CHAPTER 47

HYPERTENSION, ELEVATED
LIVER ENZYMES, AND LOW
PLATELETS (HELLP)
ALI CETIN, MD

The HELLP syndrome, originally described by

Weinstein 1 as an acronym in 1982, includes signs of
hemolysis (H), elevated liver enzymes (EL), and low
platelet count (LP), and is a variant presentation of
severe preeclampsia. Approximately two-thirds of the
cases of HELLP syndrome are first diagnosed antepartum
with the remaining patients first recognized postpartum.
The majority of the patients identified antepartum with
HELLP syndrome are diagnosed between 27 and 37
weeks. Thus, antepartum HELLP syndrome is a complication of pregnancy that usually has fetal prematurity
accompanying the onset of the disease process.2

is associated with an increased risk of adverse outcomes,

including placental abruption, renal failure, subcapsular
hepatic hematoma, recurrent preeclampsia, preterm
delivery, and even fetal or maternal death.4

Pathophysiology
HELLP syndrome is a specific manifestation of endothelial dysfunction during pregnancy. It is unknown why
some preeclamptic women develop HELLP syndrome
and others do not.5 The pathophysiologic process that
underlies HELLP syndrome appears to be microvascular
damage with endothelial injury and organ hypoperfusion. Microangiopathic hemolytic anemia is thought to
result from the passage of red blood cells through small
blood vessels with damaged intima and fibrin deposition,
leading to the appearance on peripheral smear of triangular cells, burr cells, echinocytes, and spherocytes.6
The extensive platelet activation can result in thrombocytopenia, defined as a platelet count < 100,000/;gmL.
Severe thrombocytopenia (< 50,000/;gmL) may impair
coagulation. Severe derangement of coagulation induced
by thrombotic microangiopathic anemia may in some
cases result in disseminated intravascular coagulation
(DIC). However, DIC is a distinct, different disorder.5
Periportal and/or focal parenchymal lesions with large
fibrin deposits are histopathologic abnormalities of
HELLP syndrome.7 As a result, serum liver enzymes such
as aspartate aminotransaminase (AST) and alanine
aminotransaminase (ALT) are elevated, although changes
in AST and ALT concentrations in plasma can also reflect
extrahepatic (particularly erythrocyte) rather than
hepatic damage.8 Class alpha glutathione S-transferases

HELLP syndrome includes signs of hemolysis (H),

elevated liver enzymes (EL), and low platelet count
(LP), and is a variant presentation of severe
preeclampsia.
The incidence of HELLP syndrome in women with
severe preeclampsia and eclampsia ranges from 2 to 30%
depending on the population studied and the criteria
used to establish the diagnosis. It is a disease that
commonly affects older women. This is a further distinction from the general association of preeclampsia with
the young nulliparous female. This disorder occurs
primarily in white, multiparous women above the age of
25 years, and is the most common cause of severe liver
disease in pregnant women.3
HELLP syndrome is an atypical form of severe
preeclampsia or eclampsia, and is a management
dilemma for clinicians. Variable degrees of hepatic
dysfunction, microangiopathic hemolytic anemia and
thrombocytopenia characterize this insidious disease
process.2 As with severe preeclampsia, HELLP syndrome
416

HELLP / 417

(GSTA) are found in high concentrations in human liver.

Increased plasma concentrations of GSTA 11, the most
abundant isoform of GSTA, are a very sensitive marker
for hepatocellular leakage. Plasma GSTA 11 measurements may provide a more sensitive indicator of acute
hepatic damage in preeclampsia and HELLP syndrome
compared with the assessment of aminotransferase activity and therefore may allow earlier recognition of these
syndromes.9 Severe liver disease in HELLP syndrome
sometimes develops into a spontaneous subcapsular
hepatic hemorrhage or even into a liver rupture, which is
a life-threatening situation.10
Despite extensive clinical and experimental research
on preeclampsia and HELLP syndrome, no definitive cause has been identified.

Presentation
Patients with HELLP syndrome exhibit the various signs
and symptoms commonly observed with preeclampsia.
These signs and symptoms may also be seen in women
with severe preeclampsia and eclampsia who do not have
HELLP syndrome. 6 Although HELLP syndrome
commonly has a slow initial phase followed by an accelerative phase that can result in multiorgan failure without intervention, sometimes disease expression can be
explosive. Multiple organs are affected, most often the
liver, kidneys, central nervous system, and the hematologic system.6,11 Women with HELLP syndrome usually
present remote from term with complaints of epigastric
or right upper quadrant pain. 6,12 Some women with
HELLP syndrome experience nausea or vomiting,
whereas other women with the syndrome experience
nonspecific viral-syndrome-like symptoms. 13 Most
women with HELLP syndrome present with a history of
malaise a few days prior to presentation. The most
common symptoms reported by Weinstein1 were nausea
and/or vomiting and epigastric pain. Right upper quadrant or epigastric pain is thought to be caused by
obstruction of blood flow in the hepatic sinusoids, which
are blocked by intravascular fibrin deposits.
HELLP syndrome has a slow initial phase followed
by an accelerative phase that can result in multiorgan failure without intervention.
The physical examination may be normal in patients
with HELLP syndrome. However, right upper quadrant
tenderness is present in as many as 90% of affected
women.13 Edema is not a useful marker because swelling
is a factor in up to 30% of normal pregnancies.
Hypertension and proteinuria may be absent or mild.
The differential diagnosis of HELLP syndrome includes

acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome.
Acute renal failure, cerebral edema, and hemorrhage,
eclampsia, and placental abruption are among the other
most feared complications associated with HELLP
syndrome.5

Evaluation
The diagnostic criteria used for HELLP syndrome are
variable and inconsistent.14 The diagnosis of HELLP
syndrome is based on the laborator y evidence of
microangiopathic hemolytic anemia, EL, and thrombocytopenia in the pregnant or puerperal patient with other
signs and symptoms that are consistent with a diagnosis
of preeclampsia or eclampsia.
Diagnosis of HELLP syndrome is based on the laboratory evidence of microangiopathic hemolytic
anemia, EL, and thrombocytopenia.

HEMOLYSIS
Hemolysis, defined as the presence of microangiopathic
hemolytic anemia, is the hallmark of the triad of HELLP
syndrome.13 It is confirmed by the sensitive, but not
specific, observation of burr cells (crenated, contracted,
distorted red blood cells with spiny projections along the
periphery); schistocytes (small, irregularly shaped red
blood cell fragments); polychromasia on peripheral
blood smear examination; elevated LDH levels; and
significant drop in hemoglobin levels. Red blood cell
fragmentation occurs secondary to passage through small
blood vessels with intimal damage and fibrin deposition.
Hemolysis is more common than realized, as automated
technology has resulted in a decrease of manual examination of peripheral smears. LDH levels, measurements
of indirect bilirubin, and low serum haptoglobin levels
have also been used as additional markers of evidence for
hemolysis. A significant percentage of published reports
included patients without the findings of hemolysis;
hence, these patients may fit the criteria for HELLP
syndrome.6,15

LIVER FUNCTION TESTS

No consensus exists in the literature regarding the liver
function test to be used or the degree of elevation used in
these tests to diagnose EL. 6 Hepatic dysfunction will
show an increased AST level > 40 IU/L, increased ALT
level > 40 IU/L, or both, with increased LDH > 600 IU/L.

THROMBOCYTOPENIA
LP is the third abnormality required to establish the diagnosis of HELLP syndrome. There is no consensus among

418 / Advanced Therapy in Hypertension and Vascular Disease

various published reports regarding the diagnosis of

thrombocytopenia.6 Following diagnosis, patients are
classified according to the lowest observed peripartal
platelet count. This classification is useful because the
women with the lowest maternal platelet count have been
observed to have the greatest morbidity and to take the
longest time to recover from this disease process. This LP
group has also been observed to be more likely not to
respond to conservative therapy, to require blood and
blood products, and to ultimately need plasma exchange
therapy to assist in the resolution of the HELLP
syndrome. Class 1 HELLP syndrome patients are defined
as having, in addition to laboratory evidence of hemolysis and liver dysfunction, a perinatal platelet nadir of
< 50,000/;gmL (severe thrombocytopenia); class 2
patients have a platelet nadir > 50,000 but
100,000/;gmL (moderate thrombocytopenia); and class
3 disease is associated with mild thrombocytopenia with
> 100,000 platelets but 150,000/;gmL.2
Criteria for the HELLP syndrome include (1)
microangiopathic hemolytic anemia, (2) serum AST > 70
U/L, and (3) thrombocytopenia, with a platelet count
below 100,000/ll.52.3 The diagnosis is made by maintaining a high index of suspicion in patients who present
with epigastric pain, nausea, emesis, eclampsia, severe
hypertension, and abnormal bleeding, such as from
placental abruption. After HELLP syndrome is diagnosed, immediate steps should be taken to assess the
gestational age of the fetus.

Management
The goals of management of women with HELLP
syndrome include prevention of maternal morbidity and
mortality, and reduction of perinatal morbidity and
mortality. The clinical course of women with HELLP
syndrome is characterized by usually progressive and
sometimes sudden deterioration in maternal and fetal
conditions.16 Therefore, patients with suspected diagnosis of HELLP syndrome should be hospitalized immediately and observed in a labor and delivery unit. Patients
with HELLP syndrome who are remote from term
should be referred to a tertiary care center.6
Optimal maternal and fetal outcome are dependent
on prompt recognition and treatment of HELLP
syndrome.
There is no consensus on the management of HELLP
syndrome.12 Some authors consider its presence to be an
indication for immediate delivery by cesarean section,
whereas others recommend a more conservative
approach to prolong pregnancy in cases of fetal immaturity. Consequently, the literature describes several thera-

peutic modalities to treat or reverse HELLP syndrome.

Most of these therapeutic modalities are similar to those
used in the management of severe preeclampsia remote
from term. There is a consensus of opinion that prompt
delivery is indicated if the syndrome develops beyond 34
weeks of gestation, or earlier if there is multiorgan
dysfunction, DIC, liver infarction or hemorrhage, renal
failure, suspected abruptio placentae, or nonreassuring
fetal status.12 Since HELLP syndrome is common before
term, any intervention that prolongs the time from diagnosis to delivery by stabilizing the clinical condition may
decrease perinatal morbidity and mortality.17
The traditional therapy for HELLP syndrome is stabilization, supportive care, and delivery. The first priority is
to assess and stabilize maternal condition, particularly
coagulation abnormalities. This management plan is
implemented because the only known cure for severe
preeclampsia is delivery of the fetus, removal of the
placenta, and loss of the decidual tissue. The known serious consequences of delaying delivery have brought
about the wide acceptance of this general treatment
plan.2 Such patients should be managed as patients with
severe preeclampsia and should initially receive intravenous magnesium sulfate as prophylaxis against convulsions and antihypertensive medications to keep systolic
blood pressure below 160 mm Hg or diastolic blood
pressure below 105 mm Hg as mentioned earlier. 18
During the observation period, maternal and fetal conditions are assessed. 6 The recommended regimen of
magnesium sulfate is a loading dose of 6 g given over 20
minutes, followed by a maintenance dose of 2 g/h as a
continuous intravenous solution. Magnesium sulfate is
initiated at the beginning of the observation period and
continued during labor and for at least 24 hours postpartum. The next step is to evaluate fetal well-being and to
determine gestational age. Finally, it must be decided
whether immediate delivery is indicated.6 If immediate
delivery is not indicated, magnesium infusion can be
continued to gain time for the use of corticosteroids to
promote fetal pulmonary maturity before 34 weeks
gestation.
The traditional therapy for HELLP syndrome is stabilization, supportive care, and delivery.

CORTICOSTEROID THERAPY
Administration of corticosteroids to women with HELLP
syndrome in the preterm period improves maternal
outcome by accelerating the recovery of biochemical
abnormalities and clinical signs. The stabilizing effect of
corticosteroids on activated endothelial cells and
platelets, as well as the antiinflammator y and
immunomodulative properties, may account for the

HELLP / 419

beneficial clinical effect of corticosteroids in HELLP

syndrome. 5 The recommended regimen of corticosteroids for the enhancement of fetal maturity is
betamethasone (12 mg intramuscular (IM) every 24
hours, two doses) or dexamethasone (6 mg IM every 12
hours, four doses). 19 These regimens have also been
identified as the most appropriate in HELLP syndrome,6
because they readily cross the placenta and have minimal
mineralocorticoid activity. There is a definite need for
randomized controlled trials in women with preterm
HELLP syndrome for the administration of high-dose
corticosteroids. Until these data are available, it remains
experimental to improve maternal outcome in women
with HELLP syndrome before 34 weeks gestation or in
the postpartum period.
Following delivery, laboratory abnormalities peak in
the first 1 to 2 days postpartum and return to normal
within 3 to 11 days.20 Postpartum resolution of HELLP
syndrome is defined as:
(1) controlled maternal blood pressure ( 150/100);
(2) adequate diuresis (urinary output of 100 ml/h for
2 consecutive hours without a fluid bolus or use
of diuretics);
(3) maternal platelet count > 100,000/;gmL and a
falling LDH; and
(4) patient clinically appears stable.2

LABOR AND DELIVERY

HELLP syndrome is generally considered an absolute
indication for delivery. Unlike the situation in eclampsia,
however, labor induction does not necessarily have to be
immediate and, if the mother is otherwise stable, one can
attempt to obtain the 48 hours of maximum fetal benefit
from the administration of corticosteroids. Serial laboratory analysis is needed if conservative management is
attempted, and delivery should be performed if progressively severe thrombocytopenia is encountered. As with
eclampsia, vaginal delivery is the preferred route of delivery, and cervical ripening can be performed while one is
awaiting the maximum steroid effect. Platelet transfusions are avoided if possible because they are rapidly
consumed by the underlying disease process, and there is
a risk of formation of antiplatelet antibodies. If a
cesarean section is planned, however, platelets should
ideally be at least 50,000, and preoperative transfusion
may be necessary. Epidural anesthesia is generally
contraindicated with severe thrombocytopenia.
Consideration should be given to the placement of an
early epidural when the diagnosis of HELLP syndrome is
made in the event of further decreases of platelets. After

delivery, the platelets may continue to fall for another 24

to 28 hours but always eventually return to normal.
Subcapsular hematoma, rupture of Glissons capsule,
and complete hepatic rupture are the most feared consequences of HELLP syndrome. They usually arise with
acute worsening right upper quadrant pain or new
shoulder pain with deteriorating vital signs or shock.
Emergent laparotomy and general surgery consultation
are needed. Although right upper quadrant tenderness is
important in screening patients for severe preeclampsia,
when the diagnosis of HELLP syndrome is made, palpation of the right upper quadrant should be avoided.
Blood pressures that are consistently greater than
160/110 mm Hg pose a danger to the patient and need to
be corrected as mentioned earlier.
The presence of HELLP syndrome is associated with
life-threatening maternal and fetal complications.

Outcome
Despite their similarities, HELLP syndrome is associated
with significantly greater maternal and fetal morbidity
and mortality than preeclampsia.21,22 Maternal mortality
rates vary from 0 to 24%.23 In a review of 54 maternal
deaths associated with HELLP syndrome, a delay in diagnosis was noted in 51%, with one-third the result of
patient delay, and the other two-thirds resulting from
delay in physician diagnosis. 24 Patients with HELLP
syndrome are at increased risk for DIC, abruptio placentae, acute renal failure, pulmonary edema and pleural
effusions, acute respiratory distress syndrome, liver
infarcts, and ruptured liver hematomas. Perinatal mortality associated with HELLP syndrome has been estimated
as 11%.25 Most of the perinatal complications seemed to
be the result of prematurity and placental insufficiency.
Overall, the risk for preeclampsia in a subsequent
pregnancy was 21%, but the recurrence rate of HELLP
syndrome was only 4%.24

Prevention
Until the pathogenesis of preeclampsia is well defined, it
is doubtful that we will find therapies to prevent
preeclampsia and HELLP syndrome. With improved
prenatal care, early detection of signs and symptoms of
preeclampsia and continuous education of both patients
and healthcare providers regarding the prompt reporting
and response to serious symptoms such as severe
headaches, blurred vision, mental status changes, and
epigastric pain with nausea and vomiting during pregnancy and puerperal period.

420 / Advanced Therapy in Hypertension and Vascular Disease

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