妊娠晚期硫嘌呤代谢物分流增加炎症性肠病女性妊娠期肝内胆汁淤积症的风险，可通过分剂量给药进行管理。

Thiopurine Metabolite Shunting in Late Pregnancy Increases the Risk of Intrahepatic Cholestasis of Pregnancy in Women With Inflammatory Bowel Disease, and Can be Managed With Split Dosing.

作者信息

Prentice Ralley, Flanagan Emma, Wright Emily, Prideaux Lani, Connell William, Sparrow Miles, De Cruz Peter, Lust Mark, Hardikar Winita, Goldberg Rimma, Vogrin Sara, Palmer Kirsten, Ross Alyson, Burns Megan, Greeve Tessa, Bell Sally

机构信息

Monash Health, Gastroenterology Department, Melbourne, VIC, Australia.

St Vincent's Hospital Melbourne, Gastroenterology Department, Melbourne, VIC, Australia.

出版信息

J Crohns Colitis. 2024 Aug 6;18(7):1081-1090. doi: 10.1093/ecco-jcc/jjae023.

DOI:10.1093/ecco-jcc/jjae023

PMID:38366352

Abstract

BACKGROUND AND AIMS

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.

摘要

背景与目的

妊娠期间暴露于硫唑嘌呤会增加发生妊娠期肝内胆汁淤积症（ICP）的风险。硫唑嘌呤“分流”，即6-甲基巯基嘌呤（MMP）与6-硫鸟嘌呤（TGN）的比值>11，在整个孕期会进展，并可能促进ICP的发展。我们旨在探讨硫唑嘌呤暴露与ICP之间的关联，包括硫唑嘌呤分流的假定影响，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暴露于硫唑嘌呤和生物单药治疗的孕妇。在受孕前、每个孕期、分娩时和产后获取疾病活动和产科结局数据、硫唑嘌呤代谢产物、胆汁酸和转氨酶。硫唑嘌呤剂量管理由治疗医生自行决定。

结果

纳入了131例暴露于硫唑嘌呤和147例暴露于生物单药治疗的妊娠。MMP/TGN比值从受孕前到孕晚期增加（p<0.01），约25%的参与者在孕期出现分流。孕中期分剂量给药导致分娩时MMP/TGN比值中位数从18（四分位间距[IQR]6-57）降至3[IQR 2-3.5]（p=0.04）。暴露于硫唑嘌呤的妊娠发生ICP的风险增加（6.7%[7/105]对0%[裸0/112]，p<0.001），所有ICP病例均发生在产前硫唑嘌呤分流的情况下。硫唑嘌呤剂量增加（风险比[RR]8.10，95%置信区间[CI]1.88-34.85，p=0.005）以及孕晚期[6.20，1.21-30.73，p=0.028]和分娩时[14.18，1.62-123.9，p=0.016]的分流与ICP风险增加相关。