Azathioprine Pregnancy Risk Category
Azathioprine is FDA Pregnancy Category D, meaning positive evidence of fetal risk exists, but benefits may outweigh risks in life-threatening or serious disease. 1
FDA Classification and Rationale
The FDA assigned Category D status because high-dose animal studies produced congenital malformations, and active azathioprine metabolites cross the placenta and have been detected in neonates of treated mothers. 1, 2
Category D specifically indicates that "positive evidence of fetal risk is available, but the benefits may outweigh the risk in life-threatening or serious disease." 1
Clinical Use Recommendations During Pregnancy
For severe disease requiring immunosuppression, azathioprine should be continued during pregnancy with close monitoring, as uncontrolled maternal disease poses greater risks than medication exposure. 2, 3
When to Continue Azathioprine:
Women with severe, unstable autoimmune disease (autoimmune hepatitis, inflammatory bowel disease, systemic lupus erythematosus) where discontinuation would risk maternal hepatic decompensation, disease flare, or organ failure. 2, 3
The European Association for the Study of the Liver (EASL) explicitly recommends continuation of azathioprine throughout pregnancy based on accumulated safety data showing acceptable maternal and fetal outcomes. 3
Large observational studies report 73% live birth rates with no significant increase in congenital malformations above baseline population rates. 3
When to Discontinue or Avoid:
Women with well-controlled disease should transition to corticosteroid monotherapy, particularly during the first trimester, as prednisone alone can effectively maintain remission. 2, 3
The American Association for the Study of Liver Diseases (AASLD) recommends discontinuing azathioprine "if possible" during pregnancy, reflecting a more conservative U.S. approach. 1, 2
The British Association of Dermatologists recommends limiting use to severe disease when no safer alternatives exist. 1
Actual Fetal Risks Based on Evidence
Confirmed Risks:
Prematurity occurs in 11-20% of exposed pregnancies, with increased rates of preterm delivery and low birth weight. 2, 3
Small-for-gestational-age infants are more common, though this may reflect maternal disease severity rather than drug effect alone. 1
One Swedish registry study found a moderately increased risk of ventricular/atrial septal defects (adjusted OR 3.18,95% CI 1.45-6.04). 4
Reassuring Data:
Overall congenital malformation rates (6.2%) are not dramatically elevated compared to general population (4.7%), and multiple studies in transplant recipients show no increased risk of congenital defects. 1, 4
No consistent pattern of specific malformations has emerged across studies, and the literature remains inconclusive on teratogenic effects. 1
In systemic lupus erythematosus patients, azathioprine exposure was not associated with poor fetal outcome, with no major congenital abnormalities observed. 5
Critical Management Points
Maternal Disease Monitoring:
Disease flares occur in 21-33% of pregnancies, with the highest risk (52%) in the postpartum period. 3
Resume conventional therapy pre-emptively 2 weeks before anticipated delivery and maintain throughout the postpartum period to prevent flares. 1, 3
Monitor serum AST/ALT levels at 3-week intervals for at least 3 months postpartum, as this is the highest-risk period for disease reactivation. 1, 3
Neonatal Monitoring:
Neonatal thrombocytopenia and leukopenia can occur due to in utero azathioprine exposure, requiring complete blood count monitoring at birth. 6
6-thioguanine nucleotide (6-TGN) metabolites are detectable in infant red blood cells at delivery, though at slightly lower concentrations than maternal levels. 7
Common Pitfalls to Avoid
The most dangerous error is abruptly discontinuing immunosuppression based on Category D status alone, as disease flares pose greater maternal and fetal risks than continued medication in severe disease. 2, 3
Inadequate postpartum monitoring is a major pitfall, as over half of disease flares occur in the 3 months following delivery when surveillance may inadvertently decrease. 3
Do not confuse Category D with absolute contraindication—Category D explicitly acknowledges that benefits may outweigh risks in serious disease. 1