Is azathioprine (immunosuppressive medication) safe to use during pregnancy?

Azathioprine is NOT Contraindicated in Pregnancy

Azathioprine should be continued during pregnancy in women with autoimmune hepatitis and other autoimmune conditions, as the risk of disease flare from discontinuation substantially outweighs the theoretical fetal risks, and accumulated evidence demonstrates relative safety with no established increase in major congenital malformations. 1, 2

Evidence-Based Recommendation Framework

Primary Guideline Position (Most Recent & Highest Quality)

The 2021 AASLD Hepatology guidelines explicitly state that azathioprine is compatible with pregnancy, noting that while associated with low birth weight and preterm birth, there is no increased risk of birth defects with 6-mercaptopurine (azathioprine's active metabolite). 1 The 2015 EASL guidelines in the Journal of Hepatology similarly conclude that "continuation of this drug during pregnancy appears to be justified" and recommend a strategy of "minimal adjustment to standard immunosuppression (prednisolone/azathioprine) during the course of pregnancy." 1, 2

Critical Clinical Context: FDA Category D Does Not Mean Contraindicated

The FDA Category D classification reflects animal teratogenicity data at high doses, NOT human evidence of harm. 1 This classification has created confusion, but Category D means "positive evidence of fetal risk is available, but the benefits may outweigh the risk in life-threatening or serious disease"—it is explicitly NOT a contraindication. 1, 3

Safety Data Supporting Continuation

Human Pregnancy Outcomes

• No increase in major malformations: Multiple large series show birth defect rates of 3-6% in azathioprine-exposed pregnancies, similar to the 4.7% general population baseline. 1

• Live birth rate of 73% in the largest autoimmune hepatitis cohort (81 pregnancies), with no apparent relationship between azathioprine use and adverse outcomes. 1, 2

• Meta-analysis in inflammatory bowel disease patients showed pooled odds ratio for congenital abnormalities of 1.45 (95% CI 0.99-2.13), which is not statistically significant. 1

Established Risks (Not Contraindications)

Azathioprine IS associated with: 1, 2

• Preterm birth (20-21% vs. 5% baseline; OR 1.67,95% CI 1.26-2.20)
• Low birth weight (23% vs. 6% baseline)
• Intrauterine growth restriction

These risks must be weighed against the substantially greater maternal and fetal risks from uncontrolled autoimmune disease.

The Greater Danger: Disease Flare from Discontinuation

Maternal Morbidity and Mortality Risks

• Disease flares occur in 21-33% of pregnancies in women with autoimmune hepatitis, with 52% experiencing postpartum flares. 1, 2

• Serious maternal complications (death, transplant need, or hepatic decompensation) occur in 11% of pregnancies, significantly higher in women with cirrhosis. 1, 2

• In one series, 12 of 14 patients (86%) who had immunosuppression reduced during pregnancy experienced rapid disease flare following delivery. 1, 2

Fetal Risks from Maternal Disease Activity

Uncontrolled maternal autoimmune hepatitis poses greater fetal risks than azathioprine exposure, including increased miscarriage, stillbirth, and prematurity from maternal hepatic decompensation. 1, 2

Clinical Management Algorithm

Preconception Counseling

1. Do NOT discontinue azathioprine in women with active or recently active autoimmune hepatitis. 1, 2

2. Counsel patients that:

   • Azathioprine is FDA Category D but NOT contraindicated 1, 3
   • Continuation reduces risk of life-threatening disease flare 1, 2
   • No established increase in major birth defects 1
   • Increased risk of prematurity and low birth weight 1

3. Optimize disease control before conception with minimal effective azathioprine dose (typically 1-2 mg/kg/day). 1

During Pregnancy Management

1. Continue azathioprine at prepregnancy dose with prednisolone 5-20 mg daily as needed for disease control. 1, 2

2. Monitor liver enzymes (AST/ALT) monthly during pregnancy. 2

3. Anticipate that disease may stabilize or improve during pregnancy due to pregnancy-associated immunomodulation, but do not proactively reduce therapy. 1

4. Coordinate obstetric care with high-risk maternal-fetal medicine for increased prematurity surveillance. 1

Postpartum Critical Period

1. Maintain or increase immunosuppression immediately postpartum, as this is the highest-risk period for disease flare. 1, 2

2. Monitor AST/ALT every 3 weeks for at least 3 months postpartum. 2

3. Preemptively increase immunosuppression back to prepregnancy levels if any reduction occurred during pregnancy. 1

Breastfeeding Compatibility

Azathioprine is compatible with breastfeeding. 1 Small amounts of thiopurine metabolites are detectable in breast milk, but this has not been associated with significant adverse infant outcomes. 1

Common Clinical Pitfalls to Avoid

Pitfall #1: Discontinuing Azathioprine Based on FDA Category D Status

This is the most dangerous error. The Category D classification reflects theoretical concerns from animal data, not human evidence of major teratogenicity. 1, 2 Disease flares pose documented, substantial maternal and fetal risks that exceed the theoretical risks of azathioprine. 1, 2

Pitfall #2: Inadequate Postpartum Monitoring

Over 50% of disease flares occur in the 3 months following delivery, yet surveillance often inadvertently decreases during this period. 1, 2 Maintain intensive monitoring postpartum.

Pitfall #3: Confusing Azathioprine with Mycophenolate

Mycophenolate mofetil (MMF) IS contraindicated in pregnancy with high risk of miscarriage and birth defects. 1 Do not extrapolate MMF's contraindication to azathioprine—they have completely different safety profiles.

Divergent Historical Guidance (Now Resolved)

The 2010 AASLD guidelines recommended "avoidance" of azathioprine in pregnancy based on its Category D status and theoretical concerns. 1 However, the 2021 AASLD guidelines explicitly reversed this position, now stating azathioprine is "compatible" with pregnancy. 1 The 2015 EASL guidelines similarly recommend continuation. 1 This evolution reflects accumulated safety data demonstrating that theoretical concerns were not borne out in clinical practice.

Special Monitoring Considerations

Neonatal Hematologic Monitoring

Transient neonatal lymphopenia, thrombocytopenia, or anemia may occur due to intrauterine azathioprine exposure. 1, 3, 4, 5 Obtain complete blood count in neonates born to mothers on azathioprine, though clinically significant complications are rare and typically self-limited. 1

Maternal Dose Optimization

Therapeutic drug monitoring of 6-thioguanine nucleotide (6-TGN) levels during pregnancy may allow dose optimization to minimize fetal exposure while maintaining maternal disease control. 4 Target 6-TGN levels of 230-450 pmol/8×10⁸ RBC for therapeutic efficacy.