Intrahepatic cholestasis of pregnancy (ICP) has been rarely reported in patients treated with azathioprine products and is believed to be a risk applicable to all drugs in the thiopurine class (azathioprine, mercaptopurine and tioguanine) (1):
- cholestasis of pregnancy associated with thiopurines tends to occur earlier in pregnancy than non-drug-induced cholestasis of pregnancy, and elevated bile acid levels may not reduce with ursodeoxycholic acid
- thiopurines should only be used in pregnancy where a careful benefit/risk assessment for the individual patient has been made
- the risk of developing intrahepatic cholestasis of pregnancy (ICP) has been identified from a small number of case reports in the scientific literature (1)
- ICP has been reported in some pregnant patients treated with azathioprine and mercaptopurine, and, due to similar metabolic pathways utilised by thiopurines, this risk is believed to be applicable to all drugs in the thiopurine class (azathioprine, mercaptopurine and tioguanine)
- reported cases were often serious, with some resulting in fetal death - however, reporting bias may result in the more serious cases being reported
- early diagnosis and discontinuation or dose reduction of the thiopurine may minimise adverse effects on the fetus
- in patients with ICP, measure serum bile acids to identify pregnancies at particular risk of spontaneous preterm birth (≥40uM) or stillbirth (non-fasting serum bile acids ≥100uM)
With respect to patients taking thiopurines in pregnancy:
- patients should be made aware of the signs and symptoms of ICP, which include intense itching without a rash, nausea, and loss of appetite, and advised to seek healthcare professional advice immediately if they experience these symptoms
Advice for Healthcare Professionals (1):
- cholestasis of pregnancy has rarely been reported in association with azathioprine therapy
- this risk is believed to also apply to the other thiopurine drugs, mercaptopurine and tioguanine
- it may occur earlier in pregnancy than non drug-induced cholestasis of pregnancy, and it may not respond to ursodeoxycholic acid
- withdrawal or dose reduction of the thiopurine drug may improve liver function tests
- remain vigilant to signs and symptoms of ICP in pregnant patients taking thiopurines and discuss any concerns with clinicians managing the patient’s immunosuppressant therapy and a hepatologist, as necessary
- if cholestasis of pregnancy occurs, a case-by-case assessment is required to determine the appropriate course of action. Consider the risks and benefits of remaining on the product against the risks and benefits of stopping.
- in patients with ICP, measure serum bile acids to identify pregnancies at particular risk of spontaneous preterm birth (≥40uM) or stillbirth (non-fasting serum bile acids ≥100uM)
Reference:
- MHRA Drug Safety Update volume 18, issue 10: May 2025: 2.