DMARDs and Pregnancy Planning: Which to Stop and When
TL;DR
- Not all DMARDs must be stopped before pregnancy — hydroxychloroquine, sulfasalazine, and azathioprine are considered compatible with conception and pregnancy per ACR 2020 guidelines.
- Methotrexate must be discontinued at least 3 months before attempting conception (both women and men).
- Leflunomide requires cholestyramine washout and confirmed undetectable serum levels before conception is attempted.
- Mycophenolate (CellCept) must be stopped at least 6 weeks before conception due to high teratogenicity risk.
- Pre-conception planning with both a rheumatologist and obstetrician is essential — uncontrolled disease activity itself poses pregnancy risks.
Why DMARDs Pregnancy Planning Matters
For the estimated 1.3 million adults in the United States living with rheumatoid arthritis (RA) and the approximately 200,000 with systemic lupus erythematosus (SLE), family planning presents a challenge that healthy individuals never face: balancing effective disease control against fetal safety. Disease-modifying antirheumatic drugs (DMARDs) form the backbone of treatment for these conditions, yet several carry significant teratogenic risks — meaning they can cause structural or functional harm to a developing embryo.
DMARDs pregnancy planning is not simply a matter of stopping all medications. Abrupt, unguided withdrawal of effective therapy can trigger disease flares, and active inflammatory disease during pregnancy is itself associated with adverse outcomes including preeclampsia, fetal growth restriction, and preterm birth. The 2020 American College of Rheumatology (ACR) Guideline for Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases provides the most comprehensive, evidence-graded framework currently available for navigating these decisions.
This guide categorizes commonly used DMARDs into three groups — pregnancy-compatible, requiring washout or discontinuation, and conditionally used — and details the evidence behind timing recommendations.
Understanding the Three Categories of DMARDs in Pregnancy
The ACR 2020 guideline, authored by Sammaritano et al. and endorsed by the American College of Obstetricians and Gynecologists (ACOG), uses a conditional or strong recommendation framework rather than the now-retired FDA letter categories (A, B, C, D, X). DMARDs relevant to pregnancy planning fall into three practical categories:
- Compatible with pregnancy — may be continued before, during, and (in most cases) through breastfeeding.
- Requiring discontinuation with washout — must be stopped well in advance, with some needing active drug elimination procedures.
- Requiring discontinuation without formal washout — must be stopped before conception, but the drug clears adequately with a defined waiting period.
The table below summarizes this classification for the most commonly prescribed conventional synthetic DMARDs (csDMARDs) and selected targeted synthetic DMARDs (tsDMARDs).
DMARD Pregnancy Safety Classification Table
| DMARD (INN) | Brand Example | ACR 2020 Category | Stop Before Conception? | Minimum Lead Time | Breastfeeding Compatible? |
|---|---|---|---|---|---|
| Hydroxychloroquine | Plaquenil | Compatible | No — continue | N/A | Yes (AAP compatible) |
| Sulfasalazine | Azulfidine | Compatible | No — continue | N/A | Yes (with monitoring) |
| Azathioprine | Imuran | Compatible (≤2 mg/kg/day) | No — continue at lowest effective dose | N/A | Yes (LactMed: low transfer) |
| Methotrexate | Trexall, Otrexup | Teratogenic — stop | Yes | ≥3 months (women); ≥3 months (men, conditional) | No |
| Leflunomide | Arava | Teratogenic — stop + washout | Yes | Cholestyramine washout + undetectable levels | No |
| Mycophenolate mofetil | CellCept | Teratogenic — stop | Yes | ≥6 weeks | No |
| Cyclophosphamide | Cytoxan | Teratogenic — stop | Yes | ≥3 months after last dose | No |
| Tofacitinib | Xeljanz | Insufficient data — stop | Yes | ≥1 menstrual cycle (≥4–6 weeks) | Unknown — avoid |
| Baricitinib | Olumiant | Insufficient data — stop | Yes | ≥1 week (based on half-life) | Unknown — avoid |
Pregnancy-Compatible DMARDs: What Can Stay
Hydroxychloroquine (Plaquenil)
Hydroxychloroquine holds the strongest safety profile of any DMARD in pregnancy and is conditionally recommended to be continued throughout pregnancy by the ACR 2020 guideline. This recommendation is grounded in decades of observational data, particularly from lupus pregnancy cohorts.
Key evidence:
- The OTIS (Organization of Teratology Information Specialists) Autoimmune Diseases in Pregnancy Study found no increase in major congenital malformations among hydroxychloroquine-exposed pregnancies.
- Discontinuation of hydroxychloroquine during lupus pregnancy is associated with increased flare risk, which itself worsens pregnancy outcomes.
- The drug crosses the placenta, but long-term follow-up studies of exposed children (up to 18 months) have not identified developmental concerns.
Dose in pregnancy: Standard dosing (200–400 mg daily) is maintained. The ACR does not recommend dose reduction for pregnancy.
Breastfeeding: Compatible. Hydroxychloroquine is excreted in breast milk in small quantities. The American Academy of Pediatrics (AAP) considers it compatible with breastfeeding, and LactMed notes that infant exposure is well below therapeutic thresholds.
Sulfasalazine (Azulfidine)
Sulfasalazine is conditionally recommended as compatible with pregnancy. It has been used extensively in inflammatory bowel disease and RA pregnancies.
- No consistent association with major birth defects has been identified in registry or cohort studies.
- Folic acid supplementation (at least 2 mg/day) is strongly recommended, as sulfasalazine inhibits folate absorption. Some clinicians prescribe 5 mg/day of folic acid, though evidence for the higher dose is extrapolated from neural tube defect prevention data.
- Male fertility note: Sulfasalazine causes reversible oligospermia and reduced sperm motility in men. Male partners planning conception should discuss switching to mesalamine or another agent with their rheumatologist.
Breastfeeding: Generally compatible. Sulfapyridine (the active metabolite) is excreted in milk. Healthy, full-term infants tolerate this well, but caution is advised in premature infants or those with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to theoretical hemolysis risk.
Azathioprine (Imuran)
Azathioprine is conditionally recommended as compatible at doses ≤2 mg/kg/day. It has the longest track record of any immunosuppressant in pregnancy, primarily from transplant recipient data.
- The fetal liver lacks the enzyme inosinate pyrophosphorylase needed to convert azathioprine to its active metabolite, providing a degree of natural protection.
- Higher doses (>2 mg/kg/day) are associated with a possible increase in prematurity and low birth weight, though confounding by disease severity limits causal inference.
- Complete blood counts should be monitored in both mother and neonate.
Breastfeeding: Compatible per LactMed. Active metabolite 6-mercaptopurine appears in breast milk at very low concentrations (generally <1% of the weight-adjusted maternal dose).
DMARDs Requiring Washout or Discontinuation
Methotrexate — Stop at Least 3 Months Before Conception
Methotrexate is the most widely prescribed DMARD for RA and is classified as a known human teratogen. It is an antimetabolite that inhibits dihydrofolate reductase, disrupting DNA synthesis in rapidly dividing cells — including embryonic tissues.
Teratogenic effects (methotrexate embryopathy):
- Craniofacial anomalies (wide nasal bridge, micrognathia)
- Limb defects
- Neural tube defects
- Growth restriction
- Risk is highest with doses >10 mg/week during the first trimester, but no safe dose in pregnancy has been established
ACR 2020 recommendation: Discontinue methotrexate at least 1 menstrual cycle (approximately 4 weeks) before attempting conception, though many experts and the EULAR 2016 points to consider recommend a 3-month washout to allow for complete folate repletion and drug clearance. The 3-month window is the most commonly cited in clinical practice.
For men: The ACR 2020 guideline conditionally recommends that men taking methotrexate may continue the drug when planning conception, citing reassuring (though limited) data showing no increased risk of birth defects or adverse pregnancy outcomes in partners of men on low-dose methotrexate. However, the EULAR 2016 and British Society for Rheumatology (BSR) guidelines recommend stopping 3 months before conception in men as well. This remains an area of active debate — patients should discuss individual risk-benefit with their rheumatologist.
Folate supplementation: High-dose folic acid (5 mg/day) should be started immediately upon discontinuation and continued through at least the first trimester.
Breastfeeding: Methotrexate is not compatible with breastfeeding. It is excreted in breast milk and poses immunosuppressive and mutagenic risk to the nursing infant.
Leflunomide — Cholestyramine Washout Required
Leflunomide presents a unique challenge: its active metabolite, teriflunomide, has an extremely long elimination half-life — approximately 14 to 18 days, but due to enterohepatic recirculation, detectable drug levels can persist for up to 2 years after discontinuation without active washout.
Teratogenic potential: Animal studies demonstrate craniofacial and skeletal malformations. Human data are more limited but concerning enough to warrant an FDA boxed warning and Pregnancy Category X classification (under the prior system).
ACR 2020 recommendation:
- Discontinue leflunomide before conception.
- Administer cholestyramine washout protocol: cholestyramine 8 g three times daily for 11 days.
- Verify serum teriflunomide level is <0.02 mg/L on two separate measurements taken at least 14 days apart.
- Only after confirmed undetectable levels should conception be attempted.
Alternative washout agent: Activated charcoal (50 g every 12 hours for 11 days) can be used if cholestyramine is unavailable or not tolerated, though evidence is more limited.
Leflunomide Washout Protocol
| Step | Action | Duration/Timing |
|---|---|---|
| 1 | Stop leflunomide | Immediately |
| 2 | Begin cholestyramine 8 g TID | 11 consecutive days |
| 3 | First serum teriflunomide level | After completing cholestyramine course |
| 4 | Second serum teriflunomide level | ≥14 days after first level |
| 5 | Confirm both levels <0.02 mg/L | Before attempting conception |
| 6 | Begin bridging therapy if needed | After washout confirmation |
Breastfeeding: Not recommended. Teriflunomide is excreted in breast milk in animal studies, and human data are insufficient to establish safety.
Mycophenolate Mofetil (CellCept) — Stop at Least 6 Weeks Before
Mycophenolate is widely used in lupus nephritis and is a known teratogen with an estimated first-trimester malformation rate of 23–27% in exposed pregnancies, along with an increased miscarriage rate of approximately 45%.
Associated malformations (mycophenolate embryopathy):
- Cleft lip and palate
- Microtia and anotia (external ear anomalies)
- Congenital heart defects
- Esophageal atresia
ACR 2020 recommendation: Discontinue at least 6 weeks before conception. Mycophenolic acid has a relatively short half-life (approximately 16–18 hours), so the 6-week window provides ample drug clearance.
Transition strategy: Patients on mycophenolate for lupus nephritis typically transition to azathioprine (which is pregnancy-compatible) before conception. This switch should occur well in advance — ideally 3 to 6 months before planned conception — to ensure disease stability on the new regimen before pregnancy begins.
Breastfeeding: Not recommended due to insufficient human data and potential immunosuppressive effects.
Practical Dosing and Transition Timeline
Pre-conception planning ideally begins 3 to 6 months before a couple plans to conceive. This timeline allows for:
- Medication changes and disease stabilization
- Folate optimization
- Washout completion (if leflunomide is involved)
- Baseline disease activity assessment
Recommended Pre-Conception Timeline
| Months Before Conception | Action |
|---|---|
| 6 months | Initial pre-conception counseling with rheumatologist; assess disease activity |
| 5–6 months | Begin mycophenolate → azathioprine transition (if applicable) |
| 4–6 months | Begin leflunomide washout with cholestyramine (if applicable) |
| 3 months | Stop methotrexate; start high-dose folic acid (5 mg/day) |
| 3 months | Stop cyclophosphamide (if applicable) |
| 1–3 months | Stop tofacitinib, baricitinib, or upadacitinib |
| Ongoing | Continue hydroxychloroquine, sulfasalazine, azathioprine |
| Ongoing | Confirm leflunomide washout levels <0.02 mg/L |
| At conception | Verify disease is quiescent or low-activity on compatible regimen |
Side Effects and Monitoring During Transition
Switching DMARDs or stopping them carries risks beyond teratogenicity — primarily disease flare. The following monitoring is recommended during the transition period:
Disease activity monitoring:
- Assess with validated tools (DAS28 for RA, SLEDAI for SLE) at each visit during the transition period.
- Aim for low disease activity or remission for at least 3–6 months before conception. Active disease at conception increases the risk of flare during pregnancy and adverse obstetric outcomes.
Laboratory monitoring during transition:
- Complete blood count (CBC) — especially when starting or adjusting azathioprine
- Liver function tests (LFTs) — when transitioning from methotrexate or leflunomide
- Renal function and urinalysis — particularly for lupus patients transitioning from mycophenolate
- Thiopurine methyltransferase (TPMT) or NUDT15 genotype — before initiating azathioprine, to identify patients at risk for severe myelosuppression
Common side effects of compatible DMARDs during pregnancy:
| DMARD | Common Side Effects | Monitoring in Pregnancy |
|---|---|---|
| Hydroxychloroquine | Nausea, retinal toxicity (long-term) | Ophthalmologic exam annually; baseline ECG if cardiac risk |
| Sulfasalazine | GI upset, headache, folate depletion | CBC, folate levels; supplement with ≥2 mg/day folic acid |
| Azathioprine | Nausea, leukopenia, hepatotoxicity | CBC monthly in first trimester; LFTs quarterly; neonatal CBC |
Contraindications and Drug Interactions
Several important interactions merit attention during the transition period:
Methotrexate interactions to clear before conception:
- NSAIDs can reduce methotrexate renal clearance — usually acceptable at low RA doses, but should be reviewed
- Trimethoprim/sulfamethoxazole enhances antifolate effects — avoid overlap
Azathioprine interactions relevant in pregnancy:
- Allopurinol dramatically increases azathioprine toxicity — this combination is generally contraindicated unless under specialist supervision with major dose reduction
- ACE inhibitors may compound leukopenia risk
- Warfarin effect may be reduced by azathioprine
Sulfasalazine interactions:
- Reduces absorption of folic acid and digoxin
- May potentiate effects of oral hypoglycemics
Key contraindications for DMARD use in pregnancy:
| Situation | Contraindicated DMARD(s) | Rationale |
|---|---|---|
| Active pregnancy | Methotrexate, leflunomide, mycophenolate, cyclophosphamide | Known teratogens |
| Detectable teriflunomide levels | Conception attempt | Incomplete washout |
| TPMT/NUDT15 poor metabolizer | Azathioprine (standard dose) | Severe pancytopenia risk |
| G6PD deficiency in infant | Sulfasalazine (breastfeeding) | Theoretical hemolysis |
| Renal impairment (eGFR <30) | Methotrexate | Impaired clearance |
Special Populations
Patients with Lupus Nephritis
Lupus nephritis patients face a particularly complex transition because mycophenolate — the first-line maintenance therapy for many — is teratogenic. The ACR 2020 guideline recommends:
- Transition to azathioprine at least 3–6 months before conception
- Continue hydroxychloroquine — it reduces the risk of lupus flare during pregnancy and may decrease the risk of neonatal lupus
- Consider low-dose tacrolimus (a calcineurin inhibitor) as an alternative or adjunct if azathioprine alone is insufficient. Tacrolimus is conditionally recommended as compatible with pregnancy per the ACR 2020 guideline
Patients on Biologic DMARDs
While this guide focuses on conventional DMARDs, many patients take biologic agents concurrently:
- TNF inhibitors (certolizumab, adalimumab, etanercept, infliximab): The ACR 2020 guideline conditionally recommends continuation during pregnancy. Certolizumab is often preferred because it does not cross the placenta (it lacks an Fc fragment).
- Rituximab: Discontinue at least 6 months before conception due to prolonged B-cell depletion in the neonate.
Male Patients Planning Conception
- Methotrexate: ACR 2020 conditionally allows continuation in men, though some guidelines recommend a 3-month stop (see above).
- Sulfasalazine: Causes reversible oligospermia — consider switching to an alternative 2–3 months before planned conception if fertility is a concern.
- Mycophenolate: FDA recommends men stop at least 90 days before conception, based on theoretical genotoxicity risk.
- Cyclophosphamide: Gonadotoxic — discuss sperm banking before treatment initiation.
Red Flags — When to Seek Immediate Medical Care
Contact your rheumatologist urgently if:
- You discover you are pregnant while still taking methotrexate, leflunomide, or mycophenolate — do not simply stop the medication without medical guidance, but seek same-day consultation
- You experience a severe disease flare during the transition period (new joint swelling, rash, proteinuria, fever)
- You develop signs of bone marrow suppression on azathioprine (unusual bruising, recurrent infections, fatigue, pallor)
Contact your obstetrician or go to the emergency department if:
- Vaginal bleeding or cramping in early pregnancy after recent DMARD exposure
- Signs of preeclampsia (severe headache, visual changes, upper abdominal pain, rapid swelling) — autoimmune disease increases baseline preeclampsia risk
Do not:
- Stop all medications abruptly without medical supervision — disease flare during pregnancy is dangerous for both mother and fetus
- Rely on over-the-counter supplements as DMARD replacements
- Delay pregnancy planning discussions — ideally begin at least 6 months before intended conception
Frequently Asked Questions
Q: How long after stopping methotrexate can I safely try to conceive? A: The ACR 2020 guideline recommends waiting at least one full menstrual cycle, but most rheumatologists advise 3 months to allow for complete folate repletion and drug clearance. Start taking 5 mg folic acid daily as soon as you stop methotrexate.
Q: Is hydroxychloroquine truly safe throughout pregnancy? A: Hydroxychloroquine has the most robust pregnancy safety data of any DMARD. The ACR 2020, EULAR 2016, and BSR guidelines all recommend continuing it throughout pregnancy, particularly in lupus patients. Discontinuation increases the risk of disease flare, which itself threatens the pregnancy.
Q: What happens if I accidentally become pregnant on methotrexate? A: Contact your rheumatologist immediately. Methotrexate should be stopped at once, and high-dose folic acid started. A detailed fetal ultrasound and maternal-fetal medicine consultation will be recommended. Not all exposures result in malformations, particularly at the low doses used for RA (≤25 mg/week), but careful monitoring is essential.
Q: Can my partner continue methotrexate while we try to conceive? A: The ACR 2020 guideline conditionally recommends that men may continue low-dose methotrexate when planning to father a child, based on limited but reassuring data. However, some other guidelines (EULAR, BSR) recommend a 3-month discontinuation in men as well. Discuss this with your rheumatologist for an individualized decision.
Q: Why can't I just stop all my medications to be safe? A: Uncontrolled disease activity during pregnancy is associated with increased risks of preeclampsia, preterm birth, low birth weight, and miscarriage. The goal is not to stop all medications, but to transition to a pregnancy-compatible regimen while maintaining disease control. Hydroxychloroquine, sulfasalazine, and azathioprine are available as compatible options.
Q: How long does leflunomide stay in the body? A: Without active washout, teriflunomide (the active metabolite) can be detected in blood for up to 2 years due to enterohepatic recirculation. This is why the cholestyramine washout protocol is essential — it reduces this timeline to approximately 2–4 weeks, after which serum levels must be confirmed as undetectable (<0.02 mg/L) on two occasions.
Q: Is azathioprine safe while breastfeeding? A: Yes. LactMed and the ACR 2020 guideline consider azathioprine compatible with breastfeeding. The active metabolite 6-mercaptopurine is found in breast milk at very low concentrations, and studies have not identified adverse effects in breastfed infants of mothers taking ≤2 mg/kg/day.
Q: Should I see a high-risk obstetrician (MFM specialist)? A: Most women with RA or lupus on immunosuppressive therapy benefit from co-management by a maternal-fetal medicine (MFM) specialist in addition to their rheumatologist and general obstetrician. This is particularly important for patients with lupus nephritis, antiphospholipid antibodies, or those who required DMARD changes close to conception.
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About the Author
Dr. Stanislav Ozarchuk, PharmD, is a clinical pharmacist with 15 years of experience in pharmacotherapy consultation, medication safety, and patient education. He has contributed to formulary reviews, drug utilization evaluations, and clinical guideline implementation across hospital and ambulatory care settings. Dr. Ozarchuk writes for PillsCard.com with the goal of translating complex pharmaceutical evidence into practical, accessible guidance for patients and caregivers worldwide.
Medical Disclaimer
This article is provided for educational and informational purposes only and does not constitute medical advice, diagnosis, or treatment. The information presented reflects published clinical guidelines and peer-reviewed literature available at the time of writing, but medicine evolves and individual circumstances vary. Do not start, stop, or change any medication — including DMARDs — without direct consultation with your prescribing physician or qualified healthcare provider. Pregnancy planning in the setting of autoimmune disease requires individualized medical supervision. If you are pregnant or planning to become pregnant while taking any medication discussed in this article, contact your rheumatologist and obstetrician promptly. PillsCard.com and the author assume no liability for actions taken based on the content of this article.