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Intrahepatic cholestasis of pregnancy

Authors
Keith D Lindor, MD
Richard H Lee, MD
Section Editors
Charles J Lockwood, MD, MHCM
Sanjiv Chopra, MD, MACP
Deputy Editors
Kristen M Robson, MD, MBA, FACG
Vanessa A Barss, MD, FACOG

INTRODUCTION

Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and an elevation in serum bile acid concentrations, typically developing in the second and/or third trimester and rapidly resolving after delivery. The major clinical features, diagnosis, and management of ICP will be reviewed here. A general approach to the pregnant woman who develops liver disease is presented elsewhere. (See "Approach to liver disease occurring during pregnancy".)

INCIDENCE AND EPIDEMIOLOGY

The reported incidence of ICP varies widely worldwide, ranging from <1 to 27.6 percent, for reasons that are incompletely understood [1,2]. Geographic variations may reflect differences in susceptibility between ethnic groups, as well as differences in environmental factors [3,4]. In the United States, incidence rates range from 0.32 percent in Bridgeport Hospital, Connecticut [5] to 5.6 percent in a primarily Hispanic population in Los Angeles [6]. Across Europe the incidence ranges from 0.5 to 1.5 percent, with the highest rates in Scandinavia [1]. The incidence is 1.2 to 1.5 percent in Indian-Asians and Pakistani Asians [7]. The Araucanos Indians in Chile have the highest incidence worldwide at 27.6 percent [3].

For unknown reasons, the disease occurs more commonly in the winter months in some countries (eg, Sweden, Finland, Chile) [1]. It is more common in multiple gestations (twins 20.9 versus singletons 4.7 percent in one study from Chile [8]; triplets 43 percent versus twins 14 percent in one study from Finland [9]). Other epidemiologic factors include chronic hepatitis C, prior history or family history of intrahepatic cholestasis, and advanced maternal age [10].

Women with a past history of ICP frequently have ICP in subsequent pregnancies. (See 'Recurrence in subsequent pregnancies' below.)

ETIOLOGY

The etiology of ICP is not completely understood, but likely involves a combination of genetic susceptibility, hormonal factors, and environmental factors.

                                       
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Literature review current through: Nov 2017. | This topic last updated: Oct 19, 2017.
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References
Top
  1. Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol 2009; 15:2049.
  2. Bacq Y. Intrahepatic cholestasis of pregnancy. Clin Liver Dis 1999; 3:1.
  3. Reyes H, Gonzalez MC, Ribalta J, et al. Prevalence of intrahepatic cholestasis of pregnancy in Chile. Ann Intern Med 1978; 88:487.
  4. Wikström Shemer E, Marschall HU, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12-year population-based cohort study. BJOG 2013; 120:717.
  5. Laifer SA, Stiller RJ, Siddiqui DS, et al. Ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy. J Matern Fetal Med 2001; 10:131.
  6. Lee RH, Goodwin TM, Greenspoon J, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol 2006; 26:527.
  7. Abedin P, Weaver JB, Egginton E. Intrahepatic cholestasis of pregnancy: prevalence and ethnic distribution. Ethn Health 1999; 4:35.
  8. Gonzalez MC, Reyes H, Arrese M, et al. Intrahepatic cholestasis of pregnancy in twin pregnancies. J Hepatol 1989; 9:84.
  9. Savander M, Ropponen A, Avela K, et al. Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy. Gut 2003; 52:1025.
  10. Floreani A, Gervasi MT. New Insights on Intrahepatic Cholestasis of Pregnancy. Clin Liver Dis 2016; 20:177.
  11. Pataia V, Dixon PH, Williamson C. Pregnancy and bile acid disorders. Am J Physiol Gastrointest Liver Physiol 2017; 313:G1.
  12. 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.
  13. de Vree JM, Jacquemin E, Sturm E, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci U S A 1998; 95:282.
  14. Jacquemin E, Cresteil D, Manouvrier S, et al. Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy. Lancet 1999; 353:210.
  15. Dixon PH, Weerasekera N, Linton KJ, et al. Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Hum Mol Genet 2000; 9:1209.
  16. Lucena JF, Herrero JI, Quiroga J, et al. A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis. Gastroenterology 2003; 124:1037.
  17. Müllenbach R, Linton KJ, Wiltshire S, et al. ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancy. J Med Genet 2003; 40:e70.
  18. Pauli-Magnus C, Lang T, Meier Y, et al. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics 2004; 14:91.
  19. Floreani A, Carderi I, Paternoster D, et al. Intrahepatic cholestasis of pregnancy: three novel MDR3 gene mutations. Aliment Pharmacol Ther 2006; 23:1649.
  20. Wasmuth HE, Glantz A, Keppeler H, et al. Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene. Gut 2007; 56:265.
  21. Bacq Y, Gendrot C, Perrotin F, et al. ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy. J Med Genet 2009; 46:711.
  22. Dixon PH, Williamson C. The pathophysiology of intrahepatic cholestasis of pregnancy. Clin Res Hepatol Gastroenterol 2016; 40:141.
  23. Keitel V, Vogt C, Häussinger D, Kubitz R. Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy. Gastroenterology 2006; 131:624.
  24. Van Mil SW, Milona A, Dixon PH, et al. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology 2007; 133:507.
  25. Sookoian S, Castaño G, Burgueño A, et al. Association of the multidrug-resistance-associated protein gene (ABCC2) variants with intrahepatic cholestasis of pregnancy. J Hepatol 2008; 48:125.
  26. Wånggren K, Sparre LS, Wramsby H. Severe jaundice in early IVF pregnancy. Eur J Obstet Gynecol Reprod Biol 2004; 112:228.
  27. Mutlu MF, Aslan K, Guler I, et al. Two cases of first onset intrahepatic cholestasis of pregnancy associated with moderate ovarian hyperstimulation syndrome after IVF treatment and review of the literature. J Obstet Gynaecol 2017; 37:547.
  28. Meng LJ, Reyes H, Palma J, et al. Effects of ursodeoxycholic acid on conjugated bile acids and progesterone metabolites in serum and urine of patients with intrahepatic cholestasis of pregnancy. J Hepatol 1997; 27:1029.
  29. Abu-Hayyeh S, Ovadia C, Lieu T, et al. Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum. Hepatology 2016; 63:1287.
  30. Davies MH, Ngong JM, Yucesoy M, et al. The adverse influence of pregnancy upon sulphation: a clue to the pathogenesis of intrahepatic cholestasis of pregnancy? J Hepatol 1994; 21:1127.
  31. Bacq Y, Sapey T, Bréchot MC, et al. Intrahepatic cholestasis of pregnancy: a French prospective study. Hepatology 1997; 26:358.
  32. Pařízek A, Dušková M, Vítek L, et al. The role of steroid hormones in the development of intrahepatic cholestasis of pregnancy. Physiol Res 2015; 64 Suppl 2:S203.
  33. Marschall HU, Wikström Shemer E, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study. Hepatology 2013; 58:1385.
  34. Ropponen A, Sund R, Riikonen S, et al. Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: a population-based study. Hepatology 2006; 43:723.
  35. Leevy CB, Koneru B, Klein KM. Recurrent familial prolonged intrahepatic cholestasis of pregnancy associated with chronic liver disease. Gastroenterology 1997; 113:966.
  36. Turunen K, Mölsä A, Helander K, et al. Health history after intrahepatic cholestasis of pregnancy. Acta Obstet Gynecol Scand 2012; 91:679.
  37. Hubschmann AG, Orzechowski KM, Berghella V. Severe First Trimester Recurrent Intrahepatic Cholestasis of Pregnancy: A Case Report and Literature Review. AJP Rep 2016; 6:e38.
  38. Kondrackiene J, Kupcinskas L. Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems. World J Gastroenterol 2008; 14:5781.
  39. Kenyon AP, Piercy CN, Girling J, et al. Obstetric cholestasis, outcome with active management: a series of 70 cases. BJOG 2002; 109:282.
  40. Heikkinen J, Mäentausta O, Ylöstalo P, Jänne O. Changes in serum bile acid concentrations during normal pregnancy, in patients with intrahepatic cholestasis of pregnancy and in pregnant women with itching. Br J Obstet Gynaecol 1981; 88:240.
  41. Lunzer M, Barnes P, Byth K, O'Halloran M. Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis. Gastroenterology 1986; 91:825.
  42. Brites D, Rodrigues CM, Oliveira N, et al. Correction of maternal serum bile acid profile during ursodeoxycholic acid therapy in cholestasis of pregnancy. J Hepatol 1998; 28:91.
  43. Huang WM, Gowda M, Donnelly JG. Bile acid ratio in diagnosis of intrahepatic cholestasis of pregnancy. Am J Perinatol 2009; 26:291.
  44. Furrer R, Winter K, Schäffer L, et al. Postpartum Blood Loss in Women Treated for Intrahepatic Cholestasis of Pregnancy. Obstet Gynecol 2016; 128:1048.
  45. Rolfes DB, Ishak KG. Liver disease in pregnancy. Histopathology 1986; 10:555.
  46. Manzotti C, Casazza G, Stimac T, et al. Total serum bile acids or serum bile acid profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy (Protocol). Cochrane Database Syst Rev 2017; :CD012546.
  47. 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; 3:25.
  48. Atabey S, Duvan CI, Eren U, Turhan NO. Intrahepatic cholestasis and eclampsia: a case report. Hypertens Pregnancy 2007; 26:363.
  49. Raz Y, Lavie A, Vered Y, et al. Severe intrahepatic cholestasis of pregnancy is a risk factor for preeclampsia in singleton and twin pregnancies. Am J Obstet Gynecol 2015; 213:395.e1.
  50. Marathe JA, Lim WH, Metz MP, et al. A retrospective cohort review of intrahepatic cholestasis of pregnancy in a South Australian population. Eur J Obstet Gynecol Reprod Biol 2017; 218:33.
  51. Vanjak D, Moreau R, Roche-Sicot J, et al. Intrahepatic cholestasis of pregnancy and acute fatty liver of pregnancy. An unusual but favorable association? Gastroenterology 1991; 100:1123.
  52. Rioseco AJ, Ivankovic MB, Manzur A, et al. Intrahepatic cholestasis of pregnancy: a retrospective case-control study of perinatal outcome. Am J Obstet Gynecol 1994; 170:890.
  53. 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.
  54. Zecca E, De Luca D, Baroni S, et al. Bile acid-induced lung injury in newborn infants: a bronchoalveolar lavage fluid study. Pediatrics 2008; 121:e146.
  55. Zecca E, De Luca D, Marras M, et al. Intrahepatic cholestasis of pregnancy and neonatal respiratory distress syndrome. Pediatrics 2006; 117:1669.
  56. Williamson C, Hems LM, Goulis DG, et al. Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. BJOG 2004; 111:676.
  57. 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.
  58. Estiú MC, Frailuna MA, Otero C, et al. Relationship between early onset severe intrahepatic cholestasis of pregnancy and higher risk of meconium-stained fluid. PLoS One 2017; 12:e0176504.
  59. Henderson CE, Shah RR, Gottimukkala S, et al. Primum non nocere: how active management became modus operandi for intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2014; 211:189.
  60. 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. Sepúlveda WH, González C, Cruz MA, Rudolph MI. Vasoconstrictive effect of bile acids on isolated human placental chorionic veins. Eur J Obstet Gynecol Reprod Biol 1991; 42:211.
  62. 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.
  63. 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; 65:581.
  64. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology 2004; 40:467.
  65. Laatikainen T, Tulenheimo A. Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy. Int J Gynaecol Obstet 1984; 22:91.
  66. Oztekin D, Aydal I, Oztekin O, et al. Predicting fetal asphyxia in intrahepatic cholestasis of pregnancy. Arch Gynecol Obstet 2009; 280:975.
  67. Ambros-Rudolph CM, Glatz M, Trauner M, et al. The importance of serum bile acid level analysis and treatment with ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a case series from central Europe. Arch Dermatol 2007; 143:757.
  68. 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.
  69. 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.
  70. Cui D, Zhong Y, Zhang L, Du H. Bile acid levels and risk of adverse perinatal outcomes in intrahepatic cholestasis of pregnancy: A meta-analysis. J Obstet Gynaecol Res 2017; 43:1411.
  71. Sentilhes L, Verspyck E, Pia P, Marpeau L. Fetal death in a patient with intrahepatic cholestasis of pregnancy. Obstet Gynecol 2006; 107:458.
  72. Lee RH, Incerpi MH, Miller DA, et al. Sudden fetal death in intrahepatic cholestasis of pregnancy. Obstet Gynecol 2009; 113:528.
  73. Egerman RS, Riely CA. Predicting fetal outcome in intrahepatic cholestasis of pregnancy: is the bile acid level sufficient? Hepatology 2004; 40:287.
  74. Kremer AE, Oude Elferink RP, Beuers U. Pathophysiology and current management of pruritus in liver disease. Clin Res Hepatol Gastroenterol 2011; 35:89.
  75. 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.
  76. Gurung V, Middleton P, Milan SJ, et al. Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev 2013; :CD000493.
  77. 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:e4949.
  78. Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol 2014; 124:120.
  79. Zapata R, Sandoval L, Palma J, et al. Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy. A 12-year experience. Liver Int 2005; 25:548.
  80. Ozkan S, Ceylan Y, Ozkan OV, Yildirim S. Review of a challenging clinical issue: Intrahepatic cholestasis of pregnancy. World J Gastroenterol 2015; 21:7134.
  81. 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.
  82. Mela M, Mancuso A, Burroughs AK. Review article: pruritus in cholestatic and other liver diseases. Aliment Pharmacol Ther 2003; 17:857.
  83. Glantz A, Marschall HU, Lammert F, Mattsson LA. Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid. Hepatology 2005; 42:1399.
  84. Fisk NM, Storey GN. Fetal outcome in obstetric cholestasis. Br J Obstet Gynaecol 1988; 95:1137.
  85. Alsulyman OM, Ouzounian JG, Ames-Castro M, Goodwin TM. Intrahepatic cholestasis of pregnancy: perinatal outcome associated with expectant management. Am J Obstet Gynecol 1996; 175:957.
  86. Laatikainen T. Effect of cholestyramine and phenobarbital on pruritus and serum bile acid levels in cholestasis of pregnancy. Am J Obstet Gynecol 1978; 132:501.
  87. Saleh MM, Abdo KR. Consensus on the management of obstetric cholestasis: National UK survey. BJOG 2007; 114:99.
  88. Matos A, Bernardes J, Ayres-de-Campos D, Patrício B. Antepartum fetal cerebral hemorrhage not predicted by current surveillance methods in cholestasis of pregnancy. Obstet Gynecol 1997; 89:803.
  89. Puljic A, Kim E, 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.
  90. Rook M, Vargas J, Caughey A, et al. Fetal outcomes in pregnancies complicated by intrahepatic cholestasis of pregnancy in a Northern California cohort. PLoS One 2012; 7:e28343.
  91. Obstetric Cholestasis (Green-top Guideline No. 43) https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg43/.
  92. https://www.smfm.org/publications/96-understanding-intrahepatic-cholestasis-of-pregnancy (Accessed on October 19, 2017).
  93. Roncaglia N, Arreghini A, Locatelli A, et al. Obstetric cholestasis: outcome with active management. Eur J Obstet Gynecol Reprod Biol 2002; 100:167.
  94. Fisk NM, Bye WB, Storey GN. Maternal features of obstetric cholestasis: 20 years experience at King George V Hospital. Aust N Z J Obstet Gynaecol 1988; 28:172.
  95. Maldonado M, Alhousseini A, Awadalla M, et al. Intrahepatic Cholestasis of Pregnancy Leading to Severe Vitamin K Deficiency and Coagulopathy. Case Rep Obstet Gynecol 2017; 2017:5646247.
  96. DeLeon A, De Oliveira GS, Kalayil M, et al. The incidence of coagulopathy in pregnant patients with intrahepatic cholestasis: should we delay or avoid neuraxial analgesia? J Clin Anesth 2014; 26:623.
  97. https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?./temp/~oV4054:1 (Accessed on August 16, 2017).
  98. Hirvioja ML, Kivinen S. Inheritance of intrahepatic cholestasis of pregnancy in one kindred. Clin Genet 1993; 43:315.
  99. Wikström Shemer EA, Stephansson O, Thuresson M, et al. Intrahepatic cholestasis of pregnancy and cancer, immune-mediated and cardiovascular diseases: A population-based cohort study. J Hepatol 2015; 63:456.
  100. Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016; 65:1.