ORIGINAL RESEARCH
J. Pharm. Pharm. Sci.
Intrahepatic cholestasis of pregnancy associated with azathioprine: first quantitative disproportionality analysis using the FDA adverse event reporting system
College of Pharmacy, Catholic University of Daegu, Gyeongsan, Republic of Korea
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Abstract
Introduction: Azathioprine (AZA) is an immunosuppressant approved for renal transplant rejection and rheumatoid arthritis. Recent FDA alerts have raised concerns about its link to intrahepatic cholestasis of pregnancy (ICP), a condition with serious maternal and fetal risks. This study used disproportionality analysis as a hypothesis-generating approach to evaluate the reporting association between AZA and ICP during pregnancy and to compare AZA with other drugs previously implicated in ICP. Methods: A retrospective pharmacovigilance study was conducted using the FDA Adverse Event Reporting System (FAERS) reports from 1968 to Q2 2024. Disproportionality analysis was performed using reporting odds ratios (RORs), with statistical significance defined as a lower limit of the 95% confidence interval (CI) >1 and at least three unique cases. Subgroup analyses were conducted by pregnancy status and underlying autoimmune indications, and comparative analyses were performed against drugs previously reported to induce ICP. Results: Among 35,576 AZA-related reports, 67 specifically documented ICP. A strong signal was detected for ICP ROR025 = 153.0; IC025 = 5.8; EBGM05 = 144.37), ranking among the highest AZA-associated adverse events. In pregnant women, ICP also showed a significant signal (ROR025 = 5.46; IC025 = 1.93; EBGM05 = 5.31). Subgroup analyses by indication revealed elevated risks in Crohn’s disease (ROR025 = 66.99; IC025 = 4.8; EBGM05 = 64.73), and Colitis ulcerative (ROR025 = 9.01; IC025 = 1.95; EBGM05 = 9.95). Comparative analyses demonstrated that AZA had a higher proportion of ICP cases than other drugs reported to induce ICP. Conclusion: This pharmacovigilance analysis identifies a disproportionality signal suggesting a possible association between AZA and intrahepatic cholestasis of pregnancy. These hypothesis-generating findings underscore the importance of cautious use and clinical vigilance when prescribing AZA to women of reproductive age.
Summary
Keywords
azathioprine, intrahepatic cholestasis of pregnancy, Pharmacovigilance, pregnancy safety, signals of disproportionate reporting
Received
02 September 2025
Accepted
05 December 2025
Copyright
© 2025 Kwon, Lee and Kim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yun Kim, ykim71@cu.ac.kr
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