Intrahepatic cholestasis of pregnancy
- Keith D Lindor, MD
Keith D Lindor, MD
- Section Editor — Alcoholic and Metabolic Liver Disease
- Professor of Medicine, Mayo Clinic College of Medicine
- Dean, College of Health Solutions
- Arizona State University
- Richard H Lee, MD
Richard H Lee, MD
- Assistant Professor of Clinical Obstetrics and Gynecology
- Division of Maternal Fetal Medicine
- Keck School of Medicine of the University of Southern California
- Section Editors
- Charles J Lockwood, MD, MHCM
Charles J Lockwood, MD, MHCM
- Section Editor — Obstetrics
- Senior Vice President, USF Health
- Dean, Morsani College of Medicine
- Professor, Obstetrics and Gynecology
- University of South Florida
- Sanjiv Chopra, MD, MACP
Sanjiv Chopra, MD, MACP
- Editor-in-Chief — Gastroenterology/Hepatology
- Section Editor — General Hepatology; Gallbladder and Biliary Tract Disease
- Professor of Medicine
- Harvard Medical School
- Senior Consultant in Hepatology
- James Tullis Firm Chief
- Beth Israel Deaconess Medical Center
- Deputy Editors
- Kristen M Robson, MD, MBA, FACG
Kristen M Robson, MD, MBA, FACG
- Assistant Professor
- Tufts University School of Medicine
- Vanessa A Barss, MD, FACOG
Vanessa A Barss, MD, FACOG
- Senior Deputy Editor — UpToDate
- Deputy Editor — Obstetrics, Gynecology and Women's Health
- Associate Clinical Professor of Obstetrics, Gynecology and Reproductive Biology
- Harvard Medical School
Intrahepatic cholestasis of pregnancy (ICP) occurs in the second and third trimester and is characterized by pruritus and an elevation in serum bile acid concentrations. The major clinical features, diagnosis, and treatment of intrahepatic cholestasis of pregnancy 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".)
The incidence of ICP has varied widely in various reports (ranging from 0.1 to 15.6 percent) for reasons that are incompletely understood . Geographic variations in the rates of the disease may reflect differences in susceptibility between ethnic groups. The incidence of ICP is increased in Bolivia and is highest among the Araucanos Indians in Chile . A study from Sweden that included 1.2 million births between 1997 and 2009 estimated the incidence to be 0.5 percent of all deliveries . In reports from the United States, the incidence rates have varied from 0.32 percent in Bridgeport Hospital, Connecticut , to 5.6 percent in a primarily Latina population in Los Angeles . For unknown reasons, the disease is seen more commonly in the colder months in Chile and Scandinavia.
The cause of ICP is unknown, but genetic, hormonal, and environmental factors are likely involved . Environmental factors may also influence the expression of the disease.
Genetics — Genetic factors could explain familial cases and the higher incidence in some ethnic groups. The ABCB4 (adenosine triphosphate-binding cassette, subfamily B, member 4) gene encoding the multidrug resistance 3 (MDR3) protein (a canalicular phospholipid translocator) is primarily involved in a subtype of progressive familial intrahepatic cholestasis called PFIC3 . Heterozygous mutations in this gene have been found in a large consanguineous family in whom some women had episodes of cholestasis during pregnancy [8,9]. Several heterozygous mutations in the MDR3 (ABCB4) gene were subsequently reported in patients with ICP [10-15]. The prevalence of such ABCB4 gene mutations in Caucasian patients suffering from ICP is 16 percent .
However, the genetic basis of ICP is complex, and some genes encoding for other canalicular transporters or their regulator may potentially be involved in its pathogenesis [17-19].
- Bacq Y. Intrahepatic cholestasis of pregnancy. Clin Liver Dis 1999; 3:1.
- Reyes H, Gonzalez MC, Ribalta J, et al. Prevalence of intrahepatic cholestasis of pregnancy in Chile. Ann Intern Med 1978; 88:487.
- 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.
- 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.
- 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.
- Arrese M, Macias RI, Briz O, et al. Molecular pathogenesis of intrahepatic cholestasis of pregnancy. Expert Rev Mol Med 2008; 10:e9.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Floreani A, Carderi I, Paternoster D, et al. Intrahepatic cholestasis of pregnancy: three novel MDR3 gene mutations. Aliment Pharmacol Ther 2006; 23:1649.
- 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.
- 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.
- Keitel V, Vogt C, Häussinger D, Kubitz R. Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy. Gastroenterology 2006; 131:624.
- 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.
- 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.
- Reyes H, Simon FR. Intrahepatic cholestasis of pregnancy: an estrogen-related disease. Semin Liver Dis 1993; 13:289.
- Gonzalez MC, Reyes H, Arrese M, et al. Intrahepatic cholestasis of pregnancy in twin pregnancies. J Hepatol 1989; 9:84.
- 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.
- Bacq Y, Sapey T, Bréchot MC, et al. Intrahepatic cholestasis of pregnancy: a French prospective study. Hepatology 1997; 26:358.
- Wånggren K, Sparre LS, Wramsby H. Severe jaundice in early IVF pregnancy. Eur J Obstet Gynecol Reprod Biol 2004; 112:228.
- Kenyon AP, Piercy CN, Girling J, et al. Obstetric cholestasis, outcome with active management: a series of 70 cases. BJOG 2002; 109:282.
- 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.
- 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.
- 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.
- Huang WM, Gowda M, Donnelly JG. Bile acid ratio in diagnosis of intrahepatic cholestasis of pregnancy. Am J Perinatol 2009; 26:291.
- Atabey S, Duvan CI, Eren U, Turhan NO. Intrahepatic cholestasis and eclampsia: a case report. Hypertens Pregnancy 2007; 26:363.
- 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.
- 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.
- Rolfes DB, Ishak KG. Liver disease in pregnancy. Histopathology 1986; 10:555.
- Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis 2007; 2:26.
- 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.
- Gurung V, Middleton P, Milan SJ, et al. Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev 2013; :CD000493.
- 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.
- Rodrigues CM, Marín JJ, Brites D. Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid treatment. Gut 1999; 45:446.
- Serrano MA, Brites D, Larena MG, et al. Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta. J Hepatol 1998; 28:829.
- Mazzella G, Rizzo N, Azzaroli F, et al. Ursodeoxycholic acid administration in patients with cholestasis of pregnancy: effects on primary bile acids in babies and mothers. Hepatology 2001; 33:504.
- Ribalta J, Reyes H, Gonzalez MC, et al. S-adenosyl-L-methionine in the treatment of patients with intrahepatic cholestasis of pregnancy: a randomized, double-blind, placebo-controlled study with negative results. Hepatology 1991; 13:1084.
- Frezza M, Pozzato G, Chiesa L, et al. Reversal of intrahepatic cholestasis of pregnancy in women after high dose S-adenosyl-L-methionine administration. Hepatology 1984; 4:274.
- Floreani A, Paternoster D, Melis A, Grella PV. S-adenosylmethionine versus ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy: preliminary results of a controlled trial. Eur J Obstet Gynecol Reprod Biol 1996; 67:109.
- Palma J, Reyes H, Ribalta J, et al. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo. J Hepatol 1997; 27:1022.
- 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.
- 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.
- Hirvioja ML, Tuimala R, Vuori J. The treatment of intrahepatic cholestasis of pregnancy by dexamethasone. Br J Obstet Gynaecol 1992; 99:109.
- Kretowicz E, McIntyre HD. Intrahepatic cholestasis of pregnancy, worsening after dexamethasone. Aust N Z J Obstet Gynaecol 1994; 34:211.
- 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.
- Furrer R, Winter K, Schäffer L, et al. Postpartum Blood Loss in Women Treated for Intrahepatic Cholestasis of Pregnancy. Obstet Gynecol 2016; 128:1048.
- 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.
- Hirvioja ML, Kivinen S. Inheritance of intrahepatic cholestasis of pregnancy in one kindred. Clin Genet 1993; 43:315.
- 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.
- Leevy CB, Koneru B, Klein KM. Recurrent familial prolonged intrahepatic cholestasis of pregnancy associated with chronic liver disease. Gastroenterology 1997; 113:966.
- Turunen K, Mölsä A, Helander K, et al. Health history after intrahepatic cholestasis of pregnancy. Acta Obstet Gynecol Scand 2012; 91:679.
- 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.
- Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016; 65:1.
- 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.
- 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.
- Zecca E, De Luca D, Marras M, et al. Intrahepatic cholestasis of pregnancy and neonatal respiratory distress syndrome. Pediatrics 2006; 117:1669.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Heinonen S, Kirkinen P. Pregnancy outcome with intrahepatic cholestasis. Obstet Gynecol 1999; 94:189.
- 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.
- Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology 2004; 40:467.
- Laatikainen T, Tulenheimo A. Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy. Int J Gynaecol Obstet 1984; 22:91.
- Oztekin D, Aydal I, Oztekin O, et al. Predicting fetal asphyxia in intrahepatic cholestasis of pregnancy. Arch Gynecol Obstet 2009; 280:975.
- 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.
- 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.
- 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.
- Sentilhes L, Verspyck E, Pia P, Marpeau L. Fetal death in a patient with intrahepatic cholestasis of pregnancy. Obstet Gynecol 2006; 107:458.
- Lee RH, Incerpi MH, Miller DA, et al. Sudden fetal death in intrahepatic cholestasis of pregnancy. Obstet Gynecol 2009; 113:528.
- Egerman RS, Riely CA. Predicting fetal outcome in intrahepatic cholestasis of pregnancy: is the bile acid level sufficient? Hepatology 2004; 40:287.
- Fisk NM, Storey GN. Fetal outcome in obstetric cholestasis. Br J Obstet Gynaecol 1988; 95:1137.
- 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.
- Saleh MM, Abdo KR. Consensus on the management of obstetric cholestasis: National UK survey. BJOG 2007; 114:99.
- 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.
- 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.
- Chappell LC, Gurung V, Seed PT, et al. Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial. BMJ 2012; 344:e3799.
- Linder N, Hiersch L, Fridman E, et al. The effect of gestational age on neonatal outcome in low-risk singleton term deliveries. J Matern Fetal Neonatal Med 2015; 28:297.
- 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.
- Estrogens and progesterone
- Environmental factors
- CLINICAL MANIFESTATIONS
- Laboratory findings
- Differential diagnosis
- Ursodeoxycholic acid
- Other drugs
- Complications of cholestasis
- MATERNAL FOLLOW-UP AND OUTCOME
- Recurrence in subsequent pregnancies
- Underlying liver disease
- Association with other disorders
- Hormonal contraception
- - Estrogen-progestin
- - Progestin-only
- FETAL FOLLOW-UP AND OUTCOME
- Morbidity and mortality
- Predictive value of maternal bile acid level
- Antepartum testing
- TIMING OF DELIVERY
- SUMMARY AND RECOMMENDATIONS