Abstract
INTRODUCTION: The objective of this study was to examine the effects of thiopurine exposure during pregnancy on intrahepatic cholestasis of pregnancy (ICP) in systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD) pregnancies using nationwide data from Swedish healthcare registers. METHODS: This register-based cohort study included all singleton pregnancies with prevalent SLE or IBD in Sweden, 2007-2022. Exposure was ≥1 dispensation for azathioprine or 6-mercaptopurine from last menstrual period date to 1 day before delivery or before ICP diagnosis vs no dispensation. ICP diagnosis was identified with ICD-10 code O26.6 in inpatient or outpatient care. Propensity score matching (1 thiopurine-exposed and 2 thiopurine-unexposed) controlled for confounding factors (e.g., maternal smoking, body mass index, parity, IBD subtypes, glucocorticoids, and advanced therapies). Modified Poisson models were used to estimate risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: In SLE, ICP occurred in 14 of 297 (4.7%) thiopurine-exposed pregnancies vs 11 of 594 (1.9%) matched unexposed pregnancies (adjusted RR 3.06, 95% CI 1.36-6.90; adjusted risk difference 4%, 95% CI 1%-6%). In IBD, ICP developed in 140 of 1,924 (7.3%) exposed pregnancies vs 36 of 3,848 (0.9%) matched unexposed pregnancies (adjusted RR 7.78, 95% CI 5.41-11.17; adjusted risk difference 6%, 95% CI 5%-8%). Sensitivity and subgroup analyses by ICP history, pregestational hypertension, renal diseases, liver diseases, glucocorticoid use, IBD subtypes, and thiopurine substance, and comparing thiopurines with tumor necrosis factor inhibitors exposure during pregnancy provided consistent results. DISCUSSION: In SLE and IBD, thiopurine exposure during pregnancy was associated with an increased risk of ICP, regardless of ICP history, hypertension, renal diseases, liver diseases, and glucocorticoid use.