Review

Liver disease in pregnancy

Deepak Joshi, Andra James, Alberto Quaglia, Rachel H Westbrook, Michael A Heneghan
Lancet 2010; 375: 594605
Institute of Liver Studies,
Kings College Hospital,
London, UK (D Joshi MRCP,
A Quaglia FRCPath,
R H Westbrook MRCP,
M A Heneghan MD); and
Department of Maternal-Fetal
Medicine/Obstetrics and
Gynaecology, Duke University
Medical Centre, Durham, NC,
USA (A James MD)
Correspondence to:
Dr Michael A Heneghan, Institute
of Liver Studies, Kings College
Hospital, Denmark Hill,
London SE5 9RS, UK
michael.heneghan@kch.nhs.uk

Severe liver disease in pregnancy is rare. Pregnancy-related liver disease is the most frequent cause of liver
dysfunction in pregnancy and provides a real threat to fetal and maternal survival. A rapid diagnosis dierentiating
between liver disease related and unrelated to pregnancy is required in women who present with liver dysfunction
during pregnancy. Research has improved our understanding of the pathogenesis of pregnancy-related liver
disease, which has translated into improved maternal and fetal outcomes. Here, we provide an overview of liver
diseases that occur in pregnancy, an update on the key mechanisms involved in their pathogenesis, and assessment
of available treatment options.

Introduction

Pregnancy-related liver diseases

Alterations in normal physiological and hormonal

proles occur throughout pregnancy. Moreover, changes
in liver biochemical prole are normal in pregnancy.
However, up to 3% of all pregnancies are complicated by
liver disorders.1 Severe liver disease, although rare, can
occur and leads to increased morbidity and mortality for
both mother and newborn infant. Liver disorders were
once thought to be trimester specic, but this is not
always the case. As such, liver disease in pregnancy can
be related or unrelated to pregnancy. Liver disease
unrelated to pregnancy can be further classied into preexisting disorders that might become active during
pregnancy and those co-incident with pregnancy. Panel 1
lists these liver diseases.

Hyperemesis gravidarum

Normal physiological changes in pregnancy

A rise in maternal heart rate, cardiac output, together
with a fall in blood pressure and systemic vascular
resistance, all occur during pregnancy. These alterations
mimic physiological changes in patients with
decompensated chronic liver disease. Blood volume
increases by about 50%, peaking in the second trimester.
However, blood ow to the liver remains constant and
the liver usually remains impalpable during pregnancy.
Telangiectasia or spider angiomas and palmar erythema
are normal ndings in pregnancy and are caused by the
hyperoestrogenic state. Gall bladder motility is decreased,
which increases the lithogenicity of the bile.
During a normal pregnancy, serum albumin concentration falls due to the expansion in plasma volume,
and the alkaline phosphatase activity increases due to
added placental secretion (table 1). In general, aminotransferase concentrations (alanine aminotransferase
and aspartate aminotransferase), bilirubin, and gammaglutamyl transpeptidase all remain normal throughout
pregnancy, and their change should be further
investigated. On light microscopy, the liver appears
normal or near normal.2
Ultrasonography remains the safest imaging modality
to visualise the liver during pregnancy. However, if
further detailed imaging is needed, MRI without contrast
is safe. Gadolinium-enhanced MRI should be avoided
because of transplacental transfer and unknown eects
on the fetus.3
594

Nausea and vomiting are not uncommon in pregnancy.

Hyperemesis gravidarum occurs in 0320% of all
pregnancies usually within the rst trimester.4,5 Underreporting of symptoms of this condition might account
for the variation of the reported incidence in published
reports. One of the most frequently used denitions of
hyperemesis gravidarum is that of intractable vomiting,
resulting in dehydration, ketosis, and weight loss of 5%
or more. The cause remains unclear but abnormal gastric
motility, hormonal factors, and changes in the autonomic
nervous system are all probably involved. Risk factors
include increased body-mass index (BMI), psychiatric
illness, molar pregnancy, pre-existing diabetes, and
multiple pregnancies.6,7 Hyperthyroidism is seen in an
estimated 60% of cases of hyperemesis gravidarum8,9 and
might occur because of high serum concentrations of
human chorionic gonadotropin, which has increased
thyroid-stimulating activity during pregnancy.9
Hyperemesis gravidarum can start as early as
week 4 of gestation and typically resolves by week 18.
Serum aminotransferases can be raised by as much as
20 times the upper limit of normal, but jaundice is rare
(table 2).10 Other biochemical abnormalities include
raised serum urea and creatinine concentrations, hypophosphataemia, hypomagnesiumia, and hypokalaemia.
Biochemical abnormalities resolve on resolution of
vomiting. Persistent abnormalities of the liver should
alert the physician to alternative diagnoses (ie, viral
hepatitis). Liver biopsy is not indicated, but when done,
it shows non-specic changes including mild steatosis

Search strategy and selection criteria

We searched Medline (from January, 1966, to present)
for publications containing the terms liver disease in
pregnancy in combination with jaundice and
transplantation. We selected publications mainly from the
past 5 years, but did not exclude seminal older publications.
We also reviewed reference lists of publications identied by
this search strategy and selected those we judged relevant.
Our reference list was modied on the basis of comments
from peer reviewers.

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Review

and cholestasis.2 Persistent symptoms beyond week 18

should warrant consideration of a gastroscopy to
exclude mechanical obstruction.
Treatment of hyperemesis gravidarum is supportive
and includes intravenous rehydration, antiemetics, and
gradual reintroduction of oral intake. Vitamin
supplementation, especially thiamine, is mandatory to
prevent Wernickes encephalopathy. Most patients will
need 58 days of hospital admission, but relapse
is common. No benet in outcomes is seen with the
use of steroids.11 Recurrence in subsequent pregnancies
is common.

Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis is dened as pruritus with
elevated serum bile acids occurring in the second half of
pregnancy, which resolves after delivery.12 Recurrence in
subsequent pregnancies is common. The incidence in
Europe ranges from 01% to 15% of pregnancies
compared with a much higher incidence in Scandinavia
and South America.12,13 Maternal morbidity is low and
therefore the importance of this disorder is related to its
eects on the fetus. Intrahepatic cholestasis can lead to
chronic placental insuciency, resulting in fetal
complications that include anoxia, prematurity, perinatal
death, fetal distress, and stillbirth.14 Risk factors include
women who develop cholestasis secondary to the oral
contraceptive pill and a family history of the condition.
The cause of intrahepatic cholestasis remains unclear
but is related to abnormal biliary transport across the
canalicular membrane. Direct eects of female sex
hormones induce cholestasis and inhibit the bile salt
export pump. Mutations in the bile salt export pump
have been implicated in the pathogenesis of intrahepatic
cholestasis.15,16 The multidrug resistance protein 3
(MDR3) is the key transporter for phospholipids across
the canalicular membrane (gure 1). Mutations in this
gene lead to loss of function and thus increased serum
bile acids.18 The MDR3 mutation is located on
chromosome 7q21.1 and has been identied in 15% of
cases of intrahepatic cholestasis.17 Overall, ten dierent
mutations have been identied.18,19 Floreani and
colleagues19 found that only heterozygous mutations
cause transporter dysfunction, whereas complete
absence of transport function is associated with severe
liver disease.
The key symptom is pruritus, especially of the palms
and soles, which is followed by generalised symptoms,
and this usually occurs from week 25 of gestation.
Jaundice is uncommon, but when present, arises
24 weeks after the onset of pruritus. Aminotransferase
activity can be increased by 20 times the normal level.
Raised gamma-glutamyl transferase activity is unusual
but is indicative of MDR3 mutation or underlying liver
disease unrelated to pregnancy. The key diagnostic test is
a fasting serum bile acid concentration of greater than
10 mol/L.14 Prospective studies have shown that fetal
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Panel 1: Classication of liver diseases in pregnancy

Pregnancy-related liver diseases
Hyperemesis gravidarum
Intrahepatic cholestasis of pregnancy
Pre-eclampsia and eclampsia
HELLP syndrome
Acute fatty liver of pregnancy
Pregnancy-unrelated liver diseases
Pre-existing liver diseases
Cirrhosis and portal hypertension
Hepatitis B and C
Autoimmune liver disease
Wilsons disease
Liver diseases co-incident with pregnancy
Viral hepatitis
Biliary disease
Budd-Chiari syndrome
Liver transplantation
Drug-induced hepatotoxicity
HELLP=haemolysis, elevated liver enzymes, and low platelets.

Alteration from nonpregnant state

Haemoglobin (118148 g/L)

from second trimester

White cell count (39111109/L)

Platelets (150450109/L)

None

Packed cell volume (036044 L/L)

Prothrombin time (1012 s)

None

Alkaline phosphatase (42128 IU/L)

(bone and placenta)

Albumin (3550 g/L)

ALT (070 IU/L)

None

GGT (235 IU/L)

None

Bilirubin (017 mol/L)

None

Alpha-fetoprotein (044 g/L)

Cholesterol (355 mmol/L)

Uric acid (160395 mol/L)

=increase. =decrease. ALT=alanine aminotransferase. GGT=gamma-glutamyl

transpeptidase.

Table 1: Biochemical changes during normal pregnancy

complications correlate with serum bile acid

concentrationsthe risk being inexistent if levels remain
below 40 mol/L.14,20 Patients can also develop diarrhoea
and steatorrhoea requiring fat soluble vitamin
supplementation. Liver biopsy is not needed. Histological
ndings consist of perivenular canalicular cholestasis
with preserved portal tracts.
Early recognition and diagnosis of intrahepatic
cholestasis with a multidisciplinary approach incorporating hepatological support is important. Women
before weeks 3334 of pregnancy should be referred to
obstetric centres with appropriate facilities for high-risk
premature newborn infants.
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Hypertension-related liver diseases and pregnancy

PFIC1, BRIC1

Amino phospholipids

FIC1
(ATP 8B1)

MRP2
(ABCC2)

Conjugated bilirubin
Glutathione

Bile acids

BSEP
(ABCB11)

MDR3
(ABCB4)

Phosphatidylcholine

MDR1
(ABCB1)

ABCG5/8

Sitosterol
Cholesterol

Drugs

Hypertension in pregnancy is dened as a blood pressure

greater than 140/90 mm Hg on at least two occasions.
Pre-eclampsia, eclampsia, HELLP (haemolysis elevated
liver enzymes and low platelets) syndrome, hepatic
infarction, and rupture are all related to hypertension in
pregnancy.

Dubin-Johnson syndrome

ICP, PFIC3,
drug-induced
cholestasis

Hepatocyte
Cystic brosis
PFIC2, BRIC2
Bileduct

Cl
Cl

CFTR (ABCC7)

Chloride

AE2 (SLC4A2)

Bicarbonate

HCO3

Figure 1: Hepatobiliary transporters

MDR3 translocates phosphatidylcholine across the canalicular membrane. Lack of this phospholipid leads to the
formation of toxic monomeric bile salts in the bile ducts, which in turn results in cholangiocyte injury,
pericholangitis, and periductal brosis. Mutations in the MDR3 transporter have been identied in the
pathogenesis of drug-induced cholestasis, PFIC3, and cholestasis of pregnancy. Red dotted arrows show the
phenotype expressed when a mutation occurs in the targeted transporter gene. PFIC1=progressive familial
intrahepatic cholestasis type 1. PFIC2=progressive familial intrahepatic cholestasis type 2. PFIC3=progressive
familial intrahepatic cholestasis type 3. ABCG5/8=ATP binding cassette transporters G5 and G8. AE2=anion
exchanger. BSEP=bile salt export pump. BRIC1=benign recurrent intrahepatic cholestasis type 1. BRIC2=benign
intrahepatic cholestasis type 2. CFTR=cystic brosis transmembrane conductance regulator. FIC1=familial
intrahepatic cholestasis type 1. ICP=intrahepatic cholestasis of pregnancy. Cl= chloride ion. HCO3=bicarbonate
ion. MRP2=multidrug resistance-associated protein 2. MDR1=multidrug resistance protein 1. MDR3=multidrug
resistance protein 3. Modied, with permission, from Trauner and colleagues.17

Ursodeoxycholic acid decreases plasma bile acid and

sulphated progesterone metabolite concentrations.
Studies have also shown that it increases bile salt export
pump (ATPB11, MDR3, and MRP4) expression.21
Ursodeoxycholic acid (1015 mg/kg bodyweight) provides
relief against pruritus, improve liver function tests, and
is well tolerated both by mother and fetus.22 Improvement
in pruritus might be associated with decreased urinary
excretion of progesterone metabolites specic for
intrahepatic cholestasis of pregnancy.23 Glantz and
colleagues20 showed that ursodeoxycholic acid is more
eective in alleviating pruritus than is dexamethasone
(p=001) in patients with bile acid concentrations greater
than 40 mol/L. When delivery is being considered in a
preterm fetus, the administration of dexamethasone also
promotes fetal lung maturity. Cholestyramine can also be
used, but is not very eective at decreasing serum bile
acid concentrations and can exacerbate vitamin K
deciency.
Intrahepatic cholestasis of pregnancy normally resolves
after delivery but, in rare cases of familial forms, the
condition can persist after delivery, leading to brosis
and even cirrhosis.24 In these cases, an increased risk of
cholestatic liver disease exists, irrespective of pregnancy.
Intrahepatic cholestasis of pregnancy might therefore be
a predictor for the development of liver and biliary disease
in the future.24
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Pre-eclampsia and eclampsia

Pre-eclampsia is a multisystem disorder aecting
510% of all pregnancies and can involve the kidneys,
the CNS, the haematological system, and the liver. Preeclampsia is characterised by hypertension and
proteinuria (greater than 300 mg in 24 h) after 20 weeks
of gestation and/or within 48 h after delivery. Oedema
is no longer needed for the diagnosis of pre-eclampsia.25
Presence of seizures dierentiates eclampsia from preeclampsia. Atypical pre-eclampsia is the occurrence of
the signs, symptoms, and the biochemical abnormalities
of pre-eclampsia but without hypertension or
proteinuria. Risk factors for pre-eclampsia include
extremes of maternal age (<16 years and >45 years),
primiparity, pre-existing hypertension, family history,
and occurrence in a previous pregnancy. Placental
ischaemia, leading to endothelial dysfunction and
coagulation activation, is thought to be important.26
Genetic predisposition and imbalance of prostacyclin
and thromboxane have also been implicated in the
pathogenesis of pre-eclampsia.27
Clinical features include right upper abdominal pain,
headache, nausea, and vomiting. Abnormal liver function
tests, which are thought to be secondary to vasoconstriction of the hepatic vascular bed, occur in 2030%
of patients. Aminotransferase activity could be as high
as ten times the upper limit of normal, whereas bilirubin
concentrations are rarely increased. Liver biopsy is not
indicated. Characteristic microscopic changes (gure 2)
involve periportal areas with identiable sinusoidal
brin thrombi, haemorrhage, and hepatocellular
necrosis. Portal thrombosis and haemorrhage can also
be present. Tight control of blood pressure is essential,
but liver involvement, albeit infrequent, suggests severe
disease, thus alerting the physician that immediate
delivery is necessary. Complications include maternal
hypertensive crises, renal dysfunction, hepatic rupture
or infarction, seizures, and increased perinatal morbidity
and mortality. Liver biochemical prole usually
normalises within 2 weeks of delivery.

HELLP syndrome
The combination of haemolysis with a micro-angiopathic
blood smear, increased liver enzymes, and low platelets
(HELLP) in pregnancy was rst described in 1982 by
Weinstein28 and aects six in 1000 pregnancies. 510% of
women with pre-eclampsia develop HELLP.29,30 Although
HELLP shows symptoms similar to pre-eclampsia and is
one of the criteria that can dene severe pre-eclampsia, it
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Review

can develop in women who might not have any other

signs or symptoms of pre-eclampsia. A perinatal infant
mortality rate of 670% has been reported due to
prematurity, or secondary to maternal complications.31
HELLP usually arises in the second or third trimester,
but can also develop after delivery. Risk factors include
advanced maternal age, multiparity, and white ethnic
origin.
Angiogenic markers have also been identied, which
might help to conrm the diagnosis of pre-eclampsia in
women without hypertension or proteinuria. They
include decreased placental growth factor, increased
serum soluble endoglin, and increased soluble fms-like
tyrosine kinase-1 (VEGF) receptor.3236
Patients with HELLP syndrome might be asymptomatic
or present with right upper quadrant and epigastric
pain, nausea, vomiting, and malaise. Hypertension and
proteinuria is evident in up to 85% of cases. Liver injury
is precipitated by intravascular brin deposition, hypovolaemia, and increased sinusoidal pressure resulting
in mild-to-moderate increase of aminotransferases and
mild elevation of bilirubin. Recognised classication
systems of HELLP include the Tennessee and the
Mississippi systems (panel 2).37 In the Tennessee
system classication, the result can be complete
(ie, demonstration of haemolysis [raised lactate dehydrogenase, decreased haptoglobin, raised unconjugated
bilirubin], thrombocytopenia [secondary to vascular
endothelial damage and brin deposition in vascular
walls], and elevated aminotransferases) or partial
(ie, encompassing one or two components). The
prothrombin time or international normalised ratio
remains normal unless there is evidence of disseminated
intravascular coagulation or severe liver injury. A serum
uric acid of more than 464 mol/L is associated with
increased maternal and fetal morbidity and mortality.20,31
Liver biopsy remains a high-risk procedure because of
the thrombocytopenia. Microscopic ndings may be
non-specic or similar to those of pre-eclampsia
(gure 2).

Hepatic haematoma, infarction, and rupture

CT or MRI of the liver could identify hepatic infarction
and rupture, haemorrhage, or subcapsular haematoma.
The dierential diagnosis includes acute fatty liver of
pregnancy, thrombotic thrombocytopenic purpura, and
haemolytic uraemic syndrome. Hepatic haematoma,
infarction, and rupture occur in a minority of women
with established pre-eclampsia or HELLP syndrome.
50% maternal mortality has been reported for this
complication of disease, with prevalence of hepatic
rupture being higher with severe thrombocytopenia.38
Hepatic adenoma, hepatocellular carcinoma, and
haemangiomas might also rupture during pregnancy.
Risk factors for rupture include advanced maternal
age, multiparity, and pre-eclampsia. Patients with
hepatic haematoma secondary to a ruptured liver
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Figure 2: Liver biopsy from a young woman with eclampsia

Haematoxylin and eosin staining. Liver biopsy shows an area of coagulative necrosis (marked by the arrows),
which involves perivenular and midzonal hepatocytes. The arrowhead indicates a portal tract.

Panel 2: Classication systems used in HELLP syndrome

Tennessee system
AST >70 IU/L
LDH >600 IU/L
Platelets <100109/L
Mississippi system
AST >40 IU/L and LDH >600 IU/L and:
Class I: platelets <50109/L
Class II: platelets 50100109/L
Class III: platelets 100150109/L
HELLP=haemolysis, elevated liver enzymes, and low platelets. AST=aspartate
aminotransferase. LDH=lactate dehydrogenase.

capsule typically present in the third trimester with

severe right upper quadrant pain and pyrexia, although
the presentation can also be early after delivery.
Increased aminotransferase concentrations in excess of
3000 U/L, leucocytosis, pyrexia, and anaemia are
frequently seen. Acute complications include acute
respiratory distress syndrome, acute kidney injury, and
hypovolaemic shock. CT and MRI help to identify these
pathologies (gure 3). Contained haematomas should
be managed conservatively with blood transfusion and
supportive measures for the mother. Infection can occur
within areas of hepatic infarction. Haemodynamic
instability suggests persistent active bleeding and
should prompt hepatic angiography, and when required,
invasive haemostatic measures by arterial embolisation
of the hepatic artery or surgical exploration. Surgical
options include packing, hepatic artery ligation, or
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Figure 3: Abdominal CT showing a subcapsular haematoma in a woman with HELLP syndrome

Acyl-CoA

Acute fatty liver of pregnancy

Shortened
acyl-CoA
3-ketoacyl-CoA
thiolase

Acyl-CoA
dehydrogenase

3-ketoacyl-CoA
LCHAD deciency

2,3-enoyl-CoA
Tri-functional
protein
deciency

3-hydroxyacyl-CoA
dehydrogenase
3-hydroxyacyl-CoA

2,3-enoyl-CoA
hydratase

Trifunctional protein

Figure 4: Cycle of mitochondrial oxidation

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) catalyses the third step in the oxidation of fatty acids in
mitochondria (the formation of 3-ketoacyl-CoA from 3-hydroxyacyl-CoA). The accumulation of long-chain
3-hydroxyacyl metabolites produced by the fetus or placenta is toxic to the liver. LCHAD deciency in infants can
lead to non-ketotic hypoglycaemia, hepatic encephalopathy, cardiomyopathy, peripheral neuropathy, myopathy,
and sudden death. Modied, with permission, from Ibdah and colleagues.53

resection of the aected liver. No long-term maternal

complications have been reported.
Women with HELLP syndrome might need a highdependency unit or an intensive care setting because of
the potential complications of hepatic encephalopathy,
acute renal dysfunction, hepatic rupture, and bleeding.
The cornerstone of management is delivery. Prompt
delivery should be undertaken if pregnancy is over
34 weeks of gestation, if fetal distress is present, or if
evidence exists of maternal end-organ disease
(ie, disseminated intravascular coagulation, renal failure,
or abruptia placenta).39 Management of hypertension
involves the use of labetalol, hydralazine, and nifedipine.
Diuretics are not recommended in patients with HELLP,
598

because they can cause uteroplacental hypoperfusion.39

Intravenous magnesium sulphate with platelet,
coagulation support, or both, are recommended,
especially in the presence of bleeding. If gestation is less
than 34 weeks, corticosteroids should be administered to
promote fetal lung maturity only, because they do not
provide any maternal benet.40
Women with atypical pre-eclampsia have a more
dicult diagnostic and management conundrum.
Physicians should therefore be vigilant to atypical
presentations of pre-eclampsia with careful assessment
of maternal risk factors, laboratory ndings, and timing
in the course of pregnancy.
The risk of recurrence of HELLP syndrome in
subsequent pregnancies is increased.41,42 HELLP
syndrome usually resolves rapidly after delivery.
Laboratory values, however, might worsen after delivery.
Hepatic or renal failure necessitates admission to
intensive care. Indications for liver transplantation
include persistent bleeding from haematoma, hepatic
rupture, or liver failure.43 88% of these patients survive
5 years after liver transplant.44

First described in 1934 by Stander and Cadden45 as acute

yellow atrophy of the liver, acute fatty liver of pregnancy
remains a medical and obstetric emergency. This
condition is dened as microvesicular fatty inltration
of hepatocytes during the second half of pregnancy
(usually third trimester), and it remains a common
cause of liver failure in pregnancy. Maternal and fetal
mortality rates are signicantly increased and range
between 1% and 20%.46
Acute fatty liver of pregnancy is a rare disorder aecting
from one in 7000 to one in 16 000 pregnancies,47,48
therefore making it dicult to study. A recent UK-based
prospective study involving 229 centres identied
57 conrmed cases in a total of 1 132 964 pregnancies,
giving an incidence of ve in 100 000 pregnancies.49 74%
of cases were identied at a median gestation age of
36 weeks, with 60% of cases delivered within 24 h of
diagnosis.49 The caesarean section rate was 74%.
Acute fatty liver of pregnancy is one of the mitochondrial
cytopathies, which include Reyes syndrome and other
drug-related liver diseases. Common characteristics of
these disorders include vomiting, hypoglyacaemia, lactic
acidosis, hyperammonaemia, and microvesicular fat
deposition in organs. Abnormality in mitochondrial
oxidation is recognised as the cause of this condition.48
Mitochondrial oxidation of fatty acids is a complex
process and is an important energy source for skeletal
muscle and myocardial tissue. The enzyme long-chain
3-hydoxyacyl coenzyme A dehydrogenase is part of the
mitochondrial trifunctional protein (MTP), which is an
important complex associated with the inner mitochondrial
membrane.50,51 MTP is an hetero-octamer consisting of
four subunits and four subunits52 (gure 4).
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Ibdah and colleagues53 showed that sick infants born to

mothers with acute fatty liver of pregnancy with features
of HELLP syndrome had defects in fatty acid oxidation
and were decient in the long-chain 3-hydoxyacyl
coenzyme A dehydrogenase predominately because of
the Glu47G1n mutation on one or both alleles of
the subunit of the trifunctional protein.53 Long-chain
3-hydoxyacyl coenzyme A dehydrogenase deciency in
the fetus was associated with a 79% chance of developing
either acute fatty liver of pregnancy or HELLP syndrome.53
Other studies have identied the association between the
long-chain 3-hydoxyacyl coenzyme A dehydrogenase
deciency, especially the G1528C mutation on one or
both alleles, and acute fatty liver of pregnancy.54 A 20-fold
increased risk of development of maternal liver disease
during pregnancy is present in fetuses with fatty acid
oxidation defects compared with those without the
defect.55 Fetal fatty acids accumulate and return to the
maternal circulation. These long-chain fatty acids are
deposited in the liver, thus causing liver toxicity.
Clinical presentation of acute fatty liver of pregnancy
varies from nausea and abdominal pain to hepatic
encephalopathy and jaundice. Risk factors include twin
pregnancies and nulliparity. Knight and colleagues49
identied that an inverse relation may exist between BMI
and acute fatty liver of pregnancy, in contrast to the direct
association between BMI in pre-eclampsia.56,57 Disseminated
intravascular coagulation can occur with normal hepatic
laboratory ndings, but common abnormalities include
raised aminotransferase concentrations, prothrombin
time, and serum uric acid and bilirubin concentrations.
Hypoglycaemia is a poor prognostic sign. Serum ammonia
concentration rise and lactic acidosis are present in severe
disease. Evidence of renal dysfunction is common.
Leucocytosis occurs in 98% of patients.49 Dierential
diagnosis includes HELLP syndrome and viral hepatitis.
Ultrasonography and computed tomography might be
inconsistent at detecting fatty inltration.58 Viral serology is
mandatory in every case.
Although the gold standard for diagnosis is liver biopsy
(gure 5), this is rarely necessary. The characteristic
microscopic change is microvescicular steatosis, which
can be in the form of minute cytoplasmic vacuoles or
diuse cytoplasmic ballooning that might spare the
periportal hepatocytes. This latter change might simulate
hepatocyte ballooning of other causes. Canalicular
cholestasis is also present. Necrosis of individual or
groups of hepatocytes replaced by ceroid-laden
macrophages might be present. Extra-medullary
haemopoiesis might also be present.2 These changes
disappear within days to weeks after delivery without
persistent injury. The Swansea diagnostic criteria are an
alternative to liver biopsy (panel 3).
Prompt delivery is essential in women with acute fatty
liver of pregnancy. Steroids might be needed for lung
maturation in preterm fetuses. After delivery, women
can develop a long cholestatic phase, taking up to 4 weeks
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Figure 5: Acute fatty liver of pregnancy

Haematoxylin and eosin staining. Hepatocytes show a clear cytoplasm (arrow) or many minute vacuoles
(arrowhead) consistent with steatosis. In the inset, the appearance of conventional macrosteatosis as seen in
steato-hepatitis.

for resolution. Liver transplantation warrants consideration in cases of severe hepatic encephalopathy, liver
rupture, and in case of failure of recovery of liver function.
The newborn infant should be assessed for signs of
hypoglycaemia, hepatic failure, myopathy, and other
features associated with defects in fatty acid oxidation.
An increased recurrence rate has only been reported
in women who carry the long-chain 3-hydoxyacyl
coenzyme A dehydrogenase mutations.54 However,
recurrent acute fatty liver of pregnancy might also reoccur in women without detectable mutations.59 Infants
born to mothers with acute fatty liver of pregnancy should
be screened for defects of fatty acid oxidation. Women
can, however, be reassured that chronic liver disease does
not develop in acute fatty liver of pregnancy.

Pre-existing liver diseases and pregnancy

Cirrhosis with portal hypertension
Pregnancy in cirrhotic women is rare.60 Cirrhosis leads to
anovulation and amenorrhoea due to many factors that
include disturbed oestrogen and endocrine metabolism.61,62
When pregnancy is successful in a cirrhotic woman,
spontaneous abortion rate, risk of prematurity, and
perinatal death rate are all increased.63 Cirrhotic patients
have a high risk of liver decompensation because of
worsening synthetic liver function, development of ascites,
and hepatic encephalopathy.63 Maternal mortality rate as
high as 105% has been described in this group.64 Maternal
prognosis depends on the degree of hepatic dysfunction
during pregnancy rather than its cause.46 Portal
hypertension worsens during pregnancy because of
increased blood volume and ow. Portal pressures can
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Panel 3: Swansea diagnostic criteria for diagnosis of acute

fatty liver of pregnancy1
Six or more of the following features in the absence of
another explanation
Vomiting
Abdominal pain
Polydipsia/polyuria
Encephalopathy
High bilirubin (>14 mol/L)
Hypoglycaemia (<4 mmol/L)
High uric acid (>340 mol/L)
Leucocytosis (>11106/L)
Ascites or bright liver on ultrasound scan
High AST/ALT (>42 IU/L)
High ammonia (>47 mol/L)
Renal impairment (creatinine >150 mol/L)
Coagulopathy (PT >14 s or APTT >34 s)
Microvesicular steatosis on liver biopsy
ALT=Alanine aminotransferase. AST=aspartate aminotransferase. PT=prothrombin
time. APTT=activated partial thromboplastin time.

also increase because of an increased vascular resistance

due to external compression of the inferior vena cava by
the gravid uterus. Up to 25% of patients with varices have
a bleeding episode during pregnancy.65 The greatest risk is
seen in the second trimester, when portal pressures peak,
and during delivery because of the repeated use of the
valsalva manoeuvre to help to expel the fetus.64 Rupture of
splenic artery aneurysm, although uncommon, could also
present in pregnant women with portal hypertension.
All cirrhotic patients should undergo variceal screening.
Banding before pregnancy, although not proven, is
appropriate for high-risk varices. Propranolol has also
been used safely in pregnancy but side-eects include
fetal growth retardation, neonatal bradycardia, and
hypoglycaemia. Terlipressin has not been studied in
pregnancy but concerns have been raised about decreased
placental perfusion and increased risk of placental
abruption. The use of a transjugular intrahepatic portosystemic shunt in extreme cases of variceal bleeding can
be considered but has the risk of radiation exposure to
the fetus.

Hepatitis B and hepatitis C infections

In many developed countries, pregnant women are
routinely screened for hepatitis B virus (HBV) at the
initial booking visit.66 HBV vaccine can be given safely
during pregnancy if needed.67 Women who are not
cirrhotic but HBV-positive are at risk of transmitting the
virus to the fetus. Vertical transmission remains the most
common way of transmission of HBV in endemic areas
and accounts for most HBV infection worldwide. Chronic
HBV infection is more likely in the newborn infant when
the mother is positive to both hepatitis B surface antigen
and hepatitis B e antigen, and also has a high HBV viral
600

load. HBV viral load is a key factor in transmission, with

high viral load being associated with 8090% risk of
transmission compared with 1030% transmission rates
in patients with undetectable viral load.68,69 Transmission
can occur directly via the placenta (intrauterine), during
breastfeeding, or during delivery. Mode of delivery does
not aect the risk of transmission, with similar rates seen
with normal vaginal delivery and caesarean section.70
Transmission can be reduced further by administration
of hepatitis B immunoglobulin to the neonate within 12 h
of birth.71 HBV vaccine should also be administered, with
three doses being given to the infant within the rst
6 months.
Use of lamivudine and other antiviral drugs during the
third trimester to reduce HBV viral load,72 and thus
decrease the risk of transmission to the fetus, is a source
of debate. Use of lamivudine monotherapy could
predispose to viral mutations, thus rendering the patient
susceptible to viral resistance to both lamivudine and
other antiviral drugs long term. Lamivudine, which has
been classied by the US Food and Drug Administration
(FDA) as a category C drug in pregnancy, has been used
successfully in patients with both HBV and HIV infection
during pregnancy without substantial risk to either
mother or fetus. Entecavir, a more potent nucleoside
analogue with a better long-term viral resistance prole
than lamivudine, and designated as a category C drug in
pregnancy by the FDA, also shows promise, whereas
tenofovir, widely used in HIV-positive pregnant patients,
seems to have a better safety prole than both entecavir
and lamivudine, and is regarded as a category B drug.
At present, no guidelines exist for the use of lamivudine
or any other nucleoside in HBV-positive pregnant
women, and therefore any decisions should be made on
an individual basis. We advise the use of either
lamivudine or tenofovir after week 32 of gestation in
patients with a high HBV viral load (greater than
10 copies per mL), especially in mothers who might
have already infected their child during their previous
pregnancy. However, the duration of therapy needs to be
considered carefully. Moreover, the use of antiviral
agents should not be a substitute to appropriate
vaccination.
Pregnancy in patients with hepatitis C virus (HCV) is
usually uneventful. Risk of vertical transmission of HCV
remains low, except when the fetus is exposed to large
volumes of mothers blood and vaginal uid during
delivery or if the mother is co-infected with HIV.73,74
Patients with genotypes 1 or 3 and with HIV co-infection
are more likely to transmit HCV vertically.75 Ribavirin is
teratogenic and the use of pegylated interferon in
combination with ribavirin is contra-indicated during
pregnancy, but not during breastfeeding.

Autoimmune liver disease

Successful pregnancies are achievable in women with
autoimmune hepatitis. Some studies have shown that
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Review

ares in disease activity are more likely to occur in the

rst 3 months after delivery, although autoimmune
hepatitis might present for the rst time during
pregnancy.76,77 Women with autoimmune hepatitis need
stable immunosuppression throughout pregnancy.
Although azathioprine is teratogenic in animal models,
teratogenic eects in human beings have not been
described. Two separate studies failed to show toxic
eects of azathioprine or its metabolites during
pregnancy.76,77 Fetal side-eects have been reported,
however, and include lymphopoenia, hypogammaglobulinaemia, and thymic hypolasia. If ares occur,
then they should be managed in the conventional
mannerthat is, administration of steroids or increase
in steroid dose. If an immunosuppressant is needed,
azathioprine remains the safest choice. A study76
described the presence of antibodies to SLA/LP and
Ro(SSA) as risk factors for adverse outcomes in
pregnancy.
Primary biliary cirrhosis is a chronic cholestatic disease
that leads to destruction of intrahepatic bile ducts.
Deterioration in synthetic liver function can occur during
pregnancy.78 Primary biliary cirrhosis might also present
for the rst time after delivery with protracted pruritus.
Ursodeoxycholic acid can be used safely in pregnant
women with primary biliary cirrhosis.78

Wilsons disease
Wilsons disease is a rare autosomal recessive disease of
defective biliary copper excretion, which leads to copper
deposition in the liver, brain, and kidneys. Patients
usually present with hyperbilirubinaemia, high concentrations of aminotransferases, Coombes-negative
haemolytic anaemia, and low serum alkaline phosphatase.
In pregnant women with undiagnosed Wilsons disease,
evidence of acute liver failure and haemolysis could be
misinterpreted as HELLP syndrome.
In women with known Wilsons disease, serum copper
levels and caeruloplasmin can rise during pregnancy79
without treatment, leading to a are in patient symptoms.
Zinc can be continued in pregnancy without causing
harm to the fetus.80

Liver diseases co-incident with pregnancy

Acute viral hepatitis
Hepatitis A virus (HAV) infection in pregnancy has a
clinical course similar to that in the non-pregnant
population.81 A recent study has identied the presence
of ascites and hypertension as factors that help to
dierentiate liver disease specic to pregnancy from viral
hepatitis.82 Increased severity of disease is associated with
advanced maternal age, with severe infection in the third
trimester associated with an increased risk of
prematurity.83 Treatment is supportive.
Pregnant women are more vulnerable to hepatitis E
virus (HEV) infection than to HAV, HBV, and HCV.84
HEV remains the most prevalent viral cause of acute
www.thelancet.com Vol 375 February 13, 2010

Figure 6: Percutaneous transhepatic cholangiogram showing large choledochal cysts

Two large choledochal cysts (arrows) in a patient who had previously undergone biliary reconstruction due to
repeated bouts of biliary sepsis.
Trimester

Diagnostics

HG

1, 2

Bilirubin (4 ULN), ALT/AST (24 ULN)

ICP

1, 2, 3

Bilirubin (6 ULN), ALT/AST (6 ULN), bile acids

Pre-eclampsia

2, 3

Bilirubin (25 ULN), ALT/AST (1050 ULN), platelets

HELLP

2, 3

ALT/AST (1020 ULN), LDH, platelets, uric acid

AFLP

2, 3

Bilirubin (6-8 ULN), ALT/AST (510 ULN)rarely >20

=increase. =decrease. HG=hyperemesis gravidarum. ICP=intrahepatic cholestasis of pregnancy. HELLP=haemolysis,

elevated liver enzymes, and low platelets. AFLP=acute fatty liver of pregnancy. ALT=alanine aminotransferase.
AST=aspartate aminotransferase. LDH=lactate dehydrogenase. ULN=upper limit of normal.

Table 2: Characteristic timings and diagnostic laboratory features of liver diseases related to
pregnancy

liver failure in pregnancy.85 Endemic in parts of Asia

and Africa, HEV-related hepatitis usually follows a more
severe course in pregnancy, especially in the Indian
subcontinent,8688 with these patients more likely to
develop fulminant hepatic failure.89 In-utero transmission of HEV to the fetus might add further toxic
metabolites to the maternal circulation,90,91 resulting in
increased maternal morbidity and mortality.92 Pregnant
women are more likely to acquire HEV in the second or
third trimester, with a median gestational age of
28 weeks.86 Reported maternal mortality from fulminant
hepatic failure secondary to HEV in pregnancy is
601

Review

Side-eects

FDA category

Azathioprine

Lymphopenia, hypogammaglobulinaemia, thymic hypoplasia

Ciclosporin A

Premature labour, low birthweight, neonatal hyperkalaemia, renal

dysfunction

Mycophenalate
mofetil

First trimester loss, microtia. Increased risk of congenital malformations D

Prednisolone

Cleft palate, intrauterine growth retardation, premature rupture of

membranes, fetal adrenal hypoplasia

Tacrolimus

Similar side-eects to ciclosporin. Neonatal malformation rates of 4%

FDA=US Food and Drug Administration. Pregnancy category C: animal reproduction studies have shown an
adverse effect on the fetus, but no adequate and well controlled studies in human beings exist. Potential benefits
might warrant use of the drug in pregnant women despite potential risks. Pregnancy category D: positive
evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or
studies in human beings. However, potential benefits might warrant use of the drug in pregnant women despite
potential risks.

Table 3: Common side-eects of immunosuppressants

4154%,82,93 with a fetal mortality rate of 69%.75 Poor

outcomes are associated with the development of
grade III or IV hepatic encephalopathy,75 irrespective of
which trimester the infection was contracted. Management is supportive, ideally including intensive care unit
input. Remarkably, delivery does not aect maternal
outcome.
Herpes simplex virus (HSV) hepatitis is a rare
condition, occurring predominantly in immunocompromised individuals or children.94,95 Pregnant
women, however, are more susceptible than the general
population to HSV hepatitis,96 with a 39% maternal
mortality. HSV serotypes 1 and 2 have been seen in
pregnancy and are caused by primary or latent disease.
Raised aminotransferases, thrombocytopenia, leucopenia, and coagulopathy with a normal concentration of
serum bilirubin are common laboratory ndings.
Mucocutaneous lesions associated with HSV infection
might be present, but only in 50% of cases.97 HSV
hepatitis should be considered in any pregnant woman
with hepatic failure. Liver biopsy provides the denitive
evidence of HSV hepatitis, but computed tomography
could also be useful, showing multiple low-density areas
of necrosis within the liver. Treatment with intravenous
aciclovir should not be delayed until conrmatory
results are available, and should therefore be commenced
if clinical suspicion is high. Treatment with aciclovir is
associated with improved survival rate.96 Published
reports of this rare disease are unclear as to whether
delivery improves neonatal survival.

Biliary disease
Gallstones are more common in pregnancy because of
increased cholesterol secretion in the second and third
trimester, increased lithogenicity of the bile, and
decreased gallbladder motility.98 About 10% of pregnant
women develop either gallstones or viscus biliary
sludge.99 Open or laparoscopic cholecystectomy can be
done safely and successfully during the second trimester.
Endoscopic retrograde cholangiopancreatography and
602

sphincterotomy can be done if needed, with little added

risk compared with that in non-pregnant women.100
Choledochal anomalies (gure 6) might also present in
pregnancy, as a consequence of bile stasis and stone
formation. Septic episodes can ensue.

Budd-Chiari syndrome
Budd-Chiari syndrome is dened as outow obstruction
of the hepatic veins. It is commonly associated with
myeloproliferative disorders. Up to 20% of cases of
Budd-Chiari syndrome occur in women who are on the
oral contraceptive pill, are pregnant, or have delivered in
the previous 2 months.101 Pregnancy itself represents a
prothrombotic state; a physiological decrease of
protein S concentration is seen,102 which might account
for the increased incidence of Budd-Chiari syndrome in
pregnancy.103 Patients with known Budd-Chiari syndrome
are at risk of developing an exacerbation during
pregnancy because of the increased concentrations of
female sex hormones.80
Clinical features include right upper quadrant pain,
jaundice, and ascites. Doppler ultrasound is very
important in diagnosis. The treatment is anticoagulation
at the onset, identication of procoagulant causes, and
shunting, or liver transplantation in extreme cases.

Liver transplantation
Because of the success of liver transplantation, young
patients who have been successfully grafted can become
pregnant. Pregnancy should be deferred for 1 year after
liver transplantation, which allows lower doses of
immunosuppression and more stable graft function.
Pregnancy in this group should be managed in
specialised centres. 70% of women after liver
transplantation will deliver a healthy baby,104 although
pregnancy might pose problems, such as an increased
risk of gestational diabetes and pre-eclampsia.104,105
Caesarean deliveries are also more likely in this group:
3563% versus 23% in the general population within the
UK.106108 Commonly used drugs such as tacrolimus,
mycophenalate mofetil, prednisolone, azathioprine, and
ciclosporin all carry a risk of teratogenicity. Prematurity
and low birthweights (<2500 g) occur more frequently in
women who have previously undergone liver
transplantation. Table 3 shows the side-eects of
commonly used immunosuppressants. Mycophenalate
mofetil should be stopped in all women wishing to
become pregnant, but tacrolimus and ciclosporin can be
continued. Risk proles of prednisolone and
azathioprine, however, are acceptable and should not be
withheld. Breastfeeding is not advised while women are
taking immunosuppressants because of the uncertain
eects on the newborn infant.

Conclusion
Hepatic disorders in pregnancy are rare, but remain clinically important because of serious adverse eects on both
www.thelancet.com Vol 375 February 13, 2010

Review

mother and fetus. Liver disease in pregnancy can present

with subtle changes in liver biochemical prole or with fulminant hepatic failure. These disorders are complex and
might need to be managed by experienced physicians in
specialised centres. Maternal and fetal survival has improved because of better understanding of the pathogenesis of these disorders and higher standards of clinical care.
Contributors
DJ wrote and edited the report. AJ provided obstetric expertise, and
reviewed and edited the report. RHW reviewed and edited the report.
AQ reviewed and edited the report, and provided histopathological
expertise. MAH wrote, edited, and helped to supervise the preparation of
the report.

19

20

21

22

23

Conicts of interest
We declare that we have no conicts of interest.
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