(B-277) Thiopurine treatment and intrahepatic cholestasis of pregnancy in pregnancies with systemic lupus erythematosus and inflammatory bowel disease - A Swedish cohort study

Background: The US Food and Drug Administration’s alert regarding intrahepatic cholestasis of pregnancy (ICP) risk linked to thiopurines, a therapy for pregnancies with systemic lupus erythematosus (SLE) or inflammatory bowel disease (IBD), was largely based on case reports, and prospective data are currently lacking.

Objectives: To examine effects of thiopurine exposure during pregnancy on ICP in SLE or IBD pregnancies using comprehensive Swedish national healthcare registers.

Methods: This register-based cohort study included singleton pregnancies with prevalent SLE or IBD in Sweden during 2007-2022. The exposure was ≥1 thiopurine dispensation (azathioprine or 6-mercaptopurine) from last menstrual period date to one day before delivery or before ICP diagnosis compared to no dispensation. ICP was identified with an ICD-10 code O26.6 in inpatient or outpatient care during pregnancy. Propensity score matching (one thiopurine-exposed to two thiopurine-unexposed) with nearest neighbor matching was used to control for confounding, especially confounding by indication. A wide range of confounders was addressed, including maternal smoking, BMI, parity, pregestational hypertension, IBD subtypes, glucocorticoids, and targeted therapies. Modified Poisson models estimated risk ratios and 95% confidence intervals (RR 95%CI) with robust standard errors.

Results: In SLE, ICP occurred in 14/297 (4.7%) of exposed pregnancies vs. 11/594 (1.9%) of matched unexposed pregnancies (adjusted RR 95%CI 3.06 [1.36-6.90]; adjusted risk difference 4%). In IBD, ICP developed in 140/1,924 (7.3%) of exposed pregnancies vs. 36/3,848 (0.9%) of matched unexposed pregnancies (adjusted RR 7.78 [5.41-11.17]; adjusted risk difference 6%). Stratified analyses by ICP history, pregestational hypertension, renal diseases, liver diseases, glucocorticoid use, IBD subtypes, and thiopurine substance provided consistent results. Sensitivity analyses varying timing and number of thiopurine dispensations yielded similar results. Another sensitivity analysis where we compared thiopurine exposure to tumor necrosis factor inhibitor exposure in IBD pregnancies also found a higher risk of ICP in thiopurines (adjusted RR 11.33 [3.58-35.88]; adjusted risk difference 9%).

Conclusions: In SLE or IBD pregnancies, thiopurine exposure during pregnancy was associated with an increased risk of ICP, regardless of pregestational hypertension, renal diseases, liver diseases, and glucocorticoid use. We recommend promoting awareness of this association among clinicians and patients to facilitate better diagnosis and management.