What is the management plan if a patient conceives while on Leflunomide (leflunomide)?

Management of Conception on Leflunomide

If a patient conceives while on leflunomide, immediately discontinue the medication and initiate cholestyramine washout (8 grams three times daily for 11 days) to rapidly eliminate the drug, then verify plasma levels of the active metabolite (M1) are less than 0.02 mg/L with two separate tests at least 14 days apart. 1, 2

Immediate Actions Upon Pregnancy Confirmation

Step 1: Discontinue Leflunomide Immediately

• Stop leflunomide as soon as pregnancy is confirmed 1, 2
• The active metabolite (M1) has an extremely long half-life and can persist for up to 2 years without intervention 2

Step 2: Initiate Drug Elimination Procedure

The cholestyramine washout protocol is critical and should begin immediately: 1, 2

• Administer cholestyramine 8 grams orally three times daily for 11 days 1, 2
• The 11 days do not need to be consecutive unless rapid plasma level reduction is urgently needed 2
• This procedure can reduce the time to achieve safe plasma levels from up to 2 years down to weeks 2

Step 3: Verify Drug Clearance

• Measure plasma M1 metabolite levels after completing cholestyramine course 1, 2
• Target level: less than 0.02 mg/L (0.02 mcg/mL) 1, 2
• Obtain two separate tests at least 14 days apart to confirm levels remain below threshold 2
• If levels remain above 0.02 mg/L, repeat cholestyramine treatment 2

Monitoring and Counseling

Maternal-Fetal Medicine Referral

• Strongly recommend immediate referral to a maternal-fetal medicine specialist, pregnancy medication specialist, or genetics counselor 1
• This is considered standard good practice for inadvertent exposure to teratogenic medications 1

Risk Communication

Important context for counseling: 3, 4, 5

• Animal studies demonstrated teratogenicity at doses similar to or lower than human therapeutic doses 4
• However, accumulating human data from 222 pregnancies show no consistent pattern of malformations 4
• Among 169 live births exposed to leflunomide, there were 8 congenital malformations (4.7%), which is not significantly different from the general population baseline of 3-4% 5
• Studies specifically examining women who underwent cholestyramine washout early in pregnancy found no substantial increased risk of adverse outcomes 5

Ongoing Pregnancy Management

• Close monitoring throughout pregnancy is recommended 1
• Serial ultrasounds to assess fetal growth and anatomy 1
• Document all counseling discussions regarding risks and the washout procedure 1

Common Pitfalls to Avoid

Do not delay the cholestyramine washout procedure - Every day of delay prolongs fetal exposure to the active metabolite, which can persist for months to years without intervention 2

Do not assume washout is complete without laboratory confirmation - Clinical judgment alone is insufficient; plasma M1 levels must be verified to be less than 0.02 mg/L with two separate tests 2

Do not provide false reassurance - While human data are somewhat reassuring, leflunomide remains contraindicated in pregnancy and the washout procedure is essential 1, 2

Do not forget to address disease management - After discontinuing leflunomide, transition to pregnancy-compatible medications (such as hydroxychloroquine, sulfasalazine, or azathioprine) to maintain disease control if needed 1

Evidence Quality Considerations

The 2020 American College of Rheumatology guidelines provide the highest quality recommendations for this scenario 1. The FDA drug label reinforces the critical importance of the cholestyramine washout procedure 2. While human observational data from multiple studies 3, 4, 5 suggest the actual teratogenic risk may be lower than initially feared based on animal studies, the standard of care remains immediate drug elimination given the medication's contraindication in pregnancy and the availability of an effective washout procedure.