JOURNAL OF WOMENS HEALTH Volume 16, Number 6, 2007 Mary Ann Liebert, Inc. DOI: 10.1089/jwh.2007.

0158

Intrahepatic Cholestasis of Pregnancy: Review of the Literature and Evaluation of Current Evidence
MAHMOUD M. SALEH, M.D., M.R.C.O.G.,1 and KHALIL R. ABDO, M.R.C.G.P., M.R.C.O.G.2

ABSTRACT Objective: To provide an overview of the epidemiology, etiology, pathogenesis, diagnosis, and management of intrahepatic cholestasis of pregnancy. Methods: We searched the Medline and PubMed database using the key words intrahepatic cholestasis of pregnancy, obstetric cholestasis, diagnosis, management, and complications. Results: Intrahepatic cholestasis of pregnancy, or obstetric cholestasis, is a liver condition that develops during pregnancy. It is associated with increased perinatal morbidity and mortality. Pruritus and risk of postpartum hemorrhage are the main causes of maternal morbidity. Intrahepatic cholestasis of pregnancy is a diagnosis of exclusion. The current management policies depend on regular fetal and maternal monitoring and delivery at fetal maturity. The analysis of the quality of previous studies provided in this review highlights the areas of deficiency in evidence-based knowledge of this subject. Conclusions: More research is required into the etiology, pathogenesis, and monitoring modalities that can specifically predict fetal outcome in intrahepatic cholestasis of pregnancy. Clinical trials are required to identify the most suitable drugs for treatment. INTRODUCTION
orrhage are the main causes of maternal morbidity.1 It is important to raise the awareness of this condition among clinicians dealing with maternity care because of the adverse fetal outcome.

(ICP), also known as obstetric cholestasis (OC), is a pregnancy-specific liver condition that typically occurs with generalized pruritus in the absence of skin rash in the late second trimester or third trimester.1 It is second only to viral hepatitis as a cause of jaundice during pregnancy.2 The condition is associated with increased perinatal morbidity and mortality, particularly from preterm labor, fetal distress, and intrauterine death.1,3 Maternal prognosis is good, and the condition tends to disappear quickly after delivery.4,5 Pruritus and increased predisposition to postpartum hemNTRAHEPATIC CHOLESTASIS OF PREGNANCY
1Obstetrics 2Obstetrics

EPIDEMIOLOGY
ICP has a geographically variable prevalence, being significantly more common in South Asian (0.8%1.46%)6 and South American populations (9.2%15.6%).1 It is considered to be uncommon among Europeans (0.1%0.2%),7 with the highest incidence identified in Scandinavian countries (1.5% in Sweden).8 Studies conducted in the U.K.

and Gynaecology, Rochdale Infirmary, Rochdale, Lancashire, U.K. and Gynaecology, Lancashire Teaching Hospitals, Preston, Lancashire, U.K.

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showed an overall prevalence of 0.7%, with the white population at 0.62%, Pakistani Asians at 1.46%, and Indian Asians at 1.24%.6 ICP tends to cluster within certain families and is under strong genetic influence, although the precise genetic pattern remains obscure.9 The condition occurs more frequently in women above the age of 35,10 with multiple pregnancies,1,11,12 and in those with past history of ICP in previous pregnancies.

ETIOLOGY AND PATHOGENESIS

The etiology of ICP is heterogeneous (multifactorial), with contributions from genetic and hormonal factors. Environmental conditions and seasonal variations have been found to affect the prevalence of the disease in certain areas (Chile).13 Genetic factors play an important role at least in high prevalence regions and can explain the familial aggregation over successive generations in these regions, for example, Scandinavia and Chile.14 The genetic predisposition in these areas favors a sex-limited dominant trait.15 Data suggest that there may be a novel ICP-associated gene located in the p23 region of chromosome 2.16 The consensus holds that the genetic predisposition may lead to altered membrane composition of bile ducts and hepatocytes and dysfunction of biliary canalicular transporters.7 Mutations in a phospholipid transporter known as ATP-cassette transporter B4 (ABCB4) or multidrug resistant protein-3 (MDR3) were associated with elevated gammaglutamyl transpeptidase (GGT) levels and development of ICP in heterozygous mothers.17,18 However, evidence of such mutations was not found in two ascertained Finish ICP families.7 The inherited dysfunction of biliary canalicular transporters also has been linked to familial cholestatic syndromes as recurrent familial intrahepatic cholestasis and familial intrahepatic cholestasis type 3.1 The changes caused by the genetic factors lead to increased sensitivity to normally produced estrogens and progesterones. A high level of circulating estrogen in susceptible individuals may favor intrahepatic cholestasis by impairing sulfation and transport of bile acids.1921 The role of progesterone in the pathogenesis of ICP is unclear, although evidence is accumulating for this as an additional factor in some women with pre-

disposition.2224 Reyes and Sjovall25 proposed that patients with ICP have a selective defect in the secretion of sulfated progesterone metabolites into bile and speculated that this may be caused by genetic polymorphism of canalicular transporters for steroid sulfates or their regulation. They considered that interaction with estrogen metabolites may further enhance the process of triggering ICP in genetically predisposed individuals. The normal fetal-to-maternal transfer of bile acids across the placenta is impaired in ICP. The fetus lacks the ability to excrete cholic acid, which remains elevated in meconium in cases of ICP even after treatment with ursodeoxycholic acid (UDCA).26 The excess bile acids with abnormal profile will accumulate and are potentially toxic to the fetus.27 Data obtained from studies on neonatal rat cardiomyocytes suggest that raised levels of bile acid taurocholate in the fetal serum in ICP may cause fetal dysrhythmia and sudden intrauterine fetal death.28,29 The available evidence, therefore, suggests that clinical symptoms of ICP arise when the secretory capacity of mildly malfunctioning canalicular transporters, which cause no problem outside pregnancy, are overwhelmed by the high levels of sex hormones produced in pregnancy. The etiology of pruritus in ICP is unknown. One theory is that bile salts are deposited on nerve endings of the skin, causing itching. Another theory suggests that bile salts can accumulate at the hepatocytes, causing the release of pruritogenic materials.30 The pruritus of cholestasis, in liver diseases is known to be at least partially sensitive to opioid antagonism. There is some controversy as to whether this pruritus is peripherally or centrally mediated, although there is growing evidence to support central mediation based on increased endogenous opioid neurotransmission and the alleviating effect of naloxone on the pruritus of cholestatic liver conditions.31,32 The cause of preterm delivery in ICP is unknown. There is some evidence, however, showing that increased levels of bile acids may have an effect on myometrial contractility.33 Animal studies on rats and sheep showed a dose-related increase in myometrial contractility with the administration of cholic acid.12 Whether myometrial contractility in the setting of cholestasis contributes to preterm labor and delivery in humans remains to be determined.

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DIAGNOSIS Clinical features

The classic and predominant feature is pruritus, which develops characteristically after the 30th week of gestation and becomes progressively severe.4,5 It usually starts in the palms and soles and then progresses to the arms and legs and the rest of the body. It becomes more persistent if left untreated.34 The condition is typically relieved within 48 hours of delivery.4,5 Skin rash is characteristically absent in ICP. Excoriation marks from scratching should not be confused with a rash.12 Overt jaundice is uncommon in all but the most severely affected mothers. Occasionally, it may be the initial presentation, but, typically, it develops 14 weeks after the onset of pruritus.35 The reported incidence of jaundice is between 14% and 25%.1,36,37 Borum38 mentioned a high rate of 75%, which has not been supported by other studies, particularly the large studies of Glantz et al.8 and Kondrackiene et al.37 Other symptoms associated with ICP include insomnia, fatigue, anorexia, malaise, epigastric discomfort, steatorrhea due to malabsorption of fat, and dark urine.39 Diagnosis of ICP is one of exclusion.1,3,40,41 It is important to exclude other forms of liver disease and cholestasis. Investigations should include screening for viral hepatitis and autoimmune liver disease and ultrasonography of the hepatobiliary tract for gallstones or tumors.1 Liver biopsy might be indicated when jaundice occurs without pruritus, symptoms commence before 20 weeks gestation, or serum levels of bilirubin remain high 8 weeks or more after delivery.41,42 The other pregnancy-specific causes of abnormal liver functions include severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, and acute fatty liver of pregnancy. Women with these conditions are usually unwell, and the diagnosis can be established easily on clinical grounds.1

Laboratory findings
ICP is associated with elevated total bile acid levels,41,43 which may be the only laboratory abnormality observed and is often the first to happen. Mild elevation of liver enzymes is observed in up to 60% of patients1: serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) rarely exceed two times the up-

per limits of normal for pregnancy.42 Elevated levels of GGT were found in less than one third of patients with ICP in the U.K., and when present, were associated with greater impairment of liver function tests (LFT).17 Serum alkaline phosphatase may be elevated up to 4-fold. It is usually a useful biochemical marker of cholestasis in nonpregnant patients, but it is less useful during pregnancy as it is always raised because of placental production.1 The incidence of hyperbilirubinemia may reach up to 25%,1 and the level may reach 6 mg/dL.12 Patients with cholestasis of pregnancy show significant alterations in the proportion of primary bile acids, with an increase in cholic acid and a decrease in chenodeoxycholic acid, causing marked elevation in the cholic/chenodeoxycholic acid ratio. The glycine/taurine ratio is reduced in ICP.44 Walker et al.41 considered bile acids as sensitive but not specific markers for ICP. On the other hand, Brites45 reported that the most predictive and accurate markers for diagnosis and follow-up of ICP were increased total bile acid levels (11 mol/L), enhanced cholic acid percentage (42%), and decreased glycine/taurine bile acid ratio to 1. This serum bile acid profile is potentially useful in differential diagnosis.44 Whether ICP includes pruritus despite normal bile acid levels remains debatable.39 Delayed onset of abnormal liver function tests has been reported, which is why serial liver function tests should be performed in these patients.46 There seems to be no correlation between serum levels of total bile acids and other liver tests, such as AST, ALT, and total bilirubin in cases of ICP.22,47 Other markers that might be helpful in the diagnosis of ICP have been explored. Dann et al.48 reported significantly increased levels of lowdensity lipoprotein (LDL) cholesterol in women with ICP compared with pruritus gravidarum patients and healthy pregnant controls. The increase in LDL levels started at 16 weeks of gestation, several weeks earlier than the mean gestation for diagnosis of ICP by conventional markers, and continued throughout pregnancy. The authors proposed that direct measurement of LDL cholesterol in women with pruritus in pregnancy may be a useful single test to distinguish between ICP and pruritus gravidarum. In another study, Dann et al.49 showed the possibility of using glutathione S-transferase as an additional marker for diagnosing ICP and distinguishing the condition from pruritus gravidarum.

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The median serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) concentrations in pregnancies complicated by ICP were not significantly different from those in unaffected pregnancies. There is no need to take the hepatic disorder into account in maternal serum screening for Down syndrome.50 The diagnostic features of ICP can be summarized as follows: The condition usually develops in the third trimester. It is suspected mainly by the presence of pruritus in the absence of skin lesions. Other clinical features, such as jaundice, may be present. The diagnosis is established by laboratory investigations (raised bile acids and liver enzymes) and the exclusion of other organic liver diseases. The symptoms of ICP disappear quickly after labor, and laboratory findings should normalize within 4 weeks of delivery.

MANAGEMENT Fetal issues

ICP poses little medical risk to the mother but significant risks to the fetus of perinatal mortality, preterm delivery, fetal distress, and meconium staining.12,51 The incidence of meconium staining of amniotic fluid was found to vary between 25%31 and 45%,14,52 acute onset of fetal compromise 22%, spontaneous preterm labor 44%, and intrauterine fetal demise 2%.14,52 McDonald3 reported a 5-fold increase in incidence of stillbirth, intrapartum fetal distress, and preterm labor in cases of ICP. When the condition was untreated, the perinatal mortality was found to range between 11% and 20%.33 The risks to the fetus seem to rise progressively and through to delivery regardless of the serum levels of bile acids and liver enzymes. Close monitoring of these markers is essential but does not prevent sudden fetal distress and death.27 The severity of maternal signs and symptoms as well does not seem to correlate with fetal prognosis.21 However, Glantz et al.8 showed a correlation between maternal serum bile acid levels and fetal complication rates. They found no increase in fetal risk in ICP patients with bile acid levels 40 mol/L and even proposed that these patients could be managed expectantly.

Monitoring of fetal well-being is recommended in all cases of ICP, although it is not clear which parameters predict intrauterine death. A protocol suggested by Fagan39 included weekly nonstressed cardiotocography, estimation of liquor volume, and umbilical artery Doppler together with regular growth scans from 30 weeks of gestation or diagnosis of ICP. Maternal liver tests (bile acids and liver enzymes) and blood clotting were tested weekly. Roncaglia et al.53 used a policy of weekly nonstress test and amniotic fluid volume assessment, with transcervical amnioscopy at 36 weeks for assessment of amniotic fluid color. Some investigators even considered regular amniocentesis to detect meconium staining of liquor in some cases.52 As the majority of unexplained fetal death occurs after 37 weeks of gestation, there is a general agreement that all women with ICP should be delivered no later than 3738 weeks of gestation.1,10,12,33,53 Respiratory distress syndrome is extremely uncommon at this gestation. The only disadvantage would be a greater incidence of failed induction and instrumental delivery. This outcome must be balanced against the risk of intrauterine death in the knowledge that there is no good way of detecting that risk.40 Delivery around 36 weeks or earlier should be considered for severe cases with jaundice, progressive elevations in serum bile acids, and suspected fetal distress.53

Maternal issues
The mother can be reassured of good maternal outcome. Itching and jaundice will disappear immediately after delivery. However, the recurrence rate is high (45%70%) but not inevitable and may skip consecutive pregnancies.22 It is recommended that patients with ICP should have a postnatal check of liver functions (bile acids and enzymes), which are expected to normalize within 1 month of delivery.39 Although estrogen has been linked to ICP, the use of combined oral contraceptive pills is not contraindicated in women with prior history of the condition. These women should be advised of the risk of pruritus and elevated liver enzymes when using combined pills. They can commence oral contraceptives with lowdose estrogen or progesterone-only products once the liver tests have normalized following delivery.22

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TABLE 2. STRENGTH
OF

TREATMENT
UDCA is the best available therapy and has proven efficacy in alleviating pruritus and restoring toward normal the abnormal profiles of bile acids and sulfated steroids in serum and other body fluids.32,54 UDCA seems to have no adverse effects on the fetus, but experience is insufficient to draw conclusions about teratogenicity and prevention of adverse outcomes.27 UDCA causes a significant decrease in the percentage of cholic acid, elevation in chenodeoxycholic acid, and restoration of the glycine/taurine ratio of the serum bile acid pool to normal.44 Some authors consider that it has a cardioprotective effect on the fetus against the possible toxic effect of bile acids.1 UDCA does not seem to be effective in lowering bile acid levels in patients with elevated GGT.17 A significant rise in lithocholic acid (a toxic product resulting from conversion of UDCA by the bacteria in the intestine) was observed during treatment.44 However, many authors consider the drug to be safe in the third trimester,17,21,55,56 and its use was recommended in early-onset cases (33 weeks gestation),21,56 patients with severe cholestasis (bile acid levels 70 mol/L), and patients with history of sudden fetal death.56 It is important to inform the mother that the drug is not licensed for use in pregnancy. UDCA restores the ability of the placenta to carry out bile acid transfer.43 It reduces the mean values of cholic acid and chenodeoxycholic acid in the amniotic fluid and in cord blood.44,57 The drug does not influence the concentration and proportion of bile acids in meconium,24 but it lowers the bile
TABLE 1. RATING SYSTEM A B C

RECOMMENDATIONS

At least one randomized, controlled trial of overall good quality, addressing the specific recommendations (evidence levels Ia, Ib) Well-controlled clinical studies available but not randomized, controlled trials (evidence levels IIa, IIb, III Evidence obtained from expert committee reports or opinions. Indicates an absence of directly applicable clinical studies of good quality (evidence level IV)

Quality of evidence Ia Ib IIa IIb III Evidence obtained from meta-analysis of randomized, controlled trials Evidence obtained from at least one randomized, controlled trial Evidence obtained from at least one well-designed, controlled study without randomization Evidence obtained from at least one other type of well-designed quasi-experimental study Evidence obtained from well-designed, nonexperimental, descriptive studies, such as comparative studies, correlation studies, and case studies Evidence obtained from expert committee reports, opinions, or review of literature

IV

acid levels in colostrum that are elevated in cases of ICP.58 Treatment of pruritus with cholestyramine may be associated with improved maternal morbidity without a documented improvement in fetal outcome.34 In general, it is considered to be safe in pregnancy.59 Many patients reported intolerance to cholestyramine, as it is not palatable, requires frequent dosing, and is associated with constipation. It potentiates malabsorption of dietary lipids and fat-soluble vitamins, which makes the administration of vitamin supplements essential.34 A trial comparing UDCA and cholestyramine (84 patients) showed that UDCA is safer and more effective in the treatment of ICP.37 S-Adenosyl-L-methionine has shown variable relief of pruritus, with lessening of jaundice. A randomized placebo-controlled trial from Italy (32 patients) showed the superiority of the combination of UDCA with S-adenosyl-L-methionine over either drug alone for relieving pruritus and normalizing biochemical abnormalities.60 Another clinical trial involving 46 patients showed that UDCA was more effective than S-adenosylL-methionine in improving the concentration of serum bile acids and other tests of liver function, whereas both therapies were equally effective in improving pruritus.61 Treatment with high-dose steroids (dexamethasone 12 mg/day) was reported to be effective in improving the symptoms and biochemical changes of ICP.62 However, a recent randomized controlled trial comparing dexamethasone and UDCA showed that dexamethasone produced no alleviation of pruritus or reduction of ALT and was less effective than UDCA in reducing bile acids and bilirubin.63 Antihistamines frequently are used for the treatment of pruritus. The sedating effect of antihistamines is thought to play a more significant role in the relief of pruritus than their effects on

TABLE 3. Reference 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

EVALUATION

AND

GRADING

OF THE

REFERENCES Quality of evidence IV IV IV IIa IIa III IIb IIb III III IIa IV IIa IV IIb III III IIa III IIa Ib IIb IIa IIb IV IIa IV IIb IIa IV IV Ib III IV IV IV Ib IV IV IIb IV III IIa IIa IV IIb IIa IIa IIa III III III IIb III III IV IIa IIa IV Ib Ib IIb Ib III Strength of recommendations C C C B B B B B B B B C B C B B B B B B A B B B C B C B B C C A B C C C A C C B C B B B C B B B B B B B B B B C B B C A A B A B

Type of study Review of literature Review of literature Review of literature Prospective study with control group Prospective study with control group Retrospective study with no control group Prospective study with no control group Prospective study with no control group Retrospective descriptive (correlation) study Retrospective study with control group Prospective study with control group Review of literature Prospective study with control group Review of literature Prospective study with no control group Retrospective study with control group Retrospective study with control group Prospective study with control group Case studies Prospective study with control group Randomized, controlled trial Prospective study with no control group Prospective study with control group Prospective study with no control group Review of literature Prospective study with control group Review of literature Prospective study with no control group Prospective study with control group Review of literature Review of literature Randomized, controlled trial Retrospective study with control group Review of literature Review of literature Review of literature Randomized, controlled trial Review of literature Review of literature Prospective study with no control group Review of literature Case study and review of literature Prospective study with control group Prospective study with control group Review of literature Prospective study with no control group Prospective study with control group Prospective study with control group Prospective study with control group Retrospective study with control group Retrospective study with control group Retrospective study with no control group Prospective study with no control group Retrospective study with control group Case studies Review of literature Prospective study with control group Prospective study with control group Review of literature Randomized, controlled trial Randomized, controlled trial Prospective study with no control group Randomized, controlled trial Case study

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histamine production. They may be beneficial for patients who experience nocturnal exacerbations of itching.34 Vitamin K (10 mg/day) should be administered regularly throughout pregnancy in patients with ICP, especially those using cholestyramine. Binding of vitamin K may cause elevation of the prothrombin ratio and increase the risk of fetal hemorrhage64 and postpartum hemorrhage, which have been reported in some cases of ICP.4

REFERENCES
1. Tan LK. Obstetric cholestasis: Current opinions and management. Ann Acad Med Singapore 2003;32:294. 2. Rolfes DB, Ishak KG. Liver disease in pregnancy. Histopathology 1986;10:555. 3. McDonald J. Cholestasis of pregnancy. J Gastroenterol Hepatol 1999;14:515. 4. 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. 5. Berg B, Helm G, Petersohn L, Tryding N. Cholestasis of pregnancy: Clinical and laboratory studies. Acta Obstet Gynecol Scand 1986;65:107. 6. Abedin P, Weaver JB, Egginton E. Intrahepatic cholestasis of pregnancy: Prevalence and ethnic distribution. Ethn Health 1999;4:35. 7. Savander M, Ropponen A, Avela K, et al. Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy. Gut 2003;52:1025. 8. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology 2004;40:467. 9. Eloranta MJ, Heinonen S, Mononen T, Saarikoski S. Risk of obstetric cholestasis in sisters of index patients. Clin Genet 2001;60:42. 10. Heinonen S, Kirkinen P. Pregnancy outcome with intrahepatic cholestasis. Obstet Gynecol 1999;94:189. 11. Gonzalez MC, Reyes H, Arrese M, et al. Intrahepatic cholestasis of pregnancy in twin pregnancies. J Hepatol 1989;9:84. 12. Mullally BA, Hansen WF. Intrahepatic cholestasis of pregnancy: Review of the literature. Obstet Gynecol Surv 2002;57:47. 13. Reyes H, Baez 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 Hepatol 2000;32:542. 14. Lammert F, Marschall HU, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: Molecular pathogenesis, diagnosis and management. J Hepatol 2000;33:1012. 15. Holtzbach RT, Sivak DA, Braun WE. Familial recurrent intrahepatic cholestasis of pregnancy: A genetic study providing evidence for transmission of a sexlimited, dominant trait. Gastroenterology 1983;85:175. 16. Heinonen S, Eloranta ML, Heiskanen J, et al. Maternal susceptibility locus for obstetric cholestasis maps to chromosome region 2p13 in Finnish patients. Scand J Gastroenterol 2001;36:766. 17. Milkiewicz P, Gallapher R, Chambers J, Eggington E, Weaver J, Elias E. Obstetric cholestasis with elevated gamma glutamyl transpeptidase: Incidence, presentation and treatment. J Gastroenterol Hepatol 2003;18:1283. 18. Floreani A, Carderi I, Paternoster D, Soardo G, Azzaroli F, Esposito W. Intrahepatic cholestasis of pregnancy: Three novel MDR3 gene mutations. Aliment Pharmacol Ther 2006;23:1649.

CONCLUSION
ICP is one of the primary liver disorders that adversely affect maternal well-being and fetal outcome. The etiology is unclear, although it seems to result from a combination of genetic and hormonal factors. Diagnosis is suspected on clinical grounds and established in the presence of abnormal liver function tests and raised serum bile acid levels after exclusion of other organic liver diseases. Its management is dictated by increased fetal risks and alleviating pruritus in the mother. UDCA is the only current therapy that has been proven effective in treating pruritus and restoring a normal bile acid profile. It seems to have no obvious adverse effect on the fetus. Early diagnosis, careful monitoring, and prompt delivery at fetal maturity can improve outcomes in the mother and child. There are wide gaps in our knowledge about this condition. New research is required to establish the etiology and pathogenesis of this disease, and large clinical trials are needed to evaluate the current available treatments and determine the most effective and safe one.

ANALYSIS OF QUALITY OF EVIDENCE USED IN THE CURRENT STUDY

The references in the current study were analyzed using a rating system (Table 1) that originates from the U.S. Agency for Health Care Research and Quality to identify the type of study, quality of evidence, and strength of recommendations (Table 2). The aim of the analysis is to allow the reader to judge the strength of evidence supporting the different parts of the review and highlight the areas of deficiency in evidencebased knowledge (Table 3).

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19. Leevy CB, Koneru B, Klein KM. Recurrent familial prolonged intrahepatic cholestasis of pregnancy associated with chronic liver disease. Gastroenterology 1977;113:966. 20. 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. 21. Palma J, Reyes H, Ribalta J, et al. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: A randomised, double-blind study controlled with placebo. J Hepatol 1997;27:1022. 22. Bacq Y, Sapey T, Brechot MC, Pierre F, Fignon A, Dubois F. Intrahepatic cholestasis of pregnancy: A French prospective study. Hepatology 1997;26:358. 23. Meng LJ, Reyes H, Axelson M, et al. Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: Effect of ursodeoxycholic acid therapy. Hepatology 1997;26:1573. 24. Meng LJ, Reyes H, Palma J, Hernandez I, Ribalta J, Sjovall J. 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. 25. Reyes H, Sjovall J. Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy. Ann Med 2000;32:94. 26. Rodrigues CM, Marin 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. 27. Fagan EA. Intrahepatic cholestasis of pregnancy. Clin Liver Dis 1999;3:603. 28. Gorelik J, Harding SE, Shevchuk AL, et al. Taurocholate induces changes in rat cardiomyocyte contraction and calcium dynamics. Clin Sci 2002;103:191. 29. Williamson C, Gorelik J, Eaton BM, Lab M, de Swiet M, Korchev Y. The bile acid taurcholate impairs rat cardiomyocyte function: A proposed mechanism for intra-uterine fetal death in obstetric cholestasis. Clin Sci 2001;100:363. 30. Khandelwal M, Malet PF. Pruritis associated with cholestasis: A review of pathogenesis and management. Dig Dis Sci 1994;39:1. 31. Bergasa NV, Jones EA. The pruritus of cholestasis: Potential pathogenic and therapeutic implications of opioids. Gastroenterology 1995;108:1582. 32. Bergasa NV, Alling DW, Talbot TL, et al. Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Ann Intern Med 1995;123:161. 33. 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. 34. Jenkins JK, Boothby LA. Treatment of itching associated with intrahepatic cholestasis of pregnancy. Ann Pharmacother 2002;36:1462. 35. Knox TA, Olans LB. Liver disease in pregnancy. N Engl J Med 1996;335:569.

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