Liver Diseases With Pregnancy3603

LIVER DISEASES WITH
PREGNANCY
Professor Mahmoud Farouk Midan
Prof. & Head of Obstetrics & Gynecology Dept.

Faculty of Medicine
Al-Azhar University
Introduction
Liver disease is a rare complication of pregnancy,
but when it occurs it may do so in a dramatic and
tragic fashion for both mother and infant.
Diseases such as acute fatty liver of pregnancy
(AFLP) may begin innocuously with mild
symptoms and liver enzyme abnormalities but, if
left untreated, can progress to jaundice, liver
failure, and death.
(Bacq & Riely , 2004)
• Some of the normal physiologic changes of
pregnancy can mimic abnormalities
associated with liver disease.
• Telangiectasia, particularly on the chest,
back, and face, and palmer erythema occur
in up to 60 percent of normal pregnant
women but disappear after delivery.
(Riely, 2001)
Extreme vigilance is needed to detect early signs
and symptoms of liver dysfunction and to
distinguish these from the anticipated benign
hepatic changes of pregnancy. Prompt
management can save the life of the mother and
the baby. Management of liver disease in
pregnancy requires a concerted effort between
the primary care physician, liver specialist,
obstetrician, and, on rare occasions, a liver
transplant team.
(Moskovitz et al., 2004)
Anatomical, Physiological,
and Biochemical changes
during pregnancy.
Anatomic Changes:
• Liver weight increases during pregnancy has not

been documented. Liver size is difficult to
estimate in pregnancy, but records fail to show
any substantial increase in liver weight in
comparison with nonpregnant controls.
• Therefore, detection of hepatomegaly is strong

evidence for the presence of liver disease.
(Fagan, 1986)
Physiology
• Hepatic blood flow is maintained at a constant

rate in pregnancy despite marked changes in the
cardiovascular system.
• Blood flow increases to the kidneys and other
organs, but hepatic blood flow is unaltered,
which results in a decline of approximately 35%
in the proportion of cardiac output delivered to
the liver.
(Fagan, 1986)
Biochemical changes during
pregnancy
• The total serum protein concentration declines
approximately 20% in midpregnancy, primarily a
result of the substantial decline in serum
albumin which may be attributed to simple
dilution caused by the increase in total blood
volume, although most other serum proteins
either remain unchanged or increase in
concentration.
(Maher et al., 1993)
• A significant rise in serum fibrinogen regularly
accompanies pregnancy. As a consequence of
increase fibrinogen synthesis.
• Other coagulation proteins, including factors VII,
VIII, IX, and X, may be increased during
pregnancy or after estrogen treatment.
(Steingrub, 2005)
• Most studies have failed to document
significant bilirubin Elevation in the
absence of specific cause during normal
pregnancy. Therefore, an increased serum
bilirubin level in pregnancy should be
considered presumptive evidence for the
presence of liver or hematologic disease.
(Steingrub, 2004)
• Alkaline phosphatase activity is increased
during the third trimester both because of
leakage of placental alkaline phosphatase
into the maternal circulation and because
of increased maternal bone turnover.
(Riely, 1999)
Serum bile acid level is quite helpful in any form of
cholestasis. The serum level is normal in normal
pregnancy.
Levels of serum aminotransferase-aspartate
aminotransferase (AST) and alanine
aminotransferase (ALT) are normal in normal
pregnancy. Therefore, these two serum enzyme
determinations remain sensitive indicators of liver
damage during pregnancy. The ALT is especially
useful, because significant elevation of this
enzyme does not occur with injury to tissues
other than liver.
(Bacq et al., 2004)
Summary of physiological changes in the liver during
pregnancy
• Increased:
• Blood volume and cardiac ouput rise by 35%–50%
• Alkaline phosphatase levels rise threefold or fourfold due to
• placental production
• Clotting factor changes create a hypercoagulable state
• Decreased:
• Gallbladder contractility
• Hemoglobin
• Uric acid levels
• Albumin, total protein, and antithrombin III concentrations
• No change:
• Liver aminotransferase levels (aspartate aminotransferase,
• alanine aminotransferase, gamma-glutamyl transferase)
• Bilirubin level
• Prothrombin time
Spectrum of liver diseases in
pregnancy
(Fleming & Zein, 2005)
• Preexistent liver diseases
– Portal hypertension, cirrhosis, primary biliary
cirrhosis
– Autoimmune hepatitis
– Wilson disease
– Chronic infection with hepatitis B or hepatitis
C virus
– Alcoholic liver disease
• Liver diseases coincidental with but
not induced by pregnancy
– Acute viral hepatitis and other viral infections
– Alcohol-related diseases
– Gallstone disease
– Budd-Chiari syndrome
• Liver diseases induced by pregnancy
– First trimester
• Hyperemesis gravidarum
– Second and third trimesters
• Intrahepatic cholestasis of pregnancy
• Preeclampsia, eclampsia, and the HELLP syndrome
• (hemolysis, elevated liver enzymes, low platelet
counts)
• Acute fatty liver of pregnancy
cirrhosis
– Wilson disease
C virus
• Pregnancy is uncommon in women with
established liver cirrhosis, including primary
biliary cirrhosis, because they tend to be past
childbearing age or infertile due to the
condition. A life-threatening complication of liver
cirrhosis is variceal bleeding associated with
portal hypertension. Treating bleeding
esophageal varices with nonselective beta-
blockers, band ligation, and octreotide is safe
and effective during pregnancy.
(Helmy &Hayes, 2001)
• Ursodeoxycholic acid (FDA category B) at
doses of 10 to 13 mg/kg is treatment of
choice for primary biliary cirrhosis and
may be continued during pregnancy and
breastfeeding.
(Sternlieb, 2005)
• The presence of severe portal hypertension with
esophageal varices is associated with an
increased risk of hemorrhage during pregnancy.
The use of sclerotherapy for bleeding varices
during pregnancy may provide a safe alternative
to portacaval anastomosis and has been
reported to be effective.
(Pauzner et al., 1991)
cirrhosis
– Wilson disease
C virus
• Women with autoimmune hepatitis can
become pregnant and can still carry a
successful pregnancy. The course of the
disease is unpredictable. Although
spontaneous remission may occur, maternal
death and exacerbation during pregnancy
and after delivery have been reported.
(Heneghan et al., 2001)
Corticosteroids are the treatment of choice in
autoimmune hepatitis and appear to be safe in
pregnancy. They seem to induce rapid remission
of autoimmune hepatitis, whether during the
initial onset or during a flare. Although
azathioprine is in FDA category D (positive
evidence of risk), we have little evidence that it is
toxic in pregnancy. Data from patients with
inflammatory bowel disease suggest it is likely to
be safe in pregnancy at dosages less than 100mg/
day.
(Moskovitiz et al., 2004)
cirrhosis
– Wilson disease
C virus
Wilson disease is a rare disorder
characterized by cirrhosis, neurological
abnormalities, and less commonly
hematological and renal dysfunction.
D-Penicillamine and trientine have been used
during pregnancy. However, the dosage
should be reduced to the minimum
necessary dose, which is about 25% to
50% of the dose the patient had been
taking before the pregnancy.
(Roberts & Schilsky, 2003)
• Zinc is the agent of choice for Wilson
disease during pregnancy because of its
safety for the fetus. It should be
maintained throughout the pregnancy at
50 mg three times a day.
(Brewer et al., 2000)
Liver diseases coincidental
with but not induced by
pregnancy
Liver diseases coincidental with but
Hepatitis A
Characteristics Hepatitis A
Older name Infectious hepatitis
Virus type RNA

Virus size 27 nm
Incubation period 15 – 50 days
Transmission Fecal – oral
Vertical transmission to fetus Not observed
Serologic diagnosis Hepatitis A antibody

IgM and IgG types
Maximum infectivity Prodrome
Carrier state None
Acute clinical forms Asymptomatic to
fulminant
Chronic clinical forms None
• The clinical syndrome of acute HAV infection
consists of vague flu-like symptoms with fatigue,
weakness, nausea, and loss of appetite. The
onset is usually abrupt. A variety of extrahepatic
manifestations including myalgia, arthralgias,
arthritis, and urticaria, may occur.
• Other forms of HAV infection include cholestatic
hepatitis, with a prolonged course marked by
itching and jaundice.
(Willner, et al., 1998)
• The characteristic changes in liver function
test findings include marked elevations in
AST and ALT. Most often, these reach
levels of 1000 to 2000 U during the early
part of the infection. Elevations in bilirubin
and alkaline phosphatase also occur but
are more unpredictable.
(Fiore, et al., 2003)
• There is substantial evidence that pregnancy does
not alter the course of HAV infection. However, a
higher incidence of fulminant disease during
pregnancy has been reported in developing
nations. Concurrent malnutrition has been a
suspected cause. If the course of HAV infection is
severe, it may precipitate premature labor in
women in the third trimester of pregnancy. There
is no evidence that HAV causes birth defects, and
there is no evidence of maternal-fetal transmission.
(Atkinson, et al., 2002)
• Clinical management of pregnant patients with
HAV infection does not differ from that of those
who are not pregnant. However, hospitalization
may be indicated, specially during the last
trimester and in the presence of severe anorexia,
nausea, and vomiting.
• In rare circumstances in which the mother has
acute HAV infection at the time of delivery,
immune serum globulin may be administered to
the infant. Even under these conditions, the risk
of transmission to the infant seems very small.
(Fiore, et al., 2003)
Hepatitis B
Characteristics Hepatitis B
Older name Serum hepatitis
Virus type DNA
Virus size 42 nm
Transmission Parentral or body fluid
Vertical transmission to fetus Common
Serologic diagnosis HBs Ag, HBs Ab, IgM, and IgG
types
HBe Ag, Ab, Hepatitis B virus
DNA
Maximum infectivity Prodrome or HBe Ag Positive
Carrier state 5 – 10%
Acute clinical forms Asymptomatic to fulminant
Chronic clinical forms Chronic persistent hepatitis
Chronic active hepatitis
Cirrhosis
The incidence of the HBV carrier state
among pregnant women is variable and
depends on the patient group studied. The
incidence of HBV carriers is considerably
higher in populations in which drug abuse
is commonplace or with n high incidence
of sexual promiscuity.
(Van Zonneveld, et al., 2003)
• Evidence suggests that transmission of HBV to
infants is common when mothers have acute
infection in the third trimester or when they are
chronic carriers of HBV infection and have
positive results of serum tests for HBeAg or HBV
DNA.
• The risk of transmission is highest in mothers
who are HBeAg - positive at the time of delivery.
(Su, et al., 2004)
• In women with chronic hepatitis B infection,
taking lamivudine before becoming
pregnant and continuing to take it
throughout the pregnancy has been
reported to lower rates of transmission of
the virus from mother to newborn. Lower
transmission rates have also been seen in
pregnant women with a high viral DNA
load.
(Su, et al., 2004)
• The administration of hyperimmune
globulin and HBV vaccine protects 90% to
95% of infants from HBV infection.
It is recommended that 0.5 ml, of HBIG be
given at birth and that three doses of HBV
vaccine be given beginning at birth.
(Sehgal, et al., 1992)
• Universal vaccination of all infants at birth
for HBV is now the standard of care.
Vaccinations for all children previously not
immunized is recommended as they enter
puberty, in future generations, the specter
of viral hepatitis B and its complications
could be eliminated. Vaccine for pregnant
women exposed to hepatitis B is safe.
(Watson, 2002)
Hepatitis C
Characteristics Hepatitis C
Older name Non A non B hepatitis
Virus type RNA
Virus size 30-60 nm
Transmission Parentral sporadic
Vertical transmission to fetus Uncommon
Serologic diagnosis Hepatitis C antibody

RNA by PCR
Maximum infectivity HIV co- infected
Carrier state 50 – 85%
Acute clinical forms Asymptomatic to sever
relapsing
Chronic clinical forms Chronic persistent hepatitis
Chronic active hepatitis
Cirrhosis
• The rate of vertical transmission of hepatitis
C is less than 5%. The risk is higher if the
mother is co-infected with human
immunodeficiency virus (HIV), if she is
viremic at the time of delivery, if her viral
DNA load is greater than 1 million copies/ml,
and if the time from the rupture of
membranes to delivery is more than 6
hours.
• The mode of delivery does not seem to
influence the rate of transmission from
mother to child.
(Ceci et al., 2001)
• Breastfeeding is not considered a risk
factor for transmission, even though viral
RNA has been detected in breast milk.
Spontaneous resolution of infection in the
mother and in the newborn may occur.
(Steininger et al., 2003)
• Newborns of infected mothers should be
tested at 12 to 18 months of age, when
IgG antibodies to hepatitis C virus that may
have passively transferred from the
placenta to the fetus would have been lost,
and the persistence of hepatitis C viral RNA
would indicate infection with hepatitis C.
(Ferrero et al., 2003)
• Interferon is in FDA category C, and
ribavirin is in category X. Both drugs are
contraindicated in pregnancy. If a woman
gets pregnant while on combination
therapy, then both drugs should be
stopped, and she should be advised that
she has already put the fetus at risk of
teratogenicity.
teratogenicity
(Resti et al., 2003)
Hepatitis E
Hepatitis E (HEV) is a nonenveloped, single-
stranded RNA virus. It is endemic in
developing countries and shares the route
of transmission, risk factors, and chronicity
rate with HAV. During pregnancy, HEV can
cause fulminant hepatitis indistinguishable
from AFLP. There is a significant mortality
rate of 16% in pregnant women with acute
HEV infection.
(Aggarwal & Krawczynski, 2000)
• Transmission occurs intrapartum and
peripartum through close contact of mother
and neonate. Evidence suggests significant
vertical transmission among HEV-RNA
positive mothers of up to 50%. Among
women with symptomatic infection the rate
of transmission is up to 100%, with
significant perinatal morbidity and mortality.
(Singh et al., 2003)
Management of Acute Viral
Hepatitis in Pregnancy
Establish type by serologic test
Institute appropriate isolation and precautions
Determine need for contact prophylaxis with scrum globulin
preparation and/or vaccine
Activity: determined by tolerance
Diet: patient preference, parentral if necessary Antiemetics:
phenothiazines may be used
Corticostcroids: not indicated
Immunoprophylaxis of infant: if hepatitis B is present
Herpes simplex virus
• It can cause fulminant liver failure and death if

infection occurs during pregnancy, and the rate
of transmission to the fetus can reach 30% to
50% if the primary episode occurs at delivery.
c
y
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a
t
• About 90% of pregnant women with this
e
g
infection have abnormal liver enzyme tests
o
and an abnormal prothrombin time.
r
y
Acyclovir (FDA pregnancy category B) is
B
very effective if promptly
) given at doses of
400 mg three times daily
i for 5 to 7 days,
and early delivery is not
s
required.
v
e (Nigro , et al., 2003)
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e
f
Cytomegalovirus
• Infection may remain asymptomatic in
pregnant women, and the prognosis is
favorable. The risk of transmission to the
fetus and of congenital abnormalities is
highest when acute infection occurs in the
first 22 weeks of pregnancy. Termination of
the pregnancy may be an option after
appropriate counseling regarding the
potential serious risks to the infected fetus.
(Benachi A, et al., 2003)
Alcohol use
• Women are two to four times more likely

than men to develop alcoholic liver
disease for the same amount of alcohol
ingested, and they exhibit a tendency to
disease progression even with abstinence.
(Pares et al., 1986)
• Continued drinking during pregnancy may
lead to miscarriage, stillbirth, prematurity,
growth retardation, and the fetal alcohol
syndrome (growth retardation, behavioral
disturbances, brain defects, cardiac
defects, spinal defects, and craniofacial
anomalies). Alcohol abstinence throughout
pregnancy should be emphasized.
(Lemoine et al., 2003)
Gallstone disease
• Pregnancy is a risk factor for sludge and

gallstone formation. By the end of the third
trimester, 10% to 12% of pregnant women
have gallstones. Most gallstones disappear
spontaneously without causing symptoms.
If symptoms develop, the treatment may
be conservative or surgical, depending on
the severity of the symptoms.
• Laparoscopic surgery seems to be safe
and should be considered. The optimal
time for it appears to be during the
second trimester, when fetal
organogenesis is completed and the size
of the uterus does not interfere with the
surgery.
(Halpern , 1998)
Budd-Chiari syndrome
• Budd-Chiari syndrome is very rare and

often insidious, manifesting after delivery.
It is characterized by thrombosis of the
hepatic veins and portal hypertension. Its
clinical manifestations include ascites,
hepatomegaly, and abdominal pain.
(Singh et al., 2000)
• Proper diagnosis and management require
imaging studies such as Doppler
ultrasonography and CT and liver biopsy.
Treatment with anticoagulants,
thrombolytics (warfarin is contraindicated in
pregnancy), diuretics, and portocaval
shunting may be required. Liver
transplantation is indicated when hepatic
decompensation develops.
(Deltenre et al., 2001)
– First trimester
counts)
Hyperemesis Gravidarum
• Hyperemesis gravidarum can be defined as

excessive nausea and vomiting in pregnancy
that result in dehydration and ketosis, severe
enough to necessitate hospitalization. Although
this is not primarily a liver disorder, it affects the
liver in up to 50% of patients.
(Jeffrey et al., 2003)
• The origin of the liver disease associated
with hyperemesis gravidarum is unclear. Not
all affected patients have liver disease;
therefore, the vomiting does not appear to
be secondary to the liver involvement.
Starvation alone does not seem to be an
adequate explanation for the liver
dysfunction, particularly in as much as biopsy
in affected patients fails to show the fatty
infiltration typical of starvation.
(Mazzotta & Magee, 2000)
• Factors thought to favor an increased risk
for hyperemesis gravidarum include
obesity, nulliparity, and twin gestation.
(Goodwin, 1998)
• Affected patients present in the first
trimester, usually by weeks 10 to 12. They
have persistent nausea and vomiting and
experience weight loss, often of significant
amounts. They also have ptyalism
(excessive spitting).
(Lammert et al., 2000)
• Laboratory testing demonstrates abnormal
liver values in up to 50% of affected
patients; the most sensitive test is the
ALT, which may rise as high as 1000 U.
• Severely affected patients also have
elevations in bilirubin.
(Jeffrey et al., 2003)
Improvement in the nausea and vomiting
and resolution of the liver test
abnormalities occur when most affected
patients are given intravenous fluids and
put to gut rest. Antiemetic therapy is
helpful. Corticosteroid therapy has been
reported with success. Patients affected
with hyperemesis gravidarum have no
increased rate of prematurity, infants with
low birth weight, or infants with birth
defects. (Tsang et al., 1996)
– First trimester
counts)
Intrahepatic Cholestasis of
Pregnancy
• The syndrome has been variously called
recurrent jaundice of pregnancy, cholestatic
jaundice of pregnancy, jaundice of late
pregnancy, and hepatosis of pregnancy. ICP,
however, is the preferred term, because
jaundice is inconstant in any type of cholestatic
disorder.
(Gonzalez-Peralva et al., 1996)
• The frequency of ICP is clearly higher
among certain ethnic groups, including
Scandinavians and Chileans. In the latter
group, ICP may appear in 2.4% or more of
pregnancies, the highest reported
incidence in the world. The incidence is
quite high (20.9%) in twin pregnancies.
• Several studies have demonstrated a
familial and genetic predisposition to the
syndrome in Sweden, Chile, and the United
States.
(Lammert, et al., 2000)
Clinical Description
Pruritus is the dominant and initial
symptom and appears in the third
trimester in more than 70% of cases.
Most of the remaining patients date
their onset of symptoms to the second
trimester.
The symptom may become very severe
and usually involves the trunk and the
extremities, including the palms and the
soles of the feet. As a result of the pru
ritus, insomnia, fatigue, and even mental
disturbances have been reported
(Milkiewicz et al., 2002)
Many patients report the appearance of
dark urine without frank jaundice
shortly after the onset of pruritus.
Only a minority of patients develop
obvious jaundice, and this is usually
mild.
It is notable that abdominal pain,
biliary colic, fever, anorexia, nausea,
vomiting, and arthralgias are absent.
(Milkiewicz et al., 2002)
• The improvement in both pruritus and
jaundice begins to occur quite promptly
after delivery, most often within 24 hours.
However, jaundice may continue for
several days after delivery, and some of
the abnormal chemistry profiles persist for
as long as several months.
• Subsequent pregnancies are frequently
accompanied by recurrences of the
syndrome.
(Mazella et al., 2001)
Biochemical Changes
CLINICAL FEATURES BIOCHEMICAL CHANGES
Pruritus Serum bile acid 10-to 100 fold

Jaundice* Alkaline Phosphatase 7- to 10 fold ↑
No Anorexia or malasie 5' Nucleotidase Two Folds↑
2nd or 3rd trimester onset* GGTP Normal to slight ↑
Recurrent* Bilirubin (total) Normal to 5 mg/dL
Familial* AST/ALT ↑↑
Prothrombin time Normal to twofolds↑
Cholesterol Two to Fourfolds ↑
Triglyceride Normal to twofolds ↑
*These clinical features are not invariably present. ALT, alanine

aminotransferase; AST, aspartate aminotransferase; GGTP, γ-
glutamyl-transpeptidase. ↑, increase.
Effects on the Mother
• Although earlier reports suggested that the only

effect of ICP on the mother was related to the
discomfort of pruritus, more recent studies have
suggested more serious complications. These
include an increased risk of postpartum
hemorrhage, especially in those given
cholestyramine, and an increased risk for the
development of gallstones after pregnancy.
(Glantz, et al., 2005)
Effects on the Fetus
• The implications of ICP for the fetus are
considerably more ominous. An increased
incidence of prematurity and fetal death has been
reported in several studies. Fetal distress is
reported in one third of patients, leading to
cesarean section in 30% to 60% of cases and
prematurity in over 50% in some series. Stillbirths
are recorded in more than 9%. These outcomes
are more likely if the disorder begins earlier in
pregnancy. Thus, ICP very clearly increases the
risks to the fetus.
(Glantz, et al., 2004)
Treatment
• Therapy is directed at alleviating pruritus in the
mother. Ursodeoxycholic acid has been used
successfully in the treatment of cholestasis in
other settings, most prominently primary biliary
cirrhosis. Improvement in both liver function test
results and the symptom of pruritus has been
documented in women with ICP treated with a
standard 15-mg/kg/day dosage. A larger dosage,
20 to 25 mg/kg/day has been shown to be
effective with no adverse affects on either mother
or baby.
(Mazella et al., 2001)
• Phenobarbital in a dosage of 100 mg/day has
been reported to be effective in approximately
50% of patients. Cholestyramine may be
somewhat effective and is usually given in a
dosage of 4 g four or five times per day.
• Cholestyramine may worsen the malabsorption of
fats and fat-soluble vitamins. Therefore, the
prothrombin time must be monitored in patients
treated with this regimen, and parenteral vitamin
K should be given before delivery.
(Eloranta et al., 2002)
• Intravenous or oral S'-adenosyl-1.-
methionine has been reported to lead to a
significant improvement in pruritus and in
serum transaminase and bilirubin levels,
perhaps by reducing the negative effects
of estrogens on bile secretion.
(Frezza et al., 1999)

• Some investigators recommend elective
induction at 38 weeks or as early as 36
weeks in the presence of jaundice or if the
fetus's lungs have matured.
(Rioseco et al., 1994)
– First trimester
counts)
Preeclampsia and eclampsia
• Preeclampsia affects up to 5% to 10% of

pregnancies, usually occurring in the late second
and third trimesters and less frequently
occurring before 20 weeks’ gestation.
Preeclampsia commonly occurs in nulliparous
women or multiparous women who are
nonwhite; are older than 34; or have new
partners, past or current history of hypertension,
or previous postpartum hemorrhage.
(Benedetto et al., 2002)
• The disease is characterized by a triad of
hypertension, proteinuria, and peripheral edema,
and hypertension and proteinuria
characteristically regress after delivery. Eclampsia
is characterized by seizures, coma, and other
signs of preeclampsia, including hypereflexia,
funduscopic changes in severe cases, cerebral
edema, hepatic infarction, acute renal failure,
congestive heart failure, and acute respiratory
distress syndrome.
(von Dadelszen et al., 2000)
Pathophysiology
• A uteroplacental mismatch, whereby the
demands of the fetal placenta exceeds the
maternal circulatory supply leads to
placenta hypoperfusion, local hypoxia,
endothelial cell dysfunction, abnormal
expression of inflammatory mediators,
alteration of vasomotor tone, and activation
of the coagulation cascade.
(Sawhney et al., 2000)
Clinical manifestations
• The clinical course of preeclampsia includes
nausea, vomiting, and epigastric pain and is
associated with elevated levels of LDH,
alkaline phosphatase, AST, ALT, and uric
acid. The level of uric acid is an excellent
marker for assessing disease severity and
progression. Liver function tests are
abnormal in 20% to 30% of patients with
preeclampsia and may be attributed to
vasoconstriction of the hepatic vascular bed.
(Maki et al., 2000)
Therapy and outcome
• Women who develop preeclampsia before

32 weeks of gestation are 22 fold more
likely to die than women who develop the
condition at term.
(MacKay et al., 2001)
• The maternal mortality rate is less than 1%
at institutions with special skills in treating
preeclampsia. Approximately 80% of
maternal deaths are attributed to central
nervous system complications, usually
cerebral edema. Hepatic complications,
including sub-capsular hematoma and
rupture, infarction, and hepatic failure,
account for the remaining causes of
mortality.
(Rolfes & Ishak, 1986)
• Fetal complications include
abruptioplacenta, prematurity, and IUGR.
Severe disseminated intravascular
coagulation (DIC) is a rare complication in
the absence of placenta abruption.
• The only effective treatment for preeclampsia is
delivery of the fetus and placenta, particularly if
the condition is severe or develops after 36
weeks of gestation or if the fetal lungs are
mature. Most authorities suggest that the
presence of Multi Organ system Dysfunction
(MOSD), fetal distress, or gestational age
greater than 34 weeks warrants immediate
delivery
(Sibai et al., 1994)
• If mild preeclampsia is evident in the third
trimester, expectant management with
intensive monitoring may enhance fetal
lung maturity; however, any sign of
maternal or fetal deterioration requires
emergent delivery. If eclampsia develops,
magnesium sulfate is a treatment of
choice for seizure prophylaxis.
(Bernard et al., 2001)
– First trimester
(hemolysis, elevated liver enzymes, low platelet counts)
HELLP Syndrome
• The HELLP syndrome is a multi-system
disease variant of severe preeclampsia that
is characterized by microangiopathic
hemolytic anemia (MAH), hepatic
dysfunction (hepatic necrosis),
thrombocytopenia (platelet count,
<100,000/ mm3), and, in the syndrome’s
most severe form, DIC.
• HELLP syndrome is more common among older
multiparous women.
• HELLP syndrome affects up to 20% of
pregnancies involving severe preeclampsia.
• Although up to 11% of the cases occur before
27 weeks of gestation, most cases (70%) occur
between 27 and 36 weeks of gestation and
about a third occur after delivery. Exacerbations
may occur after delivery, followed by recovery
within 72 hours.
(Martin et al., 1999)
Clinical manifestations
• Several conditions mirror HELLP
syndrome, and timing of illness and
findings may assist in differentiating
HELLP syndrome from other diseases.
(Winbery & Blaho., 2001)
differential diagnosis of HELLP
syndrome
Thrombotic coagulopathies Consumptive Miscellaneous
disorders
Hemolytic uremic syndrome AFLP Systemic lupus
Thrombotic Sepsis Antiphospholipid
thrombocytopenia purpura DIC syndrome
Drug-induced hemolytic Abruptio placentae Cholecystitis
anemia Amniotic fluid Appendicitis
Sepsis embolism
DIC
• Frequent presenting symptoms include nausea,
malaise, epigastric or right upper quadrant
abdominal pain (65%–90% of cases), and
edema. In a large series, HELLP syndrome was
observed with DIC (21% of patients), abruption
placenta (16%), acute renal failure (8%), and
pulmonary edema (6%). The maternal mortality
rate is approximately 1% to 4%, and the
perinatal mortality rate ranges from 10% to
20%, depending on gestational age and severity
of the condition at the time of delivery.
Maternal morbidity in HELLP syndrome can
be classified into the following four
categories (in decreasing order of
frequency)
• Coagulation disorders associated with
hemorrhagic complications,
• Cardiopulmonary dysfunction,
• Central nervous system disorder and
• Hepatic or gastrointestinal dysfunction.
(Isler et al., 1999)
• Women with HELLP syndrome should be
considered to be at increased risk for
obstetrical complications in subsequent
pregnancies (preterm deliveries, IUGR,
abruption-placenta), and the risk for
recurrence ranges from 4% to 25% .
Infants born to mothers with HELLP
syndrome are at risk for
thrombocytopenia.
Laboratory investigation
Risk factors for HELLP syndrome include the
following:
• LDH level, > 1400 IU/L
• AST level, > 150 IU/L
• ALT level, > 100 IU/L
• Platelet count, < 50,000/mm3
• Uric acid level, > 7.8 mg/dL
• Creatinine level, > 1.0
• Creatine phosphokinase level, > 200 IU/L
Liver function
• Patients usually are not jaundiced. Total bilirubin
concentration rarely exceeds 1 to 2 mg.
• HELLP syndrome rarely leads to subcapsular
hemorrhage; hepatic rupture often leads to death of
the mother and fetus. Typically, these patients
present with shock and hemoperitoneum. The
condition also may manifest hepatic infarcts with
associated fevers, high levels of aminotranferase
(N5000 IU/L), and anemia.
(Krueger et al., 1995)
Therapy and outcome
• The maternal morbidity rate has been reported

to be as high as 24%, but it ranges between 1%
to 4% in optimal medical environments. In
patients who died, the mean gestational age
was 31 weeks, and death was attributed to
sepsis, hemorrhagic shock, intracerebral insults,
and cardiac pulmonary failure. Investigators
found 16% maternal death rate attributed to
hepatic complications.
(Martin et al., 1999)
• The neonatal mortality rate associated
with HELLP syndrome (10%–20%) has
been attributed to placenta ischemia
leading to abruption, extreme
prematurity, and intrauterine asphyxia.
Factors associated with perinatal survival
in preterm pregnancies with HELLP
syndrome include achievement of a birth
weight of at least 600g, elapsed time of
48 hours after medical therapy with
steroids for perinatal lung maturity, and
caesarian delivery.
(Barton & Sibai, 1992)
• Termination of pregnancy and the removal
of the chorionic villi is the only therapy that
minimizes maternal and fetal compromise.
Timing of delivery depends on the severity
of the maternal condition (DIC, MOSD,
abruption), fetal condition, placenta
reserve, and gestational age. With few
exceptions, patients with pregnancies of at
least 34 weeks’ gestation and class I
pregnant patients with HELLP syndrome
require prompt delivery.
• HELLP syndrome - antepartum
management
• assess and stabilize the maternal condition
• correct coagulopathy if DIC is present
• give intravenous magnesium sulfate to prevent
seizures
• provide treatment for severe hypertension to
prevent stroke
• transfer to tertiary center if appropriate
• if subcapsular hematoma of liver, computed
tomography or ultrasound of the abdomen
• HELLP syndrome - antepartum
management
– evaluate fetal well-being
• non stress test
• biophysical profile
– timing of delivery
• if > 34 weeks gestation, deliver
• if < 34 weeks gestation, administer corticosteroids,
then deliver in 48 hours
• HELLP syndrome - management for
cesarean birth
– use general anesthesia if platelet count is
< 75,000 / mm3
– transfuse 5 to 10 units of platelets before
surgery if platelet count is < 50,000 / mm3
– leave vesicouterine peritoneum open
– install subfascial drain
• HELLP syndrome - management for
cesarean birth
– schedule secondary closure of skin incision or
subcutaneous drain
– administer postoperative transfusions as
needed
– perform intensive monitoring for at least 48
hours postpartum
– consider dexamethasone (10 mg IV every 12
hours) until postpartum resolution of disease
occurs
• HELLP syndrome - management of
women with a subcapsular liver
hematoma
– general considerations - blood bank aware for
potential need of many units of blood
– general or vascular surgeon consultation
– avoid direct and indirect manipulation of liver
– closely monitor hemodynamic status
– management of hematoma depends on
whether it is ruptured or not
– First trimester
(hemolysis, elevated liver enzymes, low platelet counts)
Acute Fatty Liver of Pregnancy
• Sheehan, first recognized this disorder as

a distinct syndrome in 1940.
• He named it Acute yellow atrophy but it is
now more commonly known as acute fatly
liver of pregnancy.
(Sheehan, 1940)
• (AFLP) is rare, encountered in a tertiary
maternity hospital approximately once a
year, with a reported incidence of 1 in
13,000 to 1 in 16,000 deliveries.
• Preeclampsia is present in 50% or more of
cases of AFLP and may play a role in its
origin.
(Vigil-De, 2001)
• Reports of occasional recurrent cases and
an association with a deficiency of long-
chain 3-hydroxyacyl-cocnzyme A (Co A)
dehydrogenase, raise the interesting
notion that, at least in some instances, this
disease results from an inborn error of
metabolism.
(Ibdah et al., 1999)
Clinical Characteristics
• AFLP occurs in the latter half of pregnancy,

usually close to term. As with HELLP syndrome,
affected patients may present after delivery. It is
reported to occur more commonly in a first
pregnancy and in the presence of multiple
pregnancy, also prevalent in preeclampsia.
There are reports of an association between
AFLP and gestation of a male fetus.
(Castro et al., 1999)
• Affected women have nonspecific
symptoms, including, prominently, nausea
and vomiting, malaise and fatigue, jaun
dice, thirst, headache, and altered mental
status. These can be signs and symptoms
of acute hepatic failure.
• In severe cases that go untreated, there is
progression over hours or days to
fulminant hepatic failure, with hepatic
coma, hypo-glycemia, severe
coagulopathy with hemorrhage from the
gastrointestinal tract or the uterus and
death.
• Most affected women have signs of
coexistent preeclampsia, including modest
elevations in blood pressure,
hyperuricemia, and proteinuria.
Polydipsia
With or without polyuria, frequently is an early

symptom in AFLP.
The patient may drink 2 or 3 liters of liquids

overnight. it often exceeds the magnitude of
vomiting. It has been interpreted as a
transient diabetes insipidus.
(Cammu et al., 1987)
Laboratory tests
Clinical features Biochemical changes
Nausea, Vomiting Bilirubin (total) Slight ↑, normal

Malaise, Fatigue AST/ALT ↑normal to 1000 U
Jaundice GGTP Slight↑
Abd. Pain Prothrombin time ↑↑
Preeclampsia Fibrinogen ↓↓
Coma Uric acid ↑
Bleeding Ammonia ↑
Onset in second half of gestation; Glucose ↓
postpartum onset possible Leukocytes ↑
platelets ↔, ↑
• Imaging may be useful; fat in the liver has
been demonstrated in AFLP with
ultrasonography and CT scanning.
• Liver biopsy is not indicated for diagnosis
(Barton et al., 1998)

Characteristics of HEELP syndrome and AFLP
HELLP AFLP
Early Early
Platelet count, 50,000-150,000/mm3 Platelet count, >100,000/mm3
LDH level, 600-1400 IU/L Uric acid – abnormal
Bilirubin/PT levels, Normal LDH level, normal
PT- Abnormal
Bilirubin/PT levels, abnormal
Late late
Platelet count, <50,000/mm3 Platelet count, <100,000/mm3
LDH level, >1400 IU/L LDH level, < 600 IU/L
Bilirubin/PT levels, abnormal Hypoglycemia
PT- Abnormal
Complications
cerebral edema,
renal failure (60%),
hypoglycemia (53%),
 infections (45%)
gastrointestinal hemorrhage (33%),
coagulopathy (30%),
fetal death
severe postpartum hemorrhage
Course and Management
• Patients with undiagnosed AFLP are at risk for
progression, with an unpredictable but often
short time course, to fulminant hepatic failure and
death for both mother and fetus.
• Now it is rare for a patient to die, with
appropriate diagnosis and aggressive
management.
• Similarly, the outlook for the fetus of the affected
pregnancy has also improved, although it remains
worse than that of the mother.
(Usta et al., 1994)
All patients should be hospitalized as
soon as the diagnosis of AFLP is
suspected
Moderate or severely affected patients

(encephalopathic, deeply jaundiced,
with a prothrombin time less than 40%
of the control), or with any extrahepatic
complications, should be attended in
intensive care units.
it seems convenient to maintain
glucose infusions . Because of the
risk of a sudden hypoglycemia until a
full metabolic recovery is obtained.
• Treatment of AFLP begins with delivery.
The route should be guided by obstetric
indications. Cesarean section is not
always necessary; vaginal delivery can
be accomplished.
• With delivery, repair of the liver disease
begins, the initial sign of improvement
being a fall in prothrombin time elevation.
• The management should include maximal
support in an intensive care unit by a team
that includes both obstetricians and
hepatologists. Liver transplantation for
AFLP has been reported.
(Paternoster et al., 2004)
• There are no residua after AFLP, and
complete recovery of the affected patient
should be expected. Cases of recurrent
AFLP, as well as cases of nonketotic
hypoglycemia in the offspring, have been
reported.
Pregnancy Following Liver
Transplantation
• With advances in transplantation, and
particularly in immunosuppression, it is
unnecessary to discourage pregnancy of
most female liver transplant recipients at
reproductive age.
(Parolin et al., 2004)
The first report of successful pregnancy after
liver transplantation was published in
1978.
(Miniero et al., 2005)
• Pregnancy after liver transplantation is
often successful, but it must be regarded as
a high risk, associated with hypertension,
preeclampsia, intrauterine growth
retardation, and prematurity. It is best
delayed until 1 to 2 years after grafting.
Pregnancy planned at least 2 years after
liver transplantation with stable allograft
function can have excellent maternal and
neonatal outcome.
(Nagy et al., 2003)
• In most female recipients studied,
pregnancy does not appear to cause
excessive or irreversible problems in graft
function if the function of transplanted
organ is stable prior to pregnancy,
including twins if the woman has stable
hepatic function before pregnancy.
(Nagy et al., 2003)
• In female recipients in contrast to the
general population, a high incidence of low
birth-weight and prematurity has been a
consistent outcome. Immunosuppressive
agents may cause hypertension,
preeclampsia and renal dysfunction in these
recipients. However, there has been no
specific pattern of malformation in their
newborns or any apparent increase in the
incidence of small-for-gestational-age
newborns.
(Armenti et al., 2000)
• immunosuppression during pregnancy is
not teratogenic and does not lead to
congenital anomalies.
• Nearly 70% of pregnancies after systemic
administration of tacrolimus resulted in a
favourable outcome without any
significant effect on intrauterine growth.
(Jabiry et al., 2005)
• Also, it was found that tacrolimus may
decrease the incidence of onset of
hypertension and toxemia of pregnancy.
Thus, during pregnancy, the female
recipient may continue the
immunosuppressive regimen to stabilize
the transplanted liver function but prevent
the effect on the intrauterine growth.
• To the present, 37 cases of pregnancies
after liver transplantation have been
reported worldwide.
• In conclusion:
Under careful monitoring a childbearing age
woman with stable and adequate liver
function may have a successful pregnancy
and a delivery after liver transplantation.
(Pan et al., 2007)

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Liver Diseases With Pregnancy3603

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LIVER DISEASES WITH

Professor Mahmoud Farouk Midan

Prof. & Head of Obstetrics & Gynecology Dept.

• Liver weight increases during pregnancy has not

• Therefore, detection of hepatomegaly is strong

• Hepatic blood flow is maintained at a constant

Virus type RNA

Serologic diagnosis Hepatitis A antibody

Serologic diagnosis Hepatitis C antibody

• It can cause fulminant liver failure and death if

• Women are two to four times more likely

• Pregnancy is a risk factor for sludge and

• Budd-Chiari syndrome is very rare and

• Hyperemesis gravidarum can be defined as

Pruritus Serum bile acid 10-to 100 fold

*These clinical features are not invariably present. ALT, alanine

• Although earlier reports suggested that the only

(Frezza et al., 1999)

• Preeclampsia affects up to 5% to 10% of

• Women who develop preeclampsia before

• The maternal morbidity rate has been reported

• Sheehan, first recognized this disorder as

• AFLP occurs in the latter half of pregnancy,

With or without polyuria, frequently is an early

The patient may drink 2 or 3 liters of liquids

Nausea, Vomiting Bilirubin (total) Slight ↑, normal

(Barton et al., 1998)

Moderate or severely affected patients

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