Selecting DMARDs and Biologics in Rheumatoid Arthritis Patients Planning Pregnancy: A Practical Guide

Dr Neeraj Manikath , claude.ai

Introduction

Rheumatoid arthritis (RA) predominantly affects women during their reproductive years, with a peak incidence between ages 30-50. Approximately 20-30% of RA patients are of childbearing age at diagnosis, making pregnancy planning a critical consideration in disease management. The challenge lies in balancing effective disease control—essential for optimal maternal and fetal outcomes—with medication safety during conception, pregnancy, and lactation. This review provides evidence-based guidance on selecting disease-modifying antirheumatic drugs (DMARDs) and biologics for women with RA planning pregnancy, incorporating practical pearls for clinical practice.

The Imperative of Disease Control in Pregnancy

Pearl #1: Disease activity, not medication exposure, is often the greater risk to pregnancy outcomes.

Uncontrolled RA during pregnancy associates with increased risks of preeclampsia, preterm delivery, low birth weight, and cesarean delivery. Studies demonstrate that women with moderate to high disease activity have 1.5-2 fold increased risk of adverse pregnancy outcomes compared to those in remission or low disease activity. The inflammatory cytokine milieu, particularly TNF-α and IL-6, may compromise placental function and fetal development.

Interestingly, approximately 50-75% of RA patients experience spontaneous improvement during pregnancy, likely mediated by increased cortisol, progesterone, and changes in immune tolerance. However, this improvement is unpredictable and often incomplete. Post-partum flares occur in 90% of patients, typically within 3-6 months of delivery, necessitating vigilant planning.

Preconception Counseling: The Foundation of Success

Hack #1: Start the pregnancy conversation early—ideally at diagnosis, regardless of patient's immediate plans.

Preconception counseling should occur 3-6 months before attempted conception, allowing time for medication transitions and disease stabilization. Key elements include:

1. Disease activity assessment: Aim for low disease activity (LDAS) or remission for at least 3 months pre-conception
2. Medication review and transition: Switch from teratogenic to pregnancy-compatible agents
3. Baseline investigations: Anti-Ro/SSA and anti-La/SSB antibodies (neonatal lupus/congenital heart block risk), hepatitis B/C serology
4. Optimization of comorbidities: Hypertension, diabetes control
5. Folic acid supplementation: 5mg daily, especially with methotrexate or leflunomide exposure

Pearl #2: The "3-month rule" for methotrexate and leflunomide is outdated in practice.

While package inserts recommend 3-month washout periods for methotrexate (MTX) and leflunomide (LEF), evidence suggests shorter intervals may suffice. MTX has a half-life of 3-10 hours, and despite theoretical concerns, prospective studies show no increased malformation rates when conception occurs shortly after discontinuation. For LEF, cholestyramine washout can reduce elimination time from 2 years to 1-2 months. Pragmatically, confirming undetectable LEF levels (<0.02 mg/L) via two measurements 14 days apart is more rational than arbitrary time intervals.

Pregnancy-Compatible DMARDs

Hydroxychloroquine (HCQ)

Classification: Compatible with pregnancy

HCQ is the cornerstone of pregnancy-compatible RA therapy. Multiple large cohort studies, including data from over 2,000 exposed pregnancies, demonstrate no increased risk of congenital malformations, spontaneous abortion, or fetal death. The Montreal cohort showed no increased risk with doses up to 400mg daily.

Hack #2: Never discontinue HCQ in pregnancy—disease flares pose greater risks than continued therapy.

HCQ offers modest efficacy as monotherapy (ACR20 response ~40%) but provides valuable disease control bridging and can be safely continued throughout pregnancy and lactation. Retinal toxicity concerns are irrelevant in pregnancy given the short exposure duration.

Sulfasalazine (SSZ)

Classification: Compatible with pregnancy

SSZ demonstrates reassuring safety data with no increased teratogenic risk in multiple studies. The theoretical folate antagonism is mitigated by supplementation with folic acid 5mg daily (not folinic acid, which may reduce efficacy). SSZ achieves ACR20 responses in approximately 50% of patients with early RA.

Pearl #3: SSZ may cause reversible oligospermia in male partners—consider temporary discontinuation 3 months pre-conception if fertility concerns arise.

SSZ remains compatible with breastfeeding, though rare cases of hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient infants warrant vigilance.

Azathioprine (AZA)

Classification: Compatible with pregnancy

Though less commonly used as first-line RA therapy, AZA (1-2mg/kg/day) provides moderate immunosuppression compatible with pregnancy. Extensive transplant literature demonstrates safety, with no increased malformation risk when used at standard rheumatologic doses. AZA can be particularly useful for patients with overlapping autoimmune conditions.

Oyster #1: TPMT testing before AZA initiation prevents life-threatening myelosuppression—approximately 0.3% of individuals have homozygous deficiency.

Pregnancy-Incompatible Conventional DMARDs

Methotrexate

Classification: CONTRAINDICATED—Category X

MTX remains the gold-standard RA therapy outside pregnancy but is a potent teratogen causing neural tube defects, skeletal abnormalities, and aminopterin syndrome when used in first trimester. Discontinue at least 1 month pre-conception (preferably 3 months for medicolegal considerations).

Leflunomide

Classification: CONTRAINDICATED—Category X

LEF's active metabolite (A771726) has a prolonged half-life (2 weeks) and demonstrates teratogenicity in animal studies. Active washout with cholestyramine (8g TID for 11 days) followed by serum level verification is essential before pregnancy attempts.

Cyclosporine and Tacrolimus

Classification: Generally compatible, use with caution

These calcineurin inhibitors show acceptable safety profiles in transplant patients. Consider for refractory RA when TNF inhibitors are contraindicated, though experience in RA pregnancy is limited. Monitor for maternal hypertension and nephrotoxicity.

Biologic DMARDs: The TNF Inhibitor Era

TNF-α Inhibitors

The five available TNF inhibitors demonstrate varying pregnancy compatibility based on molecular structure:

Certolizumab Pegol (CZP) Classification: PREFERRED biologic for pregnancy

Pearl #4: CZP is the only biologic WITHOUT active placental transfer—maternal IgG levels are 100-fold higher than cord blood.

CZP's unique pegylated Fab fragment structure lacks the Fc region responsible for FcRn-mediated placental transport. The CRIB study (Clowse et al., 2018) demonstrated minimal to undetectable infant drug levels at birth with continued maternal therapy. Over 2,000 exposed pregnancies show no increased malformation risk.

Hack #3: Continue CZP throughout pregnancy without dose adjustment—don't stop at 20-24 weeks like other biologics.

This allows optimal disease control through delivery without infant immunosuppression concerns or live vaccine restrictions.

Infliximab (IFX) and Adalimumab (ADA) Classification: Compatible through second trimester

These IgG1 monoclonal antibodies undergo active placental transfer, particularly after 20 weeks gestation when FcRn receptor expression increases. Measurable infant drug levels persist 6-12 months postpartum.

Hack #4: Discontinue IFX at 16-20 weeks and ADA at 20 weeks gestation to minimize fetal exposure while maintaining maternal disease control.

Timing accounts for drug half-lives (IFX: 8-10 days; ADA: 14 days) and allows clearance before significant placental transfer. The PreCARA study demonstrated this strategy maintains disease remission in 80% of patients through delivery.

Etanercept (ETN) Classification: Compatible, lower placental transfer than IFX/ADA

As an IgG1 fusion protein, ETN demonstrates less placental transfer than monoclonal antibodies, with cord blood levels approximately 4-7% of maternal levels. Can continue through second trimester or longer if needed for disease control.

Golimumab (GOL) Classification: Compatible, similar considerations to IFX/ADA

Limited pregnancy data (fewer than 300 exposed pregnancies) but no safety signals. Follow similar discontinuation strategy to adalimumab given monthly dosing and comparable half-life.

Pearl #5: Infant exposure via breastmilk is negligible for all TNF inhibitors—the molecular weight and gastric degradation prevent significant absorption.

Non-TNF Biologics

Rituximab (RTX) Classification: Use only if essential

This anti-CD20 monoclonal antibody crosses the placenta, causing reversible B-cell depletion in neonates lasting 3-6 months. While no clear teratogenic signal exists, limit use to refractory cases given unknowns. If used pre-conception, ensure at least 6-12 months between last dose and conception attempt.

Abatacept (ABT) Classification: Limited data, use with caution

The CTLA-4 fusion protein has approximately 200 exposed pregnancies reported without increased malformation rates, but data remain insufficient for routine recommendation. Consider stopping at pregnancy recognition.

Tocilizumab (TCZ) and Sarilumab Classification: Insufficient data, avoid

IL-6 inhibitors have limited pregnancy experience. Animal studies show no teratogenicity, but clinical experience remains sparse. Avoid unless no alternatives exist.

Janus Kinase (JAK) Inhibitors Classification: CONTRAINDICATED—insufficient data

Tofacitinib, baricitinib, and upadacitinib have minimal pregnancy data. Animal studies show dose-dependent embryo-fetal toxicity. Discontinue 1 week before conception attempts (accounting for short half-lives).

Oyster #2: JAK inhibitors may offer opportunities for rapid disease control before pregnancy—their short half-life allows quick washout, but never use during pregnancy.

Practical Decision-Making Algorithms

Scenario 1: Patient on MTX Monotherapy, Good Control, Planning Pregnancy in 6 Months

Strategy:

1. Transition to HCQ 400mg daily + SSZ 2g daily
2. Discontinue MTX after 2-4 weeks (ensuring new regimen tolerability)
3. Monitor disease activity monthly
4. Add CZP 200mg Q2 weeks if disease flares
5. Proceed with conception after 3 months of stable disease

Scenario 2: Patient on MTX + ADA, Excellent Control, Desires Immediate Pregnancy

Strategy:

1. Stop MTX immediately, start folic acid 5mg daily
2. Add HCQ 400mg daily
3. Switch ADA to CZP 200mg Q2 weeks (loading dose 400mg weeks 0, 2, 4)
4. Wait 1 month for MTX clearance
5. Proceed with conception

Hack #5: Don't switch working TNF inhibitors to CZP if conception is >6 months away—save the switch for closer to conception to avoid unnecessary medication changes.

Scenario 3: Patient on MTX + ETN, Moderate Disease Activity, Planning Pregnancy

Strategy:

1. Optimize current regimen first—consider adding HCQ + SSZ while continuing ETN
2. Once remission achieved, taper MTX over 4-8 weeks
3. Maintain ETN + HCQ + SSZ through conception
4. Discontinue ETN at 24-28 weeks gestation
5. Resume ETN immediately postpartum

Scenario 4: Patient with Severe RA, Previously Failed Multiple Agents, on RTX

Strategy:

1. Multidisciplinary discussion (rheumatology, maternal-fetal medicine, patient)
2. If RTX needed for control: time last dose 6-12 months pre-conception
3. Bridge with pregnancy-compatible agents (HCQ + SSZ + CZP)
4. Close monitoring through pregnancy
5. Consider early resumption postpartum (RTX compatible with breastfeeding)

Glucocorticoids: A Double-Edged Sword

Pearl #6: Prednisone ≤10mg daily is compatible with pregnancy but increases risks of gestational diabetes, hypertension, and premature rupture of membranes.

Prednisolone and prednisone undergo placental 11β-hydroxysteroid dehydrogenase metabolism, reducing fetal exposure to 10% of maternal levels. Use the minimum effective dose. Dexamethasone and betamethasone cross the placenta and should be avoided except for fetal lung maturation in preterm labor.

Hack #6: Intra-articular corticosteroids are underutilized in pregnancy—they provide targeted relief without systemic exposure.

Monitoring During Pregnancy

Recommended surveillance:

• Disease activity assessment each trimester (DAS28, CDAI, or patient-reported outcomes)
• Blood pressure and urinalysis each visit (preeclampsia screening)
• Fetal growth ultrasounds (especially if prednisone >10mg or active disease)
• Anti-Ro/La positive patients: fetal echocardiography weeks 18-24 (congenital heart block risk 2%)

Postpartum Management

Pearl #7: The postpartum period is high-risk for flares—resume full RA therapy immediately after delivery.

Breastfeeding compatibility:

• Compatible: HCQ, SSZ, prednisone, AZA, all TNF inhibitors, CZP (preferred), RTX
• Probably compatible: ETN, IFX, ADA, GOL
• Avoid: MTX (low-dose may be compatible per some sources, but controversial), LEF, JAK inhibitors

Hack #7: Write postpartum medication orders before delivery—include pain management, thromboprophylaxis if needed, and RA therapy resumption to avoid gaps in care.

Future Directions

Emerging data on selective JAK inhibitors with improved safety profiles, extended-release formulations allowing less frequent dosing, and biosimilars improving access to biologics will enhance options. Patient registries continue accruing data on newer agents.

Conclusion

Managing RA in women planning pregnancy requires balancing disease control with medication safety. CZP emerges as the optimal biologic choice given its lack of placental transfer, while HCQ and SSZ provide foundational therapy. Preconception planning, multidisciplinary collaboration, and individualized decision-making optimize outcomes for both mother and child. The key principle remains: controlled disease with pregnancy-compatible medications trumps uncontrolled disease with no medications.

Final Pearl: Document all preconception counseling discussions thoroughly—shared decision-making protects both patient welfare and medicolegal interests.

References

1. Götestam Skorpen C, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75(5):795-810.

2. Sammaritano LR, et al. 2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases. Arthritis Rheumatol. 2020;72(4):529-556.

3. Clowse MEB, et al. Pregnancy outcomes in the certolizumab pegol (CZP) safety database for inflammatory diseases. Arthritis Rheumatol. 2018;70(suppl 10).

4. Förger F, et al. Pregnancy mediated improvement of rheumatoid arthritis. Swiss Med Wkly. 2012;142:w13644.

5. de Man YA, et al. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum. 2008;59(9):1241-1248.

6. Bérard A, et al. Hydroxychloroquine use during pregnancy and the risk of major congenital malformations. Arthritis Rheumatol. 2021;73(8):1453-1462.

7. Mariette X, et al. Lack of placental transfer of certolizumab pegol during pregnancy. Ann Rheum Dis. 2018;77(2):228-233.

8. Vinet É, et al. Pre-pregnancy low disease activity or remission reduces adverse pregnancy outcomes in women with rheumatoid arthritis. Rheumatology. 2019;58(6):1052-1056.

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