Based on emerging evidence and expert consensus, a panel assembled by the American College of Rheumatology (ACR) released recommendations for the management of reproductive health in patients with rheumatic and musculoskeletal diseases (RMD). This report was published in Arthritis & Rheumatology.
Investigators performed a systematic review of studies relating to contraception, assisted reproductive technologies, fertility preservation, menopausal hormone therapy, pregnancy and lactation, and medication use in patients with RMD. They developed recommendations using Grading of Recommendations Assessment, Development, and Evaluation methodology to rate evidence quality.
Recommendations for Contraception
The ACR strongly recommends the use of effective contraceptives, including hormonal contraceptives and intrauterine devices (IUDs), over no contraception in reproductive-age women with RMD without systemic lupus erythematosus (SLE) or antiphospholipid antibodies (aPLs). Long-acting reversible contraceptives such as IUDs or subdermal progestin implants are encouraged as first-line contraceptive methods because of their “real-world” effectiveness. The use of emergency contraception should be discussed with all patients because the risk for unplanned pregnancy in RMD outweighs the risk related to emergency contraception.
Patients With SLE
In patients with SLE with low or stable disease activity and who are not aPL-positive, the panel recommends the use of effective contraceptives over no contraception and encourages the use of highly effective IUDs or subdermal progestin implants as first-line contraceptive methods. However, the ACR recommends against the use of the transdermal estrogen-progestin patch as it results in greater estrogen exposure compared with oral or transvaginal methods, which potentially increase risk for flare or thrombosis.
In patients with SLE with moderate or severe disease activity, progestin-only or IUD contraception is recommended over combined estrogen-progestin contraceptive methods, as the latter has not been studied in this patient population.
In aPL-positive women, the panel strongly recommends IUDs (levonorgestrel or copper) or the progestin-only pill and recommends against combined estrogen-progestin contraception because estrogen increases the risk for thromboembolism.
Other RMD Situations
In women with RMD who are receiving immune-suppressive therapy, copper or progestin IUDs are recommended as the most effective contraceptive option.
In women at risk for osteoporosis from glucocorticoid use or underlying disease, the ACR recommends against using depot medroxyprogesterone acetate (DMPA) injections as long-term contraception because DMPA is associated with declines in bone mineral density and fracture risk.
In women with RMD taking mycophenolate mofetil/mycophenolic acid, an IUD alone or 2 other contraceptive methods used together are suggested, as mycophenolate mofetil may reduce estrogen and progesterone levels and hence reduce the efficacy of oral contraceptives.
Recommendations for Assisted Reproductive Technology
The ACR strongly recommends women with uncomplicated RMD (stable/quiescent disease activity and without aPLs) who are receiving pregnancy-compatible medications proceed with assisted reproductive technology. However, rheumatologists should discuss with their patients the risks associated with assisted reproductive technology, especially lupus flare and thrombosis.
Patients With SLE
In patients with RMD who experience moderate to severe disease activity, assisted reproductive technology procedures should be deferred, as RMD disease activity may increase pregnancy-associated risks.
In women with SLE undergoing assisted reproductive technology procedures, the panel recommends against an empiric dosage increase of prednisone and recommends monitoring the patient carefully and treating a flare if it occurs.
The ARC recommends assisted reproductive technologies with anticoagulation therapy in patients with RMD and stable/quiescent disease activity and who have asymptomatic positive aPLs, obstetric antiphospholipid syndrome, or treated thrombotic antiphospholipid syndrome.
Use of prophylactic anticoagulation therapy with heparin or low-molecular-weight heparin are strongly suggested for women with RMD undergoing assisted reproductive technology procedures who report asymptomatic positive aPLs or obstetric or treated thrombotic antiphospholipid syndrome.
Embryo and Oocyte Cryopreservation
Continuation of necessary immunosuppressive and/or biologic therapies (other than cyclophosphamide) are strongly encouraged in patients with stable disease activity who undergo ovarian stimulation for the purpose of oocyte retrieval or embryo cryopreservation.
Recommendations for Fertility Preservation
The ACR recommends monthly gonadotropin-releasing hormone agonist co-therapy to prevent primary ovarian insufficiency in premenopausal women with RMD who receive a monthly intravenous cyclophosphamide dose. However, men with RMD who receive cyclophosphamide should not receive testosterone co-therapy, as it does not help preserve fertility in men. Sperm cryopreservation is a strongly suggested practice for men before being treated with cyclophosphamide.
Recommendations for Menopause and Hormone Replacement Therapy
Hormone replacement therapy is strongly suggested in postmenopausal women with RMD without SLE or positive aPLs. In patients with SLE without positive aPLs, hormone replacement therapy is recommended conditionally because a small increase in risk for mild to moderate lupus flares is associated with oral hormone replacement therapy.
Hormone replacement therapy is not recommended in women with asymptomatic aPLs, or obstetric or thrombotic antiphospholipid syndrome. Furthermore, patients receiving anticoagulation treatment for antiphospholipid syndrome — even patients who are negative for aPL — should not use hormone replacement therapy.
In patients with a history of positive aPLs but who currently test negative for aPL and have no history of clinical antiphospholipid syndrome, hormone replacement therapy may be considered if desired.
Recommendations for Pregnancy
The ACR strongly suggests counseling women with RMD who are considering pregnancy, in which improved maternal and fetal outcomes have been associated with entering pregnancy with quiescent or low disease activity. Maintaining concurrent care with obstetricians-gynecologists, neonatologists, and other appropriate specialists is recommended as good practice.
Women with RMDs planning pregnancy should switch to pregnancy-compatible medications with enough time to assess efficacy and tolerability of the new medication.
For women with RMD who are currently pregnant and whose active disease requires continuous medication, pregnancy-compatible steroid-sparing treatment is strongly recommended, as high-dose glucocorticoids can potentially cause maternal or fetal harm.
Patients With SLE
Women with SLE or similar disorders (Sjögren syndrome, systemic sclerosis, rheumatoid arthritis) should be tested for anti-Sjögren syndrome-related antigen A (RO/SSA) and anti-Sjögren syndrome-related antigen B (La/SSB) antibodies in early pregnancy. However, because of the antibodies’ relative persistence, repeat testing during pregnancy is not needed.
In pregnant patients with active scleroderma renal crisis, the ACR strongly recommends the use of angiotensin-converting enzyme inhibitor or angiotensin receptor blockade therapy because the risk for maternal or fetal death outweighs the risk associated with these medications.
The ACR strongly suggests that pregnant women with SLE be closely monitored with clinical history, examination, and laboratory tests at least once per trimester as disease activity can affect pregnancy outcomes. If possible, all women with SLE should take hydroxychloroquine during pregnancy. Pregnant patients with SLE are also recommended to begin a daily low-dose aspirin (81 mg or 100 mg) regimen during their first trimester.
Pregnant women with positive aPLs (but who do not meet criteria for obstetric or thrombotic antiphospholipid syndrome) should be treated with daily prophylactic aspirin; however, these women are advised against the combined use of aspirin and prophylactic-dose heparin as well as prophylactic hydroxychloroquine treatments.
In women who meet the criteria for obstetric antiphospholipid syndrome, the ACR strongly recommends a combined low-dose aspirin and prophylactic-dose heparin. Furthermore, these patients should be treated with prophylactic-dose anticoagulation for 6 to 12 weeks postpartum.
In women who meet the criteria for thrombotic antiphospholipid syndrome, a regimen of low-dose aspirin and therapeutic-dose heparin is strongly recommended throughout pregnancy and postpartum.
The ACR recommends against treatment with intravenous immunoglobulin or increased low-molecular-weight heparin doses. The panel also recommends against the addition of prednisone to a low-dose aspirin/prophylactic-dose heparin combination; however, the addition of hydroxychloroquine therapy to low-dose aspirin/prophylactic-dose heparin is conditionally recommended.
Anti-Ro/SSA or Anti-La/SSB Antibodies
Serial fetal echocardiography is recommended in pregnant women with anti-Ro/SSA or anti-La/SSB antibodies and should be performed starting between 16 and 18 weeks and continue through week 26. In women with a history of having an infant with complete heart block or neonatal lupus erythematosus, fetal echocardiography is recommended weekly during this time period.
If fetal first- or second-degree heart block is shown on echocardiography, daily treatment with oral dexamethasone (4 mg) is recommended; however, if a complete heart block without cardiac inflammation is shown on echocardiography, then the panel recommends against dexamethasone treatment.
All women who are positive for anti-Ro/SSA or anti-La/SSB antibodies should be treated with hydroxychloroquine during pregnancy, as hydroxychloroquine is associated with lowering risk for the fetus developing complete heart block.
Recommendations for Medication Use
Paternal Medication Use
In men with RMD planning to father a pregnancy, the panel recommends against the use of cyclophosphamide and thalidomide before attempting conception; however, continuation of hydroxychloroquine, azathioprine, 6-mercaptopurine, colchicine, and tumor necrosis factor (TNF) inhibitors are strongly recommended.
Continuation of methotrexate, mycophenolate mofetil, leflunomide, sulfasalazine, calcineurin inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) is conditionally recommended on the basis of limited evidence, as is the use of anakinra and rituximab.
Maternal Medication Use
The ACR recommends discussing medication use in women with RMD well before attempting conception as standard good practice. The panel further suggests discussing pregnancy plans before initiating treatment with medications that affect gonadal function.
Discontinuation of methotrexate, mycophenolate mofetil, and thalidomide is strongly recommended within 3 months before attempting conception, as these medications are known teratogens, or agents that disrupt fetal development. Cholestyramine washout is recommended for women treated with leflunomide before pregnancy or as soon as pregnancy is confirmed, as detectable serum levels of metabolite risk pregnancy loss and birth defects. If life-threatening conditions occur in the second or third trimester, the panel recommends treatment with cyclophosphamide.
An observation period without medication or transition to pregnancy-compatible medication is recommended to ensure disease stability. In women with exposure to teratogenic medications during or shortly before pregnancy, the panel recommends immediate referral to the appropriate specialist or genetic counselor.
Compatible pregnancy medications commonly recommended for use in patients with RMD include hydroxychloroquine, azathioprine/6-mercaptopurine, colchicine, and sulfasalazine. Calcineurin inhibitors (tacrolimus and cyclosporine) and NSAIDs are also considered compatible with pregnancy; nonselective NSAIDs are recommended over cyclooxygenase 2-specific inhibitors during the first 2 trimesters.
If the patient is having difficulty conceiving, the panel recommends discontinuing use of NSAIDs because of the possibility of NSAID-induced unruptured follicle syndrome. NSAID use should also be discontinued in the third semester to avoid risk for premature closure of the ductus arteriosus.
If indicated, the ACR recommends continuing low-dose glucocorticoid treatments (≤10 mg daily of prednisone or nonfluorinated equivalent) during pregnancy. Higher doses of nonfluorinated glucocorticoids should be tapered, and a pregnancy-compatible glucocorticoid-sparing agent should be added if necessary. Administration of stress-dose glucocorticoids during vaginal delivery is not recommended; however, such treatment may be indicated during cesarean delivery.
TNF inhibitor therapy with infliximab, etanercept, adalimumab, or golimumab may be continued before and during pregnancy, as these therapies have minimal placental transfer and fetal exposure. Similarly, continuation of certolizumab therapy is strongly recommended.
The panel recommends women continue treatment with anakinra, belimumab, abatacept, tocilizumab, secukinumab, and ustekinumab while attempting conception but should discontinue use once pregnancy is confirmed. Women may continue rituximab treatment while trying to conceive and if life-threatening or organ-threatening maternal disease warrant use during pregnancy.
Medication Use During Breastfeeding
Women with RMD are encouraged to breastfeed if they desire and are able to do so, and the ACR recommends lactation-compatible medications in order to control disease. Hydroxychloroquine, sulfasalazine, rituximab, and TNF inhibitors are strongly recommended as compatible with breastfeeding. A prednisone daily dose <20 mg is also compatible with breastfeeding; however, women who use prednisone doses ≥20 mg are recommended to delay breastfeeding or discard breast milk accumulated in 4 hours after administration.
Treatment with azathioprine/6-mercaptopurine, calcineurin inhibitors, NSAIDS, and non-TNF inhibitor biologics (anakinra, rituximab, belimumab, abatacept, tocilizumab, secukinumab, and ustekinumab) is conditionally recommended during breastfeeding.
The panel recommends against the use of cyclophosphamide, leflunomide, mycophenolate mofetil, thalidomide, and methotrexate while breastfeeding.
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
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 [published online February 23, 2020]. Arthritis Rheumatol. doi:10.1002/art.41191