Inaugural ACR Clinical Guidelines for Reproductive Health

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The American College of Rheumatology (ACR) will issue new clinical guidelines for managing reproductive health issues in patients with rheumatic and musculoskeletal diseases.

The draft guidelines were presented at the 2018 ACR/ARHP Annual Meeting in Chicago, Illinois, on October 23 by Lisa R. Sammaritano, MD. Dr Sammaritano is an attending rheumatologist at the Hospital for Special Surgery – Weill Cornell Medical Center and the principal investigator of the new guidelines. Three separate manuscripts are currently under internal review. The following recommendations were highlighted during the session.

Contraception, fertility, and menopause
The guidelines encourage physicians to discuss pregnancy intent and contraception often, especially when initiating treatment with potentially teratogenic medications. Patients should be counseled regarding appropriate contraceptive methods based on efficacy, safety, and individual values and preferences. For fertility, the major concern with the use of assisted reproductive technology (ART) is thrombosis and/or flare in systemic lupus erythematosus (SLE). If ART is being used, it is important to coordinate care with the reproductive endocrinologist.

Next: Contraception, fertility, and menopause recommendations

Contraception recommendations:
• Encourage long-acting reversible contraception for all patients.

• Avoid estrogen in antiphospholipid-positive (aPL-positive) patients or those with active SLE.

• Use IUD or (though less effective) progestin pill for aPL-positive patients.

• Avoid depot medroxyprogesterone acetate (DMPA) in patients at high risk for osteoporosis.

• Encourage patients to use over-the-counter emergency contraception if needed.

Fertility recommendations:

• ART can be recommended for patients with stable or quiescent disease.

• Consider prophylactic anticoagulation for aPL-positive or obstetric antiphospholipid antibody syndrome (APS) patients.

• Therapeutic anticoagulation is recommended for thrombotic APS patients.

• With the exception of cyclophosphamide, continue immunosuppressive medications for oocyte retrieval for cryopreservation or surrogacy.

• In general, do not treat SLE patients with prophylactic prednisone; instead, follow these patients carefully and treat only if flare develops.

• For men receiving cyclophosphamide therapy, proceed with sperm cryopreservation prior to initiating cyclophosphamide therapy if possible. Testosterone co-therapy is not recommended.

• For women undergoing IV cyclophosphamide treatment, consider co-therapy with gonadotropin-releasing hormone analog (GnRH-a). However, the voting panel recognizes this recommendation may be difficult to follow in terms of timing and insurance coverage.

Menopause recommendations:

• For women with rheumatic disease without SLE or aPL-positive, treat with hormone replacement therapy (HRT) according to the guidelines for the general postmenopausal population. This recommendation is to use the lowest dose that alleviates symptoms for the minimal time necessary within the years immediately following the onset of menopause.

• For women with SLE, consider HRT.

• For aPL-positive women, avoid HRT.

Next: Pregnancy recommendations

Assessment and management of pregnancy
Physicians are advised to discuss family planning and pregnancy issues “early and often” with their patients. It is also important to coordinate care with the OB/GYN, maternal fetal medicine specialist, and any other relevant specialist. Patients should be counseled regarding the improved maternal and pregnancy outcomes associated with having quiescent or low disease activity prior to pregnancy.

Pregnancy recommendations:
• If using a medication not compatible with pregnancy, switch to a pregnancy compatible medication prior to conception. Observe for a period of time and assess efficacy and tolerability before attempting pregnancy.

• If active disease develops during pregnancy, start a pregnancy-compatible medication.

• Check anti-Ro-SSA and anti-La/SSB antibodies before or early in pregnancy.

SLE pregnancy recommendations:

• Laboratory tests for disease activity should be conducted at least once per trimester.

• Continue hydroxychloroquine (HCQ). Consider starting if not currently taking and there’s no contraindication.

• Consider starting low-dose aspirin for preeclampsia prevention by the end of the first trimester, as SLE is considered a risk factor for preeclampsia.

aPL pregnancy recommendations:
• For aPL-positive patients who do not meet clinical APS criteria, consider treating with prophylactic low-dose aspirin during pregnancy for preeclampsia prophylaxis. Avoid treating with combination prophylactic heparin-aspirin therapy, though it may be appropriate for certain high-risk patients.

• For aPL-positive patients who do meet obstetric APS criteria but have no thrombosis, treat with prophylactic heparin and low-dose aspirin. Treat with anticoagulation during the 6- to 12-week postpartum period to reduce risk of thrombosis. If these patients fail standard therapy, the guidelines do not generally recommend therapeutic heparin, intravenous immunoglobulin (IVIG), or the addition of prednisone.

• With thrombotic APS, treat with therapeutic heparin and low-dose aspirin.

Ro/SSA and/or La/SSB pregnancy recommendations:
• Consider obtaining serial fetal echocardiograms starting at weeks 16 to 18 through week 26, and weekly if the patient has a prior affected child. (Given that the data supporting cost and inconvenience of fetal echocardiography are lacking and no clear benefit of screening has been demonstrated, Dr Sammaritano conceded that this point generated animated discussion among the voting panel. This recommendation was the final decision of the group as a whole, with some dissent.)

• Consider treating with prophylactic HCQ during pregnancy.

• With an abnormal fetal echocardiogram showing a first- or second-degree heart block, consider treating with 4 mg of oral dexamethasone daily. If there is an isolated third (complete) heart block without other cardiac inflammation, generally do not recommend treating with dexamethasone.

Next: Medication recommendations

Maternal and paternal medication use
For both male and female patients who are planning a pregnancy, the use of medications should be discussed prior to attempting to conceive. Dr Sammaritano also emphasized that physicians need to educate their patients about the impact of disease on maternal and pregnancy outcomes so that the risks and benefits of medications during pregnancy can be properly evaluated.

When initiating a treatment that may affect future fertility, such as cyclophosphamide, future pregnancy plans should be discussed. If women have inadvertent exposures to teratogenic medications during pregnancy, the medication should be discontinued immediately and the patient referred to a maternal fetal medicine or genetics specialist.

Many patients highly value the ability to breastfeed their infants if possible, and women with rheumatologic disorders should be encouraged to breastfeed if desired. Disease control should be maintained with medications compatible with lactation based on the risks/benefits of each patient’s situation.

Paternal medication recommendations

• Discontinue cyclophosphamide (12 weeks) and thalidomide (4 weeks) prior to conception.

• Continue or consider continuing: HCQ, colchicine, azathioprine, tumor necrosis factor (TNF) inhibitors, sulfasalazine, methotrexate, leflunomide, mycophenolate, cyclosporine, tacrolimus, anakinra, and rituximab.

• If the patient has difficulty conceiving on sulfasalazine, consider a semen analysis to look for change in the quality of sperm or sperm count.

• The voting panel did not vote on the remaining non-TNFi biologics or small molecules because of lack of data.

Maternal medication recommendations

• Discontinue cyclophosphamide, thalidomide, mycophenolate, methotrexate, and leflunomide or stop as soon as possible if inadvertently pregnant.

• Consider stopping NSAIDs if patient has difficulty conceiving and do not use any NSAIDs in the third trimester.

• Continue HCQ, sulfasalazine, azathioprine, and colchicine during pregnancy.

• Consider continuing cyclosporine, tacrolimus, and TNF inhibitors prior to and during pregnancy.

• Consider continuing rituximab and other non-TNFi biologic agents until conception.

• The panel did not vote on new small molecule drugs because of lack of data; however, these are likely to pass through the placenta.

• Consider cyclophosphamide in the second or third trimester or rituximab during pregnancy for organ- or life-threatening disease.

• For women on corticosteroids, continue a low-dose regimen if needed. Attempt to taper doses higher than 20 mg/d with use of pregnancy-compatible steroid-sparing medications. For patients on long-term steroid therapy, consider a stress-dose steroid for C-section, but this is not generally recommended for vaginal delivery.

Medication in lactation recommendations:
• Continue HCQ, TNF inhibitors, rituximab, and non-fluorinated corticosteroids.

• Consider starting or continuing azathioprine, sulfasalazine, cyclosporine, tacrolimus, colchicine, NSAIDs (ibuprofen is preferred), or non-TNFi biologics.

• Avoid cyclophosphamide, mycophenolate, leflunomide, thalidomide, and methotrexate.

• The panel did not vote on new small molecule drugs because of lack of data, though these most likely pass into breast milk.

References:

5T096 ACR: Reproductive Health in Rheumatology Patients: New ACR Clinical Guideline. Presented at: 2018 ACR/ARHP Annual Meeting; October 20-24; Chicago, Illinois.