Background and Aims The risk of intrahepatic cholestasis of pregnancy (ICP) is increased in thiopurine exposed pregnancies. Thiopurine ‘shunting’, with a 6-methylmecrcaptopurine (MMP) to 6-thioguanine (TGN) ratio of >11, progresses over pregnancy, and may promote ICP development. We aimed to explore the association between thiopurine exposure and ICP, including the hypothesized impact of thiopurine shunting, and identify risk minimization strategies. Methods This prospective multi-centre cohort study compared thiopurine and biologic monotherapy exposed pregnant participants. Disease activity and obstetric outcome data, thiopurine metabolites, bile acids and transaminases were obtained preconception, in each trimester, at delivery, and post-partum. Thiopurine dose management was at the discretion of the treating physician. Results 131 thiopurine and 147 biologic monotherapy exposed pregnancies were included. MMP/TGN ratio increased from preconception to third trimester (p<0.01), with approximately 25% of participants shunting in pregnancy. Second trimester split-dosing led to a decrease in the median MMP/TGN ratio from 18 (IQR 6-57) to 3 (IQR 2-3.5) at delivery (p=0.04). The risk of ICP was increased in thiopurine exposed pregnancies (6.7% (7/105) vs 0% (0/112), p<0.001), with all ICP cases occurring in the setting of antenatal thiopurine shunting. Thiopurine dose increases (RR 8.10 [95% CI 1.88-34.85] p=0.005) and shunting in third trimester (6.20 [1.21-30.73] p=0.028) and at delivery (14.18 [1.62-123.9] p=0.016) were associated with an increased risk of ICP. Conclusions Thiopurine exposure is associated with an increased risk of ICP, particularly following dose increases antenatally and with shunting in late pregnancy. The latter may be effectively managed with split dosing, although further studies are warranted.

中文翻译：

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妊娠晚期硫嘌呤代谢物分流会增加患有炎症性肠病的女性妊娠期肝内胆汁淤积的风险，可以通过分次给药来控制

背景和目的 暴露于硫嘌呤的妊娠中，妊娠期肝内胆汁淤积 (ICP) 的风险会增加。6-甲基硫嘌呤(MMP)与6-硫鸟嘌呤(TGN)之比＞11的硫嘌呤“分流”在妊娠过程中不断进展，并且可能促进ICP发展。我们的目的是探讨硫嘌呤暴露与ICP之间的关联，包括硫嘌呤分流的假设影响，并确定风险最小化策略。方法 这项前瞻性多中心队列研究比较了硫嘌呤和生物单一疗法暴露的怀孕参与者。疾病活动度和产科结果数据、硫嘌呤代谢物、胆汁酸和转氨酶均在孕前、每个妊娠期、分娩时和产后获得。硫嘌呤剂量管理由治疗医生决定。结果 纳入了 131 例硫嘌呤和 147 例生物单一疗法暴露妊娠。MMP/TGN 比率从受孕前到妊娠晚期有所增加（p<0.01），大约 25% 的参与者在怀孕期间分流。妊娠中期分次给药导致分娩时中位 MMP/TGN 比率从 18 (IQR 6-57) 降至 3 (IQR 2-3.5) (p=0.04)。暴露于硫嘌呤的妊娠中ICP的风险增加（6.7%（7/105）vs 0%（0/112），p＜0.001），所有ICP病例都发生在产前硫嘌呤分流的情况下。硫嘌呤剂量增加 (RR 8.10 [95% CI 1.88-34.85] p=0.005) 与妊娠晚期 (6.20 [1.21-30.73] p=0.028) 和分娩时 (14.18 [1.62-123.9] p=0.016) 分流相关ICP 风险增加。结论 硫嘌呤暴露与 ICP 风险增加相关，特别是在产前剂量增加和妊娠晚期分流后。尽管需要进一步研究，但通过分次给药可以有效地控制后者。