Contraception in patients with systemic lupus erythematosus and antiphospholipid syndrome LR Sammaritano Lupus 2014 23: 1242 DOI: 10.1177/0961203314528062 The online version of this article can be found at:

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Lupus (2014) 23, 1242–1245


Contraception in patients with systemic lupus erythematosus and antiphospholipid syndrome LR Sammaritano Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY, USA

Contraceptive choice in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) is challenging but important. Long-acting forms of contraception such as the progesterone intrauterine device (IUD) or subdermal implant are preferable for most patients. Estrogen-containing hormonal contraceptives may be used in stable, inactive SLE patients but are contraindicated in patients with positive antiphospholipid antibodies (aPL). The levonorgestrel IUD is a good alternative for many APS patients and often decreases menstrual blood loss. It is prudent to avoid depot medroxyprogesterone acetate (DMPA) in corticosteroid-treated or other patients at risk for osteoporosis because of the inhibition of ovulation. Effective and safe contraception in patients with SLE and APS permits planning for pregnancy during inactive disease and while on pregnancy-compatible medications, preventing a poorly timed pregnancy that may jeopardize maternal and/or fetal health. Lupus (2014) 23, 1242–1245. Key words: Contraception; systemic lupus erythematosus; antiphospholipid syndrome; intrauterine device; long-acting reversible contraception; hormonal contraceptives

Introduction Pregnancy outcome is optimized when pregnancy is planned in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Patients are generally advised to use contraception to avoid pregnancy if they have severe diseaserelated damage, during periods of active disease, and while on teratogenic medications. Rheumatologists should have a basic knowledge of available contraceptive methods and their risks and benefits for SLE and APS patients (Table 1).

Basics of contraception Currently available contraceptives include barrier methods, hormonal contraceptives, intrauterine devices (IUDs), and subdermal implants. Perfectuse efficacy for a contraceptive reflects ideal use, i.e. when used exactly as prescribed; typical use Correspondence to: Lisa R. Sammaritano, 535 E. 70th St., New York, NY 10021, USA. Email: [email protected]

represents real-life effectiveness. In general, longacting reversible contraceptives (LARC) such as IUDs or subdermal implants have the greatest typical use efficacy. In a prospective study of LARC vs. combined oral contraceptives (COCs), there were 0.27 vs. 4.55 pregnancies per 100-participant years.1

Current use of contraception by rheumatic disease patients Effective contraception is underutilized by rheumatic disease patients. In a series of 97 SLE patients at risk for pregnancy, 55% had unprotected sex occasionally and 23% ‘‘most of the time.’’2 In another series of 86 patients, 55% of those using contraceptives regularly were using less-effective barrier methods only, even when on teratogenic medications.3 Part of this inconsistent contraceptive use may reflect a lack of screening and counseling by physicians. A survey of pediatric rheumatologists found the major barrier to addressing contraception with adolescent female patients was lack of time; other factors cited included discomfort with subject area

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Contraception in patients with SLE LR Sammaritano

Not studied

Increased risk thromb. AVOID

Not studied

Increased risk thromb. AVOID

No increased flare in stable pts

Increased risk thromb. AVOID Increased bleeding; no risk thromb. APS

Decreased bleeding; little/no risk thromb.

Risk low bone density; no risk flare Decreased bleeding; little/no risk thromb. No risk low bone density; no risk flare Decreased bleeding; little/no risk thromb. Uncertain risk inf; no risk flare Uncertain risk inf; no risk flare SLE

Copper IUD: copper intrauterine device; LNG-IUD: levonorgestrel intrauterine device; DMPA: depot medroxyprogesterone acetate; COC: combined oral contraceptives; Prothromb. effect: prothrombotic effect; Freq med interaction: frequent medication interaction; SLE: systemic lupus erythematosus; APS: antiphospholipid syndrome; Uncertain risk inf: uncertain risk of infection; Thromb: thrombosis; pts: patients; MD: medical doctor.

Pro-thromb. effect Freq med interaction Pro-thromb. effect Freq med interaction Pro-thromb. effect Freq med interaction Side effects

Every 10 years; insertion by MD Increase cramps/ bleeding Ease of use

Every 5 years; insertion by MD Little systemic progestin effect Decreased cramps/bleeding

Break-through bleeding

Every 3 years; insertion by MD Rapid return to fertility Every 3 months; injection by MD Delayed return to fertility Decreased bone density Take oral pill same time daily

Low risk low bone density; no risk flare Decreased bleeding; Unknown risk thromb.

Patient placement weekly Patient insertion monthly Daily oral pill

Progestin Implant DMPA Progestin pill LNG-IUD Copper IUD

Table 1 Benefits and risk of contraceptives in systemic lupus erythematosus and antiphospholipid syndrome

Patch Vaginal ring COC

1243 4

and ambivalence regarding screening. Efforts at formalizing patient education may improve counseling: For example, distribution of a methotrexate booklet to outpatients increased awareness of the need for contraception from 60% to 100%.5 Externally imposed contraceptive education includes the Mycophenolate Risk Evaluation and Mitigation Strategy (REMS) program, a United States Food and Drug Administration (FDA)mandated education program regarding necessity of contraception in patients starting this medication. Recently formulated SLE quality indicators also cite the need for patient education regarding potential teratogenicity of medications and necessity of contraception.6

Contraceptive methods Barrier or natural methods of contraception are the least effective. The most effective methods include IUDs, subdermal implants, and other formulations of progesterone-only or combined hormonal contraceptives. IUDs The most commonly used IUDs are the levonorgesterol IUD and the copper-containing IUD. The levonorgestrel IUD is highly effective and remains in place for five years; additional advantages include a reduction in dysmenorrhea and menstrual bleeding and a low incidence of systemic side effects. The copper IUD remains in place for 10 years; it has no systemic side effects but often increases dysmenorrhea and menstrual bleeding. Hormonal contraceptives Hormonal contraceptives may be combined estrogen-progesterone or progesterone only and are delivered through a variety of methods. Combined hormonal contraceptives include the pill, transdermal patch, and vaginal ring. There are potential serious side effects including a three- to five-fold increased risk of venous thromboembolism (VTE) and a two-fold increased stroke risk. Thrombotic risk is determined by amount of estrogen and type of progesterone. Third-generation progestins impart greater risk for VTE than do second generation. Common medications may have potential interactions with combined hormonal contraceptives, including warfarin, cyclosporine, mycophenolate, and certain anticonvulsants. Lupus

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Contraception in patients with SLE LR Sammaritano


Progesterone-only contraceptives include oral and intramuscular (IM) forms, IUD, and the subdermal etonorgestrel implant. Disadvantages include irregular bleeding. The progestin pill is slightly less effective. More stable hormone levels are achieved with IM depot medroxyprogesterone acetate (DMPA) and the implant. There is a risk of osteoporosis with DMPA due to inhibition of ovulation. The risk of thromboembolism is very low but not well defined: It is clearly far less than that of combined hormonal medications. World Health Organization/Centers for Disease Control recommendations support use for most patients. Listed diagnoses where theoretical risk of use may exceed benefit include current VTE and SLE with antiphospholipid antibody (aPL).7 In clinical practice, however, progesterone-only contraceptives are used commonly in patients both with SLE and APS with little evidence of adverse effect. Ultimately, decisions regarding any contraceptive method in patients with APS or SLE must take into account not only the risk of the method but also the risk of unplanned pregnancy, the ease of use, and the efficacy of each method. Emergency contraception Emergency contraception is an option for patients with SLE and APS and includes the copper IUD, prescription progesterone-receptor modulators and over-the-counter levonorgestrel. Levonorgestrel is effective, convenient and not contraindicated in patients with thrombophilia or cardiovascular disease.

Contraception in SLE Two prospective controlled studies have shown no increased risk of flare with use of COCs in SLE patients with mild or stable disease activity8,9 and COCs are an option for some SLE patients. COCs differ in progesterone components: The fourth-generation progestins (e.g. drospironone) may increase potassium levels and should be used with caution in patients with nephritis or on angiotensin-converting enzyme (ACE) inhibitors. In the general population, the vaginal ring provides equal or lower estrogen levels than the pill; the patch provides 60% greater estrogen levels. No studies of the vaginal ring or transdermal patch are reported in SLE patients. IUDs are safe and effective with low risk of infection for most patients, including nulliparous women (in the absence of multiple sexual partners).

The risk of IUD-associated infection in SLE patients treated with immunosuppressive medications has not been specifically studied; however, studies show no increased infection risk in immunocompromised women with human immunodeficiency virus.10 Prolonged DMPA use is associated with an increased risk of osteoporosis and is best avoided for long-term use, especially in corticosteroid-treated patients.

Contraception in APS Presence of additional (acquired or genetic) prothrombotic risk factors increases thrombosis risk both in aPL-positive patients and in patients taking combined hormonal contraceptives (i.e. those containing estrogen). Given the additive effects of multiple risk factors, combined hormonal contraceptives are not advised for use in aPL-positive patients. The Safety of Estrogens in Lupus Erythematosus—National Assessment (SELENA) oral contraceptive study excluded positive lupus anticoagulant and moderate- to hightiter anticardiolipin (aCL) and anti-beta 2 glycoprotein I (ab2GPI) patients: Thromboses were reported in five of 183 patients, with no significant difference between patient and placebo groups.10 Sa´nchez-Guerrero et al.9 excluded SLE patients with a history of thrombosis in their contraceptive study, and found no significant differences in thromboses among the different patient groups. Progesterone-only contraceptives likely represent the best option for aPL-positive patients, maximizing both safety and efficacy. There is little-to-no demonstrated increased risk for thrombosis, and these methods frequently decrease menstrual bleeding, a potential benefit for patients on warfarin. The levonorgestrel IUD and the progesterone implant are effective and long-lasting with few systemic side effects. DMPA may reduce risk of hemorrhagic rupture of luteal ovarian cysts, a potentially life-threatening complication in anticoagulated young women. The progesterone-only pill is effective but long-term use is limited by side effects.

Conclusion Long-acting, reversible contraception methods offer convenience, safety, and efficacy for many patients with SLE and APS. Knowledge of the risks and benefits for each method of contraception

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Contraception in patients with SLE LR Sammaritano


in autoimmune disease patients is important for every rheumatologist. The choice of the optimal method of birth control for any individual patient will depend on multiple factors, both medical and psychosocial, and requires both patient education and counseling.

Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.

Conflict of interest statement The author has no conflict of interest to declare.


2 Schwartz EB, Manzi S. Risk of unintended pregnancy among women with systemic lupus erythematosus. Arthritis Rheum 2008; 59: 863–866. 3 Yazdany J, Trupin L, Kaiser R, et al. Contraceptive counseling and use among women with systemic lupus: A gap in health care quality? Arthritis Care and Research (Hoboken) 2011; 63: 358–365. 4 Britto MT, Rosenthal SL, Taylor J, Passo MH. Improving rheumatologists’ screening for alcohol and sexual activity. Arch Ped Adolesc Med 2000; 154: 478–483. 5 Mohammad A, Kilcoyne A, Bond U, Regan M, Phelan M. Methotrexate information booklet study 2008. Clin Exp Rheumatol 2009; 27: 649–650. 6 Yazdany J, Panopalis P, Gillis J, et al. A quality indicator set for systemic lupus erythematosus. Arthritis Care and Research 2009; 61: 370–377. 7 U.S. Medical Eligibility Criteria for Contraceptive Use, 2010, adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th ed. Morbidity and Mortality Weekly Report: June 18, 2010/59(RR04); 1–6. 8 Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med 2005; 353: 2550–2558. 9 Sa´nchez-Guerrero J, Uribe AG, Jime´nez-Santana L, et al. A trial of contraceptive methods in women with systemic lupus erythematosus. N Engl J Med 2005; 353: 2539–2549. 10 Stringer EM, Kaseba C, Levy J, et al. A randomized trial of the intrauterine device versus hormonal contraception in women who are infected with the human immunodeficiency virus. Am J Obstet Gynecol 2007; 197: 144-e1–144.e8.

1 Winner B, Peipert JF, Zhao Q, et al. Effectiveness of long-acting reversible contraception. N Engl J Med 2012; 366: 1998–2007.

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Contraception in patients with systemic lupus erythematosus and antiphospholipid syndrome.

Contraceptive choice in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) is challenging but important. Long-acting...
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