Hypertension in Pregnancy, 31:7990, 2012

Copyright Informa Healthcare USA, Inc.

ISSN: 1064-1955 print/1525-6065 online
DOI: 10.3109/10641955.2010.525277

Standardized Mississippi Protocol

1525-6065
1064-1955
LHIP
Hypertension in Pregnancy
Pregnancy, Vol. 1, No. 1, Sep 2010: pp. 00

Treatment of 190 Patients with HELLP

Syndrome: Slowing Disease Progression
and Preventing New Major Maternal
Morbidity
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Mississippi
Martin et al.Protocol Management of HELLP Syndrome

James N. Martin Jr. MD, Michelle Y. Owens MD, MS,

Sharon D. Keiser MD, MS, Marc R. Parrish DO,
Kiran B. Tam Tam MD, Justin M. Brewer MD,
Julie L. Cushman RN, and Warren L. May PhD
Division of MaternalFetal Medicine, Department of Obstetrics and Gynecology, and
the Biostatistics Center, University of Mississippi Medical Center, Jackson, MS, USA

Objective. To evaluate the effectiveness of the Mississippi Protocol (MP) to treat

For personal use only.

HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Methods.
Uniform early initiation of MP (corticosteroids, magnesium sulfate, systolic blood pres-
sure control) was studied prospectively in patients admitted with severe preeclampsia/
class 1 or class 2 HELLP syndrome. Results. One hundred and ninety patients between
2000 and 2007 received MP without suffering maternal death, stroke, or liver rupture.
Only 39 of 163 patients (24%) not class 1 when MP began progressed to class 1 disease;
only 18.2% of class 1 and 2.4% of class 2 subsequently developed major maternal
morbidity. Conclusion. Early initiation of MP inhibits HELLP syndrome disease
progression and severity.

Keywords HELLP syndrome, Hypertension, Preeclampsia, Thrombocytopenia.

INTRODUCTION
One of the most feared presentations within the pantheon of preeclampsia-
related disease affecting the obstetric patient is the development of HELLP
(hemolysis, elevated liver enzymes, and low platelets) syndrome, a form of
severe preeclampsia/eclampsia manifested by laboratory evidence of hepatic
dysfunction and damage, microangiopathic hemolytic anemia, and thrombocy-
topenia (14). The risk of serious morbidity correlates in general with increas-
ingly severe signs, symptoms, and laboratory abnormalities. This is
fundamental to the development and clinical utilization of the Mississippi
three-class system for patient management with HELLP syndrome pregnan-

Presented at the Central Association of Obstetricians and Gynecologists 76th Annual

Meeting, Wailea, Maui, Hawaii, October 2528, 2009.
Address correspondence to James N. Martin Jr., Division of MaternalFetal Medicine,
Department of Obstetrics and Gynecology, and the Biostatistics Center, University
of Mississippi Medical Center, Jackson, MS 39216, USA. E-mail: jnmartin@ob-gyn.
umsmed.edu
 80 Martin et al.

cies (2,4). Because maternal morbidity is greatest and maternal mortality is

most likely when HELLP syndrome deteriorates to a class 1 designation, a
fundamental tenet of management is a protocol to prevent disease progression
once diagnosed. Delivery is the cornerstone of therapy because it removes the
placenta from the mothers uterus and eliminates placental production of
factors important in the pathogenesis of the disorder. During the induction
and delivery process as well as the early puerperium, magnesium sulfate is
given intravenously to the patient to reduce systemic vascular resistance and
to prevent eclamptic seizures, and antihypertensives are utilized to prevent
stroke and other complications related to severe systolic and/or diastolic
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hypertension (46).
Retrospective casecontrol studies and small prospective randomized trials
in the early 1990s suggested that use of certain corticosteroids, in addition to
seizure prevention and blood pressure control, appeared to benefit both perin-
atal and maternal care of patients with HELLP syndrome (4). Having
witnessed ongoing evidence of apparent intravenous dexamethasone efficacy
while caring for hundreds of HELLP syndrome patients managed from the
early 1990s onward, in addition to being aware of the high morbidity and
multiple complications of HELLP syndrome patients managed in the 1980s
without corticosteroid administration, the senior investigator increasingly
integrated the routine use of intravenous dexamethasone into the care of all
For personal use only.

patients developing evidence of HELLP syndrome after 1994 at the University

of Mississippi Medical Center. In combination with magnesium sulfate and
efforts to minimize severe systolic hypertension, these three therapies were
incorporated into a uniform, aggressively applied protocol of HELLP syndrome
management that was initiated at the beginning of 2000 as the Mississippi
Protocol (MP). The rationale and literature evidence to support this manage-
ment approach was summarized only recently (4). This report is the first sum-
mary of our experience with this expanded approach to further improving
patient outcomes with this form of severe preeclampsia.
The purpose of this report is to evaluate maternal and perinatal outcomes
with MP management of patients with a final diagnosis of complete class 1 or
class 2 HELLP syndrome who received tertiary care in our regional medical
center after 1999.

MATERIALS AND METHODS

All pregnant patients diagnosed with HELLP syndrome at the Winfred L.
Wiser Hospital for Women & Infants, University of Mississippi Medical
Center in Jackson after January 1, 2000, were prospectively managed by the
MP and considered for study inclusion. Data were entered into a much more
detailed and expanded database from that used (Mississippi HELLP
Syndrome Database) for prior studies (2,7). For this report, only patients who
satisfied all criteria to merit a final diagnosis of class 1 or class 2 HELLP syn-
drome were included. Patients with class 1 HELLP exhibited severe thromb-
ocytopenia with a perinatal platelet nadir 50,000/L, a total serum lactate
dehydrogenase (LDH) of 600 IU/L, and serum transaminase level of 70 IU/L
as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT).
 Mississippi Protocol Management of HELLP Syndrome 81

Evidence of red cell hemolysis was present with regard to abnormal cell forms or
fragments and the presence of urinary bilirubin or increased indirect biliru-
bin. Patients with class 2 HELLP syndrome had similar laboratory thresholds
to class 1, except for less profound thrombocytopenia (platelet nadir between
>50,000 and 100,000/L). All patients also had signs, symptoms, and labora-
tory findings that were consistent with a diagnosis of preeclampsia/eclampsia
during their antepartum/postpartum course. Patients who satisfied all crite-
ria to merit a final diagnosis of class 3 HELLP syndrome (mild thrombocy-
topenia with platelet nadir >100,000 but 150,000, total LDH 600 IU/L, and
AST or ALT 40 IU/L) or incomplete HELLP syndrome (only two of three
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platelet/LDH/AST criteria present) are excluded from this report. We empha-

size that a patients HELLP classification is dynamic and can change over
time; the most advanced class developed is the final diagnosis coded. If a
patient was originally considered to exhibit probable HELLP syndrome but
was subsequently determined to have a different disease process (HELLP
laboratory parameters developed secondary to thrombotic thrombocytopenic
purpura (TTP), disseminated intravascular coagulation (DIC), acute fatty
liver of pregnancy, connective tissue disease flare, vasoocclusive sickle cell cri-
sis, severe placental abruption, or sepsis-initiated hypoxic/hypovolemic shock
tissue injury particularly to the kidney), she was excluded from this report
and included in a separate publication for these uniquely complex patients (8).
For personal use only.

Major maternal morbidity incurred by any study patient includes any of

the following by category: cardiopulmonary complications of pulmonary edema,
pleural or pericardial effusion, required intubation with ventilator support, con-
gestive heart failure, myocardial infarction or arrest; hematologic/coagulation
complications of DIC (partial thromboplastin time 40 s and fibrinogen <200
mg/dL) or transfusion of blood products; central nervous system/visual compli-
cations of stroke, cerebral edema, hypertensive encephalopathy, or vision loss;
hepatic complications of subcapsular liver hematoma or rupture; and renal
complications if serum creatinine >1.2 mg/dL with acute tubular necrosis or
acute renal failure. Major perinatal morbidity includes any of the following:
respiratory distress syndrome, hyaline membrane disease, intraventricular
hemorrhage, 5-min Apgar 3, or arterial cord gas pH 7.0 at birth. Standard
diagnostic criteria for each entity were used and evaluated for accuracy for
each study subject.
The MP for management of HELLP syndrome (MPRx) includes three major
components: (i) magnesium sulfate by intravenous infusion primarily for
eclampsia seizure prophylaxis and reduction of systemic vascular resistance,
through delivery and up to 24 h postpartum with duration dependent on dis-
ease acuity and whether HELLP syndrome is first-evidenced postpartum; (ii)
blood pressure control using oral or intravenous medication (hydralazine or
labetalol) to sustain systolic blood pressure <160 mmHg and diastolic blood
pressure <100 mmHg; and (iii) intravenous dexamethasone 10 mg at 12-h
intervals until platelet normalization is trending toward 100,000/L at which
time 5 mg dexamethasone at 12-h intervals is administered twice intrave-
nously before cessation to minimize the risk of rebound thrombocytopenia.
Intravenous dexamethasone for patients with HELLP syndrome is initiated in
the following circumstance(s): (i) a diagnosis of class 1 or class 2 HELLP
 82 Martin et al.

syndrome is made ante- or postpartum; or (ii) a diagnosis of class 3 HELLP

syndrome is made in association with one of the following complications: (a)
eclampsia, (b) difficult to control severe systolic hypertension, (c) severe epi-
gastric pain, and/or (d) evidence of significant system/multiorgan compromise
involving the heart, lungs, kidneys, or central nervous system (4). This is
depicted in Figure 1. Intravenous dexamethasone for HELLP syndrome treat-
ment purposes is adequate for fetal lung maturation treatment purposes if fetal
lung immaturity is present. Once a diagnosis of class 1 or class 2 HELLP syn-
drome is made, the MP is begun with planned delivery to occur within 4872 h
to enable fetal lung maturation corticosteroid benefit to be achieved and for
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maternal laboratory parameters of HELLP syndrome to begin a normalizing

trend. With rare exception and not in this series, the so-called expectant
management is not undertaken even if gestational age is <2324 weeks. Once
completed, the findings in patients with final diagnoses of class 3 HELLP
syndrome or incomplete HELLP syndrome during the same time interval are
planned for later publication.
Implementation of the MP has five goals of therapy: (i) to prevent the
development of class 1 HELLP syndrome from class 2 or complicated class 3
HELLP syndrome; (ii) to minimize the development of major maternal mor-
bidity as defined; (iii) to prevent maternal mortality; (iv) to shorten the course
For personal use only.

Preeclampsia/Eclampsia/HELLP Syndrome
>16 weeks gestation

Class 1 or 2 HELLP Syndrome? Class 3 or Partial

(PLT <100K/uL, LDH>600 NO HELLP
YES Eclampsia?
AST/ALT>70, +Schistocytes, Syndrome?
Ind. Bili >1.2)
YES NO
NO
YES
Severe Hypertention
Difficult to Control,
INITIATE IV or CNS Symptoms?
DEXAMETHASONE CONSIDER IV
10mg IV q 12 DEXAMETHASONE YES
HOURS 10mg IV q 12 HOURS NO

YES Severe
Epigastric Pain?
YES

Continue Current NO
End-Organ Injury (renal,
Management without NO hepatic, CVS, CNS) and/or
IV Dexamethasone abruption-DIC?

Figure 1: Intravenous dexamethasone for patients with HELLP syndrome.

 Mississippi Protocol Management of HELLP Syndrome 83

of disease and the length of hospitalization; and (v) to minimize perinatal

mortality and major morbidity.
Data were collected and analyzed by appropriate tests for continuous (inde-
pendent samples t-tests, MannWhitney) or categorical (chi-square, Fishers
exact test) outcomes with differences considered significant if p < 0.05.

RESULTS
During the 8-year span between 2000 and 2007, 27,494 live births occurred in
the University of Mississippi Medical Center (Winfred L. Wiser Hospital for
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Women & Infants) including 190 patients who met the study inclusion criteria
and were treated with the MP (1 every 145 live births; 0.7%). No maternal
deaths, strokes, or liver ruptures occurred among 66 patients with class 1
(34.7%) and 124 patients with class 2 (65.3%) HELLP syndrome. Demographic
and delivery details are shown in Table 1 for the two class groups, and the
profile of presentation indicating disease severity in each group is detailed in
Table 2. Details of laboratory findings including the LDH to AST ratio are
shown in Table 3. Placental abruption occurred in 15.2% of class 1 and 8.1% of
class 2 HELLP patients (p = 0.14). Most of the 190 patients in the series had
antepartum-onset disease (85%).
Approximately 40% of the patients who developed complete class 1 HELLP
For personal use only.

syndrome (27 of 66 or 40.9%) had met criteria for the most advanced stage of
disease at the time of transfer and/or hospital admission. Following the initia-
tion of MP, only 39 of the other 163 patients with class 2 HELLP syndrome
progressed to class 1 (23.9%). Major maternal morbidity was present at
admission in 33.3% versus 9.7% of the class 1 and class 2 groups, respectively
(p < 0.001); following admission and MP initiation, only 18.2% of class 1 versus
2.4% of class 2 HELLP patients (p < 0.001) developed new onset major mater-
nal morbidity (see Table 4).

Table 1: Maternal demographics and delivery data for patients with a FINAL diagnosis of
class 1 or class 2 HELLP syndrome.

Class 1 HELLP Class 2 HELLP

Final diagnosis of syndrome syndrome p-Value

N 66 patients 124 patients

Maternal age at delivery (years) 24.6 5.6 24.2 6.1 NS
Maternal weight at admission (lbs) 183 57 189 47 NS
Maternal BMI at admission 32 9 32 7 NS
Race/ethnicity (% African-American) 74% 78% NS
Nulliparous 47% 58% NS
Multiparous 59% 52% NS
Gestational age at delivery (weeks) 30.7 4.5 31.2 5.1 NS
Cesarean delivery 67% 60% NS
Prior cesarean delivery 15% 15% NS
Patient transfer to UMMC for care 86% 84% NS

Note: Means are 1 SD; NS, Non-Significant difference with p > 0.05.
 84 Martin et al.

Table 2: Admission signs and symptoms before initiating Mississippi Protocol (MP) treatment.

Class 1 HELLP Class 2 HELLP

Final diagnosis of syndrome syndrome p-Value

N 66 patients 124 patients

Systolic blood pressure (mmHg) 150 21 154 19 NS
Diastolic blood pressure (mmHg) 90 18 94 15 NS
Mean arterial pressure (mmHg) 110 18 114 15 NS
Dipstick proteinuria (1+ or 2+) 24% 13% NS
Dipstick proteinuria (3+ or 4+) 53% 55% NS
Hematuria (micro/macro) 32% 23% NS
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Nausea/vomiting 33% 15% 0.0041

Epigastric pain 30% 14% 0.006
Headache 50% 51% NS
Visual impairment 12% 15% NS
Facial edema 14% 13% NS
Eclampsia 6% 4% NS
Uric acid >5.5 mg/dL (%) 76% 69% NS
LDH 600 IU/L 100% 89% 0.0026
AST 70 IU/L 68% 49% 0.0142
ALT 70 IU/L 44% 23% 0.0034
Creatinine > 1.2 mg/dL 12% 9% NS
Platelet count 50,000/L 41% 0% <0.001
Platelet count >50,000 100,000/L 24% 53% <0.001
For personal use only.

Platelet count >100,000 150,000/L 21% 24% NS

Platelet count >150,000/L 14% 23% NS

Note: The values reported above are the ADMISSION values for patients who eventually
achieved a FINAL diagnosis of class 1 HELLP syndrome or class 2 HELLP syndrome; NS,
Non-Significant difference with p > 0.05.

Table 3: Peak severity of laboratory values according to FINAL HELLP syndrome

classification.

Class 1 HELLP Class 2 HELLP

Final diagnosis of syndrome syndrome p-Value

N 66 patients 124 patients

Platelet nadir (L) 34,800 12,500/L 75,500 14,200/L <0.001
Peak total LDH (IU/L) 5288 4190 IU/L 2553 3329 IU/L <0.001
Peak AST (IU/L) 671 743 IU/L 319 695 IU/L 0.0014
LDH: AST ratio (mean) 15.4 15.4 17.3 13.5 NS
LDH: AST ratio (range) 1.1 88.4 1.6 62.2 NS
Uric acid (mg/dL) 7.5 2 7.2 2 NS
Creatinine (mg/dL) 1.25 0.9 0.99 0.8 0.0396

Note: NS, Non-Significant difference with p > 0.05.

With regard to interventions, 47% of patients in class 1 received blood

product transfusions of some type versus 11.3% in class 2 (p < 0.001); after
admission and initiation of MP, only 4.6% of patients in class 1 required
platelet transfusions versus 22.7% who had received them before transfer and
initiation of MP. One patient who developed criteria to merit a final diagnosis
of class 2 HELLP group had a subcapsular liver hematoma noted before hospital
 Mississippi Protocol Management of HELLP Syndrome 85

Table 4: Major maternal morbidity pre- and post-MP initiation.

Class 1 HELLP Class 2 HELLP

Final diagnosis of syndrome syndrome p-Value

N 66 patients 124 patients

Pre-MP/hospital admission 22/66 (33.3%) 12/124 (9.7%) <0.001
Hematologic/coagulation 21 12
Cardiopulmonary 3 1
CNS/visual 0 0
Renal 3 1
Hepatic 0 1
During MP/hospitalization 12/66 (18.2%) 3/124 (2.4%) <0.001
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Hematologic/coagulation 10 2
Cardiopulmonary 1 1
CNS/visual 0 0
Renal 2 0
Hepatic 0 0

Note: MP, Mississippi Protocol treatment.

transfer and initiation of MP; at the time of diagnosis of the liver hematoma
the patient met class 3 HELLP syndrome criteria. All patients in the series
received intravenous dexamethasone; most patients (71.2% in class 1, 78.2%
For personal use only.

in class 2) had them initiated antepartum, the remainder intrapartum or post-

partum with one exception (a patient barely meeting criteria for class 2
HELLP syndrome). Magnesium sulfate was administered to 98.8% of patients
in this series; antihypertensives were required in 43.9% of class 1 patients
and 41.1% of class 2 to reduce systolic blood pressure to less than 160 mmHg,
an insignificant difference. Length of hospitalization before delivery did not dif-
fer between class 1 and class 2 groups (mean 12.5 vs. 14 h, p = 0.39); length of
hospitalization following delivery, however, was significantly longer in class 1
patients than in class 2 (mean 108 vs. 96 h, 4.5 vs. 4 days, p < 0.001).
Important perinatal outcomes for class 1 and class 2 HELLP syndrome preg-
nancies, respectively, included mean birthweights (1348 691 g, 1531 942 g),
major perinatal morbidity (59.1%, 55.7%), and perinatal mortality (197 : 1000
vs. 186 : 1000) based on 19.7% stillbirths and no neonatal deaths in the class
1 group and 12.1% stillbirths and 6.5% neonatal deaths in the class 2 group.
All stillbirths happened before hospital admission or during labor in a patient
deemed to be not a candidate for cesarean delivery for reasons of extreme
prematurity. The high perinatal mortality rate for both groups was negatively
impacted by the 17 mothers (6 in class 1 and 11 in class 2) who required
delivery before 24-week gestation.

DISCUSSION
The current investigation, adding emphasis on reducing systolic blood pres-
sures to less than 160 mmHg in addition to intravenously infused magnesium
sulfate and dexamethasone, further expands upon the reported experience of
our institution with HELLP syndrome which previously spanned the years
between the early 1980s and 2000. After the failure in 1999 of a proposal to
 86 Martin et al.

NIH to fund a 26-center prospective randomized and placebo-blinded trial

involving 1000+ patients with class 1 and class 2 HELLP syndrome to com-
pare intravenous dexamethasone versus placebo administration upon
antepartumpostpartum, pretermterm, and disease progression issues with/
without major maternal morbidity, we initiated the present single institution
series to explore how well an expanded MP might help achieve the five goals
of HELLP syndrome therapy in a variety of clinical circumstances. Uniform,
early, and aggressive application of the MP as described for the management
of patients with HELLP syndrome usually resulted in successful maternal
outcomes. Only patients with a final diagnosis of class 1 or class 2 HELLP
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syndrome as severe preeclampsia were considered in this report, and the pro-
tocol therapy was begun quickly as soon as a diagnosis was made; 85% of
cases had treatment initiated before delivery. This series achieved four of five
goals: absence of maternal mortality, a reduction of major maternal morbidity
to <20% in class 1 and <5% in class 2, a low rate of class 3 or class 2 HELLP
syndrome disease progression to the most advanced disease class 1 HELLP
syndrome in patients managed with this protocol, and a mean length of hospi-
talization following delivery of only 44.5 days. A fifth goal of improved perin-
atal outcome was not clearly achieved; poor perinatal outcome because of
extreme prematurity remains a significant concern with this disease entity
regardless of treatment(s) employed. The overall value of the clinical strategy
For personal use only.

using corticosteroids (intravenous dexamethasone) as an early and integral

component of care for patients with HELLP syndrome is again affirmed in
this latest series of 190 patients among more than 400 patients so managed in
this tertiary care center since the early 1990s.
Between the initiation and conclusion of the present 8-year observational
trial, two large prospective randomized clinical trials using intravenous dex-
amethasone versus placebo in patients with HELLP syndrome have been
reported. The first, undertaken in Columbia by Fonseca and colleagues with
132 patients, has been severely criticized for multiple shortcomings that ren-
der untenable their conclusion that dexamethasone treatment does not
improve the outcome of women with HELLP syndrome (9). Indeed, close
inspection of the data demonstrated that patients with class 1 HELLP
syndrome who received intravenous dexamethasone recovered significantly
faster than the untreated control group, suggesting that the sickest patients
benefit the most from this treatment (4,10). The second trial, undertaken in
Brazil by Katz et al. in 105 patients, likewise is seriously flawed because of
inclusion of HELLP syndrome patients who were not class 1 or class 2, a
lack of stratification of case outcome into classes of disease so that class 1
disease response to therapy could be evaluated, delay of drug initiation until
postpartum after most disease morbidity is already established, small
patient numbers, and inclusion of patients in the control group that had
recently received corticosteroids for fetal lung maturation purposes (11).
Moreover, their complication rates for transfusion, renal failure, and mater-
nal death in both treatment and placebo groups were substantially higher
than those witnessed in the present or prior series reported from our mater-
nalfetal unit. In the absence of a single, very large, well-constructed multi-
center prospective blinded and placebo-controlled clinical trial undertaken
 Mississippi Protocol Management of HELLP Syndrome 87

in the United States with CONSORT guidelines and a professional external

trial monitoring group to assure compliance and accuracy, debate about the
clinical value of this third component to care of the patient with HELLP syn-
drome will continue and divide the subspecialty of maternalfetal medicine
into the users and nonusers of this treatment modality (12). Clearly, the con-
clusion stated by the authors of these two trials that intravenous dexam-
ethasone offers no benefit to patients with HELLP syndrome is invalidated
by weak data.
The principle of limiting HELLP syndrome progression with the MP is an
important concept to emphasize. A strength of the Mississippi classification of
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HELLP syndrome is its assignment of patients into three classes of progres-

sively worsening disease from class 3 (mild) to class 1 (most severe) (4). Use of
this classification allows the clinician to better appreciate the magnitude of
illness and the peril to a particular patient, analogous to systems in place to
stratify disease severity for patients with diabetes mellitus or hypertension.
In addition, it allows the clinician and the investigator to better appreciate the
impact of any therapeutic intervention(s) upon the course and progression of
disease. Following initiation of MP, only 18.2% of patients who developed
class 1 HELLP syndrome had evidence of new major maternal morbidity, com-
pared with 33.3% present on admission. Similarly, the numbers were 2.4%
versus 9.7% for patients in class 2. A substantial number of patients did not
For personal use only.

progress beyond class 2 HELLP to class 1, likely in part because of Protocol

management. The highest maternal morbidity, particularly in the cardiopul-
monary system, occurs in patients with class 1 HELLP syndrome (2,4). Hence,
arrest of disease progression to prevent the development of class 1 HELLP
syndrome is a major therapeutic goal of treating any patient with HELLP syn-
drome. Early initiation of intravenous dexamethasone, especially when used
in association with the other components of MP, provides the clinician with a
tool to interdict HELLP syndrome disease progression until removal of the
placenta and associated pregnancy decidua from the mother through timely
delivery can be accomplished.
As emphasized recently by Vigil-deGracia, developing HELLP syndrome
places any woman at significant risk of mortality (13). In both of the major
published reviews on maternal mortality related to HELLP syndrome (13,14),
maternal death had major contributing factors of cerebral hemorrhage and
other serious multisystem disease developing typically in clinical circum-
stances of delayed diagnosis of HELLP syndrome, absence of early intrave-
nous dexamethasone initiation, and absence of successful prevention of severe
elevations of blood pressure (systolic, diastolic, mean arterial). Central ner-
vous system hemorrhage is the single most common cause of maternal death
in patients with HELLP syndrome pregnancies. As demonstrated recently in
28 patients with stroke and severe preeclampsia/eclampsia, the prevention of
severe systolic hypertension is likely very important to the possible preven-
tion of these deaths and residual disabilities (6). The absence of maternal
death in the present 8-year, 190-patient series stands in stark contrast to the
five largest, most recent published series of patients with HELLP syndrome
since 2005 in which there were 21 maternal deaths among 215 patients
treated by other protocols of management (1519).
 88 Martin et al.

Importantly, excluded from this study were patients that exhibited laboratory
criteria of a HELLP-like syndrome that developed secondary to a variety of other
medical [TTP, DIC, prolonged hypoxemia/hypotension with unsuccessful intuba-
tion for general anesthesia, systemic lupus erythematosus (SLE)/scleroderma,
sickle cell crisis with complications] and obstetrical (catastrophic placental
abruption with fetal demise and renal insult, acute fatty liver of pregnancy) com-
plications apart from severe preeclampsia/eclampsia. Between 1994 and 2008 we
treated 11 patients as described. In each instance, plasma exchange therapy dur-
ing the postpartum period was initiated to facilitate maternal recovery and in
most cases (8/11) the mother survived (20). Another patient excluded from this
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investigation was reported in 2006 to have either HELLP syndrome or TTP mas-
querading as HELLP syndrome (8). Because the ADAMTS13 activity level <5%
was not drawn until postmortem, it is now known to be invalid for differential
diagnosis; the patient suffered a cardiopulmonary arrest and sudden renal dete-
rioration before plasma exchange could be initiated.
It is conceptually erroneous to assume that almost all serious maternal
morbidity with HELLP syndrome does not develop until the mother
progresses through class 3 and class 2 to the stage of class 1 HELLP syndrome
(4). It appears that both hepatic and renal morbidity are initiated well in
advance of the mother evidencing severe thrombocytopenia and other criteria
for class 1 or class 2 HELLP syndrome it is instead more likely that these
For personal use only.

complications arise subsequent to adverse action on tissue by pathogenic fac-

tors released from the placenta, which subsequently produce the laboratory
and clinical information we require presently to make the diagnosis (21). This
series is again illustrative of this inasmuch as the only patient to reveal evi-
dence of a liver hematoma did so while her platelet count was >100,000/L; it
is possible that initiation of the corticosteroid component of MP was instru-
mental in stabilizing hepatic tissue deterioration and preventing progression
of the hematoma to the stage of rupture. Given the large number of case
reports of hepatic rupture with HELLP syndrome in the absence of early
intravenous dexamethasone initiation that have appeared in the recent
obstetric literature (more than 20 reports in the last 5 years) and the recent
publication of two case series of liver transplantation for patients with
HELLP syndrome (22,23), the avoidance of liver rupture in the present series
of 200 patients is very significant.
Perinatal outcome with HELLP syndrome remains very problematic
because many patients present with disease requiring delivery prior to a ges-
tational age that is highly likely to produce intact perinatal survival.
Although utilization of MP appears to greatly benefit the mother and lessen
her morbidity and mortality risks, a perinatal benefit is less likely to be
clearly achieved as long as delivery cannot be safely postponed for a pro-
tracted period of time to attain greater fetal maturation. The next major
milestone in the improvement of HELLP syndrome pregnancy management
awaits the availability of therapeutic agents to prevent the development of
HELLP syndrome altogether or, failing that, significant postponement of
disease onset until well into the third trimester.
The authors recognize the limitations of this prospective observational study
which combines three-component management pieces into one protocol. The
 Mississippi Protocol Management of HELLP Syndrome 89

intravenous dexamethasone protocol used was empiric and might have produced
better results if higher doses had been used in the most severe cases as advo-
cated by others (24). Better results in our series compared with others could be
due to years of provider education to referring physicians in Mississippi that
resulted in earlier referrals of patients and earlier treatment initiation of MP.

Declaration of Interest
The authors report no conflicts of interest. The authors alone are responsible
for the content and writing of the paper.
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REFERENCES
1. Sibai BM, Ramadan MK, Usta I, et al. Maternal morbidity and mortality in 442 pregnancies
with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet
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