Clinical Expert Series

Intrahepatic Cholestasis of Pregnancy

Catherine Williamson, MD, and Victoria Geenes, MBBS, PhD

Intrahepatic cholestasis of pregnancy is the most common pregnancy-specific liver disease that
typically presents in the third trimester. The clinical features are maternal pruritus in the absence
of a rash and deranged liver function tests, including raised serum bile acids. Intrahepatic
cholestasis of pregnancy is associated with an increased risk of adverse perinatal outcomes,
including spontaneous preterm delivery, meconium staining of the amniotic fluid, and stillbirth. It
is commonly treated with ursodeoxycholic acid. There is accumulating evidence to suggest that
intrahepatic cholestasis of pregnancy has a lasting influence on both maternal and fetal health. We
review the etiology, diagnosis, and management of this intriguing condition.
(Obstet Gynecol 2014;124:120–33)
DOI: 10.1097/AOG.0000000000000346

I ntrahepatic cholestasis of pregnancy, also known as

obstetric cholestasis, is the most common pregnancy-
specific liver disease. It classically presents in the
third trimester with pruritus, typically of the palms
and soles, abnormal liver function, and raised serum
bile acid levels. The symptoms and biochemical
abnormalities resolve rapidly after delivery but
may recur in subsequent pregnancies and with the
use of hormonal contraception. This is typically
reported with the use of the combined hormonal
contraceptive and may precede pregnancy. Intrahe-
patic cholestasis of pregnancy has been consistently
associated with a higher incidence of adverse preg-
nancy outcomes, including spontaneous and iatro-
genic preterm delivery, nonreassuring fetal status,
meconium staining of the amniotic fluid, and still-
birth.1–14 The risk of complications for the fetus is
associated with the serum level of maternal serum
bile acids, and women with more severe cholestasis
are at greater risk.2,5,6,8,9,11,12,14,15
From the Women’s Health Academic Centre, King’s College London, and
Department of Obstetrics and Gynaecology, University College London, London,
United Kingdom.
Continuing medical education for this article is available at http://links.lww.
com/AOG/A523.
Corresponding author: Catherine Williamson, MD, Professor of Women’s
Health, Women’s Health Academic Centre, King’s College London, Guy’s Hos-
pital Campus, London, U.K.; e-mail: catherine.williamson@kcl.ac.uk.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2014 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/14
The incidence of intrahepatic cholestasis of
pregnancy is reported to be between 0.2% and 2%
but varies widely with ethnicity and geographic
location. It is most common in South America and
northern Europe. There is a higher incidence of
intrahepatic cholestasis of pregnancy in women
with a multiple pregnancy (up to 22% in one
study),16,17 in women who have conceived after
in vitro fertilization treatment (2.7% compared
with 2%),18 and in women older than 35 years of
age. 19 In a large, Swedish epidemiologic study that
included 10,067 cholestasis cases and 94,863
women with uncomplicated pregnancy, there was
a higher incidence of cholelithiasis (11.6% com-
pared with 4.6%; hazard ratio 2.72, confidence
interval [CI] 2.55–2.91) and seropositivity for hep-
atitis C (0.7% compared with 0.2%; hazard ratio
4.16, CI 3.14–5.51) in women with intrahepatic
cholestasis of pregnancy.20
The etiology of intrahepatic cholestasis of preg-
nancy is complex and appears to relate to the
cholestatic effect of reproductive hormones in genet-
ically susceptible women. Evidence for genetic sus-
ceptibility to intrahepatic cholestasis of pregnancy
includes familial clustering of the disorder, and there
are reported pedigrees in which the mode of inheri-
tance has a sex-limited, dominant pattern.21 Several
studies have identified genetic variation in genes en-
coding biliary transport proteins and in the principal
bile acid receptor, farnesoid X receptor. Evidence for
a role for the reproductive hormones in the etiology of
intrahepatic cholestasis of pregnancy comes from the

120 VOL. 124, NO. 1, JULY 2014 OBSTETRICS & GYNECOLOGY

natural history of the disease and also from studies in
which oral progesterone was administered to prevent
preterm labor.22 Rodent studies have demonstrated
that estrogen contributes to the development of cho-
lestasis by causing reduced expression of hepatic bil-
iary transport proteins and through internalization of
the bile acid transporter bile salt export pump. More
recent studies have established that sulphated proges-
terone metabolites are partial agonists of farnesoid X
receptor, thereby impairing hepatic bile acid homeo-
stasis by reducing the function of the main hepatic bile
acid receptor.23 Several environmental factors are also
reported to play a role in the etiology of intrahepatic
cholestasis of pregnancy, including dietary selenium
levels.24 Interestingly, intrahepatic cholestasis of preg-
nancy is more common in some countries during the
winter, when natural selenium levels are lower. This is
also a time when vitamin D levels are likely to be
lower, and deficiency of this vitamin has been re-
ported in women with intrahepatic cholestasis of preg-
nancy.25 The etiology of the fetal complications is
likely to relate to the deleterious effects of toxic bile
acids, which accumulate in the fetal compartment.26
Intrahepatic cholestasis of pregnancy is com-
monly treated with ursodeoxycholic acid, which has
been shown to be effective at improving maternal
symptoms and reducing serum bile acid levels in
several small studies. However, there are no random-
ized controlled trials large enough to establish
whether ursodeoxycholic acid reduces the risk of
adverse perinatal outcomes, although the data from
two recent studies were encouraging.27,28 Many au-
thors advocate active management strategies involv-
ing increased antenatal surveillance and elective early
delivery. However, the evidence base for these prac-
tices is limited, and clinicians must make an individ-
ualized judgment as to whether the risks of early
delivery outweigh those of continuing a pregnancy
complicated by intrahepatic cholestasis.
DIAGNOSIS
The presenting feature of intrahepatic cholestasis of
pregnancy is pruritus in the majority of cases. This
typically occurs in the third trimester, with up to 80%
of women presenting after 30 weeks of gestation3,14
and some patients presenting as early as in the seventh
gestational week. Intrahepatic cholestasis of pregnancy
may present earlier in multiple pregnancies, and there
is currently no evidence to suggest that women who
present earlier have more severe disease or worse peri-
natal outcomes. The diagnosis is usually confirmed
after demonstration of abnormal liver function tests
VOL. 124, NO. 1, JULY 2014 Williamson and Geenes
and a subsequent blood test to reveal raised maternal
serum bile acids.
Pruritus
Pruritus is defined as an unpleasant sensation of the
skin that provokes the desire to scratch. It is often the
only symptom associated with intrahepatic cholestasis
of pregnancy and may be so severe that it disturbs
sleep. The pruritus typically affects the palms of the
hands and the soles of the feet but may occur
anywhere. It is often worse at night and gradually
deteriorates as the pregnancy advances. There are no
specific dermatologic features associated with intra-
hepatic cholestasis of pregnancy, although excoriation
marks are not uncommon. Other skin complaints in
women with intrahepatic cholestasis of pregnancy
may include pigmented lesions that resemble prurigo,
friction blisters, and abrasions. The relationship
between the onset of pruritus and deranged liver
function or raised serum bile acids is not clear, and
there are reports of the onset of pruritus both before
and after abnormal biochemistry is detected.29 Two
recent studies have shown that itch can be mimicked
in animal models or in vitro studies of nerve fibers by
administration of individual bile acids or by a prurito-
gen called lysophosphatidic acid that is produced by
the enzyme autotaxin, all of which are increased in the
blood of women with intrahepatic cholestasis of
pregnancy.30,31
Symptoms of Cholestasis
Women with intrahepatic cholestasis of pregnancy
may have systemic symptoms of cholestasis, including
dark urine and pale stools. Some women also may
become clinically jaundiced, but this is rare.
Serum Biochemistry
Intrahepatic cholestasis of pregnancy is a diagnosis of
exclusion and other causes of pruritus, hepatic
impairment, or both should be investigated (Table 1).
The most sensitive and specific marker for diagnosis is
the serum bile acid level,32 which if raised in a woman
with typical pruritus is considered to be diagnostic of
intrahepatic cholestasis of pregnancy in the absence of
evidence for an alternative diagnosis. The reference
range for bile acids depends on the technique used to
assay them and also whether the patient had fasted
before venepuncture. Most studies use an upper limit
of normal of between 10 and 14 micromoles/L for an
enzymatic assay of total serum bile acids, but this may
be reduced to between 6 and 10 micromoles/L in
fasted women. If individual bile salts are measured,
intrahepatic cholestasis of pregnancy is associated
Intrahepatic Cholestasis of Pregnancy 121
Table 1. Differential Diagnosis of Intrahepatic Cholestasis of Pregnancy

Differential Diagnosis Typical Clinical Presentation Distinguishing Features

Pregnancy-specific causes
of pruritus
Pruritus gravidarum Pruritus, usually in the third trimester Similar presentation to intrahepatic cholestasis of
pregnancy, but normal liver function tests and bile
acids
Atopic eruption of Pruritus, usually in the first trimester Dry, red rash with or without small blisters
pregnancy Typically affects trunk and limb flexures
Polymorphic eruption of Pruritus, usually in the third trimester Typically affects lower abdominal striae with
pregnancy umbilical-sparing
Urticarial papules or plaques, vesicles, and target
lesions
Pemphigoid gestationis Itchy rash, usually in the second or third Rare autoimmune condition characterized by
trimester complement-fixing immunoglobulin G antibodies
Rash develops into large, tense blisters
Associated with increased risk of preterm delivery and
SGA
Recurs in subsequent pregnancies and with combined
oral contraceptive
Prurigo of pregnancy Pruritus, usually in the third trimester Groups of red–brown papules on the abdomen and
extensor surfaces of the limbs
Papules may persist postpartum
Pruritic folliculitis of Pruritus, usually in the third trimester Acneiform eruption on the shoulders, upper back,
pregnancy thighs, and arms
Follicular papules and pustules, which may be filled
with pus, but culture is typically sterile; rash usually
improves with advancing gestation
Preexisting causes of
pruritus
Atopic dermatitis Pruritus, any gestation History of atopy
Allergic or drug reaction Pruritus, any gestation History of exposure to allergen or drug
Maculopapular rash
Systemic disease History of liver, renal, or thyroid disease Signs and symptoms of systemic disease
History of pruritus before conception
Pregnancy-specific causes
of hepatic
impairment
Acute fatty liver of Nausea, vomiting, headache, abdominal New nausea and vomiting in the third trimester are not
pregnancy pain, polyuria, polydipsia in the third caused by hyperemesis gravidarum
trimester Women with AFLP are more unwell and often have
associated renal impairment, coagulopathy,
hypoglycemia, and preeclampsia
Hemolysis, elevated Hypertension, proteinuria, headache, Hypertension and proteinuria are predominant
liver enzymes and epigastric pain, visual disturbance in the features
low platelets second or third trimester
syndrome
Hyperemesis gravidarum Nausea and vomiting in the first trimester Presentation in early pregnancy, abnormal liver
function test resolves with successful treatment
Preexisting causes of
hepatic impairment
Viral hepatitis Jaundice, nausea, vomiting, abdominal pain Systemic symptoms, generally unwell, contacts
Primary biliary cirrhosis Pruritus, jaundice, lethargy, other Symptoms before pregnancy; associated
or primary sclerosing autoimmune disorders autoantibodies
cholangitis
Autoimmune hepatitis Nausea, lethargy, jaundice, other Symptoms before pregnancy; associated
autoimmune disorders autoantibodies
(continued )

122 Williamson and Geenes Intrahepatic Cholestasis of Pregnancy OBSTETRICS & GYNECOLOGY
Table 1. Differential Diagnosis of Intrahepatic Cholestasis of Pregnancy (continued )
Differential Diagnosis Typical Clinical Presentation Distinguishing Features

Drug-induced liver Pruritus, jaundice Ingestion of drugs before onset of symptoms or

injury biochemical abnormalities
Biliary obstruction Abdominal pain, pale stools, dark urine Liver ultrasound scan abnormalities
Venoocclusive disease Abdominal pain, distension (ascites), Thrombosis demonstrated on imaging, thrombophilia
jaundice, gastrointestinal bleeding
SGA, small for gestational age; AFLP, acute fatty liver of pregnancy.

with a rise in conjugated primary bile salts, particu-
larly the tauroconjugates of cholic and chenodeoxy-
cholic acid.33
Bile acids are the end products of hepatic
cholesterol metabolism. They are inherently cytotoxic
and thus their metabolism is tightly regulated. In
intrahepatic cholestasis of pregnancy and other cho-
lestatic disorders, the transport of bile salts from the
liver to the gallbladder is disrupted and there is
compensatory transport of bile salts from the hepato-
cytes into the blood.
In the majority of cases, liver transaminases will
also be elevated. This may occur before or after the
rise in serum bile acids,34,35 and there is a poor corre-
lation between the levels. Alanine transaminase (ALT)
is more sensitive than aspartate transaminase in the
diagnosis of intrahepatic cholestasis of pregnancy
and may be raised twofold to 30-fold.15,34,36 If serum
bile acid measurement is not available, the U.K. Royal
College of Obstetricians and Gynecologists guidelines
currently recommend that intrahepatic cholestasis of
pregnancy may be diagnosed in a woman with typical
pruritus and abnormal liver function tests with reso-
lution of both after delivery.37 It is recommended that
pregnancy-specific reference ranges are used for the
interpretation of ALT, aspartate transaminase, and
other liver function tests. Typical reference ranges
for liver function tests in each trimester are shown
in Table 2.38 However, the authors believe that serum
bile acids should be used for diagnosis, because there
are accumulating data to show that they are important
to identify women at increased risk of adverse preg-
nancy outcome (see the Complications section).
Alkaline phosphatase is produced in large quan-
tities by the placenta during pregnancy and is
therefore not usually useful in the diagnosis of intra-
hepatic cholestasis of pregnancy. Gamma glutamyl
transferase (GGT) may be elevated but is more
commonly normal.15,22,39 Elevated levels of GGT
may give insight into the genetic etiology of intrahe-
patic cholestasis of pregnancy, because it is more com-
monly raised in women with mutations in the biliary
transporter ABCB4 (MDR3). However, it is not rou-
tinely used for diagnosis.
Bilirubin is raised in up to 10% of women with
intrahepatic cholestasis of pregnancy and if raised
tends to be a mild conjugated hyperbilirubinaemia.34
One study reported prolonged prothrombin
times in up to 20% of women with intrahepatic
cholestasis of pregnancy,40 but this finding is not con-
sistent with the author’s experience. However, in
women with intrahepatic cholestasis of pregnancy
and steatorrhea, clotting profiles should be checked
because they may be abnormal as a consequence of
malabsorption of vitamin K, and this should be taken
into consideration at the time of delivery.

Table 2. Reference Ranges for Liver Function in Pregnancy

Liver Enzyme Nonpregnant Pregnant 1st Trimester 2nd Trimester 3rd Trimester

ALT (international units/L) 0–40 — 6–32 6–32 6–32

AST (international units/L) 7–40 — 10–28 11–29 11–30
Bilirubin (micromoles/L) 0–17 — 4–16 3–13 3–14
GGT (international units/L) 11–50 — 5–37 5–43 3–41
Alkaline phosphatase (international units/L) 30–130 — 32–100 43–135 133–418
Albumin (g/L) 35–46 28–37 — — —
Bile acids (micromoles/L) 0–14 0–14 — — —
ALT, alanine transaminase; AST, aspartate transaminase; GGT, gamma glutamyl transferase.
Modified from Walker I, Chappell LC, Williamson C. Abnormal liver function tests in pregnancy. BMJ 2013;347:f6055. Table in BMJ
adapted from Girling JC, Dow E, Smith JH. Liver function tests in pre-eclampsia: importance of comparison with a reference range
derived for normal pregnancy. BJOG 1997;104:246–50. Copyright 2005 John Wiley and Sons, used with permission. Additional data in
BMJ table from Nelson-Piercy C. Handbook of obstetric medicine. 4th ed. London (UK): Informa Healthcare; 2010.

VOL. 124, NO. 1, JULY 2014 Williamson and Geenes Intrahepatic Cholestasis of Pregnancy 123
 Several studies have reported derangements in
lipid and glucose metabolism in women with intra-
hepatic cholestasis of pregnancy.12,41 This may suggest
maternal susceptibility to the metabolic syndrome or
may be simply a consequence of raised serum bile
acids and therefore limited to pregnancy.
Liver ultrasound scanning may be useful in
excluding other cause of cholestasis. Gallstones are
reported in 13% of women with intrahepatic chole-
stasis of pregnancy but are often asymptomatic, and
the disease has been reported in women with previous
cholecystectomy.13,20 In intrahepatic cholestasis of
pregnancy, the ultrasound appearance of the intrahe-
patic bile ducts is usually normal, but the fasting and
ejection volumes of the gallbladder are increased.42,43
Family History
Up to 14% of women with intrahepatic cholestasis of
pregnancy in the U.K. report a positive family history
for the condition in their parous sisters, and the
relative risk for the sisters of affected women is
reported to be 12.13,44 Reported pedigrees with small
numbers of affected women suggest an autosomal-
dominant, sex-limited inheritance pattern.21,45 Further
insights into the genetic etiology of intrahepatic cho-
lestasis of pregnancy come from studies of the familial
cholestasis syndromes, progressive familial intrahe-
patic cholestasis, and benign recurrent intrahepatic
cholestasis. These autosomal-recessive childhood liver
diseases are caused by mutations in genes encoding
of intrahepatic cholestasis of pregnancy has been identified in several of the hepatobiliary transporters (indicated in red
font). Green ovals indicate canalicular export, red ovals indicate sinusoidal uptake, and blue ovals indicate alternative
export, induced in the presence of cholestasis.
Williamson. Intrahepatic Cholestasis of Pregnancy. Obstet Gynecol 2014.
124 Williamson and Geenes Intrahepatic Cholestasis of Pregnancy
biliary transport proteins. A subgroup of the hetero-
zygous mothers of affected children had intrahepatic
cholestasis of pregnancy. There are three subtypes of
progressive familial intrahepatic cholestasis (progres-
sive familial intrahepatic cholestasis 1, 2, and 3),
which are caused by mutations in ATP8B1 (FIC1),
ABCB11 (BSEP), and ABCB4 (MDR3), respectively.
The localization and substrate specificity of these
transporters is shown in Figure 1.
In intrahepatic cholestasis of pregnancy, the muta-
tions in ABCB4 are the most extensively studied.
ABCB4 encodes the multidrug resistance protein 3,
a phosphatidylcholine floppase that transports phos-
phatidylcholine from the inner to the outer leaflet of
the canalicular membrane. Genetic variation of multi-
drug resistance protein 3 in women with intrahepatic
cholestasis of pregnancy was first described in the
mother of a child with progressive familial intrahepatic
cholestasis type 3.21 Subsequently, a spectrum of differ-
ent genetic variants affecting the majority of the exons,
an ABCB4 haplotype and four splicing mutations, has
been reported.46 Early studies suggested that multidrug
resistance protein 3 mutations were only found in
women with a raised serum GGT, but more recent
studies have identified genetic variation in women with
normal GGT levels. Mutations in ABCB4 have also
been reported in association with estrogen-induced
cholestasis and low phospholipid cholelithiasis, and
women with intrahepatic cholestasis of pregnancy are
at an increased risk of these conditions.
Fig. 1. Schematic showing the
major hepatobiliary uptake and
export proteins involved in bile
acid homeostasis and their sub-
strate specificities. Synthesis and
homeostasis of bile acids are
tightly regulated by the nuclear
hormone receptor farnesoid X
receptor (FXR). In response to
raised intracellular levels of bile
acids, FXR downregulates (t)
synthesis and uptake, acting
through the promoter-specific
repressor SHP, and upregulates
(/) export. Pregnane X receptor
(PXR) and constitutive androstane
receptor (CAR) also play a role in
bile acid homeostasis, regulating
alternative pathways. Genetic var-
iation contributing to the etiology
OBSTETRICS & GYNECOLOGY
 Heterozygous mutations in the bile salt export
pump occur in approximately 5% of women with
intrahepatic cholestasis of pregnancy.46,47 More com-
mon is a single-nucleotide polymorphism (V444A),
which was recently confirmed as a susceptibility locus
for intrahepatic cholestasis of pregnancy in a large
white European cohort of 491 cases.48
Genetic variation in ATP8B1, which encodes the
phosphatidylserine flippase FIC1, has been identified
in a small number of intrahepatic cholestasis of preg-
nancy cases.46 The functional significance of these var-
iants remains unclear. Of the other hepatobiliary
transporters, ABCC2 is the only one to be implicated
in the etiology of intrahepatic cholestasis of pregnancy
to date. A polymorphism in exon 28 has been re-
ported in South American women with intrahepatic
cholestasis of pregnancy,49 but this was not identified
in a white European population. Similarly, intrahe-
patic cholestasis of pregnancy-associated single-nucle-
otide polymorphisms in the xenobiotic receptor,
pregnane X receptor (encoded by NR1I2), were re-
ported in South American women with intrahepatic
cholestasis of pregnancy but were not seen in white
European women.50,51 Finally, bile acid homeostasis
and transport within the hepatocyte is tightly regu-
lated by the nuclear hormone receptor, farnesoid X
receptor, encoded by NR1H4. Four rare heterozygous
variants in farnesoid X receptor have been described
in a white European cohort of women with intrahe-
patic cholestasis of pregnancy, of which three have
functional effects.52
THERAPEUTIC APPROACHES
Pharmacotherapy
The Appendix (available online at http://links.lww.
com/AOG/A524) summarizes the drugs that have been
used in trials of intrahepatic cholestasis of pregnancy
treatment. Most trials have only evaluated maternal
symptoms and biochemical abnormalities, although
a small number also considered perinatal outcomes.
Intrahepatic cholestasis of pregnancy is com-
monly treated with ursodeoxycholic acid, a tertiary
bile acid present in trace amounts in normal human
serum. Although not licensed for use in pregnancy, it
has been widely used in the management of intra-
hepatic cholestasis of pregnancy, and data from several
case reports and small studies suggest that it has
a beneficial effect in some but not all women.28,53–62
The largest randomized controlled trial of ursodeoxy-
cholic acid in 125 women with intrahepatic cholestasis
of pregnancy demonstrated a significant reduction
in pruritus in women taking ursodeoxycholic acid
compared with those taking placebo.28 Furthermore,
VOL. 124, NO. 1, JULY 2014 Williamson and Geenes
after ursodeoxycholic acid treatment, ALT, GGT, and
bilirubin were significantly lower, but there was no
difference in the serum bile acid level. This may in
part be explained by the diagnostic criteria used for
this study, because 12% of patients had raised ALT
and normal serum bile acids, and 63% had mild cho-
lestasis with serum bile acid levels ranging from 11 to
40 micromoles/L. A recent meta-analysis of nine
other randomized controlled trials, but not including
the two most recent studies listed in the Appendix
(http://links.lww.com/AOG/A524), reported signifi-
cant improvements in pruritus and liver function test
results, including a reduction in serum bile acid levels
after treatment.27 No single study has been large
enough to establish whether ursodeoxycholic acid
has a beneficial effect on adverse perinatal outcomes,
although the recent meta-analysis indicated that this
may be the case. This study compared pregnancies
with intrahepatic cholestasis of pregnancy treated with
several therapeutic agents, including ursodeoxycholic
acid (n5207) or placebo (n570), and indicated that
ursodeoxycholic acid treatment reduces the risk of
preterm labor, nonreassuring fetal status, respiratory
distress, and hospitalization in a neonatal unit.27 How-
ever, the meta-analysis included only three small stud-
ies that specifically compared ursodeoxycholic acid
and placebo, comprising a total of 62 and 63 partic-
ipants in each respective group. Furthermore, several
small studies have suggested an improvement in out-
comes after the introduction of policies of active man-
agement of intrahepatic cholestasis of pregnancy,
which include pharmacotherapy with ursodeoxy-
cholic acid, but the evidence for a beneficial effect
of ursodeoxycholic acid on fetal outcomes remains
inconclusive and further research is warranted. The
dose of ursodeoxycholic acid can be titrated to symp-
toms and usually ranges from 500 mg to 2 g/d. The
most commonly reported side effect is gastrointestinal
upset; nausea, vomiting, or loose stools was reported
by 16% (9/56 women) of the ursodeoxycholic acid
arm compared with 9% (5/55 women) of the placebo
arm in a recent placebo-controlled study.28 There do
not appear to be any detrimental effects on the fetus.
The mechanism of action is not fully understood, but
studies have shown that after treatment, there is
a reduction in total serum bile acids in both the mater-
nal and umbilical cord serum and a qualitative change
in the serum bile acid pool with a reduction in the
hydrophobicity of the pool.63 Furthermore, ursodeox-
ycholic acid treatment also reduces bile acid levels in
other biofluids, including amniotic fluid and colos-
trum,64–66 and improves placental morphology and
function.67,68
Intrahepatic Cholestasis of Pregnancy 125
 There are case reports, small randomized con-
trolled trials, and small placebo-controlled trials of
several other drugs in the management of intra-
hepatic cholestasis of pregnancy (see the Appendix,
http://links.lww.com/AOG/A524). However, none
has been shown to be as effective as ursodeoxycholic
acid in reducing serum biochemical markers of cho-
lestasis or improving symptoms and therefore are not
considered first-line therapy and are only discussed
here briefly.
Rifampicin is an antibiotic with choleretic pro-
perties that has been successfully used in the manage-
ment of primary biliary cirrhosis. There are no
randomized controlled trials of rifampicin treatment
in intrahepatic cholestasis of pregnancy in the litera-
ture, but the authors are aware of several cases of
severe intrahepatic cholestasis of pregnancy that have
not responded to monotherapy with ursodeoxycholic
acid. Patients in these cases experienced biochemical
and symptomatic improvement after combined ther-
apy with rifampicin and ursodeoxycholic acid. Fur-
ther studies are needed to fully establish the extent to
which rifampicin may be useful in intrahepatic
cholestasis of pregnancy and also to investigate any
potential effect on perinatal outcomes. The proposed
mechanism of action for rifampicin in cholestasis is
enhanced bile acid detoxification and excretion, an
effect that is complementary to the upregulation of
hepatic bile acid export by ursodeoxycholic acid63
(Fig. 2). It has been suggested therefore that the two
drugs used in combination may be more effective than
monotherapy alone.
Cholestyramine is an anion exchange resin.
Although several small studies have suggested that
it is effective at reducing pruritus in intrahepatic
cholestasis of pregnancy, it does not improve serum
bile acid levels or liver function tests.56 Given that
cholestyramine may reduce intestinal absorption of
ursodeoxycholic acid or of fat-soluble vitamins,
and thereby increase the risk of intrapartum or
postpartum hemorrhage, it is no longer considered
a first-line treatment in intrahepatic cholestasis of
pregnancy.
S-adenosyl-L-methionine influences hepatic
membrane composition and therefore biliary excre-
tion of bile acids and other steroid hormones. Early
studies suggested a beneficial effect on both symp-
toms and serum biochemistry, but these results were
inconsistently reproduced in subsequent stud-
ies.53,55,58,60,69–71 S-adenosyl-L-methionine is often
administered using a twice-daily intravenous regi-
men, making it a less attractive option in the man-
agement of intrahepatic cholestasis of pregnancy.
126 Williamson and Geenes Intrahepatic Cholestasis of Pregnancy
Some patients have reported thrombophlebitis with
peripheral veins after prolonged administration, but
there do not appear to be any adverse effects on the
fetus. It has now largely been superseded by urso-
deoxycholic acid.
An early observational study reporting the use of
dexamethasone in intrahepatic cholestasis of preg-
nancy suggested that it improved symptoms and
serum biochemistry including bile acid levels,72 but
these findings were not reproduced in follow-up stud-
ies.61,73,74 It is now rarely used for the management of
intrahepatic cholestasis of pregnancy.
Antihistamines such as chlorpheniramine are
often used in intrahepatic cholestasis of pregnancy.
They have no effect on serum biochemistry but may
reduce the sensation of pruritus in some women.
Furthermore, they may have the additional beneficial
effect of inducing drowsiness and therefore aiding
women with disturbed sleep secondary to pruritus.
Intrahepatic cholestasis of pregnancy may be
associated with a risk of malabsorption of fat-soluble
vitamins as a result of a reduced enterohepatic
circulation of bile acids and therefore a reduction in
uptake in the terminal ileum. Although the data
regarding the risk of intrapartum and postpartum
hemorrhage in intrahepatic cholestasis of pregnancy
are limited, some clinicians choose to treat women
with oral vitamin K to guard against this risk. There
are no randomized controlled trials to support or
refute this practice and the decision to treat should be
made on an individualized basis.
Other drugs reported in the management of
intrahepatic cholestasis of pregnancy including phe-
nobarbital, guar gum, and activated charcoal have
not been subjected to randomized controlled trials
and have largely been superseded by ursodeoxy-
cholic acid.
Topical Emollients
Some women may find that aqueous cream with 2%
menthol relieves their pruritus, but it has no effect on
the biochemical abnormalities associated with intra-
hepatic cholestasis of pregnancy.
Herbal Medicines
There is no evidence to support the use of herbal
medicines or dietary supplements in the treatment of
intrahepatic cholestasis of pregnancy.
Fetal Monitoring
No method of fetal monitoring has been shown to
either predict those at risk of adverse perinatal
outcomes or to reduce the risk. However, many
OBSTETRICS & GYNECOLOGY
Fig. 2. Schematic showing the com-
plementary effects of ursodeox-
ycholic acid (orange arrows) and
rifampicin (purple arrows) in the
treatment of cholestatic liver disease.
Ursodeoxycholic acid enhances the
canalicular excretion of bile acids
and phosphatidylcholine by upregu-
lation of BSEP and multidrug resis-
tance protein (MDR) 3, respectively. It
also upregulates expression of MRP4
at the basolateral membrane, facili-
tating further excretion of bile acids
through alternative export pathways.
Rifampicin enhances excretion of
bilirubin through induction of MRP2
and also facilitates the conversion of
hydrophobic bile acids to more
hydrophilic species through the
induction of CYP3A4. This then pro-
motes bile acid excretion through the
basolateral exporter MRP3. Pregnane
X receptor (PXR) is directly upregu-
lated by rifampicin.
Williamson. Intrahepatic Cholestasis of
Pregnancy. Obstet Gynecol 2014.

women, and some clinicians, find it reassuring to have
regular cardiotocography, fetal growth scans, or both.
However, it should be noted that there are several
case reports of normal cardiotocography in the hours
and days preceding fetal death.
Elective Early Delivery
Many authors have advocated the implementation of
elective early delivery of pregnancies with intrahepatic
cholestasis of pregnancy. These policies arise from the
demonstration of a clustering of stillbirths from 37
weeks of gestation onward13,75 and are aimed at reduc-
ing the risk of late stillbirth. At present, the American
College of Obstetricians and Gynecologists does not
have a guideline on the management of intrahepatic
cholestasis of pregnancy. The current Royal College
of Obstetricians and Gynecologists guideline for intra-
hepatic cholestasis of pregnancy states that there is no
evidence to support or refute this practice, but it nev-
ertheless has been widely adopted by many clinicians;
a recent population-based study from the United King-
dom reported iatrogenic preterm delivery rates of
17%.14 The majority of early deliveries are induced
and there is no evidence that this results in higher rates
of emergency cesarean delivery. Indeed, it has been
shown in two retrospective cohorts and one prospec-
tive study that rates of operative and instrumental
delivery are not increased in women with intrahepatic
cholestasis of pregnancy after induction of labor.28,76,77
As discussed subsequently, the risk of adverse
perinatal outcomes has been related to the degree of
maternal serum bile acid elevations. Thus, some clini-
cians effect delivery at 37 weeks of gestation in
pregnancies complicated by intrahepatic cholestasis of
pregnancy in which bile acids reach a certain threshold
(eg, 40 micromoles/L) and allow those in which this
threshold is not met to continue to 39 weeks of gestation.
We emphasize, however, that no randomized studies
have established the optimal timing for pregnancies
complicated by intrahepatic cholestasis of pregnancy.
COMPLICATIONS
Intrahepatic cholestasis of pregnancy has consistently
been associated with an increased incidence of adverse
perinatal outcomes, including spontaneous preterm
delivery, nonreassuring fetal status, meconium staining
of the amniotic fluid, and stillbirth (Fig. 3). More recent
studies have also suggested an association with respira-
tory distress syndrome that is independent of the risk of
premature birth.78 However, there has been much
debate in the literature regarding the precise nature
of the risk to the fetus and the true incidence of these
outcomes. This is largely the result of a lack of consen-
sus on diagnostic criteria for intrahepatic cholestasis of
pregnancy and recent changes in management practi-
ces, making it difficult to assess the risk fully.
The fetal complications in intrahepatic cholestasis
of pregnancy are believed to relate to high levels of
bile acids in the fetal serum. The fetus can synthesize

VOL. 124, NO. 1, JULY 2014 Williamson and Geenes Intrahepatic Cholestasis of Pregnancy 127
 20
Percent of pregnancies affected
15
10
5
0 severe intrahepatic cholestasis of pregnancy.
No intrahepatic Mild intrahepatic
cholestasis of cholestasis of
pregnancy pregnancy
Fig. 3. Graph showing the incidence of spontaneous pre-
term delivery in studies that have investigated the associa-
tion between maternal serum bile acid levels and rates of
adverse perinatal outcomes.7,14,25 Intrahepatic cholestasis
of pregnancy has been classified according to the maternal
bile acid level; no intrahepatic cholestasis of pregnancy
(less than 10 micromoles/L), mild (10–39 micromoles/L),
and severe (40 micromoles/L or greater). Glantz et al7 used
fasting maternal bile acid levels and Geenes et al25 used
nonfasting maternal bile acid levels; Lee et al6 did not
report whether the mothers were fasted. Glantz et al7 and
Geenes et al25 used peak bile acid levels, Geenes et al25
only studied perinatal outcomes in women with severe
intrahepatic cholestasis of pregnancy.
Williamson. Intrahepatic Cholestasis of Pregnancy. Obstet
Gynecol 2014.
bile acids from around 12 weeks of gestation, but it is
thought that in intrahepatic cholestasis of pregnancy,
some of the bile acids in the fetal compartment are
derived from the mother. In normal pregnancy, there
is a transplacental gradient for bile acids that facilitates
excretion of these toxic compounds from the fetus.
This gradient is reversed in intrahepatic cholestasis of
pregnancy, leading to an accumulation of bile acids in
the fetal serum and meconium.26,35,79
Many studies have attempted to establish a rela-
tionship between maternal serum biochemical param-
eters and fetal outcomes, particularly the association
between maternal serum bile acid levels and the risk of
adverse outcomes, which has been examined in
numerous small studies.5,15 The first study large enough
to conclusively demonstrate an association between
intrahepatic cholestasis of pregnancy and adverse peri-
natal outcomes investigated a cohort of 690 Swedish
women diagnosed with intrahepatic cholestasis of preg-
nancy between 1999 and 2002.2 It reported increased
incidences of spontaneous preterm delivery; asphyxial
events (defined as operative delivery resulting from
asphyxia, Apgar score less than 7 at 5 minutes, or arte-
rial cord pH less than 7.05); meconium staining of the
amniotic fluid, placenta, or amniotic fluid and placenta;
128 Williamson and Geenes
and membranes in women with intrahepatic cholestasis
of pregnancy. Furthermore, a relationship between the
maternal serum bile acid level and adverse outcomes
was established such that for every 1–2 micromoles/L
Glantz increase in the bile acid level, there was a 1–2%
Lee increase in risk of adverse outcome. However, it should
Geenes
be noted that the increase in risk only became statisti-
cally significant in severe intrahepatic cholestasis of
pregnancy (ie, if the bile acid level exceeded 40 micro-
moles/L), and only 17% (96 women) in this study had
Severe intrahepatic
cholestasis of
Subsequent studies in Hispanic, Turkish, and
pregnancy Swedish populations supported the findings of
increased rates of meconium staining of the amniotic
fluid, low Apgar scores at 5 minutes, and preterm
delivery in small numbers of women with severe
intrahepatic cholestasis of pregnancy.6,8,9,11,12 Taken
together, these studies highlight the importance of reg-
ular monitoring of serum bile acid levels in women
diagnosed with intrahepatic cholestasis of pregnancy
and suggest that women with bile acid levels that do
not exceed 40 micromoles/L may not be at an
increased risk of fetal complications. This suggestion
is supported by the findings of a study of 713 women
with severe intrahepatic cholestasis of pregnancy
(defined as nonfasting serum bile acids greater than
40 micromoles/L) from the United Kingdom, which
was the first study of perinatal outcomes large enough
to assess the risk of stillbirth in the condition.14 This
study reported significantly increased risks of preterm
delivery both spontaneous (odds ratio [OR] 2.05, 95%
CI 1.43–2.94) and iatrogenic (OR 7.39, 95% CI 5.33–
10.25), neonatal unit admission (OR 2.34, 95% CI
1.74–3.15) and stillbirth (OR 3.05, 95% CI 1.29–
7.21) compared with women with a healthy, singleton
pregnancy. Like with previous studies, there was a linear
relationship between maternal serum bile acid levels
and the rates of adverse outcomes (Fig. 4).14 Further-
more, higher rates of meconium staining of the
amniotic fluid were reported in association with
intrahepatic cholestasis of pregnancy, and this occurred
at earlier gestational weeks in women with intrahepatic
cholestasis of pregnancy compared with women in a con-
trol group.
Proposed Mechanisms to Explain Adverse
Pregnancy Outcome in Intrahepatic
Cholestasis of Pregnancy
Higher rates of both gestational diabetes and pre-
eclampsia have been reported in women with intra-
hepatic cholestasis of pregnancy.12,35,80,81 Interestingly,
of the 10 stillbirths described in a recent population
based study from the United Kingdom, seven had
Intrahepatic Cholestasis of Pregnancy OBSTETRICS & GYNECOLOGY
Fig. 4. Graphs showing the rela-

Spontaneous premature
164 events 50 events

delivery (probability)
tionship between maternal serum 1.0 1.0

Premature delivery
bile acid levels and adverse peri-

(probability)
natal outcomes in a U.K. cohort of
0.5 0.5
women with severe intrahepatic
cholestasis of pregnancy. The esti-
mated probability and 95% confi- 0.0 500 no event 0.0
614 no event
dence intervals of preterm delivery
(A), spontaneous preterm delivery A 40 100 200 500 B 40 100 200 500
(B), stillbirth (C), and meconium Bile acids (μmol/L), log scale Bile acids (μmol/L), log scale
staining of the amniotic fluid (D) in
relation to the maternal serum bile
acid level are shown. Reprinted 10 events 106 events

Stillbirth (probability)

Meconium staining
from Geenes V, Chappell LC, Seed 1.0 1.0

(probability)
PT, Steer PJ, Knight M, Williamson
C. Association of severe intra- 0.5 0.5
hepatic cholestasis of pregnancy
with adverse pregnancy outcomes:
a prospective population-based 0.0 0.0
654 no event 546 no event
case-control study. Hepatology
2014;59:1482–91. C 40 100 200 500 D 40 100 200 500
Williamson. Intrahepatic Cholestasis of Bile acids (μmol/L), log scale Bile acids (μmol/L), log scale
Pregnancy. Obstet Gynecol 2014.

additional coexistent pregnancy complications, hypothesis is given from in vitro experiments in which
including three with gestational diabetes and two administration of bile acids to rodent neonatal cardio-
with preeclampsia.14 These data suggest that coexis- myocytes and to human and murine embryonic stem
tent maternal pregnancy complications may worsen cell-derived cardiomyocytes causes arrhythmias, an effect
the fetal prognosis of intrahepatic cholestasis of that is ameliorated by coadministration of ursodeoxy-
pregnancy. cholic acid.87 Bile acids have also been shown to cause
In animal studies, bile acids have been shown to marked vasoconstriction of placental chorionic vessels,
stimulate gut motility, and meconium-stained amni- which may lead to acute anoxia and sudden death.88
otic fluid was observed in 100% of lambs that
received cholic acid infusion.82 Cholic acid infusion FOLLOW-UP
in sheep also led to an increased incidence of pre- All women with intrahepatic cholestasis of pregnancy
term labor.82 These findings are supported by rodent should have their liver function and serum bile acids
studies, which have demonstrated a dose-dependent checked 6–8 weeks postnatally to ensure resolution.
response in myometrial contractility to cholic acid.83 The biochemical abnormalities associated with intra-
Bile acids cause increased expression and response of hepatic cholestasis of pregnancy typically resolve rap-
the oxytocin receptor in human myometrial cells, idly after delivery, but there are reports of ongoing
and contractility studies of myometrial strips showed hepatic impairment in some women.89,90 Women with
that less oxytocin was required to produce contrac- continued derangement of liver function or persis-
tion in strips that had been incubated in bile acids tently raised serum bile acids should have this fully
compared with controls.84,85 investigated, and other causes of hepatic impairment
With respect to a mechanism for sudden intra- such as primary biliary cirrhosis and hepatitis C infec-
uterine death in intrahepatic cholestasis of pregnancy, tion should be ruled out.
postmortem studies of stillborn neonates from preg- A recent large cohort study of more than 11,000
nancies with intrahepatic cholestasis of pregnancy women with a history of intrahepatic cholestasis of
have shown that the majority of neonates are of pregnancy in one or more pregnancies has identified
appropriate weight and have no signs of chronic a higher incidence of hepatobiliary disease later in
uteroplacental insufficiency but do have evidence of life.20 Furthermore, hepatitis C, chronic hepatitis,
acute anoxia.10 One hypothesis is therefore that bile hepatic fibrosis or cirrhosis, and gallstones or cholan-
acids cause sudden cardiac death secondary to arrhyth- gitis were all more common in women with a history
mia. There have been case reports of fetal arrhythmia of intrahepatic cholestasis of pregnancy compared
in intrahepatic cholestasis of pregnancy cases86 and in with a control population. In addition to these find-
neonates with cholestasis. Further support for this ings, the children born to women with intrahepatic

VOL. 124, NO. 1, JULY 2014 Williamson and Geenes Intrahepatic Cholestasis of Pregnancy 129
cholestasis of pregnancy are reported to be at higher
risk of raised body mass index and dyslipidemia at the
age of 16 years.91
Cholestasis and pruritus may recur in some
women when they are challenged with oral contra-
ceptives.13 In these women, alternative methods of
contraception should be advised.
Up to 90% of women have a recurrence of
intrahepatic cholestasis of pregnancy in subsequent
pregnancies.16 The risk of recurrence is thought to be
lower if the index pregnancy was a multiple preg-
nancy. Women with a history of intrahepatic cholesta-
sis of pregnancy should receive prepregnancy
counseling before subsequent pregnancies so that they
can be informed of the risk of recurrence.
CONCLUSION
Intrahepatic cholestasis of pregnancy is a common
liver disorder of pregnancy. It is diagnosed in women
presenting with pruritus and raised serum bile acid
levels. Affected women have increased rates of
hepatobiliary disorders in later life but usually have
transient gestational cholestasis. Bile acid levels
should be monitored throughout pregnancy, because
there is accumulating evidence that higher levels are
associated with an increased risk of adverse perinatal
outcomes, including stillbirth. The risk of fetal com-
plications is increased in women whose serum bile
acid level exceeds 40 micromoles/L and may be
further increased if the woman has other coexistent
pregnancy complications such as gestational diabetes
or preeclampsia. Intrahepatic cholestasis of pregnancy
is commonly treated with ursodeoxycholic acid,
which reduces maternal pruritus and improves liver
function. Policies of active management with
increased antenatal surveillance and early elective
delivery are common and aim to reduce the risk of
late stillbirth. However, there is lack of strong
evidence to either support or refute these practices,
and an individualized judgment should be made to
determine whether the risks of preterm or early-term
delivery outweigh those of allowing pregnancy con-
tinuation in the face of intrahepatic cholestasis of
pregnancy. Induction of preterm labor in women with
intrahepatic cholestasis of pregnancy does not
increase the risk of emergency cesarean delivery. To
date, there is no robust evidence that ursodeoxycholic
acid improves perinatal outcomes or subsequent long-
term health of mothers with intrahepatic cholestasis of
pregnancy and their children. If future research can
address these issues, obstetricians will have much-
needed data on which to base treatment decisions.
130 Williamson and Geenes Intrahepatic Cholestasis of Pregnancy
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References
1. Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 statement: updated guidelines for
reporting parallel group randomized trials. Obstet Gynecol 2010;115:1063–70.

2. DeAngelis CD, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial registration: a statement from the
International Committee of Medical Journal Editors. JAMA 2004;292:1363–4.

3. International Committee of Medical Journal Editors. Frequently asked questions: questions about clinical trial registration.
Available at: http://www.icmje.org/faq_clinical.html. Retrieved November 6, 2013.
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