Understanding and Managing HELLP Syndrome Ajog Martin Jr
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7/30/2019 Understanding and Managing HELLP Syndrome Ajog Martin Jr
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Understanding and managing HELLP syndrome:The integral role of aggressive glucocorticoidsfor mother and child
James N. Martin Jr, MD, Carl H. Rose, MD, Christian M. Briery, MD
Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS
Received for publication April 21, 2005; revised July 13, 2005; accepted August 18, 2005
KEY WORDSHELLP syndrome
Severe preeclampsia/
eclampsia
Aggressive
glucocorticoids/
corticosteroids
Obstetric
Antepartum or postpartum HELLP syndrome constitutes an obstetric emergency that requires
expert knowledge and management skills. The insidious and variable nature of disease presenta-
tion and progression challenges the clinician and complicates consensus on universally accepted
diagnostic and classification criteria. A critical review of published research about this variant
form of severe preeclampsia, focused primarily on what is known about the pathogenesis of this
disorder as it relates to patient experience with corticosteroids for its management, leads to the
conclusion that there is maternal-fetal benefit realized when potent glucocorticoids are aggres-
sively used for its treatment. Although acknowledging the need for definitive multicenter trialsto better define the limits of benefit and the presence of any maternal or fetal risk, and given
an understanding of the nature of the disorder with its potential to cause considerable maternal
morbidity and mortality, we recommend for the present that aggressively used potent gluco-
corticoids constitute the cornerstone of management for patients considered to have HELLP
syndrome.
2006 Mosby, Inc. All rights reserved.
Recognition that a particularly potent form of pree-
clampsia-eclampsia exists has been evident since case
reports first appeared in the late nineteenth1 and early
twentieth century.2-5 Between 1950 and 1980, several
case series were published that related patients and
poor obstetric outcomes to clinical and laboratory find-
ings that are consistent with what we recognize today as
HELLP syndrome.6-17 Credit for formally consolidating
the concept and creating the acronym of HELLP (H =
hemolysis, EL = elevated liver enzymes and LP = low
platelets) goes to Louis Weinstein who in 1982 reported
a group of 29 pregnant patients he considered to have a
distinct subset of severe preeclampsia/eclampsia.18 All
patients expressed findings suggestive of microangio-
pathic hemolytic anemia with moderate-to-severe throm-
bocytopenia, misshapened erythrocytes on peripheral
smear, and abnormal liver function tests usually in con-
junction with epigastric pain, nausea, and vomiting.
Severe hypertension and proteinuria were frequently
coexistent as well.
Since 1982 there has been an outpouring of obstetric
literature seeking to better define the pathogenesis, natu-
ral history, clinical spectrum, classification and manage-
ment strategies for patients considered to have HELLP
syndrome. Because the incidence of this disorder is lowReprints not available from the authors.
0002-9378/$ - see front matter 2006 Mosby, Inc. All rights reserved.
doi:10.1016/j.ajog.2005.08.044
American Journal of Obstetrics and Gynecology (2006) 195, 91434
www.ajog.org
http://www.ajog.org/http://www.ajog.org/ -
7/30/2019 Understanding and Managing HELLP Syndrome Ajog Martin Jr
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(1-6 per 100019,20), most clinical research endeavors have
been small, single institution case series or randomized
trials. Until definitive large multicenter trials are under-
taken, clinicians must rely on less robust information to
guide patient care. Despite several recent comprehensive
reviews on the subject of HELLP syndrome,21-24 none to
date have examined the available data and patient experi-
ence primarily from the perspective of corticosteroidimpact on disease expression and progression. The cur-
rent review is constructed from this perspective, synthesi-
zing and summarizing the pertinent English literature on
HELLP syndrome to understand how corticosteroids
appear to play an integral role in its management.
Pathogenesis and natural history
HELLP syndrome usually develops suddenly during
pregnancy (27-37 weeks gestation) or in the immediate
puerperium.25-28 As a form of severe preeclampsia, itlikely has its origins in aberrant placental development,
function, and ischemia-producing oxidative stress,
which triggers the release of factor(s) that systematically
injure the endothelium via activation of platelets, vaso-
constrictors, and loss of normal pregnancy vascular
relaxation.29-36 Although variable, HELLP syndrome
onset and progression usually is rapid (35%-50% de-
crease in platelets per 24 hours; mean daily reduction
of 40,000/mL platelets) as lactic acid dehydrogenase
(LDH) and aminotransaminases (aspartate [AST] and
alanine [ALT]) rise until 24 to 48 hours postpartum
when laboratory values begin to recover.37-42
Absentcorticosteroids, most patients (85%-90%) achieve plate-
lelets 100,000/mL or greater within 6 to 8 days of deliv-
ery or within 72 hours of platelet nadir, and total LDH/
transaminases trend toward normal within 96 hours
postpartum.37,41-43 Onset of disease occurs postpartum
in approximately 15% to 25% of cases.25-28
Although most patients with HELLP syndrome even-
tually exhibit hypertension and proteinuria, these 2 major
signs of severe preeclampsia bear no consistent relation-
ship with laboratory parameters of the underlying vascu-
lopathy.26-28,37,38 A variety of symptoms can be elicited
that are ambiguous, subtle, and focused primarilyon the gastrointestinal-hepatic systems.28 The central
place that the liver occupies in the disorder of HELLP
syndrome is an important clue to pathogenesis. Severe
epigastric/right upper quadrant pain often heralds under-
lying rapidly progressive disease.44 The extent of peri-
portal hepatocyte dysfunction or cell death in a given
patient probably correlates with the severity of maternal
illness. Recall that CD95 (APO-1, Fas)-mediated apopto-
sis of hepatocytes is a major pathogenic mechanism
for liver disease in general.45 The Fas-Fas ligand system
is a well-studied cell death system that can mediate apo-
ptosis. As a member of the tumor necrosis factor receptor
superfamily, Fas is a 36 to 45 kDa type I surface protein
containing a single transmembrane region.46 It induces
apoptosis by binding to Fas-ligand, a 40 kDa type II
transmembrane protein of the tumor necrosis factor re-
ceptor family.47 In the context of pregnancy and patients
with HELLP syndrome, apoptosis in liver tissue and cyto-
toxic activity for primary human hepatocytes has been
reported in serum from patients with HELLP syndrome(CD95 ligand produced by placenta) that increases over
time and in proportion to disease severity.45 In addition,
caspases 3, 8, and 9 are all required to effect apoptotic
cell death, and active forms of all 3 are detected in liver
extracts of HELLP patients. Blocking of CD95 signaling
reduces the hepatocytotoxic activity of HELLP serum.
Thus, systemic CD95L is a placenta-derived humoral
factor that is involved in the pathogenesis of HELLP
syndrome. CD95L-rich membrane fragments or soluble
CD95L are postulated by Strand et al45 to be shed into
the maternal circulation as important progenitors in the
pathogenesis of HELLP syndrome.The previously described findings and the proposal
that placenta-derived proteins damage hepatic cells are
compatible with many other findings that cast HELLP
syndrome as a placenta-instigated, liver-targeted acute
inflammatory condition and disordered immunologic
process.21 The similarity between HELLP syndrome and
systemic inflammatory response syndrome (SIRS) has
been emphasized by several researchers.48-50 The pertur-
bations present in patients who have HELLP syndrome
develop may be additive to, or altered by, the patho-
physiology leading to preeclampsia in general. A listing
of some of the supportive evidence for these conceptsis contained in Table I. Decreases in haptoglobin are
a sequel, not an instigator of the vascular hemolytic
process.68 In patients with HELLP syndrome, the metal-
loprotease ADAMTS-13 is not severely deficient or
undetectable as it is in many patients with throm-
botic thrombocytopenic purpura (TTP).69,70 No genetic
markers or evidence for association with thrombophilic
or antiphospholipid disorders have been established.71-75
Diagnosis
The diagnosis of HELLP syndrome is most assured ina pregnant patient with signs and symptoms of
preeclampsia-eclampsia and a triad of laboratory ab-
normalities suggesting red cell trauma (H = hemolysis),
hepatic damage and dysfunction (EL = elevated liver
enzymes), and thrombocytopenia (LP = low platelets).
The greater the extent of laboratory abnormalities, the
greater is the physicians confidence in the diagnosis.
Thrombocytopenia may be the first indicator of dis-
ease when the results of a complete blood count return to
the physician. A platelet count less than 150,000/mL
represents mild (100,000-150,000/mL), moderate (50,000-
100,000/mL), or severe (!50,000/mL) thrombocytopenia
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in the nonpregnant as well as pregnant patient.76 Requir-
ing a threshold of less than 100,000/mL to consider the
diagnosis of thrombocytopenia is ill advised. Maternal
morbidity doubles from 11% to more than 20% when
patients with severe preeclampsia have mild thrombocy-
topenia develop in association with increasing LDH
(R600 IU/L) and transaminases (AST and/or ALT
R40 IU/L).21,27 Significant pathology such as hepatic
hemorrhage and rupture can first appear in the patient
with HELLP syndrome before the platelet count falls
below 100,000/mL.28 Indeed, the onset of epigastric pain
in patients who are eventually diagnosed with HELLP
syndrome has occurred at a platelet count as high as
283,000/mL in our patient population (unpublished).
Hepatic injury and dysfunction
In Weinsteins initial 1982 report, thresholds of what
constituted abnormal serum levels of aspartate transam-
inase (AST), alanine transferase (ALT) and bilirubin to
merit a diagnosis of HELLP syndrome were not stated.18
Most healthy pregnant patients in our hospital laboratoryexhibited normal transaminase values less than 20 IU/L,
with greater than 48 IU/L for AST 3 SD above the
mean.27 A threshold for AST of 70 IU/L or greater to
qualify for the diagnosis of HELLP syndrome when
platelets are 100,000/mL or less has been consistently
advocated by Martin et al21 and Sibai.22 Transaminase
values between 40 and 70 IU/L reflect borderline hepatic
dysfunction regardless of the platelet count (especially in
the 100,000-150,000/mL range).28 Glutathione S-transfer-
ase alpha has been proposed as a better marker for acute
liver injury than the aminotransferases,but there has been
limited work on this possibility.77
Erythrocyte injury and death
Evidence for hemolysis is the third laboratory criterion for
HELLP syndrome. In addition to a progressive anemia,
other laboratory evidence of hemolysis classically in-
cludes decreased serum levels of haptoglobin, increased
serum total LDH 600 IU/L or greater,26,28 increased se-
rumAST, increased serum indirect bilirubin, an abnormal
peripheral smear showing variable amounts of disrupted
or destroyed red blood cells (schistocytes, echinocytes,burr cells), and/or a declining hematocrit or hemoglobin.
Depending on laboratory methodology, LDH thresholds
for abnormal values begin between 200 and 600 IU/L.
Classification
Classification systems have been created to enable phy-
sicians to identify patients at risk for significant mater-
nal morbidity, to guide therapeutic intervention and
assess efficacy or outcome, and to provide a common
platform for comparison of research results. The 2 most
commonly used systems for diagnosis and classificationwere developed in the 1980s by investigators at the
Universities of Tennessee and Mississippi (Table II).
The Tennessee Classification78 defines true or
complete HELLP syndrome if all of the following cri-
teria are met: (1) moderate to severe thrombocytopenia
with platelets 100,000/mL or less; (2) hepatic dysfunction
with AST 70 IU/L or greater; and (3) evidence of hemol-
ysis with an abnormal peripheral smear in addition to
either total serum LDH 600 IU/L or greater or bilirubin
1.2 mg/dL or greater. The patient who exhibits some but
not all of these parameters is termed partial or in-
complete HELLP syndrome: ELLP syndrome (missing
Table I Research findings contributory to an inflammatory pathogenesis for HELLP syndrome
Elevated serum concentrations of soluble Fas.51
Cytokine and neutrophil-mediated liver injury in necropsy liver specimens with strong staining for tumor necrosis factor-alpha and
neutrophil elastase antibody.52
Leukocytosis proportionate to disease severity.53
Increased plasma concentrations of anaphylatoxins C3a and C5a.54
Decreased unstimulated neutrophil oxygen radical production possibly secondary to an exhausted cellular response.55
Abnormal circulating cytokine concentrations.52,56
Increased bioactive tumor necrosis factor alpha possibly secondary to immune injury of the vascular endothelium or muscle.57
Depression of both T- and B-cell potential and impaired monocyte handling of intracellular pathogens precedes clinical/laboratory
disease by 1-2 wks.58
Decreased placental vascular endothelial growth factor (VEGF) expression in placentas from HELLP syndrome pregnancies59,60 analagous to
decreased circulating levels of free VEGF and platelet-derived growth factor (PlGF) in preeclamptic patients without HELLP syndrome.61
Dysregulation of VEGF ligands and receptors with higher serum VEGF compared to h ealthy matched
pregnant controls (but less elevated than patients with non-HELLP preeclampsia.62
Hypersensitivity to pressors using laser-doppler digital fluxometry microcirculation studies.63
Substantially decreased vascular smooth muscle-relaxing adrenomedullin and calcitonin gene-related peptide messenger RNA
in the placenta.64
Increased intracellular retention of cadherin-5.65
Increased plasma and red cell thiobarbituric acid reactive substances (TBARS) and glutathione peroxidase activity.66,67
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evidence for hemolysis), EL syndrome (severe pree-
clampsia with mildly elevated liver enzymes only), HEL
(hemolysis and elevated liver enzymes absent thrombo-cytopenia), or LP syndrome (low platelets syndrome as
severe preeclampsia with thrombocytopenia, gestational
thrombocytopenia, or immune thrombocytopenic pur-
pura).22 Maternal and perinatal outcomes are progres-
sively worse for patients with preeclampsia, partial
HELLP syndrome, and complete HELLP syndrome, re-
spectively.79 Incomplete criteria initially can progress to
complete expression of HELLP syndrome.
The Mississippi-Triple Class System for HELLP syn-
drome divides patients into 3 classes or groups that are
based primarily on the platelet portion of the laboratory
diagnosis.21,28,38
Final class assignment or diagnosis isbased on the lowest platelet count registered during
the disease course. The span of thrombocytopenia be-
tween zero and 150,000 platelets is divided into 3 equal
ranges consistent with mild, moderate, and severe
thrombocytopenia. For a patient to merit a diagnosis
of HELLP syndrome, class 1 requires severe thrombocy-
topenia (platelets %50,000/mL), evidence of hepatic
dysfunction (AST and/or ALTR70 IU/L), and evidence
suggestive of hemolysis (total serum LDHR600 IU/L);
class 2 requires similar criteria except thrombocytopenia
is moderate (O50,000 to %100,000/mL); and class 3
includes patients with mild thrombocytopenia (plate-lets O100,000 but%150,000/mL), mild hepatic dysfunc-
tion (AST and/or ALTR40 IU/L), and hemolysis (total
serum LDHR600 IU/L). Peripheral smear findings and
bilirubin abnormalities are not obtained.
Neither classification system is ideal; both have short-
comings. Because class 1 and 2 HELLP syndrome
patients are combined in the Tennessee system, discrim-
ination between groups and outcomes is difficult and
benefit from corticosteroids (arrest of disease in class 2,
prevention of progression from class 3 to 2 or even 1)
cannot be demonstrated. On the other hand, the Mis-
sissippi classification system is very useful for directing
individual patient therapy with aggressive corticosteroids
and for comparing pregnancy outcomes. The Mississippi
system, although including class 3 patients, does notinclude those with incomplete or partial forms of the
disease, and excludes patients from analysis when causes
of consumptive coagulopathy such as placental abruption
are present. Two (Tennessee) or even 3 (Mississippi)
groupings or classes insufficiently describe the multitude
of clinical scenarios (antepartum vs postpartum, epigas-
tric pain present or absent, degrees of laboratory value
abnormality, different gestational age epochs) encoun-
tered by the clinician. The importance of a transitional
group of patients is clearly demonstrated by instances of
hepatic ruptures in patients with class 3 HELLP syn-
drome80
and other reports of increased eclampsia andhigher perinatal morbidity/mortality in patients with
incomplete/partial HELLP syndrome.21
Imitators of HELLP Syndrome
Patients presumptively diagnosed with HELLP syn-
drome can have other disorders concurrent with HELLP
syndrome or other disorders altogether. Lack of response
to aggressive corticosteroid administration, especially
with persistence of disease or first presentation of disease
more than 7 days after delivery, should instigate testing to
evaluate other diagnostic possibilities (Table III). In ourexperience, the most common HELLP imitators are
patients with well-advanced acute fatty liver of pregnancy
(AFLP), acute renal failure with acute tubular necrosis
(usually not hemolytic uremic syndrome), neglected
class 1 HELLP syndrome coming to medical attention
too late for aggressive corticosteroids to prevent progres-
sion and multiorgan dysfunction, previously undiag-
nosed systemic lupus erythematosus/antiphospholipid
syndrome, and either immune thrombocytopenic pur-
pura (ITP) or thrombotic thrombocytopenic purpura
(TTP).98 See the excellent reviews of potentially con-
founding conditions written by Goodlin16,99
and Sibai.100
Table II Classification systems of HELLP syndrome
HELLP class Mississippi classification21,36,46 Tennessee classification22,165
1 Platelet count %50,000/mL
AST or ALT R70 IU/L
LDH R600 IU/L
Platelet count%100,000/uL
AST R70 IU/L
LDH R600 IU/L
2 50,000/ mL %Platelet count %100,000/mL
AST or ALTR
70 IU/LLDH R600 IU/L
3 100,000/ mL %Platelet count %150,000/mL
AST or ALT R40 IU/L
LDH R600 IU/L
N/A
Partial HELLP/
incomplete HELLP
N/A (Severe preeclampsia C one of the following: ELLP, EL, LP)
ELLP, Absence of hemolysis; EL, elevated liver functions; LP, low platelets.
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Clinical presentation
Signs and symptoms with HELLP syndrome are varia-
ble but depend largely on the stage of the patients
disease, whether class 1, class 2, or class 3.28
Right upperquadrant/epigastric pain is the most important symptom
suggestive of underlying HELLP syndrome, found in
100% of Weinsteins initial 1982 series of 29 advanced
cases.18 Half of patients with class 1 HELLP syndrome,
33% with class 2, and 16% with class 3 compared with
only 13% of severely preeclamptic patients without
HELLP syndrome exhibit epigastric pain or right upper
quadrant discomfort.28 Frequently epigastric pain oc-
curs in association with nausea or vomiting. Overall,
the incidence of epigastric pain/nausea/vomiting ranges
between 30% and 90%.20,22,26 Any pregnant patient
presenting in the second half of gestation with epigastricor right upper quadrant pain, particularly if associated
with nausea and/or vomiting, has HELLP syndrome
until proven otherwise.44 A pregnant patient with signs
and symptoms of severe preeclampsia who suddenly has
severe, writhing epigastric/upper abdominal pain develop
likely has hepatic bleeding or rupture constituting an
obstetric emergency.
Malaise or viral syndrome-like symptoms can occur
with advanced HELLP syndrome.22,26 Headache occurs
in a substantial number (33%-68%)22,28 of patients with
any form of preeclampsia whether HELLP syndrome
is present, with visual complaints in a lesser number.22
Hypertension and proteinuria are not always pre-
sent.21,22,101 Neither of these signs bears a consistent rela-
tionship in the individual patient with stage of disease,
although on a population basis higher blood pressures
and more proteinuria tend to occur more frequently as
HELLP syndrome worsens from class 3 to 2 to 121,28,102
and eventually almost all patients are mildly hypertensiveduring the course of their disease and recovery.28 Signifi-
cant dipstick proteinuria (3-4C) at presentation occurs in
approximately half of patients with class 1 or 2 HELLP
syndrome, but no proteinuria is detected in approxi-
mately 1:6 patients.
Although the presence and severity of symptomatol-
ogy (epigastric pain, nausea, vomiting) and hypertension
(systolic, diastolic) in general are related to maternal
disease severity and the potential to develop severe mor-
bidity,28,38,103 individual patient predictive value (with the
probable exception of severe epigastric pain) is low.104
Significant maternal morbidity becomes more likelywhen 1 or more of the laboratory thresholds are exceeded
as listed in Table IV.102,105,106 Very high LDH, AST,
and/or uric acid have the highest predictive value and
are risk-additive with worsening thrombocytopenia.28,107
Maternal morbidity and mortality
The development of HELLP syndrome places the
pregnant patient at significant risk for morbidity and
mortality. Morbidity is categorized by major organ
system(s) affected and is stratified by extent of diseaseusing the Mississippi classification system.28 Constitu-
ents of these categories are listed in Table V and pre-
sented in decreasing order of frequency, emphasizing
that there is enormous variability among patients.
Hematologic-coagulation
The prevalence of disseminated intravascular coagula-
tion (DIC) increased from 2 of 193 patients (0.5%) with
severe preeclampsia to 35 of 201 (17.4%) with class 1
HELLP syndrome,28 the latter very similar to the
15% incidence of DIC and 9% incidence of placental
abruption reported by Audibert et al79
for classes 1
Table III Confounders and concurrent conditions: differen-
tial diagnosis50,134
AFLP81
Lupus flare: Exacerbation of systemic lupus erythematosus
(SLE)82,83
TTP84
Hemolytic uremic syndrome (HUS)85
ITPThrombophilias
Antiphospholipid syndrome75,83,86-91
Homozygous factor V Leiden
Prothrombin gene mutation
Severe folate deficiency92
Cholangitis/cholecystitis/pancreatitis/ruptured bile duct
Gastric ulcer
Cardiomyopathy
Dissecting aortic aneurysm
Systemic viral sepsis (herpes, cytomegalovirus)93
SIRS/sepsis
Hemorrhagic or hypotensive shock
Stroke in pregnancy or puerperiumParoxysmal nocturnal hemoglobinuria94
Pheochromocytoma
Advanced embryonal cell carcinoma of the liver95
Acute cocaine intoxication
Myasthenia gravis96
Pseudocholinesterase deficiency97
Table IV Admission risk factors for significant maternal
morbidity/mortality HELLP syndrome
Signs/symptoms Laboratory values
Epigastric pain Platelets !50,000/mL
Nausea Total serum LDH O1400 IU/L
Vomiting AST O150 IU/L
Severe systolic hypertension ALTO
100 IU/LSevere diastolic hypertension Uric acidO7.8 mg/dL
Placental abruption CPK O200 IU/L
Eclampsia Serum creatinine O1.0
Adapted from Martin et al.102
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and 2 combined. Clinically significant bleeding requiring
transfusion and wound hematoma formation follow a
similar pattern of increasing incidence with worsening
disease.21,25-28,79,104,108 Approximately 10% of patients
with class 1 or 2 HELLP syndrome exhibit microscopic
or macroscopic hematuria.28
Cardiopulmonary
The odds of developing a cardiopulmonary problem,
particularly pulmonary edema, is more than doubled
(2.2!) for patients with class 1 HELLP syndrome
(22%) compared with non-HELLP severe preeclamp-
sia.28,109 The overall percentage of 14.5% (74/501) in the
Mississippi series is similar to the combined 8% inci-
dence of pulmonary edema and less than 1% incidence
of adult respiratory distress syndrome in the Tennessee
series.79 Copious large volume ascites identifies a patient
at high risk for cardiopulmonary complications.110
Central nervous system/visual
Patients with noneclamptic class 1 or 2 HELLP syn-
drome (11/501 or 2.2%) are 3.5 times more likely to have
significant central nervous system (CNS) morbidity com-
pared with class 3 HELLP syndrome or non-HELLP
severe preeclampsia.28 This includes stroke, mental status
changes and/or coma.111-114 Visual complications
including retinal detachment, vitreal hemorrhage, and
cortical blindness are infrequent in proportion to disease
severity (1.4% in class 1 and 2).28 These are usually short
lived with full recovery within 1 to 6 months, exceptwhen cerebral hemorrhage/stroke is the cause.115-126
Renal
Placental abruption and puerperal onset of HELLP syn-
drome place the patient at increased risk for renal insult.
In general, renal system morbidity increases as disease
status worsens.28 All 4 of the patients with acute tubular
necrosis in the Mississippi series had class 1 HELLP syn-
drome develop; acute renal failure complicated 3% of
cases of class 1 or 2 HELLP syndrome in the Tennessee
series.26,79 However, acute renal dysfunction and/or fail-
ure has been described as often as 54% and 33% insome international series19,127 and as the most common
cause of maternal morbidity in a report from Mexico.128
Hepatic
Catastrophic liver complications are relatively infre-
quent. Liver hemorrhage/rupture affected only 1% of
patients with class 1 or 2 HELLP syndrome in the
Tennessee series26,79 and only 3 patients had significant
hepatic complications develop (2 subcapsular hemato-
mas in class 2 and 3 HELLP syndrome patients, 1 liver
rupture in a class 1 HELLP syndrome patient) in the
Mississippi seriesdimportantly all were classified as
class 3 HELLP syndrome when the complication was
first detected.27 According to Wicke et al,129 at least 1 of
5 patients with eventual liver rupture caused by HELLP
syndrome had early subcapsular liver hematoma forma-
tion compatible with the class 3 level of disease.
Infection/sepsis
Patients with HELLP syndrome more often have infec-
tious morbidity develop than those with non-HELLP
severe preeclampsia (43% vs 20%).25,27 At least 3 im-
portant variables are involved: corticosteroids, transfu-
sion, and delivery. Corticosteroid utilization appears
to reduce infectious morbidity from 43% to 18% by re-
ducing or eliminating the need for transfusion of blood
products.27,28 Abdominal delivery doubles infectious
morbidity from 19% to 41%.28
Table V Categories of significant maternal morbidity with
HELLP syndrome
Hematologic/coagulation
Clinically significant bleeding requiring transfusion
Ecchymoses
Hematoma
DIC
HematuriaCardiopulmonary
Cardiogenic/noncardiogenic pulmonary edema
Cardiac/pulmonary arrest
Pulmonary embolus
Indicated invasive hemodynamic monitoring
Intubation/mechanical ventilation/continuous positive
airway pressure
Myocardial ischemia/chest pain
CNS/vision
Cerebral hemorrhage/stroke
Central venous thrombosis
Hypertensive encephalopathy
Cerebral edemaSensorium change/coma
Impaired vision
Retinal/macular detachment
Vitreal hemorrhage
Cortical blindness
Eclamptic seizure
Renal
Acute tubular necrosis
Acute renal failure
Renal dialysis
Transient renal impairment
Hepatic
Subcapsular/intrahepatic hematomaHepatic rupture/hemorrhage
Pancreatitis
Infection/sepsis
Obstetric
Other
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Obstetric issues
Cesarean delivery has been performed more often forpatients with class 1 HELLP syndrome (61%) than
class 2 (57%), class 3 (53%), or non-HELLP severe
preeclampsia (48%).25,28 Mode of delivery is strongly
influenced by gestational age, maternal-fetal status, class
of disease, and corticosteroid utilization. Overall abdom-
inal delivery is associated with a doubling of maternal
morbidity (cardiopulmonary, hematologic-coagulation,
and infectious) compared with vaginal delivery.28 In
addition, risk for placental abruption, placenta previa,
eclampsia, and episiotomy breakdown is increased
compared to non-HELLP pregnancies.20,25,130,131
Parity-eclampsia
The incidence of complications in hypertensive pregnant
women varies by parity but not by gravidity.132 When
HELLP syndrome complicates eclampsia, parous pa-
tients have double the incidence of significant maternal
morbidity compared with nulliparous patients (50% vs
25%).133
Other morbidity
Pancreatitis is uncommon in patients with preeclampsia
or HELLP syndrome; the hemorrhagic form is uniquely
associated with acute fatty liver of pregnancy.134 Dia-
betes insipidus,135 bone marrow necrosis with cerebral
hemorrhage,88 and myocardial infarction136 are rarecomplications.
Mortality
Most deaths in patients with HELLP syndrome occur
with class 1 disease (60%), and neurologic abnormality
due mostly to cerebral hemorrhage/stroke is the most
common system involved at autopsy (45%) (Figure 1).137
Delay in diagnosis appeared to be a factor in half of
the deaths that could be adequately evaluated, and
none of the 54 maternal deaths in the Isler et al series137
or in a subsequent case report138 occurred in association
with the aggressive use of corticosteroids.
Perinatal morbidity and mortality
Perinatal morbidity and mortality are substantially
higher in pregnancies with severe preeclampsia com-
plicated by HELLP syndrome, primarily because of
required preterm delivery.25,139 Fetal growth restriction
and fetal distress after 32 weeks also may be more fre-
quent.140 Although neonatal deaths and perinatal mor-
tality rates tend to be progressively higher in parallel
with increasingly severity of disease, outcomes are
Figure 1 Contributing factors to deaths of women with HELLP syndrome are shown in order of decreasing frequency. DIC,
Disseminated coagulopathy; ARDS, adult respiratory distress syndrome; Enceph, encephalopathy. Reprinted from Isler CM, Rine-
hart BK, Terrone DA, Martin RW, Magann EF, Martin JN. Maternal mortality associated with HELLP (hemolysis, elevated liver
enzymes, and low platelets) syndrome. Am J Obstet Gynecol 1999;181:924-8 with permission from Elsevier.
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primarily related to gestational age at delivery and not
to disease status.28,141-146 Similarly, earlier prematurity
is responsible for the higher perinatal mortality recorded
in eclamptic pregnancies with HELLP syndrome com-
pared with non-HELLP eclampsia.20,25,147 Neonatal
survival was 100% in the Mississippi experience if new-
born weight was 600 g or greater and following a full
course and time interval (48 hours) of antenatal cortico-steroids for fetal lung maturation.148
Continuation of HELLP syndrome pregnancy be-
yond 26 weeks and the time necessary for steroid
enhancement of fetal lung maturation increases the
risk of stillbirth substantially.144,149 In the Mississippi
series, stillbirth was almost tripled for class 1 or 2 com-
pared with class 3 or non-HELLP severe preeclampsia,28
in part related to fetal growth restriction and placental
abruption. Fetal growth restriction and abnormal Dop-
pler velocimetry impact up to 39% and 48% of patients,
respectively.22,130,150 Although neonatal thrombocyto-
penia occurs in a substantial percentage (up to38%)130 of newborn infants, a higher incidence of intra-
ventricular hemorrhage has not resulted.151,152 Long-
term prognosis for the children of mothers with HELLP
syndrome is comparable to controls matched for gesta-
tional age.152 Small-for-gestational-age neonates signifi-
cantly increase weight and length over the first 4 years of
life compared with matched controls.153 Newborn
infants weighing less than 1250 g compared with birth
weight-matched controls had significantly less cerebral
palsy and mental disability at 3 years of life.146
The integral role of corticosteroids
The probability that HELLP syndrome is a SIRS-like
inflammatory form of severe preeclampsia50 leads to
consideration of anti-inflammatory/immunosuppressive
agents for treatment, specifically corticosteroids. The
consistently favorable response of HELLP syndrome
laboratory parameters to corticosteroids suggests the
presence of an underlying corticosteroid-responsive
step(s) in its pathogenesis and a therapeutic benefit to
their use. Corticosteroids may act by one or more mech-
anisms to alter endothelial activity/interaction with cir-
culating cells including erythrocytes and platelets,impact translation/transcription, interrupt hepatocyte
damage by placenta-derived CD95-L and/or to disrupt
signaling for inflammatory cytokine production by the
endogenous immune system.154 A recent publication
that thoroughly explores the pharmacology and physiol-
ogy of corticosteroids relevant to pregnancy and
HELLP syndrome is recommended to the interested
reader for review.154
The potential therapeutic value of corticosteroids for
patients with HELLP syndrome was first recognized in
the early 1990s by 2 groups of investigators, one in
Denver155
and the other in Jackson, MS.156,157
The first
2 small randomized clinical trials (nonblinded, nonpla-
cebo controlled) were undertaken in Jackson using in-
travenous (IV) high-dose dexamethasone versus no
steroids during 1992 through 1993 in 65 patients with
antepartum or postpartum HELLP syndrome.158,159
Stabilization and significant improvement in laboratory
and clinical parameters associated with HELLP syn-
drome occurred in women who received antenatal and/or postpartum corticosteroids.158,159 Subsequent to the
publication of these findings, retrospective scrutiny of
selected data present in several published series of
patients with severe preeclampsia from the 1970s and
1980s revealed findings consistent with this new observa-
tion that high-dose dexamethasone appeared to arrest
the deterioration of laboratory parameters in patients
fulfilling criteria for HELLP syndrome.16,139,160-162
Four other small randomized, controlled trials have
been undertaken comparing the use of high-dose dexa-
methasone or prednisolone (50 mg twice daily) with
either no treatment, placebo, or with betamethasone.Two HELLP trials were undertaken antepartum63,163
and 2 evaluated postpartum corticosteroid treat-
ment.164,165 Significantly improved biochemical para-
meters of HELLP syndrome and clinical parameters
of mean arterial pressure and urinary output were
consistently reported. In the most recently reported
trial from The Netherlands,80 the prednisolone-treated
group of 15 antepartum patients had a 50% reduction
in HELLP syndrome exacerbations compared with 15
placebo-treated controls and a significantly shorter time
to normalize postpartum platelets. All 3 major mater-
nal complications occurred in the placebo groupdformation of a liver hematoma in 2 patients and rupture
of the liver in a third patient with maternal death.
No significant neonatal differences between groups
were noted in the immediate neonatal period or at infant
follow-up.80
On the basis of the findings from the first 2 prospec-
tive clinical trials and the preceding case series findings
that led to the trials, interpreting them to collectively
indicate a clear patient benefit to treatment, practice
guidelines at University Hospital in Jackson were
revised in mid-1993 to routinely initiate IV high dose
(10 mg IV every 12 hours) dexamethasone antepartumor postpartum for (1) any patient with class 1 or 2
HELLP syndrome and (2) any patient with class 3
HELLP syndrome associated with epigastric pain,
eclampsia, severe hypertension, and/or any evidence of
major organ system morbidity. Patients with uncompli-
cated class 3 disease were monitored and subsequently
treated if they met either of the 2 criteria.21,27,166,167 The
dosage of drug used is approximately double that
recommended for fetal lung maturation purposes and
half the amount used for adults with newly diagnosed
immune thrombocytopenic purpura.168,169 Postpartum
and approximately 12 hours after the last antepartum
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dose, IV dexamethasone is given twice more at 10 mg IV
every 12 hours and usually tapered with 2 lesser doses of
5 mg IV every 12 hours for a full course. The regimen is
lengthened or shortened to fit individual patient
circumstances.167
Routine high-dose IV dexamethasone according to
the Mississippi regimen is now in its twelth year of
practice utilization in Jackson; historical control groupsfrom the era before 1992 when corticosteroid trials
began are the only potential comparison groups of
patients. Compared with 246 patients with class 1 or 2
HELLP syndrome treated between 1985 and 1991 when
only 16% received a complete or incomplete course of
corticosteroids to enhance fetal lung maturation, signif-
icantly reduced composite maternal disease was ob-
served in 228 patients managed between 1994 and 2000
with 90% aggressive corticosteroid utilization. There
were significantly improved laboratory parameters, less
progression to class 1 HELLP syndrome, less frequent
need for antihypertensive therapy, less requirement fortransfusion, lower incidence of major maternal morbid-
ity, and shortened postpartum recovery.170 Overall
maternal morbidity rates of 64% for class 1 HELLP syn-
drome, 54% for class 2, and 40% for class 3 improved to
49%, 22%, and 21%, respectively, with an aggressive
corticosteroid regimen compared with an 11% baseline
for non-HELLP severe preeclampsia.25,27,28 Compara-
ble quantitative and qualitative benefits occurred in
similarly treated patients with postpartum HELLP syn-
dromeda more rapid normalization of platelet counts
and LDH values and a clinically significant reduction
of indicated transfusion, need for intubation or intensiverespiratory therapy, invasive hemodynamic monitoring,
infectious- or bleeding-related morbidity, and length of
postpartum hospital course.171
At least 7 other groups have also retrospectively
reviewed case series and found that corticosteroids im-
prove laboratory indices and positively impact HELLP
syndrome severity and pathogenesis.172-178 Tompkins
and Thiagarajah,173 for instance, interpret their data
to show best benefit using 2 doses of intramuscular
(IM) betamethasone (12 mg each) given 12 hours apart
rather than the National Institutes of Health (NIH)179
recommended interval of 24 hours. The findings ofOBrien et al175 point toward accelerated (shorter inter-
val) standard dose fetal lung maturation steroids (either
12 mg betamethasone IM every 12 hours ! 2 or dexa-
methasone IV 6 mg every 6 hours), or a higher than
Mississippi regimen of IV dexamethasone (10 mg every
6 hours ! 2, then 6 mg every 6 hours ! 2-4 doses)
given to patients with antepartum HELLP syndrome
to improve platelet counts, reduce liver enzyme abnor-
malities, and prolong latency to delivery in a dose-
dependent manner.
In addition to these 13 publications, several other
observations are offered that favor the routine inclusion
of aggressive corticosteroids for patients with HELLP
syndrome:
Liver hemorrhage or rupture is rarely encountered in
the undelivered pregnant patient with preeclampsia/
eclampsia who is receiving corticosteroids for fetal
lung maturation or aggressive corticosteroids for
treatment of HELLP syndrome.21,28 Liver complications may be particularly susceptible
to interdiction with early aggressive corticosteroids,
especially in the symptomatic class 3 HELLP syn-
drome patient with other underlying pathology.86
Pauzner et al86 noted recently that antiphospholipid
syndrome was present in all 4 patients with hepatic
infarction and HELLP syndrome (described as in-
complete in 3 of 4 cases), and their literature survey
noted that anticardiolipin antibodies and/or lupus
anticoagulant were positive in 15 or 16 patients
with hepatic complications for whom laboratory
data were available. A similar series and a case reportwere published recently from France.90,91
Because renal and/or hepatic dysfunction with
HELLP syndrome exhibit can be exhibited very early
in disease development before class 1 or 2 criteria are
met, it is possible that routine initiation of aggressive
corticosteroids in class 3 and partial HELLP
patients might prevent disease progression and sig-
nificant maternal hepatorenal morbidity.
When aggressive corticosteroids are not used, signif-
icant maternal morbidity180 or mortality can occur
that might otherwise have been avoided. For in-
stance, HELLP syndrome developing in associationwith severe systolic hypertension above 160 mm Hg
may enhance the potential of cerebral blood vessels
to bleed when corticosteroids are absent from man-
agement. Among a highly selected group of 28
women with preeclampsia-induced severe systolic hy-
pertension who had cerebral hemorrhage and stroke,
18 (64%) had evidence for concurrent class 1, 2, or 3
HELLP syndrome before the cerebral catastrophe
and no patient had been a recent corticosteroid recip-
ient.181 None of 54 patients dying with HELLP syn-
drome in the Isler series received corticosteroids,
many of whom had CNS pathology.138
Corticoste-roids use was not described in 104 patients from
France with a 79% complication rate in the class
1 HELLP category,106 or in recent series from Ger-
many, China, and Turkey with high rates of maternal
morbidity,130,182,183 and they were usually absent
from the management of patients with significant
maternal morbidity reported before 1990.6-17
Aggressive corticosteroids can effect an increase in
platelet count sufficiently to undertake regional
anesthesia (from 0% to 42%) and to enable cervical
ripening, induction of labor and vaginal deliv-
ery.184,185
Up to 75% of patients with HELLP
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syndrome can become candidates for regional anes-
thesia after high-dose corticosteroid administration
if a platelet threshold of 75,000/mL is deemed
adequate, and a higher rate of vaginal delivery can
be accomplished than would otherwise be possible
especially in relatively preterm gestations.185 In the
absence of corticosteroid use, the cesarean rate is
high and vaginal delivery is a rare event.128,186 A recent prospective randomized clinical trial under-
taken in the authors hospital found no clear treatment
benefit with postpartum high-dose dexamethasone
for puerperal patients with non-HELLP severe pre-
eclampsia at diagnosis.187The only 2 patients to subse-
quently have postpartum HELLP syndrome develop
were in the placebogroup, and both responded quickly
to the emergent initiation of IV dexamethasone after
study assignment as placebo was ascertained.
Choice of corticosteroid
Although approximately equivalent in potency, IV dex-
amethasone appears to be more effective than IM
betamethasone, perhaps by delivering the drug directly
into the vasculature of the affected organ systems.163,188
Preferences for other regimens by others were listed
earlier. Sibai recommends an aggressive corticosteroid
regimen similar in potency to the Mississippi protocol
(dexamethasone 10 mg IV every 12 hours) for antepar-
tum HELLP syndrome to improve maternal status,
using 2 doses of either betamethasone 12 mg IM every
12 hours (instead of every 24 hours) or dexamethasone
12 mg IV (instead of 5 or 6 mg) every12 hours with de-livery to be accomplished within 24 hours after the last
dose of corticosteroids.22 Determination of preferred
drug, dosage, and regimen specific to clinical circum-
stances awaits large multicenter studies.
Potential maternal-fetal risks
Potential maternal risks include rebound thrombocyto-
penia, adrenal suppression, infection, and the masking
of potential complications or other disease processes.
The available data are insufficient to estimate if there
are any adverse short- or long-term neonatal-infant
effects from brief aggressive corticosteroids for HELLPsyndrome. Neither dexamethasone or betamethasone
is preferable from the fetal perspective in regard to
short-term outcomes.189 The use of aggressive cortico-
steroids for antepartum HELLP syndrome is recom-
mended exclusively as a short-term intervention;
continuation of pregnancy after more than 48 hours of
aggressive corticosteroid administration for very pre-
term HELLP syndrome pregnancy can lead to signifi-
cant maternal and fetal morbidity and mortality.149
Evidence is meager (few case reports) regarding cortico-
steroid prolongation for many days to weeks of a pre-
viable HELLP syndrome pregnancy to viability, and
long-term potentially adverse implications to the new-
born infant remain a question.172,190-192 Lower birth
weight, lower head circumference, neonatal adrenal
suppression, and increased infection are theoretical risks
to a newborn infant exposed to even a very short course
of high-dose corticosteroids, but evidence for this is
lacking. Potent glucocorticoids used for pregnancies
with HELLP syndrome may actually impart a fetal ad-vantage because placental vascular resistance by Dop-
pler assessment appears to be reduced briefly in
singleton and multiple gestations after maternal beta-
methasone administration.193,194 In pregnant ewes re-
ceiving extended dexamethasone prenatally (20 days
with 20 mg/kg maternal body weight), no evidence of
altered renal function or predisposition to adult hyper-
tension compared with controls was found.195
Summary
Despite current limitations in sample size and study
structure, a consistent positive picture of patient benefit
emerges from a review of the present literature that we
suspect will be shown definitively once large multicenter
clinical trials are undertaken. This is consistent with our
considerable bedside experience gained over many years
and in a multitude of patient circumstances and situa-
tions that a routine practice of initiating aggressive
corticosteroids early in HELLP syndrome pregnancies
will prevent them from progressing along a continuum
of worsening morbidity, a critically important concept
for clinicians to embrace to reduce maternal mortality
rates in patients with this disease.196 In view of the
absence of a demonstrated downside to this approach
either for the mother or the fetus, given the body of
affirmative available literature, we believe it most bene-
ficial to patients now to be managed according to the
recommendations that follow.
Fundamentals of practicedThe applicationof aggressive corticosteroids
The fundamental management concepts for treatment of
patients with HELLP syndrome using aggressive corti-
costeroids is presented in core concepts (Table VI) andas an algorhythm (Figures 2 and 3). Further consider-
ations are discussed in paragraphs to follow.
In any patient suspected of having HELLP syn-
drome, basic laboratory evaluation includes a complete
blood count with platelets, serum AST, and total serum
LDH. Extended assessment can include serum creati-
nine, glucose, bilirubin, coagulation studies, and a
peripheral smear. Elevation of direct bilirubin and
prolongation of coagulation studies out of proportion
to mild thrombocytopenia occurs early in patients with
AFLP but is unusual with HELLP syndrome unless the
disease is very advanced (class 1).
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An aggressive corticosteroid regimen is initiated as
soon as the diagnosis of class 1 or 2 HELLP syndrome is
made or if the patient has complicated class 3 HELLPsyndrome. Continuation during cervical ripening and
induction of labor can be used to facilitate attempted
vaginal delivery or to improve the mothers hematologic
status before abdominal delivery. If the fetus is preterm
and previable such that cesarean delivery is not a fetal
consideration, presence or absence of fetal heart tones
is assessed intermittently to determine whether a neona-
tal team should be summoned at delivery to assess the
reasonableness of resuscitation efforts. Rarely a preg-
nancy with borderline viability has been prolonged
with aggressive corticosteroids but this is not usually
recommended.190-192,197,198
It is particularly discouragedin a patient with a fetal abnormality or major maternal
morbidity such as renal failure.199 HELLP syndrome
detected before fetal viability may identify a pregnancy
complicated by partial mole/triploidy,200 trisomy 13,201
antiphospholipid syndrome,87 autoantibodies to angio-
tensin AT(1)-receptor,202 or severe preterm preeclamp-
sia with mirror syndrome.203
Maternal-fetal status, gestational age, presence of
labor, cervical Bishop score, prior maternal obstetric
history, and response to aggressive corticosteroids all
impact management of the patient with a preterm viable
fetus and HELLP syndrome. Immediate cesarean
delivery is not generally indicated or recommended; vag-
inal or cesarean delivery after 24 to 48 hours of cortico-
steroids are better options to achieve maximal maternaland fetal benefit.204 Vaginal delivery rates of 32% for
gestations less than 30 weeks, 61% at 30 to 31 weeks,
and 62% at 32 to 33 weeks (overall induction success
145/247 or 59%, 37% !28 weeks) can be achieved.186
Nevertheless, because vaginal delivery rates with
HELLP syndrome are below 50% for gestations less
than 30 weeks, Sibai22 advocates elective cesarean deliv-
ery for all women diagnosed with HELLP syndrome at
a gestation age less than 30 weeks when spontaneous
labor is not present and the Bishop score is less than 5.
A patient with a low Bishop score in association with
fetal growth restriction and/or oligohydramnios maynot be a good candidate for trial of labor. Otherwise,
vaginal delivery is attempted in patients in active labor
less than 30 weeks with ruptured membranes or with a
Bishop score 5 or more in the absence of obstetric con-
traindications. Once the 30-week gestational age thresh-
old is reached, an attempt at vaginal delivery is usually
recommended while aggressive corticosteroids are
initiated.
Epidural or spinal anesthesia is the preferred anes-
thetic for patients with preeclampsia.205 Approximately
50% of patients with HELLP syndrome can be candi-
dates for regional anesthesia during a trial of labor using
Table VI Fundamental principles of HELLP syndrome management with aggressive corticosteroids
Laboratory testing to detect HELLP syndrome is recommended for any pregnant patient presenting with possible preeclampsia,
especially pretermdearly detection is preferred.
Whether a patient presents with class 1, 2, or 3 HELLP syndrome or has complete/incomplete disease parameters does not lessen the
clinicians pressing need to undertake appropriate evaluation and intervention for the patient.
HELLP syndrome is a systemic and progressive pregnancy disease process that usually shows signs of recovery only after delivery is
accomplished. The first priority is to assess the maternal-fetal condition and to determine secondarily whether delivery is immediately
indicated or can be delayed while aggressive corticosteroids are used to accelerate fetal lung maturation, enhance maternal status,and optimize conditions either for vaginal or abdominal delivery to occur.
Aggressive corticosteroids clearly benefit the mother with HELLP syndrome according to stage of disease when drug therapy is
initiated, agent used, amount and route of administration.
A proactive, preventative early aggressive application of corticosteroids for the patient with antepartum or postpartum HELLP
syndrome probably realizes the greatest maternal benefit regardless of gestational age (Figures 2 and 3).
The patient with HELLP has severe preeclampsia and is managed accordingly with intensive surveillance and care during the
peripartum interval, including magnesium sulfate and aggressive antihypertensive therapy to minimize systolic blood pressures
above 160 mm Hg.22,170
The CNS is the most commonly affected system in mothers dying from HELLP syndromedthe aggressive use corticosteroids and
antihypertensives probably lessens the risks of stroke and death. Early aggressive corticosteroids may also lessen hepatorenal
morbidity.
Aggressive corticosteroids in patients with HELLP syndrome increases the providers chance to provide regional anesthesia during
labor and delivery and to maximize the potential for vaginal delivery. Early transfer of the patient with HELLP syndrome to a suitable facility that can provide 24-h intensive care and consultation for
maternal-fetal-neonatal needs should be considered if appropriate.
Perinatal outcome is predominantly gestational age-dependent. Because stillbirth and placental abruption occur with increased
frequency in relation to impaired fetal growth and maternal disease severity, efforts to prolong HELLP syndrome pregnancy more than
48-72 h (regardless of gestational age) are undertaken at some risk to mother and child.
The clinician must be mindful that the patient considered to have HELLP syndrome may have some other disorder, especially AFLP
that is relatively uncommon but has a much worse prognosis.
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a threshold of 100,000/mL platelets.187 In these cir-
cumstances, the decision of abdominal versus vaginal
delivery becomes more of an obstetric issue ratherthan a response to a rapidly worsening maternal-fetal
condition. Furthermore, patients who receive regional
anesthesia avoid the greater risks associated with gen-
eral anesthesia. When motivated, providers can depend
on corticosteroids to improve maternal platelet counts
sufficiently to increase the epidural rate for patients
with HELLP syndrome from 0% to 57%.184 When ce-
sarean delivery without trial of labor is planned, waiting
approximately 6 hours after beginning an aggressive
corticosteroid regimen is recommended to stabilize the
disease process, improve laboratory parameters, enable
institution of regional anesthesia, and reduce the needfor platelet or red cell transfusion. Given the absence
of neurologic or hematologic complications with re-
gional anesthesia in HELLP syndrome patients man-
aged in Panama without corticosteroids or platelet
count restrictions, the likelihood of bleeding complica-
tions with regional anesthesia is small.205
Aggressive corticosteroid administration is associated
with a significant decrease in the required use of blood
products21 and consequently a secondary decrease in in-
fectious morbidity. When emergent cesarean delivery
must proceed without waiting for a steroid effect and/
or in the rare patient with advanced disease and a
platelet count less than 40,000/mL that is unresponsive
to corticosteroid use, platelet transfusion of 6 to 10 units
of platelets is recommended immediately prior tointubation.206
Prevention of severe systolic hypertension (O160 mm
Hg) is paramount; recommendations to maintain sys-
tolic pressures under 155 mm Hg and diastolic pressures
under 105 mm Hg are reasonable goals.22,181 Labetolol,
hydralazine, or nifedipine are the preferred agents for
treatment of acute hypertension in this setting with
infused dilute nitroglycerin held in reserve.207
There have been no randomized trials of cesarean
operative technique for patients with HELLP syndrome.
Delayed skin closure or type of skin incision do not
appear to influence the frequency of wound complica-tions.208 In the absence of postpartum aggressive corti-
costeroids, a high incidence of hematoma formation
can occur despite placement of a subfascial drain and
keeping the skin incision open for 48 hours.22
Most of the fundamental principles of management
for patients with antepartum HELLP syndrome apply
equally to postpartum/postoperative patients. New-
onset postpartum disease appears usually within the
first days after delivery and is treated with aggressive
corticosteroids similar to antepartum disease.21,170,171
The treatment is tailored to the patient; corticosteroid
dosage is reduced once an upward trend in platelets and
Figure 2 HELLP management algorithm: aggressive corticosteroids.
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a downward trend in total serum LDH is recorded, and
discontinued with normalization of HELLP laboratory
parameters and resolution of signs and symptoms of
preeclampsia.
Significant renal injury is infrequently encountered
in patients with HELLP syndrome unless placental
abruption or a major hemorrhage also occurs.209 Most
often renal dysfunction responds to measures short
of dialysis or only a brief course of dialysis.19,209,210
Because a convincing renal benefit to aggressive cortico-
steroids has not been demonstrated, the basic patient
management principles for patients with acute renalfailure are used.211
Almost all instances of spontaneous subcapsular
hematomas or hepatic rupture in pregnancy occur in
association with HELLP syndrome.212-214 As thrombo-
cytopenia worsens into the lowest ranges (class 1), in
conjunction with the onset of sudden epigastric pain,
the likelihood of finding abnormal hepatic imaging
with computed tomography or magnetic resonance
imaging increases. For reasons given earlier, we specu-
late that it benefits patient care to immediately begin ag-
gressive corticosteroids for any patient with suspected
HELLP syndrome and having hepatic injury develop,
regardless of disease class. Several excellent treatises
have been published recently that review the manage-
ment of HELLP-related hepatic complications such as
hepatic rupture.129,212-217
Beyond corticosteroids
Plasma exchange or plasma infusion have been used
sparingly for recalcitrant and/or complicated HELLP
syndrome that is unresponsive to standard ther-
apy.83,218-224 Some of the postulated mechanism of
actions include (1) clearance from the circulation ofdebris, toxins, antigen-antibody complexes, damaged
red cell components or other substances that may be
compromising normal coagulation and organ function;
and (2) replacement of fluid, clotting factors, proteins,
and other plasma components that are required to
achieve homeostasis and healing. Prevention of intravas-
cular fluid overload is enhanced versus straight transfu-
sion, particularly in the patient with compromised renal
function. Collaborative care with intensivists and hema-
tologist/transfusion medicine subspecialists is impera-
tive. Because patients in these circumstances are rare,
unique, and difficult to accurately quantify, randomized
Figure 3 Class 3 or incomplete/partial HELLP syndrome.
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clinical trials are unlikely to be undertaken or even fea-
sible. Thus, the role of plasma exchange in HELLP syn-
drome management remains controversial but less
frequently a concern we speculate because of early diag-
nosis and aggressive corticosteroids.
There is little evidence suggesting efficacy to the use
of heparin,178,225 activated factor VII,226 or haptoglo-
bin227 for treatment of HELLP syndrome. Attemptedprolongation of pregnancy with hydration and antihy-
pertensives is not recommended because it is associated
with increased maternal and perinatal morbidity related
to placental abruption and hepatic rupture.80,228
Prognosis: Recovery
Patients with HELLP syndrome usually recover com-
pletely, although relapses can occur in the absence of
corticosteroid administration.224 After-effects of disease
can persist for extended periods if hepatic or renal dam-
age has occurred.229
Long-term follow-up of mothersand children from HELLP syndrome pregnancies are
few in number. Renal function was not permanently im-
paired in 23 women with acute renal failure and HELLP
syndrome who were monitored an average of 4.6 years;
8 patients had 11 subsequent pregnancies, 9 of which
were term gestations.230 Similar normalization of renal
function after a HELLP syndrome pregnancy was
reported by Jacquemyns Belgian group,229 but higher
systolic and diastolic blood pressures were observed at
5 years compared with controls. In Amsterdam, the in-
cidence of subsequent hypertension requiring treatment
was 3 times higher than controls.230
In the absence ofacute renal failure, there was no detectable impairment
of renal function at least 5 years after HELLP syndrome
in 10 patients. Stroke in patients with HELLP syndrome
left residual defects in 10 of 13 patients (77%) who sur-
vived the acute insult.181 No permanent adverse effects
on liver function have been reported. Emotional trauma,
both immediate and delayed, can be a significant patient
issue.231,232
Patient counseling: Future pregnancy
Women with a prior history of HELLP syndrome carryan increased risk of at least 20% (range 16%-52%) that
some form of gestational hypertension will recur in a
subsequent gestation. The rate of recurrent HELLP
syndrome itself varies between 2% and 19% depending
on the population studied, gestational age at onset,
whether there is concurrent vascular disease of any type,
and very likely the unique genetic profile of the individ-
ual patient, her partner, and her progeny.233,234
In the Mississippi study with a 75% African-American
profile, the recurrence risk was 42% to 43% for any type
of preeclampsia-eclampsia, but this increased to 61%
if the preceding affected pregnancy was very preterm
(!32 weeks).234 To date, anything other than close
monitoring of subsequent pregnancies for problems of
prematurity and preeclampsia (preterm labor, bleeding,
fetal growth restriction) has not been superceded by
specific testing or augmented by effective preventative
measures. Testing for LCHAD mutation (long-chain
3-hydroxyacyl coenzyme A dehydrogenase deficiency)
is rarely positive in patients with HELLP syndrome incontrast to the situation with AFLP235-237 and therefore
not recommended.238
Challenges and conclusions
An expanded, more inclusive disease classification
system for HELLP syndrome is needed particularly if
the potential for early aggressive corticosteroids to avert
most significant maternal morbidity is to be studied
adequately in appropriately structured, large multicen-
ter clinical trials. Some form of a composite maternal
morbidity index also is needed to better describe thespectrum of systemic morbidity potentially experienced
by mothers with this condition. As expected with a
disease process with variable rates of progression, dif-
ferent stages at initial presentation, alteration by various
interventions, and characterization by inconsistent and
variable laboratory methodologies, there has been a lack
of consensus among researchers and confusion among
clinicians. The issue of standardization of diagnosis
and disease classification is an important goal, so that
research findings are comparable and recommended
clinical managements can become progressively more
evidence based.We believe that the scientific community is on the
threshold of a much better understanding of the patho-
genesis of HELLP syndrome specifically and preeclamp-
sia-eclampsia in general. Knowledge of the findings
related to the pathogenesis and pathophysiology of
this disorder and the ameliorating effect of corticoste-
roids on the disease process is foundational to under-
standing the challenges of diagnosis, classification, and
management. A patient can present initially anywhere
along the spectrum of disease development, and disease
expression is influenced by whether corticosteroids have
been given for any reason. Thus, the accurate interpre-tation of any publication about HELLP syndrome
requires a clear description of when in the development
of HELLP syndrome laboratory or research testing was
performed to study its pathogenesis or make its clin-
ical diagnosis, including a statement of the presence or
absence of corticosteroids during patient management
ideally noting at what stage in disease these agents and
dosages were given to the patient. Large-scale multicen-
ter trials investigating various corticosteroid regimens
for patients with this spectrum of HELLP syndrome
conditions are desirable (including various types that
cross or do not cross into the fetal circulation63
), with
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particular attention to define benefits and limitations
according to the stage and circumstances in which ther-
apy is initiated. Risk factors for severe renal and hepatic
complications of HELLP syndrome require further
investigation with regard to concurrent predisposing
conditions such as antiphospholipid syndrome. Al-
though short-term utilization of corticosteroids as cur-
rently used has not been shown to negatively impactthe fetus or neonate, surveillance for possible adverse
effects should continue. We believe that widespread dis-
semination of the information presented herein to prac-
ticing cliniciansdbetter recognition through cognition
and a management scheme focused on early aggressive
corticosteroid administrationdis needed now to mini-
mize maternal-perinatal morbidity and mortality with
this condition while more extensive study continues.
References
1. Schmorl G. Pathologisch-anatomische Untersuchungen uberPuerperal-Eklampsie. Leipzig: FCW Vogel; 1893.
2. Dienst A. Experimentaelle Studien uber die Aetiologische Bedeu-
tung des Fibrinsferments und Fibrinogens fur die Schwanger-
schaftsniere und die Eklampsie. Arch Gynaekol 1912;96:43-170.
3. Denecke G. Blut and lymphe. In: Hinselman H, editor. Die
Eklampsie. Bonn: Cohen; 1924. p. 293-360.
4. Chesley LC. Disseminated intravascular coagulation. In:
Chesley LC, editor. Chesleys hypertensive disorders in preg-
nancy. New York: Appleton-Century-Crofts; 1978. p. 88-118.
5. Dieckmann WJ. Toxemias of pregnancy, 3rd ed. St Louis:
Mosby; 1952. p. 362-9.
6. Pritchard JA, Weisman R Jr, Ratnoff OD, Vosburgh GJ. Intra-
vascular hemolysis, thrombocytopenia and other hematologic ab-
normalities associated with severe toxemia of pregnancy. N EnglJ Med 1954;250:89-98.
7. Pritchard JA, Cunningham FG, Mason RA. Coagulation
changes in eclampsia: their frequency and pathogenesis. Am J
Obstet Gynecol 1976;124:855-64.
8. Brain MC, Kuah K-B, Dixon HG. Heparin treatment of haemol-
ysis and thrombocytopenia in pre-eclampsia. J Obstet Gynaecol
Br Commonw 1967;74:702-11.
9. Scott R, Gordon S, Schatz A, Casella S. Acute hemolysis and
thrombocytopenia in eclampsia. Obstet Gynecol 1970;36:128-31.
10. McKay DG. Hematologic evidence of disseminated intravascu-
lar coagulation in eclampsia. Obstet Gynecol Surv 1972;27:
399-407.
11. Kitzmiller JL, Lang JF, Yellenosky PF, Lucas WE. Hematologic
assays in pre-eclampsia. Am J Obstet Gynecol 1974;118:362-7.
12. Vardi J, Fields GA. Microangiopathic hemolytic anemia in severe
pre-eclampsia. Am J Obstet Gynecol 1974;119:617-22.
13. Killam AP, Dillard SH Jr, Patton RC, Pederson PR. Pregnancy-
induced hypertension complicated by acute liver disease and
disseminated intravascular coagulation. Am J Obstet Gynecol
1975;123:823-8.
14. Lopez-Llera M, de la Luz Espinosa M, Diaz de Leon M, Linares
GR. Abnormal coagulation and fibrinolysis in eclampsia: a clini-
cal and laboratory correlation study. Am J Obstet Gynecol 1976;
128:681-92.
15. Schwartz ML, Brenner WE. The obfuscation of eclampsia by
thrombotic thrombocytopenic purpura. Am J Obstet Gynecol
1978;131:18-24.
16. Goodlin RC. Severe pre-eclampsia: another great imitator. Am J
Obstet Gynecol 1976;126:855-64.
17. Goodlin RC, Cotton DB, Haesslein HC. Severe EPH gestosis.
Am J Obstet Gynecol 1978;132:595-8.
18. Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and
low platelet count: a severe consequence of hypertension in preg-
nancy. Am J Obstet Gynecol 1982;142:159-67.
19. Abraham KA, Connolly G, Farrell J, Walshe JJ. The HELLP
syndrome, a prospective study. Ren Fail 2001;23:705-13.
20. Vigil-De Gracia P. Pregnancy complicated by pre-eclampsia-
eclampsia with HELLP syndrome. Int J Gynecol Obstet 2001;72:17-23.
21. Martin JN Jr, Magann EF, Isler CM. HELLP Syndrome: the
scope of disease and treatment. In: Belfort MA, Thornton S,
Saade GR, editors. Hypertension in pregnancy. Chap 7. Oxford:
Marcel Dekker; 2003. p. 141-88.
22. Sibai BM. Diagnosis, controversies, and management of the syn-
drome of hemolysis, elevated liver enzymes and low platelet
count. Obstet Gynecol 2004;103:981-91.
23. Barton JR, Sibai BM. Diagnosis and management of hemolysis,
elevated liver enzymes and low platelets syndrome. Clinical
Perinatol 2004;31:807-33.
24. Baxter JK, Weinstein L. HELLP syndrome: the state of the art.
Obstet Gynecol Surv 2004;59:838-45.
25. Martin JN Jr, Magan EF, Blake PG. Analysis of 454 pregnancies
with severe preeclampsia/eclampsia/HELLP syndrome using the3-class system of classification. Am J Obstet Gynecol 1993;
168:386.
26. Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Fried-
man SA. Maternal morbidity and mortality in 442 pregnancies
with HELLP syndrome. Am J Obstet Gynecol 1993;169:1000-6.
27. Martin JN Jr, Magann EF. HELLP syndrome: current principles
and recommended practices. Curr Obstet Med 1996;4:129-75.
28. Martin JN Jr, Rinehart K, May WL, Magann EF, Terrone DA,
Blake PG. The spectrum of severe preeclampsia: comparative
analysis by HELLP syndrome classification. Am J Obstet Gyne-
col 1999;180:1373-84.
29. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA,
McLaughlin MK. Preeclampsia: an endothelial cell disorder.
Am J Obstet Gynecol 1989;161:1200-4.30. Roberts JM. Objective evidence of endothelial dysfunction in
preeclampsia. Am J Kidney Dis 1999;33:992-7.
31. Friedman SA, Taylor RN, Roberts JM. Pathophysiology of
preeclampsia. Clin Perinatol 1991;18:661-82.
32. Lindheimer M, Cunningham FG. Hypertension in pregnancy.
N Engl J Med 1992;326:927-32.
33. Zeeman GG, Dekker GA, van Geijn HP, Kraayenbrink AA.
Endothelial function in normal and preeclamptic pregnancies:
a hypothesis. Eur J Obstet Gynecol Reprod Biol 1992;43:113-22.
34. Roberts JM, Redman CWG. Preeclampsia: more than pregnancy-
induced hypertension. Lancet 1993;341:1447-54.
35. Stratta P, Canavese C, Vercellone A. HELLP, microangiopathic
hemolytic anemia, and preeclampsia. Hypertens Pregnancy 1993;
12:487-96.
36. Roberts JM, Gammill HS. Preeclampsia: recent insights. Hyper-
tension 2005;46:1243-9.
37. Martin JN Jr, Blake PG, Perry KG, McCaul JF, Hess LW,
Martin RW. The natural history of HELLP syndrome: patterns
of disease progression and regression. Am J Obstet Gynecol
1991;164:1500-13.
38. MartinJN Jr,Blake PG,Lowery SL,PerryKG, Files JC,Morrison
JC. Pregnancy complicated by preeclampsia-eclampsia with
HELLP syndrome: how rapid is postpartum recovery? Obstet
Gynecol 1990;76:737-41.
39. Katz VL, Thorp JM Jr, Rozas L, Bowes WA Jr. The natural
history of thrombocytopenia associated with preeclampsia.
Am J Obstet Gynecol 1990;163:1142-3.
40. Neiger R, Contag SA, Coustan DR.The resolutionof preeclampsia-
related thrombocytopenia. Obstet Gynecol 1991;77:692-5.
928 Martin, Rose, and Briery
-
7/30/2019 Understanding and Managing HELLP Syndrome Ajog Martin Jr
16/21
41. Figini E, Za G, Squarcina M, Marras M, Passamonti U, Bocchino
G, et al. Course and regression of HELLP syndrome. Minerva
Ginecol 1996;48:405-8.
42. Makkonen N, Harju M, Kirkinen P. Postpartum recovery after
severe preeclampsia and HELLP syndrome. J Perinat Med 1996;
24:641-9.
43. Rychel V, Williams KP. Correlation of platelet count changes
with liver cell destruction in HELLP syndrome. Hypertens Preg-
nancy 2003;22:57-61.44. Faridi A, Rath W. Differential HELLP syndrome diagnosis.
Z Gerburtschilfe 1996;200:88-95.
45. Strand S, Strand D, Seufert R, Mann A, Lotz J, Blessing M, et al.
Placenta-derived CD95 ligand causes liver damage in HELLP
syndrome. Gastroenterology 2004;126:849-58.
46. Tanaka M, Suda T, Haze K, Nakamura N, Sato K, Kimura F,
et al. Fas ligand in human serum. Nat Med 1996;2:317-22.
47. Hiramatsu N, Hayashi N, Katayama K, Mochizuki K, Kawanish
Y, Kashahara A, et al. Immunohistochemical detection of fas an-
tigen in liver tissue of patient with chronic hepatitis C. Hepatol-
ogy 1994;19:1354-9.
48. Bone RC. Immunologic dissonance: a continuing evolution in our
understanding of the systemic inflammatory response syndrome
(SIRS) and the multiple organ dysfunction syndrome (MODS).
Ann Intern Med 1996;125:680-7.49. Balderas-Pena LM, Canales-Munoz JL, Angulo-Vazqule J,
Anaya-Prado R, Gonzalez Ojeda A. The HELLP syndrome: evi-
dence of a possible systemic inflammatory response in preeclamp-
sia? Ginecol Obstet Mex 2002;70:328-37.
50. Redman CWG, Sargent IL. Preeclampsia and the systemic in-
flammatory response. Semin Nephrol 2004;24:565-70.
51. Harirah H, Donia SE, Hsu C-D. Serum Soluble FAS in HELLP
Syndrome. Obstet Gynecol 2001;98:295-8.
52. Halim A, Kanayama N, El Maradny E, Maehara K, Takahaski
A, Nosaka K, et al. Immunohistological study in cases of HELLP
syndrome and acute fatty liver of pregnancy. Gynecol Obstet
Invest 1996;41:106-12.
53. Terrone DA, Rinehart BK, May WL, Moore A, Magann EF,
Martin JN Jr. Leukocytosis is proportional to HELLP syndromeseverity: evidence for an inflammatory form of preeclampsia.
South Med J 2000;93:768-71.
54. Haeger M, Unander AM, Bengtsson A. Enhanced anaphylatoxin
and terminal C5b-9 complement formation in patients with
HELLP syndrome. Obstet Gynecol 1990;76:698-702.
55. Zusterzeel PLM, Wanten GJA, Peters WHM, Merkus HMWM,
Steegers EAP. Neutrophil oxygen radical production in pre-
eclampsia with HELLP syndrome. Eur J Obstet Gynecol 2001;99:
213-8.
56. Riordan SM, Williams R. Acute liver failure: targeted artificial
and hepatocyte-based support of liver regeneration and reversal
of multiorgan failure. J Hepatol 2000;32:63-76.
57. Visser W, Beckmann I, Bremer HA, LIIM HL, Wallenburg HC.
Bioactive tumour necrosis factor in preeclampsic patients with
and without the HELLP syndrome. BJOG 1994;101:1081-2.
58. Cunningham DS, Christie TL, Evans EE, McCaul JF. Effect of
the HELLP syndrome on maternal immune function. J Reprod
Med 1993;38:459-64.
59. Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen
T, et al. Vascular endothelial growth factor ligands and receptors
that regulate human cytotrophoblast survival are dysregulated in
severe preeclampsia with HELLP syndrome. Am J Pathol 2002;
160:1405-23.
60. Sgambati E, Marini M, Thyrion GDZ, Parretti E, Mello G,
Orlando C, et al. VEGF expression in the placenta from opreg-
nancies complicated by hypertensive disorders. BJOG 2004;111:
564-70.
61. Maynard SE, Min J-Y, Merchan J, Lim K-H, Li J, Mondal
S, et al. Excess placental soluble fms-like tyrosine kinase
1 (sFlt1) may contribute to endothelial dysfunction, hyperten-
sion, and proteinuria in preeclampsia. J Clin Invest 2003;111:
649-58.
62. Bussen S, Rieger L, Sutterlin M, Dietl J. Plasma VEGF levels are
increased in women with severe preeclampsia or HELLP syn-
drome. Z Geburtshilfe Neonatol 2003;207:101-6.
63. Schlembach D, Beinder E. Measurement of microcirculation in
normal pregnancy, preeclampsia and HELLPsyndrome [abstract].
Hypertens Pregnancy 2000;19(Suppl 1):114.64. Knerr I, Dachert C, Beinder E, Metzler M, Dotsch J, Repp R,
et al. Adenomedullin, calcitonin gene-related peptide and their
receptors: evidence for a decreased placental mRNA content in
preeclampsia and HELLP syndrome. Eur J Obstet Gynecol 2002;
101:47-53.
65. Groten T, Kreienberg R, Fialka I, Huber L, Wedlich D. Altered
subcellular distribution of cadherin-5 in endothelial cells caused
by the serum of preeclamptic patients. Mol Hum Reprod 2000;
6:1027-32.
66. Diedrich F, Renner A, Rath W, Kuhn W, Wieland E. Lipid hy-
droperoxides and free radical scavenging enzyme activities in pre-
eclampsia and HELLP syndrome: no evidence for circulating
primary products of lipid peroxidation. Am J Obstet Gynecol
2001;185:166-72.
67. Knapen MFCM, Mulder TPJ, Van Rooij IALM, Peters WHM,Steegers EAP. Low whole blood glutathione levels in pregnancies
complicated by preeclampsia or the hemolysis, elevated liver
enzymes, low plaelets syndrome. Obstet Gynecol 1998;92:1012-5.
68. Raijmakers MTM, Roes EM, te Morsche RHM, Steegers EAP,
Peters WHM. Haptoglobin and its association with the HELLP
syndrome. J Med Genetics 2003;40:214-6.
69. Moake JL. Thrombotic microangiopathies. N Engl J Med 2002;
347:589-900.
70. Lattuada A, Rossi E, Calzarossa C, Candolfi R, Mannucci PM.
Mild to moderate reduction of a von Willebrand factor cleaving
protease (ADAMTS-13) in pregnant women with HELLP micro-
angiopathic syndrome. Haemotologica 2003;88:1029-34.
71. Benedetto C, Marozio L, Salton L, Maula V, Chieppa G, Masso-
brio M. Factor V Leiden and factor II G20210A in preeclampsiaand HELLP syndrome. Acta Obstet Gynecol Scand 2002;81:
1095-100.
72. Bozzo M, Carpani G, Leo L, Marcozzi S, Sacchi E, Morono G,
et al. HELLP syndrome and factor V Leiden. Eur J Obstet Gyne-
col Reprod Biol 2001;95:55-8.
73. Van Pampus MG, Folf H, Koopman MM, van den Ende A,
Butler HR, Reitsma PH. Prothrombin 20210G: a mutation
and Factor V Leiden mutation in women with a history of
severe preeclampsia and HELLP syndrome. Hypertens Preg-
nancy 2001;20:291-8.
74. Schlembach D, Beinder E, Zingsem J, Wunsiedler U, Beckmann
MW, Fischer T. Association of maternal and/or fetal factor V
Leiden and G20210A prothrombin mutation with HELLP syn-
drome and intrauterine growth restriction. Clin Sci 2003;105:
279-85.
75. Queyrel V, Ducloy-Bouthors AS, Michon-Pasturel U, Hachulla
E, Dubuequoi S, Caron C, et al. Antiphospholipid antibodies in
HELLP syndrome: clinical and biological study in 68 women.
Rev Med Interne 2003;24:158-64.
76. Samuels P. Disseminated intravascular coagulopathy and throm-
bocytopenia complicating pregnancy: an acute care approach. In:
Foley MR, Strong TH Jr, Garite TJ, editors. Obstetric intensive
care manual. 2nd ed. New York: McGraw-Hill; 2004.
77. Steegers EAP, Mulder TPJ, Bisseling JGA, Delemarre FMC, Pe-
ters WHM. Glutathione S-transferase alpha as marker for hepa-
tocellular damage in pre-eclampsia and HELLP syndrome.
Lancet 1995;345:1571-2.
78. Sibai BM, Taslimi MM, el-Nazer A, Amon E, Mabie BC,
Ryan GM. Maternal-perinatal outcome associated with the
Martin, Rose, and Briery 929
-
7/30/2019 Understanding and Managing HELLP Syndrome Ajog Martin Jr
17/21
syndrome of hemolysis, elevated liver enzymes and low platelets
in severe preeclampsia-eclampsia. Am J Obstet Gynecol 1986;
155:501-9.
79. Audibert F, Friedman SA, Frangieh AY, Sibai BM. Clinical util-
ity of strict diagnostic criteria for the HELLP syndrome. Am J
Obstet Gynecol 1996;175:460-4.
80. van Runnard Heimel PH, Juisjes AJM, Franx A, Koopman C,
Bots ML, Bruinse HW. A randomized placebo-controlled trial
of prolonged prednisolone administration to patients withHELLP synrome remote from term: maternal and neonatal com-
plications. Am J Obstet Gynecol 2004;191:S41.
81. Vigil-DeGracia P. Acute fatty liver and HELLP syndrome: two
distinct pregnancy disorders. Int J Gynaecol Obstet 2001;73:
215-20.
82. Matsuda M, Mitsuhashi S, Watarai M, Yamamoto K, Hashi-
moto T, Ikeda S. HELLP syndrome associated with systemic
lupus erythematosis. Intern Med 2003;42:1052-3.
83. Roberts G, Gordon MM, Porter D, Jardine AG, Gibson IW.
Acute renal failure complicating HELLP syndrome, SLE and
antiphospholipid syndrome: successful outcome using plasma
exchange therapy. Lupus 2003;12:251-7.
84. Sullivan CA, Martin JN Jr, editors. Thrombotic microangiopa-
thies in critical care obstetrics. 4th ed. Oxford: Blackwell Publish-
ing; 2003. p. 408-19.85. Pitton MA, Petolillo M, Papi S, Grismondi GL, Masin GP,
Forcelline F. Hemolytic uremic syndrome in twin pregnancy at
32 weeks with HELLP syndrome: a case report. Minerva Ginecol
2001;53:279-81.
86. Pauzner R, Dulitzky M, Carp H, Mayan H, Kenett R, Farfel Z,
Many A. Hepatic infarctions during pregnancy are associated
with the antiphospholipid syndrome and in addition with com-
plete or incomplete HELLP syndrome. J Thromb Haemost
2003;1:1758-63.
87. Haram K, Trovik J, Sandset PM, Hordnes K. Severe HELLP
syndrome in the 18th week of pregnancy associated with the anti-
phospholipid-antibody syndrome. Acta Obstet Gynecol Scant
2003;82:679-80.
88. Sinha J, Chowdhry I, Sedan S, Barland P. Bo