Clinical Dilemmas in Women's Health: Using Current Evidence to Answer Questions about Hormonal Contraception in the Middle Years

Abstract

Introduction

Controversies exist about the care of women in the middle years. This article addresses common clinical dilemmas faced when caring for women in the middle years who desire hormonal contraception. Case vignettes and the discussions that follow focus particularly on the risk/benefit ratio of providing hormonal contraception to women with hypertension (HTN), obesity, or migraine headaches, women who smoke, and women with a family history of breast cancer or venous thromboembolism. Evidence supporting management strategies and formal guidelines is reviewed when available. Each section concludes with the authors' clinical recommendations and Take Home Points.

Case Reports

Case 1

A 41-year-old woman requests “the pill.” She is sexually active with her fiancée, and they are discussing whether or not they will try to conceive. She used Depo-Provera (Upjohn, Kalamazoo, MI) in the past but could not tolerate the associated abnormal bleeding. She is more comfortable when “things are regular.” She denies dysmenorrhea or heavy menses. She is in good health, quit smoking 3 years ago, and has a family history of breast cancer in her mother. Her blood pressure is 125/85 on 12.5 mg of hydrochlorothiazide (HCTZ); her body mass index (BMI) is 25.

Is it safe to prescribe an oral contraceptive pill to this woman given her age and her HTN?

In response to the patient's request, the data presented in this section refer to oral contraceptive pills (OCPs); however, it is generally accepted that the risks and benefits for other combined hormonal contraceptives, such as the Ortho Evra Patch (Raritan, NJ) or NuvaRing (Organon USA Inc., Roseland, NJ), are similar to those of OCPs. Prescribing hormonal contraception, including OCPs, to healthy, nonsmoking women >35 years old is generally safe provided that other contraindications to combined hormonal contraception do not exist. In particular, data from U.S. trials suggest that stroke and myocardial infarction (MI) risks for OCP users compared with nonusers are similar in younger and older nonsmoking women.^1,2 However, most OCPs have been shown to elevate systolic and diastolic blood pressure by about 8 and 6 mm Hg, respectively, and caution should be used in starting OCPs in women who already have elevated blood pressures, especially women aged >35 years. Guidelines from both the World Health Organization (WHO) and the American College of Obstetricians and Gynecologists (ACOG) suggest that the risks of OCPs outweigh the benefits if blood pressure is uncontrolled, particularly if the blood pressure is >140/90 mm Hg. The risks of MI and stroke among users of OCPs who have medication-controlled HTN are not known. Drosperinone-containing OCPs, such as Yaz and Yasmin (Bayer HealthCare Pharmaceuticals Inc, Wayne, NJ), may be safer than other OCPs in women with mild HTN because of their antimineralocorticoid activity and have been shown to lower both systolic and diastolic blood pressure by about 4 mm Hg.³ Progestin-only contraceptives may provide a lower cardiovascular risk for women with HTN.^4,5

A third-generation OCP instead of a second-generation OCP may also provide less of a risk for MI depending on the progestin component used,⁶ but relative risks (RR) remain high among OCP users who smoke or have diabetes mellitus or hypercholesterolemia.⁷ It is also important to note that venous thromboembolism (VTE) risk is higher in women who are obese⁸ and in women who use OCP formulas that contain specific third-generation progestins, such as desogestrel and gestodene.^19
–21 Most studies suggest that VTE risk is highest in the first year of use and diminishes with increasing duration of use. These risks should be balanced with the risk of pregnancy and pregnancy-related complications.

How does the patient's smoking history affect your decision?

It is well established that providing OCPs to smokers >35 years provides substantial and unacceptable risks for MI and stroke and is ill advised. These risks also apply to the other combined hormonal contraceptives. The RR of stroke or MI in OCP users who smoke and are >35 years of age is 20 times greater than that of smoking OCP users <25 years old and 10 times greater than that of aged-matched nonsmokers taking OCPs (Table 1).⁸ Cardiovascular risks for former smokers who subsequently take OCPs are not known regardless of age. However, the cardiac risks associated with cigarette smoking are thought to diminish relatively soon after smoking cessation in those with and without cardiovascular disease (CVD) and continue to fall with increasing length of time since quitting.^20,21 Thus, smoking and other cardiovascular risk factors need to be taken into account when weighing the risks and benefits of combined hormonal contraceptive use. Table 1 outlines the estimated number of excess cases of ischemic stroke or MI attributable to OCP use among nonsmokers, smokers, and women with HTN according to age. Table 2 outlines recommendations from the WHO and ACOG about acceptable risks.

Table 1.

Age-Specific Estimates of Excess Cases of MI and Stroke Attributable to Low-Dose OCPs ^a

Number of excess cases of MI or stroke (per 100,000 woman-years)	20–24 years	30–34 years	40–44 years
Among nonsmokers	0.4	0.6	2
Among smokers	1	2	20
Among women with HTN	4	7	29
Number of pregnancy-related deaths (per 100,000 live births)	10	12	45

Adapted from Petitti.⁸

OCPs, oral contraceptive pills; MI, myocardial infarction; HTN, hypertension.

Table 2.

Summary of WHO ^a and ACOG Guidelines for OCP Use in Women with Risk Factors

Variable	ACOG guidelines	WHO guidelines
Smokers >35 years old	Risk unacceptable	Risk unacceptable
Hypertension
BP controlled	Risk acceptable^b	Risk usually outweighs benefit if systolic BP is 140–159 and diastolic BP is 90–99
BP uncontrolled	Risk unacceptable^c	Risk unacceptable if systolic BP is ≥160 mm Hg or diastolic BP is ≥100 mm Hg
Migraine headache
Age >35 years	Risk usually outweighs benefit	Risk usually outweighs benefit
Focal symptoms	Risk unacceptable	Risk unacceptable

Adapted from Petitti.⁸

WHO, World Health Organization; ACOG, American College of Obstetricians and Gynecologists; OCP, oral contraceptive pill; BP, blood pressure.

No definition of BP control.

No definition of uncontrolled BP.

Does a family history of breast cancer preclude the woman from using OCPs?

Although a family history of breast cancer increases her risk for developing breast cancer, OCPs are not likely to further increase that risk. The Women's Care study,²² a large case-control study of >7000 women aged 35–64 years, found no increased risk of breast cancer with current or past OCP use compared with never using OCPs, including among those with a family history of breast cancer. Data about breast cancer risk for mutation carriers of the BRCA1 or BRCA2 gene taking OCPs are more controversial and must be balanced with the known risk reduction for ovarian cancer in mutation carriers on OCPs. Family history of breast cancer is not a contraindication for prescribing OCPs in our patient, and according to the ACOG Practice Bulletin,²³ family history of BRCA1 or BRCA2 mutations should not preclude provision of OCPs.

On further review of systems, the patient reveals a history of 8–10 migraine headaches a year that are associated with nausea, photophobia, and phonophobia. She has no neurological symptoms with her migraines. Would this history affect your decision to prescribe OCPs?

Migraine headaches are common among reproductive age women, and although menstrual migraines often improve on OCPs, other women can experience worsening of their symptoms on OCPs. Migraine headaches with aura have been associated with up to a 2-fold increased risk of stroke in otherwise healthy women on OCPs^24,25; smoking further increases this risk.²⁴ In contrast, OCP use does not appear to increase stoke risk in migraine patients without aura. It is important to note that our patient's symptoms do not constitute an aura. Auras are characterized by reversible neurological symptoms that last 5–60 minutes and most commonly involve visual disturbances, such as flickering uncolored zigzag lines or scotomas; sensory, motor, or speech disturbances can occur but are less common.²⁶ Because stroke risk is not increased in migraine without aura, OCPs are not contraindicated unless the patient has other major risk factors for stroke (smoking, hypertension, diabetes) or the patient's headaches are exacerbated when OCPs are started.²⁶

Recommendations for OCP provision in women with migraines are shown in Table 3. In general, OCPs can be considered for women with migraines if they do not have focal neurological signs, do not smoke, are <35 years of age, and are otherwise healthy.^7,8 Other studies indicate that women with migraines without aura and without other risk factors can take OCPs up until age 40.²⁷ Whether nonsmoking young women with migraines who are already taking OCPS should stop taking them at age 35 is not known. Although stroke is rare among women with migraines who use OCPs, the impact is so devastating that alternative birth control methods, such as progestin-only Intrauterine System (IUS), Depo-Provera, or barrier methods, should be considered first⁷ in women at increased risk of stroke.

Table 3.

Recommendations for OCP ^a Use in Patients with Migraines

When women with migraines are prescribed OCPs, they should be carefully monitored for increasing headache frequency and severity and for the development of new focal neurological symptoms.

Specific recommendations

1. Women who have migraine without aura can probably use OCPs with relative safety unless other significant stroke risk factors, such as smoking or HTN, are present, although caution should be exercised over age 40.

2. For women who have significant worsening of migraine without aura while taking OCPs, discontinuation should be considered, especially if the worsening is dramatic.

3. Women who have migraine with a visual aura <30 minutes probably have significantly increased ischemic stroke risk if OCPs are used. This risk probably increases with age as baseline stroke rates increase, so that the increased risk may be acceptable to the younger patient but not to the older patient (>age 30).

4. Women who have prolonged migraine auras (beyond 60 minutes) or multiple or less common aura symptoms (e.g., dysphasia, hemiparesis) should be strongly discouraged from using OCPs.

5. Patients who develop a migraine aura for the first time while taking OCPs or whose previous typical migraine aura becomes more prolonged should discontinue OCPs.

6. OCPs should be discontinued in women with migraine of any type who develop transient ischemic attacks, stroke, or ischemic vascular disease elsewhere.

Adapted from Becker.²⁷

OCP, oral contraceptive pill; HTN, hypertension.

Are there noncontraceptive benefits for the woman in selecting OCPs over an alternative form of birth control?

Women >age 35, including perimenopausal women, may have noncontraceptive benefits from OCPs in addition to their effectiveness in preventing acne and in minimizing dysmenorrhea and menorrhagia. These benefits likely apply to the use of other combined hormonal contraceptives as well, such as the patch or ring. Older reproductive age women may experience a positive effect on bone mineral density (BMD) and reduced fracture rate,²⁸ a reduction in perimenopausal symptoms, and well-established risk reductions for endometrial and ovarian cancer. Our patient will also benefit from cycle regularity, which is important to her and is likely to worsen in the perimenopausal period without treatment. The contraceptive benefit in older reproductive age women deserves mention, as these women are more likely than younger women to have adverse consequences if they do conceive. For example, one study of pregnant women identified an increased risk of death for women ≥35 years compared with younger women regardless of parity, time of entry into prenatal care, and level of education.²⁹ These data underscore the importance of effective contraception for women in this age group; contraceptive risks must be balanced with risks of pregnancy and noncontraceptive health benefits.

Case 2

A 43-year-old woman requests “the patch,” as she finds it difficult to remember to take pills daily. Her sister had a deep venous thrombosis (DVT) after a femoral fracture; there is no other family history of thromboembolism. There is no family history of osteoporosis. She weighs 175 lbs, and her BMI of 31 places her in the obese range.

Does her weight affect her risk of VTE?

Increased weight appears to increase the risk of thromboembolic disease.³⁰ In a study in the Netherlands that recruited patients from anticoagulation clinics, compared with people with a normal BMI, the RR of VTE was 1.7 (confidence interval [CI] 1.6-1.9) for those with a BMI >25 and <30, and 2.4 (CI 2.15-2.78) for BMI >30. Maximal risk was 23.78 (CI 13.35-42.34) for women on OCPs with a BMI >30. The mechanism for the association between BMI and VTE is thought to be an increase in procoagulant factors (factors VII, VIII, XII, and fibrinogen) and increased venous stasis. Exogenous estrogen has additional procoagulant effects by increasing factor X as well as factor VII and fibrinogen.

Is the woman's family history of DVT a contraindication to combined hormonal contraceptives? Should she be tested for factor V Leiden or other measures of hypercoaguability?

A family history of VTE is not considered to be a contraindication to estrogen-containing contraceptives.²³ Current consensus recommendations are that tests for hypercoaguable states should not be done in patients such as ours who have an increased risk for thrombosis based only on weight or contraceptive use.³¹

Does her risk of VTE vary with contraceptive methods?

Alternative reversible methods that would be equally or more effective than combination hormonal contraception and would confer lower risk of clot include both progestin and copper IUDs or progestin-only options of Depo-Provera or Implanon (N.V. Organon, Oss, The Netherlands) subcutaneous progestin implants. If combination hormonal contraceptives are prescribed after a careful discussion of risks of VTE, a combination oral contraceptive or the NuvaRing may be safer options than the Ortho Evra patch. As noted previously, oral combinations containing the older progestins levonorgestrol and norethindrone may confer a lower risk of VTE than those containing gestodene or desogestrel.

Although there are no randomized controlled trial data that compared the incidence of VTE among any of these preparations, postmarketing surveillance suggests an increased clot risk with Ortho Evra. The original concern was reported by the Associated Press and was based on data obtained from the Food and Drug Administration (FDA) under the Freedom of Information Act. That original analysis was never published in the peer-reviewed literature and appeared only on the web and in the media. A subsequent case-control study sponsored by the manufacturer of the patch looking at data from a managed care claims database found no increased risk of VTE with Ortho Evra compared with oral contraceptive with norgestimate and 35 μg ethinylestradiol.³² Despite the conflicting data, the FDA in Januray 2008 required the manufacturer to post a warning of increased risk of VTE with the patch compared with combination contraceptive pills If there is a true increased risk of the patch, the mechanism may be related to serum estrogen levels. A study sponsored by the manufacturers of NuvaRing measured serum estrogen levels in 24 women with BMI <30. Cumulative levels of exposure to ethinylestradiol were lowest in the patients on NuvaRing compared with the patch and with an OCP containing 30 μg ethinylestradiol.³³

Are adherence and efficacy better with nonoral combination hormonal contraception?

Studies indicate that even though adherence to transdermal hormonal contraception is superior to that of oral contraceptives, pregnancy rates are not significantly different.⁹ Contraceptive Technology, ¹⁰ the compendium of contraceptive efficacy, rates oral, transdermal, and combined contraceptive hormones as equally efficacious, with an 8% unintended pregnancy rate per 100 woman-years with average use and 0.3% with perfect use; 68% of women continue any combination hormonal method for at least 1 year. Thus, even though our patient might be more likely to use the transdermal method correctly, that might not translate into higher efficacy. In fact, contraceptive failure rates are higher in obese users of the patch who weigh >198 lbs.¹¹ IUD or IUS placement would be a good option to achieve even greater contraceptive efficacy, but this method does not involve combined hormones.

If the patient decides to pursue a progestin-only contraceptive method, would this method be safe to use now through the menopausal transition?

There is currently a black box warning on Depo-Provera suggesting a maximum use of 2 years and continuing beyond that only if “other contraceptive methods are inadequate.” The warning was prompted by evidence of bone loss with prolonged use. The manufacturer's insert quotes up to 6% bone loss in 6 years, with losses occurring in the spine, total hip, and femoral neck in adults. The FDA warning also suggests bone mineral density (BMD) measurement in women continuing use beyond 2 years. Several studies, however, have suggested that decline in BMD is reversible. In a study in the developing world, BMD in women with at least 24 months of lifetime use of combination OCPs, Depo-Provera, and progestin implants was compared.¹² Women currently using Depo-Provera and progestin implants had lower BMD than women who had not used hormonal contraception or women on combination OCP, but past users of both of these progestin-only methods had BMD that was no different from that of never users. In a cross-sectional study of postmenopausal women with a mean age of 60, the 10% of past users of Depo-Provera had BMD that was not statistically different from that of non-Depo-Provera users.¹³ Those who had used Depo-Provera for >2 years did have a trend toward lower BMD, with a maximum of 3.1% difference at the femoral neck. Women in this study had continued Depo-Provera until a mean of 2 years prior to menopause.

A Group Health Cooperative¹⁴ study followed 18–39-year-old women prospectively with serial BMD every 6 months and compared 183 women on Depo-Provera with 274 controls. Mean BMD declined in women on Depo-Provera, with maximal decline in the first 12 months of treatment; BMD increased slightly in control women. BMD improved when Depo-Provera was discontinued, with no significant difference between users and non-users at the end of follow-up. The rate of BMD recovery in prior Depo-Provera users was slower at the hip than at the spine; women were followed for a maximum of 30 months after stopping Depo-Provera.

In contrast to the FDA, ACOG has synthesized these data and recommended that “skeletal health concerns should not restrict use of Depo-Provera in adult women… . Regardless of age, short or long term use of Depo-Provera in healthy women likewise should not be considered an indication for DXA… .”²³ There is no warning on BMD for implantable progestin contraception, but some of these data suggest similar BMD loss at least in international settings. A prospective comparison study of Implanon vs. a progestin-releasing IUS showed no decline in BMD in up to 2 years use.¹⁵ Implanon may be safer than Depo-Provera for bone health. Implanon users continue to have near normal estrogen levels despite anovulation,¹⁶ which may explain its relative safety for bone health compared with Depo-Provera.

Footnotes

Acknowledgments

We gratefully acknowledge Dr. Shobhina Cheda for her helpful editorial comments on the manuscript.

Disclosure Statement

The authors have no conflicts of interest to report.

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