Immunosuppressants During Pregnancy

Immunosuppressants in pregnancy treat transplantation, lupus, rheumatoid arthritis, inflammatory bowel disease, vasculitis, multiple sclerosis and other autoimmune disease. Active disease at conception and in pregnancy is the main driver of poor outcomes (flare, pre-eclampsia, growth restriction, preterm birth), so most women should continue compatible drugs and stop only those that are teratogenic.

Planning. Disease should be quiescent for 3 to 6 months before conception on a pregnancy-compatible regimen. Drugs with long washout (leflunomide, mycophenolate, methotrexate, cyclophosphamide) are stopped well before conception.

Maternal IgG biologics. Infliximab, adalimumab and other IgG1 monoclonal antibodies cross the placenta actively from the second trimester, and the newborn carries drug for up to 6 months.

Compatible, continue.

• Hydroxychloroquine 200 to 400 mg orally daily (maximum 5 mg/kg actual body weight daily); reduces lupus flare and congenital heart block risk.
• Azathioprine 1 to 2 mg/kg orally daily (maximum 2 mg/kg); avoid starting during pregnancy if possible; check thiopurine methyltransferase status before starting.
• Sulfasalazine 1 to 2 g orally twice daily with folic acid 5 mg daily; mesalazine 2 to 4 g daily.
• Ciclosporin 2 to 5 mg/kg daily in 2 doses (trough 100 to 200 ng/mL, adjusted to indication); tacrolimus 0.05 to 0.15 mg/kg daily in 2 doses (trough 5 to 10 ng/mL in most transplants, with levels adjusted in pregnancy).
• Prednisolone 5 to 10 mg orally daily for maintenance, with short courses of 20 to 60 mg daily for flares.

Biologics.

• Certolizumab pegol 200 mg subcutaneously every 2 weeks or 400 mg every 4 weeks: minimal placental transfer, may continue throughout.
• Infliximab, adalimumab, etanercept, golimumab: continue to 24 to 30 weeks (stop the last dose then in quiescent disease; practice varies), or continue throughout if active disease would risk a flare, accepting infant exposure.
• Vedolizumab and ustekinumab: limited data; continue if needed to control disease.
• Rituximab: avoid in pregnancy; may be used for life-threatening disease, with neonatal B-cell and infection review.

Avoid, stop before conception.

• Methotrexate: stop at least 3 months before conception (folic acid 5 mg daily); if exposed, stop at once and arrange anomaly scanning.
• Mycophenolate mofetil: stop at least 6 weeks before conception and replace with azathioprine; major pregnancy loss and malformation risk.
• Leflunomide and teriflunomide: stop at least 2 years before conception, or give colestyramine 8 g orally 3 times daily for 11 days (washout) then confirm plasma level under 0.02 mg/L on 2 occasions 14 days apart.
• Cyclophosphamide, thalidomide, lenalidomide, tofacitinib, baricitinib, upadacitinib and other JAK inhibitors, sirolimus and everolimus (except after specialist review).

Transplant recipients. Conceive when graft function is stable for at least 12 months, creatinine under 150 micromol/L, no rejection in the last year, and prednisolone 15 mg or less daily. Replace mycophenolate with azathioprine and review sirolimus.

Infant vaccines. Defer live vaccines (BCG, rotavirus) in infants exposed in utero to infliximab, adalimumab, golimumab, ustekinumab or vedolizumab until 6 months of age (12 months after infliximab by many); certolizumab and etanercept exposure does not need delay. This matters in East Africa, where BCG is given at birth.

Maternal adverse effects. Infection (including tuberculosis reactivation), pancytopenia and pancreatitis with azathioprine, nephrotoxicity, hypertension, hyperglycaemia, tremor and hyperkalaemia with calcineurin inhibitors, and drug-induced lupus with TNF inhibitors.

Interactions. Azathioprine with allopurinol or febuxostat: severe marrow suppression (reduce azathioprine to a quarter or a third). Ciclosporin and tacrolimus with azoles, macrolides, diltiazem, grapefruit and rifampicin: marked level changes. NSAIDs with calcineurin inhibitors: acute kidney injury.

Special groups.

• Kidney impairment: avoid NSAIDs; adjust by eGFR; calcineurin inhibitor levels guide dosing (clearance rises in pregnancy).
• Liver impairment: reduce azathioprine; monitor tacrolimus.
• Breastfeeding: azathioprine, ciclosporin, tacrolimus, hydroxychloroquine, sulfasalazine (watch infant jaundice and G6PD deficiency), TNF inhibitors and prednisolone are compatible; avoid cyclophosphamide, methotrexate and mycophenolate.
• Regional: screen for latent tuberculosis, hepatitis B and HIV before starting biologics or high-dose immunosuppression; hepatitis B reactivation prophylaxis may be needed.

Monitoring. Calcineurin inhibitor trough levels every 2 to 4 weeks, with creatinine, potassium, glucose and blood pressure. Azathioprine: full blood count and liver tests monthly. Disease activity scores each visit. Foetal growth scans at 28, 32 and 36 weeks; Doppler in lupus and antiphospholipid syndrome. In anti-Ro or anti-La positive women, foetal PR interval scans weekly from 16 to 26 weeks.

Adjustment. Titrate to disease activity and drug level. Treat a lupus flare with prednisolone 20 to 60 mg daily and add azathioprine or tacrolimus.

Stopping rules. Stop azathioprine for neutrophils under 1.0 x 10^9/L or transaminases over 3 times the upper limit. Stop mycophenolate, methotrexate and leflunomide at the time of any positive pregnancy test.

Referral and escalation. Refer transplant recipients, lupus, vasculitis, antiphospholipid syndrome and any teratogen exposure to a combined rheumatology, nephrology or transplant and obstetric medicine clinic. Neonatal team review for anti-Ro or anti-La positivity (heart block, neonatal lupus).