CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2021; 81(08): 940-947
DOI: 10.1055/a-1522-5178
GebFra Science
Review/Übersicht

Intrahepatic Cholestasis of Pregnancy

Article in several languages: English | deutsch
Stanisław M. Jurk
1   Leipzig, Germany
,
Andreas E. Kremer
2   Medizinische Klinik 1, Universitätsklinikum Erlangen, Erlangen, Germany
3   Klinik für Gastroenterologie und Hepatologie, Universitätsspital Zürich, Zürich, Switzerland
,
Ekkehard Schleussner
4   Klinik für Geburtsmedizin, Universitätsklinikum Jena, Jena, Germany
› Author Affiliations
› Further Information
   Permissions and Reprints

Abstract

Intrahepatic cholestasis of pregnancy (ICP) is a rare but potentially serious complication of pregnancy, the main symptom of which is intense pruritus with elevated serum levels of bile acids. The elevated serum bile acid concentration is regarded as a predictor for poor perinatal outcome including intrauterine death. Ursodeoxycholic acid (UDCA) has become established as the treatment of choice in clinical management to achieve a significant improvement in symptoms and reduce the cholestasis. Pregnant women with severe intrahepatic cholestasis should always be managed in a perinatal centre with close interdisciplinary monitoring and treatment involving perinatologists and hepatologists to minimise the markedly increased perinatal morbidity and mortality as well as maternal symptoms.

Key words

cholestasis of pregnancy - pruritus - bile acids - antenatal care - induction of labor - fetal death


Publication History

Received: 19 June 2020

Accepted after revision: 02 June 2021

Article published online:
09 August 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References/Literatur

  • 1 Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis 2007; 2: 26 DOI: 10.1186/1750-1172-2-26.
    CrossrefPubMedGoogle Scholar
  • 2 Floreani A, Gervasi MT. New insights on intrahepatic cholestasis of pregnancy. Clin Liver Dis 2016; 20: 177-189
    CrossrefPubMedGoogle Scholar
  • 3 Ovadia C, Williamson C. Intrahepatic cholestasis of pregnancy: recent advances. Clin Dermatol 2016; 34: 327-334
    CrossrefPubMedGoogle Scholar
  • 4 Geenes V, Williamson C, Chappel LC. Intrahepatic cholestasis of pregnancy. Obstet Gynaecol 2016; 18: 273-281 DOI: 10.1111/tog.12308.
    CrossrefGoogle Scholar
  • 5 Smith DD, Rood KM. Intrahepatic Cholestasis of Pregnancy. Clin Obstet Gynecol 2020; 63: 134-151 DOI: 10.1097/GRF.0000000000000495.
    CrossrefPubMedGoogle Scholar
  • 6 Ahlfeld F. Berichte und Arbeiten aus der geburtshilflich-gynaekologischen Klinik zu Giessen 1881 – 1882. Leipzig: Grunow FW; 1883: 148
    Google Scholar
  • 7 Dixon PH, Wadsworth CA, Chambers J. et al. A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy. Am J Gastroenterol 2014; 109: 76-84
    CrossrefPubMedGoogle Scholar
  • 8 Jacquemin E, De Vree JM, Cresteil D. et al. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 2001; 120: 1448-1458
    CrossrefPubMedGoogle Scholar
  • 9 Lammert F, Marschall HU, Glantz A. et al. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 2000; 33: 1012-1021
    CrossrefPubMedGoogle Scholar
  • 10 Reyes H, Sjövall J. Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy. Ann Med 2000; 32: 94-106
    CrossrefPubMedGoogle Scholar
  • 11 Gonzalez MC, Reyes H, Arrese M. et al. Intrahepatic cholestasis of pregnancy in twin pregnancies. J Hepatol 1989; 9: 84-90
    CrossrefPubMedGoogle Scholar
  • 12 Raz Y, Lavie A, Vered Y. et al. Severe intrahepatic cholestasis of pregnancy is a risk faktor for preeclampsia in singleton and twin pregnancies. Am J Obstet Gynecol 2015; 213: 395.e1-395.e8 DOI: 10.1016/j.ajog.2015.05.011.
    CrossrefPubMedGoogle Scholar
  • 13 Kremer AE, Wolf K, Ständer S. Intrahepatische Schwangerschaftscholestase. Hautarzt 2017; 68: 95-102
    CrossrefPubMedGoogle Scholar
  • 14 Kauppila A, Korpela H, Mäkilä UM. et al. Low serum selenium concentration and glutathione peroxidase activity in intrahepatic cholestasis of pregnancy. Br Med J (Clin Res Ed) 1987; 294: 150-152
    CrossrefPubMedGoogle Scholar
  • 15 Wikström Shemer E, Marschall HU. Decreased 1,25-dihydroxy vitamin D levels in women with intrahepatic cholestasis of pregnancy. Acta Obstet Gynecol Scand 2010; 89: 1420-1423 DOI: 10.3109/00016349.2010.515665.
    CrossrefPubMedGoogle Scholar
  • 16 Gençosmanoğlu Türkmen G, Vural Yilmaz Z, Dağlar K. et al. Low serum vitamin D level is associated with intrahepatic cholestasis of pregnancy. J Obstet Gynaecol Res 2018; 44: 1712-1718 DOI: 10.1111/jog.13693.
    CrossrefPubMedGoogle Scholar
  • 17 Marshall HU, Wikstrom Shermer E, Ludvigsson JF. Intrahepatic cholestasis of pregnancy ans associated hepatobiliary disease: a population-base cohort study. Hepatology 2013; 58: 1385-1391
    CrossrefPubMedGoogle Scholar
  • 18 Wijarnpreecha K, Thongprayoon C, Sanguankeo A. et al. Hepatitis C infection and intrahepatic cholestasis of pregnancy: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2017; 41: 39-45 DOI: 10.1016/j.clinre.2016.07.004.
    CrossrefPubMedGoogle Scholar
  • 19 Bolubkas FF, Bolubkas C, Balaban HY. et al. Intrahepatic Cholestasis of Pregnancy: Spontaneous vs. in vitro Fertilization. Euroasian J Hepat-Gastroenterol 2017; 7: 126-129
    CrossrefPubMedGoogle Scholar
  • 20 Abu-Hayyeh S, Ovadia C, Lieu T. et al. Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of preganancy and pruritus gravidarum. Hepatology 2016; 63: 1287-1298
    CrossrefPubMedGoogle Scholar
  • 21 Tsur A, Kan P. et al. Datoc i et al. 68: Vaginal progesterone treatment is associated with intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2020; 222: S58-S59 DOI: 10.1016/j.ajog.2019.11.084.
    CrossrefGoogle Scholar
  • 22 Glantz A, Marshall HU, Mattsson LA. Intraheptaic cholestasis of pregnancy: relationship between bile acid levels and fetal complication rates. Hepatology 2004; 40: 467-474
    CrossrefPubMedGoogle Scholar
  • 23 WHO. Medical Eligibility Criteria for Contraceptive Use. 5th ed. World Health Organization; 2015
    Google Scholar
  • 24 Kondrackiene J, Kupcinskas L. Intrahepatic cholestasis of pregnancy – current achievements and unsolved problems. World J Gastroenterol 2008; 14: 5781-5788
    CrossrefPubMedGoogle Scholar
  • 25 Geenes V, Lövgren-Sandblom A, Benthin L. et al. The Reversed Feto-Maternal Bile Acid Gradient in Intrahepatic Cholestasis of Pregnancy IS Corrected by Ursodeoxycholic Acid. PLoS One 2014; 9: e83828 DOI: 10.1371/journal.pone.0083828.
    CrossrefPubMedGoogle Scholar
  • 26 Brites D. Intrahepatic cholestasis of pregnancy: changes in maternal-fetal bile acid balance and improvement by ursodeoxycholic acid therapy in cholestasis of pregnancy. Ann Hepatol 2002; 1: 20-28
    CrossrefPubMedGoogle Scholar
  • 27 Keitel V, Dröge C, Häussinger D. Genetische Ursachen cholestatischer Lebererkrankungen. Falk Gastro-Kolleg 3/2019. Accessed March 30, 2020 at: https://www.drfalkpharma.de/uploads/tx_toccme2/FGK_3_19_Keitel_Web.pdf
    Google Scholar
  • 28 Dixon PH, Williamson C. The pathophysiology on intrahepatic cholestasis pf pregnancy. Clin Res Hepatol Gastroenterol 2016; 40: 141-153 DOI: 10.1016/j.clinre.2015.12.008.
    CrossrefPubMedGoogle Scholar
  • 29 Dixon PH, van Mil SW, Chambers J. et al. Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut 2009; 58: 537-544
    CrossrefPubMedGoogle Scholar
  • 30 Dixon PH, Sambrotta M, Chambers J. et al. An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy. Sci Rep 2017; 7: 11823 DOI: 10.1038/s41598-017-11626-x.
    CrossrefPubMedGoogle Scholar
  • 31 Henkel SA, Squires JH, Ayers M. et al. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol 2019; 11: 450-463 DOI: 10.4254/wjh.v11.i5.450.
    CrossrefPubMedGoogle Scholar
  • 32 Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol 2014; 124: 120-133 DOI: 10.1097/AOG.0000000000000346.
    CrossrefPubMedGoogle Scholar
  • 33 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: 1482-1491
    CrossrefPubMedGoogle Scholar
  • 34 Brouwers L, Koster MP, Page-Christiaens GC. et al. Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels. Am J Obstet Gynecol 2015; 212: 100.e1-100.e7 DOI: 10.1016/j.ajog.2014.07.026.
    CrossrefPubMedGoogle Scholar
  • 35 Arthuis C, Diguisto C, Lorphelin H. et al. Perinatal outcomes of intrahepatic cholestasis during pregnancy: An 8-year case-control study. PLoS One 2020; 15: e0228213 DOI: 10.1371/journal.pone.0228213.
    CrossrefPubMedGoogle Scholar
  • 36 Ovadia C, Seed PT, Sklavounos A. et al. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet 2019; 393: 899-909 DOI: 10.1016/S0140-6736(18)31877-4.
    CrossrefPubMedGoogle Scholar
  • 37 Al Inizi S, Gupta R, Gale A. Fetal tachyarrhythmia with atrial flutter in obstetric cholestasis. Int J Gynecol Obstet 2006; 93: 53-54
    CrossrefPubMedGoogle Scholar
  • 38 Ataalla WM, Ziada DH, Gaber R. et al. The impact of total bile acid levels on fetal cardiac function in intrahepatic cholestasis of pregnancy using fetal echocardiography: a tissue Doppler imaging study. J Matern Fetal Neonatal Med 2016; 29: 1445-1450
    CrossrefPubMedGoogle Scholar
  • 39 Sanhal CY, Kara O, Yucel A. Can fetal left ventricular modified myocardial performance index predict adverse perinatal outcomes in intrahepatic cholestasis of pregnancy?. J Matern Fetal Neonatal Med 2017; 30: 911-916
    CrossrefPubMedGoogle Scholar
  • 40 Williamson C, Miragoli M, Sheikh Abdul Kadir S. et al. Bile acid signaling in fetal tissues: implications for intrahepatic cholestasis of pregnancy. Dig Dis 2011; 29: 58-61 DOI: 10.1159/000324130.
    CrossrefPubMedGoogle Scholar
  • 41 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: 577-582
    CrossrefPubMedGoogle Scholar
  • 42 Zhao P, Zhang K, Yao Q. et al. Uterine contractility in intrahepatic cholestasis of pregnancy. J Obstet Gynaecol 2014; 34: 221-224 DOI: 10.3109/01443615.2013.834878.
    CrossrefPubMedGoogle Scholar
  • 43 Chappell LC, Bell JL, Smith A. et al. for the PITCHES study group. Ursodeoxycholic acid versus placebo in women with intraheptic cholestasis of pregnancy (PITCHES): a randomised controlled trial. Lancet 2019; 394: 849-860
    CrossrefPubMedGoogle Scholar
  • 44 Kawakita T, Parikh LI, Ramsey PS. et al. Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2015; 213: 570.e1-570.e8 DOI: 10.1016/j.ajog.2015.06.021.
    CrossrefPubMedGoogle Scholar
  • 45 Di Mascio D, Quist-Nelson J, Riegel M. et al. Perinatal death by bile acid levels in intrahepatic cholestasis of pregnancy: a systematic review. J Matern Fetal Neonatal Med 2019; DOI: 10.1080/14767058.2019.1685965.
    CrossrefPubMedGoogle Scholar
  • 46 Altshuler G, Arizawa M, Molnar-Nadasdy G. Meconium-induced Umbilical Cord Vascular Necrosis and Ulceration: A Potential Link Between the Placenta and Poor Pregnancy Outcome. Obstet Gynecol 1992; 79 (5 Pt 1): 760-766
    PubMedGoogle Scholar
  • 47 Lammert F, Rath W, Matern S. Lebererkrankungen in der Schwangerschaft. Molekulare Pathogenese und interdisziplinäres Management. Gynäkologe 2004; 37: 418-426
    Google Scholar
  • 48 Lammert F, Rath W. Lebererkrankungen. In: Kainer F. Hrsg. Facharztwissen Geburtsmedizin. 3. Aufl.. München: Elsevier GmbH; 2016: 450-453
    Google Scholar
  • 49 Ghent CN, Bloomer JR, Klatskin G. Elevations in skin tissue levels of bile acids in human cholestasis: relation to serum levels and topruritus. Gastroenterology 1977; 73: 1125-1130
    CrossrefPubMedGoogle Scholar
  • 50 Kremer AE, Bolier R, Dixon PH. et al. Autotaxin activity has a high accuracy to diagnose intrahepatic cholestasis of pregnancy. J Hepatol 2015; 62: 897-904 DOI: 10.1016/j.jhep.2014.10.041.
    CrossrefPubMedGoogle Scholar
  • 51 Wikström Shemer EA, Stephansson O, Thuresson M. et al. Intrahepatic cholestasis of pregnancy and cancer, immunemediated and cardiovascular diseases: A population-based cohort study. J Hepatol 2015; 63: 456-461
    CrossrefPubMedGoogle Scholar
  • 52 Mor M, Shmueli A, Krispin E. et al. Intrahepatic cholestasis of pregnancy as a risk factor for preeclampsia. Arch Gynecol Obstet 2020; 301: 655-664 DOI: 10.1007/s00404-020-05456-y.
    CrossrefPubMedGoogle Scholar
  • 53 Martineau MG, Raker C, Dixon PH. et al. The metabolic profile of intrahepatic cholestasis of pregnancy is associated with impaired glucose tolerance, dysllipidemia, and increased fetal growth. Diabetes Care 2015; 38: 243-248
    CrossrefPubMedGoogle Scholar
  • 54 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: 458-463 DOI: 10.5603/GP.2019.0079.
    CrossrefPubMedGoogle Scholar
  • 55 Ropponen A, Sund R, Riikonen S. et al. Intrahepatic cholestasis of pregnancy an an indicator of liver and biliary diseases: a population-based study. Hepatology 2006; 43: 723-728 DOI: 10.1002/hep.21111.
    CrossrefPubMedGoogle Scholar
  • 56 Sinakos E, Marshall HU, Kowdley KV. et al. Bile acid chnages after high-dose ursodeoxycholic acid treatment in primary sclerosing cholangitis: Relation to disease progression. Hepatology 2010; 52: 197-203
    CrossrefPubMedGoogle Scholar
  • 57 Hammoud GM, Ibdah JA. The Liver in Pregnancy. In: Boyer TD, Manns MP, Sanyal AS. eds. Zakim and Boyerʼs Hepatology. A Textbook of Liver Disease. 6th ed. Philadelphia: Saunders; 2012: 919-940
    Google Scholar
  • 58 Parquet M, Metman EH, Raizman A. et al. Bioavailability, gastrointestinal transit, solubilization and faecal excretion of orsodeoxycholic acid in man. Eur J Clin Invest 1985; 15: 171-178
    CrossrefPubMedGoogle Scholar
  • 59 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009; 51: 237-267
    CrossrefPubMedGoogle Scholar
  • 60 Accessed June 17, 2021 at: https://www.icpsupport.org/protocol.shtml
  • 61 Bacq Y, Sentilhes L, Reyes HB. et al. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology 2012; 143: 1492-1501
    CrossrefPubMedGoogle Scholar
  • 62 Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol 2009; 15: 2049-2066
    CrossrefPubMedGoogle Scholar
  • 63 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: 1633-1640
    CrossrefPubMedGoogle Scholar
  • 64 Gurung V, Middleton P, Milan SJ. et al. Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev 2013; (06) CD000493
    PubMedGoogle Scholar
  • 65 GrandʼMaison S, Durand M, Mahone M. The effects of ursodeoxycholic acid treatment for intrahepatic cholestasis of pregnancy on maternal and fetal outcomes: a meta-analysis including non-randomized studies. J Obstet Gynaecol Can 2014; 36: 632-641
    CrossrefPubMedGoogle Scholar
  • 66 Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy. Gastroenterology 2005; 129: 894-901
    CrossrefPubMedGoogle Scholar
  • 67 Roncaglia N, Locatelli A, Arreghini A. et al. A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-l-methionine in the treatment of gestational cholestasis. BJOG 2004; 111: 17-21
    CrossrefPubMedGoogle Scholar
  • 68 Zhang Y, Lu L, Victor DW. et al. Ursodeoxycholic Acid and S-adenosylmethionine for the Treatment of Intrahepatic Cholestasis of Pregnancy: A Meta-analysis. Hepat Mon 2016; 16: e38558
    CrossrefPubMedGoogle Scholar
  • 69 Triunfo S, Tomaselli M, Ferraro MI. et al. Does mild intrahepatic cholestasis of pregnancy require an aggressive management? Evidence from a prospective observational study focused on adverse perinatal outcomes and pathological placental findings. J Matern Fetal Neonatal Med 2020; DOI: 10.1080/14767058.2020.1714583.
    CrossrefPubMedGoogle Scholar
  • 70 Geenes V, Chambers J, Khurana R. et al. Rifampicin in the treatment of severe intrahepatic cholestasis of pregnancy. Eur J Obstet Gynecol Reprod Biol 2015; 189: 59-63
    CrossrefPubMedGoogle Scholar
  • 71 Walker KF, Chappell LC, Hague WM. et al. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev 2020; (07) CD000493 DOI: 10.1002/14651858.CD000493.pub3.
    CrossrefPubMedGoogle Scholar
  • 72 Bicocca MJ, Sperling JD, Chauhan SP. Intrahepatic cholestasis of pregnancy: Review of six national and regional guidelines. Eur J Obstet Gynecol Reprod Biol 2018; 231: 180-187 DOI: 10.1016/j.ejogrb.2018.10.041.
    CrossrefPubMedGoogle Scholar
  • 73 Kehl S, Abou-Dakn M. et al. für die DGGG und Arbeitsgemeinschaft für Geburtshilfe und Pränatalmedizin in der DGGG e. V.. S2k-Leitlinie Geburtseinleitung. Accessed December 27, 2020 at: https://www.awmf.org/uploads/tx_szleitlinien/015-088l_S2k_Geburtseinleitung_2020-12.pdf
    Google Scholar
  • 74 Royal College of Obstetricians and Gynaecologists. Obstetric Cholestasis. RCOG Green-top Guideline No. 43. London: RCOG; 2011
    Google Scholar
  • 75 Bile Acid Effects in Fetal Arrhythmia Study (BEATS). Accessed August 31, 2020 at: https://clinicaltrials.gov/ct2/show/NCT03519399
    Google Scholar
  • 76 Lo JO, Shaffer BL, Allen AJ. et al. Intrahepatic Cholestasis of Pregnancy and Timing of Delivery. J Matern Fetal Neonatal Med 2015; 28: 2254-2258 DOI: 10.3109/14767058.2014.984605.
    CrossrefPubMedGoogle Scholar
  • 77 Puljic A, Kim A, Page J. et al. The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age. Am J Obstet Gynecol 2015; 212: 667.e1-e667.e5
    CrossrefPubMedGoogle Scholar
  • 78 Mitchell A, Ovadia C, Syngelaki A. et al. Re-evaluating diagnostic thresholds for intrahepatic cholestasis of pregnancy: case-control and cohort study. Br J Obstet Gynaecol 2021; DOI: 10.1111/1471-0528.16669.
    CrossrefPubMedGoogle Scholar
  • 79 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: 547-558 Online: https://www.thelancet.com/journals/langas/article/PIIS2468-1253(21)00074-1/fulltext
    CrossrefPubMedGoogle Scholar