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Hormonal Contraception in Women of Older Reproductive Age

Andrew M. Kaunitz, M.D.
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors clinical recommendations.

A healthy, lean 46-year-old woman who is a nonsmoker requests advice about contraception. She notes that her menstrual periods are less regular than previously, and she also reports intermittent bothersome hot flashes. She is in a new relationship after a divorce, and she is sexually active. She asks if she can begin to use an oral contraceptive. What would you advise?

The Cl inic a l Probl e m

From the Department of Obstetrics and Gynecology, University of Florida College of MedicineJacksonville, Jacksonville. N Engl J Med 2008;358:1262-70.
Copyright 2008 Massachusetts Medical Society.

During the transition toward their final spontaneous menses, many perimenopausal women have menstrual-cycle alterations and vasomotor symptoms. Although sporadic ovulation continues until menopause,1,2 fecundity declines as the final menses approaches. For instance, in one study involving women undergoing insemination with frozen donor sperm, the fecundity of women older than 40 years of age was less than half that of those 35 years of age or younger.3 Women of older reproductive age are more likely than younger women to have adverse consequences when they do conceive. In the United States, pregnancyrelated mortality ratios (deaths per 100,000 live births) among women 40 years of age or older are five times those of women between 25 and 29 years of age; coexisting conditions during pregnancy, including diabetes and hypertension, also increase with maternal age.4,5 In 2001, there were 304 induced abortions per 1000 live births among women 40 years of age or older in the United States; this ratio was higher than that among all other age groups except adolescents.6 These data underscore the importance of effective contraception for women of older reproductive age. A previous Clinical Practice article addressed long-acting methods of contraception.7 The present review focuses on hormonal contraception, primarily the use of combination estrogenprogestin contraceptives, in women of older reproductive age (Tables 1 and 2).

S t r ategie s a nd E v idence
CONTRACEPTIVE EFFICACY

Women of older reproductive age are less fecund and more likely to use contraceptives correctly and consistently than younger women. Accordingly, women in this age group have lower rates of contraceptive failure than do younger women.8
SAFETY

Venous Thromboembolism

Older age and obesity are independent risk factors for venous thromboembolism among women using combination oral contraceptives, and obesity is increasingly
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Table 1. Oral Contraceptives Available in the United States.* Pregnancy Rate (First Year of Typical Use) % Combination estrogenprogestin 21 active tablets and 7 placebo tablets Ethinyl estradiol, 20 g Levonorgestrel, 0.1 mg (Aviane, Lutera) Norethindrone acetate, 1 mg (Junel 21 1/20) Norgestimate, 0.18 mg, 7 tablets; norgestimate, 0.215 mg, 7 tablets; and norgestimate, 0.25 mg, 7 tablets (Ortho Tri-Cyclen Lo) Levonorgestrel, 0.15 mg (Portia) Norethindrone, 1 mg (Necon 1/35) Ethinyl estradiol, 20 g desogestrel, 0.15 mg, 21 tablets; 2 placebo tablets and ethinyl estradiol, 10 g, 5 tablets (Kariva) Ethinyl estradiol, 20 g drospirenone, 3 mg, 24 tablets; and 4 placebo tablets (Yaz) Ethinyl estradiol, 30 g levonorgestrel, 0.15 mg, 84 tablets; and 7 placebo tablets (Quasense) Norethindrone, 0.35 mg (Camila, Errin) 8 Greater suppression of ovarian follicular activity than with 7-day placebo interval More unscheduled bleeding than formulations with higher estrogen dose; data do not confirm greater safety than formulations containing 30 or 35 g of ethinyl estradiol 8 Most formulations available as generics

Formulation

Regimens

Comments

Ethinyl estradiol, 25 g

Ethinyl estradiol, 30 g Ethinyl estradiol, 35 g 28-day with reduced hormonefree interval

Extended oral contraceptives

Initially more unscheduled bleeding than with monthly regimens; scheduled bleeding episodes each 3 mo More unscheduled bleeding than with combined oral contraceptives; dose may be inadequate to suppress ovulation; failure rate may be higher than with combination estrogenprogestin oral contraceptives

Progestin-only, 28 active tablets

* This list is not exhaustive. Progestins found in U.S. oral-contraceptive formulations include desogestrel, drospirenone, levonorgestrel, norethindrone, norethindrone acetate, norgestimate, and norgestrel. Pregnancy rates are expected to be lower among contraceptive users of older reproductive age (data are from Trussell8). This is a generic drug. Data are from Gallo et al.9 There is no generic version of this drug in the United States.

common with older age. The risk of venous thromboembolism rises sharply after 39 years of age among women who receive combination oral contraceptives, with an estimated incidence of more than 100 cases per 100,000 person-years among women who are older than 39 years of age, as compared with 25 cases per 100,000 personyears among adolescents.12 The risk is nearly twice as high among obese women as it is among nonobese women who receive oral contraceptives.13 Thus, combination contraceptives should be used with caution in women of older reproductive age who are obese; progestin-only contraceptives or intrauterine devices are generally preferred in these women.14 The estrogen component of combination oral contraceptives is considered to be the major conn engl j med 358;12

tributor to the risk of venous thromboembolism associated with the use of oral contraceptives, with higher doses of estrogen associated with a greater risk.13 However, the progestin component may also affect the risk of venous thromboembolism. For example, oral contraceptives formulated with the progestin desogestrel are associated with a risk of venous thromboembolism that is about twice the risk associated with oral contraceptives formulated with the progestins levonorgestrel and norgestimate.15 Although oral contraceptives containing 20 g of estrogen are increasingly prescribed in women of older reproductive age, evidence is lacking to confirm that these formulations are safer than those containing 30 to 35 g of estrogen.9 Women with familial thrombophilic synmarch 20, 2008

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Table 2. Nonoral Hormonal Contraceptives.* Daily Hormone Release Pregnancy Rate (First Year of Typical Use) % Combination estrogenprogestin Transdermal patch (Ortho Evra) Ethinyl estradiol, 20 g; norelgestromin, 150 g Ethinyl estradiol, 15 g; etonogestrel, 120 g Approximately 20 g Use 1 patch/week for 3 weeks, remove for 1 week, repeat with new patch Bleeding during patch-free week 8

Type of Contraceptive

Schedule of Use

Bleeding Profile

Vaginal ring (NuvaRing)

Insert ring for 3 weeks, Bleeding during ring-free week remove for 1 week, repeat with new ring Up to 5 yr Initial increase in days of bleeding and spotting; 12 mo after insertion, 20 50% of users amenorrheic Variable; infrequent, prolonged, and frequent bleeding episodes are common initially; 3 mo after insertion, 1420% of users amenorrheic Initial unpredictable bleeding and spotting common; 12 mo after initiation, 50% of users amenorrheic Initial unpredictable bleeding and spotting common; 12 mo after initiation, 50% of users amenorrheic

Progestin only Levonorgestrel-releasing intrauterine device (Mirena) 0.1

Etonogestrel implant (Implanon) 6070 g initially; 2530 g by end of year 3 Injectable DMPA Depo-Provera

Up to 3 yr

<1

150 mg, intramuscular Every 3 mo

Depo-SubQ Provera

104 mg, subcutaneous Every 3 mo

<1

* Except for intramuscular Depo-Provera, all of these contraceptives are available only as branded formulas. DMPA denotes depot medroxyprogesterone acetate. Pregnancy rates are expected to be lower among contraceptive users of older reproductive age. Data are from Trussell.8 Data are from Peterson and Curtis.7 Data are from Funk et al.10 Data are from Kaunitz.11

dromes, including carriers of the factor V Leiden mutation, have a higher risk of venous thromboembolism with the use of combination oral contraceptives than women who do not have these syndromes.13 Because screening costs would exceed benefits, routine screening for thrombophilic conditions before oral contraceptive use is not recommended14,16,17; however, combination oral contraceptives should be avoided in women with a known thrombophilic condition.
Myocardial Infarction and Stroke

In women who use oral contraceptives, smoking and hypertension are synergistic risk factors for myocardial infarction and stroke. Thus, combination estrogenprogestin contraceptives should not be used by women of older reproductive age who smoke or who have hypertension.14
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Although some studies conducted abroad have shown an increased risk of myocardial infarction and stroke with oral-contraceptive use, the prevalence of smoking and untreated hypertension was high among study participants. It is therefore uncertain whether findings from these studies are applicable to healthy women of older reproductive age who are nonsmokers.14,16 A large casecontrol study that was based on data from two health maintenance organizations (HMOs) in the United States included few oral-contraceptive users older than 35 years of age who smoked or had hypertension. This study reported no evidence of an increased risk of myocardial infarction or stroke among women of older reproductive age who were current users of oral contraceptives containing less than 50 g of ethinyl estradiol.18,19 A recent large, prospective study involvmarch 20, 2008

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ing Swedish women between 30 and 49 years of age at enrollment, including 1761 current oralcontraceptive users between 40 and 49 years of age, provided further reassurance regarding the use of oral contraceptives containing an estrogen dose of less than 50 g of ethinyl estradiol.20 As compared with women who had never used oral contraceptives, neither former nor current oralcontraceptive users had an increased risk of myocardial infarction over a mean period of 11 years of follow-up. In addition, the initiation of oralcontraceptive use in women 30 years of age or older was not associated with an elevated risk of myocardial infarction, as compared with initiation at a younger age.20 On the basis of an increased risk of cardiovascular disease associated with diabetes among both premenopausal and postmenopausal women, it is prudent to limit the use of combination oral contraceptives in women with diabetes to those who are younger than 35 years of age and are free of hypertension, other vascular diseases, and nephropathy. Progestin-only and intrauterine contraceptives are reasonable choices in women who are not good candidates for combination oral contraceptives.14 Although controversial, some data suggest that women with migraine headaches are at increased risk for stroke with the use of oral contraceptives.19 In a large HMO-based, casecontrol study in the United States, oral-contraceptive use was associated with a risk of stroke that was twice as high among women with migraines as among women without a history of migraines.19 This study did not distinguish between migraines with aura and those without aura. In another study, women who had migraine headaches accompanied by aura, but not those who had migraine headaches without aura, had an increased risk of stroke; among women who had migraine headaches with aura, oral-contraceptive users who smoked had a further increase in the risk of stroke.21 Current guidelines from the American College of Obstetricians and Gynecologists and the World Health Organization (WHO) recommend progestin-only or intrauterine contraceptives in women of older reproductive age with migraines.14,17

concern that the use of hormonal contraception might increase the risk of breast cancer. However, in a large British cohort study involving more than 1 million person-years of follow-up, the use of oral contraceptives (in most cases containing 50 g or more of ethinyl estradiol) was not associated with an increased risk of breast cancer, even among women who used these contraceptives for long periods of time. The risk was also not increased with current or recent oral-contraceptive use or with use decades earlier. However, this report did not provide information regarding the age at which women in the cohort used oral contraceptives.22 The Womens Contraceptive and Reproductive Experiences (CARE) Study, a population-based casecontrol study, showed no increased risk of invasive or in situ breast cancer among women who were current or previous users of oral contraceptives as compared with women who had never used them23,24; this study included an analysis that was limited to women who had begun to use oral contraceptives in their 40s. The CARE study also showed no significant association between the use of progestin-only injectable depot medroxyprogesterone acetate (DMPA) or implantable contraceptives and the risk of breast cancer.25 A recent large, population-based casecontrol study in the United States similarly showed no increase in the risk of death from breast cancer among women who had previously used oral contraceptives, as compared with the risk among those who had never used them; this study included a subgroup of women who had begun to use oral contraceptives at 30 years of age or older.26 Although the available data indicate that the use of combination oral contraceptives or progestin-only contraceptives does not affect the risk of breast cancer, these reports have included relatively few women older than 45 years of age. A potential increase in the risk of breast cancer associated with the use of hormonal contraceptives is a particular concern for women at high risk for breast cancer on the basis of family history. However, available data suggest that familial risk should not be viewed as a contraindication to the use of combination estrogenprogestin or progestin-only contraception in women of older reproductive age. In a large, Canadian prospecBreast Cancer tive study involving women with a family history The recognized association between long-term of breast cancer (mean age, 49 years), neither estrogen exposure and breast cancer has raised former nor current oral-contraceptive use was
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associated with an increased risk of breast cancer27; information on BRCA mutation status was not available. Studies among known BRCA mutation carriers have yielded mixed results.28,29 In one study,28 the use of oral contraceptives was associated with a modestly increased risk of breast cancer among women with BRCA1 mutations (odds ratio, 1.20; 95% confidence interval, 1.02 to 1.40) but not among women with BRCA2 mutations, whereas another study29 showed no significant increase in risk among women in either group.
NONCONTRACEPTIVE BENEFITS

Irregular and Heavy Uterine Bleeding

In the United States, hysterectomy rates are highest among women between 40 and 44 years of age.30 This surgery and endometrial ablation or resection are most commonly performed in women in this age group for heavy menstrual bleeding, which is often associated with uterine fibroids or adenomyosis. The use of oral contraceptives can restore cyclic, predictable bleeding in women of older reproductive age with dysfunctional uterine bleeding. In a trial involving women between 15 and 50 years of age with dysfunctional uterine bleeding, more than 80% of those who were randomly assigned to receive an oral contraceptive as compared with less than 50% of women in the placebo group had improvement in their bleeding patterns.31 In addition, significant reductions in menstrual blood loss associated with the use of oral contraceptives have been reported in women with menorrhagia as well as those with normal menses.32 The use of the levonorgestrel intrauterine device effectively treats menorrhagia, including menorrhagia associated with fibroids and adenomyosis.33-35 Since long-term use of injectable forms of contraception characteristically results in amenorrhea, some clinicians recommend DMPA injections to treat menorrhagia; however, data in support of this approach are limited.11
Vasomotor Symptoms

contraceptives reduces vasomotor symptoms in perimenopausal women, although this has not been well studied. In one double-blind trial, the number and severity of vasomotor symptoms appeared to be reduced by a factor of about two in perimenopausal women who were randomly assigned to receive an oral contraceptive containing 20 g of estrogen, as compared with women who received placebo, but the differences were not statistically significant.36 In a prospective observational study, 90% of perimenopausal women with vasomotor symptoms who used an oral contraceptive containing 30 g of ethinyl estradiol had complete relief of symptoms 2 months or more after the start of oral-contraceptive use, whereas only 40% of nonusers reported improvement in their vasomotor symptoms.37 In a trial involving symptomatic perimenopausal women, the use of oral conjugated equine estrogen (at a dose of 1.25 mg daily) and a levonorgestrel-releasing intrauterine device resulted in substantial improvement in vasomotor symptoms; most participants became amenorrheic, and endometrial hyperplasia did not develop in any subject.38 In placebo-controlled trials, contraceptive doses of DMPA have been shown to suppress vasomotor symptoms in menopausal women.39 Vasomotor symptoms may occur in perimenopausal women using oral contraceptive formulations with 21 active tablets during the hormonefree days. Some clinicians prescribe extended or continuous oral-contraceptive regimens to reduce such symptoms, although this approach has not been studied extensively.
Skeletal Health

Vasomotor symptoms are common in perimenopausal women. Hormonal therapy is effective in treating these symptoms, but doses of estrogen that are typically used in postmenopausal women (generally the equivalent of 5 to 10 g of ethinyl estradiol) are inadequate to prevent ovulation.2 Clinical experience suggests that the use of oral
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Bone mineral density (BMD) decreases in women of older reproductive age.40 Data from a randomized trial indicate that the use of oral contraceptives increases BMD in women in this age group.40 Furthermore, in a population-based, casecontrol study of postmenopausal Swedish women, a history of oral-contraceptive use was associated with a 25% reduction in the risk of hip fracture; greater reductions were noted among women who had used oral contraceptives in their 40s and among those who had used oral contraceptives for extended periods of time.41 In contrast, an analysis of data from the observational cohort study of the Womens Health Initiative did not show a reduced risk of fractures among postmenopausal women
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who were previous users of oral contraceptives, but the subjects were not stratified according to the age at which oral contraceptives were used.42 Current use of intramuscular DMPA (at a dose of 150 mg) or subcutaneous DMPA (at a dose of 104 mg) is associated with reductions in BMD. However, in former users, including women who began to use DMPA at 40 years of age or older, BMD has been found to be similar to that in women who never used DMPA.11,43 Data on the risk of fracture among postmenopausal women who previously used DMPA are lacking.
Cancer

A r e a s of Uncer ta in t y
The use of oral contraceptives among women of older reproductive age is increasing, with 11% of women between 40 and 44 years of age in the United States who used contraception reporting oral-contraceptive use in 2002, as compared with 6% in 1995.50,51 Nonetheless, women of older reproductive age are underrepresented in studies of oral-contraceptive use, and information on the safety and noncontraceptive benefits of hormonal contraception in women in this age group is limited. Data on the noncontraceptive benefits and risks of the contraceptive vaginal ring, which releases estrogen and progestin, are also lacking. Although pharmacokinetic data regarding the contraceptive patch indicate that it results in more estrogen exposure than oral contraceptives or the vaginal ring,52 the findings of studies comparing the risk of venous thromboembolism associated with use of the patch with the risk associated with oral contraceptives are conflicting.53 Pending further data, contraindications to the use of combination oral contraceptives should also be considered to apply to the ring and the patch.14,17 The optimal timing for discontinuation of the use of oral contraceptives in women of older reproductive age remains uncertain. The measurement of follicle-stimulating hormone (FSH) levels has been suggested as a means of identifying women who are menopausal and thus no longer need contraception, but this measurement may be misleading and is not recommended. Elevated FSH levels suggestive of menopause may occur in ovulatory women of older reproductive age.2 Moreover, in one study, suppressed FSH levels suggesting premenopausal status were reported in a majority of postmenopausal women evaluated 1 month after the discontinuation of oral contraceptives.54 A reasonable strategy for healthy women who are nonsmokers and doing well using a combination contraceptive is to discontinue this method of contraception in their early to mid-50s, when the likelihood of ovulation is low.14 Barrier contraception until 55 years of age is prudent for menstruating women who discontinue the use of oral contraceptives closer to 50 years of age.

Women who use low-estrogen oral contraceptive formulations have at least a 50% lower risk of subsequent epithelial ovarian cancer than women who have never used these formulations.16 A longer duration of use is associated with greater protection.22,44 Although the protection associated with the use of oral contraceptives may decrease over time, it appears to persist for at least three decades after the last use.44 Since the incidence of ovarian cancer increases with age, the protection associated with oral-contraceptive use may be particularly relevant for women of older reproductive age. The use of oral contraceptives has been associated with a reduced risk of ovarian cancer among both BRCA mutation carriers and noncarriers.45,46 Extensive observational data indicate that the use of contraceptives containing 30 g or more of estrogen is associated with a reduction of approximately 50% in the risk of endometrial cancer,16 with protection increasing with a longer duration of oral-contraceptive use and persisting for at least two decades after the discontinuation of oral contraceptives.32,47 The use of DMPA is associated with an 80% reduction in the risk of endometrial cancer.48 The use of oral contraceptives has been associated with an approximately 20% reduced risk of colorectal cancer.22,49 In contrast to protection against ovarian and endometrial cancer, the protection against colorectal cancer associated with the use of oral contraceptives does not appear to increase with the duration of use. The use of oral contraceptives within the past 5 years may be associated with greater protection against colorectal cancer than more remote use.22,49

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Table 3. Guidelines Regarding the Use of Combination EstrogenProgestin Contraceptives in Women 35 Years of Age, According to Risk Factors.* Risk Factor ACOG Obesity Progestin-only or intrauterine contraception may be safer than combination estrogenprogestin contraception Progestin-only or intrauterine contraception should be used Progestin-only or intrauterine contraception should be used Progestin-only or intrauterine contraception should be used Progestin-only or intrauterine contraception should be used Healthy women who are nonsmokers doing well with the use of a combination contraceptive can continue this method until 5055 yr, after weighing the risks and benefits Guidelines WHO Benefit usually outweighs risks

Smoking Hypertension Diabetes Migraine None of the above

Risk unacceptable Risk unacceptable Risk unacceptable Risk unacceptable For women 40 yr, the risk of cardiovascular disease increases with age and may also increase with combined hormonal contraceptive use; in the absence of other adverse clinical conditions, combined hormonal contraceptives can be used until menopause

* Recommendations are from the American College of Obstetricians and Gynecologists (ACOG)14 and the World Health Organization (WHO).17 This category includes progestin-only oral contraceptives, depot medroxyprogesterone acetate, contraceptive implants, and copper and progestin-releasing intrauterine devices. Obesity in women 35 years of age and older is not specifically addressed.

Guidel ine s from Profe s siona l S o cie t ie s

The WHO and the American College of Obstetricians and Gynecologists have developed similar guidelines addressing the use of combination estrogenprogestin hormonal contraception in women of older reproductive age (Table 3).

C onclusions a nd R ec om mendat ions

Healthy, lean women of older reproductive age who are nonsmokers, like the woman in the vignette, can safely use combination estrogenprogestin contraceptives. Benefits include effective contraception and reductions in irregular bleeding and vasomotor symptoms associated with the perimenopausal transition. Available epidemiologic data also suggest potential long-term benefits, including reductions in the risks of fractures
References 1. Bastian LA, Smith CM, Nanda K. Is this woman perimenopausal? JAMA 2003; 289:895-902. 2. Gebbie AE, Glasier A, Sweeting V. In-

among postmenopausal women and of ovarian, endometrial, and colorectal cancer. However, for women of older reproductive age who are obese, smoke cigarettes, or have hypertension, diabetes, or migraine headaches, the cardiovascular risks associated with combination oral contraceptives are considered to outweigh the benefits. For these women, reasonable options include progestin-only and intrauterine contraceptive methods14 as well as barrier contraceptives and sterilization (in women who have completed childbearing or do not want to have children).7 Regardless of other contraceptive use, consistent use of condoms should be encouraged for all women at risk for sexually transmitted infections.
Dr. Kaunitz reports receiving consulting fees or lecture fees and grant support (to the University of Florida Research Foundation) from Bayer, Barr Pharmaceuticals, Johnson & Johnson, Organon, and Warner Chilcott. No other potential conflict of interest relevant to this article was reported. I thank Karen Koppel Kaunitz, Esq., for invaluable editorial support with an earlier version of the manuscript.

cidence of ovulation in perimenopausal women before and during hormone replacement therapy. Contraception 1995;52: 221-2.

3. Kang BM, Wu TC. Effect of age on in-

trauterine insemination with frozen donor sperm. Obstet Gynecol 1996;88:93-8. 4. Callaghan WM, Berg CJ. Pregnancy-

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related mortality among women aged 35 years and older, United States, 1991-1997. Obstet Gynecol 2003;102:1015-21. 5. Viegas OA, Leong WP, Ahmed S, Ratnam SS. Obstetrical outcome with increasing maternal age. J Biosoc Sci 1994;26: 261-7. 6. Strauss LT, Herndon J, Chang J, et al. Abortion surveillance United States, 2001. MMWR Surveill Summ 2004;53 (SS-9):1-32. 7. Peterson HB, Curtis KM. Long-acting methods of contraception. N Engl J Med 2005;353:2169-75. 8. Trussell J. Contraceptive failure in the United States. Contraception 2004;70:8996. 9. Gallo MF, Nanda K, Grimes DA, Schulz KF. Twenty micrograms vs. >20 microg estrogen oral contraceptives for contraception: systematic review of randomized controlled trials. Contraception 2005;71: 162-9. 10. Funk S, Miller MM, Mishell DR Jr, et al. Safety and efficacy of Implanon, a singlerod implantable contraceptive containing etonogestrel. Contraception 2005;71:31926. 11. Kaunitz AM. Depot medroxyprogesterone acetate for contraception. In: Rose BD, ed. UpToDate. Wellesley, MA: UpToDate, 2008. 12. Nightingale AL, Lawrenson RA, Simpson EL, Williams TJ, MacRae KD, Farmer RDT. The effects of age, body mass index, smoking and general health on the risk of venous thromboembolism in users of combined oral contraceptives. Eur J Contracept Reprod Health Care 2000;5:265-74. 13. Sidney S, Petitti DB, Soff GA, Cundiff DL, Tolan KK, Quesenberry CP Jr. Venous thromboembolic disease in users of lowestrogen combined estrogen-progestin oral contraceptives. Contraception 2004; 70:3-10. 14. ACOG practice bulletin. No. 73: use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol 2006;107:1453-72. 15. Jick SS, Kaye JA, Russman S, Jick H. Risk of nonfatal venous thromboembolism with oral contraceptives containing norgestimate or desogestrel compared with oral contraceptives containing levonorgestrel. Contraception 2006;73:566-70. 16. Petitti DB. Combination estrogen progestin oral contraceptives. N Engl J Med 2003;349:1443-50. [Erratum, N Engl J Med 2004;350:92.] 17. Medical eligibility criteria for contraceptive use. 3rd ed. Geneva: World Health Organization, 2004. 18. Sidney S, Siscovick DS, Petitti DB, et al. Myocardial infarction and use of low-dose oral contraceptives: a pooled analysis of 2 US studies. Circulation 1998;98:1058-63. 19. Schwartz SM, Petitti DB, Siscovick DS, et al. Stroke and use of low-dose oral contraceptives in young women: a pooled analysis of two US studies. Stroke 1998;29: 2277-84. 20. Margolis KL, Adami H-O, Luo J, Ye W, Weiderpass E. A prospective study of oral contraceptive use and risk of myocardial infarction among Swedish women. Fertil Steril 2007;88:310-6. 21. MacClellan LR, Giles W, Cole J, et al. Probable migraine with visual aura and risk of ischemic stroke: the stroke prevention in young women study. Stroke 2007; 38:2438-45. 22. Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iversen L, Lee AJ. Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioners oral contraception study. BMJ 2007;335:651. 23. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med 2002; 346:2025-32. 24. Gill JK, Press MF, Patel AV, Bernstein L. Oral contraceptive use and risk of breast carcinoma in situ (United States). Cancer Causes Control 2006;17:1155-62. 25. Strom BL, Berlin JA, Weber AL, et al. Absence of an effect of injectable and implantable progestin-only contraceptives on subsequent risk of breast cancer. Contraception 2004;69:353-60. 26. Wingo PA, Austin A, Marchbanks PA, et al. Oral contraceptives and the risk of death from breast cancer. Obstet Gynecol 2007;110:793-800. 27. Silvera SA, Miller AB, Rohan TE. Oral contraceptive use and risk of breast cancer among women with a family history of breast cancer: a prospective cohort study. Cancer Causes Control 2005;16: 1059-63. 28. Narod SA, Dub MP, Klijn J, et al. Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2002;94:1773-9. 29. Haile RW, Thomas DC, McGuire V, et al. BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50. Cancer Epidemiol Biomarkers Prev 2006;15:1863-70. 30. Keshavarz H, Hillis SD, Burney AK, Marchbanks PA. Hysterectomy surveillance United States, 19941999. MMWR Surveill Summ 2002;51(SS-5):1-8. 31. Davis A, Godwin A, Lippman J, Olson W, Kafrissen M. Triphasic norgestimateethinyl estradiol for treating dysfunctional uterine bleeding. Obstet Gynecol 2000; 96:913-20. 32. Kaunitz AM. Noncontraceptive health benefits of oral contraceptives. Rev Endocr Metab Disord 2002;3:277-83. 33. Hurskainen R, Teperi J, Rissanen P, et al. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up. 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