ICP Overview for Healthcare Professionals
ICP Overview for providers

Overview of Intrahepatic Cholestasis of Pregnancy (ICP)

Intrahepatic Cholestasis of Pregnancy (ICP) is a pregnancy-specific liver disorder in which bile transport through the liver is altered leading to elevated serum bile acids. The hallmark symptom is pruritus. Classically, pruritus involves the palms and the soles but in many women itching is severe and generalized, and some do not experience itching on the palms or soles. The majority of cases occur in the second and third trimesters, but there have been cases reported in the literature as early as five weeks.1 This diagnosis should be considered even in patients with itching in the first trimester.

Primary Symptom

Pruritus

Moderate to severe pruritus is the hallmark symptom of ICP, and in most cases is the only symptom reported. The most common presentation is pruritus which is worse on the hands and feet and becomes more intense at night. In many women, the pruritis becomes generalized, or occurs in locations other than hands and feet. In most cases cholestasis is not associated with a rash, but excoriations can occur with severe itching.

Severity of pruritus does not correlate with severity of the disease and may precede any abnormal laboratory findings.2 Lysophosphatidic acid is increased as a result of increased autotaxin activity in patients with ICP and may be a mediator of pruritus as it correlates well with the intensity of pruritus.3

Other Symptoms

  • RUQ Pain with or without the presence of gallstones or sludge.4 One study found that 13% of women with ICP have gallstones concurrently.5 Reasons for RUQ pain are as yet unclear.
  • Pale stool and/or steatorrhea6
  • Dark urine7
  • Fatigue/malaise7
  • Nausea/lack of appetite7
  • Mild depression

Etiology

The etiology of ICP is complex and not fully understood. Several factors are known or suspected to contribute.

Genetics

Several genes have been identified which appear to contribute to ICP. Many of the genes contribute to the functionality of the bile salt export protein (BSEP). Heterozygosity for all known mutations puts the patient at risk of developing ICP.8,9,10 However, not all heterozygous women will develop ICP, so in practice some forms appear to follow a dominant mode of inheritance, where others appear to follow a recessive mode of inheritance. Multiple mutations may cause a more severe form of the disorder,11 and first trimester onset may be associated with a specific mutation.12

Hormonal influences

It has generally been assumed that elevated levels of estrogen is responsible for contributing to ICP.13,14 However, more recent investigations have found that progesterone may be as much at fault.15,16,17 The role of hormones is also supported by the observation that assisted reproductive technology and multifetal pregnancies increase the risk of developing ICP.15,18,19

Prior Liver Disorders

Cholestasis risk is increased in patients with other liver disorders such as Hepatitis C and autoimmune hepatitis.20 In severe or early onset cases, evaluation by a hepatologist may be considered to determine if there is an underlying cause for cholestasis.

Exogenous factors

Insufficient selenium intake and pregnancy during winter months has been associated with higher rates of ICP in some populations.21 In these populations, improved nutrition has been accompanied by a decrease of ICP incidence in winter months, though no causal relationship has been established. Patients with ICP have higher rates of drug-induced cholestasis.22

Diagnosis

Total bile acids (TBA)/Serum bile acids

TBA over 10 μmol/L indicates ICP.23,24 Pruritis may precede any abnormal laboratory findings.2 Normal bile acids do not rule out a diagnosis of ICP. If symptoms persist, TBA should be repeated for diagnosis.

  • Of note, many of the bile acid tests will have a reference range that is not a pregnancy reference range. The level of 10 μmol/L can be used even on tests with a different reference range as this level for diagnosis has been confirmed in studies comparing the level of bile acid elevation between a cholestasis pregnancy and a non-cholestasis pregnancy
  • There are fractionated bile acid tests on the market that have been validated for diagnosis at a lower reference range (usually either 6.8 or 8.6). These tests are not necessary for diagnosis and a total bile acid test can be used.24
  • Fasting is not recommended for bile acid testing.24 Recent studies have shown that many patient would have a missed diagnosis had testing been performed fasting.25

Hepatic panel

Transaminases are elevated in approximately 60% of cases and may provide more timely results.24 ALT is considered the most sensitive of the transaminases for diagnosis of ICP, followed by AST.26 Bilirubin and GGT are normal in most patients.7 However, normal liver function tests do not rule out cholestasis.

Maternal Effects

The main maternal effect of cholestasis is pruritus which can be severe and debilitating. Cholestasis is also linked with an increased risk of gestational diabetes and pre-eclampsia.27,28,29

Prior studies had shown an increased risk of maternal hemorrhage at the time of delivery.30 However recent observations in treated populations have shown that coagulopathy is rare in this group.7,31

Fetal Effects

Preterm labor and delivery

The prevalence of spontaneous preterm delivery may be as high as 20-40% without active management but appears to be reduced with active management.27,30,32,33,34,35,36 The risk of preterm labor has been shown in some studies to be increased when ICP presents prior to the 30th week of gestation,37 and in patients with severe ICP (defined as >40 μmol/L TBA),38 and further increased when TBA exceeds 100 μmol/L.39 The increased incidence of preterm labor may be due, at least in part, to increased sensitivity to oxytocin as a result of exposure to bile acids.40

Meconium staining of the amniotic fluids (MSAF)

At 37 weeks gestation the incidence of MSAF is significantly higher than controls at the same gestational age (17.9 as compared to 2.9%).41 Higher TBA is associated with greater risk of MSAF and appears to increase linearly.36,38,42

Respiratory distress syndrome (RDS) and asphyxial events

RDS and asphyxial events are more common in ICP when adjusted for gestational age.37,38,43,44,45,46 Major predictors for risk are gestational age at diagnosis and total bile acid levels. These risks are present even in the presence of documented pulmonary maturity.37,47,48 Bile acids may enter the lungs, interfering with surfactant in a process sometimes termed bile acid pneumonia.49,50 Increased bile acids may also induce an inflammatory response in lung tissues.51

Fetal distress/CTG abnormalities

Fetal distress is common in cases of ICP (21-44%) and does not appear to correlate well with TBA in most studies.32,33,35,37,52,53,54,55 Arrhythmias most commonly include decelerations, tachycardia, and bradycardia.

Stillbirth (Intrauterine fetal demise/IUFD)

Stillbirth is the most troubling of the potential complications of ICP. The mechanisms by which it occurs are not fully understood. The main theories are either a development of a fetal arrhythmia or vasospasm of the placental vessels due to the elevated bile acids.24 It is known that stillbirth can occur without warning and cannot always be predicted with fetal surveillance.56,57,58,59 In one case study, IUFD occurred in the midst of reassuring monitoring.56

A recent meta-analysis by Ovadia et al in 2019 was better able to quantify the risk of stillbirth dependent on bile acid levels.60 It has been established in prior studies that increasing bile acid levels lead to an increase in stillbirth risk. In the meta-analysis, the risk of stillbirth was 0.13% with bile acids under 40 μmol/L, 0.28% with bile acids 40-99 μmol/L and 3.44% with bile acids over 100 μmol/L. 25.3% of women with bile acids under 100 delivered preterm, and about 63% before 38 weeks. The authors note that no conclusions on risk can be made past 39 weeks of gestation as too few participants remained pregnant. It is known there is a dramatic increase in stillbirth for bile acids over 100, therefore these pregnancies need more aggressive management. Overall, the results were reassuring for lower bile acids acknowledging that most were delivered by 38 weeks.

Management

Medication

Ursodeoxycholic acid (UDCA) is considered the first line treatment for ICP as indicated by SMFM.24 Dosing should start at 10-15 mg/kg per day in divided doses. The medication can be increased up to 21 mg/kg per day if bile acid levels are not controlled on lower doses or maternal pruritus is not improved.24 A prior meta-analysis has shown that UDCA is superior to other medications at relieving maternal symptoms, and improves laboratory parameters.33,61,62

There is less evidence that UDCA improves fetal outcomes. There are several laboratory investigations which provide insights into ways in which UDCA may confer benefits to the fetus. UDCA appears to protect fetal heart cells from the changes which can be induced by bile acids,63 prevents changes to the placenta which may be induced by bile acids,64,65 and corrects the placenta’s ability to transport bile acids away from the fetus, at least in part via upregulation of breast cancer resistant protein (BCRP).66,67,68 UDCA also upregulates placental expression of ABCG2 which may protect the fetus from detrimental effects of bile acids and progesterone metabolites.69

A recent randomized, placebo-controlled trial of the use of Ursodiol did not find a difference of a composite outcome of perinatal death, preterm delivery or NICU admission with the treatment.70 This study was not able to be powered to detect solely a reduction in stillbirth rates. These findings make the true fetal benefit of this medication less clear.24

A more recent meta-analysis published in 2021 looked at the RCT data in conjunction with other studies in the literature and was able to show that the use of ursodeoxycholic acid reduced spontaneous preterm birth in singleton pregnancies. This study was not able to be powered to detect the effects of the medication solely on stillbirth due to its rare occurrence and so it can not be concluded that Ursodiol is able to reduce stillbirth.86 Ursodiol has been proven to be safe in pregnancy33,62 and given that it might have benefit, it is still recommended for use by SMFM.24

Other medications have been studied for use in cholestasis pregnancies. Rifampin and S-Adenosyl-L-methionine (SAMe) have been studied as treatments for cholestasis and can be considered in addition to ursodeoxycholic acid treatment in refractory cases.71,72  Cholestyramine is no longer recommended for use in ICP as it has no effect on maternal biochemical abnormalities and has limited effectiveness in relieving maternal symptoms. 52,73

Elective early delivery

Stillbirths in a cholestasis pregnancy tend to cluster between 37-39 weeks of gestation and early delivery has been recommended to decrease the risk of stillbirth.74,75

The two governing boards (Society for Maternal Fetal Medicine and American College of Obstetrics and Gynecology) in the United States agree on the following recommendations.24,76

  • Bile acids over 100 μmol/L: Delivery at 36 0/7 weeks; Delivery prior to 36 weeks (34-36 weeks) may occur with unremitting maternal pruritus, a prior history of a stillbirth before 36 weeks gestation due to ICP or preexisting or acute hepatic disease with worsening liver function.
  • Bile acids 40-99 μmol/L : Delivery at 36 0/7-39 0/7 weeks with delivery in the EARLIER portion of the window
  • Bile acids less than 40μmol/L : Delivery 36 0/7-39 0/7 weeks

The changes in the SMFM guidelines are largely based on the article by Ovadia et al.60 Prior studies had determined that an optimal delivery strategy was delivery between 36-37 weeks.77,78 The new delivery windows allows for a less aggressive approach to pregnancies with mild elevations in bile acids as the meta-analysis clarified that the majority of the stillbirth risk occurs in pregnancies with levels over 100 μmol/L. However, it must be noted that many of the pregnancies in the Ovadia meta-analysis were delivered early and SMFM acknowledges that this might have mitigated some of the stillbirth risk.24 A conversation between provider and patient should discuss the risks and benefits to decisions on delivery timing.

In 2017, a US-based retrospective cohort study examined severe ICP pregnancies (defined as BA over 40 μmol/L). Delivery at 36-37 weeks was the optimal strategy for this group, and did not adversely affect other maternal or neonatal outcomes. This supports delivery in the earlier portion of the window for women with bile acids greater than 40 μmol/L.79

For a more detailed discussion of how delivery recommendations have been developed based on the research and literature, please see delivery timing page.

Monitoring Bile Acids

Most US labs have a turn around time of 4-7 days for bile acids, which makes it difficult to base management decisions solely based upon bile acid levels. SMFM recommends following bile acids throughout the pregnancy, especially for determination of delivery timing.24 They do not recommend weekly bile acid tests but do recommend testing frequently enough to formulate a delivery plan. Also, ursodeoxycholic acid doses can be adjusted based on bile acid levels.

Fetal surveillance

Stillbirths in a cholestasis pregnancy are thought to be an acute event and fetal surveillance has not been shown to prevent stillbirth.56,57,58,59 However, surveillance can possibly detect fetal distress in cases of ICP, in which cases timely intervention can occur.24,80

SMFM endorses antepartum surveillance starting at a reasonable timeframe when delivery would be considered.24 There is no set schedule or recommendations for what this testing should entail.

Betamethasone

Betamethasone administration is recommended for any pregnancies with planned delivery prior to 37 weeks gestation by SMFM.24 It is a well-documented risk that babies with cholestasis have a higher risk of RDS compared to matched gestational age infants.

Follow Up Care

In most cases, symptoms will disappear within 48 hours of delivery.  Follow up testing is recommended for all patients at 3-6 months postpartum with a CMP and possibly a bile acid level.81 If laboratory parameters do not return to normal within 6 months, referral to hepatology should be pursued to determine if there is an underlying condition which may have contributed to the development of ICP.82

There is minimal risk for long term maternal effects from ICP. Recently it has been suggested that women who suffered from ICP may be at a slightly increased risk for developing biliary tree cancer, diabetes, and autoimmune diseases.83 The risk of cancer is thought to be a consequence of the relationship between cholelithiasis and the development of ICP and not a process of ICP itself. A large study found that long term liver-related diseases were rare, with the exception of cholelithiasis and cholecystitis.82

One study examined 18 female and 27 male children of women who were affected by ICP in their pregnancies. In this study a small but significant risk of metabolic disorders such as increased hip girth or diabetes was found. The pregnancies in this study received neither medication nor active management.84 However two larger studies examining 187 women95 and 138 men born to women who were affected by ICP failed to find any impact on the long term health of the offspring.85

Healthcare Professional Brochure Printable PDF

Resource for ICP familiesMaternal 911 online multi-module course designed to provide updated education to all health care providers working at the bedside of a pregnant woman. Continuing Medical Education credits will be awarded upon successful completion of the modules and simulation drills from Michigan State University College of Human Medicine.

References
  1. Wongjarupong N, Bharmal S, Lim N. Never Too Soon: An Unusual Case of Intrahepatic Cholestasis of Pregnancy at Five Weeks Gestation. Cureus. 2020 Sep 19;12(9):e10540. doi: 10.7759/cureus.10540. PMID: 33094079; PMCID: PMC7574978.
  2. Kenyon et al. Pruritus may precede abnormal liver function tests in pregnant women with obstetric cholestasis: a longitudinal analysis. Br J Obstet Gynaec 2001;108:1190-1192.
  3. Kremer AE, Martens JJWW, Kulik W, et al: Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroeneterology 2010;139:1008-1018.
  4. Pusl T, Beuers U: Intrahepatic cholestasis of pregnancy. Orphanet J Rare Diseases 2007;2:26.
  5. Williamson et al: Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. Br J Obstet Gynecol 2004;111:676-681.
  6. Reyes et al. Steatorrhea in patients with intrahepatic cholestasis of pregnancy. Gastroenterology 1987;93:584-590.
  7. Geenes V, Williamson C: Intrahepatic Cholestasis of pregnancy. World J Gastro 2009;15:2049- 2066.
  8. Hirvioja ML, Kivinen S: Inheritance of intrahepatic cholestasis of pregnancy in one kindred. Clinical Genetics 1993;43:315-317.
  9. 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 Gastro 2014;109:76-84.
  10. Savander M, Rapponen A, Avela K, et al: Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy. Gut 2003;52:1025-1029.
  11. Keitel V, Vogt C, Haussinger D, Kubitz R: Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy. Gastroenterology 2006;131:624-629.
  12. Johnston RC, Stephenson ML, Nageotte MP: Novel heterozygous ABCB4 gene mutation causing recurrent first-trimester intrahepatic cholestasis of pregnancy. J Perinat 2014;34:711-712.
  13. Reyes H: Sex hormones and bile acids in intrahepatic cholestasis of pregnancy. Hepatology 2008;47:376-378.
  14. Steiger B, Fattinger K, Madon J, et al: Drug- and Estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 2000;118:422-430.
  15. Bacq Y, Sapey T, Brechot MC, et al: Intrahepatic cholestasis of pregnancy: a French prospective study. Hepatology 1997;26:358-364.
  16. Bacq Y, Myara A, Brechot MC, et al: Serum conjugated bile acid profile during intrahepatic cholestasis of pregnancy. Journal of Hepatology 1995;22:66-70.
  17. 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, 2015;doi:10.1002/hep.28265
  18. Pacella G, Salsi G, Archangeli T, et al: The impact of assisted reproductive technology and chorionicity in twin pregnancies complicated by obstetric cholestasis. J Matern Fetal Neonatal Med, 2015; doi:10.3109/14767058.2015.1051954.
  19. Gonzalez MC, Reyes J, Arrese M, et al: Intrahepatic cholestasis of pregnancy in twin pregnancies. J Hepatology 1989;9:84-90.
  20. Marschall HU, Wikström Shemer E, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study. Hepatology. 2013 Oct;58(4):1385-91. doi: 10.1002/hep.26444. Epub 2013 Aug 6. PMID: 23564560.
  21. Reyes H, Maez ME, Gonzalez MC, et al: Selenium, zinc and copper plasma levels in intrahepatic cholestasis of pregnancy, in normal pregnancies and in healthy individuals, in Chile. J Hepatology 2000;32:542-549.
  22. Johnston WG, Baskett TF: Obstetric Cholestasis. A 14 year review. Am J Obstet Gynecol. 1979;133:299-301.
  23.  Lee RH, Ouzounian JG, Goodwin TM, et al: Bile acid concentration reference ranges in a pregnant Latina population. Am J Perinatology 2013;30(5):389-393.
  24. Society for Maternal-Fetal Medicine (SMFM), Lee RH, Pettker CM. Society for Maternal-Fetal Medicine (SMFM) Consult Series #53: Intrahepatic Cholestasis of Pregnancy. Am J Obstet Gynecol. 2020 Nov 13:S0002-9378(20)31284-9. doi: 10.1016/j.ajog.2020.11.002. Epub ahead of print. PMID: 33197417.
  25. Mitchell AL, Ovadia C, Syngelaki A, Souretis K, Martineau M, Girling J, Vasavan T, Fan HM, Seed PT, Chambers J, Walters JRF, Nicolaides K, Williamson C. Re-evaluating diagnostic thresholds for intrahepatic cholestasis of pregnancy: case-control and cohort study. BJOG. 2021 Feb 15. doi: 10.1111/1471-0528.16669. Epub ahead of print. PMID: 33586324.
  26. Davies MH, Silva RCMA, Jones SR et al: Fetal mortality associated with cholestasis of pregnancy and the potential benefit of therapy with ursodeoxycholic acid. Gut 1995;37:580-584.
  27. Wikstrom SE, Marschall HU, Ludvigsson JF, Stephansson O: Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12-year population-based cohort study. Br J Obstet Gynaec 2013;120:717-723.
  28. Martineau M, Raker C, Powrie R, Williamson C: Intrahepatic cholestasis of pregnancy is associated with an increased risk of gestational diabetes. Eur J Obstet Gynecol Reprod Biol 2014;176:80-85.
  29. 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(3)395.e1-395.e8
  30. Reid R, Ivey KJ, Rencoret RH, Storey B: Fetal complications of obstetric cholestasis. Br Medical J 1976;1:870-872.
  31. 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 Clinical Anesthesia 2014;26(8):623-627.
  32. Fisk NM, Storey GN: Fetal outcome in obstetric cholestasis. Br J Obstet Gynaec 1988;95:1137- 1143.
  33. 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.
  34. Glantz A, Marschall HU, Mattsson LA: Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology 2004;40:467-474.
  35. Recoret R, Aste H: Jaundice during pregnancy. Med J Australia. 1973;1:167-169.
  36. Lee RH, Kwok KM, Ingles S, et al: Pregnancy outcomes in an era of aggressive management for intrahepatic cholestasis of pregnancy. Am J Perinatology 2008;25:341-345.
  37. Madazli R, Yuksel MA, Oncul M: Pregnancy outcomes and prognostic factors in patients with intrahepatic cholestasis of pregnancy. J Obstet Gynaec. 2015;35(4).
  38. 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. Heptatology. 2014;59(4):1482-1491.
  39. Brouwers L, Koster MPH, Page-Christiaens GCML, et al: Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acids. Am J Obstet Gynec 2015;212(1);100.e1-100.e7.
  40. Germain AM, Kato S, Carvajal JA, et al: Bile acids increase response and expression of human myometrial oxytocin receptor. Am J of Obstet Gynecol 2003;189:577-582.
  41. Roncaglia N, Arreghini A, Locatelli A, et al: Obstetric cholestasis: outcome with active management. Eur J Obstet Gynecol Reprod Biol. 2002;100(2):167-170.
  42. Kawakita T, Parikh LI, Ramsey PS, et al: Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy. Am J Obstet Gynec. 2015;213(4):570.e1-570.e2.
  43. 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.
  44. Zecca E, De Luca D, Marras M, et al: Intrahepatic cholestasis of pregnancy and neonatal respiratory distress syndrome. Pediatrics 2006;117:1669-1673.
  45. 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.
  46. Kowalski A, Janosz-Galdys I, Olejek A, et al: Correlation between serum levels of bile acids in pregnant women with intrahepatic cholestasis of pregnancy and condition of their newborns. Ginekol Pol 2014;85(2):101-104.
  47. Zecca E, De Luca D, Barbato, G, et al: Predicting respiratory distress syndrome in neonates from mothers with intrahepatic cholestasis of pregnancy. Early Human Development 2008;84:337-341.
  48. Oztekin D, Aydal I, Oztekin O, et al: Predicting fetal asphyxia in intrahepatic cholestasis of pregnancy. Archives Gynecol Obstet 2009;280:975-979.
  49. Zecca E, Costa S, Lauriola V, et al: Bile acid pneumonia: A “new” form of neonatal respiratory distress syndrome? Pediatrics 2003;114:269-272.
  50. Zecca E, De Luca D, Baroni S, et al: Bile acid-induced injury in newborn infants: a bronchoalveolar study. Pediatrics 2008;121:e146-149.
  51. Herraez E, Lozano E, Poli E, et al: Role of macrophages in bile acid-induced inflammatory response of fetal lung during maternal cholestasis. J Molec Medicine 2014;92(4):359-372.
  52. Shaw D, Frohlich J, Wittmann BA, Willms M: A prospective study of 18 patients with cholestasis of pregnancy. Am J Obstet Gynecol 1982;142:621-625.
  53. Sheibani L, Urinak ABS, Lee RH et al: Intrahepatic cholestasis of pregnancy: the effect of bile acids on fetal heart rate tracings. Obstet Gynec 2014;123:78S-79S.
  54. Henry A, Welsh AW: Monitoring intrahepatic cholestasis of pregnancy using the fetal myocardial performance index: a cohort study. Ultrasound Obstet Gynecol 2015;46:571-578.
  55. Floreani A, Caroli D, Lazzari R et al: Intrahepatic cholestasis of pregnancy: new insights into its pathogenesis. J Matern Fetal Neonatal Med 2013;26(14):1410-1415.
  56. Lee RH, Incerpi MH, Miller D, et al: Sudden fetal death in intrahepatic cholestasis of pregnancy. Obstet Gynecol 2009;113:528-531.
  57. Laatikainen T, Tulenheimo A: Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy. Internat J Gynaecol Obstet 1984;22:91-94.
  58. Alsulyman OM, Ouszounian JG, Ames-Castro M, Goodwin TM: Intrahepatic cholestasis of pregnancy: perinatal outcome associated with expectant management. Am J Obstet Gynecol 1996;175:957-960.
  59. Sentilhes L, Verspyck E, Pia P, Marpeau L: Fetal death in a patient with intrahepatic cholestasis of pregnancy. Obstet Gynecol 2006;107:458-460.
  60. Ovadia C, 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 Mar 2;393(10174):899-909. doi: 10.1016/S0140-6736(18)31877-4. Epub 2019 Feb 14. Erratum in: Lancet. 2019 Mar 16;393(10176):1100. PMID: 30773280; PMCID: PMC6396441.
  61. Carey E, White P: Ursodeoxycholic acid for intrahepatic cholestasis of pregnancy: good for the mother, not bad for the baby. Evid Based Med 2013;18(6):e55.
  62. Grand’Maison S, Durand M, Mohone 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 Gynaec Can 2014;36(7):632-641.
  63. Williamson C, Miragoli M, Kadir SSA et al: Bile acid signaling in fetal tissues: implications for intrahepatic cholestasis of pregnancy. Digestive Diseases 2011;29:58-61.
  64. Shemer EW, Thorsell M, Ostlund E, et al: Stereological assessment of placental morphology in intrahepatic cholestasis of pregnancy. Placenta 2012;33:914-918.
  65. Geenes VL, Lim YH, Bowman N, et al: A placental phenotype for intrahepatic cholestasis of pregnancy. Placenta 2011;32: 1026-1032.
  66. 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 Hepatology 1998;28:829-839.
  67. Geenes V, Lovgren-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(1):e83828.
  68. Azzaroli F, Raspanti ME, Simoni P, et al: High doses of ursodeoxycholic acid up-regulate the expression of placental breast cancer resistance protein in patients affected by intrahepatic cholestasis of pregnancy. Plos One 2013;8:e64101.
  69. Estiu MC, Monte MJ, Rivas L: Effect of ursodeoxycholic acid on the altered progesterone and bile acid homeostasis in the mother-placenta-foetus trio during cholestasis of pregnancy. Br J Clinical Pharm 2015;79(2):316-329.
  70. Chappell LC, et al. Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy. Lancet 2019; 394(10201):849-860. doi:https://doi.org/10.1016/S0140-6736(19)31270-X
  71. Geenes V, Chambers J, Khurana R: Rifampicin in the treatment of severe intrahepatic cholestasis of pregnancy. Eur J Obstet Gynecol Reprod Biol 2015;189:59-63.
  72. Nicastri PL, Diaferia A, Tartagni M, et al: A randomized placebo-controlled trial of ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol 1998;105(11):1205-1207.
  73. Heikkinen J, Maentausta O, Ylostalo P, et al: Serum bile acid levels in intrahepatic cholestasis of pregnancy during treatment with phenobarbital or cholestyramine. Eur J Obstet Gynec Reprod Biol 1982;14:153-162.
  74. Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol. 2014 Jul;124(1):120-133. doi: 10.1097/AOG.0000000000000346. PMID: 24901263.
  75. Davies MH, Silva RCMA, Jones SR et al: Fetal mortality associated with cholestasis of pregnancy and the potential benefit of therapy with ursodeoxycholic acid. Gut 1995;37:580-584.
  76. Medically Indicated Late-Preterm and Early-Term Deliveries: ACOG Committee Opinion, Number 818. Obstet Gynecol. 2021 Feb 1;137(2):e29-e33. doi: 10.1097/AOG.0000000000004245. PMID: 33481529.
  77. 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(5):667.e1-5.
  78. Lo JO, Shaffer BL, Allen AJ, et al: Intrahepatic cholestasis of pregnancy and timing of delivery. J Matern Fetal Neonatal Med 2015;28(18):2254-2258.
  79. Kohari KS, et al: Outcome after implementation of a modern management strategy for intrahepatic cholestasis of pregnancy. J Mat-fetal & Neo Medicine 2017;30:1342-1346.
  80. Ammala P, Kariniemi V: Short-term variability of fetal heart rate in cholestasis of pregnancy. American Journal of Obstetrics and Gynecology 1981;141:217-220.
  81. Hardikar W, Kansal S, Elferink RPJO, Angus P: Intrahepatic cholestasis of pregnancy: when should you look further? World J Gastroent 2009;15:1126-1129.
  82. 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;43:723-729.
  83. Serge E: Intrahepatic cholestasis of pregnancy: A risk factor for cancer, autoimmune and cardiovascular disease? Clinical Research Hep Gastro 2015;doi:10.1016/j.clinre.2015.09.003
  84. Papacleovoulou G, Abu-Hayyeh S, Nikolopoulou E, et al: Maternal cholestasis during pregnancy programs metabolic disease in offspring. J Clinic Invest 2013;123(7):3172-3181.
  85. Hamalainen S, Turunen K, Kosunen E, et al: Men’s health is not affected by their mother’s intrahepatic cholestasis of pregnancy. Am J Men’s Health 2015;pii:1557988315584795
  86. Ovadia C, Sajous J, Seed PT, Patel K, Williamson NJ, Attilakos G, Azzaroli F, Bacq Y, Batsry L, Broom K, Brun-Furrer R, Bull L, Chambers J, Cui Y, Ding M, Dixon PH, Estiú MC, Gardiner FW, Geenes V, Grymowicz M, Günaydin B, Hague WM, Haslinger C, Hu Y, Indraccolo U, Juusela A, Kane SC, Kebapcilar A, Kebapcilar L, Kohari K, Kondrackienė J, Koster MPH, Lee RH, Liu X, Locatelli A, Macias RIR, Madazli R, Majewska A, Maksym K, Marathe JA, Morton A, Oudijk MA, Öztekin D, Peek MJ, Shennan AH, Tribe RM, Tripodi V, Türk Özterlemez N, Vasavan T, Wong LFA, Yinon Y, Zhang Q, Zloto K, Marschall HU, Thornton J, Chappell LC, Williamson C. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis. Lancet Gastroenterol Hepatol. 2021 Apr 26:S2468-1253(21)00074-1. doi: 10.1016/S2468-1253(21)00074-1. Epub ahead of print. PMID: 33915090.