Understanding and Managing HELLP Syndrome Ajog Martin Jr

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/


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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

Martin, Rose, and Briery 915


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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

916 Martin, Rose, and Briery


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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



10/21

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).



11/21

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.



12/21

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.



13/21

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.



14/21

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



15/21

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


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.



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



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


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

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