Understanding and managing HELLP syndrome: The …€¦ · Antepartum or postpartum HELLP syndrome...

American Journal of Obstetrics and Gynecology (2006) 195, 914–34

www.ajog.org

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 syndromeSevere preeclampsia/

eclampsia

Aggressiveglucocorticoids/corticosteroids

Obstetric

Antepartum or postpartum HELLP syndrome constitutes an obstetric emergency that requiresexpert knowledge and management skills. The insidious and variable nature of disease presenta-

tion and progression challenges the clinician and complicates consensus on universally accepteddiagnostic and classification criteria. A critical review of published research about this variantform 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 theconclusion that there is maternal-fetal benefit realized when potent glucocorticoids are aggres-sively used for its treatment. Although acknowledging the need for definitive multicenter trials

to better define the limits of benefit and the presence of any maternal or fetal risk, and givenan understanding of the nature of the disorder with its potential to cause considerable maternalmorbidity 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 casereports first appeared in the late nineteenth1 and earlytwentieth century.2-5 Between 1950 and 1980, severalcase series were published that related patients andpoor obstetric outcomes to clinical and laboratory find-ings that are consistent with what we recognize today asHELLP syndrome.6-17 Credit for formally consolidatingthe concept and creating the acronym of HELLP (H =hemolysis, EL = elevated liver enzymes and LP = lowplatelets) goes to Louis Weinstein who in 1982 reported

Reprints not available from the authors.

0002-9378/$ - see front matter � 2006 Mosby, Inc. All rights reserved.

doi:10.1016/j.ajog.2005.08.044

a group of 29 pregnant patients he considered to have adistinct subset of severe preeclampsia/eclampsia.18 Allpatients expressed findings suggestive of microangio-pathic hemolytic anemia with moderate-to-severe throm-bocytopenia, misshapened erythrocytes on peripheralsmear, and abnormal liver function tests usually in con-junction with epigastric pain, nausea, and vomiting.Severe hypertension and proteinuria were frequentlycoexistent as well.

Since 1982 there has been an outpouring of obstetricliterature seeking to better define the pathogenesis, natu-ral history, clinical spectrum, classification and manage-ment strategies for patients considered to have HELLPsyndrome. Because the incidence of this disorder is low

http://www.ajog.org

Martin, Rose, and Briery 915

(1-6 per 100019,20), most clinical research endeavors havebeen small, single institution case series or randomizedtrials. Until definitive large multicenter trials are under-taken, clinicians must rely on less robust information toguide patient care. Despite several recent comprehensivereviews on the subject of HELLP syndrome,21-24 none todate 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 onHELLP syndrome to understand how corticosteroidsappear to play an integral role in its management.

Pathogenesis and natural history

HELLP syndrome usually develops suddenly duringpregnancy (27-37 weeks’ gestation) or in the immediatepuerperium.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 systematicallyinjure the endothelium via activation of platelets, vaso-constrictors, and loss of normal pregnancy vascularrelaxation.29-36 Although variable, HELLP syndromeonset and progression usually is rapid (35%-50% de-crease in platelets per 24 hours; mean daily reductionof 40,000/mL platelets) as lactic acid dehydrogenase(LDH) and aminotransaminases (aspartate [AST] andalanine [ALT]) rise until 24 to 48 hours postpartumwhen 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 hourspostpartum.37,41-43 Onset of disease occurs postpartumin approximately 15% to 25% of cases.25-28

Although most patients with HELLP syndrome even-tually exhibit hypertension and proteinuria, these 2majorsigns 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 elicitedthat are ambiguous, subtle, and focused primarilyon the gastrointestinal-hepatic systems.28 The centralplace that the liver occupies in the disorder of HELLPsyndrome is an important clue to pathogenesis. Severeepigastric/right upper quadrant pain often heralds under-lying rapidly progressive disease.44 The extent of peri-portal hepatocyte dysfunction or cell death in a givenpatient probably correlates with the severity of maternalillness. Recall that CD95 (APO-1, Fas)-mediated apopto-sis of hepatocytes is a major pathogenic mechanismfor liver disease in general.45 The Fas-Fas ligand systemis a well-studied cell death system that can mediate apo-ptosis. As amember of the tumor necrosis factor receptor

superfamily, Fas is a 36 to 45 kDa type I surface proteincontaining a single transmembrane region.46 It inducesapoptosis by binding to Fas-ligand, a 40 kDa type IItransmembrane protein of the tumor necrosis factor re-ceptor family.47 In the context of pregnancy and patientswithHELLP syndrome, apoptosis in liver tissue and cyto-toxic activity for primary human hepatocytes has beenreported in serum from patients with HELLP syndrome(CD95 ligand produced by placenta) that increases overtime and in proportion to disease severity.45 In addition,caspases 3, 8, and 9 are all required to effect apoptoticcell death, and active forms of all 3 are detected in liverextracts of HELLP patients. Blocking of CD95 signalingreduces the hepatocytotoxic activity of HELLP serum.Thus, systemic CD95L is a placenta-derived humoralfactor that is involved in the pathogenesis of HELLPsyndrome. CD95L-rich membrane fragments or solubleCD95L are postulated by Strand et al45 to be shed intothe maternal circulation as important progenitors in thepathogenesis of HELLP syndrome.

The previously described findings and the proposalthat placenta-derived proteins damage hepatic cells arecompatible with many other findings that cast HELLPsyndrome as a placenta-instigated, liver-targeted acuteinflammatory condition and disordered immunologicprocess.21 The similarity between HELLP syndrome andsystemic inflammatory response syndrome (SIRS) hasbeen emphasized by several researchers.48-50 The pertur-bations present in patients who have HELLP syndromedevelop may be additive to, or altered by, the patho-physiology leading to preeclampsia in general. A listingof some of the supportive evidence for these conceptsis contained in Table I. Decreases in haptoglobin area sequel, not an instigator of the vascular hemolyticprocess.68 In patients with HELLP syndrome, the metal-loprotease ADAMTS-13 is not severely deficient orundetectable as it is in many patients with throm-botic thrombocytopenic purpura (TTP).69,70 No geneticmarkers or evidence for association with thrombophilicor antiphospholipid disorders have been established.71-75

Diagnosis

The diagnosis of HELLP syndrome is most assured ina pregnant patient with signs and symptoms ofpreeclampsia-eclampsia and a triad of laboratory ab-normalities suggesting red cell trauma (H = hemolysis),hepatic damage and dysfunction (EL = elevated liverenzymes), and thrombocytopenia (LP = low platelets).The greater the extent of laboratory abnormalities, thegreater is the physician’s confidence in the diagnosis.

Thrombocytopenia may be the first indicator of dis-ease when the results of a complete blood count return tothe physician. A platelet count less than 150,000/mLrepresents mild (100,000-150,000/mL), moderate (50,000-100,000/mL), or severe (!50,000/mL) thrombocytopenia

916 Martin, Rose, and Briery

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 andneutrophil 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/laboratorydisease by 1-2 wks.58

Decreased placental vascular endothelial growth factor (VEGF) expression in placentas from HELLP syndrome pregnancies59,60 analagous todecreased 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 healthy matchedpregnant 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 RNAin 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

in the nonpregnant as well as pregnant patient.76 Requir-ing a threshold of less than 100,000/mL to consider thediagnosis of thrombocytopenia is ill advised. Maternalmorbidity doubles from 11% to more than 20% whenpatients with severe preeclampsia have mild thrombocy-topenia develop in association with increasing LDH(R600 IU/L) and transaminases (AST and/or ALTR40 IU/L).21,27 Significant pathology such as hepatichemorrhage and rupture can first appear in the patientwith HELLP syndrome before the platelet count fallsbelow 100,000/mL.28 Indeed, the onset of epigastric painin patients who are eventually diagnosed with HELLPsyndrome has occurred at a platelet count as high as283,000/mL in our patient population (unpublished).

Hepatic injury and dysfunction

In Weinstein’s initial 1982 report, thresholds of whatconstituted abnormal serum levels of aspartate transam-inase (AST), alanine transferase (ALT) and bilirubin tomerit 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 themean.27 A threshold for AST of 70 IU/L or greater toqualify for the diagnosis of HELLP syndrome whenplatelets are 100,000/mL or less has been consistentlyadvocated by Martin et al21 and Sibai.22 Transaminasevalues between 40 and 70 IU/L reflect borderline hepaticdysfunction regardless of the platelet count (especially inthe 100,000-150,000/mL range).28 Glutathione S-transfer-ase alpha has been proposed as a better marker for acuteliver injury than the aminotransferases, but there has beenlimited work on this possibility.77

Erythrocyte injury and death

Evidence for hemolysis is the third laboratory criterion forHELLP syndrome. In addition to a progressive anemia,other laboratory evidence of hemolysis classically in-cludes decreased serum levels of haptoglobin, increasedserum total LDH 600 IU/L or greater,26,28 increased se-rumAST, increased serum indirect bilirubin, anabnormalperipheral smear showing variable amounts of disruptedor destroyed red blood cells (schistocytes, echinocytes,burr cells), and/or a declining hematocrit or hemoglobin.Depending on laboratory methodology, LDH thresholdsfor 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 andassess efficacy or outcome, and to provide a commonplatform for comparison of research results. The 2 mostcommonly used systems for diagnosis and classificationwere developed in the 1980s by investigators at theUniversities 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 thrombocytopeniawith platelets 100,000/mL or less; (2) hepatic dysfunctionwith AST 70 IU/L or greater; and (3) evidence of hemol-ysis with an abnormal peripheral smear in addition toeither total serum LDH 600 IU/L or greater or bilirubin1.2 mg/dL or greater. The patient who exhibits some butnot all of these parameters is termed ‘‘partial’’ or ‘‘in-complete’’ HELLP syndrome: ELLP syndrome (missing


Table II Classification systems of HELLP syndrome

HELLP class Mississippi classification21,36,46 Tennessee classification22,165

1 Platelet count %50,000/mLAST or ALT R70 IU/LLDH R600 IU/L

Platelet count %100,000/uLAST R70 IU/LLDH R600 IU/L

2 50,000/mL %Platelet count %100,000/mLAST or ALT R70 IU/LLDH R600 IU/L

3 100,000/mL %Platelet count %150,000/mLAST or ALT R40 IU/LLDH 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.

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 assevere preeclampsia with thrombocytopenia, gestationalthrombocytopenia, or immune thrombocytopenic pur-pura).22 Maternal and perinatal outcomes are progres-sively worse for patients with preeclampsia, partialHELLP syndrome, and complete HELLP syndrome, re-spectively.79 Incomplete criteria initially can progress tocomplete expression of HELLP syndrome.

The Mississippi-Triple Class System for HELLP syn-drome divides patients into 3 classes or groups that arebased primarily on the platelet portion of the laboratorydiagnosis.21,28,38 Final class assignment or diagnosis isbased on the lowest platelet count registered duringthe disease course. The span of thrombocytopenia be-tween zero and 150,000 platelets is divided into 3 equalranges consistent with mild, moderate, and severethrombocytopenia. For a patient to merit a diagnosisof HELLP syndrome, class 1 requires severe thrombocy-topenia (platelets %50,000/mL), evidence of hepaticdysfunction (AST and/or ALT R70 IU/L), and evidencesuggestive of hemolysis (total serum LDH R600 IU/L);class 2 requires similar criteria except thrombocytopeniais moderate (O50,000 to %100,000/mL); and class 3includes patients with mild thrombocytopenia (plate-lets O100,000 but %150,000/mL), mild hepatic dysfunc-tion (AST and/or ALT R40 IU/L), and hemolysis (totalserum LDH R600 IU/L). Peripheral smear findings andbilirubin abnormalities are not obtained.

Neither classification system is ideal; both have short-comings. Because class 1 and 2 HELLP syndromepatients are combined in the Tennessee system, discrim-ination between groups and outcomes is difficult andbenefit 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 corticosteroidsand for comparing pregnancy outcomes. The Mississippisystem, although including class 3 patients, does notinclude those with incomplete or partial forms of thedisease, and excludes patients from analysis when causesof consumptive coagulopathy such as placental abruptionare present. Two (Tennessee) or even 3 (Mississippi)groupings or classes insufficiently describe the multitudeof clinical scenarios (antepartum vs postpartum, epigas-tric pain present or absent, degrees of laboratory valueabnormality, different gestational age epochs) encoun-tered by the clinician. The importance of a transitionalgroup of patients is clearly demonstrated by instances ofhepatic ruptures in patients with class 3 HELLP syn-drome80 and other reports of increased eclampsia andhigher perinatal morbidity/mortality in patients withincomplete/partial HELLP syndrome.21

Imitators of HELLP Syndrome

Patients presumptively diagnosed with HELLP syn-drome can have other disorders concurrent with HELLPsyndrome or other disorders altogether. Lack of responseto aggressive corticosteroid administration, especiallywith persistence of disease or first presentation of diseasemore than 7 days after delivery, should instigate testing toevaluate other diagnostic possibilities (Table III). In ourexperience, the most common HELLP imitators arepatients 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 attentiontoo late for aggressive corticosteroids to prevent progres-sion and multiorgan dysfunction, previously undiag-nosed systemic lupus erythematosus/antiphospholipidsyndrome, and either immune thrombocytopenic pur-pura (ITP) or thrombotic thrombocytopenic purpura(TTP).98 See the excellent reviews of potentially con-founding conditions written byGoodlin16,99 and Sibai.100


Clinical presentation

Signs and symptoms with HELLP syndrome are varia-ble but depend largely on the stage of the patient’sdisease, whether class 1, class 2, or class 3.28 Right upperquadrant/epigastric pain is the most important symptomsuggestive of underlying HELLP syndrome, found in100% of Weinstein’s initial 1982 series of 29 advancedcases.18 Half of patients with class 1 HELLP syndrome,33% with class 2, and 16% with class 3 compared withonly 13% of severely preeclamptic patients withoutHELLP syndrome exhibit epigastric pain or right upperquadrant discomfort.28 Frequently epigastric pain oc-curs in association with nausea or vomiting. Overall,the incidence of epigastric pain/nausea/vomiting rangesbetween 30% and 90%.20,22,26 Any pregnant patientpresenting in the second half of gestation with epigastricor right upper quadrant pain, particularly if associatedwith nausea and/or vomiting, has HELLP syndromeuntil proven otherwise.44 A pregnant patient with signsand symptoms of severe preeclampsia who suddenly hassevere, writhing epigastric/upper abdominal pain developlikely has hepatic bleeding or rupture constituting anobstetric emergency.

Malaise or viral syndrome-like symptoms can occurwith advanced HELLP syndrome.22,26 Headache occursin a substantial number (33%-68%)22,28 of patients withany form of preeclampsia whether HELLP syndromeis present, with visual complaints in a lesser number.22

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

ITPThrombophiliasAntiphospholipid syndrome75,83,86-91

Homozygous factor V LeidenProthrombin gene mutationSevere folate deficiency92

Cholangitis/cholecystitis/pancreatitis/ruptured bile ductGastric ulcerCardiomyopathyDissecting aortic aneurysmSystemic viral sepsis (herpes, cytomegalovirus)93

SIRS/sepsisHemorrhagic or hypotensive shockStroke in pregnancy or puerperiumParoxysmal nocturnal hemoglobinuria94

PheochromocytomaAdvanced embryonal cell carcinoma of the liver95

Acute cocaine intoxicationMyasthenia gravis96

Pseudocholinesterase deficiency97

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 pressuresand more proteinuria tend to occur more frequently asHELLP 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 inapproximately half of patients with class 1 or 2 HELLPsyndrome, 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 maternaldisease severity and the potential to develop severe mor-bidity,28,38,103 individual patient predictive value (with theprobable exception of severe epigastric pain) is low.104

Significant maternal morbidity becomes more likelywhen 1 or more of the laboratory thresholds are exceededas listed in Table IV.102,105,106 Very high LDH, AST,and/or uric acid have the highest predictive value andare risk-additive with worsening thrombocytopenia.28,107

Maternal morbidity and mortality

The development of HELLP syndrome places thepregnant patient at significant risk for morbidity andmortality. Morbidity is categorized by major organsystem(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, emphasizingthat there is enormous variability among patients.

Hematologic-coagulation

The prevalence of disseminated intravascular coagula-tion (DIC) increased from 2 of 193 patients (0.5%) withsevere preeclampsia to 35 of 201 (17.4%) with class 1HELLP syndrome,28 the latter very similar to the15% incidence of DIC and 9% incidence of placentalabruption reported by Audibert et al79 for classes 1

Table IV Admission risk factors for significant maternalmorbidity/mortality HELLP syndrome

Signs/symptoms Laboratory values

Epigastric pain Platelets !50,000/mLNausea Total serum LDH O1400 IU/LVomiting AST O150 IU/LSevere systolic hypertension ALT O100 IU/LSevere diastolic hypertension Uric acid O7.8 mg/dLPlacental abruption CPK O200 IU/LEclampsia Serum creatinine O1.0

Adapted from Martin et al.102


and 2 combined. Clinically significant bleeding requiringtransfusion and wound hematoma formation follow asimilar pattern of increasing incidence with worseningdisease.21,25-28,79,104,108 Approximately 10% of patientswith class 1 or 2 HELLP syndrome exhibit microscopicor 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 theMississippi series is similar to the combined 8% inci-dence of pulmonary edema and less than 1% incidenceof adult respiratory distress syndrome in the Tennesseeseries.79 Copious large volume ascites identifies a patientat 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 havesignificant central nervous system (CNS) morbidity com-pared with class 3 HELLP syndrome or non-HELLPsevere preeclampsia.28 This includes stroke, mental statuschanges and/or coma.111-114 Visual complicationsincluding retinal detachment, vitreal hemorrhage, andcortical blindness are infrequent in proportion to diseaseseverity (1.4% in class 1 and 2).28 These are usually shortlived 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 diseasestatus worsens.28 All 4 of the patients with acute tubularnecrosis in the Mississippi series had class 1 HELLP syn-drome develop; acute renal failure complicated 3% ofcases of class 1 or 2 HELLP syndrome in the Tennesseeseries.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 commoncause of maternal morbidity in a report from Mexico.128

Hepatic

Catastrophic liver complications are relatively infre-quent. Liver hemorrhage/rupture affected only 1% ofpatients with class 1 or 2 HELLP syndrome in theTennessee series26,79 and only 3 patients had significanthepatic complications develop (2 subcapsular hemato-mas in class 2 and 3 HELLP syndrome patients, 1 liverrupture in a class 1 HELLP syndrome patient) in the

Mississippi seriesdimportantly all were classified asclass 3 HELLP syndrome when the complication wasfirst detected.27 According to Wicke et al,129 at least 1 of5 patients with eventual liver rupture caused by HELLPsyndrome 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-HELLPsevere preeclampsia (43% vs 20%).25,27 At least 3 im-portant variables are involved: corticosteroids, transfu-sion, and delivery. Corticosteroid utilization appearsto reduce infectious morbidity from 43% to 18% by re-ducing or eliminating the need for transfusion of bloodproducts.27,28 Abdominal delivery doubles infectiousmorbidity from 19% to 41%.28

Table V Categories of significant maternal morbidity withHELLP syndrome

Hematologic/coagulationClinically significant bleeding requiring transfusionEcchymosesHematomaDICHematuria

CardiopulmonaryCardiogenic/noncardiogenic pulmonary edemaCardiac/pulmonary arrestPulmonary embolusIndicated invasive hemodynamic monitoringIntubation/mechanical ventilation/continuous positive

airway pressureMyocardial ischemia/chest pain

CNS/visionCerebral hemorrhage/strokeCentral venous thrombosisHypertensive encephalopathyCerebral edemaSensorium change/comaImpaired visionRetinal/macular detachmentVitreal hemorrhageCortical blindnessEclamptic seizure

RenalAcute tubular necrosisAcute renal failureRenal dialysisTransient renal impairment

HepaticSubcapsular/intrahepatic hematomaHepatic rupture/hemorrhagePancreatitis

Infection/sepsisObstetricOther


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 liverenzymes, and low platelets) syndrome. Am J Obstet Gynecol 1999;181:924-8 with permission from Elsevier.

Obstetric issues

Cesarean delivery has been performed more often forpatients with class 1 HELLP syndrome (61%) thanclass 2 (57%), class 3 (53%), or non-HELLP severepreeclampsia (48%).25,28 Mode of delivery is stronglyinfluenced by gestational age, maternal-fetal status, classof disease, and corticosteroid utilization. Overall abdom-inal delivery is associated with a doubling of maternalmorbidity (cardiopulmonary, hematologic-coagulation,and infectious) compared with vaginal delivery.28 Inaddition, risk for placental abruption, placenta previa,eclampsia, and episiotomy breakdown is increasedcompared to non-HELLP pregnancies.20,25,130,131

Parity-eclampsia

The incidence of complications in hypertensive pregnantwomen varies by parity but not by gravidity.132 WhenHELLP syndrome complicates eclampsia, parous pa-tients have double the incidence of significant maternalmorbidity compared with nulliparous patients (50% vs25%).133

Other morbidity

Pancreatitis is uncommon in patients with preeclampsiaor HELLP syndrome; the hemorrhagic form is uniquely

associated with acute fatty liver of pregnancy.134 Dia-betes insipidus,135 bone marrow necrosis with cerebralhemorrhage,88 and myocardial infarction136 are rarecomplications.

Mortality

Most deaths in patients with HELLP syndrome occurwith class 1 disease (60%), and neurologic abnormalitydue mostly to cerebral hemorrhage/stroke is the mostcommon system involved at autopsy (45%) (Figure 1).137

Delay in diagnosis appeared to be a factor in half ofthe deaths that could be adequately evaluated, andnone of the 54 maternal deaths in the Isler et al series137

or in a subsequent case report138 occurred in associationwith the aggressive use of corticosteroids.

Perinatal morbidity and mortality

Perinatal morbidity and mortality are substantiallyhigher in pregnancies with severe preeclampsia com-plicated by HELLP syndrome, primarily because ofrequired preterm delivery.25,139 Fetal growth restrictionand 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 parallelwith increasingly severity of disease, outcomes are

Martin, Rose, and Briery

primarily related to gestational age at delivery and notto disease status.28,141-146 Similarly, earlier prematurityis responsible for the higher perinatal mortality recordedin eclamptic pregnancies with HELLP syndrome com-pared with non-HELLP eclampsia.20,25,147 Neonatalsurvival was 100% in the Mississippi experience if new-born weight was 600 g or greater and following a fullcourse 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 steroidenhancement of fetal lung maturation increases therisk of stillbirth substantially.144,149 In the Mississippiseries, 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 placentalabruption. 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 HELLPsyndrome 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 oflife compared with matched controls.153 Newborninfants weighing less than 1250 g compared with birthweight-matched controls had significantly less cerebralpalsy and mental disability at 3 years of life.146

The integral role of corticosteroids

The probability that HELLP syndrome is a SIRS-likeinflammatory form of severe preeclampsia50 leads toconsideration of anti-inflammatory/immunosuppressiveagents for treatment, specifically corticosteroids. Theconsistently favorable response of HELLP syndromelaboratory parameters to corticosteroids suggests thepresence of an underlying corticosteroid-responsivestep(s) in its pathogenesis and a therapeutic benefit totheir 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 hepatocytedamage by placenta-derived CD95-L and/or to disruptsignaling for inflammatory cytokine production by theendogenous immune system.154 A recent publicationthat thoroughly explores the pharmacology and physiol-ogy of corticosteroids relevant to pregnancy andHELLP syndrome is recommended to the interestedreader for review.154

The potential therapeutic value of corticosteroids forpatients with HELLP syndrome was first recognized inthe early 1990s by 2 groups of investigators, one inDenver155 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 nosteroids during 1992 through 1993 in 65 patients withantepartum or postpartum HELLP syndrome.158,159

Stabilization and significant improvement in laboratoryand clinical parameters associated with HELLP syn-drome occurred in women who received antenatal and/or postpartum corticosteroids.158,159 Subsequent to thepublication of these findings, retrospective scrutiny ofselected data present in several published series ofpatients with severe preeclampsia from the 1970s and1980s revealed findings consistent with this new observa-tion that high-dose dexamethasone appeared to arrestthe deterioration of laboratory parameters in patientsfulfilling criteria for HELLP syndrome.16,139,160-162

Four other small randomized, controlled trials havebeen undertaken comparing the use of high-dose dexa-methasone or prednisolone (50 mg twice daily) witheither 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 parametersof mean arterial pressure and urinary output wereconsistently reported. In the most recently reportedtrial from The Netherlands,80 the prednisolone-treatedgroup of 15 antepartum patients had a 50% reductionin HELLP syndrome exacerbations compared with 15placebo-treated controls and a significantly shorter timeto normalize postpartum platelets. All 3 major mater-nal complications occurred in the placebo groupdformation of a liver hematoma in 2 patients and ruptureof the liver in a third patient with maternal death.No significant neonatal differences between groupswere noted in the immediate neonatal period or at infantfollow-up.80

On the basis of the findings from the first 2 prospec-tive clinical trials and the preceding case series findingsthat led to the trials, interpreting them to collectivelyindicate a clear patient benefit to treatment, practiceguidelines at University Hospital in Jackson wererevised 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 2HELLP syndrome and (2) any patient with class 3HELLP syndrome associated with epigastric pain,eclampsia, severe hypertension, and/or any evidence ofmajor organ system morbidity. Patients with uncompli-cated class 3 disease were monitored and subsequentlytreated if they met either of the 2 criteria.21,27,166,167 Thedosage of drug used is approximately double thatrecommended for fetal lung maturation purposes andhalf the amount used for adults with newly diagnosedimmune thrombocytopenic purpura.168,169 Postpartumand approximately 12 hours after the last antepartum

921


dose, IV dexamethasone is given twice more at 10 mg IVevery 12 hours and usually tapered with 2 lesser doses of5 mg IV every 12 hours for a full course. The regimen islengthened or shortened to fit individual patientcircumstances.167

Routine high-dose IV dexamethasone according tothe Mississippi regimen is now in its twelth year ofpractice utilization in Jackson; historical control groupsfrom the era before 1992 when corticosteroid trialsbegan are the only potential comparison groups ofpatients. Compared with 246 patients with class 1 or 2HELLP syndrome treated between 1985 and 1991 whenonly 16% received a complete or incomplete course ofcorticosteroids to enhance fetal lung maturation, signif-icantly reduced composite maternal disease was ob-served in 228 patients managed between 1994 and 2000with 90% aggressive corticosteroid utilization. Therewere significantly improved laboratory parameters, lessprogression to class 1 HELLP syndrome, less frequentneed for antihypertensive therapy, less requirement fortransfusion, lower incidence of major maternal morbid-ity, and shortened postpartum recovery.170 Overallmaternal morbidity rates of 64% for class 1 HELLP syn-drome, 54% for class 2, and 40% for class 3 improved to49%, 22%, and 21%, respectively, with an aggressivecorticosteroid regimen compared with an 11% baselinefor non-HELLP severe preeclampsia.25,27,28 Compara-ble quantitative and qualitative benefits occurred insimilarly treated patients with postpartum HELLP syn-dromeda more rapid normalization of platelet countsand LDH values and a clinically significant reductionof indicated transfusion, need for intubation or intensiverespiratory therapy, invasive hemodynamic monitoring,infectious- or bleeding-related morbidity, and length ofpostpartum hospital course.171

At least 7 other groups have also retrospectivelyreviewed case series and found that corticosteroids im-prove laboratory indices and positively impact HELLPsyndrome severity and pathogenesis.172-178 Tompkinsand Thiagarajah,173 for instance, interpret their datato show best benefit using 2 doses of intramuscular(IM) betamethasone (12 mg each) given 12 hours apartrather than the National Institutes of Health (NIH)179

recommended interval of 24 hours. The findings ofO’Brien et al175 point toward accelerated (shorter inter-val) standard dose fetal lung maturation steroids (either12 mg betamethasone IM every 12 hours ! 2 or dexa-methasone IV 6 mg every 6 hours), or a higher thanMississippi regimen of IV dexamethasone (10 mg every6 hours ! 2, then 6 mg every 6 hours ! 2-4 doses)given to patients with antepartum HELLP syndrometo 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 otherobservations are offered that favor the routine inclusion

of aggressive corticosteroids for patients with HELLPsyndrome:

� Liver hemorrhage or rupture is rarely encountered inthe undelivered pregnant patient with preeclampsia/eclampsia who is receiving corticosteroids for fetallung maturation or aggressive corticosteroids fortreatment of HELLP syndrome.21,28

� Liver complications may be particularly susceptibleto 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 antiphospholipidsyndrome was present in all 4 patients with hepaticinfarction and HELLP syndrome (described as in-complete in 3 of 4 cases), and their literature surveynoted that anticardiolipin antibodies and/or lupusanticoagulant were positive in 15 or 16 patientswith hepatic complications for whom laboratorydata were available. A similar series and a case reportwere published recently from France.90,91

� Because renal and/or hepatic dysfunction withHELLP syndrome exhibit can be exhibited very earlyin disease development before class 1 or 2 criteria aremet, it is possible that routine initiation of aggressivecorticosteroids in class 3 and ‘‘partial’’ HELLPpatients might prevent disease progression and sig-nificant maternal hepatorenal morbidity.� When aggressive corticosteroids are not used, signif-icant maternal morbidity180 or mortality can occurthat might otherwise have been avoided. For in-stance, HELLP syndrome developing in associationwith severe systolic hypertension above 160 mm Hgmay enhance the potential of cerebral blood vesselsto bleed when corticosteroids are absent from man-agement. Among a highly selected group of 28women with preeclampsia-induced severe systolic hy-pertension who had cerebral hemorrhage and stroke,18 (64%) had evidence for concurrent class 1, 2, or 3HELLP syndrome before the cerebral catastropheand 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 fromFrance with a 79% complication rate in the class1 HELLP category,106 or in recent series from Ger-many, China, and Turkey with high rates of maternalmorbidity,130,182,183 and they were usually absentfrom the management of patients with significantmaternal morbidity reported before 1990.6-17

� Aggressive corticosteroids can effect an increase inplatelet count sufficiently to undertake regionalanesthesia (from 0% to 42%) and to enable cervicalripening, induction of labor and vaginal deliv-ery.184,185 Up to 75% of patients with HELLP


syndrome can become candidates for regional anes-thesia after high-dose corticosteroid administrationif a platelet threshold of 75,000/mL is deemedadequate, and a higher rate of vaginal delivery canbe accomplished than would otherwise be possibleespecially in relatively preterm gestations.185 In theabsence of corticosteroid use, the cesarean rate ishigh and vaginal delivery is a rare event.128,186

� A recent prospective randomized clinical trial under-taken in the authors’ hospital found no clear treatmentbenefit with postpartum high-dose dexamethasonefor puerperal patients with non-HELLP severe pre-eclampsia at diagnosis.187 The only 2 patients to subse-quently have postpartum HELLP syndrome developwere in the placebo group, andboth respondedquicklyto the emergent initiation of IV dexamethasone afterstudy assignment as placebo was ascertained.

Choice of corticosteroid

Although approximately equivalent in potency, IV dex-amethasone appears to be more effective than IMbetamethasone, perhaps by delivering the drug directlyinto the vasculature of the affected organ systems.163,188

Preferences for other regimens by others were listedearlier. Sibai recommends an aggressive corticosteroidregimen 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 every12 hours (instead of every 24 hours) or dexamethasone12 mg IV (instead of 5 or 6 mg) every12 hours with de-livery to be accomplished within 24 hours after the lastdose of corticosteroids.22 Determination of preferreddrug, 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 maskingof potential complications or other disease processes.The available data are insufficient to estimate if thereare any adverse short- or long-term neonatal-infanteffects from brief aggressive corticosteroids for HELLPsyndrome. Neither dexamethasone or betamethasoneis preferable from the fetal perspective in regard toshort-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 ofaggressive 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 birthweight, lower head circumference, neonatal adrenalsuppression, and increased infection are theoretical risksto a newborn infant exposed to even a very short courseof high-dose corticosteroids, but evidence for this islacking. Potent glucocorticoids used for pregnancieswith HELLP syndrome may actually impart a fetal ad-vantage because placental vascular resistance by Dop-pler assessment appears to be reduced briefly insingleton and multiple gestations after maternal beta-methasone administration.193,194 In pregnant ewes re-ceiving extended dexamethasone prenatally (20 dayswith 20 mg/kg maternal body weight), no evidence ofaltered renal function or predisposition to adult hyper-tension compared with controls was found.195

Summary

Despite current limitations in sample size and studystructure, a consistent positive picture of patient benefitemerges from a review of the present literature that wesuspect will be shown definitively once large multicenterclinical trials are undertaken. This is consistent with ourconsiderable bedside experience gained over many yearsand in a multitude of patient circumstances and situa-tions that a routine practice of initiating aggressivecorticosteroids early in HELLP syndrome pregnancieswill prevent them from progressing along a continuumof worsening morbidity, a critically important conceptfor clinicians to embrace to reduce maternal mortalityrates in patients with this disease.196 In view of theabsence of a demonstrated downside to this approacheither for the mother or the fetus, given the body ofaffirmative available literature, we believe it most bene-ficial to patients now to be managed according to therecommendations that follow.

Fundamentals of practicedThe applicationof aggressive corticosteroids

The fundamental management concepts for treatment ofpatients 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 completeblood count with platelets, serum AST, and total serumLDH. Extended assessment can include serum creati-nine, glucose, bilirubin, coagulation studies, and aperipheral smear. Elevation of direct bilirubin andprolongation of coagulation studies out of proportionto mild thrombocytopenia occurs early in patients withAFLP but is unusual with HELLP syndrome unless thedisease is very advanced (class 1).


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

clinician’s 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 immediatelyindicated 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 pressuresabove 160 mm Hg.22,170

� The CNS is the most commonly affected system in mothers dying from HELLP syndromedthe aggressive use corticosteroids andantihypertensives probably lessens the risks of stroke and death. Early aggressive corticosteroids may also lessen hepatorenalmorbidity.� Aggressive corticosteroids in patients with HELLP syndrome increases the provider’s 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 than48-72 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.

An aggressive corticosteroid regimen is initiated assoon as the diagnosis of class 1 or 2 HELLP syndrome ismade or if the patient has complicated class 3 HELLPsyndrome. Continuation during cervical ripening andinduction of labor can be used to facilitate attemptedvaginal delivery or to improve the mother’s hematologicstatus before abdominal delivery. If the fetus is pretermand previable such that cesarean delivery is not a fetalconsideration, presence or absence of fetal heart tonesis assessed intermittently to determine whether a neona-tal team should be summoned at delivery to assess thereasonableness of resuscitation efforts. Rarely a preg-nancy with borderline viability has been prolongedwith aggressive corticosteroids but this is not usuallyrecommended.190-192,197,198 It is particularly discouragedin a patient with a fetal abnormality or major maternalmorbidity such as renal failure.199 HELLP syndromedetected before fetal viability may identify a pregnancycomplicated 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 oflabor, cervical Bishop score, prior maternal obstetrichistory, and response to aggressive corticosteroids allimpact management of the patient with a preterm viablefetus 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% forgestations less than 30 weeks, 61% at 30 to 31 weeks,and 62% at 32 to 33 weeks (overall induction success145/247 or 59%, 37% !28 weeks) can be achieved.186

Nevertheless, because vaginal delivery rates withHELLP syndrome are below 50% for gestations lessthan 30 weeks, Sibai22 advocates elective cesarean deliv-ery for all women diagnosed with HELLP syndrome ata gestation age less than 30 weeks when spontaneouslabor is not present and the Bishop score is less than 5.A patient with a low Bishop score in association withfetal growth restriction and/or oligohydramnios maynot be a good candidate for trial of labor. Otherwise,vaginal delivery is attempted in patients in active laborless than 30 weeks with ruptured membranes or with aBishop 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 usuallyrecommended while aggressive corticosteroids areinitiated.

Epidural or spinal anesthesia is the preferred anes-thetic for patients with preeclampsia.205 Approximately50% of patients with HELLP syndrome can be candi-dates for regional anesthesia during a trial of labor using


Figure 2 HELLP management algorithm: aggressive corticosteroids.

a threshold of 100,000/mL platelets.187 In these cir-cumstances, the decision of abdominal versus vaginaldelivery becomes more of an obstetric issue ratherthan a response to a rapidly worsening maternal-fetalcondition. Furthermore, patients who receive regionalanesthesia avoid the greater risks associated with gen-eral anesthesia. When motivated, providers can dependon corticosteroids to improve maternal platelet countssufficiently to increase the epidural rate for patientswith HELLP syndrome from 0% to 57%.184 When ce-sarean delivery without trial of labor is planned, waitingapproximately 6 hours after beginning an aggressivecorticosteroid regimen is recommended to stabilize thedisease process, improve laboratory parameters, enableinstitution of regional anesthesia, and reduce the needfor platelet or red cell transfusion. Given the absenceof neurologic or hematologic complications with re-gional anesthesia in HELLP syndrome patients man-aged in Panama without corticosteroids or plateletcount restrictions, the likelihood of bleeding complica-tions with regional anesthesia is small.205

Aggressive corticosteroid administration is associatedwith a significant decrease in the required use of bloodproducts21 and consequently a secondary decrease in in-fectious morbidity. When emergent cesarean deliverymust 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 unresponsiveto corticosteroid use, platelet transfusion of 6 to 10 unitsof platelets is recommended immediately prior tointubation.206

Prevention of severe systolic hypertension (O160 mmHg) is paramount; recommendations to maintain sys-tolic pressures under 155 mm Hg and diastolic pressuresunder 105 mm Hg are reasonable goals.22,181 Labetolol,hydralazine, or nifedipine are the preferred agents fortreatment of acute hypertension in this setting withinfused dilute nitroglycerin held in reserve.207

There have been no randomized trials of cesareanoperative technique for patients with HELLP syndrome.Delayed skin closure or type of skin incision do notappear to influence the frequency of wound complica-tions.208 In the absence of postpartum aggressive corti-costeroids, a high incidence of hematoma formationcan occur despite placement of a subfascial drain andkeeping the skin incision open for 48 hours.22

Most of the fundamental principles of managementfor patients with antepartum HELLP syndrome applyequally to postpartum/postoperative patients. New-onset postpartum disease appears usually within thefirst days after delivery and is treated with aggressivecorticosteroids similar to antepartum disease.21,170,171

The treatment is tailored to the patient; corticosteroiddosage is reduced once an upward trend in platelets and


Figure 3 Class 3 or incomplete/partial HELLP syndrome.

a downward trend in total serum LDH is recorded, anddiscontinued with normalization of HELLP laboratoryparameters and resolution of signs and symptoms ofpreeclampsia.

Significant renal injury is infrequently encounteredin patients with HELLP syndrome unless placentalabruption or a major hemorrhage also occurs.209 Mostoften renal dysfunction responds to measures shortof 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 patientmanagement principles for patients with acute renalfailure are used.211

Almost all instances of spontaneous subcapsularhematomas or hepatic rupture in pregnancy occur inassociation with HELLP syndrome.212-214 As thrombo-cytopenia worsens into the lowest ranges (class 1), inconjunction with the onset of sudden epigastric pain,the likelihood of finding abnormal hepatic imagingwith computed tomography or magnetic resonanceimaging increases. For reasons given earlier, we specu-late that it benefits patient care to immediately begin ag-gressive corticosteroids for any patient with suspectedHELLP syndrome and having hepatic injury develop,

regardless of disease class. Several excellent treatiseshave been published recently that review the manage-ment of HELLP-related hepatic complications such ashepatic rupture.129,212-217

Beyond corticosteroids

Plasma exchange or plasma infusion have been usedsparingly for recalcitrant and/or complicated HELLPsyndrome that is unresponsive to standard ther-apy.83,218-224 Some of the postulated mechanism ofactions include (1) clearance from the circulation ofdebris, toxins, antigen-antibody complexes, damagedred cell components or other substances that may becompromising normal coagulation and organ function;and (2) replacement of fluid, clotting factors, proteins,and other plasma components that are required toachieve homeostasis and healing. Prevention of intravas-cular fluid overload is enhanced versus straight transfu-sion, particularly in the patient with compromised renalfunction. 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


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 lessfrequently a concern we speculate because of early diag-nosis and aggressive corticosteroids.

There is little evidence suggesting efficacy to the useof 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 associatedwith increased maternal and perinatal morbidity relatedto placental abruption and hepatic rupture.80,228

Prognosis: Recovery

Patients with HELLP syndrome usually recover com-pletely, although relapses can occur in the absence ofcorticosteroid administration.224 After-effects of diseasecan persist for extended periods if hepatic or renal dam-age has occurred.229 Long-term follow-up of mothersand children from HELLP syndrome pregnancies arefew in number. Renal function was not permanently im-paired in 23 women with acute renal failure and HELLPsyndrome who were monitored an average of 4.6 years;8 patients had 11 subsequent pregnancies, 9 of whichwere term gestations.230 Similar normalization of renalfunction after a HELLP syndrome pregnancy wasreported by Jacquemyn’s Belgian group,229 but highersystolic and diastolic blood pressures were observed at5 years compared with controls. In Amsterdam, the in-cidence of subsequent hypertension requiring treatmentwas 3 times higher than controls.230 In the absence ofacute renal failure, there was no detectable impairmentof renal function at least 5 years after HELLP syndromein 10 patients. Stroke in patients with HELLP syndromeleft residual defects in 10 of 13 patients (77%) who sur-vived the acute insult.181 No permanent adverse effectson liver function have been reported. Emotional trauma,both immediate and delayed, can be a significant patientissue.231,232

Patient counseling: Future pregnancy

Women with a prior history of HELLP syndrome carryan increased risk of at least 20% (range 16%-52%) thatsome form of gestational hypertension will recur in asubsequent gestation. The rate of recurrent HELLPsyndrome itself varies between 2% and 19% dependingon 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 theMississippi study with a 75%African-Americanprofile, the recurrence risk was 42% to 43% for any typeof preeclampsia-eclampsia, but this increased to 61%if the preceding affected pregnancy was very preterm

(!32 weeks).234 To date, anything other than closemonitoring of subsequent pregnancies for problems ofprematurity and preeclampsia (preterm labor, bleeding,fetal growth restriction) has not been superceded byspecific testing or augmented by effective preventativemeasures. Testing for LCHAD mutation (long-chain3-hydroxyacyl coenzyme A dehydrogenase deficiency)is rarely positive in patients with HELLP syndrome incontrast to the situation with AFLP235-237 and thereforenot recommended.238

Challenges and conclusions

An expanded, more inclusive disease classificationsystem for HELLP syndrome is needed particularly ifthe potential for early aggressive corticosteroids to avertmost significant maternal morbidity is to be studiedadequately in appropriately structured, large multicen-ter clinical trials. Some form of a composite maternalmorbidity index also is needed to better describe thespectrum of systemic morbidity potentially experiencedby mothers with this condition. As expected with adisease process with variable rates of progression, dif-ferent stages at initial presentation, alteration by variousinterventions, and characterization by inconsistent andvariable laboratory methodologies, there has been a lackof consensus among researchers and confusion amongclinicians. The issue of standardization of diagnosisand disease classification is an important goal, so thatresearch findings are comparable and recommendedclinical managements can become progressively moreevidence based.

We believe that the scientific community is on thethreshold of a much better understanding of the patho-genesis of HELLP syndrome specifically and preeclamp-sia-eclampsia in general. Knowledge of the findingsrelated to the pathogenesis and pathophysiology ofthis disorder and the ameliorating effect of corticoste-roids on the disease process is foundational to under-standing the challenges of diagnosis, classification, andmanagement. A patient can present initially anywherealong the spectrum of disease development, and diseaseexpression is influenced by whether corticosteroids havebeen given for any reason. Thus, the accurate interpre-tation of any publication about HELLP syndromerequires a clear description of when in the developmentof HELLP syndrome laboratory or research testing wasperformed to study its pathogenesis or make its clin-ical diagnosis, including a statement of the presence orabsence of corticosteroids during patient managementideally noting at what stage in disease these agents anddosages were given to the patient. Large-scale multicen-ter trials investigating various corticosteroid regimensfor patients with this spectrum of HELLP syndromeconditions are desirable (including various types thatcross or do not cross into the fetal circulation63), with


particular attention to define benefits and limitationsaccording to the stage and circumstances in which ther-apy is initiated. Risk factors for severe renal and hepaticcomplications of HELLP syndrome require furtherinvestigation with regard to concurrent predisposingconditions 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 adverseeffects should continue. We believe that widespread dis-semination of the information presented herein to prac-ticing cliniciansdbetter recognition through cognitionand a management scheme focused on early aggressivecorticosteroid administrationdis needed now to mini-mize maternal-perinatal morbidity and mortality withthis condition while more extensive study continues.

References

1. Schmorl G. Pathologisch-anatomische Untersuchungen uber

Puerperal-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. Chesley’s 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 Engl

J 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 the

3-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.


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. Martin JN 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.


40. NeigerR,ContagSA,CoustanDR.The resolutionofpreeclampsia-

related thrombocytopenia. Obstet Gynecol 1991;77:692-5.


41. Figini E, Za G, SquarcinaM,MarrasM, 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 syndrome

severity: 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 andHELLP syndrome [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 preeclampsia

and 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


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 with

HELLP 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. Bone marrow necrosis

and refractory HELLP syndrome in a patient with catastrophic

antiphospholipid antibody syndrome. J Rheumatol 2002;29:195-7.

89. Veres K, Papp K, Lakos G, Szomjak E, Szegedi G, Soltesz P.

Primary antiphospholipid syndrome associated with HELLP syn-

drome in pregnancy. Orv Hetil 2003;144:1353-6.

90. Thuong DLT, Tieulie’ N, Costedoat N, Andreu M-R, Wechsler

B, Vauthier-Brouzes D, et al. The HELLP syndrome in the anto-

phospholipid syndrome: retrospective study of 16 cases in 15

women. Ann Rheum Dis 2005;64:273-8.

91. Koenig M, Roy M, Baccot S, Cuilleron M, de Filippis J-P,

Cathebras P. Thrombotic microangiopathy with liver, gut, and

bone infarction (catastrophic antiphospholipid syndrome) associ-

ated with HELLP syndrome. Clin Rheum 2005;24:166-8.

92. Gupta RS, Rajaram S, Goel N, Singh KC. Severe folate deficiency

mimicking HELLP syndromedreport of two cases. J Indian Med

Assoc 2003;101:32-4.

93. Ohkuchi A, Minakami H, Suzuki I, Ayustawati Izumi A, Sato I.

Liver dysfunction in pregnancy: CMV-induced hepatitis or

HELLP syndrome? J Obstet Gynaecol Res 2001;27:319-23.

94. Higgins SP, McMahan LP, Brennecks SP. Paroxysmal nocturnal

haemoglobinuria in pregnancydnot to be confused with pree-

clampsia or HELLP syndrome: case report and literature review.

J Obstet Gynaecol 2004;24:83-5.

95. Akerbook-Straberger BM, Lotgering FK. Embryonal sarcoma of

the liver in pregnancy associated with HELLP syndrome. Am J


96. Sardo ADS, Taylor A, Pellicano M, Romano L, Acunzo G,

Bifulco G, et al. Myasthenia and HELLP syndrome. Eur J

Obstet Gynecol Reprod Biol 2004;116:108-11.

97. Lurie S, Sadan O, Glezerman M, Ezri T. Psuedocholinesterase

deficiency associated with HELLP syndrome. Am J Perinatol

2004;21:315-7.

98. Martin JN Jr, Stedman C. Imitators of preeclampsia and HELLP

syndrome. Obstet Gynecol Clin North Am 1991;18:181-98.

99. Goodlin RC. Preeclampsia is the great imposter. Am J Obstet

Gynecol 1991;164:1577-80.

100. Sibai BM. Imitators of severe preeclampsia/eclampsia. Clin Peri-

natol 2004;31:835-52.

101. Goodlin RC. Expanded toxemia syndrome or gestosis. Am J Ob-

stet Gynecol 1986;154:1227-33.

102. Martin JN Jr, May WL, Magann EF, Terrone DA, Rinehart BK,

Blake PG. Early risk assessment of severe preeclampsia: admis-

sion batter of symptoms and laboratory tests to predict likelihood

of subsequent significant maternal morbidity. Am J Obstet Gyne-

col 1999;180:1407-14.

103. Carpani G, Bozzo M, Ferrazzi E, D’Amato B, Pizzotti D, Ra-

daelli T, et al. The evaluation of maternal parameters at diagnosis

may predict HELLP syndrome severity. J Matern Fetal Neonatal

Med 2003;13:147-51.

104. Haddad B, Barton JR, Livingston JC, Chahine R, Sibai BM. Risk

factors for adverse maternal outcome among women with

HELLP syndrome. Am J Obstet Gynecol 2000;183:444-8.

105. Rinehart BK, TerroneDA,MayWL,Magann EF, Isler CM,Mar-

tin JN Jr. Change in platelet count predicts eventual maternal out-

come with HELLP syndrome. J Matern Fetal Med 2001;10:28-34.

106. Roussillon E, Estrade JP, Guyon F, Ekouevi D, Guillaume V,

Horovitz J. Importance of thrombocytopenia for the manage-

ment of HELLP syndrome: a report of 104 cases. J Gynecol

Obstet Biol Reprod (Paris) 2003;32:541-8.

107. Catanzarite VA, Steinberg SM, Mosley CA, Landers CF, Cousins

LM, Schneider JM. Severe preeclampsia with fulminant and ex-

treme elevation of aspartate aminotransferase and lactate dehy-

drogenase levels: high risk for maternal death. Am J Perinatol

1995;12:310-3.

108. Sibai BM. The HELLP syndrome: much ado about nothing? Am

J Obstet Gynecol 1990;162:311-6.

109. Terrone DA, Isler CM, May WL, Magann EF, Norman PF,

Martin JN JrCardiopulmonary morbidity as a complication of

severe preeclampsia-HELLP syndrome. J Perinatol 2000;20:78-81.

110. Woods JB, Blake PG, Perry KG Jr, Magann EF, Martin RW,

Martin JN Jr. Ascites: a portent of cardiopulmonary complica-

tions in the preeclampsic patient with HELLP syndrome. Obstet

Gynecol 1992;80:87-91.

111. Soh Y, Yasuhi I, Nakayama D, Isimaru T. A case of postpartum

cerebellar infection with HELLP syndrome. Gynecol Obstet In-

vest 2002;53:240-2.

112. Onrust S, Santema JG, Aarnoudse JG. Preeclampsia and the

HELLP syndrome still cause maternal mortality in the Nether-

lands and other developed countries: can we reduce it? Eur J


113. Ezri T, Aboutleish E, Lee C, Evron S. Intracranial subdural hem-

atooma following dural puncture in a parturient with HELLP

syndrome. Can J Anaesth 2002;49:820-3.

114. Knopp U, Kehler U, Riskmann H, Arnold H, Gliemroth J. Cere-

bral haemodynamic pathologies in HELLP syndrome. Clin Neu-

rol Neurosurg 2003;105:256-61.

115. Marano E, Scuteri N, Vacca G, Orefice G. HELLP syndrome

with reversible posterior leukoencephalopathy. Neurol Sci 2003;

24:82-4.

116. Takanami K, Hasegawa T, Miyamori T, Matsumoto T,

Yoshimoto Y, Tidor TReversible posterior leukoencephalopa-

thy syndrome accompanied by HELLP syndrome and eclampsia:

a case report. No Shinkei Geka 2001;29:967-70.

117. Wenzel M, Lehnan H. A case of mild ocular manifestations in

pregnancy-induced hypertension with HELLP syndrome. Acta

Ophthalmol 1994;72:391-2.


118. Bumke JP, Whyte I, Macewen CJ. Bilateral serous retinal detach-

ments in the HELLP syndrome. Acta Ophthalmol 1989;67:322-4.

119. Leff SR, Yarian DL, Mascuilli L, Green SN, Baldomero RE.

Vitreous haemorrhage as a complication of HELLP syndrome.

Br J Ophthalmol 1990;74:498.

120. Lavavi H, Neri A, Zoldan J, Segal J, Ovadia J. Preeclampsia

‘‘HELLP’’ syndrome and postictal cortical blindness. Acta Obstet

Gynaecol Scand 1987;66:91-2.

121. Gupta LY, Mansour SE. Bilateral bullous retinal detachment as a

complication of the HELLP syndrome. Can J Ophthalmol 1994;

29:242-5.

122. Sanchez Vicente JL, Ruiz Aragon J, Nanwani K, Sanchez Vicente

P, Guitoe Linares JR, Diez Garretas C, et al. Retinal detachment

in preeclampsia and HELLP syndrome. Arch Soc Esp Oftalmol

2003;78:335-8.

123. Tung CF, Peng YC, Chen GH, Chow WK, Yang DY, Hu WH.

Hemolysis, elevated liver enzymes, and low platelet count

(HELLP) syndrome with acute cortical blindness. Zhonghua Yi

Xue Zhi 2001;64(8):482-5.

124. Tara PN, Byrne H, Francis PJ, Shennan A. HELLP syndrome

complicated by visual loss. J Obstet Gynaecol 2003;23:562-3.

125. Tranos PG, Wickremasinghe SS, Hundal KS, Foster PJ, Jagger J.

Bilateral serous retinal detachment as a complication of HELLP

syndrome. Eye 2002;16:491-2.

126. Soltes L, Schmalfuss IM, Bhatti MT. Cortical blindness due to re-

versible posterior leukoencephalopathy syndrome in a patient

with thrombotic thrombocytopenic purpura and preeclampsia.

Arch Ophthalmol 2004;122:1885-7.

127. Celik C, Gezgine K, Altintepe L, Tonbul HZ, Yaman ST,

Akyruek C, et al. Results of pregnancies with HELLP syn-

drome. Ren Fail 2003;25:613-8.

128. Basavilvazo Rodriguez A, Pacheco Perez C, Lemus Rocha R,

Martinez Perez JM, Martinez Martineez A, Hernandez-Valencia

M. Maternal and perinatal surgical complications in low platelet

count with HELLP syndrome and severe preeclampsia-eclampsia.

Ginecol Obstet Mex 2003;71:379-86.

129. Wicke C, Pereira PL, Neeser E, Flesch I, Rodegerdts EA, Becker

HD. Subcapsular liver hematoma in HELLP syndrome: Evalua-

tion of diagnostic and therapeutic optionsda unicenter study.


130. Ertan AK, Wagner S, Hendrik HJ, Tanriverdi HA, Schmidt W.

Clinical and biophysical aspects of HELLP syndrome. J Perinat

Med 2002;30:483-9.

131. Martin JN Jr, Perry KG Jr, Miles JF, Blake PG, Magann EF,

Roberts WE, et al. The interrelationship of eclampsia HELLP

syndrome and prematurity: cofactors for significant maternal

and perinatal risk. BJOG 1993;100:1095-100.

132. Williams KP, Wilson S. The impact of parity on the incidence

of HELLP syndrome and small for gestational age infants in

hypertensive pregnant women. J Obstet Gynaecol Can 2002;24:

485-9.

133. Isler CM, Rinehart BK, Terrone DA, May WL, Magann EF,

Martin JN Jr. The importance of parity to major maternal mor-

bidity in the eclamptic mother with HELLP syndrome. Hypertens

Pregnancy 2003;22:287-94.

134. Moldenhauer JS, O’Brien JM, Barton JR, Sibai BM. Acute fatty

liver of pregnancy associated with pancreatitis: a life-threatening

complication. Am J Obstet Gynecol 2004;190:502-5.

135. Yamanaka Y, Takeuchi K, Konda E, Samoto T, Satou A,

Mizudori M, et al. Transient postpartum diabetes insipidus in

twin pregnancy associated with HELLP syndrome. J Perinatal

Med 2002;30:273-5.

136. Mak K-H, Chee J-J. Myocardial infarction and HELLP: a case of

heightened vasomotor activity. Int J Cardiol 2004;97:151-2.

137. Isler CM, Rinehart BK, Terrone DA, Martin RW, Magann EF,

Martin JN Jr. Maternal mortality associated with HELLP syn-

drome. Am J Obstet Gynecol 1999;181:924-8.

138. Ding D-C, Chu T-W, Liu J-Y. Maternal death associated with

Eisenmenger’s syndrome complicated with HELLP syndrome.

Int J Obstet Gynecol 2003;83:189-91.

139. Sibai BM, Taslimi MM, el-Nazer A, Amon E, Mabie BC, Ryan

GM. Maternal-perinatal outcome associated with HELLP syn-

drome in severe preeclampsia-eclampsia. Am J Obstet Gynecol

1986;155:501-9.

140. Aslan H, Gul A, Cebeci A. Neonatal outcome in pregnancies

after preterm delivery for HELLP syndrome. Gynecol Obstet

Invest (Switzerland) 2004;58:96-9.

141. Visser W, Wallenburg HCS. Temporising management of severe

preeclampsia with and without the HELLP syndrome. BJOG

1995;102:111-7.

142. Magann EF, Perry KG Jr, Chauhan SP, Graves GR, Blake PG,

Martin JN Jr. Neonatal salvage by weeks’ gestation in pregnan-

cies complicated by HELLP syndrome. J Soc Gynecol Investig

1994;1:206-9.

143. Abramovici D, Friedman SA, Mercer BM, Audibert F, Lao L,

Sibai BM. Neonatal outcome in severe preeclampsia at 24 to

26 weeks’ gestation: does HELLP syndrome matter? Am J


144. Van Pampus MG, Wolf H, Westenberg SM, van der Post JA,

Bonsel GJ, Treffers PE. Maternal and perinatal outcome after

expectant management of HELLP syndrome compared with pre-

eclampsia without HELLP syndrome. Eur J Obstet Gynecol

Reprod Biol 1998;76:31-6.

145. Roelofsen AC, van Pampus MG, Aarnoudse JG. The HELLP

syndromedmaternal-fetal outcome and follow up of infants.

J Perinat Med 2003;31:201-8.

146. Singhal N, Amin HJ, Pollard JK, Tough SC, Johnston DW,

Clark DJ, et al. Maternal HELLP syndrome: perinatal and neu-

rodevelopmental neonatal outcomes for infants weighing less

than 1250 g. J Paediatr Child Health 2004;40:121-6.

147. Miles JF, Martin JN Jr, Blake PG, Perry KG Jr, Martin RW,

Meeks GR. Postpartum eclampsia: a recurring perinatal di-

lemma. Obstet Gynecol 1990;76:328-31.

148. Ascarelli MH, Perry KG Jr, Magann EF, May WL, Blake PG,

Martin JN Jr. A birth weight of 600 grams: cutpoint on the

cusp of perinatal viability in pregnancies delivered very preterm

for HELLP syndrome. J Matern Fetal Invest 1997;7:184-7.

149. Qureshi NS, Tomlinson AJ. Prenatal corticosteroid therapy for

elevated liver enzyme/low platelet count syndrome: a case report.

J Reprod Med 2005;50:64-6.

150. Bush KD, O’Brien JM, Barton JR. The utility of uterine artery

Doppler investigation in women with the HELLP syndrome.


151. Harms K, Rath W, Herting E, Kuhn W. Maternal hemolysis,

elevated liver enzymes, low platelet count, and neonatal outcome.

Am J Perinatol 1994;12:1-6.

152. Kandler C, Kevekordes B, Zenker M, Kandler M, Beinder E,

Lang N, et al. Prognosis of children born to mothers with

HELLP syndrome. J Perinat Med 1998;26:486-90.

153. Brune T, Baytar-Dagly B, Hentschel R, Harms E, Louwen F. In-

fants of mothers with HELLP syndrome compensate intrauterine

growth retardation faster than unaffected premature infants: does

HELLLP change fetal programming? Biol Neonate 2002;82:

174-80.

154. van Runnard Heimel PJ, Franx A, Schobben AFAM, Huijes

AJM, Derks JB, Bruinse HW. Corticosteroids, pregnancy and

HELLP syndrome: a review. Obstet Gynecol Surv 2004;60:57-70.

155. Heybourne KD, Burke MS, Porreco RP. Prolongation of prema-

ture gestation in women with HELLP syndrome. J Reprod Med

1990;35:53-7.

156. Magann EF, Graves GR, Roberts WE, Blake PG, Morison JC,

Martin JN Jr. Corticosteroids for enhanced fetal lung maturatio

in patients with HELLP syndrome: impact on neonates. Aust N

Z J Obstet Gynaecol 1993;33:131-5.


157. Magann EF, Martin RW, Isaacs JD, Blake PG, Morrison JC,

Martin JN Jr. Corticosteroids for the enhancement of fetal lung

maturity: impact on the gravida with preeclampsia and HELLP

syndrome. Aust N Z J Obstet Gynaecol 1993;33:127-30.

158. Magann EF, Bass D, Chauhan SP, Sullivan DL, Martin RW,

Martin JN Jr. Antepartum corticosteroids: disease stabilization

in patients with HELLP syndrome. Am J Obstet Gynecol 1994;

171:1148-53.

159. Magann EF, Perry KG Jr,Meydrech EF, Harris RL, Chauhan SP,

Martin JN Jr. Postpartum corticosteroids: accelerated recovery

from HELLP syndrome. Am J Obstet Gynecol 1994;171:1154-8.

160. Thiagarajah S, Bourgeois FS, Harbert GM, Caudle MR. Throm-

bocytopenia in preeclampsia: associated abnormalities and man-

agement principles. Am J Obstet Gynecol 1984;150:1-7.

161. Clark SL, Phelan JR, Allen SH, Golde SR. Antepartum reversal

of hematologic abnormalities associated with the HELLP syn-

drome. J Reprod Med 1986;31:70-2.

162. Yeast JD, Coronado S. Hepatic dysfunction, thrombocytopenia

and late-onset preeclampsia. J Reprod Med 1987;32:781-4.

163. Isler CM, Barrilleaux PS, Magann EF, Bass JD, Martin JN Jr. A

prospective, randomized trial comparing the efficacy of dexa-

methasone and betamethasone for the treatment of antepartum


164. Vigil-DeGracia P, Garcia-Caceres E. Dexamethasone in the post-

partum treatment of HELLP syndrome. Int J Gynaecol Obstet

1997;59:217-21.

165. Yalcin OT, Sener T, Hass H, Ozalp S, Okur A. Effects of post-

partum corticosteroids in patients with HELLP syndrome. Int J

Gynaecol Obstet 1997;61:141-8.

166. Magann EF, Martin JN Jr. Critical care of HELLP syndrome

with corticosteroids. Am J Perinatol 2000;17:417-22.

167. Martin JN Jr, Magann EF. High-dose dexamethasone: a promis-

ing therapeutic option for HELLP. Contemp Ob Gyn 1999;44:

55-65.

168. Cheng Y, Wong RS, Soo YO, Chui CH, Lau FY, Chan NP, et al.

Initial treatment of immune thrombocytopenic purpura with

high-dose dexamethasone. N Engl J Med 2003;349:831-6.

169. George JN, Vesely SK. Immune thrombocytopenic purpuradlet

the treatment fit the patient. N Engl J Med 2003;349:903-5.

170. Martin JN Jr, Thigpen BD, Rose CH, Cushman J, Moore A,

May WL. Maternal benefit of high-dose intravenous corticoste-

roid therapy for HELLP syndrome. Obstet Gynecol 2003;189:

830-4.

171. Martin JN Jr, PerryKG, Blake PG,MayWL,MooreA, Robinette

L. Better maternal outcomes are achieved with dexamethasone

therapy for postpartum HELLP syndrome. Am J Obstet Gynecol

1997;177:1011-7.

172. Heller CS, Elliott JP. High order multiple pregnancies compli-

cated by HELLP syndrome: a report of four cases with corticoste-

roid therapy to prolong gestation. J Reprod Med 1997;42:743-6.

173. Tompkins MJ, Thiagarajah S. HELLP syndrome: the benefit of

corticosteroids. Am J Obstet Gynecol 1999;181:304-9.

174. Fischer T, Krause M, Beinder E, Schlembach D, Rabenbauer B,

Wildt L, et al. Prolongation of pregnancy in patients suffering

from HELLP syndrome. Geburtsh Frauenhielk 1998;59:335-8.

175. O’Brien JM, Milligan DA, Barton JR. Impact of high-dose corti-

costeroid therapy for patients with HELLP syndrome. Am J


176. Crane JM, Tabarsi B, Hutchens D. The maternal benefits of cor-

ticosteroids with HELLP (hemolysis, elevated liver enzymes, low

platelet count) syndrome. J Obstet Gynaecol Can 2003;25:650-5.

177. Varol F, Aydin T, Gucer F. HELLP syndrome and postpartum

corticosteroids. Int J Gynaecol Obstet 2001;73:157-9.

178. Mecacci F, Carignani L, Cioni R, Parretti E, MognosaM, Piccioli

A, et al. Time course of recovery and complications ofHELLP syn-

drome with two different treatments: heparin or dexamethasone.

Thromb Res 2001;102:99-105.

179. Antenatal corticosteroids revisited: repeat courses. NIH Consens

Statement 2000;17:1-100.

180. Calderon EG, Khawar S, Cunningham JA, Russell LD, Alpert

MA. Pulmonary artery thrombus and subcapsular hematoma in

a patient with HELLP syndrome: a therapeutic conundrum.

Am J Med Sci 2002;323:151-4.

181. Martin JN Jr, Thigpen BD, Moore RC, Rose CH, Cushman J,

May WL. Stroke and severe preeclampsia and eclampsia: a para-

digm shift focusing on systolic blood pressure. Obstet Gynecol

2005;104:246-54.

182. Tanner B, Ohler WG, Hawighorst S, Shaffer U, Knapstein PG.

Complications in HELLP syndrome due to peripartal hemostatic

disorder. Zentrablbl Gynakol 1996;118:213-20.

183. Wu SQ, Zu XH, Liu HL, Guo SL. Maternal and perinatal prog-

nosis affected by the time of termination of pregnancy in patients

with HELLP syndrome. Zonghua Fu Chan Ke Za Zhi 2003;38:

334-6.

184. O’Brien JM, Shumate SA, Satchwell SL, Milligan DA, Barton

JR. Maternal benefits of corticosteroid therapy in patients with

HELLP syndrome: impact on the rate of regional anesthesia.


185. Rose CH, Thigpen BD, Bofill JA, Cushman J, May WL, Martin

JN Jr. Obstetric implications of antepartum corticosteroid ther-

apy for HELLP syndrome. Obstet Gynecol 2004;104:1011-4.

186. Magann EF, Roberts WE, Perry KG Jr, Chauhan SP, Blake PG,

Martin JN Jr. Factors relevant to mode of preterm delivery with


187. Barrilleaux PS, Martin JN Jr, Klauser CK, Bufkin L, May WL.

Postpartum intravenous dexamethasone for severely preeclamptic

patients without hemolysis, elevated liver enzymes, low platelets

(HELLP) syndrome: a randomized trial. Obstet Gynecol 2005;

105:843-8.

188. Isler CM, Magann EF, Rinehart BK, Terrone DA, Bass JD, Mar-

tin JN Jr. Dexamethasone compared with betamethasone for glu-

cocorticoid treatment of postpartum HELLP syndrome. Int J

Gynaecol Obstet 2003;80:291-7.

189. Bar-Lev MRR, Maayan-Metzger A, Matok I, Heyman Z, Sivan

E, Kuint J. Short-term outcomes in low birth weight infants fol-

lowing antenatal exposure to betamethasone versus dexametha-

sone. Obstet Gynecol 2004;104:484-8.

190. Magann EF, Washburne JF, Sullivan CA, Chauhan SP, Morri-

son JC, Martin JN Jr. Corticosteroid-induced arrest of HELLP

syndrome progression in a marginally viable pregnancy. Eur J


191. O’Boyle JD, Magann EF, Washburne JF, Sullivan CA, Schorr

SJ, Morrison JC, et al. Dexamethasone-facilitated postponement

of delivery in an extremely preterm pregnancy complicated by

HELLP syndrome. Mil Med 1999;164:316-8.

192. Schlembach D, Munz W, Fischer T. Effect of corticosteroids

on HELLP syndrome: a case report. J Perinat Med 2000;28:

502-5.

193. Wallace EM, Baker LS. Effect of antenatal betamethasone ad-

ministration on placental vascular resistance. Lancet 1999;353:

1404-7.

194. Barkehall-Thomas A, Thompson M, Baker LS, Edwards A,

Wallace EM. Betamethasone-associated changes in umbilical

artery flow velocity waveforms in multiple pregnancies with

umbilical artery absent end diastolic flow. Aust N Z J Obstet

Gynaecol 2003;43:360-3.

195. Dodic M, Tersteeg M, Jefferies A, Wintour EM, Moritz K.

Prolonged low-dose dexamethasone treatment, in early gestation,

does not alter blood pressure or renal function in adult sheep.

J Endocrin 2003;179:275-80.

196. Geller SE, Rosenberg D, Cox SM, Brown ML, Simonson L,

Driscoll CA, et al. The continuum of maternal morbidity and

mortality: factors associated with severity. Am J Obstet Gynecol

2001;191:939-44.


197. Dreyfus M, Tissier I, Ndocko MA, Denoual I, Baldauf JJ, Ritter

J. Corticosteroid therapy for conservative management in mar-

ginally viable pregnancy complicated by HELLP syndrome. Eur

J Obstet Gynecol Reprod Biol 1999;85:233-4.

198. Gardeil F, Gaffney G, Morrison JJ. Severe HELLP syndrome

remote from term. Ir Med J 2001;94:54.

199. Stefos T, Pachouras N, Mari G, Cosmi E, Lolis D. A case of par-

tial mole and atypical type I triploidy associated with severe

HELLP syndrome at 18 weeks gestation. Ultrasound Obstet

Gynecol 2002;20:403-4.

200. Chuileannain FN, MacPhail S. HELLP syndrome at 21 weeks’

gestation in association with trisomy 13. J Obstet Gynaecol 1999;

19:74-5.

201. Fischer T, Tallukat G, Schneider MP, Schlembach D, Munz W,

Homuth V. HELLP syndrome in the 18th week of gestation in

association with elevated angiotensin AT(1)-receptor auto-

antibodies. Eur J Obstet Gynecol Reprod Biol 2001;97:255-7.

202. Vidaeff AC, Pschirrer ER, Mastrobattista JM, Gilstrap LC,

Ramin SM. Mirror syndrome: a case report. J Reprod Med 2002;

47:770-4.

203. Antenatal corticosteroid therapy for fetal maturation. ACOG

Committee on Obstetric Practice Committee Opinion. Number

273. Washington (DC): The College; 2002.

204. Report of the National High Blood Pressure Education Program

Working Group on High Blood Pressure in Pregnancy. Am J

Obstet Gynecol 2000;183:S1-22.

205. Vigil-de Gracia P, Silva S, Montufar C, Carrol I, De Los Rios S.

Anesthesia in pregnant women with HELLP syndrome. Int J

Gynecol Obstet 2001;74:23-7.

206. Roberts WE, Perry KG, Woods JB, Files JC, Blake PG, Martin

JN Jr. The intrapartum platelet count in patients with HELLP

syndrome: is it predictive of later hemorrhagic complications?


207. Cetin A, Yurtcu N, Guvenal T, Imir AG, Duran B, Cetin M. The

effect of glyceryl trinitrate on hypertension in women with severe

preeclampsia. HELLP syndrome and eclampsia. Hypertens Preg-

nancy 2004;23:37-46.

208. Briggs R, Chari RS, Mercer B, Sibai BM. Postoperative incision

complications after cesarean section in patients with antepartum

syndrome of hemolysis, elevated liver enzymes, and low platelets

(HELLP): does delayed primary closure make a difference? Am J


209. Selcuk NY, Odabas AR, Centikaya R, Tonbul HZ, San A. Out-

come of pregnancies with HELLP syndrome complicated by

acute renal failure. Ren Fail 2000;22:319-27.

210. Abraham KA, Kennelly M, Dorman AM, Walshe JJ. Pathogen-

esis of acute renal failure associated with the HELLP syndrome:

a case report and review of the literature. Eur J Obstet Gynecol

Reprod Biol 2003;108:99-102.

211. Asrat T, Nageotte MP. Acute renal failure in pregnancy. In:

Foley MR, Strong TH Jr, Garite TJ, editors. Obstetric intensive

care manual. 2nd ed. New York: Mc-Graw Hill; 2004. p. 184-95.

212. Reck T, Bussenius-Kammerer M, Ott R, Muller V, Beinder E,

Hohenberger W. Surgical treatment of HELLP syndrome-associ-

ated liver rupturedan update. Eur J Obstet Gynecol Reprod Biol

2001;99:57-65.

213. Rinehart BK, Terrone DA, Magann EF, Martin RW, May WL,

Martin JN Jr. Preeclampsia-associated hepatic hemorrhage and

rupture: mode of management related to maternal and perinatal

outcome. Obstet Gynecol Surv 1999;54:196-202.

214. Barton JR, Sibai BM. Diagnosis and management of hemolysis,

elevated liver enzymes, and low platelets syndrome. Clin Perinatol

2004;31:807-33.

215. Juarez-Azpilcueta A, Motta-Martinez E, Montano-Uzcanga A.

Hepatic rupture as a maternal complication of hypertensive dis-

ease of pregnancy with HELLP syndrome. Gac Med Mex 2003;

139:276-80.

216. Aldemir M, Bac B, Tacyildiz I, Yagmur Y, Keles C. Spontaneous

liver hematoma and hepatic rupture in HELLP syndrome: report

of two cases. Surg Today 2002;32:450-3.

217. Skukla D, Veillon DM, Scott LK, Heldmann M, Lewis DF,

Cotelingam JD. Abdominal pain in pregnancy: HELLP syn-

drome with subcapsular hematoma of the liver. J La State

Med Soc 2003;155:77-9.

218. Martin JN Jr, Files JC, Blake PG, Perry KG Jr, Morrison JC,

Norman PH. Postpartum plasma exchange for atypical pree-

clampsia-eclampsia as HELLP syndrome. Am J Obstet Gynecol

1995;172:1107-25.

219. Eckford SD, MacNab JL, Turner ML, Plews D, Liston WA. Plas-

mapheresis in the management of HELLP syndrome. J Obstet

Gynaecol 1998;18:377-9.

220. Julius CJ, Dunn ZL, Blazina JF. HELLP syndrome: laboratory

parameters and clinical course in four patients treated with

plasma exchange. J Clin Apheresis 1994;9:228-35.

221. HamadaS,TakishitaY,TamuraT,NakaO,HiguchiK,Takahashi

H. Plasma exchange in a patient with postpartum HELLP

syndrome. J Obstet Gynaecol Res 1996;22:371-4.

222. Mahalati K, Dawson RB, Collina JO, Bell WR, McCrae KR,

Martin JN. Persistant pre-eclampsia post partum with elevated

liver enzymes and hemolytic uremic syndrome. J Clin Apheresis

1999;14:69-78.

223. Forster JG, Peltonen S, Kaaja R, Lampinen K, Pettila V. Plasma

exchange in severe postpartum HELLP syndrome. Acta Anaes-

thesiol Scand 2002;46:955-8.

224. Lombano F, Kidder MY, Lilly M, Gollin YG, Block BS. Recur-

rence of microangiopathic hemolytic anemia after apparent re-

covery from HELLP syndrome: a case report. J Reprod Med

2002;47:875-7.

225. Detti L, Meccaci F, Piccioli A, Ferrarello S, Carignani L, Mello

G, et al. Postpartum heparin therapy for patients with the syn-

drome of hemolysis, elevated liver enzymes, and low platelets

(HELLP) is associated with significant hemorrhagic complica-

tions. J Perinatol 2005;25:236-40.

226. Dart BW 4th, Cockerham WT, Torres C, Kipikasa JH, Maxwell

RA. A novel use of recominant factor VIIa in HELLP syndrome

associated with spontaneous hepatic rupture and abdominal com-

partment syndrome. J Trauma 2004;57:171-4.

227. Yamamoto H, Nishikawa S, Yamazaki K, Kudo R. Efficacy of

haptoglobin administration in the early postoperative course of

patients with a diagnosis of HELLP syndrome. J Obstet Gynaecol

2000;20:610-1.

228. Tsatsaris V, Carbonne B, La Tour MD, Cabrol D, Milliez J. Is

conservative treatment of HELLP syndrome safe? Eur J Obstet

Gynecol Reprod Biol 1998;80:139-41.

229. Jacquemyn Y, Jochems L, Duiker E, Bosmans JL, Van Hoof V,

Van Campenhout C. Long-term renal function after HELLP

syndrome. Gynecol Obstet Invest 2004;57:117-20.

230. Van Pampus MG, Wolf H, Mayruhu G, Treffers PE, Blecker OP.

Long-term follow-up in patients with a history of HELLP syn-

drome. Hypertens Pregnancy 2001;20:15-23.

231. Kidner MC, Flanders-Stepans MB. A model for the HELLP syn-

drome: the maternal experience. J Obstet Gynecol Neonatal Nurs

2004;33:44-53.

232. Beal JA, Freda MC. A model for the HELLP syndrome: the

maternal experience. Am J Matern Child Nurs 2004;29:332.

233. Chames MC, Haddad B, Barton JR, Livingston JC, Sibai BM.

Subsequent pregnancy outcome in women with a history of

HELLP syndrome at %28 weeks of gestation. Am J Obstet

Gynecol 2003;188:1504-7.

234. Sullivan CA, Magann EF, Perry KG Jr, Roberts WE, Blake

PG, Martin JN Jr. The recurrence risk of the syndrome of

hemolysis, elevated liver enzymes and low platelets (HELLP)

in subsequent gestations. Am J Obstet Gynecol 1994;171:

940-3.


235. Wilcken B, Leung KC, Hammond J, Kamath R, Leonard JV.

Pregnancy and fetal long-chain 3-hydroxyacl coenzyme A dehy-

drogenase deficiency. Lancet 1993;341:407-8.

236. Tyni T, Ekholm E, Pihko H. Pregnancy complications are fre-

quent in long-chain 3-hydroxyacyl-coenzyme A dehydrogenase

deficiency. Am J Obstet Gynecol 1998;178:603-8.

237. Strauss AW, Bennett MJ, Rinaldo P, Sims HF, O’Brien LK, Zhao

Y, et al. Inherited long-chain 3-hydroxyacyl-CoA dehydrogenase

deficiency and a fetal-maternal interaction causematernal liver dis-

ease and other pregnancy complications. Semin Perinatol 1999;23:

100-12.

238. den Boer ME, Ijlst L, Wijburg FA, Oostheim W, van Werkhoven

MA, van Pampus MG, et al. Heterozygosity for the common

LCHAD mutation (1528gOC) is not a major cause of HELLP

syndrome and the prevalence of the mutation in the Dutch pop-

ulation is low. Pediatr Res 2000;48:151-4.

Understanding and managing HELLP syndrome: The …€¦ · Antepartum or postpartum HELLP syndrome...

Documents

Transcript of Understanding and managing HELLP syndrome: The …€¦ · Antepartum or postpartum HELLP syndrome...