than with conventionallyReprints not available from the author. 0002-9378/$ - see front matter 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.12.091 American Journal of Obstetrics and Gynecology (2005) 192, 998–1004 www.ajog.org
scheduled pills; however, over time, unscheduled spotting declines substantially. Injectable contraception Approved for contraceptive use in 1992, depot medroxyprogesterone acetate (DMPA; Depo-Provera IM) contraceptive injections provide reversible long-acting birth control that is as effective as sterilization. The most recent national survey data indicates that DMPA is used currently as the primary contraceptive by 4% of US reproductive age women. 2 In the 12 years since it was introduced, growing use of DMPA is responsible, to a large degree, for the declining rates of unintended pregnancies and abortions among US women, particularly teens. 7 With O3 decades of experience with use abroad, an extensive and reassuring safety track record has accumulated with the use of DMPA. 8 In addition, the use of DMPA is associated with an impressive array of noncontraceptive health benefits (Table II). Nonetheless, concerns that the use of DMPA causes weight gain and an increased future risk of osteoporotic fractures continue to make some women reluctant to use this highly effective birth control method. Given the growing epidemic of obesity in the United States, it is no surprise that users frequently cite weight gain as a reason for quitting the use of hormonal contraception. In contrast with popular perception, however, randomized clinical trial data confirm that OC use does not cause weight gain. 9 Likewise, evidence that suggests that DMPA causes weight gain comes from observational studies. 8 The only randomized clinical trial to address this issue found that DMPA impacted neither appetite nor weight in short-term users. 8 Certain ethnic groups (including black and Navaho women) and women with high baseline body mass index may be predisposed to weight gain with use of DMPA. 8 Given the increasing prevalence of obesity in US women, counseling regarding diet, exercise, and weight is appropriate for all contraceptive candidates. Because the use of DMPA suppresses ovarian estradiol production, bone mineral density (BMD) declines during the use of DMPA. Fortunately, BMD is regained rapidly after the discontinuation of DMPA, and studies of BMD in former users demonstrate no deficit compareTable I Noncontraceptive health benefits of combination OCs* Established benefit Reduced risk/effective treatment maintained with current low estrogen-dose formulations Endometrial cancer Ovarian cancer Dysmenorrhea and menorrhagia Iron deficiency anemia Ectopic pregnancy Benign breast conditions Pelvic inflammatory disease Acne Reduced risk/effective treatment attenuated with current low estrogen-dose formulations Functional ovarian cysts Emerging benefit Growing body of evidence that supports reduced risk/effective treatment Benign ovarian tumors (particularly endometrioma) Colorectal cancer Dysfunctional uterine bleeding Osteopenia and postmenopausal osteoporotic fractures Perimenopausal vasomotor symptoms Preliminary evidence that suggests reduced risk/ effective treatment Premenstrual syndrome/ premenstrual dysphoric disorder Bacterial vaginosis 32 * The FDA has approved 2 OCs specifically for the treatment of acne: triphasic norgestimate (35 mg ethinyl estradiol [Ortho TriCyclen]) and norethindrone acetate (20, 30, and 35 mg ethinyl estradiol [Estrostep]). The use of OCs for any of the other indications listed constitutes off-label use that is not approved by the FDA. 31 Table II Noncontraceptive health benefits of depot-medroxyprogesterone acetate (DMPA) 10,* Use of DMPA decreases risk Endometrial cancer Iron deficiency anemia Pelvic inflammatory disease Ectopic pregnancy Uterine leiomyomata Use of DMPA may improve Menorrhagia/dysmenorrhea Premenstrual syndrome symptoms Pain in women with endometriosis Seizures refractory to conventional anticonvulsants Hemoglobinopathy Endometrial hyperplasia Vasomotor symptoms in menopausal women Pelvic pain/dyspareunia of ovarian origin after hysterectomy Metastatic breast cancer Metastatic endometrial cancery * Use of DMPA for indications other than contraception or endometrial cancer constitutes off-label use that is not approved by the FDA. y Approved indication for DMPA injectable suspension that contains 400 mg/mL of medroxyprogesterone acetate. Kaunitz 999 with women who have never used DMPA. 8 The reversible decline in BMD that occurs with DMPA use appears to mirror transient BMD changes that occur during another hypoestrogenic state, lactation. 10 Neither DMPA use nor lactation has been linked to osteoporotic fractures. Concerns regarding BMD should not prevent obstetrician-gynecologists from prescribing this highly effective method of birth control. Recommending adequate calcium intake is appropriate for all reproductive age women, including DMPA users. The current DMPA formulation is (150 mg/mL), which is delivered intramuscularly each 3 months. Subcutaneous administration is more patient-friendly than intramuscularly and would facilitate access to injectable contraception. A new subcutaneous formulation (104 mg/0.65 mL), which is also administered each 3 months, has been developed 11 and may become available, pending regulatory approval. Since 2000, 3 estrogen-progestin combination hormonal contraceptive methods and 1 intrauterine contraceptive have been introduced in the United States (Table III). Longer-acting combination estrogen-progestin contraceptives In 2000, medroxyprogesterone, estradiol, and sodium chloride (Lunelle, Pfizer, Inc, Morris Plains, NJ), a highly effective monthly injectable estrogen-progestin contraceptive was first marketed in the United States. In contrast with DMPA, use is associated with regular bleeding episodes and rapid return to fertility. 12 Unfortunately, in 2003 the manufacturer elected to discontinue availability of this effective contraceptive option. In 2002, a 1-week transdermal contraceptive patch (Ortho Evra, Ortho-McNeil Pharmaceuticals, Raritan, NJ) became available in the United States and currently is used by 2% of US women. 2 Patches are applied for 3 weeks; subsequently, withdrawal bleeding is anticipated during a patch-free week. In a randomized clinical trial, the contraceptive efficacy of the patch was comparable to that of oral contraception. 13 However, in efficacy trials of the patch, the participants who were !20 years of age were noted to be more likely to use the patch correctly than the pill, 14 which underscores the potential for longer-acting methods to achieve lower typical failure rates in clinical practice than OCs. Also introduced to the United States in 2002, the contraceptive vaginal ring (NuvaRing, Organon USA, Inc, Roseland, NJ) is used currently by 0.3% of US women of reproductive age. 2 The ring is worn for 3 weeks; subsequently, withdrawal bleeding is anticipated during a ring-free week. In comparative clinical trials, rates of breakthrough bleeding and spotting were lower with the ring than with OCs. 15 More than three quarters of the users indicate that they do not note discomfort related to the ring in general or during sexual relations. 16 Use of hormonal contraception and risk of breast cancer Since the July 2002 publication of findings from the Women’s Health Initiative, which found an increased breast cancer risk with the use of menopausal combination hormone therapy, 17 concerns that the use of combination hormonal contraception might also increase this risk have been heightened. Many physicians and patients are not aware of the Women’s CARE study, a large Centers for Disease Control and National Institutes of Health–sponsored study of breast cancer risk that was associated with use of hormonal contraceptives. Initial findings, which were published in August 2002, indicated that, regardless of length of OC use and age during use or user family history, use of OC was not associated with an elevated breast cancer risk. 18 A more recent publication from this same study found that the use of neither DMPA nor progestin-only implants is linked with an increase breast cancer risk. 19 Intrauterine contraception Widely used worldwide, intrauterine devices (IUDs) offer women convenient, reversible birth control that is as effective as surgical sterilization. In the mid 1970s, IUDs accounted for nearly 10% of birth control methods use by women in the United States 20; today, however, only 1% of our patients use IUDs. 2 Concerns among clinicians and women that IUDs cause salpingitis Table III Longer-acting methods of contraception introduced in the United States since 2000 Type Duration of use Typical failure rate during first year of use (%) 4 Mirena (levonorgestrel-releasing intrauterine system) 5 Y 0.1 Lunelle (medroxyprogesteroneacetate/estradiol cypionate) injection* 1Mo 3 Ortho Evra (norelgestromin/ethinyl estradiol transdermal contraceptive system) 1 Wk 8 NuvaRing (etonogestrel/ethinyl estradiol vaginal ring) 3 Wk 8 * Not available in the United States since 2003. 000 Kaunitz
and tubal infertility, which were heightened because of morbidity and litigation that was associated with the flawed Dalkon Shield IUD, account for much of this decline. A high-quality systematic review found that, if any increase risk in salpingitis is associated with IUD use, the risk is small and appears confined to the first month after insertion. 21 Likewise, the use of an IUD is not associated with a subsequent increased risk of tubal infertility. 21,22 Two IUDs are marketed currently in the United States. The copper IUD (Paragard), which was introduced in 1988 and approved for up to 10 years of use, is appropriate for women who prefer regular cycles. Because the use of the copper IUD can increase flow and cramps, it is appropriate for women who have no excess menstrual flow or cramps at baseline. The levonorgestrel -releasing IUD (Mirena), which was introduced in 2000 and approved for up to 5 years of use, reduces menstrual flow and is therefore appropriate for women who would like their birth control method to reduce flow. However, women who are interested in using the levonorgestrel-releasing IUD should be aware of that initial irregular spotting or bleeding is common after the insertion of this device. Hormonal side effects, which include acne and ovarian cysts, also occur in some users. Noncontraceptive benefits that are associated with the use of the levonorgestrel IUD are detailed in Table IV. Almost one quarter of female obstetrician-gynecologists in the United States report personal use of IUDs (Figure), which underscores that, among women who understand the benefits and risks and have access to IUDs, many women will choose to use intrauterine contraception. Emergency contraception The use of emergency (postcoital) contraception (EC) is estimated to have averted O51,000 induced abortions in 2000. 1 With the manufacturer no longer making a dedicated combination EC formulation (Preven) as of summer 2004, the only dedicated EC formulation currently available is the progestin-only formulation (Plan B), which consists of 2 levonorgestrel 0.75 mg tablets. Progestin-only EC is more effective and causes less nausea and emesis than combination EC. 23 Package labeling for Plan B indicates 1 tablet should be taken within 72 hours of unprotected intercourse, followed 12 hours later by a second tablet. However, taking the 2 tablets together may be as effective in preventing pregnancy as dividing the dose. 23 Furthermore, Plan B may retain its efficacy in pregnancy prevention when Figure Contraceptive use by female ACOG Fellows. (From American College of Obstetricians and Gynecologists. ACOG unveils survey of women ob-gyns at media briefing. ACOG Today 2004;48:1,6. With permission.) Kaunitz 1001
taken up to 5 days after unprotected intercourse. 23 In December 2003 the Food and Drug Administration’s (FDAs) Reproductive Health Advisory Committee recommended over-the-counter access for Plan B. Unfortunately, in what some have called a politically motivated decision, the FDA indicated that concerns regarding the safety of EC in users who are !16 years of age prevented designation of over-the-counter status. 24 Because over-the-counter availability of EC holds great potential for the reduction of unintended pregnancies and induced abortions, it is hoped that on-going negotiations between the manufacturer and the FDA will result in some degree of over-the-counter access. Contraception for women with medical problems For most medical conditions, pregnancy is associated with more risks than the use of contraception. Nonetheless, in the presence of certain situations (eg, immediately after delivery) or medical conditions, contraceptives that do not contain estrogen may be the safest option (Table V). More detailed information that is useful for helping women with medical conditions to choose appropriate contraceptive methods is available from the American College of Obstetricians and Gynecologists 25 and the World Health Organization. 26 Future contraceptives Progestin-releasing contraceptive implants provide highly effective, convenient birth control. Although 2 highly effective contraceptive implant systems (the 6 rod Norplant and the 2 rod Jadelle levonorgestrel systems) are FDA approved, neither system is currently marketed. Difficulty with insertion and, in particular, removal of the 6 capsules in the Norplant levonorgestrel implant system along with frequent complaints of irregular bleeding among users to a large degree explains the reason that US manufacturers and clinicians lost interest in this contraceptive system, which initially was in great demand when introduced in 1991. A single rod implant (Implanon), which releases 60 mg of etonogestrel (the progestin released by NuvaRing) each day, addresses concerns that are associated with the Norplant system. It is easier and quicker to insert and remove than Norplant, and its use is associated with less bleeding. 27 The manufacturer has submitted a New Drug Application to the FDA; hopefully, Implanon will become available to our patients in 2005. Despite increasing awareness that maternal food fortification and dietary supplementation with folic acid reduces the risk of neural tube defects in offspring, US women of reproductive age continue to have an inadequate intake of folic acid. More than 1 million pregnancies may occur annually in US women who use OCs. 28 Given these 2 observations, a major manufacturer of OCs approached the FDA regarding the concept of developing an OC formulation that is supplemented with folic acid. Because of its potential to reduce neural tube defects, the FDA’s Reproductive Health Drugs Advisory Committee unanimously supported this concept in December 2003. 29 Hopefully, an OC–folic acid formulation will become available by the end of this decade. Although condoms and vasectomy represent important available birth control methods, many clinicians and patients await the development of an effective, reversible hormonal contraceptive for men. Progestins, through their impact on the hypothalamus, suppress spermatogenesis and testosterone production. Combination approaches that use progestin implants with long-acting ‘‘add-back’’ testosterone injections have the potential to induce azospermia without causing hypogonadal side effects in men. One particularly promising male contraceptive combines etonogestrel implants with intramuscular testosterone undecanoate injections. 30 Table V Indications for methods other than combined (estrogen-progestin) hormonal contraception 25 In women with the following conditions, the use of progestinonly pills, DMPA, or a copper or levonorgestrel-releasing IUD may be safer then combination hormonal contraception: Age O35 y and smoke cigarettes Migraine headaches with vascular risk factors, vascular disease, or age O35 y History of thromboembolic disease Coronary artery disease Cerebrovascular disease Chronic liver disease !2 weeks after delivery* Hypertension with vascular disease or age O35 y Diabetes mellitus with vascular disease or age O35 y Systemic lupus erythematosus with vascular disease, nephritis, or antiphospholipid antibodies Hypertriglyceridemia * IUD insertion appropriate once uterine involution has occurred (approximately 6 weeks after delivery). Table IV Noncontraceptive health benefits of the levonorgestrel-releasing IUD Treatment of menorrhagia, 33,34 including in women with uterine fibroid tumors 35 and adenomyosis36 Treatment of pain in women with endometriosis 37 Alternative to hysterectomy for women with menorrhagia 34 Prevention of endometrial hyperplasia in menopausal women using estrogen therapy 33 Prevention of endometrial proliferation and polyps in breast cancer survivors taking tamoxifen 33 1002 Kaunitz
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