Review article 1

Intrahepatic cholestasis of pregnancy

Mohammed K. Ali, Ahmed Y. Abdelbadee, Sherif A. Shazly, Ahmed M. Abbas
and Safwat A. Mohammed

Department of Gynecology and Obstetrics,
Women Health Hospital, Assiut University Hospitals,
Assiut, Egypt
Correspondence to Mohammed K. Ali, MBBCh, MSc,
Woman’s Health Center, Assiut University, Assiut
71111, Egypt
Tel: + 20 882 4621; fax: + 088 236 8377;
e-mail: mohammedelkosy@yahoo.com
Received 12 December 2011
Accepted 6 March 2012
Evidence Based Women’s Health Journal
Downloaded from https://journals.lww.com/ebjwh by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3StWKv21BgexPso+LD2R5fXJ3hdUIIN+ATo/2ekgkqcg= on 05/29/2018
Intrahepatic cholestasis of pregnancy is a pregnancy-specific liver disorder. It is
characterized by pruritus, jaundice, and elevated serum bile acids, mainly in the third
trimester, with different fetal outcomes. The pathophysiology involves abnormal bile
acid metabolism, with deposition of bile acids in the maternal tissues and the placenta.
It is commonly (B70% of cases) accompanied by elevated maternal serum total bile
acids. Abnormal liver function tests (transaminase levels in the 60–200 range U/l and
alkaline phosphatase 200–400 U/l range) are typically present, but hyperbilirubinemia
with clinical jaundice is rare. The etiology of intrahepatic cholestasis of pregnancy
is complex and not fully understood, but it is likely to result from the cholestatic effects
of reproductive hormones and their metabolites.

2013, 3:1–4

Keywords:
bile acid, cholestasis, pregnancy, pruritus

Evid Based Women Health J 3:1–4

& 2013 Evidence Based Women’s Health Journal
2090-7265

appear to reflect changing diagnostic criteria, which have

Introduction
Intrahepatic cholestasis of pregnancy (ICP), which is also
known as obstetric cholestasis, was originally described in
1883 by Ahlfeld as recurrent jaundice in pregnancy that
resolved following delivery. Over the years, ICP has also
been described as jaundice in pregnancy, recurrent
jaundice in pregnancy, idiopathic jaundice of pregnancy,
obstetric hepatosis, hepatosis gestationalis, or obstetric
cholestasis [1]. Apart from the severe maternal sympto-
matology, the chief perinatal risk is intrauterine
fetal death, which is typically very poorly predicted by
fetal surveillance. Late preterm birth (34–36 weeks),
fetal intolerance of labor, and meconium-stained fluid are
also more common in these pregnancies. Maternal
symptoms resolve promptly after delivery, but there is
a 40–70% recurrence rate in subsequent pregnancies [2].
The livers of postmenopausal women with a history of
ICP well tolerated the short-term exposure to oral and
transdermal estradiol, although the doses used were
higher than those in routine clinical use. The response of
serum levels of sex hormone-binding globulin to oral
estradiol was slightly reduced in the ICP group.
Transdermal estradiol had no effect on C-reactive protein
or sex hormone-binding globulin. A number of liver and
biliary diseases were found to be associated with ICP [3].
Epidemiology
The incidence of ICP varies widely with geographical
location and ethnicity. It is most common in Chile, where
early reports have described an overall incidence of 10%,
with higher rates found in women of Araucanian Indian
descent. However, this has decreased to B1.5–4% [4,5].
The reasons for this decline are unclear, but do not
2090-7265 & 2013 Evidence Based Women’s Health Journal
become more inclusive in recent studies.
ICP is more common in the winter months in Finland,
Sweden, Chile, and Portugal [6]. A higher incidence is
found in twin pregnancies and following in-vitro fertiliza-
tion treatment [7]. One study has suggested that it is
more common in women older than 35 years of age [8].
Etiology and pathogenesis
Over the last decade, it has become increasingly apparent
that the etiology of ICP is multifactorial, involving
genetic and hormonal factors. Hormonal factors may lead
to transient decompensation of the heterozygous state for
genes encoding hepatobiliary transport proteins that fail
during pregnancy, leading to ICP [9].
Estrogens and progesterone
ICP occurs mainly during the third trimester, when serum
concentrations of estrogens and progesterone reach their
peak. ICP is also more common in twin pregnancies, which
are associated with higher levels of hormones than
singleton pregnancies [10]. All hormones are metabolized
by the liver, and an excess of metabolites influences the
activity of biliary canalicular transporters. The function of
hepatocellular transporters such as ABCB11 and ABSB4
has been shown to be impaired at the post-transcriptional
level in vitro by high loads of estrogen glucuronides and
progesterone [11]. In addition, estrogens impair basolateral
as well as canalicular bile acid transporter expression
of liver cells in vitro by transcriptional mechanisms [12,13].
Genetic factors
There is increasing evidence that interaction between
genetically determined dysfunction in the canalicular
DOI: 10.1097/01.EBX.0000422793.57061.6b

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 2 Evidence Based Women’s Health Journal
ABC transporters and high levels of sex hormones
produced in pregnancy can predispose toward the
development of ICP [14]. Genetic factors could explain
familial cases and the higher incidence in some ethnic
groups. Also supporting genetic factors are the high rate
of recurrence of ICP in subsequent pregnancies and the
susceptibility of affected women to progesterone [15].
Other factors
Some characteristics of ICP, such as incomplete recur-
rence at subsequent pregnancies, the decrease in
prevalence, and seasonal variations, suggest that environ-
mental factors may contribute toward the pathogenesis of
this disorder [16].
Clinical features
Maternal presentation
The most common presenting symptom of ICP is
pruritus, which usually presents in the third trimester.
This increases progressively as the pregnancy advances
and usually resolves after delivery. It most frequently
affects the palms of the hands and soles of the feet, but
without dermatological features other than excoriation
marks. Approximately 80% of affected women present
after 30 weeks of gestation, but ICP may be presented as
early as 8 weeks.
The relationship between onset of pruritus and develop-
ment of hepatic dysfunction is not clear. It has been
reported that itch may be present either before or after an
abnormal liver function is detected. Clinical jaundice is
rare with ICP, and if it does occur, it tends to be mild,
with bilirubin levels rarely exceeding 100 mmol/l, and does
not deteriorate with advancing gestation. Constitutional
symptoms including anorexia, malaise, and abdominal
pain may be present. Pale stools and dark urine have been
reported and steatorrhea may occur. There is also an
association between steatorrhea and an increased risk of
postpartum hemorrhage as a result of malabsorption
of vitamin K.
Fetal disease
There are consistent reports of adverse fetal outcomes in
association with the condition, although most studies are
not sufficiently large to allow accurate quantification of
the frequency of the complications. Many studies have
attempted to correlate maternal serum biochemistry with
fetal outcomes. The sensitivity of bile acids is used as
a predictive marker of fetal risk in several studies.
Meconium staining of the amniotic fluid
The incidence of meconium staining of amniotic fluid
(MSAF) in normal-term pregnancies is B15% and is
considered to be a sign of fetal distress. In ICP, MSAF has
been reported in 16–58% of all cases and up to 100% of
cases affected by intrauterine death. The frequency of
MSAF is greater in pregnancies with higher reported
levels of maternal serum bile acids.
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Cardiotocography abnormalities
Both antepartum and intrapartum cardiotocograpic
abnormalities have been reported in association with
ICP, including reduced fetal heart rate variability,
tachycardia, and bradycardia [17].
Preterm labor
There is an increased risk of spontaneous preterm labor,
which has been reported in as many as 60% of deliveries
in some studies, but most studies report rates of 30–40%
in ICP cases without active management. The rate of this
complication was significantly higher in ICP pregnancies
with maternal fasting serum bile acids greater than
40 mmol/l in the larger study of Swedish ICP cases.
Respiratory distress syndrome
Studies have shown that there is an increased risk of
respiratory distress syndrome with either induction of
labor or elective cesarean section at 37 weeks’ gestation.
It should be noted that the risk of neonatal respiratory
distress is considerably higher with elective cesarean
section, and it should be borne in mind that labor is
induced in the majority of women with ICP. Also, there
are some data to suggest that neonatal respiratory distress
following ICP may be a consequence of the disease
process.
Sudden intrauterine death
Older studies using biochemical abnormalities to diag-
nose ICP have reported a perinatal mortality rate of
10–15%.This has been reduced to 3.5% or less in more
recent studies using policies of active management. The
term active management may encompass many different
clinical practices, including increased fetal monitoring,
frequent biochemical testing, pharmacotherapy with
ursodeoxycholic acid (UDCA), or delivery at 37–38
weeks’ gestation. These management protocols are based
on evidence showing that stillbirths in ICP tend to
cluster around 37–39 weeks [18].
Other findings
Several studies have shown that there is no increase in
the number of small for gestational age infants born to
women with ICP.
Investigations
The diagnosis of ICP is one of exclusion, and alternative
causes of hepatic impairment or pruritus should be
considered before the diagnosis is made.
Liver function tests
In ICP, alanine aminotransferase and aspartate amino-
transferase may increase before or after serum bile acids.
Alanine aminotransferase is considered to be a more
sensitive marker of ICP; there is a 2–10-fold increase in
serum levels that is generally more marked than the
increase in aspartate aminotransferase. Bilirubin is normal
in the majority of ICP cases and is of limited value in
diagnosis or follow-up.

Bile acids
The primary bile acids, cholic acid and chenodeoxycholic
acid are the end products of hepatic cholesterol
metabolism and represent the major route for the
excretion of cholesterol. UDCA is a tertiary bile acid as
it results from bacterial modification, followed by hepatic
metabolism. It is normally detectable in trace amounts in
normal serum. Serum bile acid measurement is now
considered to be the most suitable biochemical marker
for both the diagnosis and the monitoring of ICP.
Other serum biochemistry
Lipids
Many studies have reported deranged lipid profiles in
association with ICP, especially LDL and cholesterol.
Glucose
ICP is usually associated with impaired glucose tolerance.
Clotting
A prolonged prothrombin time is reported in 20% of
patients.
Liver biopsy
Several studies have reported that there is a normal liver
structure, with no evidence of liver cell damage, and only
mildly dilated bile ducts, bile stasis in canaliculi, bile
plugs, and mild portal tract inflammation in liver biopsies
from women with ICP.
Management options
Fetal monitoring
There are several case reports of normal cardiotocography
and/or normal fetal movements in the hours preceding
fetal loss [19]. However, these forms of fetal surveillance
do not prevent intrauterine death. However, they may
be reassuring to women with ICP and the clinicians
responsible for their care at the time they are
performed [20].
Elective delivery
Some studies have reported good outcomes with a policy
of induction of labor at 37 or 38 weeks’ gestation.
Drugs
Ursodeoxycholic acid
UDCA is a naturally occurring hydrophilic bile acid that
constitutes less than 3% of the physiological bile acid pool
in humans. It has been used with positive effects in the
management of primary biliary cirrhosis and other
cholestatic disorders for several years, and is gaining
popularity as a treatment for ICP.
Dexamethasone
Dexamethasone inhibits placental estrogen synthesis by
reducing the secretion of the precursor, dehydroepian-
drosterone sulfate, from the fetal adrenal glands.
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Intrahepatic cholestasis of pregnancy Ali et al. 3
Rifampicin
Although there are no published studies reporting the use
of rifampicin in ICP, it has been used with good results in
several other liver diseases, including gallstones and
primary biliary cirrhosis.
Vitamin K
ICP is associated with a risk of malabsorption of fat-
soluble vitamins because of reduced enterohepatic
circulation of bile acids and the subsequent reduction
of uptake in the terminal ileum. Therefore, many clini-
cians advice treatment of women with oral vitamin K to
protect against the theoretical risk of fetal antepartum
and maternal postpartum hemorrhage.
Prognosis
Most women have no lasting hepatic damage, but ICP
recurs in the majority of cases, with variations in intensity
in subsequent pregnancies. Recurrence is less likely
following multiple pregnancies. Women with a history of
ICP may also develop symptoms if taking the combined
oral contraceptive pill or in the second half of the
menstrual cycle [21]. Additional studies in ICP popula-
tions from different countries are required to further
characterize the genetic background in these patients.
UDCA is currently considered as first-line therapy for
ICP. Future prospective controlled studies may provide
a better understanding of the underlying pathophysiolo-
gical mechanisms of fetal risk, identify the most suitable
monitoring modalities, and clarify the obstetrical manage-
ment near term.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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