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American Journal of Obstetrics and Gynecology (2006) 195, 914–34
www.ajog.org
Understanding and managing HELLP syndrome:
The integral role of aggressive glucocorticoids
for 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 WORDS
HELLP syndrome
Severe preeclampsia/
eclampsia
Aggressive
glucocorticoids/
corticosteroids
Obstetric
Antepartum or postpartum HELLP syndrome constitutes an obstetric emergency that requires
expert knowledge and management skills. The insidious and variable nature of disease presentation and progression challenges the clinician and complicates consensus on universally accepted
diagnostic and classification criteria. A critical review of published research about this variant
form of severe preeclampsia, focused primarily on what is known about the pathogenesis of this
disorder as it relates to patient experience with corticosteroids for its management, leads to the
conclusion that there is maternal-fetal benefit realized when potent glucocorticoids are aggressively 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 given
an understanding of the nature of the disorder with its potential to cause considerable maternal
morbidity and mortality, we recommend for the present that aggressively used potent glucocorticoids constitute the cornerstone of management for patients considered to have HELLP
syndrome.
Ó 2006 Mosby, Inc. All rights reserved.
Recognition that a particularly potent form of preeclampsia-eclampsia exists has been evident since case
reports ﬁrst appeared in the late nineteenth1 and early
twentieth century.2-5 Between 1950 and 1980, several
case series were published that related patients and
poor obstetric outcomes to clinical and laboratory ﬁndings that are consistent with what we recognize today as
HELLP syndrome.6-17 Credit for formally consolidating
the concept and creating the acronym of HELLP (H =
hemolysis, EL = elevated liver enzymes and LP = low
platelets) goes to Louis Weinstein who in 1982 reported
Reprints not available from the authors.
0002-9378/$ - see front matter Ó 2006 Mosby, Inc. All rights reserved.
doi:10.1016/j.ajog.2005.08.044
a group of 29 pregnant patients he considered to have a
distinct subset of severe preeclampsia/eclampsia.18 All
patients expressed ﬁndings suggestive of microangiopathic hemolytic anemia with moderate-to-severe thrombocytopenia, misshapened erythrocytes on peripheral
smear, and abnormal liver function tests usually in conjunction with epigastric pain, nausea, and vomiting.
Severe hypertension and proteinuria were frequently
coexistent as well.
Since 1982 there has been an outpouring of obstetric
literature seeking to better deﬁne the pathogenesis, natural history, clinical spectrum, classiﬁcation and management strategies for patients considered to have HELLP
syndrome. Because the incidence of this disorder is low
Martin, Rose, and Briery
(1-6 per 100019,20), most clinical research endeavors have
been small, single institution case series or randomized
trials. Until deﬁnitive large multicenter trials are undertaken, clinicians must rely on less robust information to
guide patient care. Despite several recent comprehensive
reviews on the subject of HELLP syndrome,21-24 none to
date have examined the available data and patient experience primarily from the perspective of corticosteroid
impact on disease expression and progression. The current review is constructed from this perspective, synthesizing and summarizing the pertinent English literature on
HELLP syndrome to understand how corticosteroids
appear to play an integral role in its management.
Pathogenesis and natural history
HELLP syndrome usually develops suddenly during
pregnancy (27-37 weeks’ gestation) or in the immediate
puerperium.25-28 As a form of severe preeclampsia, it
likely has its origins in aberrant placental development,
function, and ischemia-producing oxidative stress,
which triggers the release of factor(s) that systematically
injure the endothelium via activation of platelets, vasoconstrictors, and loss of normal pregnancy vascular
relaxation.29-36 Although variable, HELLP syndrome
onset and progression usually is rapid (35%-50% decrease in platelets per 24 hours; mean daily reduction
of 40,000/mL platelets) as lactic acid dehydrogenase
(LDH) and aminotransaminases (aspartate [AST] and
alanine [ALT]) rise until 24 to 48 hours postpartum
when laboratory values begin to recover.37-42 Absent
corticosteroids, most patients (85%-90%) achieve platelelets 100,000/mL or greater within 6 to 8 days of delivery or within 72 hours of platelet nadir, and total LDH/
transaminases trend toward normal within 96 hours
postpartum.37,41-43 Onset of disease occurs postpartum
in approximately 15% to 25% of cases.25-28
Although most patients with HELLP syndrome eventually exhibit hypertension and proteinuria, these 2 major
signs of severe preeclampsia bear no consistent relationship with laboratory parameters of the underlying vasculopathy.26-28,37,38 A variety of symptoms can be elicited
that are ambiguous, subtle, and focused primarily
on the gastrointestinal-hepatic systems.28 The central
place that the liver occupies in the disorder of HELLP
syndrome is an important clue to pathogenesis. Severe
epigastric/right upper quadrant pain often heralds underlying rapidly progressive disease.44 The extent of periportal hepatocyte dysfunction or cell death in a given
patient probably correlates with the severity of maternal
illness. Recall that CD95 (APO-1, Fas)-mediated apoptosis of hepatocytes is a major pathogenic mechanism
for liver disease in general.45 The Fas-Fas ligand system
is a well-studied cell death system that can mediate apoptosis. As a member of the tumor necrosis factor receptor
915
superfamily, Fas is a 36 to 45 kDa type I surface protein
containing a single transmembrane region.46 It induces
apoptosis by binding to Fas-ligand, a 40 kDa type II
transmembrane protein of the tumor necrosis factor receptor family.47 In the context of pregnancy and patients
with HELLP syndrome, apoptosis in liver tissue and cytotoxic activity for primary human hepatocytes has been
reported in serum from patients with HELLP syndrome
(CD95 ligand produced by placenta) that increases over
time and in proportion to disease severity.45 In addition,
caspases 3, 8, and 9 are all required to eﬀect apoptotic
cell death, and active forms of all 3 are detected in liver
extracts of HELLP patients. Blocking of CD95 signaling
reduces the hepatocytotoxic activity of HELLP serum.
Thus, systemic CD95L is a placenta-derived humoral
factor that is involved in the pathogenesis of HELLP
syndrome. CD95L-rich membrane fragments or soluble
CD95L are postulated by Strand et al45 to be shed into
the maternal circulation as important progenitors in the
pathogenesis of HELLP syndrome.
The previously described ﬁndings and the proposal
that placenta-derived proteins damage hepatic cells are
compatible with many other ﬁndings that cast HELLP
syndrome as a placenta-instigated, liver-targeted acute
inﬂammatory condition and disordered immunologic
process.21 The similarity between HELLP syndrome and
systemic inﬂammatory response syndrome (SIRS) has
been emphasized by several researchers.48-50 The perturbations present in patients who have HELLP syndrome
develop may be additive to, or altered by, the pathophysiology leading to preeclampsia in general. A listing
of some of the supportive evidence for these concepts
is contained in Table I. Decreases in haptoglobin are
a sequel, not an instigator of the vascular hemolytic
process.68 In patients with HELLP syndrome, the metalloprotease ADAMTS-13 is not severely deﬁcient or
undetectable as it is in many patients with thrombotic thrombocytopenic purpura (TTP).69,70 No genetic
markers or evidence for association with thrombophilic
or antiphospholipid disorders have been established.71-75
Diagnosis
The diagnosis of HELLP syndrome is most assured in
a pregnant patient with signs and symptoms of
preeclampsia-eclampsia and a triad of laboratory abnormalities suggesting red cell trauma (H = hemolysis),
hepatic damage and dysfunction (EL = elevated liver
enzymes), and thrombocytopenia (LP = low platelets).
The greater the extent of laboratory abnormalities, the
greater is the physician’s conﬁdence in the diagnosis.
Thrombocytopenia may be the ﬁrst indicator of disease when the results of a complete blood count return to
the physician. A platelet count less than 150,000/mL
represents mild (100,000-150,000/mL), moderate (50,000100,000/mL), or severe (!50,000/mL) thrombocytopenia
916
Table I
Martin, Rose, and Briery
Research findings contributory to an inflammatory pathogenesis for HELLP syndrome
Elevated serum concentrations of soluble Fas.51
Cytokine and neutrophil-mediated liver injury in necropsy liver specimens with strong staining for tumor necrosis factor-alpha and
neutrophil elastase antibody.52
Leukocytosis proportionate to disease severity.53
Increased plasma concentrations of anaphylatoxins C3a and C5a.54
Decreased unstimulated neutrophil oxygen radical production possibly secondary to an exhausted cellular response.55
Abnormal circulating cytokine concentrations.52,56
Increased bioactive tumor necrosis factor alpha possibly secondary to immune injury of the vascular endothelium or muscle.57
Depression of both T- and B-cell potential and impaired monocyte handling of intracellular pathogens precedes clinical/laboratory
disease by 1-2 wks.58
Decreased placental vascular endothelial growth factor (VEGF) expression in placentas from HELLP syndrome pregnancies59,60 analagous to
decreased circulating levels of free VEGF and platelet-derived growth factor (PlGF) in preeclamptic patients without HELLP syndrome.61
Dysregulation of VEGF ligands and receptors with higher serum VEGF compared to healthy matched
pregnant controls (but less elevated than patients with non-HELLP preeclampsia.62
Hypersensitivity to pressors using laser-doppler digital fluxometry microcirculation studies.63
Substantially decreased vascular smooth muscle-relaxing adrenomedullin and calcitonin gene-related peptide messenger RNA
in the placenta.64
Increased intracellular retention of cadherin-5.65
Increased plasma and red cell thiobarbituric acid reactive substances (TBARS) and glutathione peroxidase activity.66,67
in the nonpregnant as well as pregnant patient.76 Requiring a threshold of less than 100,000/mL to consider the
diagnosis of thrombocytopenia is ill advised. Maternal
morbidity doubles from 11% to more than 20% when
patients with severe preeclampsia have mild thrombocytopenia develop in association with increasing LDH
(R600 IU/L) and transaminases (AST and/or ALT
R40 IU/L).21,27 Signiﬁcant pathology such as hepatic
hemorrhage and rupture can ﬁrst appear in the patient
with HELLP syndrome before the platelet count falls
below 100,000/mL.28 Indeed, the onset of epigastric pain
in patients who are eventually diagnosed with HELLP
syndrome has occurred at a platelet count as high as
283,000/mL in our patient population (unpublished).
Erythrocyte injury and death
Evidence for hemolysis is the third laboratory criterion for
HELLP syndrome. In addition to a progressive anemia,
other laboratory evidence of hemolysis classically includes decreased serum levels of haptoglobin, increased
serum total LDH 600 IU/L or greater,26,28 increased serum AST, increased serum indirect bilirubin, an abnormal
peripheral smear showing variable amounts of disrupted
or destroyed red blood cells (schistocytes, echinocytes,
burr cells), and/or a declining hematocrit or hemoglobin.
Depending on laboratory methodology, LDH thresholds
for abnormal values begin between 200 and 600 IU/L.
Classification
Hepatic injury and dysfunction
In Weinstein’s initial 1982 report, thresholds of what
constituted abnormal serum levels of aspartate transaminase (AST), alanine transferase (ALT) and bilirubin to
merit a diagnosis of HELLP syndrome were not stated.18
Most healthy pregnant patients in our hospital laboratory
exhibited normal transaminase values less than 20 IU/L,
with greater than 48 IU/L for AST 3 SD above the
mean.27 A threshold for AST of 70 IU/L or greater to
qualify for the diagnosis of HELLP syndrome when
platelets are 100,000/mL or less has been consistently
advocated by Martin et al21 and Sibai.22 Transaminase
values between 40 and 70 IU/L reﬂect borderline hepatic
dysfunction regardless of the platelet count (especially in
the 100,000-150,000/mL range).28 Glutathione S-transferase alpha has been proposed as a better marker for acute
liver injury than the aminotransferases, but there has been
limited work on this possibility.77
Classiﬁcation systems have been created to enable physicians to identify patients at risk for signiﬁcant maternal morbidity, to guide therapeutic intervention and
assess eﬃcacy or outcome, and to provide a common
platform for comparison of research results. The 2 most
commonly used systems for diagnosis and classiﬁcation
were developed in the 1980s by investigators at the
Universities of Tennessee and Mississippi (Table II).
The Tennessee Classiﬁcation78 deﬁnes ‘‘true’’ or
‘‘complete’’ HELLP syndrome if all of the following criteria are met: (1) moderate to severe thrombocytopenia
with platelets 100,000/mL or less; (2) hepatic dysfunction
with AST 70 IU/L or greater; and (3) evidence of hemolysis with an abnormal peripheral smear in addition to
either total serum LDH 600 IU/L or greater or bilirubin
1.2 mg/dL or greater. The patient who exhibits some but
not all of these parameters is termed ‘‘partial’’ or ‘‘incomplete’’ HELLP syndrome: ELLP syndrome (missing
Martin, Rose, and Briery
Table II
917
Classification systems of HELLP syndrome
HELLP class
Mississippi classification21,36,46
Tennessee classification22,165
1
Platelet count %50,000/mL
AST or ALT R70 IU/L
LDH R600 IU/L
50,000/mL %Platelet count %100,000/mL
AST or ALT R70 IU/L
LDH R600 IU/L
100,000/mL %Platelet count %150,000/mL
AST or ALT R40 IU/L
LDH R600 IU/L
N/A
Platelet count %100,000/uL
AST R70 IU/L
LDH R600 IU/L
2
3
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 preeclampsia with mildly elevated liver enzymes only), HEL
(hemolysis and elevated liver enzymes absent thrombocytopenia), or LP syndrome (low platelets syndrome as
severe preeclampsia with thrombocytopenia, gestational
thrombocytopenia, or immune thrombocytopenic purpura).22 Maternal and perinatal outcomes are progressively worse for patients with preeclampsia, partial
HELLP syndrome, and complete HELLP syndrome, respectively.79 Incomplete criteria initially can progress to
complete expression of HELLP syndrome.
The Mississippi-Triple Class System for HELLP syndrome divides patients into 3 classes or groups that are
based primarily on the platelet portion of the laboratory
diagnosis.21,28,38 Final class assignment or diagnosis is
based on the lowest platelet count registered during
the disease course. The span of thrombocytopenia between zero and 150,000 platelets is divided into 3 equal
ranges consistent with mild, moderate, and severe
thrombocytopenia. For a patient to merit a diagnosis
of HELLP syndrome, class 1 requires severe thrombocytopenia (platelets %50,000/mL), evidence of hepatic
dysfunction (AST and/or ALT R70 IU/L), and evidence
suggestive of hemolysis (total serum LDH R600 IU/L);
class 2 requires similar criteria except thrombocytopenia
is moderate (O50,000 to %100,000/mL); and class 3
includes patients with mild thrombocytopenia (platelets O100,000 but %150,000/mL), mild hepatic dysfunction (AST and/or ALT R40 IU/L), and hemolysis (total
serum LDH R600 IU/L). Peripheral smear ﬁndings and
bilirubin abnormalities are not obtained.
Neither classiﬁcation system is ideal; both have shortcomings. Because class 1 and 2 HELLP syndrome
patients are combined in the Tennessee system, discrimination between groups and outcomes is diﬃcult and
beneﬁt from corticosteroids (arrest of disease in class 2,
prevention of progression from class 3 to 2 or even 1)
cannot be demonstrated. On the other hand, the Mississippi classiﬁcation system is very useful for directing
individual patient therapy with aggressive corticosteroids
and for comparing pregnancy outcomes. The Mississippi
system, although including class 3 patients, does not
include those with incomplete or partial forms of the
disease, and excludes patients from analysis when causes
of consumptive coagulopathy such as placental abruption
are present. Two (Tennessee) or even 3 (Mississippi)
groupings or classes insuﬃciently describe the multitude
of clinical scenarios (antepartum vs postpartum, epigastric pain present or absent, degrees of laboratory value
abnormality, diﬀerent gestational age epochs) encountered by the clinician. The importance of a transitional
group of patients is clearly demonstrated by instances of
hepatic ruptures in patients with class 3 HELLP syndrome80 and other reports of increased eclampsia and
higher perinatal morbidity/mortality in patients with
incomplete/partial HELLP syndrome.21
Imitators of HELLP Syndrome
Patients presumptively diagnosed with HELLP syndrome can have other disorders concurrent with HELLP
syndrome or other disorders altogether. Lack of response
to aggressive corticosteroid administration, especially
with persistence of disease or ﬁrst presentation of disease
more than 7 days after delivery, should instigate testing to
evaluate other diagnostic possibilities (Table III). In our
experience, the most common HELLP imitators are
patients with well-advanced acute fatty liver of pregnancy
(AFLP), acute renal failure with acute tubular necrosis
(usually not hemolytic uremic syndrome), ‘‘neglected’’
class 1 HELLP syndrome coming to medical attention
too late for aggressive corticosteroids to prevent progression and multiorgan dysfunction, previously undiagnosed systemic lupus erythematosus/antiphospholipid
syndrome, and either immune thrombocytopenic purpura (ITP) or thrombotic thrombocytopenic purpura
(TTP).98 See the excellent reviews of potentially confounding conditions written by Goodlin16,99 and Sibai.100
918
Martin, Rose, and Briery
Table III Confounders and concurrent conditions: differential diagnosis50,134
Table IV Admission risk factors for significant maternal
morbidity/mortality HELLP syndrome
AFLP81
Lupus flare: Exacerbation of systemic lupus erythematosus
(SLE)82,83
TTP84
Hemolytic uremic syndrome (HUS)85
ITP
Thrombophilias
Antiphospholipid syndrome75,83,86-91
Homozygous factor V Leiden
Prothrombin gene mutation
Severe folate deficiency92
Cholangitis/cholecystitis/pancreatitis/ruptured bile duct
Gastric ulcer
Cardiomyopathy
Dissecting aortic aneurysm
Systemic viral sepsis (herpes, cytomegalovirus)93
SIRS/sepsis
Hemorrhagic or hypotensive shock
Stroke in pregnancy or puerperium
Paroxysmal nocturnal hemoglobinuria94
Pheochromocytoma
Advanced embryonal cell carcinoma of the liver95
Acute cocaine intoxication
Myasthenia gravis96
Pseudocholinesterase deficiency97
Signs/symptoms
Laboratory values
Epigastric pain
Nausea
Vomiting
Severe systolic hypertension
Severe diastolic hypertension
Placental abruption
Eclampsia
Platelets !50,000/mL
Total serum LDH O1400 IU/L
AST O150 IU/L
ALT O100 IU/L
Uric acid O7.8 mg/dL
CPK O200 IU/L
Serum creatinine O1.0
Clinical presentation
Signs and symptoms with HELLP syndrome are variable but depend largely on the stage of the patient’s
disease, whether class 1, class 2, or class 3.28 Right upper
quadrant/epigastric pain is the most important symptom
suggestive of underlying HELLP syndrome, found in
100% of Weinstein’s initial 1982 series of 29 advanced
cases.18 Half of patients with class 1 HELLP syndrome,
33% with class 2, and 16% with class 3 compared with
only 13% of severely preeclamptic patients without
HELLP syndrome exhibit epigastric pain or right upper
quadrant discomfort.28 Frequently epigastric pain occurs in association with nausea or vomiting. Overall,
the incidence of epigastric pain/nausea/vomiting ranges
between 30% and 90%.20,22,26 Any pregnant patient
presenting in the second half of gestation with epigastric
or right upper quadrant pain, particularly if associated
with nausea and/or vomiting, has HELLP syndrome
until proven otherwise.44 A pregnant patient with signs
and symptoms of severe preeclampsia who suddenly has
severe, writhing epigastric/upper abdominal pain develop
likely has hepatic bleeding or rupture constituting an
obstetric emergency.
Malaise or viral syndrome-like symptoms can occur
with advanced HELLP syndrome.22,26 Headache occurs
in a substantial number (33%-68%)22,28 of patients with
any form of preeclampsia whether HELLP syndrome
is present, with visual complaints in a lesser number.22
Adapted from Martin et al.102
Hypertension and proteinuria are not always present.21,22,101 Neither of these signs bears a consistent relationship in the individual patient with stage of disease,
although on a population basis higher blood pressures
and more proteinuria tend to occur more frequently as
HELLP syndrome worsens from class 3 to 2 to 121,28,102
and eventually almost all patients are mildly hypertensive
during the course of their disease and recovery.28 Signiﬁcant dipstick proteinuria (3-4C) at presentation occurs in
approximately half of patients with class 1 or 2 HELLP
syndrome, but no proteinuria is detected in approximately 1:6 patients.
Although the presence and severity of symptomatology (epigastric pain, nausea, vomiting) and hypertension
(systolic, diastolic) in general are related to maternal
disease severity and the potential to develop severe morbidity,28,38,103 individual patient predictive value (with the
probable exception of severe epigastric pain) is low.104
Signiﬁcant maternal morbidity becomes more likely
when 1 or more of the laboratory thresholds are exceeded
as listed in Table IV.102,105,106 Very high LDH, AST,
and/or uric acid have the highest predictive value and
are risk-additive with worsening thrombocytopenia.28,107
Maternal morbidity and mortality
The development of HELLP syndrome places the
pregnant patient at signiﬁcant risk for morbidity and
mortality. Morbidity is categorized by major organ
system(s) aﬀected and is stratiﬁed by extent of disease
using the Mississippi classiﬁcation system.28 Constituents of these categories are listed in Table V and presented in decreasing order of frequency, emphasizing
that there is enormous variability among patients.
Hematologic-coagulation
The prevalence of disseminated intravascular coagulation (DIC) increased from 2 of 193 patients (0.5%) with
severe preeclampsia to 35 of 201 (17.4%) with class 1
HELLP syndrome,28 the latter very similar to the
15% incidence of DIC and 9% incidence of placental
abruption reported by Audibert et al79 for classes 1
Martin, Rose, and Briery
and 2 combined. Clinically signiﬁcant bleeding requiring
transfusion and wound hematoma formation follow a
similar pattern of increasing incidence with worsening
disease.21,25-28,79,104,108 Approximately 10% of patients
with class 1 or 2 HELLP syndrome exhibit microscopic
or macroscopic hematuria.28
Cardiopulmonary
The odds of developing a cardiopulmonary problem,
particularly pulmonary edema, is more than doubled
(2.2!) for patients with class 1 HELLP syndrome
(22%) compared with non-HELLP severe preeclampsia.28,109 The overall percentage of 14.5% (74/501) in the
Mississippi series is similar to the combined 8% incidence of pulmonary edema and less than 1% incidence
of adult respiratory distress syndrome in the Tennessee
series.79 Copious large volume ascites identiﬁes a patient
at high risk for cardiopulmonary complications.110
Central nervous system/visual
Patients with noneclamptic class 1 or 2 HELLP syndrome (11/501 or 2.2%) are 3.5 times more likely to have
signiﬁcant central nervous system (CNS) morbidity compared with class 3 HELLP syndrome or non-HELLP
severe preeclampsia.28 This includes stroke, mental status
changes and/or coma.111-114 Visual complications
including retinal detachment, vitreal hemorrhage, and
cortical blindness are infrequent in proportion to disease
severity (1.4% in class 1 and 2).28 These are usually short
lived with full recovery within 1 to 6 months, except
when cerebral hemorrhage/stroke is the cause.115-126
Renal
Placental abruption and puerperal onset of HELLP syndrome place the patient at increased risk for renal insult.
In general, renal system morbidity increases as disease
status worsens.28 All 4 of the patients with acute tubular
necrosis in the Mississippi series had class 1 HELLP syndrome develop; acute renal failure complicated 3% of
cases of class 1 or 2 HELLP syndrome in the Tennessee
series.26,79 However, acute renal dysfunction and/or failure has been described as often as 54% and 33% in
some international series19,127 and as the most common
cause of maternal morbidity in a report from Mexico.128
Hepatic
Catastrophic liver complications are relatively infrequent. Liver hemorrhage/rupture aﬀected only 1% of
patients with class 1 or 2 HELLP syndrome in the
Tennessee series26,79 and only 3 patients had signiﬁcant
hepatic complications develop (2 subcapsular hematomas in class 2 and 3 HELLP syndrome patients, 1 liver
rupture in a class 1 HELLP syndrome patient) in the
919
Table V Categories of significant maternal morbidity with
HELLP syndrome
Hematologic/coagulation
Clinically significant bleeding requiring transfusion
Ecchymoses
Hematoma
DIC
Hematuria
Cardiopulmonary
Cardiogenic/noncardiogenic pulmonary edema
Cardiac/pulmonary arrest
Pulmonary embolus
Indicated invasive hemodynamic monitoring
Intubation/mechanical ventilation/continuous positive
airway pressure
Myocardial ischemia/chest pain
CNS/vision
Cerebral hemorrhage/stroke
Central venous thrombosis
Hypertensive encephalopathy
Cerebral edema
Sensorium change/coma
Impaired vision
Retinal/macular detachment
Vitreal hemorrhage
Cortical blindness
Eclamptic seizure
Renal
Acute tubular necrosis
Acute renal failure
Renal dialysis
Transient renal impairment
Hepatic
Subcapsular/intrahepatic hematoma
Hepatic rupture/hemorrhage
Pancreatitis
Infection/sepsis
Obstetric
Other
Mississippi seriesdimportantly all were classiﬁed as
class 3 HELLP syndrome when the complication was
ﬁrst detected.27 According to Wicke et al,129 at least 1 of
5 patients with eventual liver rupture caused by HELLP
syndrome had early subcapsular liver hematoma formation compatible with the class 3 level of disease.
Infection/sepsis
Patients with HELLP syndrome more often have infectious morbidity develop than those with non-HELLP
severe preeclampsia (43% vs 20%).25,27 At least 3 important variables are involved: corticosteroids, transfusion, and delivery. Corticosteroid utilization appears
to reduce infectious morbidity from 43% to 18% by reducing or eliminating the need for transfusion of blood
products.27,28 Abdominal delivery doubles infectious
morbidity from 19% to 41%.28
920
Martin, Rose, and Briery
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, Rinehart BK, Terrone DA, Martin RW, Magann EF, Martin JN. Maternal mortality associated with HELLP (hemolysis, elevated liver
enzymes, and low platelets) syndrome. Am J Obstet Gynecol 1999;181:924-8 with permission from Elsevier.
Obstetric issues
Cesarean delivery has been performed more often for
patients with class 1 HELLP syndrome (61%) than
class 2 (57%), class 3 (53%), or non-HELLP severe
preeclampsia (48%).25,28 Mode of delivery is strongly
inﬂuenced by gestational age, maternal-fetal status, class
of disease, and corticosteroid utilization. Overall abdominal delivery is associated with a doubling of maternal
morbidity (cardiopulmonary, hematologic-coagulation,
and infectious) compared with vaginal delivery.28 In
addition, risk for placental abruption, placenta previa,
eclampsia, and episiotomy breakdown is increased
compared to non-HELLP pregnancies.20,25,130,131
Parity-eclampsia
The incidence of complications in hypertensive pregnant
women varies by parity but not by gravidity.132 When
HELLP syndrome complicates eclampsia, parous patients have double the incidence of signiﬁcant maternal
morbidity compared with nulliparous patients (50% vs
25%).133
Other morbidity
Pancreatitis is uncommon in patients with preeclampsia
or HELLP syndrome; the hemorrhagic form is uniquely
associated with acute fatty liver of pregnancy.134 Diabetes insipidus,135 bone marrow necrosis with cerebral
hemorrhage,88 and myocardial infarction136 are rare
complications.
Mortality
Most deaths in patients with HELLP syndrome occur
with class 1 disease (60%), and neurologic abnormality
due mostly to cerebral hemorrhage/stroke is the most
common system involved at autopsy (45%) (Figure 1).137
Delay in diagnosis appeared to be a factor in half of
the deaths that could be adequately evaluated, and
none of the 54 maternal deaths in the Isler et al series137
or in a subsequent case report138 occurred in association
with the aggressive use of corticosteroids.
Perinatal morbidity and mortality
Perinatal morbidity and mortality are substantially
higher in pregnancies with severe preeclampsia complicated by HELLP syndrome, primarily because of
required preterm delivery.25,139 Fetal growth restriction
and fetal distress after 32 weeks also may be more frequent.140 Although neonatal deaths and perinatal mortality rates tend to be progressively higher in parallel
with increasingly severity of disease, outcomes are
Martin, Rose, and Briery
primarily related to gestational age at delivery and not
to disease status.28,141-146 Similarly, earlier prematurity
is responsible for the higher perinatal mortality recorded
in eclamptic pregnancies with HELLP syndrome compared with non-HELLP eclampsia.20,25,147 Neonatal
survival was 100% in the Mississippi experience if newborn weight was 600 g or greater and following a full
course and time interval (48 hours) of antenatal corticosteroids for fetal lung maturation.148
Continuation of HELLP syndrome pregnancy beyond 26 weeks and the time necessary for steroid
enhancement of fetal lung maturation increases the
risk of stillbirth substantially.144,149 In the Mississippi
series, stillbirth was almost tripled for class 1 or 2 compared with class 3 or non-HELLP severe preeclampsia,28
in part related to fetal growth restriction and placental
abruption. Fetal growth restriction and abnormal Doppler velocimetry impact up to 39% and 48% of patients,
respectively.22,130,150 Although neonatal thrombocytopenia occurs in a substantial percentage (up to
38%)130 of newborn infants, a higher incidence of intraventricular hemorrhage has not resulted.151,152 Longterm prognosis for the children of mothers with HELLP
syndrome is comparable to controls matched for gestational age.152 Small-for-gestational-age neonates signiﬁcantly increase weight and length over the ﬁrst 4 years of
life compared with matched controls.153 Newborn
infants weighing less than 1250 g compared with birth
weight-matched controls had signiﬁcantly less cerebral
palsy and mental disability at 3 years of life.146
The integral role of corticosteroids
The probability that HELLP syndrome is a SIRS-like
inﬂammatory form of severe preeclampsia50 leads to
consideration of anti-inﬂammatory/immunosuppressive
agents for treatment, speciﬁcally corticosteroids. The
consistently favorable response of HELLP syndrome
laboratory parameters to corticosteroids suggests the
presence of an underlying corticosteroid-responsive
step(s) in its pathogenesis and a therapeutic beneﬁt to
their use. Corticosteroids may act by one or more mechanisms to alter endothelial activity/interaction with circulating cells including erythrocytes and platelets,
impact translation/transcription, interrupt hepatocyte
damage by placenta-derived CD95-L and/or to disrupt
signaling for inﬂammatory cytokine production by the
endogenous immune system.154 A recent publication
that thoroughly explores the pharmacology and physiology of corticosteroids relevant to pregnancy and
HELLP syndrome is recommended to the interested
reader for review.154
The potential therapeutic value of corticosteroids for
patients with HELLP syndrome was ﬁrst recognized in
the early 1990s by 2 groups of investigators, one in
Denver155 and the other in Jackson, MS.156,157 The ﬁrst
921
2 small randomized clinical trials (nonblinded, nonplacebo controlled) were undertaken in Jackson using intravenous (IV) high-dose dexamethasone versus no
steroids during 1992 through 1993 in 65 patients with
antepartum or postpartum HELLP syndrome.158,159
Stabilization and signiﬁcant improvement in laboratory
and clinical parameters associated with HELLP syndrome occurred in women who received antenatal and/
or postpartum corticosteroids.158,159 Subsequent to the
publication of these ﬁndings, retrospective scrutiny of
selected data present in several published series of
patients with severe preeclampsia from the 1970s and
1980s revealed ﬁndings consistent with this new observation that high-dose dexamethasone appeared to arrest
the deterioration of laboratory parameters in patients
fulﬁlling criteria for HELLP syndrome.16,139,160-162
Four other small randomized, controlled trials have
been undertaken comparing the use of high-dose dexamethasone or prednisolone (50 mg twice daily) with
either no treatment, placebo, or with betamethasone.
Two HELLP trials were undertaken antepartum63,163
and 2 evaluated postpartum corticosteroid treatment.164,165 Signiﬁcantly improved biochemical parameters of HELLP syndrome and clinical parameters
of mean arterial pressure and urinary output were
consistently reported. In the most recently reported
trial from The Netherlands,80 the prednisolone-treated
group of 15 antepartum patients had a 50% reduction
in HELLP syndrome exacerbations compared with 15
placebo-treated controls and a signiﬁcantly shorter time
to normalize postpartum platelets. All 3 major maternal complications occurred in the placebo groupd
formation of a liver hematoma in 2 patients and rupture
of the liver in a third patient with maternal death.
No signiﬁcant neonatal diﬀerences between groups
were noted in the immediate neonatal period or at infant
follow-up.80
On the basis of the ﬁndings from the ﬁrst 2 prospective clinical trials and the preceding case series ﬁndings
that led to the trials, interpreting them to collectively
indicate a clear patient beneﬁt to treatment, practice
guidelines at University Hospital in Jackson were
revised in mid-1993 to routinely initiate IV high dose
(10 mg IV every 12 hours) dexamethasone antepartum
or postpartum for (1) any patient with class 1 or 2
HELLP syndrome and (2) any patient with class 3
HELLP syndrome associated with epigastric pain,
eclampsia, severe hypertension, and/or any evidence of
major organ system morbidity. Patients with uncomplicated class 3 disease were monitored and subsequently
treated if they met either of the 2 criteria.21,27,166,167 The
dosage of drug used is approximately double that
recommended for fetal lung maturation purposes and
half the amount used for adults with newly diagnosed
immune thrombocytopenic purpura.168,169 Postpartum
and approximately 12 hours after the last antepartum
922
dose, IV dexamethasone is given twice more at 10 mg IV
every 12 hours and usually tapered with 2 lesser doses of
5 mg IV every 12 hours for a full course. The regimen is
lengthened or shortened to ﬁt individual patient
circumstances.167
Routine high-dose IV dexamethasone according to
the Mississippi regimen is now in its twelth year of
practice utilization in Jackson; historical control groups
from the era before 1992 when corticosteroid trials
began are the only potential comparison groups of
patients. Compared with 246 patients with class 1 or 2
HELLP syndrome treated between 1985 and 1991 when
only 16% received a complete or incomplete course of
corticosteroids to enhance fetal lung maturation, significantly reduced composite maternal disease was observed in 228 patients managed between 1994 and 2000
with 90% aggressive corticosteroid utilization. There
were signiﬁcantly improved laboratory parameters, less
progression to class 1 HELLP syndrome, less frequent
need for antihypertensive therapy, less requirement for
transfusion, lower incidence of major maternal morbidity, and shortened postpartum recovery.170 Overall
maternal morbidity rates of 64% for class 1 HELLP syndrome, 54% for class 2, and 40% for class 3 improved to
49%, 22%, and 21%, respectively, with an aggressive
corticosteroid regimen compared with an 11% baseline
for non-HELLP severe preeclampsia.25,27,28 Comparable quantitative and qualitative beneﬁts occurred in
similarly treated patients with postpartum HELLP syndromeda more rapid normalization of platelet counts
and LDH values and a clinically signiﬁcant reduction
of indicated transfusion, need for intubation or intensive
respiratory therapy, invasive hemodynamic monitoring,
infectious- or bleeding-related morbidity, and length of
postpartum hospital course.171
At least 7 other groups have also retrospectively
reviewed case series and found that corticosteroids improve laboratory indices and positively impact HELLP
syndrome severity and pathogenesis.172-178 Tompkins
and Thiagarajah,173 for instance, interpret their data
to show best beneﬁt using 2 doses of intramuscular
(IM) betamethasone (12 mg each) given 12 hours apart
rather than the National Institutes of Health (NIH)179
recommended interval of 24 hours. The ﬁndings of
O’Brien et al175 point toward accelerated (shorter interval) standard dose fetal lung maturation steroids (either
12 mg betamethasone IM every 12 hours ! 2 or dexamethasone IV 6 mg every 6 hours), or a higher than
Mississippi regimen of IV dexamethasone (10 mg every
6 hours ! 2, then 6 mg every 6 hours ! 2-4 doses)
given to patients with antepartum HELLP syndrome
to improve platelet counts, reduce liver enzyme abnormalities, and prolong latency to delivery in a dosedependent manner.
In addition to these 13 publications, several other
observations are oﬀered that favor the routine inclusion
Martin, Rose, and Briery
of aggressive corticosteroids for patients with HELLP
syndrome:
Liver hemorrhage or rupture is rarely encountered in
the undelivered pregnant patient with preeclampsia/
eclampsia who is receiving corticosteroids for fetal
lung maturation or aggressive corticosteroids for
treatment of HELLP syndrome.21,28
Liver complications may be particularly susceptible
to interdiction with early aggressive corticosteroids,
especially in the symptomatic class 3 HELLP syndrome patient with other underlying pathology.86
Pauzner et al86 noted recently that antiphospholipid
syndrome was present in all 4 patients with hepatic
infarction and HELLP syndrome (described as incomplete in 3 of 4 cases), and their literature survey
noted that anticardiolipin antibodies and/or lupus
anticoagulant were positive in 15 or 16 patients
with hepatic complications for whom laboratory
data were available. A similar series and a case report
were published recently from France.90,91
Because renal and/or hepatic dysfunction with
HELLP syndrome exhibit can be exhibited very early
in disease development before class 1 or 2 criteria are
met, it is possible that routine initiation of aggressive
corticosteroids in class 3 and ‘‘partial’’ HELLP
patients might prevent disease progression and signiﬁcant maternal hepatorenal morbidity.
When aggressive corticosteroids are not used, significant maternal morbidity180 or mortality can occur
that might otherwise have been avoided. For instance, HELLP syndrome developing in association
with severe systolic hypertension above 160 mm Hg
may enhance the potential of cerebral blood vessels
to bleed when corticosteroids are absent from management. Among a highly selected group of 28
women with preeclampsia-induced severe systolic hypertension who had cerebral hemorrhage and stroke,
18 (64%) had evidence for concurrent class 1, 2, or 3
HELLP syndrome before the cerebral catastrophe
and no patient had been a recent corticosteroid recipient.181 None of 54 patients dying with HELLP syndrome in the Isler series received corticosteroids,
many of whom had CNS pathology.138 Corticosteroids use was not described in 104 patients from
France with a 79% complication rate in the class
1 HELLP category,106 or in recent series from Germany, China, and Turkey with high rates of maternal
morbidity,130,182,183 and they were usually absent
from the management of patients with signiﬁcant
maternal morbidity reported before 1990.6-17
Aggressive corticosteroids can eﬀect an increase in
platelet count suﬃciently to undertake regional
anesthesia (from 0% to 42%) and to enable cervical
ripening, induction of labor and vaginal delivery.184,185 Up to 75% of patients with HELLP
Martin, Rose, and Briery
syndrome can become candidates for regional anesthesia after high-dose corticosteroid administration
if a platelet threshold of 75,000/mL is deemed
adequate, and a higher rate of vaginal delivery can
be accomplished than would otherwise be possible
especially in relatively preterm gestations.185 In the
absence of corticosteroid use, the cesarean rate is
high and vaginal delivery is a rare event.128,186
A recent prospective randomized clinical trial undertaken in the authors’ hospital found no clear treatment
beneﬁt with postpartum high-dose dexamethasone
for puerperal patients with non-HELLP severe preeclampsia at diagnosis.187 The only 2 patients to subsequently have postpartum HELLP syndrome develop
were in the placebo group, and both responded quickly
to the emergent initiation of IV dexamethasone after
study assignment as placebo was ascertained.
Choice of corticosteroid
Although approximately equivalent in potency, IV dexamethasone appears to be more eﬀective than IM
betamethasone, perhaps by delivering the drug directly
into the vasculature of the aﬀected organ systems.163,188
Preferences for other regimens by others were listed
earlier. Sibai recommends an aggressive corticosteroid
regimen similar in potency to the Mississippi protocol
(dexamethasone 10 mg IV every 12 hours) for antepartum HELLP syndrome to improve maternal status,
using 2 doses of either betamethasone 12 mg IM every
12 hours (instead of every 24 hours) or dexamethasone
12 mg IV (instead of 5 or 6 mg) every12 hours with delivery to be accomplished within 24 hours after the last
dose of corticosteroids.22 Determination of preferred
drug, dosage, and regimen speciﬁc to clinical circumstances awaits large multicenter studies.
923
long-term potentially adverse implications to the newborn infant remain a question.172,190-192 Lower birth
weight, lower head circumference, neonatal adrenal
suppression, and increased infection are theoretical risks
to a newborn infant exposed to even a very short course
of high-dose corticosteroids, but evidence for this is
lacking. Potent glucocorticoids used for pregnancies
with HELLP syndrome may actually impart a fetal advantage because placental vascular resistance by Doppler assessment appears to be reduced brieﬂy in
singleton and multiple gestations after maternal betamethasone administration.193,194 In pregnant ewes receiving extended dexamethasone prenatally (20 days
with 20 mg/kg maternal body weight), no evidence of
altered renal function or predisposition to adult hypertension compared with controls was found.195
Summary
Despite current limitations in sample size and study
structure, a consistent positive picture of patient beneﬁt
emerges from a review of the present literature that we
suspect will be shown deﬁnitively once large multicenter
clinical trials are undertaken. This is consistent with our
considerable bedside experience gained over many years
and in a multitude of patient circumstances and situations that a routine practice of initiating aggressive
corticosteroids early in HELLP syndrome pregnancies
will prevent them from progressing along a continuum
of worsening morbidity, a critically important concept
for clinicians to embrace to reduce maternal mortality
rates in patients with this disease.196 In view of the
absence of a demonstrated downside to this approach
either for the mother or the fetus, given the body of
aﬃrmative available literature, we believe it most beneﬁcial to patients now to be managed according to the
recommendations that follow.
Potential maternal-fetal risks
Potential maternal risks include rebound thrombocytopenia, adrenal suppression, infection, and the masking
of potential complications or other disease processes.
The available data are insuﬃcient to estimate if there
are any adverse short- or long-term neonatal-infant
eﬀects from brief aggressive corticosteroids for HELLP
syndrome. Neither dexamethasone or betamethasone
is preferable from the fetal perspective in regard to
short-term outcomes.189 The use of aggressive corticosteroids for antepartum HELLP syndrome is recommended exclusively as a short-term intervention;
continuation of pregnancy after more than 48 hours of
aggressive corticosteroid administration for very preterm HELLP syndrome pregnancy can lead to signiﬁcant maternal and fetal morbidity and mortality.149
Evidence is meager (few case reports) regarding corticosteroid prolongation for many days to weeks of a previable HELLP syndrome pregnancy to viability, and
Fundamentals of practicedThe application
of aggressive corticosteroids
The fundamental management concepts for treatment of
patients with HELLP syndrome using aggressive corticosteroids is presented in core concepts (Table VI) and
as an algorhythm (Figures 2 and 3). Further considerations are discussed in paragraphs to follow.
In any patient suspected of having HELLP syndrome, basic laboratory evaluation includes a complete
blood count with platelets, serum AST, and total serum
LDH. Extended assessment can include serum creatinine, glucose, bilirubin, coagulation studies, and a
peripheral smear. Elevation of direct bilirubin and
prolongation of coagulation studies out of proportion
to mild thrombocytopenia occurs early in patients with
AFLP but is unusual with HELLP syndrome unless the
disease is very advanced (class 1).
924
Table VI
Martin, Rose, and Briery
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 immediately
indicated or can be delayed while aggressive corticosteroids are used to accelerate fetal lung maturation, enhance maternal status,
and optimize conditions either for vaginal or abdominal delivery to occur.
Aggressive corticosteroids clearly benefit the mother with HELLP syndrome according to stage of disease when drug therapy is
initiated, agent used, amount and route of administration.
A proactive, preventative early aggressive application of corticosteroids for the patient with antepartum or postpartum HELLP
syndrome probably realizes the greatest maternal benefit regardless of gestational age (Figures 2 and 3).
The patient with HELLP has severe preeclampsia and is managed accordingly with intensive surveillance and care during the
peripartum interval, including magnesium sulfate and aggressive antihypertensive therapy to minimize systolic blood pressures
above 160 mm Hg.22,170
The CNS is the most commonly affected system in mothers dying from HELLP syndromedthe aggressive use corticosteroids and
antihypertensives probably lessens the risks of stroke and death. Early aggressive corticosteroids may also lessen hepatorenal
morbidity.
Aggressive corticosteroids in patients with HELLP syndrome increases the 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 than
48-72 h (regardless of gestational age) are undertaken at some risk to mother and child.
The clinician must be mindful that the patient considered to have HELLP syndrome may have some other disorder, especially AFLP
that is relatively uncommon but has a much worse prognosis.
An aggressive corticosteroid regimen is initiated as
soon as the diagnosis of class 1 or 2 HELLP syndrome is
made or if the patient has complicated class 3 HELLP
syndrome. Continuation during cervical ripening and
induction of labor can be used to facilitate attempted
vaginal delivery or to improve the mother’s hematologic
status before abdominal delivery. If the fetus is preterm
and previable such that cesarean delivery is not a fetal
consideration, presence or absence of fetal heart tones
is assessed intermittently to determine whether a neonatal team should be summoned at delivery to assess the
reasonableness of resuscitation eﬀorts. Rarely a pregnancy with borderline viability has been prolonged
with aggressive corticosteroids but this is not usually
recommended.190-192,197,198 It is particularly discouraged
in a patient with a fetal abnormality or major maternal
morbidity such as renal failure.199 HELLP syndrome
detected before fetal viability may identify a pregnancy
complicated by partial mole/triploidy,200 trisomy 13,201
antiphospholipid syndrome,87 autoantibodies to angiotensin AT(1)-receptor,202 or severe preterm preeclampsia with ‘‘mirror’’ syndrome.203
Maternal-fetal status, gestational age, presence of
labor, cervical Bishop score, prior maternal obstetric
history, and response to aggressive corticosteroids all
impact management of the patient with a preterm viable
fetus and HELLP syndrome. Immediate cesarean
delivery is not generally indicated or recommended; vaginal or cesarean delivery after 24 to 48 hours of corticosteroids are better options to achieve maximal maternal
and fetal beneﬁt.204 Vaginal delivery rates of 32% for
gestations less than 30 weeks, 61% at 30 to 31 weeks,
and 62% at 32 to 33 weeks (overall induction success
145/247 or 59%, 37% !28 weeks) can be achieved.186
Nevertheless, because vaginal delivery rates with
HELLP syndrome are below 50% for gestations less
than 30 weeks, Sibai22 advocates elective cesarean delivery for all women diagnosed with HELLP syndrome at
a gestation age less than 30 weeks when spontaneous
labor is not present and the Bishop score is less than 5.
A patient with a low Bishop score in association with
fetal growth restriction and/or oligohydramnios may
not be a good candidate for trial of labor. Otherwise,
vaginal delivery is attempted in patients in active labor
less than 30 weeks with ruptured membranes or with a
Bishop score 5 or more in the absence of obstetric contraindications. Once the 30-week gestational age threshold is reached, an attempt at vaginal delivery is usually
recommended while aggressive corticosteroids are
initiated.
Epidural or spinal anesthesia is the preferred anesthetic for patients with preeclampsia.205 Approximately
50% of patients with HELLP syndrome can be candidates for regional anesthesia during a trial of labor using
Martin, Rose, and Briery
925
Figure 2
HELLP management algorithm: aggressive corticosteroids.
a threshold of 100,000/mL platelets.187 In these circumstances, the decision of abdominal versus vaginal
delivery becomes more of an obstetric issue rather
than a response to a rapidly worsening maternal-fetal
condition. Furthermore, patients who receive regional
anesthesia avoid the greater risks associated with general anesthesia. When motivated, providers can depend
on corticosteroids to improve maternal platelet counts
suﬃciently to increase the epidural rate for patients
with HELLP syndrome from 0% to 57%.184 When cesarean delivery without trial of labor is planned, waiting
approximately 6 hours after beginning an aggressive
corticosteroid regimen is recommended to stabilize the
disease process, improve laboratory parameters, enable
institution of regional anesthesia, and reduce the need
for platelet or red cell transfusion. Given the absence
of neurologic or hematologic complications with regional anesthesia in HELLP syndrome patients managed in Panama without corticosteroids or platelet
count restrictions, the likelihood of bleeding complications with regional anesthesia is small.205
Aggressive corticosteroid administration is associated
with a signiﬁcant decrease in the required use of blood
products21 and consequently a secondary decrease in infectious morbidity. When emergent cesarean delivery
must proceed without waiting for a steroid eﬀect and/
or in the rare patient with advanced disease and a
platelet count less than 40,000/mL that is unresponsive
to corticosteroid use, platelet transfusion of 6 to 10 units
of platelets is recommended immediately prior to
intubation.206
Prevention of severe systolic hypertension (O160 mm
Hg) is paramount; recommendations to maintain systolic pressures under 155 mm Hg and diastolic pressures
under 105 mm Hg are reasonable goals.22,181 Labetolol,
hydralazine, or nifedipine are the preferred agents for
treatment of acute hypertension in this setting with
infused dilute nitroglycerin held in reserve.207
There have been no randomized trials of cesarean
operative technique for patients with HELLP syndrome.
Delayed skin closure or type of skin incision do not
appear to inﬂuence the frequency of wound complications.208 In the absence of postpartum aggressive corticosteroids, a high incidence of hematoma formation
can occur despite placement of a subfascial drain and
keeping the skin incision open for 48 hours.22
Most of the fundamental principles of management
for patients with antepartum HELLP syndrome apply
equally to postpartum/postoperative patients. Newonset postpartum disease appears usually within the
ﬁrst days after delivery and is treated with aggressive
corticosteroids similar to antepartum disease.21,170,171
The treatment is tailored to the patient; corticosteroid
dosage is reduced once an upward trend in platelets and
926
Martin, Rose, and Briery
Figure 3
Class 3 or incomplete/partial HELLP syndrome.
a downward trend in total serum LDH is recorded, and
discontinued with normalization of HELLP laboratory
parameters and resolution of signs and symptoms of
preeclampsia.
Signiﬁcant renal injury is infrequently encountered
in patients with HELLP syndrome unless placental
abruption or a major hemorrhage also occurs.209 Most
often renal dysfunction responds to measures short
of dialysis or only a brief course of dialysis.19,209,210
Because a convincing renal beneﬁt to aggressive corticosteroids has not been demonstrated, the basic patient
management principles for patients with acute renal
failure are used.211
Almost all instances of spontaneous subcapsular
hematomas or hepatic rupture in pregnancy occur in
association with HELLP syndrome.212-214 As thrombocytopenia worsens into the lowest ranges (class 1), in
conjunction with the onset of sudden epigastric pain,
the likelihood of ﬁnding abnormal hepatic imaging
with computed tomography or magnetic resonance
imaging increases. For reasons given earlier, we speculate that it beneﬁts patient care to immediately begin aggressive corticosteroids for any patient with suspected
HELLP syndrome and having hepatic injury develop,
regardless of disease class. Several excellent treatises
have been published recently that review the management of HELLP-related hepatic complications such as
hepatic rupture.129,212-217
Beyond corticosteroids
Plasma exchange or plasma infusion have been used
sparingly for recalcitrant and/or complicated HELLP
syndrome that is unresponsive to standard therapy.83,218-224 Some of the postulated mechanism of
actions include (1) clearance from the circulation of
debris, toxins, antigen-antibody complexes, damaged
red cell components or other substances that may be
compromising normal coagulation and organ function;
and (2) replacement of ﬂuid, clotting factors, proteins,
and other plasma components that are required to
achieve homeostasis and healing. Prevention of intravascular ﬂuid overload is enhanced versus straight transfusion, particularly in the patient with compromised renal
function. Collaborative care with intensivists and hematologist/transfusion medicine subspecialists is imperative. Because patients in these circumstances are rare,
unique, and diﬃcult to accurately quantify, randomized
Martin, Rose, and Briery
927
clinical trials are unlikely to be undertaken or even feasible. Thus, the role of plasma exchange in HELLP syndrome management remains controversial but less
frequently a concern we speculate because of early diagnosis and aggressive corticosteroids.
There is little evidence suggesting eﬃcacy to the use
of heparin,178,225 activated factor VII,226 or haptoglobin227 for treatment of HELLP syndrome. Attempted
prolongation of pregnancy with hydration and antihypertensives is not recommended because it is associated
with increased maternal and perinatal morbidity related
to placental abruption and hepatic rupture.80,228
(!32 weeks).234 To date, anything other than close
monitoring of subsequent pregnancies for problems of
prematurity and preeclampsia (preterm labor, bleeding,
fetal growth restriction) has not been superceded by
speciﬁc testing or augmented by eﬀective preventative
measures. Testing for LCHAD mutation (long-chain
3-hydroxyacyl coenzyme A dehydrogenase deﬁciency)
is rarely positive in patients with HELLP syndrome in
contrast to the situation with AFLP235-237 and therefore
not recommended.238
Prognosis: Recovery
An expanded, more inclusive disease classiﬁcation
system for HELLP syndrome is needed particularly if
the potential for early aggressive corticosteroids to avert
most signiﬁcant maternal morbidity is to be studied
adequately in appropriately structured, large multicenter clinical trials. Some form of a composite maternal
morbidity index also is needed to better describe the
spectrum of systemic morbidity potentially experienced
by mothers with this condition. As expected with a
disease process with variable rates of progression, different stages at initial presentation, alteration by various
interventions, and characterization by inconsistent and
variable laboratory methodologies, there has been a lack
of consensus among researchers and confusion among
clinicians. The issue of standardization of diagnosis
and disease classiﬁcation is an important goal, so that
research ﬁndings are comparable and recommended
clinical managements can become progressively more
evidence based.
We believe that the scientiﬁc community is on the
threshold of a much better understanding of the pathogenesis of HELLP syndrome speciﬁcally and preeclampsia-eclampsia in general. Knowledge of the ﬁndings
related to the pathogenesis and pathophysiology of
this disorder and the ameliorating eﬀect of corticosteroids on the disease process is foundational to understanding the challenges of diagnosis, classiﬁcation, and
management. A patient can present initially anywhere
along the spectrum of disease development, and disease
expression is inﬂuenced by whether corticosteroids have
been given for any reason. Thus, the accurate interpretation of any publication about HELLP syndrome
requires a clear description of when in the development
of HELLP syndrome laboratory or research testing was
performed to study its pathogenesis or make its clinical diagnosis, including a statement of the presence or
absence of corticosteroids during patient management
ideally noting at what stage in disease these agents and
dosages were given to the patient. Large-scale multicenter trials investigating various corticosteroid regimens
for patients with this spectrum of HELLP syndrome
conditions are desirable (including various types that
cross or do not cross into the fetal circulation63), with
Patients with HELLP syndrome usually recover completely, although relapses can occur in the absence of
corticosteroid administration.224 After-eﬀects of disease
can persist for extended periods if hepatic or renal damage has occurred.229 Long-term follow-up of mothers
and children from HELLP syndrome pregnancies are
few in number. Renal function was not permanently impaired in 23 women with acute renal failure and HELLP
syndrome who were monitored an average of 4.6 years;
8 patients had 11 subsequent pregnancies, 9 of which
were term gestations.230 Similar normalization of renal
function after a HELLP syndrome pregnancy was
reported by Jacquemyn’s Belgian group,229 but higher
systolic and diastolic blood pressures were observed at
5 years compared with controls. In Amsterdam, the incidence of subsequent hypertension requiring treatment
was 3 times higher than controls.230 In the absence of
acute renal failure, there was no detectable impairment
of renal function at least 5 years after HELLP syndrome
in 10 patients. Stroke in patients with HELLP syndrome
left residual defects in 10 of 13 patients (77%) who survived the acute insult.181 No permanent adverse eﬀects
on liver function have been reported. Emotional trauma,
both immediate and delayed, can be a signiﬁcant patient
issue.231,232
Patient counseling: Future pregnancy
Women with a prior history of HELLP syndrome carry
an increased risk of at least 20% (range 16%-52%) that
some form of gestational hypertension will recur in a
subsequent gestation. The rate of recurrent HELLP
syndrome itself varies between 2% and 19% depending
on the population studied, gestational age at onset,
whether there is concurrent vascular disease of any type,
and very likely the unique genetic proﬁle of the individual patient, her partner, and her progeny.233,234
In the Mississippi study with a 75% African-American
proﬁle, the recurrence risk was 42% to 43% for any type
of preeclampsia-eclampsia, but this increased to 61%
if the preceding aﬀected pregnancy was very preterm
Challenges and conclusions
928
particular attention to deﬁne beneﬁts and limitations
according to the stage and circumstances in which therapy is initiated. Risk factors for severe renal and hepatic
complications of HELLP syndrome require further
investigation with regard to concurrent predisposing
conditions such as antiphospholipid syndrome. Although short-term utilization of corticosteroids as currently used has not been shown to negatively impact
the fetus or neonate, surveillance for possible adverse
eﬀects should continue. We believe that widespread dissemination of the information presented herein to practicing cliniciansdbetter recognition through cognition
and a management scheme focused on early aggressive
corticosteroid administrationdis needed now to minimize maternal-perinatal morbidity and mortality with
this condition while more extensive study continues.
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