Is azathioprine safe to continue during pregnancy in a woman of child‑bearing age with inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, or organ transplantation, and what are the recommended dose limit, TPMT testing, maternal/fetal monitoring, and breastfeeding guidelines?

Azathioprine in Pregnancy

Azathioprine should be continued throughout pregnancy in women with inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, or organ transplantation when disease control requires it, as the risks of uncontrolled maternal disease substantially outweigh the modest fetal risks associated with the medication. 1

Safety Profile and Continuation Recommendations

The European Association for the Study of the Liver (EASL) explicitly recommends continuing azathioprine during pregnancy based on substantial accumulated safety data, despite its FDA Category D classification. 1 This represents the most current guideline position (2015) and supersedes older recommendations to discontinue the drug. 1

Evidence Supporting Continuation

• Large observational studies demonstrate a 73% live birth rate with no apparent relationship between azathioprine use and adverse fetal outcomes. 2, 1
• Congenital malformation rates are not significantly elevated above baseline population rates when azathioprine is used during pregnancy. 2, 1
• In transplant recipients and autoimmune hepatitis patients, azathioprine use shows no increased risk of congenital defects, though prematurity and low birth weight occur more frequently. 2
• A study of 87 SLE pregnancies exposed to azathioprine found no difference in live births, spontaneous abortions, mean birth weight, or congenital abnormalities compared to unexposed pregnancies. 3

Critical Risk of Discontinuation

Discontinuing immunosuppression during pregnancy poses greater maternal and fetal risks than continued medication. 1 In a case series of 14 patients who had immunosuppression reduced during pregnancy, 12/14 experienced rapid disease flares following delivery. 2 Disease flares during pregnancy increase the risk of hepatic decompensation and serious maternal complications. 2, 1

Dosing and Monitoring

Dose Recommendations

• Continue standard maintenance dosing (1-3 mg/kg daily) used prior to pregnancy. 2
• Do not reduce azathioprine dose unless clinically indicated by disease activity or adverse effects. 1
• For women with well-controlled disease, transitioning to corticosteroid monotherapy during the first trimester may be considered, though this is not mandatory. 4

TPMT Testing Requirements

TPMT status must be known before initiating azathioprine—this is non-negotiable. 2, 5 Very low or absent TPMT activity is an absolute contraindication due to life-threatening pancytopenia risk. 2, 5 For women already on azathioprine who become pregnant, TPMT testing should have been completed prior to initial drug initiation. 2

Maternal Monitoring Protocol

• Monitor complete blood counts weekly during the first month, twice monthly for months 2-3, then monthly thereafter. 6
• Check liver enzymes (AST/ALT), bilirubin, and immunoglobulin levels regularly throughout pregnancy. 1
• Intensify monitoring postpartum with AST/ALT levels every 3 weeks for at least 3 months, as this is the highest-risk period for disease reactivation (52% flare rate). 1

Fetal Monitoring

• Standard obstetric monitoring is appropriate; no additional fetal surveillance is required specifically for azathioprine exposure. 2, 1
• Be aware that prematurity occurs in 11-20% of pregnancies, requiring neonatal intensive care in approximately 11% of cases. 2, 1

Specific Risks and Outcomes

Maternal Risks

• Disease flares occur in 21-33% of pregnancies, more commonly in women without therapy or with recent pre-conception flares. 2, 1
• Serious maternal complications (death, transplant need, or hepatic decompensation) occur in approximately 11% of pregnancies, significantly higher in women with established cirrhosis. 2, 1
• Postpartum flares are most common, occurring in up to 52% of patients. 1

Fetal and Neonatal Outcomes

• Live birth rate is approximately 73% in treated patients. 2, 1
• Prematurity and low birth weight are increased, but this may be confounded by maternal disease severity. 2, 7
• One Swedish registry study found a possible association with ventricular/atrial septal defects (adjusted OR 3.18), though this may reflect disease severity rather than drug effect. 7
• Azathioprine and its metabolites cross the placenta, with 6-thioguanine nucleotides detectable in neonatal red blood cells at slightly lower concentrations than maternal levels. 8

Breastfeeding Guidance

Azathioprine is considered safe for breastfeeding despite small amounts of metabolites being detectable in breast milk. 2, 1 This does not appear to result in complications for the nursing infant. 2, 1 The manufacturer's contraindication to breastfeeding is not supported by clinical evidence. 2

Critical Pitfalls to Avoid

Most Dangerous Error

The most dangerous clinical error is discontinuing azathioprine during pregnancy based on outdated concerns about teratogenicity. 1 Uncontrolled maternal disease poses substantially greater risks to both mother and fetus than continued medication. 1

Inadequate Postpartum Surveillance

Over half of disease flares occur in the 3 months following delivery when clinical surveillance may inadvertently decrease. 1 Resume or intensify immunosuppression pre-emptively 2 weeks before anticipated delivery and maintain throughout the postpartum period. 4

Contraindication Oversights

• Never initiate azathioprine without confirming TPMT status. 2, 5
• Avoid concurrent allopurinol use (absolute contraindication); if unavoidable, reduce azathioprine dose to 25-33% of usual dose. 5, 6
• Do not use in women with known hypersensitivity to azathioprine or 6-mercaptopurine. 5

Preconception Counseling

• Women with advanced liver disease and portal hypertension should be counseled about variceal hemorrhage risk during pregnancy. 4
• For women with stable, mild disease, attempting to discontinue azathioprine before conception may be considered, but this must be weighed against flare risk. 4
• Low-dose prednisone monotherapy can suppress disease activity long-term as an alternative for women who prefer to avoid azathioprine. 4

Divergent Guideline Positions

The 2010 American Association for the Study of Liver Diseases (AASLD) guidelines recommend avoiding azathioprine during pregnancy when possible, while the 2015 EASL guidelines recommend continuation based on accumulated safety data. 1 The EASL position represents the more recent evidence synthesis and should guide current practice. 1 The British Association of Dermatologists (2011) recommends limiting azathioprine use to severe disease without safer alternatives. 2