The ACR Introduces New Reproductive Health Guideline

Reproductive health can be a concern for patients with rheumatic diseases, and practitioners in both rheumatology and obstetrics/gynecology often work closely together. The 2020 ACR Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases, new clinical recommendations developed by an ACR-convened group for pregnant women, post-menopausal women, lactating women, and women and men trying to conceive or delay conception, was published online in Arthritis & Rheumatology and Arthritis Care & Research Feb. 24.¹

The evidence-based guideline includes contraceptive recommendations and suggestions for rheumatologists co-managing patients with obstetrician-gynecologists (OB/GYNs) and other specialists.

Methodology
The guideline’s literature review team accepted 319 out of 11,760 published manuscripts for systematic review, said Eliza Chakravarty, MD, MS, associate member, Arthritis and Clinical Immunology Research Program at the Oklahoma Medical Research Foundation, Oklahoma City. Other fields have many well-structured, randomized, controlled trials, but “we wound up working with relatively lower-quality evidence based on the available studies,” she said. Thus, most of the recommendations are conditional, not strong.

The Voting Panel included rheumatologists, OB/GYNs, reproductive medicine specialists and patients. The panel required 70% agreement to reach consensus on whether to include or discard recommendations. The guideline also includes good practice statements, which are clinical suggestions, such as counseling rheumatic and musculoskeletal disease (RMD) patients on the use of potentially teratogenic medications.

Lisa R. Sammaritano, MD

Principal investigator Lisa R. Sammaritano, MD, associate professor of clinical medicine at Weill Cornell Medicine and associate attending physician at the Hospital for Special Surgery, New York, reviewed the final recommendations, the result of a three-year effort with input from medical professionals and patients. Patients on the panel had a consistent message, she said: “My rheumatologist knows me much better than my gynecologist.” Even if you are pressed for time, “patients really do want to talk to their rheumatologists about these topics,” she said.

Contraception
Condoms and the estrogen-progestin combination pill have lower efficacy in preventing pregnancy, so the guideline suggests the more effective long-acting reversible contraception (LARC) methods, such as intrauterine devices or implants, when possible.²

Good practice statements on contraception: Discuss contraception and pregnancy plans at an initial or early office visit or when initiating treatment with potentially teratogenic medications, and counsel patients on contraceptive methods based on efficacy, safety and personal values.

Recommendations include:

• Encourage the use of effective LARC for all patients;
• Avoid estrogen in antiphospholipid antibody (aPL) positive patients or those with active systemic lupus erythematosus (SLE), using an intra-uterine device or the less-effective progestin-only pill in these patients;
• Avoid depot medroxyprogesterone acetate injections in patients at high risk for osteoporosis; and
• Encourage all patients to use over-the-counter morning-after emergency contraception, if desired.

Fertility/Assisted Reproductive Technology (ART)
Fertility is becoming more of a concern for patients, because women may delay pregnancy until their disease is inactive, said Dr. Sammaritano. “As a result, they may end up needing fertility therapy. Oocyte or embryo cryopreservation is now standard care, rather than experimental, and if you haven’t yet had patients ask you about this, I guarantee that you will.”

Elevated estrogen levels during ovarian stimulation and retrieval mean flare and/or thrombosis are major concerns for women with SLE. Coordinate care with a patient’s reproductive endocrinologist in these cases, the Voting Panel suggested.

Recommendations include:

• Encourage ART for patients with stable or quiescent disease;
• Consider prophylactic anti-coagulation for aPL-positive or obstetric antiphospholipid syndrome (APS) patients;
• Use therapeutic anticoagulation for thrombotic APS patients;
• Continue immunosuppressants, other than cyclophosphamide, for oocyte retrieval for cryopreservation or surrogacy; and
• Do not automatically use prophy­lactic prednisone in SLE patients; treat with prednisone if a flare develops.

Fertility preservation: Patients undergoing therapy with monthly intravenous cyclophosphamide are at risk for impaired fertility.

Good practice statement: Men on intravenous cyclophosphamide who wish to preserve fertility should cryopreserve their sperm, ideally before initiating cyclophosphamide, but testosterone co-therapy is not recommended.

Recommendations: Consider co-therapy with a gonadotropin-releasing hormone analog (such as leuprolide acetate) for women on intravenous cyclo­phosphamide. Challenges include a need to administer this drug 10–14 days before starting cyclophosphamide and insurance coverage.

Menopause
Guidelines on menopause include a good practice statement: Rheumatologists should treat women with RMD other than SLE or those with positive aPL with hormone-replacement therapy (HRT) according to the guidelines for the general post-menopausal population.³ Use the lowest dose to alleviate symptoms for the minimum time necessary immediately following menopause onset.

“Long-term HRT therapy, we now understand, has significant risks, including stroke and breast cancer,” and should be reserved for patients with severe symptoms that don’t respond to non-hormonal therapies, Dr. Sammaritano said.

Recommendations include:

• Consider HRT in aPL-negative women with SLE (one study found a small increase in mild to moderate flares);⁴ and
• Avoid HRT in aPL-positive women.

Consider transdermal over oral HRT to reduce venous thromboembolism risk, the panel suggested.

Pregnancy Assessment & Management
“The impression that we got from our Patient Panel is that they want to discuss family planning issues early and often” with their rheumatologists, Dr. Sammaritano said.

Good practice statements include counseling patients on how quiescent or low disease activity prior to pregnancy results in good outcomes, and that in pregnant women with SLE, rheumatologists should monitor their disease activity at least once per trimester.

Recommendations include:

• In patients taking medications not compatible with pregnancy, switch to a pregnancy-compatible medication, observe for a time, and assess for tolerability and efficacy of the new drug before attempting pregnancy;
• Start a pregnancy-compatible medication if active disease develops during pregnancy; and
• Check anti-Ro/SSA and anti-La/SSB antibodies before or early in pregnancy.

In women with SLE:

• Check aPL antibodies (including anti-cardiolipin, anti-beta2-glycoprotein I and lupus anticoagulant) before or early in pregnancy;
• Continue hydroxychloroquine; and
• Consider low-dose aspirin to prevent preeclampsia, and start this in the first trimester.

In women with systemic sclerosis:

• Start angiotensin-converting enzyme inhibitor therapy if the patient develops scleroderma renal crisis.

Numerous, specific recommendations were made for pregnancy management in aPL-positive women, both those who do and don’t meet APS Classification Criteria clinical thresholds, and for women positive for anti-Ro/SSA and anti-La/SSB antibodies.⁵ Most of the patient panelists supported frequent fetal echocardiograms for women who are anti-Ro and anti-La positive, and consideration of hydroxychloroquine in patients not already taking this medication to reduce risk of congenital heart block, Dr. Sammaritano noted.

Medication Use
The guideline encourages both women and men to discuss medication use with their rheumatologist before conceiving, and to discuss future pregnancy plans before initiating treatment with medications that may affect fertility, such as cyclophosphamide. It also urges rheumatologists to counsel women who have inadvertent exposure to teratogenic medications during pregnancy to stop the drug immediately and refer these patients to a maternal-fetal medicine or genetics specialist.

Recommendations for men include:

• Discontinue cyclophosphamide 12 weeks before and thalidomide four weeks before attempting to conceive with his partner;
• Continue hydroxychloroquine, colchicine, azathioprine, tumor necrosis factor inhibitors, sulfasalazine, methotrexate, leflunomide, mycophenolate, cyclosporine, tacrolimus, anakinra and rituximab; and
• Consider semen analysis if a couple has trouble conceiving while the man is on sulfasalazine.

Patient panelists suggested rheuma­tologists counsel female patients on the risk of not taking pregnancy-compatible medications—that is the risk of uncontrolled rheumatic disease during pregnancy. The guideline’s many recom­mendations for pregnant women include:

• Discontinue cyclophosphamide, thalidomide, mycophenolate, methotrexate and leflunomide, with a “wash out” of leflunomide before pregnancy and immediately if pregnant;
• Consider stopping non-steroidal anti-inflammatory drugs (NSAIDs) if a woman has difficulty conceiving, and don’t use NSAIDs in the third trimester;
• Continue hydroxychloroquine, sulfasalazine, colchicine and azathioprine during pregnancy. Continue TNF-inhibitors during pregnancy if clinically necessary;
• Consider cyclophosphamide (in the second or third trimester) or rituximab during pregnancy in women with organ- or life-threatening disease; and
• In women on non-fluorinated steroid therapy, continue low-dose steroids if needed.

Good practice statements on breastfeeding: Rheumatologists should encourage their female patients to breastfeed if they desire, maintain disease control with medications compatible with lactation, and review the risks and benefits particular to each patient.

Other recommendations:

• While breastfeeding, women should avoid cyclophosphamide, thalidomide, mycophenolate, leflunomide and methotrexate;
• While breastfeeding, women should continue hydroxychloroquine, TNF inhibitors, rituximab and non-fluorinated steroids; and
• Women on higher (20 mg or more per day) steroid doses should avoid breastfeeding within four hours of taking their drug—and discard any milk pumped or expressed in that same window.

Susan Bernstein is a freelance medical journalist based in Atlanta, Ga.

References

1. Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol. [online first]
2. Committee on Gynecologic Practice Long-Acting Reversible Contraception Working Group. Committee Opinion No. 642. Increasing access to contraceptive implants and intrauterine devices to reduce unintended pregnancy. Obstet Gynecol. 2015 Oct;126:e44–e48.
3. American College of Obstetricians and Gynecologists—Committee on Practice Bulletins: Gynecology. Practice Bulletin No. 141: Management of menopausal symptoms. Obstet Gynecol. 2014 Jan;123(1):202–216.
4. Buyon JP, Petri MA, Kim MY, et al. The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: A randomized trial. Ann Intern Med. 2005 Jun 21;142(12 Pt 1):953–962.
5. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update on the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006 Feb;4(2):295–306.

Editor’s note: Updated from an article in the January 2019 issue of The Rheumatologist.