REVIEW
Intrahepatic Cholestasis of Pregnancy:
Diagnosis and Management
Yannick Bacq MD,* and Lo€ıc Sentilhes MD, PhD†
Intrahepatic cholestasis of pregnancy (ICP) is a liver dis-
ease unique to pregnancy. It is characterized by pruritus
associated with elevated serum bile acids and/or amino-
transferase levels. ICP usually manifests during the second
or third trimester of pregnancy and spontaneously improves
after delivery.1 ICP has been identified worldwide, but its
prevalence varies considerably depending on country and
ethnicity.2 The highest rates of prevalence reported were
those in Bolivia and in Chile in the 1970s. In the United
States, the prevalence has been estimated to range from
0.3% in Connecticut to 5.6% in Los Angeles (in a predomi-
nantly Latina population).3 In Europe, the prevalence is
about 0.5% to 1.5%.2
Pathophysiology
ICP is a complex disease that has been shown to be pri-
marily associated with hormonal and genetic factors.4 The
role of estrogens has been clearly established in ICP and
animal studies have shown that estrogens are cholestatic.
Progesterone probably also plays a role, and oral adminis-
tration of natural progesterone in cases of threatened pre-
term labor increases the risk of ICP.1 A multigenic disease,
mutations of genes encoding several proteins involved in
the hepatobiliary transport have been associated with ICP.
Heterozygous mutations in gene ABCB4 (adenosine
triphosphate-binding cassette, subfamily B, member 4),
which encodes the hepatic phospholipid transporter MDR3
(multidrug resistance 3), have been found in patients with
ICP.4,5 Mutations in genes ATP8B1, ABCB11, or NRH1HA
encoding familial intrahepatic cholestasis 1 protein (FIC1),
the bile salt export pump, or farnesoid X receptor (a regula-
tor of bile acid synthesis and transport in the hepatocyte),
respectively, have less frequently been found in patients
Abbreviations: ALT, alanine aminotransferase; ICP, intrahepatic cholestasis of pregnancy; IUFD, intrauterine fetal death; RCT, randomized controlled trial;
UDCA, ursodeoxycholic acid.
From the *Department of Hepatogastroenterology, Tours University Hospital Center, Tours, France
†
Department of Obstetrics and Gynecology, Angers University Hospital, Angers, France
Potential conflict of interest: Yannick Bacq was speaker for Aptalis Pharma.
View this article online at wileyonlinelibrary.com
C 2014 by the American Association for the Study of Liver Diseases
V
doi: 10.1002/cld.398
58 Clinical Liver Disease, Vol 4, No 3, September 2014
with ICP.4 In addition, environmental factors may be
involved in the expression of the disease.4
Clinical Presentation and Diagnosis
Pruritus is the main symptom of ICP and is very uncom-
fortable and often difficult for patients to tolerate. It is often
generalized but predominantly affects the palms and soles.
It is more severe at night and interferes with sleep. The
intensity of the pruritus can be monitored using either a
prefixed score (Table 1) or a 100-mm visual analogue
scale.5 Pruritus disappears spontaneously within the first
few days after delivery. Clinical examination findings are
normal except for evidence of scratching. Patients may have
jaundice in more severe forms (less than 10%). ICP with
jaundice but without pruritus is very rare.1 Patients do not
experience fever, abdominal pain, or encephalopathy. Ultra-
sound examination may reveal gallstones in the gallbladder,
but there should be no evidence to suggest biliary obstruc-
tion such as dilation of the biliary tract.
Measurement of aminotransferase activity, especially ala-
nine aminotransferase (ALT), provides a very sensitive test
for the diagnosis of ICP.1 Patients with ICP may exhibit very
significant increases in serum ALT activity, suggesting acute
viral hepatitis, which should be ruled out by suitable sero-
logic tests.1 The serum bile acid concentrations also are
usually elevated, and the cutoff values chosen for diagnosis
of ICP are usually values of more than 10 mmol/L. Normal
bile acid concentrations do not exclude the diagnosis. It
should be noted that the determination of the serum bile
acid concentration is not a routine test and is not available
in all centers. Measurement of serum bile acid concentra-
tions is especially useful for the diagnosis of ICP in patients
with pruritus when ALT levels are in normal limits. In some
An Official Learning Resource of AASLD
 R E V I E W Intrahepatic Cholestasis of Pregnancy Bacq and Sentilhes

patients with ICP, pruritus may precede liver test abnormal-
ities. In contrast to ALT, serum bile acid determinations
may be of interest for fetal prognosis. Indeed, a relationship
between maternal serum bile acid levels and fetal distress
has been found in severe ICP, which is defined as serum
bile acid concentrations of more than 40 mmol/L.6-8 The
serum bile acid concentration and serum ALT activity
decrease rapidly after delivery—and as a rule return to nor-
mal within a few weeks. Remarkably, serum gamma-
glutamyltransferase activity, which is increased in most hep-
atobiliary diseases, is normal or only slightly increased in
ICP.1 Alkaline phosphatase levels increase during the second
and third trimesters in normal pregnancy, mainly as a result
of the production of the placental isoenzyme, so this is not
a useful test for the diagnosis of cholestasis during preg-
nancy. The prothrombin time is usually normal, and there
is no liver failure. Prolonged prothrombin time, if present,
is caused by vitamin K deficiency and should be treated
before delivery to prevent postpartum hemorrhage.
Liver biopsy is rarely necessary for the diagnosis of ICP;
however, if it is carried out, the histopathology is character-
ized by pure cholestasis, with bile plugs sometimes visible
in the hepatocytes and canaliculi.
Diagnosis of ICP is usually based on pruritus occurring
during pregnancy that is associated with elevated serum
aminotransferase and/or serum bile acids, after other causes
of liver test abnormalities have been excluded.9 ICP may
rarely be associated with another liver disease unique to
pregnancy, such as preeclampsia or acute fatty liver of preg-
nancy, which also may occur during late pregnancy.5 Inter-
current causes of liver diseases during pregnancy include
acute viral hepatitis or cytomegalovirus infection, as well as
drug liver injury. Urinary tract infection may cause cholesta-
sis or be associated with ICP. Chronic liver diseases may
occasionally worsen during pregnancy or be detected by
chance during pregnancy. Consequently, liver function tests
should be carried out after delivery to check for any persis-
tent abnormalities that should lead to further diagnostic
investigations and appropriate follow-up.

TABLE 1 Monitoring of the Intensity of Pruritus in Patients With ICP Maternal Outcome
Using a Prefixed Score.
Score 0: Absence of pruritus
The maternal prognosis during pregnancy and postpar-
Score 1: Occasional pruritus (not every day) tum is good, without severe maternal morbidity. Cholestasis
Score 2: Discontinuous pruritus every day, prevailing asymptomatic lapses
(i.e., pruritus is present less than 50% of time)
frequently recurs in subsequent pregnancies (60%-70%).
Score 3: Discontinuous pruritus every day, prevailing symptomatic lapses The administration of oral contraceptives to women with a
(i.e., pruritus is present more than 50% of time)
Score 4: Permanent pruritus (day and night) history of ICP rarely results in cholestasis, and ICP is not a
contraindication for oral contraceptives. Oral contraception

TABLE 2 Efficacy of UDCA in Treating ICP: Meta-Analysis of Nine RCTs.

Outcome parameters UDCA versus All Controls or Placebo Rate Combined OR (95% CI)

Total resolution of pruritus UDCA versus all controls 41.6% versus 6.1% 0.23 (0.07-0.74); P < .01
UDCA versus placebo 41.6% versus 8.6% 0.39 (0.12-1.32); P 5 0.13
Improvement of pruritus UDCA versus all controls 61.3% versus 26.8% 0.27 (0.13-0.55); P < 0.0001
UDCA versus placebo 61.3% versus 25.7% 0.21 (0.07-0.62); P < 0.01
Normalization of serum ALT levels UDCA versus all controls 27.8% versus 9.4% 0.23 (0.10-0.50); P < 0.001
UDCA versus placebo 27.8% versus 14.3% 0.18 (0.06-0.52); P < 0.001
Decrease in serum ALT levels* UDCA versus all controls 65.9% versus 25.4% 0.24 (0.11-0.52); P < 0.0001
UDCA versus placebo 65.9% versus 20.0% 0.12 (0.05-0.31); P < 0.0001
Decrease in serum bile acid concentrations† UDCA versus all controls 54.3% versus 24.4% 0.37 (0.19-0.75); P < 0.001
UDCA versus placebo 54.3% versus 18.6% 3.32 (1.38-8.06); P < 0.01
Total prematurity‡ UDCA versus all controls 15.9% versus 33.6% 0.44 (0.24-0.79); P < 0.01
UDCA versus placebo 15.9% versus 40.0% 0.59 (0.19-1.77); P 5 0.43
Spontaneous prematurity UDCA versus all controls 8.7% versus 19.3% 0.51 (0.22-1.20); P 5 0.15
UDCA versus placebo 8.7% versus 18.6% 0.88 (0.32-2.43); P 5 0.93
Fetal distress§ UDCA versus all controls 18.6% versus 33.3% 0.46 (0.25-0.86); P < 0.01
UDCA versus placebo 18.6% versus 35.7% 0.63 (0.23-1.72); P 5 0.50
Respiratory distress syndrome UDCA versus all controls 3.3% versus 16.3% 0.30 (0.12-0.74); P < 0.01
UDCA versus placebo 3.3% versus 9.1% 0.66 (0.11-3.91); P 5 0.64
Apgar score < 7 at 5 minutes UDCA versus all controls 5.0% versus 10.1% 0.53 (0.25-1.10); P 5 0.09
UDCA versus placebo 5.0% versus 10.0% 0.33 (0.07-1.47); P 5 0.15
Hospitalization in neonatal intensive care unit UDCA versus all controls 9.1% versus 18.1% 0.49 (0.25-0.98); P 5 0.04
UDCA versus placebo 9.1% versus 9.1% 0.36 (0.05-2.81); P 5 0.33

This table has been adapted from Bacq et al.12

Abbreviations: CI, confidence interval; OR, odds ratio; UDCA, ursodeoxycholic acid;
*More than 50% decrease in serum ALT levels.
†
More than 50% decrease in serum total bile acid concentrations.
‡
Spontaneous or iatrogenic delivery before 37 weeks’ gestation.
§
Meconium staining and/or fetal asphyxia.

59 Clinical Liver Disease, Vol 4, No 3, September 2014 An Official Learning Resource of AASLD
 R E V I E W Intrahepatic Cholestasis of Pregnancy Bacq and Sentilhes

TABLE 3 Tips for Patients Affected by ICP

 Diagnosis of ICP should be considered when a pregnant women presents with a generalized pruritus (itching) during the second or third trimester.
 Diagnosis of ICP should be confirmed by blood tests (liver function tests and bile acids, if available) and other liver diseases should be excluded.
 Ursodeoxycholic acid is the most effective treatment of pruritus in ICP and is prescribed until delivery.
 ICP carries a risk for the fetus, especially in severe cases. Sudden intrauterine fetal death (IUFD) is a rare event (1%-2%), but is unpredictable and remains the
most feared complication of ICP.
 Active management, i.e., routine deliveries at 37-38 weeks of gestation, has been proposed to prevent the risk of IUFD. The obstetric team should discuss the
risk related to prematurity and the maternal morbidity related to inducing labor against the risk of sudden IUFD with patients.
 ICP is not a contraindication to breastfeeding.
 Patients should be followed after delivery to ensure resolution of pruritus and to carry out blood tests (liver function tests and bile acids, if available).
 An appointment with a medical practitioner may be proposed 2 and 3 months after delivery to check persistent liver abnormalities that should lead to appropri-
ate follow-up. This is also the time to discuss contraceptives choice and the risk of recurrence in subsequent pregnancies.

(either combined contraceptives with a low dose of estrogen
or progestin-only contraceptives) can be initiated after the
liver test values have normalized. The patient should be
informed of the possibility of pruritus during such contra-
ception, and routine liver tests should be checked after 3 or
6 months of oral contraception.
As a rule, long-term maternal prognosis is good. However,
two recent longitudinal population-based studies from Fin-
land and Sweden found that patients with ICP have substan-
tially increased risks for later gallstone-related diseases,
nonalcoholic liver cirrhosis, and hepatitis C.10,11 The results
of these studies highlight the importance of carrying out hep-
atitis C serology tests in all patients with ICP and confirming
that serum liver tests have returned to normal after delivery.
Fetal Outcome
ICP does carry a risk for the fetus, especially in severe
cases.7 Total (i.e., spontaneous and induced) prematurity,
consisting mainly of late preterm deliveries (34 0/7-36 6/7
weeks of gestation), is more frequent in patients with ICP
than in the general population. The rate of prematurity varies
greatly from study to study, depending on the rate of multi-
ple pregnancies, which is increased in patients with ICP, and
the obstetric management of ICP at the end of the pregnancy.
The active management and induction of labor, undertaken
because of the risk of intrauterine fetal death (IUFD), may be
responsible for higher prematurity rates. Indeed, IUFD
remains the most feared complication of ICP but rarely
occurs before the last month of pregnancy; its prevalence
may currently be estimated to be between 1% and 2%.8,12
Medical Treatment
Vitamin K should be supplemented if the prothrombin
time is prolonged.9 The efficacy of topical emollients to
improve pruritus is unknown. However, they are safe in
pregnancy and may be useful in some patients.9,13
Ursodeoxycholic acid (UDCA) is currently the most effec-
tive treatment of pruritus in ICP.9,12 UDCA also improves
the liver tests. The results of a meta-analysis also suggest
that UDCA therapy is beneficial for fetal outcome12
(Table 2). No side effects of UDCA have been reported for
mothers or babies. The authors of this study usually pre-
scribe 500 mg twice a day (or 15 mg/kg per day) until
delivery. The mechanism underlying the beneficial effect of
UDCA is unclear. UDCA, which is a hydrophilic bile acid,
may decrease signs of cholestasis in the mother by provid-
ing cytoprotection against the hepatotoxic effects of the
hydrophobic bile acids and by improving the hepatobiliary
bile acid transport. UDCA may also have a specific effect by
improving the transport of bile acid across the placenta.12
Cholestyramine, which decreases the ileal absorption and
increases the fecal excretion of bile acids, has been used in
ICP. Nevertheless, cholestyramine is less effective than urso-
deoxycholic acid in improving pruritus and liver tests and
is also associated with more side effects.14
Obstetric Management
Active management has usually been recommended to
prevent the risk of IUFD, and routine deliveries at 37 to
38 weeks of gestation are commonplace in maternity
units.5,8,15 Fortunately, IUFD is a rare event, and there is
no consensus for the best gestational age for delivery.
Moreover, the usefulness of a policy of the induction of
labor has never been demonstrated by appropriate random-
ized controlled trials (RCTs). In the absence of evidence-
based recommendations, the timing of delivery should be
discussed on an individual basis after weighing the risk
related to prematurity, and the maternal morbidity
(increase risk of cesarean section) related to inducing labor,
against the risk of sudden IUFD, which thus far remains
unpredictable.9,13 Moreover, from 37 weeks’ gestation, a
serum bile acid concentration higher than 40 mmol/L
should lead caregivers to envisage measures to ensure
prompt delivery.
ICP:The Patient’s Perspective
A summary of tips for the patient affected by ICP is given
in Table 3. n
CORRESPONDENCE
Yannick Bacq, MD, Service d’Hepatogastroent
erologie, CHRU de Tours,
37044 Tours Cedex, France. E-mail: bacq@med.univ-tours.fr.

60 Clinical Liver Disease, Vol 4, No 3, September 2014 An Official Learning Resource of AASLD
 R E V I E W
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