Abstract：
OBJECTIVE: The risk of intrahepatic cholestasis of pregnancy [ICP] is increased in thiopurine-exposed pregnancies. Thiopurine \'shunting\', with a 6-methylmercaptopurine [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 hypothesised impact of thiopurine shunting, and identify risk minimisation strategies.
METHODS: This prospective multicentre cohort study compared thiopurine and biologic monotherapy-exposed pregnant participants. Disease activity and obstetric outcome data, thiopurine metabolites, bile acids, and transaminases were obtained before conception, in each trimester, at delivery, and postpartum. Thiopurine dose management was at the discretion of the treating physician.
RESULTS: Included were 131 thiopurine and 147 biologic monotherapy-exposed pregnancies. 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 (interquartile range [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 (risk ratio [RR] 8.10, 95% confidence interval [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.
METHODS: This prospective multicentre cohort study compared thiopurine and biologic monotherapy-exposed pregnant participants. Disease activity and obstetric outcome data, thiopurine metabolites, bile acids, and transaminases were obtained before conception, in each trimester, at delivery, and postpartum. Thiopurine dose management was at the discretion of the treating physician.
RESULTS: Included were 131 thiopurine and 147 biologic monotherapy-exposed pregnancies. 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 (interquartile range [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 (risk ratio [RR] 8.10, 95% confidence interval [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.
摘要：
目的：在硫嘌呤暴露的妊娠中，妊娠肝内胆汁淤积症（ICP）的风险增加。硫嘌呤\'分流\',6-甲基甲酚嘌呤（MMP）与6-硫鸟嘌呤（TGN）的比例>11，在怀孕期间进展，并可能促进ICP的发展。我们旨在探讨硫嘌呤暴露与ICP之间的关系，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药治疗暴露的孕妇。疾病活动和产科结果数据，硫嘌呤代谢物，胆汁酸和转氨酶在孕前获得，在每三个月，交货时，和产后。硫嘌呤剂量管理由治疗医师自行决定。
结果：包括131个硫嘌呤和147个生物单药治疗暴露妊娠。MMP/TGN比值从孕前到孕晚期增加（p<0.01），大约25％的参与者在怀孕期间分流。妊娠中期分开给药导致分娩时MMP/TGN比值中位数从18（IQR6-57）降低至3（IQR2-3.5）（p=0.04）。硫嘌呤暴露妊娠的ICP风险增加（6.7％（7/105）对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(RR8.10[95%CI1.88-34.85]p=0.005)和妊娠晚期分流(6.20[1.21-30.73]p=0.028)和分娩时分流(14.18[1.62-123.9]p=0.016)与ICP风险增加相关。
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。后者可以通过分次给药进行有效管理，尽管需要进一步的研究.
方法：这项前瞻性多中心队列研究比较了硫嘌呤和生物单药治疗暴露的孕妇。疾病活动和产科结果数据，硫嘌呤代谢物，胆汁酸和转氨酶在孕前获得，在每三个月，交货时，和产后。硫嘌呤剂量管理由治疗医师自行决定。
结果：包括131个硫嘌呤和147个生物单药治疗暴露妊娠。MMP/TGN比值从孕前到孕晚期增加（p<0.01），大约25％的参与者在怀孕期间分流。妊娠中期分开给药导致分娩时MMP/TGN比值中位数从18（IQR6-57）降低至3（IQR2-3.5）（p=0.04）。硫嘌呤暴露妊娠的ICP风险增加（6.7％（7/105）对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(RR8.10[95%CI1.88-34.85]p=0.005)和妊娠晚期分流(6.20[1.21-30.73]p=0.028)和分娩时分流(14.18[1.62-123.9]p=0.016)与ICP风险增加相关。
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。后者可以通过分次给药进行有效管理，尽管需要进一步的研究.
