Key Points
- Pregnancy in women with rheumatic and musculoskeletal diseases (RMD) may lead to serious maternal or fetal adverse outcomes. Accordingly, contraception, tailored to the individual patient with emphasis on safety and efficacy, should be discussed and encouraged.
- Because risk for pregnancy complications depends on diagnosis, disease activity and damage, medications, and the presence of anti-Ro/SSA, anti-La/SSB, and antiphospholipid (aPL) antibodies, pre-pregnancy assessment is critical to informing pregnancy management, therapy, and outcomes.
- In addition, patients are vulnerable to disease flare postpartum, and medications for RMD must be screened for safety while breastfeeding.
- Minimizing risk of gonadal insufficiency in the setting of cyclophosphamide therapy is important. Patients with RMD may require assisted reproductive technology and therefore a discussion about oocyte preservation and in vitro fertilization should also be part of the management of patients contemplating parenthood.
Quality of Evidence and Strength of Recommendations
| Quality of Evidence | Interpretation |
|---|---|
| High-quality evidence | Studies that provide high confidence in the effect estimate. New data from future studies are thought unlikely to change the effect. |
| Moderate-quality evidence | Studies that provide confidence that the true effect is likely to be close to the estimate but could be substantially different. |
| Low-quality evidence | Studies that provide limited confidence about the effect. The true effect may be substantially different from the estimate. |
| Very low-quality evidence | Studies that provide very little certainty about the effect. The true effect may be quite different from the estimate. |
| Strength of Recommendation | Interpretation |
| Strong recommendation | Action should be favored in almost all patients, usually requiring high-quality evidence, high confidence that future research will not alter the conclusion, AND an assessment that the desirable effects of the intervention outweigh the undesirable effects. Should not be taken to imply that the intervention has large clinical benefits. |
| Conditional recommendation | Action should be followed in only selected cases, often limited by low-quality evidence, OR when the desirable and undesirable consequences of an intervention are more balanced, OR if patients’ preferences for the intervention are thought to vary widely. |
| Good practice statement (GPS) | Good practice statements were agreed upon when indirect evidence was sufficiently compelling that a formal vote was unnecessary. |
Treatment
Table 1. Reproductive health care in patients with RMD: concise recommendation summarya
| Topic | Recommendation | Strength |
|---|---|---|
| Contraception | ||
| All RMD | Contraception/pregnancy discussion early and regularly; choose contraception based on safety, efficacy, and patient preference | GPS |
| Use barrier methods if unable to use other methods | GPS | |
| Use emergency contraception if necessary [6] | Strong | |
| Women receiving immunosuppressive medications: Use intrauterine device (IUD) if desired [7] | Strong | |
| Women at risk for osteoporosis: Avoid depot medroxyprogesterone acetate (DMPA) [10] | Conditional | |
| Women receiving mycophenolate mofetil (MMF): Use IUD or 2 other methods together [11] | Conditional | |
| RMD without systemic lupus erythematosus (SLE) or antiphospholipid antibody (aPL): Use highly effective or effective methodsb [1] | Strong | |
| Highly effective methods preferred to effective methods [1A] | Conditional | |
| SLE | SLE with negative aPL and low/stable disease activity: Use highly effective or effective methodsb [2] | Strong |
| Highly effective methods preferred to effective methods [2A] | Conditional | |
| Avoid transdermal estrogen-progestin patch [2B] | Conditional | |
| SLE with negative aPL and moderate-to-high disease activity: Use progestin-only contraceptives or IUD [2C] | Strong | |
| Positive aPL | Do not use combined estrogen-progestin contraceptives [3]; use IUD or progestin-only pill [4] | Strong |
| Topic | Recommendation | Strength |
|---|---|---|
| Assisted reproductive technology | ||
| All RMD | Stable disease and negative aPL: Proceed with assisted reproductive technology: | |
| In vitro fertilization (IVF) if pregnancy-compatible medications [24] | Strong | |
| Oocyte cryopreservation: Continue medications except cyclophosphamide (CYC) [28] | Strong | |
| Active disease: Defer assisted reproductive technology until disease is stable/quiescent [27] | Strong | |
| SLE | Active SLE: Defer assisted reproductive technology until disease is stable/quiescent [27] | Strong |
| Do not treat with prophylactic prednisone [29] | Conditional | |
| Positive aPL | Asymptomatic aPL: No prior thromboses or history of obstetric antiphospholipid syndrome (OB APS): Prophylactic heparin or low molecular weight heparin (LMWH) [25A] | Conditional |
| No prior thromboses but history of OB APS: Prophylactic heparin or LMWH [25A2] | Strong | |
| Prior thromboses: Therapeutic heparin or LMWH [26A] | Strong | |
| Fertility preservation | Women: Use gonadotropin-releasing hormone agonist therapy during IV CYC treatment [31] | Conditional |
| Men: Sperm cryopreservation pre–CYC treatment | GPS | |
| Men: Do not use gonadotropin-releasing hormone agonist therapy during IV CYC treatment [35] | Conditional | |
| Topic | Recommendation | Strength |
|---|---|---|
| Menopause/hormone replacement therapy | ||
| All RMD | RMD without SLE or aPL: Treat with hormone replacement therapy if indicatedc | GPS |
| SLE | SLE and negative aPL: Treat with hormone replacement therapy if indicatedc [79] | Conditional |
| Positive aPL | If no prior thrombosis or OB APS: Do not treat with hormone replacement therapy [80] | Conditional |
| If current titers negative, treat with hormone replacement therapy if indicatedc [83] | Conditional | |
| If prior thrombosis or OB APS and not receiving anticoagulation treatment: Do not treat with hormone replacement therapy [81] | Strong | |
| If current titers negative, do not treat with hormone replacement therapy [83A] | Conditional | |
| If prior thrombosis or OB APS and receiving anticoagulation treatment: Do not treat with hormone replacement therapy [82] | Conditional | |
| Topic | Recommendation | Strength |
|---|---|---|
| Pregnancy | ||
| All RMD | Counseling: Outcomes improved with pregnancy planning, stable disease, compatible medications, and co-management by rheumatology and obstetrics-gynecology/maternal-fetal medicine | GPS |
| Pre-pregnancy: Change to pregnancy-compatible medication and observe for stability [42] | Strong | |
| If active disease during pregnancy: Initiate pregnancy-compatible medication [54] | Strong | |
| If SLE or SLE-like disease, Sjögren’s syndrome (SS), systemic sclerosis (SSc), or rheumatoid arthritis (RA): Test once (early) for anti-Ro/SSA and anti-La/SSB [60, 62] | Strong | |
| If SSc and renal crisis during pregnancy: Treat with angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) for life-threatening disease [55] | Strong | |
| SLE | SLE or SLE-like disease: Test once (early) for aPL (anticardiolipin antibody [aCL], anti–β2-glycoprotein [anti-β2GPI], lupus anticoagulant [LAC]) [59, 61] | Strong |
| Continue hydroxychloroquine (HCQ) during pregnancy [57] | Strong | |
| If not taking HCQ, start HCQ during pregnancy if no contraindications [58] | Conditional | |
| Monitor laboratory values at least once per trimester | GPS | |
| Treat with low-dose aspirin starting in first trimester [56] | Conditional | |
| Positive aPL | Positive aPL only: If no prior thrombosis or OB APS, treat with low-dose aspirin starting in first trimester [45] | Conditional |
| Positive aPL only: Do not treat with combination prophylactic heparin or LMWH/low-dose aspirin [46] | Conditional | |
| Positive aPL only: Do not treat with HCQ [44A] | Conditional | |
| OB APS: If no thrombosis but meet OB APS criteria, treat with combination prophylactic heparin or LMWH/low-dose aspirin [48] | Strong | |
| OB APS: Do not treat with combination therapeutic heparin or LMWH/low-dose aspirin [49] | Conditional | |
| OB APS: Do not treat with addition of IV immunoglobulin (IVIG) [50] | Conditional | |
| OB APS: Do not treat with addition of prednisone [51] | Strong | |
| OB APS: Treat with addition of HCQ for combination heparin/low-dose aspirin failure [44B] | Conditional | |
| OB APS: Treat with prophylactic anticoagulation during post partum period [84] | Strong | |
| Thrombotic-APS: If prior thrombosis (meeting or not meeting OB APS criteria), treat with therapeutic heparin or LMWH/low-dose aspirin [52] | Strong | |
| Thrombotic-APS: Treat with addition of HCQ for therapeutic heparin or LMWH/low-dose aspirin therapy failure [44B] | Conditional | |
| Positive anti-Ro/SSA with or without anti-La/SSB | Treat with HCQ during pregnancy [69, 70] | Conditional |
| If no prior history of neonatal lupus: Serial (interval uncertain) fetal echocardiography in weeks 16–26 [67] | Conditional | |
| If prior history of neonatal lupus: Weekly fetal echocardiography in weeks 16–26 [68] | Conditional | |
| Abnormal fetal echocardiography: If first- or second-degree heart block, treat with dexamethasone 4 mg daily [71, 72] | Conditional | |
| If isolated third-degree heart block (and no other cardiac inflammation), do not treat with dexamethasone [73] | ||
| Topic | Recommendation | Strength |
|---|---|---|
| Medication | ||
| Paternal Medication | If planning to father a child: Discuss medication use including CYC | GPS |
| Discontinue CYC and thalidomide [133, 139] | Strong/conditional | |
| Continue HCQ, AZA, infliximab, etanercept, adalimumab, golimumab, certolizumab, colchicine [90, 115, 143, 146, 149, 152, 155, 97] | Strong | |
| Continue leflunomide, MMF, nonsteroidal anti-inflammatory drugs (NSAIDs), sulfasalazine, cyclosporine, tacrolimus, anakinra, rituximab [108, 119, 85, 94, 126, 130, 159, 163] | Conditional | |
| Maternal Medication | If planning pregnancy: Discuss medication use including CYC | GPS |
| If pregnant and exposed to teratogenic medications: Discontinue immediately, pursue counseling | GPS | |
| Discontinue NSAIDs if difficulty conceiving [86] | Conditional | |
| Avoid NSAIDs in third trimester [87] | Strong | |
| Use nonselective rather than cyclooxygenase 2 (COX-2)–specific NSAIDs [88] | Conditional | |
| Discontinue methotrexate (MTX), MMF, thalidomide, CYC prior to conception [102, 120, 140, 134] | Strong | |
| Use CYC for life-threatening disease only in second and third trimester [136] | Conditional | |
| Discontinue leflunomide 24 months prior to conception or check serum metabolite levels and treat with cholestyramine washout [109, 110] | Strong | |
| Continue HCQ, sulfasalazine, azathioprine (AZA), colchicine [91, 95, 116, 98] | Strong | |
| Continue cyclosporine and tacrolimus [127, 131] | Conditional | |
| Continue certolizumab [156] | Strong | |
| Continue infliximab, etanercept, adalimumab, golimumab [144, 147, 150, 153] | Conditional | |
| Stop when pregnancy confirmed: rituximab, belimumab, anakinra, abatacept, tocilizumab, secukinumab, ustekinumab [164, 169, 160, 173, 177, 181, 185] | Conditional | |
| Use rituximab for organ- or life-threatening disease during pregnancy [165] | Conditional | |
| No recommendations for tofacitinib, baricitinib, apremilast due to lack of data [189, 193, 197] | ||
| Continue regular low-dose prednisone [201] | Conditional | |
| Taper high-dose prednisone with addition of pregnancy-compatible drug if needed [202] | Strong | |
| Stress-dose steroid at delivery: do not treat for vaginal delivery, do treat for cesarean delivery [206, 207] | Conditional | |
| Breastfeeding | Encourage breastfeeding and maintain disease control with compatible medications if possible | GPS |
| Compatible medications: | ||
| HCQ, infliximab, etanercept, adalimumab, golimumab, certolizumab, rituximab [92, 143, 146, 149, 152, 155] | Strong | |
| NSAIDs, sulfasalazine, colchicine, AZA, cyclosporine, tacrolimus, anakinra, belimumab, abatacept, tocilizumab, secukinumab, ustekinumab [89, 96, 99, 117, 128, 132, 161, 170, 174, 178, 182, 186] | Conditional | |
| Prednisone or nonfluorinated steroid equivalent <20 mg daily [204] | Strong | |
| For prednisone ≥20 mg daily, discard breast milk obtained within 4 hours following medication [205] | Strong | |
| Do not treat with leflunomide, MMF, CYC, thalidomide [113, 124, 137, 142] | Strong | |
| Do not treat with MTX [106] | Conditional | |
a Recommendation numbers, shown in brackets, allow for cross-referencing with supplementary appendices. For more detailed/complete recommendations, see text or Supplementary Appendix 7 (on the ACR website at https://www.rheumatology.org/Practice-Quality/Clinical-Support/ Clinical-Practice-Guidelines/Reproductive-Health-in-Rheumatic-Diseases).
b Highly effective contraceptives are long-acting reversible contraceptives including progestin or copper intrauterine device (IUD) and progestin implant. Effective contraceptives are estrogen-progestin contraceptives (oral, patch, or vaginal ring) and progestin-only (oral, depot medroxyprogesterone acetate [DMPA]).
c General indication for hormone replacement therapy: Current recommendations suggest limiting hormone replacement therapy use in healthy postmenopausal women and using the lowest dose that alleviates symptoms for the minimum time necessary. Benefit-risk balance is most favorable for severe vasomotor symptoms in women <60 years old or within 10 years of menopause onset.
Table 2. Safety and efficacy of various contraceptive methods in women with RMD
| Method | Safety in Women with RMD | 1-year Failure rate, %a |
|---|---|---|
| Highly effective long-acting reversible contraception (LARC) | ||
| Copper IUD | Safe in all women with RMD; may increase menstrual bleeding | <1 |
| Progestin IUD | Safe in all women with RMD; may decrease menstrual bleeding | <1 |
| Progestin implant | Limited data, but likely safe in all women with RMD | <1 |
| Effective | ||
| Progestin-only pill (daily) | Safe in all women with RMD; higher rate of breakthrough bleeding than with combined contraceptives; must take same time every day for efficacy | 5–8 |
| DMPA (IM injection every 12 weeks) | Safe in most women with RMD; exceptions: positive aPL, at high risk for OP | 3 |
| Combined estrogen and progesterone pill (daily) | Safe in most women with RMD; exceptions: positive aPL, very active SLE | 5-8 |
| Transdermal patch (weekly) | Safe in most women with RMD; exceptions: positive aPL, SLE; serum estrogen levels higher than with pill or vaginal ring | 5-8 |
| Vaginal ring (monthly) | Safe in most women with RMD; exceptions: positive aPL, very active SLE | 5-8 |
| Less effective | ||
| Diaphragm | Safe in all women with RMD | 12 |
| Condom | Safe in all women with RMD; only form to prevent STD | 18 |
| Fertility awareness–based methodsb | Safe in all women with RMD; limited efficacy, especially if menses are irregular | 24 |
| Spermicide | Safe in all women with RMD; use with condoms or diaphragm to improve efficacy | 28 |
a Percent of women who will become pregnant within the first year of typical use.
b Methods based on the timing of the menstrual cycle.
Table 3. Recommendations regarding medication use for men with rheumatic and musculoskeletal disease who are planning to father a child
| Strongly recommend continuing | Azathioprine/6-mercaptopurine Colchicine Hydroxychloroquine Tumor necrosis factor inhibitors (all) |
|---|---|
| Conditionally recommend continuing | Anakinra Cyclooxygenase 2 inhibitors Cyclosporine Leflunomide Methotrexate Mycophenolate mofetil Mycophenolic acid Nonsteroidal anti-inflammatory drugs Rituximab Sulfasalazine (semen analysis if delayed conception) Tacrolimus |
| Strongly recommend discontinuing | Cyclophosphamide (discontinue 12 weeks prior to attempted conception) |
| Conditionally recommend discontinuing | Thalidomide (discontinue 4 weeks prior to attempted conception) |
| Unable to make a recommendation due to limited data | Abatacept Apremilast Baricitinib Belimumab Secukinumab Tocilizumab Tofacitinib Ustekinumab |
Table 4. Maternal medication use: overview of medication use before and during pregnancy, and during breastfeeding
| Medication | Pre-conception | During pregnancy | Breastfeeding |
|---|---|---|---|
| Conventional medications | |||
| Hydroxychloroquine | ++ | ++ | ++ |
| Sulfasalazine | ++ | ++ | ++ |
| Colchicine | ++ | ++ | ++ |
| Azathioprine, 6-mercaptopurine | ++ | ++ | + Low transfer |
| Prednisone | + Taper to <20 mg/day by adding pregnancy-compatible immunosuppressant | + Taper to <20 mg/day by adding pregnancy-compatible immunosuppressant | + After a dose of >20 mg, delay breastfeeding for 4 hours |
| Cyclosporine, tacrolimus | + Monitor blood pressure | + Monitor blood pressure | + Low transfer |
| NSAIDs (OX-2 inhibitors not preferred) | + Discontinue if the woman is having difficulty conceiving | + Continue in first and second trimesters; discontinue in third trimester | + Ibuprofen preferred |
| Tumor necrosis factor inhibitors (tumor necrosis factor inhibitors are considered compatible with pregnancy) | |||
| Certolizumab | ++ | ++ | ++ |
| Infliximab, etanercept, adalimumab, golimumab | + Continue through conception | + Continue in first and second trimesters; discontinue in third trimester several half-lives prior to delivery | ++ |
| Rituximab | + Discontinue at conception | + Life-/organ-threatening disease | ++ |
| Other biologics (limited safety data; limited transfer in early pregnancy but high transfer in second half of pregnancy) | |||
| Anakinra, belimumab, abatacept, tocilizumab, secukinumab, ustekinumab | + Discontinue at conception | x Discontinue during pregnancy | + Expect minimal transfer due to large molecular size, but no available data |
| Not compatible with pregnancy | |||
| Methotrexate | xx Stop 1–3 months prior to conception | xx Stop and give folic acid 5 mg/day | x Limited data suggest low transfer |
| Leflunomide | xx Cholestyramine washout if detectable levels | xx Stop and give cholestyramine washout | xx |
| Mycophenolate mofetil and mycophenolic acid | xx Stop >6 weeks prior to conception to assess disease stability | xx | xx |
| Cyclophosphamide | xx Stop 3 months prior to conception | + Life-/organ-threatening disease in second and third trimesters | xx |
| Thalidomide | xx Stop 1–3 months prior to conception | xx | xx |
| Tofacitinib, apremilast, baricitinib | Unable to determine due to lack of data; small molecular size suggests transfer across the placenta and into breast milk | ||
| ++ | Strongly recommend | |
| + | Conditionally recommend | |
| x | Conditionally recommend against | |
| xx | Strongly recommend against |
Figure 1. Recommendations and good practice statements (GPS) for use of contraception in women with RMD
Figure 2. Recommendations for use of assisted reproductive technology (ART) in women with RMD
Figure 3. Recommendations and GPS for HRT use in postmenopausal women with RMD
Figure 4. Recommendations and GPS for pregnancy counseling, assessment, and management in women with RMD
