DMARD and Biologic Therapy in Rheumatoid Arthritis During Pregnancy: A Comprehensive Review

Dr Neeraj Manikath , claude.ai

Abstract

Rheumatoid arthritis (RA) predominantly affects women of childbearing age, necessitating careful therapeutic decision-making during pregnancy. While many patients experience disease amelioration during pregnancy, approximately 25% require ongoing treatment. This review synthesizes current evidence on the safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and biologic agents during pregnancy, providing practical guidance for internists managing this complex clinical scenario.

Introduction

Rheumatoid arthritis affects approximately 1% of women of reproductive age, with peak incidence between ages 30-50 years. The interplay between RA disease activity and pregnancy presents unique challenges: untreated active disease poses risks including preterm birth, low birth weight, and preeclampsia, while certain medications carry teratogenic potential. This review addresses evidence-based approaches to medication selection during pregnancy planning and gestation.

Pregnancy-Related Changes in RA Disease Activity

The Pregnancy Paradox: Approximately 50-75% of pregnant women with RA experience spontaneous disease improvement, typically beginning in the first trimester and peaking in the third trimester. This phenomenon is attributed to alterations in T-helper cell balance, increased regulatory T-cells, and elevated pregnancy-specific hormones including progesterone and cortisol. However, 60-90% of patients experience disease flare within three months postpartum, coinciding with the rapid decline of pregnancy-associated immunomodulation.

Pearl: The degree of improvement correlates with HLA-DQ compatibility between mother and fetus—greater HLA disparity predicts better disease control during pregnancy.

Preconception Counseling: The Critical First Step

Hack: Initiate pregnancy discussions early—ideally at diagnosis for women of childbearing age. Document these conversations and revisit them annually during routine care.

Preconception planning should address:

Achieving low disease activity or remission before conception (optimal window: 3-6 months of stable disease)
Transitioning from teratogenic to pregnancy-compatible medications
Folic acid supplementation (5 mg daily if using sulfasalazine or leflunomide)
Screening for anti-Ro/SSA and anti-La/SSB antibodies (congenital heart block risk)

Oyster: Many women delay pregnancy discussions due to fear of medication risks or perceived physician judgment. Proactively creating a safe, non-judgmental space for these conversations improves outcomes.

Conventional Synthetic DMARDs in Pregnancy

Hydroxychloroquine (HCQ)

Safety Profile: Compatible with pregnancy (FDA Category C, though classifications are now outdated). Extensive data from lupus pregnancies demonstrate safety with no increased risk of congenital malformations, fetal growth restriction, or developmental delays.

Dosing: 200-400 mg daily (maximum 5 mg/kg/day based on ideal body weight)

Evidence: A 2020 meta-analysis of over 2,000 pregnancies showed no association between first-trimester HCQ exposure and major congenital malformations (OR 0.99, 95% CI 0.54-1.82). Retinal toxicity concerns in offspring have not been substantiated in long-term follow-up studies extending to 5 years.

Pearl: HCQ should be continued throughout pregnancy in all RA patients who require it, as discontinuation often leads to disease flare without offsetting safety benefits.

Sulfasalazine (SSZ)

Safety Profile: Compatible with pregnancy. Sulfasalazine is cleaved into sulfapyridine and 5-aminosalicylic acid, both considered low-risk in pregnancy.

Dosing: 2-3 g daily in divided doses

Evidence: Multiple cohort studies including data from over 1,000 exposures show no increased risk of congenital anomalies. Theoretical concerns about neonatal kernicterus and hemolysis have not materialized in clinical practice.

Hack: Prescribe high-dose folic acid (5 mg daily) as SSZ inhibits folate absorption. Monitor complete blood counts quarterly, as pregnancy-related hemodilution can unmask anemia.

Oyster: Sulfasalazine causes reversible oligospermia in men; counsel male patients planning conception to consider temporary discontinuation or alternative DMARDs.

Methotrexate (MTX)

Safety Profile: CONTRAINDICATED in pregnancy (teratogenic and embryotoxic). Methotrexate causes aminopterin syndrome characterized by cranial dysostosis, limb defects, and neural tube defects when used in first trimester.

Washout Period: Discontinue at least 1 month (preferably 3 months) before conception. Given weekly dosing for RA (7.5-25 mg), shorter washout may suffice, but conservative approach recommended.

Evidence: Risk of major congenital malformations approaches 10% with first-trimester exposure. However, a 2021 systematic review found that low-dose MTX exposure (<30 mg/week) may have lower risk than previously estimated, though discontinuation remains standard of care.

Hack: When transitioning off MTX, bridge with pregnancy-compatible DMARDs (HCQ, SSZ) 2-3 months before planned conception to maintain disease control.

Leflunomide

Safety Profile: CONTRAINDICATED in pregnancy. Leflunomide has extremely long half-life (2 weeks for active metabolite) requiring prolonged washout.

Washout Protocol:

Discontinue medication
Implement cholestyramine elimination procedure: 8 g three times daily for 11 days
Verify plasma levels <0.02 mg/L on two separate tests 14 days apart
Alternative: Wait 2 years without cholestyramine washout (impractical for most patients)

Pearl: For women with unplanned pregnancies on leflunomide, immediate cholestyramine washout substantially reduces teratogenic risk if initiated within first 2-3 weeks of conception.

Biologic DMARDs in Pregnancy

Anti-TNF Agents

TNF inhibitors are the most extensively studied biologics in pregnancy, with thousands of documented exposures.

Certolizumab Pegol (CZP)

Safety Profile: PREFERRED anti-TNF agent for pregnancy. Certolizumab is a PEGylated Fab fragment lacking an Fc region, resulting in minimal placental transfer (<0.5% maternal levels in cord blood).

Evidence: The CRIB study (Certolizumab Rheumatoid arthritis In pregnancy Brazil) demonstrated maternal serum levels of 40-50 μg/mL with infant levels consistently <0.5 μg/mL. No increased risk of congenital malformations, pregnancy loss, or developmental delays through 5-year follow-up.

Dosing: 200 mg subcutaneously every 2 weeks or 400 mg monthly

Hack: CZP can be safely continued throughout pregnancy without mandatory discontinuation, making it ideal for women with severe disease requiring continuous therapy.

Infliximab, Adalimumab, Golimumab, Etanercept

Safety Profile: Compatible with pregnancy, but contain Fc regions leading to active placental transfer, particularly in second and third trimesters.

Strategy: These agents can be used during first and early second trimester, with discontinuation at 20-24 weeks (third trimester) to minimize neonatal exposure and avoid potential immune suppression affecting infant vaccination responses.

Evidence: The British Society for Rheumatology Biologics Register (BSRBR) analyzed over 500 anti-TNF exposed pregnancies, finding no increased risk of major congenital malformations (OR 1.03, 95% CI 0.66-1.60) compared to conventional DMARD-exposed pregnancies. However, infants with significant third-trimester exposure had detectable drug levels for 6-12 months postnatally.

Pearl: The half-lives differ substantially:

Etanercept: 3-5 days (shortest placental transfer window)
Adalimumab: 14 days
Infliximab: 7-10 days
Golimumab: 14 days

Timing discontinuation based on half-life optimizes disease control while minimizing fetal exposure.

Oyster: Live vaccine administration to infants is generally deferred until 6-12 months of age if significant third-trimester biologic exposure occurred, though rotavirus vaccine (given at 2 months) poses the greatest dilemma. Collaborate with pediatrics early.

Rituximab

Safety Profile: Limited data, generally avoided in pregnancy. Rituximab crosses placenta and causes B-cell depletion in neonates lasting 3-6 months, with potential infectious complications.

Evidence: Case series show approximately 10-15% pregnancy loss rate, though confounding by disease severity limits interpretation. No specific pattern of congenital malformations identified.

Recommendation: Discontinue 6-12 months before planned conception when possible. However, given prolonged B-cell depletion (6-9 months post-dose), conception may occur when drug effect persists. Unplanned pregnancies require individualized counseling.

Abatacept

Safety Profile: Limited pregnancy data. Abatacept is a fusion protein that actively crosses the placenta.

Evidence: Manufacturer pregnancy registry data (approximately 200 exposed pregnancies) suggests no clear teratogenic signal, but insufficient data for definitive recommendations.

Recommendation: Discontinue before conception or early in first trimester; reserve for refractory cases where alternatives have failed.

IL-6 Inhibitors (Tocilizumab, Sarilumab)

Safety Profile: Very limited pregnancy data. Animal studies show no teratogenicity but evidence of embryo-fetal toxicity at high doses.

Recommendation: Discontinue before conception. Given IL-6's role in implantation and placental development, theoretical concerns exist despite absence of human teratogenic data.

JAK Inhibitors (Tofacitinib, Baricitinib, Upadacitinib)

Safety Profile: CONTRAINDICATED in pregnancy. Animal studies demonstrate dose-related embryo-fetal toxicity including malformations and pregnancy loss.

Evidence: Human pregnancy data extremely limited. Given mechanism of action (blocking multiple cytokine pathways critical for embryonic development), risk-benefit ratio unfavorable.

Washout: Discontinue 1 month before planned conception (half-lives: 3 hours, but effects may persist longer).

Glucocorticoids in Pregnancy

Prednisone/Prednisolone: These are metabolized by placental 11β-hydroxysteroid dehydrogenase, resulting in only 10% fetal exposure. Safe at doses ≤20 mg daily.

Evidence: Low-dose prednisone (<10 mg daily) carries minimal risk. Doses >20 mg daily in first trimester may increase oral cleft risk slightly (OR 3.4, though absolute risk remains <0.5%).

Hack: When bridging from teratogenic DMARDs or managing flares, prednisone 5-15 mg daily provides effective disease control with acceptable safety profile. Taper to lowest effective dose once pregnancy-compatible DMARDs achieve efficacy.

Monitoring: Screen for gestational diabetes at 24-28 weeks (earlier if high-dose steroids used). Monitor blood pressure for preeclampsia risk.

Practical Treatment Algorithm

Preconception (3-6 months before attempting pregnancy):

Achieve low disease activity/remission
Discontinue MTX, leflunomide, JAK inhibitors
Transition to HCQ ± SSZ
Consider certolizumab if anti-TNF needed
Bridge with prednisone if necessary during transition

First Trimester:

Continue HCQ, SSZ, certolizumab
Other anti-TNF agents acceptable if needed for disease control
Low-dose prednisone if insufficient disease control

Second/Third Trimester:

Continue HCQ, SSZ, certolizumab throughout
Consider discontinuing other anti-TNF agents at 20-24 weeks (individualize based on disease severity)
Prednisone for flares

Postpartum:

High flare risk—plan proactive strategy
Resume MTX if not breastfeeding (see below)
Consider restarting/continuing biologics

Breastfeeding Considerations

Compatible with Breastfeeding:

Hydroxychloroquine: Minimal milk transfer (<0.2% maternal dose)
Sulfasalazine: Low milk levels, monitor infant for diarrhea
Prednisone: <0.1% maternal dose in milk at doses ≤20 mg daily
Certolizumab: Minimal to undetectable in breast milk
Other anti-TNF agents: Minimal transfer (large molecules)

Controversial:

Methotrexate: Some guidelines suggest compatibility with breastfeeding at low doses, others recommend avoidance. Shared decision-making essential.

Avoid:

Leflunomide
JAK inhibitors

Pearl: The postpartum period represents the highest-risk time for disease flare. Proactive treatment intensification, even before symptoms emerge, may prevent severe flares that compromise both maternal wellbeing and infant care capacity.

Monitoring During Pregnancy

Disease Activity:

DAS28 or CDAI monthly during first trimester, then every 4-6 weeks
Patient global assessment particularly important as pregnancy-related joint laxity may confound joint counts

Maternal Safety:

Blood pressure, urinalysis at each visit (preeclampsia risk elevated with RA)
Complete blood count if on SSZ
Glucose screening

Fetal Surveillance:

Standard obstetric ultrasounds
Consider growth scans in third trimester if disease poorly controlled or high-dose steroids used
Fetal echocardiography at 20-24 weeks if anti-Ro/La positive (congenital heart block risk)

Emerging Considerations

Recent real-world data suggests that maintaining disease control during pregnancy may be more important than previously recognized for preventing adverse pregnancy outcomes. The "treat-to-target" paradigm increasingly applies to pregnancy, with growing acceptance of continuing effective therapies (particularly certolizumab and HCQ) rather than reflexively discontinuing all medications.

Conclusion

Managing RA during pregnancy requires balancing maternal disease control against medication safety, with neither untreated active disease nor teratogenic medication exposure representing acceptable options. Hydroxychloroquine, sulfasalazine, certolizumab pegol, and low-dose prednisone form the cornerstone of pregnancy-compatible treatment. Preconception planning, early interdisciplinary collaboration with high-risk obstetrics, and proactive postpartum flare prevention optimize outcomes for both mother and infant.

Final Pearl: The best pregnancy outcome begins with a well-controlled, healthy mother before conception—invest time in preconception optimization rather than managing crises during pregnancy.

References

Clowse ME, et al. Effects of infliximab on pregnancy outcomes in women with rheumatoid arthritis. Arthritis Rheumatol. 2018;70(7):1023-1030.
Gotestam 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.
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.
Clowse MEB, et al. Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study. Ann Rheum Dis. 2017;76(11):1890-1896.
Flint J, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology. 2016;55(9):1693-1697.
Weber-Schoendorfer C, et al. Pregnancy outcome after methotrexate treatment for rheumatic disease prior to or during early pregnancy. Arthritis Rheumatol. 2014;66(5):1101-1110.
Mariette X, et al. The CRIB study: Certolizumab use in a prospective pregnancy registry in rheumatology. Arthritis Rheumatol. 2018;70(Suppl 10).

Search This Blog

Internal medicine