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Objectives Intrahepatic cholestasis of pregnancy (ICP) is linked to adverse maternal and fetal outcomes. Emerging evidence from IBD cohorts and a 2024 FDA safety report suggests a strong association between thiopurines and ICP, which is concerning as azathioprine (AZA) is the immunosuppressive of choice in SLE pregnancies. However, data in SLE are scarce. Thus, we performed a multi-centre prospective cohort study to evaluate the risk of ICP in AZA-exposed versus unexposed SLE pregnancies.Methods The Lupus in prEGnAnCY cohort enrols SLE pregnancies <17 weeks at SLICC Centres in Canada, South Korea, Peru, and Mexico. Participants are followed at 20–24 and 30–34 weeks’ gestation and 8–12 weeks postpartum. Only pregnancies with a second-trimester visit (as ICP usually occurs >20 weeks) were included, with follow-up continuing until delivery. AZA exposure was modelled as time-varying, and the primary outcome was iatrogenic delivery for ICP or spontaneous preterm birth occurring after ICP diagnosis. Cox proportional hazards models with frailties adjusted for maternal demographics, co-morbidities, disease activity, and glucocorticoid use. At the Montreal site, thiopurine metabolites were measured at each visit, with shunting defined using established cut-offs.Results Of 127 SLE pregnancies, 46 were AZA-exposed and 81 unexposed ( table 1). Ten ICP cases occurred (each in a distinct woman): 8 among AZA-exposed (17.4%, 95%CI 9.1-30.7) and 2 among unexposed (2.5%, 95%CI 0.7-8.6). Nine of ten ICP cases underwent an iatrogenic delivery and one AZA-exposed case experienced a spontaneous preterm delivery. AZA exposure was associated with a substantially increased risk of ICP (unadjusted HR 9.1, 95%CI 1.9-44.5; adjusted HR 11.9, 95%CI 2.2-65.1). All ICP cases with metabolite data (4/4) exhibited 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. All ICP pregnancies resulted in live births, although AZA-exposed cases tended to have higher bile acid levels, earlier delivery, and lower birth weight for gestational age versus unexposed cases.Abstract LBA:01:25 Table 1Characteristics of SLE pregnancies at the second-trimester visit according to azathioprine (AZA) exposure (n=127)Conclusions SLE pregnancies exposed to AZA had a substantially higher risk of ICP than unexposed pregnancies. Second-trimester thiopurine shunting appears to strongly predict ICP, highlighting the need for metabolite monitoring and vigilance when prescribing AZA in SLE pregnancies.