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While azathioprine has been found to cross the placenta, low amounts of the active metabolite are found in fetal blood. In humans, azathioprine circulates in the fetus primarily as the inactive metabolite, thiouric acid. It appears that the fetus may be protected from adverse effects of the medication because the fetal liver lacks the enzyme, inosinate pyrophosphorylase, which converts azathioprine to its active metabolites. Most studies on the affects of azathioprine in pregnancy involve pregnant renal transplant patients rather than patients with Crohn's disease. Many studies found an increased risk of fetal growth retardation, lymphopenia, decreased thymus size and prematurity (Bermas and Hill, 1995, Connell and Miller, 1999 and Witter et al., 1981). This risk was increased above the risk for renal transplant patients who did not take azathiaprine. Still, the malformation rate was 3.9%, which is close to the general population rate. The association between azathioprine and IUGR appears to be the highest when used in combination with a corticosteroid such as prednisone. Thus the direct role of azathioprine in infants with IUGR is difficult to determine as other medications (corticosteroids have been associated with IUGR), maternal hypertension, maternal vascular disease, and maternal renal impairment may also have a role.

Connell and Miller (1999) stated that because there have been isolated cases of neonatal myelotoxicity and immunosuppression, a dose of 2mg/kg/day or less should be used in pregnancy. However, this dose may not be high enough to produce a therapeutic effect. Another alternative is to reduce maternal dose in the third trimester.

A potential risk for chromosome anomalies has been raised following a case report of a woman with lupus who took the drug during two different pregnancies. She delivered two infants with separate de novo translocations. Due to these being isolated cases it is unlikely a true association. However, further investigation is required to determine if this is a true risk from gestational exposure to azathioprine (Bermas and Hill, 1995, Connell and Miller 1999, Reprotox #1459, 1980 and Witter et al., 1981).

There is one study of azathioprine use in pregnant patients with inflammatory bowel disease. This study did not find an increased risk for congenital abnormalities or subsequent health problems (Connell and Miller, 1999 and Connell and Sandborn 1999). Still, due to the potential risks, azathioprine and mercaptopurine are usually not prescribed in pregnancy unless the disease is severe (Connell and Sandborn 1999). (CONTINUE)