Intrahepatic cholestasis of pregnancy

Czech version

Authors: Luděk Kostka; Lukáš Hruban; Petra Morávková
Authors‘ workplace: Gynekologicko-porodnická klinika LF MU a FN Brno
Published in: Ceska Gynekol 2024; 89(5): 405-410
Category:
doi: https://doi.org/10.48095/cccg2024405

Overview

Objective: The aim of this work is to summarize current scientific information focusing on the diagnosis, management, and treatment of intrahepatic cholestasis in pregnancy according to available literature. Methodology: Literature sources were searched using the Web of Science, Scopus, and PubMed/Medline databases. Conclusion: For the diagnosis and proper management of intrahepatic cholestasis of pregnancy, the postprandial serum bile acid value of the pregnant woman is crucial. Postprandial testing allows for a higher likelihood of identifying patients with significantly elevated bile acid levels. Bile acid values above 100 µmol/l, especially in the 3^rd trimester, are associated with a significant risk of severe complications, particularly intrauterine fetal death. Ursodeoxycholic acid, the first-line treatment, according to available data, does not improve perinatal outcomes and has minimal effect on the sensation of itching in patients. The routine administration of ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy is controversial.

Keywords:

ursodeoxycholic acid – bile acids – intrahepatic cholestasis of pregnancy

Sources

1. Binder T, Zima T, Vítek L. Biochemické aspekty těhotenské cholestatické hepatózy. Ceska Gynekol 2007; 72 (2): 90–94.

2. Sarkar M, Brady CW, Fleckenstein J et al. Reproductive health and liver dis ease: practice guidance by the American association for the study of liver dis eases. Hepatology 2021; 73 (1): 318–365. doi: 10.1002/hep.31559.

3. Lee RH, Greenbert M, Metz TD e tal. Society for Maternal-Fetal Medicine (SMFM). Society for Maternal-Fetal Medicine consult series #53: intrahepatic cholestasis of pregnancy: replaces consult #13, April 2011. Am J Obstet Gynecol 2021; 224 (2): B2–B9. doi: 10.1016/j.ajog.2020.11.002.

4. Intrahepatální cholestáza v těhotenství, Doporučený postup ČGPS ČLS JEP. Ceska Gynekol 2017; 82 (2): 168–169.

5. Pillarisetty LS, Sharma A. Pregnancy intrahepatic cholestasis. Treasure Island (FL): StatPearls Publishing. 2023 [online]. Available from: https: //www.ncbi.nlm.nih.gov/books/NBK551503/.

6. Tsur A, Leonard SA, Kan P et al. Vaginal progesterone is associated with intrahepatic cholestasis of pregnancy. Am J Perinatol 2023; 40 (11): 1158–1162. doi: 10.1055/a-2081-2573.

7. Abu-Hayyeh S, Papacleovoulou G, Lövgren-Sandblom A et al. Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype. Hepatology 2013; 57 (2): 716–726. doi: 10.1002/hep. 26055.

8. Wang H, Yan Z, Dong M et al. Alteration in placental expression of bile acids transporters OATP1A2, OATP1B1, OATP1B3 in intrahepatic cholestasis of pregnancy. Arch Gynecol Obstet 2012; 285 (6): 1535–1540. doi: 10.1007/s00404- 011-2183-4.

9. Dixon PH, Williamson C. The pathophysiology of intrahepatic cholestasis of pregnancy. Clin Res Hepatol Gastroenterol 2016; 40 (2): 141–153. doi: 10.1016/j.clinre.2015.12.008.

10. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of liver dis eases in pregnancy. J Hepatol 2023; 79 (3): 768–828. doi: 10.1016/j.jhep.2023.03.006.

11. Anzivino C, Odoardi MR, Meschiari E et al. ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population. Dig Liver Dis 2013; 45 (3): 226–232. doi: 10.1016/j.dld.2012.08.011.

12. Ontsouka E, Schroeder M, Albrecht C. Revisited role of the placenta in bile acid homeostasis. Front Physiol 2023; 14: 1213757. doi: 10.3389/fphys.2023.1213757.

13. Ontsouka E, Schroeder M, Ok L et al. The placenta – a new source of bile acids during healthy pregnancy? First results of a gene expression study in humans and mice. Int J Mol Sci 2023; 24 (11): 9511. doi: 10.3390/ijms24119511.

14. Huri M, Seravalli V, Lippi C et al. Intrahepatic cholestasis of pregnancy – time to redefine the reference range of total serum bile acids: a cross- -sectional study. BJOG 2022; 129 (11): 1887–1896. doi: 10.1111/1471-0528.17174.

15. Mitchell AL, Ovadia C, Syngelaki A et al. Re-evaluating dia gnostic thresholds for intrahepatic cholestasis of pregnancy: case-control and cohort study. BJOG 2021; 128 (10): 1635–1644. doi: 10.1111/1471-0528.16669.

16. Williamson C, Miragoli M, Abdul Kadir SS et al. Bile acid signaling in fetal tissues: implications for intrahepatic cholestasis of pregnancy. Dig Dis 2011; 29 (1): 58–61. doi: 10.1159/000324130.

17. Ovadia C, Seed PT, Sklavounos A et al. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with bio chemical markers: results of aggregate and individual patient data meta-analyses. Lancet 2019; 393 (10174): 899–909. doi: 10.1016/S0140-6736 (18) 31877-4.

18. Sargın Oruç A, Seçkin B, Özcan N et al. Role of postprandial bile acids in prediction of perinatal outcome in intrahepatic cholestasis of pregnancy. J Obstet Gynaecol Res 2014; 40 (7): 1883–1889. doi: 10.1111/jog.12444.

19. Girling J, Knight CL, Chappell L. Royal College of Obstetricians and Gynaecologists. Intrahepatic cholestasis of pregnancy: green-top guideline no. 43 June 2022. BJOG 2022; 129 (13): e95–e114. doi: 10.1111/1471-0528.17206.

20. Hague WM, Briley A, Callaway L et al. Intrahepatic cholestasis of pregnancy – dia gnosis and management: a consensus statement of the Society of Obstetric Medicine of Australia and New Zealand (SOMANZ): executive summary. Aust N Z J Obstet Gynaecol 2023; 63 (5): 656–665. doi: 10.1111/ajo.13719.

21. Intrahepatic cholestasis of pregnancy. South Australian Perinatal Practice Guideline. 2024 [online]. Available from: https: //www.sahealth.sa.gov.au/wps/wcm/connect/f91fbf004ee530b2a5ebadd150ce4f37/Intrahepatic+cholestasis+of+pregnancy_PPG_v4_0.pdf?MOD=AJPERES& CACHEID=ROOTWORKSPACE-f91fbf004ee530b2a5ebadd150ce4f37-ocQJ9qe.

22. Walker IA, Nelson-Piercy C, Williamson C. Role of bile acid measurement in pregnancy. Ann Clin Biochem 2002; 39 (Pt 2): 105–113. doi: 10.1258/0004563021901856.

23. Kenyon AP, Tribe RM, Nelson-Piercy C et al. Pruritus in pregnancy: a study of anatomical distribution and prevalence in relation to the development of obstetric cholestasis. Obstet Med 2010; 3 (1): 25–29. doi: 10.1258/om.2010.090055.

24. Fleminger J, Seed PT, Smith A et al. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a secondary analysis of the PITCHES trial. BJOG 2021; 128 (6): 1066–1075. doi: 10.1111/1471-0528.16567.

25. Walker KF, Chappell LC, Hague WM et al. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev 2020; 7 (7): CD000493. doi: 10.1002/14651858.CD000493.pub3.

26. Majewska A, Godek B, Bomba-Opon D et al. Association between intrahepatic cholestasis in pregnancy and gestational diabetes mellitus. A retrospective analysis. Ginekol Pol 2019; 90 (8): 458–463. doi: 10.5603/GP.2019.0079.

27. Wikström Shemer E, Marschall HU, Ludvigsson JF et al. Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12-year population-based cohort study. BJOG 2013; 120 (6): 717–23. doi: 10.1111/1471-0528.12174.

28. Marschall HU, Wikström Shemer E, Ludvigsson JF et al. Intrahepatic cholestasis of pregnancy and associated hepatobiliary dis ease: a population-based cohort study. Hepatology 2013; 58 (4): 1385–1391. doi: 10.1002/hep.26444.

29. Wikström Shemer EA, Stephansson O, Thuresson M et al. Intrahepatic cholestasis of pregnancy and cancer, immune-mediated and cardiovascular dis eases: a population-based cohort study. J Hepatol 2015; 63 (2): 456–461. doi: 10.1016/j.jhep.2015.03.010.

30. Zhan Y, Xu T, Chen T et al. Intrahepatic cholestasis of pregnancy and fetal cardiac dysfunction: a systematic review and meta-analysis. Am J Obstet Gynecol MFM 2023; 5 (8): 100952. doi: 10.1016/j.ajogmf.2023.100952.

31. Vasavan T, Deepak S, Jayawardane IA et al. Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations. J Hepatol 2021; 74 (5): 1087–1096. doi: 10.1016/j.jhep.2020.11.038.

32. Sepúlveda WH, González C, Cruz MA et al. Vasoconstrictive effect of bile acids on isolated human placental chorionic veins. Eur J Obstet Gynecol Reprod Biol 1991; 42 (3): 211–215. doi: 10.1016/0028-2243 (91) 90222-7.

33. Kawakita T, Parikh LI, Ramsey PS et al. Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2015; 213 (4): 570.e1–570.e8. doi: 10.1016/j.ajog.2015.06.021.

34. Germain AM, Kato S, Carvajal JA et al. Bile acids increase response and expression of human myometrial oxytocin receptor. Am J Obstet Gynecol 2003; 189 (2): 577–582. doi: 10.1067/s0002-9378 (03) 00545-3.

35. Israel EJ, Guzman ML, Campos GA. Maximal response to oxytocin of the isolated myometrium from pregnant patients with intrahepatic cholestasis. Acta Obstet Gynecol Scand 1986; 65 (6): 581–582. doi: 10.3109/00016348609158391.

36. Liu X, Landon MB, Chen Y et al. Perinatal outcomes with intrahepatic cholestasis of pregnancy in twin pregnancies. J Matern Fetal Neonatal Med 2016; 29 (13): 2176–2181. doi: 10.3109/14767058.2015.1079612.

37. Wan JF, Chu SF, Zhou X et al. Ursodeoxycholic acid protects interstitial Cajal-like cells in the gallbladder from undergoing apoptosis by inhibiting TNF-a expression. Acta Pharmacol Sin 2018; 39 (9): 1493–1500. doi: 10.1038/aps.2017.206.

38. Pusl T, Vennegeerts T, Wimmer R et al. Tauroursodeoxycholic acid reduces bile acid-induced apoptosis by modulation of AP-1. Biochem Biophys Res Commun 2008; 367 (1): 208–212. doi: 10.1016/j.bbrc.2007.12.122.

39. Beuers U, Hohenester S, de Buy Wenniger LJ et al. The biliary HCO (3) (-) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology 2010; 52 (4): 1489–1496. doi: 10.1002/hep.23810.

40. Manna LB, Ovadia C, Lövgren-Sandblom A et al. Enzymatic quantification of total serum bile acids as a monitoring strategy for women with intrahepatic cholestasis of pregnancy receiving ursodeoxycholic acid treatment: a cohort study. BJOG 2019; 126 (13): 1633–1640. doi: 10.1111/1471-0528.15926.

41. Ridlon JM, Bajaj JS. The human gut sterol bio me: bile acid-microbio me endocrine aspects and therapeutics. Acta Pharm Sin B 2015; 5 (2): 99–105. doi: 10.1016/j.apsb.2015.01.006.

42. Bacq Y, Sentilhes L, Reyes HB et al. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology 2012; 143 (6): 1492–1501. doi: 10.1053/j.gastro.2012.08.004.

43. Gurung V, Middleton P, Milan SJ et al. Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev 2013; 2013 (6): CD000493. doi: 10.1002/14651858.CD000493.pub2.

44. Kong X, Kong Y, Zhang F et al. Evaluating the effectiveness and safety of ursodeoxycholic acid in treatment of intrahepatic cholestasis of pregnancy: a meta-analysis (a prisma-compliant study). Medicine (Baltimore) 2016; 95 (40): e4949. doi: 10.1097/MD.0000000000004949.

45. Chappell LC, Bell JL, Smith A et al. Urso deoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial. Lancet 2019; 394 (10201): 849–860. doi: 10.1016/S0140-67 36 (19) 31270-X.

46. Ovadia C, Sajous J, Seed PT et al. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis. Lancet Gastroenterol Hepatol 2021; 6 (7): 547–558. doi: 10.1016/S2468-1253 (21) 00074-1.

47. Geenes V, Chappell LC, Seed PT et al. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study. Hepatology 2014; 59 (4): 1482–1491. doi: 10.1002/hep.26617.

ORCID autorů

L. Kostka 0009-0001-6553-4471

L. Hruban 0000-0001-8594-2678

P. Morávková 0000-0001-6613-9476

Doručeno/Submitted: 18. 6. 2024

Přijato/Accepted: 22. 7. 2024

doc. MUDr. Lukáš Hruban, Ph.D.

Gynekologicko-porodnická klinika

LF MU a FN Brno

Obilní trh 11

625 00 Brno

hruban.lukas@fnbrno.cz