Contraception and Pregnancy in Patients with Rheumatic Disease

11. Contraception in Rheumatic Disease Patients

Lisa R. Sammaritano 

(1)

Division of Rheumatology, Hospital for Special Surgery, Weill Cornell Medical College, 535 East 70th Street, New York, NY 10021, USA

Lisa R. Sammaritano

Email: sammaritanol@hss.edu

Introduction

The importance of safe and effective contraception for women with rheumatic disease cannot be overstated. Counseling patients about the increased risks of pregnancy during certain periods of their illness—during active disease, or while on teratogenic medications, for example—relies on the assumption that patients can safely and knowledgably prevent pregnancy through the use of contraception. For the rheumatologist, a basic knowledge of currently available contraceptive methods is essential; for the obstetrician, it is similarly critical to be able to identify which methods are safe (or unsafe) for particular rheumatic disease patients.

Effective contraceptive methods have been underutilized by rheumatic disease patients for many years; this may be due at least in part to the fact that until recently all systemic lupus erythematosus (SLE) patients were advised to avoid estrogen-containing contraceptives due to risk of flare and/or thrombosis. Despite advances in methods of birth control as well as knowledge about safety in rheumatic disease, however, many patients still do not utilize effective birth control.

Over 20 years ago, Julkunen and colleagues documented a decreased use of contraception by SLE patients compared to corresponding healthy women (59 % vs. 77 %); in addition, sexually active SLE patients more often used less effective barrier and natural methods [1]. Recent reports continue to identify lower-than-expected rates of contraception use in rheumatic disease patients. A 2008 survey of contraceptive use among 309 women with SLE of reproductive age (18–50 years old) evaluated likelihood of unintended pregnancy [2]. Of the 212 patients who responded, 97 had some risk of unplanned pregnancy during the previous 3 months; of these, 53 (55 %) reported unprotected sex on at least one occasion, and 22 (23 %) reported unprotected sex “most of the time.” In 2011, Yazdany et al. found a similar lack of consistent contraceptive use in their survey of 206 women with SLE aged less than 45 years. Eighty-six patients were at risk for unplanned pregnancy: 22 % of these reported inconsistent contraceptive use, and 55 % depended solely on (less effective) barrier methods. Most importantly, women on teratogenic medications were no more likely than women not on these medications to have used effective contraception [3].

The current pattern of inconsistent contraceptive use is not limited to the USA: a recent Swiss survey of rheumatic disease patients found that 27 % of the women on the potentially teratogenic drugs methotrexate or leflunomide were not using any form of contraception, although most of these patients indicated that they were aware of the medications’ potential teratogenicity [4]. As a point of comparison, a recent survey of reproductive-aged women in the general population revealed that only 11 % of those at risk for unintended pregnancy do not regularly use any form of contraception [5], demonstrating a decreased attention to contraception in women with rheumatologic disorders.

At least part of the problem may be that rheumatologists do not always screen patients for sexual activity and contraceptive use, whether due to time constraints or for other reasons. A prospective study of pediatric rheumatology clinic visits looked at screening for sexual activity and alcohol use in 178 adolescent patients [6]. Investigators then implemented an office-based intervention to improve rheumatologists’ identification of risk factors: as a result, screening for sexual activity increased from 12.4 to 36.2 %. Time was reported by physicians to be the major barrier to screening, although other factors cited included logistical problems, discomfort with the subject area, and ambivalence about the role of the rheumatologist in behavior screening. In a survey of adult female SLE patients at the University of California San Francisco, 59 % of 86 women at risk for unintended pregnancy stated they had not received contraceptive counseling in the past year, and women on teratogenic medicines were no more likely to have received contraceptive counseling than those not on these medications [3].

Efforts are underway within the rheumatology community to remedy this inconsistent attention to contraceptive issues. Counseling patients regarding the importance of contraception while on teratogenic medications is becoming increasingly formalized (internally or externally imposed) to assure all patients are educated regarding risk. For example, distribution of a methotrexate information booklet in a rheumatology outpatient clinic increased the awareness of the need for contraception from 60 to 100 % in one placebo-controlled trial [7]. In a recently published quality indicator set for SLE, of 20 quality indicators presented as priorities in lupus care, three focus on reproductive health: one of these cites the need for patient education regarding potential teratogenicity of medications and the necessity of contraception when starting a new lupus medication [8].

In addition to the proposed quality guidelines above, the Food and Drug Administration (FDA) has mandated patient education regarding need for contraception for certain medications [9]. In September 2012, the FDA mandated an educational program for medical professionals and patients to prevent unplanned pregnancies in patients using mycophenolate-containing medicines commonly used to treat SLE and other connective tissue diseases. The system, called the Mycophenolate REMS (Risk Evaluation and Mitigation Strategy), includes a medication guide, training for health care professionals, and the establishment of a pregnancy registry for women who become pregnant while on the medication and who agree to participate [10]. Formalized education will hopefully lead to both better rates of counseling by physicians and contraception use by patients.

Contraception: The Basics

Not all contraceptives are created equal: effectiveness varies widely, and so counseling for patients must include not only the necessity of contraceptive use but also guidance on the most effective and safe methods. Effectiveness of contraceptive methods is described in two ways: the “perfect use” (or theoretical) effectiveness is the effectiveness when used exactly as prescribed, and the “typical use” (or actual) effectiveness reflects “real world” use that includes forgotten pills or misplaced diaphragms. Perfect use and typical use effectiveness are closest for those methods not directly related to the act of intercourse, such as oral contraceptives, and are nearly identical for long-acting reversible contraceptives that require no effort on the part of the patient, such as an intrauterine device (IUD) or progesterone implant [11]. Rates for perfect and typical use for commonly used contraceptive methods are summarized in Table 11.1.

Table 11.1

Perfect use and typical use effectiveness for contraceptive methods

 

Effectivenessa

Method

Perfect use (%)

Typical use (%)

None

85

85

Barrier methods

Condom

2

15

Diaphragm

6

16

IUDs

Copper IUD

0.6

0.8

Levonorgestrel IUD

0.2

0.2

Progesterone-only

Progesterone pill

0.5

8

Progesterone implant

0.05

0.05

DMPA injection

0.3

3

Combined hormonal (pill, patch, vaginal ring)

0.3

8

Adapted from U.S. Medical Eligibility Criteria for Contraceptive Use, 2010 [12]

IUD intrauterine device, DMPA depot medroxyprogesterone acetate

aPercentage of women experiencing pregnancy during first year of use

Long-acting reversible contraception is widely considered the most effective form of contraception. A recent prospective cohort study of 9,256 women using contraception for a 3-year period found that long-acting reversible contraception (IUD or implant) was more effective than other commonly prescribed contraceptives (including oral contraceptive pills, patch, and vaginal ring). The contraceptive failure rate was 4.55 per 100 participant-years for the oral, patch and vaginal ring contraceptives compared to 0.27 per 100 participant-years for the long-acting methods. The failure rate for the depot medroxyprogesterone acetate (DMPA) injection was also quite low, and similar to that for the IUD and implant [13]. Despite the demonstrated greater efficacy for long-acting methods, the most common contraceptive methods overall used by women of childbearing age (15–44 years) in the USA are the oral contraceptive pill (27 %) and female sterilization (28 %). Rate of IUD use has increased from 1995 (when it was 0.8 %) to the present, but only to 5.6 %, despite its greater effectiveness and convenience [5].

Contraception may be reversible or nonreversible. This discussion of methods will focus on reversible contraception. Nonreversible contraception for women should only be performed after counseling and is achieved through tubal ligation or obstruction. It may be performed as a surgical ligation, with mechanical blockage by clips or plugs, or through coagulation-induced blockage [14].

Reversible contraception includes barrier methods, intrauterine devices, and hormonal contraceptives. “Natural” or fertility awareness methods are least effective and are not generally recommended as acceptable forms of contraception for rheumatic disease patients, especially for those on teratogenic medications.

Barrier Methods

Barrier methods include the condom (male and female), diaphragm, cervical cap, and contraceptive sponge. Importantly, barrier methods of contraception have a significantly lower typical use effectiveness than do hormonal methods or intrauterine devices. Despite the lower effectiveness, condoms offer certain advantages. The male condom is easily available and protects against sexually transmitted diseases including human immunodeficiency virus (HIV). A female condom is also available: approved by the FDA in 1993, it is composed of two flexible polyurethane rings (inner and outer) surrounding a polyurethane sheath and is designed to protect against both pregnancy and sexually transmitted diseases. The diaphragm is available only by prescription, since it must be fitted by a health care professional. It is a soft rubber cap on a wound metal spring that is inserted vaginally, and must be used with spermicide. The cervical cap is similar to the diaphragm, but may remain in place for up to 48 h, as opposed to 6–9 h for the diaphragm. The over-the-counter contraceptive sponge may remain in place for up to 24 h. Spermicide, most commonly nonoxynol-9, may be used alone or in combination with other methods [14]. Efficacy of barrier contraception is increased if two methods are used, e.g. condom and spermicide: as a result, this should be a standard recommendation for patients who wish to use barrier protection [15].

Intrauterine Devices

The IUD is an effective form of birth control even for most adolescents and nulliparous women, with few contraindications to use [12]. The IUD is the most commonly used form of reversible contraception worldwide [16], although prevalence of use in the USA is relatively low. The IUD is available worldwide in a medicated or non-medicated (inert) form; however, only medicated devices are available in the USA. Medicated IUDs contain either copper or levonorgestrel (20 mcg/24 h), a second generation progesterone. The mechanisms of action include an inflammatory endometrial foreign-body response as well as local changes due to release of medication. The less expensive copper-containing IUDs may remain in place for 10 years, but are associated with heavier menses and dysmenorrhea. The levonorgestrel-containing IUD (LNG IUD) remains in place for 5 years, but has several advantages over both the copper IUD and alternative progesterone-only contraceptives [14]. Unlike the copper IUD, the LNG IUD generally reduces dysmenorrhea and menstrual bleeding: complete amenorrhea occurs in up to 50 % of patients by 24 months [17]. In contrast to other progesterone-containing contraceptives that are administered orally, subdermally, or intramuscularly, the progestin effect of the LNG IUD is primarily local (although a small proportion of patients do report systemic side effects). Fertility quickly returns to normal with removal of the device.

Complications associated with IUD use include risk of expulsion of the device (5 % over 5 years) and risk of pelvic inflammatory disease (PID) [18]. With current IUDs, the risk of PID is mildly increased only in the 20 days following insertion and then returns to near baseline; the overall rate of infection from World Health Organization data is 1.6 infections per 1,000 woman-years [19]. This rate is quite low in comparison with older, less well-designed IUDs; as a result, IUDs are now recommended for use in nulliparous women.

Risk of infection is of particular concern in rheumatic disease patients especially in those patients treated with immunosuppressive therapy. Nonetheless, these are most often the patients with the greatest need for effective contraception. Although there are limited data on risk of infection with IUD use in patients treated with immunosuppressive medications, several reports show no increased risk of infection in immunocompromised HIV-infected women [20]. Most experts agree that the minimal risk of infection with IUD use is far outweighed by the significant risks associated with unintended pregnancy in women with active inflammatory disease on immunosuppressive medications [21].

In general, the efficacy of IUDs seems unaffected by medication use, but a single case report has described failure of the copper IUD in two patients on immunosuppressive regimens for renal transplant, perhaps related to an alteration in the local immune response generated by the copper [22] Absolute contraindications to any IUD use include current pregnancy or acute pelvic infection, unexplained uterine bleeding, and severe uterine distortion. Specific IUD type contraindications include current breast, uterine, or endometrial cancer (LNG IUD); or Wilson’s disease or copper allergy (copper IUD) [23]. IUD use is discouraged in women at high risk for sexually transmitted diseases, i.e. those with multiple sexual partners.

For patients with underlying chronic disease and ongoing health issues, it is helpful to know that women with IUDs in place may safely undergo magnetic resonance imaging when necessary.

Hormonal Contraception

Hormonal contraception is generally divided into two major categories: combined estrogen–progesterone preparations, and progestin-only preparations. Hormonal contraceptives may be administered through a variety of methods. Limited to “the pill” in previous years, various types of hormonal contraception may now be given orally or through a transdermal patch, vaginal ring, injection, subdermal implant, or IUD.

Combined Hormonal Contraceptives

The first birth control pill contained 150 mcg of the synthetic estrogen mestranol, three to five times the estrogen content of most current oral contraceptives. Current combined oral contraceptives contain a synthetic estrogen (ethinyl estradiol or mestranol, 20–50 mcg) and a progestin, one of multiple 17-α ethinyl analogs of 19-nortestosterone. The 19-nortestosterones include norethindrone, norethindrone acetate, levonorgestrel, and others, and are commonly termed “second generation progestins.” “Third generation progestins” include norgestimate, desogestrel, and gestodene; these were developed to decrease androgenic side effects (such as acne, hirsutism, nausea, and lipid changes) and increase progestational effects. Drospirenone is considered a “fourth generation progestin”: it is an analog of spironolactone and exhibits progestational, anti-androgenic, and anti-mineralocorticoid activity [14]. Importantly, progestins’ potential side effects differ according to their generation, which is especially pertinent for evaluation of suitability for rheumatic disease patients.

Combination hormonal contraceptives may be “monophasic” or “multiphasic”: monophasic contraceptives offer the same dose of each hormone over 21 days followed by a drug-free 7-day period. Newer formulations tend to be multiphasic (biphasic or triphasic): these formulations vary the amounts of estrogen and progestin over the course of the menstrual cycle in an effort to reduce total drug exposure while maintaining efficacy. Extended-cycle hormonal contraception preparations can safely limit menses to several times per year without loss of efficacy or increased risk of side effects.

Newer formulations of combined hormonal contraceptives with novel administration methods meant to enhance convenience and compliance include the transdermal patch and the intravaginal ring. The transdermal patch is applied weekly for 3 weeks, followed by 1 week with no patch: it delivers 20 mcg ethinyl estradiol and 150 mcg norelgestromin (an active metabolite of norgestimate) per 24 h. Efficacy is similar to the pill, however overall estrogen exposure is increased, with a suggested increased risk of venous thromboembolism [2426]. The intravaginal ring releases 15 mcg ethinyl estradiol and 120 mcg etonogestrel (an active metabolite of desogestrel) per 24 h: it is kept in place for 3 weeks and removed for 1 week every month before a new ring is inserted.

Combined hormonal contraceptives have multiple effects on the reproduction system that account for the high rate of effectiveness with perfect use: ovulation is blocked due to inhibition of the mid-cycle surge of gonadotropins, sperm penetration is inhibited because of changes in cervical mucous, uterine and tubal motility is altered, and blastocyst survival is impaired by inhibition of endometrial gland function [14].

Occasionally non-contraceptive benefits of combined hormonal contraceptives are the primary indication for use: these include regulation of menstrual dysfunction and dysmenorrhea, prevention of functional ovarian cysts, and treatment of endometriosis. In addition, combination oral contraceptive has been shown to decrease risk of PID and certain cancers (ovarian, uterine, and colorectal) and to exert a positive effect on bone mass [27].

Mild side effects of combined hormonal contraceptives include nausea, edema, malar facial pigmentation (chloasma), breast tenderness, and abnormal mid-cycle uterine bleeding: these may be significant enough in certain patients to cause discontinuation or a change to an alternative preparation. Impaired glucose tolerance and increased risk of hypertension are possible. Likelihood of specific side effects depends on amount of estrogen and amount and type of progestin. For example, mid-cycle ovulatory spotting is more likely with the lower-dose estrogen preparations. The more androgenic progestins (i.e. the second generation progestins) are more likely to have an adverse effect on the lipid profile than are later (third or fourth) generation progestins [14]. A positive effect on mood and acne has been suggested for combined contraceptives containing the fourth generation progestin drospirenone, due to its anti-mineralocorticoid and anti-androgenic effects [28].

While risk of serious complications is low with combined hormonal contraceptives, they do occur. Such complications can be limited with careful assessment to exclude patients at greatest risk. Usual contraindications to use are listed in Table 11.2. Serious complications are usually vascular in nature, including venous thromboembolism, stroke, and myocardial infarction. Risk of cerebral vein thrombosis appears to be particularly increased with combined hormonal contraceptive use [29]. There is also an increased risk of cervical cancer [30] and a slightly increased risk of breast cancer in current (but not past) users [31].

Table 11.2

Absolute and relative contraindications to the use of estrogen-containing contraceptives

Absolute contraindications

Pregnancy

Postpartum <21 days

Age >35 and >15 cigarettes/day

Multiple risk factors for cardiovascular disease

Uncontrolled hypertension, hypertension with vascular disease

Acute DVT/PE

History of DVT/PE with high risk for recurrence including

Thrombophilia

History of estrogen-induced DVT/PE

Recurrent DVT/PE

DVT/PE associated with active cancer

Surgery with prolonged immobilization

Known thrombogenic mutations

Current and history of ischemic cardiac disease

Stroke

Complicated valvular disease

Peripartum cardiomyopathy (acute mild or severe)

Systemic lupus erythematosus with positive or unknown aPL

Migraine with aura or age ≥35

Current/recent breast cancer

Diabetes with complications, >20 years duration, other vascular disease

Acute viral hepatitis, severe cirrhosis, other severe liver disease

Hepatocellular adenoma or hepatoma

Complicated organ transplant (rejection or vasculopathy)

Undiagnosed genital bleeding

Relative contraindications

Postpartum >21 days with other risk factors for VTE, or breastfeeding

Age >35 and <15 cigarettes/day

Bariatric surgery (malabsorptive procedure)

Hypertension

History DVT/PE with no risk factors

Known hyperlipidemia

Peripartum cardiomyopathy (chronic mild)

Migraine without aura (<35)

History of breast cancer, NED >5 years

Inflammatory bowel disease

Symptomatic current gallbladder disease, OC related cholestasis

Certain antiretroviral therapies

Certain anticonvulsant therapies

Rifampin therapy

Adapted from US Medical Eligibility Criteria for Contraceptive Use, 2010 [12]

Effects of combined hormonal contraceptives on the hemostatic system are complex and involve multiple mechanisms, although the overall net effect is clearly prothrombotic. Plasma levels of most coagulation factors (except factor V) increase while antithrombin III levels decrease. APC resistance is demonstrated that is only partly explained by an observed decrease in protein S. Multiple changes in the fibrinolytic system lead to an overall down-regulation of fibrinolysis. As a result of these multiple and additive effects on hemostasis, the overall risk of venous thromboembolism in women on current combined hormonal contraceptives is increased by a factor of 3–5 from the baseline annual risk in healthy women of 1 in 10,000 [32]. While the likelihood of venous thromboembolism overall is still low given the low baseline risk in healthy young females, the estimated 100 million women worldwide who use combined hormonal contraception make the absolute number of events significant. Non-oral preparations have at least similar risks to the oral preparations, and the transdermal patch has been suggested to have a greater risk of thrombosis due to about 60 % greater estrogen exposure [33].

Although focus is commonly on level of estrogen as the primary culprit in promoting thrombosis, both estrogen and progestin components may contribute to increased venous thrombosis risk. The relative risk of venous thromboembolism was increased by a factor of 10 with the earliest oral contraceptives: reducing the estrogen content has markedly reduced the thrombosis risk of oral preparations. Since lower doses of estrogens have been used, variation in type of progestin now accounts for some of the variability in venous thrombosis risk among different preparations of hormonal contraceptives: the third generation progestins confer greater venous thrombosis risk than do second generation progestins due to greater demonstrated APC resistance. Lowest risk of venous thromboembolism is in combined contraceptives containing levonorgestrel [34]. Duration of use also affects risk: risk is highest in the first year of use and decreases in later years; increased risk disappears once the drug is discontinued.

Combined hormonal contraceptive-associated risk of venous thromboembolism is increased further in the presence of genetic or acquired thrombophilia: the presence of a family history of thrombosis should prompt a prothrombotic work-up prior to institution of combined hormonal contraception. Risk of clotting events is also increased in the presence of smoking (more than ten cigarettes per day), age over 35 years, and obesity. Obesity—defined as a body mass index (BMI) > 25 kg/m2—increases the risk of venous thromboembolism by a factor of 2 in the general population and by a factor of 10 in users of combined hormonal contraception [3536]. Although combined hormonal contraceptives may be continued in patients undergoing low risk surgery, if possible they should be discontinued 4–6 weeks before planned moderate or high risk surgery and only restarted when the patient returns to ambulatory status.

There is an observed twofold stroke risk among all combination oral contraceptive users that is dependent on the presence of additional risk factors such as hypertension, migraine, smoking, and age greater than 35 years [37]. Healthy normotensive non-smoking women aged 35 years or younger do not have an increased risk of ischemic stroke with current low dose combination oral contraceptives [38]. Risk of hemorrhagic stroke is also increased in women over age 35 [39]. Lower estrogen content of oral contraceptives (20 mcg versus 50 mcg) is associated with a lower risk of ischemic stroke. In contrast to venous thromboembolism risk, likelihood of stroke associated with use of third generation progestins is no higher than that associated with second generation progestins, and may in fact be slightly lower [40]. Myocardial infarction risk is twice as high among all users of oral combined contraceptives, and risk is greatest among patients with the classical risk factors of older age, cigarette use, hypertension, diabetes mellitus, hyperlipidemia, and obesity. As with ischemic stroke, risk for myocardial infarction may be lower in patients using contraceptives containing third generation rather than second generation progestins [41]. Likelihood of peripheral arterial disease is also increased in users of combination hormonal contraceptives [42].

Progesterone-Only Contraceptives

Progesterone-only contraceptives present an alternative and highly effective option for patients who cannot or will not take estrogen-containing preparations. They may also be a good option for patients on hepatic enzyme-inducing drugs, such as anticonvulsants, depending on the preparation. Although recommendations differ, most authorities agree that progesterone-only contraceptives are safe and effective for patients who are at increased risk for venous or arterial thromboembolism. In general, the progestins used are most often second generation, which have a lower relative risk for venous thrombosis.

Oral progestin-only contraceptives contain norethindrone or norgestrel: they are less popular than combination contraceptive pills because they have greater rates of side effects, particularly irregular vaginal bleeding, and are slightly less effective in perfect and typical use rates (Table 11.1). Progestin-only pills do not reliably inhibit ovulation, as do combination estrogen-progestin pills, although other mechanisms of action are present including changes in cervical mucous, altered tubal motility, and inhibition of endometrial gland function. It is important to take the progestin-only pill (also called the “mini-pill”) at the same time each day to ensure a stability in serum level that maximizes effectiveness [43]. Unlike combination pills, the progesterone-only pill is considered safe to use while breastfeeding.

Other progesterone contraceptives reliably confer more stable serum levels through different methods of delivery. The progesterone-only contraceptive DMPA is administered as an intramuscular or subcutaneous injection every 3 months: it is convenient and efficacy is greater than with the oral progestin preparations due to the additional mechanism of ovulation suppression. Another advantage is that efficacy of DMPA is not reduced by high BMI or use of concurrent medications, and it can be initiated without a pelvic or breast exam or routine labs.

Although the first generation of subdermal implantable contraceptive devices were withdrawn from the market, a currently available single rod subdermal implant placed in the inner upper arm releases etonogestrel over a 3-year period. It may initially inhibit ovulation for a time in the period following insertion, but does not consistently inhibit ovulation in the latter part of the 3 years, although other mechanisms remain intact [14]. A two-rod subdermal device that releases levonorgestrel has also been FDA-approved but is not marketed in the USA.

Non-contraceptive benefits of progesterone-only contraceptives are occasionally the primary reason for use and include decreased menstrual bleeding, cessation of menses, and amelioration of endometriosis symptoms. Minor side effects are more common than with combined contraceptives, however: progestin-only preparations are more likely to cause irregular, “break-through” bleeding (the most common cause of discontinuation) and weight gain [44]. Unpredictable bleeding with progesterone-only contraceptives is greatest within the first 3 months of use and diminishes significantly with time [45]. While later-generation progestins may increase blood pressure, DMPA does not impair glucose tolerance or cause hypertension. In general, progestin-only contraceptives have little effect on lipid levels. Importantly for rheumatic disease patients, DMPA, but not the progesterone-only pill or LNG IUD, may cause reversible bone loss due to inhibition of ovulation: the reduction in bone density in healthy women is 5.7–7.5 % after 2 years of use [46]. History of fragility fracture, known osteoporosis, or strong risk factors for osteoporosis (such as corticosteroid use or rheumatoid arthritis) are generally considered contraindications to use of DMPA. An additional disadvantage of DMPA is that there may be a delayed return to fertility: it is not recommended for patients who plan pregnancy within the next year.

Risk for thromboembolism with progesterone-only contraception, while clearly lower than for combination hormonal contraceptives, is uncertain. Package inserts often list a history of venous thromboembolism as a contraindication to use of progesterone-containing products, but the WHO and CDC believe these methods to be generally safe for use in such patients with benefit outweighing risk [47]: this discrepancy has been a source of some confusion among physicians and patients [4849]. Woman with multiple risk factors for arterial cardiovascular disease, women with a history of stroke or ischemic heart disease, and women with current venous thromboembolism are still classified by the WHO and CDC as “category 3” (where “the risk of use may exceed the benefits”) [47]. These patients also require effective contraception, however, and decisions are must be made on a case-by-case basis, weighing the relative risk of unintended pregnancy against the risk of the contraceptive method.

Emergency Contraception

Emergency contraception, to prevent pregnancy after unprotected intercourse, is widely available. Options include physician placement of a copper IUD within 5 days, prescription-only oral selective progesterone receptor modulators (ulipristal or mifepristone) within 120 h, and non-prescription oral levonorgestrel within 72 h (currently available over the counter for patients age 17 or older). There is an ongoing movement to remove the age restriction for over-the-counter sales to younger women [50] and recent legal decisions suggest the medication may soon be available to individuals aged 15 or older without a prescription.

The copper IUD is widely considered to be the most effective form of emergency contraception, but placement requires a doctor’s visit and exclusion of pregnancy first (as does the ulipristal or mifepristone pill). The copper IUD has the advantage of providing continued long-term protection after insertion. Oral levonorgestrel, available as a single 1.5 mg pill or as two 0.75 mg tablets, is slightly less effective, but it is the most readily available and safest method: it does not interrupt an established pregnancy and can be obtained without a prescription. The most common side effects are nausea and vomiting. Both of the oral preparations (levonorgestrel and selective progesterone receptor modulators that require a prescription) are strongly affected by BMI and, as a result, risk of pregnancy is four times higher in obese women using these methods. Thus, the copper IUD may be the preferred choice for emergency contraception in obese women. Cardiovascular disease and thrombophilia are not contraindications to the use of any form of emergency contraception. Drugs that induce hepatic enzymes may reduce the efficacy of the oral medications [51].

Specific Issues for Rheumatic Diseases

Certain issues are of obvious concern when evaluating risk of contraceptive methods in patients with rheumatic diseases. For example, a long-held perception that estrogen’s immunostimulatory effects promote flare in systemic lupus has limited use of combined hormonal contraceptives in these patients. Studies published within the last 10 years, however, have established that risk of flare from estrogen-containing oral contraceptives is low in stable lupus patients without significant renal disease. Presence of antiphospholipid antibodies (with the associated thrombosis risk) should limit choice of hormonal contraception, however, to non-estrogen (progesterone-only) medications or devices. Additionally, hormonal contraceptives have the potential to interact with many medications used for rheumatic disease patients: medication interactions for these chronically ill patients must be carefully evaluated.

Systemic Lupus Erythematosus

Multiple observations contribute to the reluctance of many rheumatologists to consider estrogen-containing contraceptives for their patients with SLE, including disease demographics with a female-to-male ratio of 9:1 during the reproductive years (when estrogen levels are at their highest), exacerbation of lupus in mouse models with administration of exogenous estrogen [52], estrogen metabolism alterations in patients with SLE [53] and clinical reports [54]. Estrogen has demonstrated an in vitro immunostimulatory effect that includes depression of cell-mediated immunity, natural killer cell function, and immune surveillance [55]. In addition, physicians may have personal experience with patients flaring or developing SLE in the setting of new oral contraceptive use.

Large-scale epidemiology studies offer conflicting data on whether oral contraceptive use in the general population increases risk of development of new SLE. A slight increase in risk of developing SLE with past use of oral contraceptives was demonstrated in the prospective Nurses’ Health Study (RR 1.9; 95 % CI 1.1–3.3) [56] and others [57] but alternate population-based case–control studies do not confirm an increased risk [5859]. Early reports suggested risk of flare of lupus in patients with established disease exposed to combined oral contraceptives [546061].

Two randomized controlled clinical trials published in 2005 suggest no significant increase in risk of flare from combination hormonal contraceptives in well-defined lupus populations with stable disease activity. The Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA) trial randomized 183 lupus patients with inactive or stable-active disease to either oral contraceptive (triphasic ethinyl estradiol 35 mcg/norethindrone 0.5–1 mg) or placebo for twelve 28-day cycles. Patients with any history of thrombosis or the presence of antiphospholipid antibodies (moderate to high anticardiolipin antibody or positive lupus anticoagulant) were excluded, as were patients with significant disease activity. The severe flare rates at one year did not differ between the treated and the placebo groups (0.084 vs. 0.087 for treatment group vs. placebo group, respectively). Mild-moderate flares were also equivalent in both groups, and there was no difference in overall combined flare rates between the two groups [60].

Rather than utilizing a placebo control, the study by Sanchez-Guerrero and colleagues compared use of combined oral contraceptive (ethinyl estradiol 30 mcg/levonorgestrel 150 mcg/day) in patients with SLE with two other commonly used methods of birth control, a progestin-only contraceptive (levonorgestrel 0.3 mg/day) and a copper IUD. Disease activity was similar among the three groups, including rates of severe flare, global disease activity, and overall flare. The progesterone-only group had a higher rate of discontinuation, and the severe infection rate was slightly higher in the copper IUD group (although there were no instances of pelvic infection in the IUD group) [61].

A systematic review published in 2009 evaluated 14 articles concerning contraceptive use in patients with SLE, including the two randomized trials cited above. The authors concluded that many women with SLE are good candidates for most contraceptive methods including hormonal contraception, but discouraged use of combined hormonal contraception in women with antiphospholipid antibodies [62].

In summary, combined hormonal contraceptives are an effective and generally safe form of birth control for many patients with SLE. Even in the general population, however, they are not for everyone: 16 % of unselected women ages 20–51 in a USA national sample [63] were ineligible for combined hormonal contraceptives based on traditional contraindications (Table 11.2). It is to be expected that a higher proportion of lupus patients will be ineligible based on the presence of antiphospholipid antibodies, active or severe disease, and the presence of traditional contraindications. However, combined hormonal contraceptives do not appear to significantly increase risk of flare in the subset of lupus patients with inactive or stable-active SLE (who do not have antiphospholipid antibodies) and offer an attractive option for these patients.

In contrast, progesterone has not been suggested to increase risk of lupus flare or risk of thrombosis in these patients. Progestin contraceptives have also been evaluated: the oral pregnane progestins chlormadinone acetate and cyproterone acetate (anti-androgenic, anti-estrogenic weak progestins available in Europe but not in the USA) have been recently studied as a potential contraceptive alternative in patients with SLE. The authors reported a decrease in disease activity with a low incidence of thrombosis (one venous and two arterial thromboses) in 187 patients treated for a mean period of 46 months [64].

Clearly, use of any form of contraception in lupus patients involves careful thought. Important considerations in choice of contraceptive method include details particular to the individual patient as well as the specifics of the contraceptive under consideration. To minimize risk of increased disease activity, it would seem prudent to avoid combined hormonal contraceptive methods with higher estrogen exposures than were used in the published studies, particularly the transdermal patch with its overall higher estrogen exposure. In addition, the type of progesterone may be of concern: in addition to the differences in thrombotic risk associated with the different generations, the fourth generation progestin drospirenone (a spironolactone analog) may cause hyperkalemia in susceptible individuals. Women taking medications that increase serum potassium or alter renal function (such as angiotensin converting enzyme inhibitors) or women with renal insufficiency require careful monitoring of serum potassium if taking drospirenone-containing oral contraceptives.

For SLE or other rheumatic disease patients unable to take estrogen-containing preparations, the progesterone-only contraceptives offer an alternative to barrier methods. The LNG IUD is an option that appears to be safe for most patients. Although risk of infection (PID) is not well studied in patients on immunosuppressive medications, extrapolation from safety data in immunocompromised HIV-infected patients suggests low risk of infection. DMPA is not a good long-term option for patients with osteoporosis or long-term corticosteroid use due to risk of decrease in bone density. There are no good data on the etonorgestrel subdermal implant in SLE patients, although thrombosis risk might, in theory, be slightly higher than with levonorgestrel-containing preparations due to the inclusion of a third generation progestin.

Antiphospholipid Syndrome

Antiphospholipid antibodies (aPL) are well recognized as significant risk factors for thrombosis and pregnancy morbidity in patients with primary antiphospholipid syndrome as well as those with underlying SLE and other rheumatic diseases. About 30 % of SLE patients have positive aPL although rates of antiphospholipid syndrome (APS)—presence of the antibody as well as typical clinical complications—are lower. Ability to predict risk of thrombosis or pregnancy complications for an asymptomatic aPL-positive patient is limited, although risk appears to be highest for those patients with lupus anticoagulant and/or high titer IgG anticardiolipin [65]. Current data suggest that presence of additional prothrombotic risk factors, whether genetic variants, medical comorbidities, or exogenous factors, additionally increase risk [66]. Genetic factors include factor V Leiden, prothrombin gene (G20210A) mutation, hyperhomocysteinemia due to MTHFR homozygous mutations, and deficiencies of proteins C, S and antithrombin III. Medical factors include malignancy, pregnancy, nephrotic syndrome, and traditional cardiovascular disease risk factors such as hypercholesterolemia and hypertension. Exogenous factors include cigarette smoking, estrogen use, surgery, and prolonged bedrest.

Combinations of prothrombotic risk factors are surprisingly frequent. aPL are rare in the general population, but certain of the prothrombotic genotypes are quite common. Heterozygous factor V Leiden affects 3–8 % of the population and accounts for 20 % of first time venous thromboembolism; the prothrombin gene mutation (G20210A) affects 2–4 % of the Caucasian population and, by increasing plasma prothrombin levels, leads to a two to fourfold increased risk of thrombosis [67]. Use of a combined hormonal contraceptive exerts an additive effect on the risk of thrombosis in patients with hereditable thrombophilias, many of whom are not aware of their increased thrombotic risk [68]. In general, experts do not recommend screening for inherited thrombophilias in patients without a personal or family history of thrombosis before starting combined hormonal contraceptives, due to the low yield and high cost [69]; patients with a family history of thrombosis or other relevant risk factors are usually screened.

As might be expected, the addition of aPL to other prothrombotic conditions increases the overall risk of thrombosis. For example, aPL-positive patients with thrombosis are far more likely to be positive for heritable risk factors such as factor V Leiden and prothrombin gene mutation than are asymptomatic aPL-positive patients [70]. Factor V Leiden and the prothrombin gene mutation have been shown to contribute to risk of venous thromboembolism in patients with systemic lupus, and risk was potentiated when combined with presence of antiphospholipid antibodies [71].

No prospective controlled studies have been designed to specifically evaluate the thrombotic risk of combined hormonal contraceptive use in patients with aPL for obvious reasons. Multiple case reports and series, however, describe aPL-positive patients who have developed vascular thrombosis presumably triggered by oral contraceptives [7276]. Since aPL increase risk of arterial as well as venous thrombosis, use of combined hormonal contraceptives will almost certainly increase risk of both types of vascular events in these patients. Additional factors which increase risk of arterial vascular complications—such as complicated migraine, atherosclerosis, or hyperlipidemia—may be present or increased in patients with aPL and may further increase risk of stroke or myocardial infarction. These case reports, as well as the more general demonstration of potentiated thrombotic risk with multiple prothrombotic risk factors, have generated significant concern regarding use of combined hormonal contraceptives in women with aPL, especially those with high titer aCL antibody or the lupus anticoagulant. In the SELENA (Safety of Estrogen in Lupus Erythematosus—National Assessment) study, designed to assess risk of flare in stable SLE patients treated with combined oral contraceptives, the study design specifically excluded patients with moderate to high titer IgG, IgM, or IgA aCL’s or any positive lupus anticoagulant, including patients with positive antibody but no history of thrombosis. Although some patients in both treatment and placebo groups presumably had low titer aCL (no numbers are reported), there was no increase in thrombotic complications in the oral contraceptive group versus the placebo group: two treated patients and three placebo patients developed clots [60]. In another group of SLE patients, treatment with either combined or progestin-only oral contraceptives resulted in the same rate of thrombosis, two patients out of 54 in each group (all four were reported to be aPL positive) [61].

Non-thrombotic aPL manifestations are not uncommon, and it is not known whether they might be affected by combined oral contraceptives. Risk of chorea, however, which is associated with both aPL and SLE, may be increased further by addition of combined oral contraceptives [7778]. It has been suggested that combined oral contraceptives may induce development of aPLs in healthy women, specifically anti-β2 Glycoprotein I IgG [79], but this is not generally accepted and has yet to be confirmed.

Use of progesterone-containing contraceptive methods, while still debatable, is generally accepted as a lower risk but effective method of birth control in patients unable to use estrogen-containing methods. In addition, they may offer a unique advantage in addition to contraceptive efficacy in patients on warfarin: they can reduce heavy menstrual blood flow associated with anticoagulation. Several reports describe life-threatening luteal ovarian cyst hemorrhagic rupture in APS patients on warfarin requiring surgical hemostasis and blood transfusion; post-surgical treatment with certain progesterone contraceptives was shown to be protective [8081].

Rheumatoid Arthritis and Other Inflammatory Arthritides

In distinct contrast to the concerns expressed for SLE patients regarding risk of combined hormonal contraceptives, it has been suggested that rheumatoid arthritis (RA) patients may potentially benefit from treatment with combined hormonal contraceptives. This is based on anecdotal reports, as well a demonstrated improvement of symptoms during pregnancy [82] and an increased risk of flare postpartum [83].

Most clinical research on contraceptive use in RA, however, has focused on the related but different question of whether combined oral contraceptives reduce the risk of developing new RA: this issue remains unresolved. A number of reports suggest the rate of RA development to be reduced in current oral contraceptive users [8487]. Hazes et al. demonstrated a relative risk of new RA in current users of oral contraceptives to be 0.58, and 0.39 in ever-users, independent of dose, duration of use, or presence of HLA DR4 [87]. Other studies have suggested a duration-dependent protective effect [88] as well as a protective effect against development of severe or seropositive RA [89], while others show no effect [9092]. Analysis from the Nurses’ Health Study did not show a protective effect of past use of oral contraceptives, although authors could not rule out a modest protective effect of current use [93].

Several epidemiologic studies do suggest a reduction in development of severe disease in current RA patients who are using oral contraceptives. A meta-analysis by Spector et al. suggested that oral contraceptive use does not have a protective effect on the development of RA, but may prevent the progression to severe disease [88]. A case–control study evaluated 176 women with RA and 145 control subjects; RA patients were further categorized as having severe or mild disease. Use of oral contraceptives seemed to have a protective effect on the development of severe RA: 44 % of patients with mild RA used oral contraceptives as compared with just 21.7 % of those with severe RA (p < 0.001) [89]. In addition, after adjusting for age, parity, and breastfeeding, the relative risk of developing severe disease for RA patients using oral contraceptives for greater than 5 years was 0.1 (95 % CI 0.01–0.6). Another study following an inception cohort of 132 female RA patients for an average of 12 years suggested a trend for patients using oral contraceptives to have both less radiographic joint damage and a better functional level than those patients not using them [92]. A recent limited systematic review of contraceptive methods in rheumatoid arthritis did not identify any effect of hormonal contraceptives on RA progression [94].

Post-menopausal use of estrogen therapy has also been evaluated in RA patients and showed no significant effect on disease activity but was associated with an increase in bone density [9596].

Despite the suggestion of benefit in protecting against severe disease progression, therapeutic use of combined hormonal contraceptives in established RA has not been studied in a placebo-controlled manner. Part of the reason may rest on the fact that hormone studies in RA patients do not suggest unusually low endogenous estrogen levels: rather, they show normal estrogen levels with low androgen levels: low levels of gonadal and adrenal androgens (testosterone and dehydroepiandrosterone) have been demonstrated in serum and synovial fluid of RA patients of both sexes [9798], yielding a reduced ratio of androgen/estrogen that suggests a potential reduction in immunosuppressive effect.

Based on these data, several hormonal attempts at RA therapy have focused on androgenic supplementation, with mixed results [99101]. Early efforts with testosterone therapy showed improvement in disease activity but patients developed complications of masculinization and menstrual disturbances [99]. Treatment with the anabolic androgenic steroid nandrolone (19-nortestosterone) was not helpful in reducing disease activity [100]. A more recent double-blind placebo-controlled study of testosterone in post-menopausal RA patients suggested a response in pain score, ESR and disability; 21 % patients showed improvement that was not statistically significant [101].

In summary, although there are suggestions that combined hormonal contraceptives may protect against development of severe disease in RA patients, they have not been definitively shown to have a non-contraceptive benefit on RA disease activity. There is certainly no evidence, however, to suggest that their use would exacerbate disease and so hormonal contraceptive methods represent a safe and effective option for patients with RA.

While purely theoretical, given the low androgen levels demonstrated in some RA patients, a case could be made for use of oral contraceptives containing the relatively more androgenic (second generation) progestins, to maximize androgenic immunosuppression, if one is hoping for a non-contraceptive disease modifying benefit.

In terms of the particular method chosen for RA patients, combination oral hormonal contraceptives or the transdermal patch may be effective and especially convenient for patients with RA. Insertion of a diaphragm or of the vaginal ring may be difficult for patients with severe arthritis affecting the hands or hips. The LNG IUD, placed by a physician for 5 years, offers convenient and long-lasting protection although safety with intensive immunosuppressive treatment regimens has not been evaluated. Finally, the subdermal etonorgestrel implant may provide convenience without concern for pelvic infection, although ovulation may be inhibited in the early months of use leading to a theoretical (and as yet undocumented) negative effect on bone density. DMPA, with its attendant risk of decreasing bone density, would not seem a good long-term choice for the RA patient.

Other Rheumatic Diseases

Contraceptive methods in patients with other rheumatic diseases have not been well studied. Estrogen alone has been evaluated as a potential vasodilator therapy in several cases of severe Raynaud’s phenomenon associated with systemic sclerosis. Estrogen administered intravenously improved endothelial function in ten female patients with systemic sclerosis and Raynaud’s phenomenon with a significant increase in endothelium-dependent dilatation [102], and similarly reversed cold-induced myocardial ischemia on nuclear imaging in a patient with Raynaud’s and systemic sclerosis [103]. Use of oral estrogen in the form of combined hormonal contraceptives has not been demonstrated to affect patient-reported frequency, severity, or duration of Raynaud’s attacks, however, although many patients do report improvement in Raynaud’s symptoms during pregnancy [104]. In contrast, exogenous hormones administered in the form of hormone replacement therapy potentially prevents the development of isolated pulmonary hypertension in post-menopausal women with systemic sclerosis [105], presumably by replicating the protective effect of estrogen on the endothelium.

There are no significant data on effects of estrogen in patients with vasculitis, but it seems reasonable to avoid estrogen-containing contraceptives in patients with atherosclerosis or vasculitis who have increased risk for ischemia or stroke. While most vasculitides affect males and older individuals preferentially, Takayasu’s arteritis affects women during the reproductive years and use of estrogen-containing contraceptives may be a concern in these patients.

There are interesting and preliminary animal data that demonstrate that estrogen may positively influence the degree of disruption in skeletal muscle after ischemia-reperfusion-induced damage, suggesting a theoretical potential for estrogen to positively influence rate of skeletal muscle recovery [106]; how this might translate to clinical myositis in humans is not clear. Conversely, anti-estrogen medications (tamoxifen and anastrozole) have been reported to improve dermatomyositis rash in two patients; however, no data suggest that exogenous estrogen in any form worsens dermatomyositis rash [107].

Medication Interactions

Potential interactions of hormonal contraceptives with other medications are well recognized, and may lead to decreased efficacy of either the contraceptive or the alternative medication. Since many rheumatic disease patients are on multiple medications, it is important to check for pharmacologic interactions before advising hormonal contraception (Table 11.3). Medications commonly used in rheumatic disease patients that have potential interactions with estrogen-containing contraceptives include anticonvulsants, corticosteroids, warfarin, cyclosporine, and mycophenolate [108109]. Most antibiotics, with the exception of rifampin, do not significantly affect efficacy [110]. Herbal medications may also increase clearance of oral contraceptives and decrease efficacy, for example St. John’s wort [111].

Table 11.3

Medication interactions with combined hormonal contraceptives

Medication

Effect with concomitant combined hormonal contraceptive (CHC)

Antibiotics

 

Penicillins, cephalosporins, macrolides, metronidazole, sulfa, tetracyclines

Rifampin; Griseofulvin; Certain antivirals

↓ CHC efficacy due to ↑ intestinal transport and ↓ enterohepatic reabsorption (small effect)

↓ CHC efficacy

Anticonvulsants

 

Barbiturates; Carbamazepine, Oxacarbazine; Topiramate

Phenytoin

Lamotrigine

↓ CHC efficacy

↑ phenytoin concentration and ↓ CHC efficacy

↓ lamotrigine concentration

Modafinil

↓ CHC efficacy

Corticosteroids

↑ steroid concentration

Cyclosporin

↑ cyclosporine concentration

Mycophenolate

Possible ↓ CHC efficacy

Warfarin

↑ or ↓ warfarin effect due to alterations in metabolism

Thyroid hormone

↓ levels of free thyroxine due to ↑ levels of thyroxine binding globulin

Potassium-sparing diuretics

Hyperkalemia risk with drospirenone-containing CHC

Adapted from Fotherby [108] and Amy and Tripathi [11]

Summary

There are several general points regarding various modes of contraception that are relevant to most patients with rheumatic disease (Table 11.4). While general guidelines are useful, contraceptive choice ultimately depends on the individual patient, her medical condition, and her stage in reproductive life; it may also be influenced by social and religious factors.

Table 11.4

Benefits and disadvantages of various contraceptives for rheumatic disease patients

Contraceptive method:

Relative efficacy

Ease of use

Risk of flare

Risk of thrombosis

Risk of infection

Risk of osteoporosis

Gynecologic side effects

Barrier

Condom

+

OTC; some protection against STI’s

None (NT)

Diaphragm

+

Rx by MD; possible difficulty with insertion hand or hip arthritis

None (NT)

IUD

Copper

++++

Placed by MD; lasts 10 years

None

Low risk first 20 days; NT in IC pts

Increased cramps and bleeding

LNG

++++

Placed by MD; Lasts 5 years

None (NT)

Low risk first 20 days; NT in IC pts

Decreased cramps and bleeding; fewer hormonal SE than systemic prog methods

Progesterone-only

Pill

++

Rx by MD; must take same time every day; only method rec for use during lactation

None

Min-none

Spotting and decreased menstrual bleeding

Implant

++++

Insertion by MD; lasts 3 years

None (NT)

NT likely min

 

Unknown (inhibits ovulation for some time after initial placement)

Initial spotting then decreased menstrual bleeding

DMPA

++++

Injection by MD; Every 3 month

None (NT)

Min-none

Decreases bone density: avoid with known low bone density, steroid use or RA

Initial spotting then decreased menstrual bleeding; delayed return to fertility

Morning-after pill

++

OTC (most ages)

None (NT)

Min-none

Combined

Pill

+++

Rx by MD; take daily

No increased risk in stable aPL(-) inactive patients

Increased: avoid in aPL(+) or other thrombotic risk factors

May increase bone density

Regular cycle

Patch

+++

Rx by MD; replace weekly

NT but estrogen levels higher than pill

Increased: avoid in aPL(+) or other thrombotic risk factors may be higher than other CHC’s

May increase bone density

Regular cycle

Vaginal ring

+++

Rx by MD; replace weekly; possible difficulty with insertion hand or hip arthritis

NT estrogen levels similar to pill

Increased: avoid in aPL(+) or other thrombotic risk factors

May increase bone density

Regular cycle

Relative efficacy: + Poor effectiveness, ++ Moderate effectiveness, +++ Good effectiveness, ++++ Excellent effectiveness

OTC available over-the-counter, STI sexually transmitted infection, NT not tested, IC pts Immunocompromised patients, RA rheumatoid arthritis, Prog progesterone, SE side effects, Min minimal, Combined and CHC combined estrogen–progesterone contraceptives, aPL antiphospholipid antibody

Combined hormonal contraceptives may be used in most rheumatic disease patients but should not be used in those with active SLE or increased risk for thrombosis including those with history of thrombosis, positive aPL, or active vasculitis. Progesterone-containing methods are good alternatives for most patients who cannot take estrogen, and may be useful for decreasing heavy menstrual blood loss in patients on warfarin. Long-acting methods of birth control, such as the IUD, are effective and convenient for most patients. While use of IUDs has previously been discouraged in women who have not completed childbearing, IUDs are now recommended for use in most women including nulliparous women who are not at increased risk for sexually transmitted diseases (i.e., those without multiple partners). While unclear how to best assess risk for IUD-associated infection in rheumatic disease patients on immunosuppressive therapy, peri-insertion antibiotic treatment has been suggested to reduce the slight risk of post-insertion infection in the first 20 days [21]. Finally, when prolonged immobilization is necessary in patients with rheumatologic illness, whether due to flare of disease, surgery, or other hospitalization; estrogen-containing contraceptives should be discontinued if possible, and prophylactic heparin therapy added to reduce risk of venous thromboembolism.

Whatever the patient’s clinical and social situation, ongoing discussion between the patient, her rheumatologist, and her gynecologist is the best way to ensure use of the most appropriate safe, effective, and acceptable contraceptive method.

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