Increased Risk of Intrahepatic Cholestasis of Pregnancy in Women With Systemic Lupus Erythematosus Exposed to Azathioprine

Objective: To evaluate the risk of intrahepatic cholestasis of pregnancy (ICP) in azathioprine (AZA)–exposed versus unexposed systemic lupus erythematosus (SLE) pregnancies within the multicenter prospective Lupus in Pregnancy (LEGACY) cohort. Methods: LEGACY is conducted at Systemic Lupus International Collaborating Clinics in Canada, South Korea, Peru, and Mexico. Pregnant women with SLE are enrolled before 17 weeks and followed in the second (20–24 weeks) and third (30–34 weeks) trimesters and postpartum (8–12 weeks). Because ICP occurs after 20 weeks, only pregnancies with a second-trimester visit were included. Follow-up began at that visit and continued until delivery. AZA exposure was modeled as time varying. The primary outcome was iatrogenic delivery for ICP or spontaneous preterm birth occurring after ICP diagnosis. Multivariable Cox models with frailties adjusted for relevant covariates. At the Montreal site, thiopurine metabolites and shunting were assessed. Results: Among 127 SLE pregnancies (46 AZA exposed, 81 unexposed), 10 ICP cases occurred (each in a distinct woman): 8 among AZA exposed (17.4%, 95% confidence interval [CI] 9.1–30.7) and 2 among unexposed (2.5%, 95% CI 0.7–8.6). AZA exposure was associated with a substantially increased risk of ICP (adjusted hazard ratio 12.1, 95% CI 2.4–59.7). All ICP cases with metabolite data (4 of 4) showed second-trimester shunting. Among all pregnancies with second-trimester metabolite data (n = 22), 36.4% (95% CI 19.7–57.0) were shunting, and 50.0% (95% CI 21.5–78.5) of these developed ICP. Conclusion: We observed that AZA exposure may be strongly associated with ICP in SLE pregnancies. Second-trimester thiopurine shunting may identify women at high risk, supporting the value of metabolite monitoring.