Is azathioprine (Imuran) safe during pregnancy?

From the Guidelines

Azathioprine can be used during pregnancy when the benefits outweigh the risks, particularly for women with autoimmune conditions requiring ongoing immunosuppression. This is based on the most recent and highest quality study available, which suggests that azathioprine is one of the safer immunosuppressants during pregnancy, with extensive clinical experience supporting its use 1. The typical dosing ranges from 1-3 mg/kg/day, which should be continued at the pre-pregnancy dose if the condition is well-controlled.

While azathioprine crosses the placenta, the fetal liver lacks the enzyme inosinate pyrophosphorylase needed to convert it to its active metabolite, providing some protection to the developing fetus. There is no significant increase in congenital malformations with azathioprine use during pregnancy, as reported in a large series of patients with autoimmune hepatitis 1. However, there may be a small increased risk of preterm birth, low birth weight, and transient neonatal leukopenia or thrombocytopenia.

Regular monitoring of maternal blood counts and liver function is recommended during pregnancy. Breastfeeding is generally considered compatible with azathioprine use, as minimal amounts appear in breast milk. The decision to use azathioprine during pregnancy should be made after careful discussion between the patient and healthcare provider, weighing the risks of untreated maternal disease against potential medication risks. Key considerations include:

• The presence of severe disease, particularly if there is no safer alternative treatment 1
• The potential for flares in disease activity during pregnancy or postpartum 1
• The need for regular monitoring of maternal and fetal health during pregnancy
• The importance of careful discussion and shared decision-making between the patient and healthcare provider.

From the FDA Drug Label

AZASAN can cause fetal harm when administered to a pregnant woman AZASAN should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of AZASAN in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women. AZASAN is teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily) Abnormalities included skeletal malformations and visceral anomalies.

It is not safe to give azathioprine in pregnancy. The drug can cause fetal harm, and its use should be avoided whenever possible. Azathioprine is teratogenic in animals, and there have been reports of abnormalities in infants born to mothers taking the drug. The risk versus benefit must be carefully weighed before using azathioprine in patients of reproductive potential 2.

From the Research

Azathioprine Use in Pregnancy

• Azathioprine is used during pregnancy by women with inflammatory bowel disease (IBD), other autoimmune disorders, malignancy, and organ transplantation 3.
• The rate of congenital malformations was 6.2% in the azathioprine group and 4.7% among all infants born, with an association between early pregnancy azathioprine exposure and ventricular/atrial septal defects 3.
• Infants exposed to azathioprine in early pregnancy may be at a moderately increased risk of congenital malformations, specifically ventricular/atrial septal defects, as well as growth restriction and preterm delivery 3.
• The placenta forms a relative barrier to azathioprine and its metabolites, which may minimize intrauterine exposure to 6-thioguaninenucleotides (6-TGN) with careful therapeutic drug monitoring of the mother during pregnancy 4.
• A retrospective analysis of 16 pregnancies in 14 women receiving azathioprine for inflammatory bowel disease found no congenital abnormalities or subsequent health problems in the children, suggesting that azathioprine may be safe in pregnancy in inflammatory bowel disease patients 5.
• Prospective cohort studies suggest that azathioprine is safe for the fetus during pregnancy, although some studies note that the severity of maternal illness may confound the associations between azathioprine use and pregnancy outcomes 3, 6.

Key Findings

• Azathioprine use during pregnancy may be associated with an increased risk of congenital malformations, growth restriction, and preterm delivery 3.
• The placenta forms a relative barrier to azathioprine and its metabolites, which may minimize intrauterine exposure 4.
• Azathioprine may be safe in pregnancy in inflammatory bowel disease patients, although termination of pregnancy is not mandatory for those who conceive while taking the drug 5.
• Prospective cohort studies suggest that azathioprine is safe for the fetus during pregnancy 6.