Documenti di Didattica
Documenti di Professioni
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1525-6065
1064-1955
LHIP
Hypertension
in Pregnancy
Pregnancy, Vol. 1, No. 1, Sep 2010: pp. 00
Mississippi
Martin
et al.Protocol Management of HELLP Syndrome
INTRODUCTION
One of the most feared presentations within the pantheon of preeclampsiarelated 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 thrombocytopenia (14). The risk of serious morbidity correlates in general with increasingly 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 pregnanPresented 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
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Martin et al.
Evidence of red cell hemolysis was present with regard to abnormal cell forms or
fragments and the presence of urinary bilirubin or increased indirect bilirubin. 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 laboratory findings that were consistent with a diagnosis of preeclampsia/eclampsia
during their antepartum/postpartum course. Patients who satisfied all criteria to merit a final diagnosis of class 3 HELLP syndrome (mild thrombocytopenia 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
platelet/LDH/AST criteria present) are excluded from this report. We emphasize 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 crisis, 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).
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, congestive 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 complications 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 disease 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 intravenously 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
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Martin et al.
Preeclampsia/Eclampsia/HELLP Syndrome
>16 weeks gestation
Class 1 or 2 HELLP Syndrome?
(PLT <100K/uL, LDH>600
AST/ALT>70, +Schistocytes,
Ind. Bili >1.2)
Class 3 or Partial
HELLP
Syndrome?
NO
INITIATE IV
DEXAMETHASONE
10mg IV q 12
HOURS
YES
NO
YES
Eclampsia?
YES
Severe Hypertention
Difficult to Control,
or CNS Symptoms?
CONSIDER IV
DEXAMETHASONE
10mg IV q 12 HOURS
YES
YES
YES
Continue Current
Management without
IV Dexamethasone
NO
NO
NO
Severe
Epigastric Pain?
NO
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
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
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 initiation 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 maternal 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.
Final diagnosis of
N
Maternal age at delivery (years)
Maternal weight at admission (lbs)
Maternal BMI at admission
Race/ethnicity (% African-American)
Nulliparous
Multiparous
Gestational age at delivery (weeks)
Cesarean delivery
Prior cesarean delivery
Patient transfer to UMMC for care
Class 1 HELLP
syndrome
Class 2 HELLP
syndrome
p-Value
66 patients
24.6 5.6
183 57
32 9
74%
47%
59%
30.7 4.5
67%
15%
86%
24.2 6.1
189 47
32 7
78%
58%
52%
31.2 5.1
60%
15%
84%
124 patients
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
Note: Means are 1 SD; NS, Non-Significant difference with p > 0.05.
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Table 2: Admission signs and symptoms before initiating Mississippi Protocol (MP) treatment.
Final diagnosis of
N
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Mean arterial pressure (mmHg)
Dipstick proteinuria (1+ or 2+)
Dipstick proteinuria (3+ or 4+)
Hematuria (micro/macro)
Nausea/vomiting
Epigastric pain
Headache
Visual impairment
Facial edema
Eclampsia
Uric acid >5.5 mg/dL (%)
LDH 600 IU/L
AST 70 IU/L
ALT 70 IU/L
Creatinine > 1.2 mg/dL
Platelet count 50,000/L
Platelet count >50,000 100,000/L
Platelet count >100,000 150,000/L
Platelet count >150,000/L
Class 1 HELLP
syndrome
Class 2 HELLP
syndrome
p-Value
66 patients
150 21
90 18
110 18
24%
53%
32%
33%
30%
50%
12%
14%
6%
76%
100%
68%
44%
12%
41%
24%
21%
14%
124 patients
154 19
94 15
114 15
13%
55%
23%
15%
14%
51%
15%
13%
4%
69%
89%
49%
23%
9%
0%
53%
24%
23%
NS
NS
NS
NS
NS
NS
0.0041
0.006
NS
NS
NS
NS
NS
0.0026
0.0142
0.0034
NS
<0.001
<0.001
NS
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.
Final diagnosis of
N
Platelet nadir (L)
Peak total LDH (IU/L)
Peak AST (IU/L)
LDH: AST ratio (mean)
LDH: AST ratio (range)
Uric acid (mg/dL)
Creatinine (mg/dL)
Class 1 HELLP
syndrome
Class 2 HELLP
syndrome
p-Value
66 patients
34,800 12,500/L
5288 4190 IU/L
671 743 IU/L
15.4 15.4
1.1 88.4
7.5 2
1.25 0.9
124 patients
75,500 14,200/L
2553 3329 IU/L
319 695 IU/L
17.3 13.5
1.6 62.2
7.2 2
0.99 0.8
<0.001
<0.001
0.0014
NS
NS
NS
0.0396
Final diagnosis of
Class 1 HELLP
syndrome
Class 2 HELLP
syndrome
N
Pre-MP/hospital admission
Hematologic/coagulation
Cardiopulmonary
CNS/visual
Renal
Hepatic
During MP/hospitalization
Hematologic/coagulation
Cardiopulmonary
CNS/visual
Renal
Hepatic
66 patients
22/66 (33.3%)
21
3
0
3
0
12/66 (18.2%)
10
1
0
2
0
124 patients
12/124 (9.7%)
12
1
0
1
1
3/124 (2.4%)
2
1
0
0
0
p-Value
<0.001
<0.001
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%
in class 2) had them initiated antepartum, the remainder intrapartum or postpartum 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 differ 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 pregnancies, 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 pressures 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
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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 intubation 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) complications apart from severe preeclampsia/eclampsia. Between 1994 and 2008 we
treated 11 patients as described. In each instance, plasma exchange therapy during the postpartum period was initiated to facilitate maternal recovery and in
most cases (8/11) the mother survived (20). Another patient excluded from this
investigation was reported in 2006 to have either HELLP syndrome or TTP masquerading 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 deterioration 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
complications arise subsequent to adverse action on tissue by pathogenic factors 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 evidence 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 instrumental 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 gestational 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 protracted 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
intravenous dexamethasone protocol used was empiric and might have produced
better results if higher doses had been used in the most severe cases as advocated 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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