Controversies With

the Diagnosis and

Management of
HELLP Syndrome
JOHN M. OBRIEN, MD and JOHN R. BARTON, MD
Perinatal Diagnostic Center, Central Baptist Hospital,
Lexington, Kentucky
Introduction
The spectrum of disease resulting from the
pathophysiology of preeclampsia continues
to challenge the diagnostic acumen of clini-
cians. One of preeclampsias various mani-
festations includes the specic entity of
HELLP syndrome. Recently, investigators
have provided evidence some cases of
HELLP syndrome represent a vasculopathy
mediated by an abnormal concentration of
vascular growth factors.
1
However, until
the underlying etiology for preeclampsia is
better dened and testing for such factors
is commonplace, controversies in the diag-
nosis and management of HELLP syndrome
will persist as its numerous clinical ndings
will lead to varied inpressions of severity
and to varied thresholds for intervention.
Controversies in Diagnosis
The preeclamptic patient with the constella-
tion of hemolysis, hepatic dysfunction, and
low platelets has been described in the liter-
ature for decades with early accurate descrip-
tions by Prichard et al and Chesley.
2,3
It was
not until 1982, however, when Weinstein
coined the acronym HELLP syndrome (he-
molysis, elevated liver enzymes, and low
platelets) that clinicians could more easily
recognize and discuss this group of patients
with remarkable hepatic involvement by
severe preeclampsia.
4
Investigations into the pathophysiology
of preeclampsia, and specically HELLP
syndrome, have revealed a disorder charac-
terized by hepatic endothelial disruption
followed by platelet activation, aggregation,
and consumption ultimately resulting in dis-
tal ischemia and hepatocyte death.
5,6
This
vasculopathy can be limited to a hepatic
segment or occur diffusely throughout the
liver. Most commonly, HELLP syndrome
involves smaller terminal arterioles yielding
a process with characteristic histologic fea-
tures. The classic hepatic lesion associa-
ted with HELLP syndrome is periportal or
focal parenchymal necrosis in which hyaline
deposits of brin-like material can be seen
Correspondence: John M. OBrien, MD, Director, Perinatal
Diagnostic Center, Central Baptist Hospital, 1740 Nicholas-
ville Road, Lexington, KY40503. E-mail: jobrien@bhsi.com
CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 48 / NUMBER 2 / JUNE 2005
CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 48, Number 2, 460477
2005, Lippincott Williams & Wilkins
460
in the sinusoids.
79
Alternatively and less
frequently, larger-vessel disease can impact
wider vascular distributions in the liver with
more catastrophic outcomes such as hepatic
infarction or subcapsular hematoma. This
rare large-vessel disease is more readily vis-
ible by imaging studies such as magnetic
resonance imaging (MRI) or computed to-
mography (CT) scanning and is associated
with worse laboratory values indicating more
dramatic hepatic dysfunction.
10
The greatest controversy involving HELLP
syndrome is in the diagnosis of the condi-
tion. The syndrome outlined by Weinstein
in the early 1980s provided a description
of the disease process and gave clinicians
an easier framework to understand the path-
ophysiology. Namely, his group of 29 pa-
tients with severe preeclampsia/eclampsia
manifested more pronounced hepatic in-
volvement rather than primarily cerebral or
renal disease. Later, Sibai et al established
laboratory criteria for the diagnosis and pro-
vided standards for subsequent discussions
in the literature (see Table 1).
11
In his clas-
sication, Sibai dened laboratory abnor-
malities sufcient for the diagnosis of each
element of the syndrome: hemolysis by an
abnormal peripheral smear, elevated biliru-
bin .1.2 mg/dL, or elevated lactate dehy-
drogenase (LDH) .600 U/L; elevated liver
enzymes by an aspartate aminotransferase
(AST) .70 IU/L (which was greater than
2 standard deviations of normal) and lactate
dehydrogenase (LDH) .600 U/L; and low
platelets dened as 100,000/mm
3
, as this value
was standard in other elds of medicine.
Martin et al also attempted to classify the
disease noting an increase in untoward out-
comes, including cardiopulmonary, central
nervous system, and renal dysfunction, as
the degree of thrombocytopenia worsened.
12
In their retrospective review of 302 cases
of HELLP syndrome, they dened class 1
HELLP syndrome as a platelet nadir below
50,000/mm
3
, whereas those with platelet na-
dirs between 51,000 and 100,000/mm
3
were
dened as class 2. Class 3 HELLP syn-
drome represented a newly classied group
of patients with hepatocyte death but
a higher platelet count nadir, 101,000 to
150,000/mm
3
. In this series, thrombocyto-
penia in women with HELLP syndrome
was found to represent a marker for more
extensive endothelial disruption and hepato-
cyte death as peak aminotransferase values
correlated well with platelet nadirs. Still
others have offered differing criteria for
the diagnosis of HELLP syndrome to Sibais
and Martins, each assessing varying
degrees of hepatic involvement as evidenced
by liver function test abnormalities to repre-
sent thresholds for diagnosis (see Table
1).
13,14
Despite the best of intentions, these
differing depictions of HELLP syndrome
with differing criteria for platelet count
and liver function test abnormalities have
created a rationale for questioning ndings
of individual reports and have likely con-
fused clinicians.
Compared with the 1980s, when Weinstein
rst coined the term, HELLP syndrome and
its variants are now more commonly recog-
nized earlier when platelet consumption yields
TABLE 1. Classications of HELLP Syndrome
Platelet Count AST LDH
Sibai et al
11
,100,000/mm
3
$70 U/L $600 U/L
Martin et al
12
,150,000/mm
3
$40 U/L $600 U/L
van Pampus
13
,100,000/mm
3
.50 U/L .600 U/L
Visser and Wallenburg
14
,100,000/mm
3
.30 U/L *
* Not included in their criteria.
Reprinted from Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low
platelet count. Obstet Gynecol. 2004;103:981991.
AST, aspartate aminotransferase; LDH, lactic dehydrogenase.
Controversies With HELLP Syndrome 461
milder degrees of thrombocytopenia and ele-
vated liver function tests document hepatic
ischemia. It appears, however, the same path-
ophysiology is ongoing whether the patient
has evidence of thrombocytopenia and elevated
liver function tests alone or whether schisto-
cytes are present in the peripheral smear, the
serum bilirubin is elevated, or other abnor-
malities such as coagulopathy or renal insuf-
ciency have unfolded. With greater involve-
ment of the endothelium of the liver by
preeclampsia, more red blood cells are he-
molyzed and more hepatic ischemia re-
sults with the combination yielding higher
bilirubin levels and impaired coagulation
studies.
Thus, the primary controversy in the di-
agnosis of HELLP syndrome has been in
precisely dening when in the spectrum
of the hepatic involvement with preeclamp-
sia does the true HELLP syndrome de-
velop. Some patients have been termed as
having partial HELLP syndrome, ELLP
syndrome, or class 3 HELLP syndrome.
These women are also at risk for signif-
icant maternal and fetal morbidity as a
result of this same pathophysiology despite
criticisms that elements of the true dis-
ease may be missing. In a study by Van
Pampus et al, 10% of women with ELLP
syndrome were identied as having serious
complications, including eclampsia, cerebral
ischemia, and abruptio placentae compared
with a 24% rate for women with true
HELLP.
13
In a study by Abramovici et al,
the rate of fetal distress (13% vs. 18%) and
intrauterine growth restriction (28% vs.
31%) was lower in women with HELLP syn-
drome versus the partial HELLP group.
15
These data do not demonstrate that a suf-
ciently different outcome occurs in patients
with hepatic involvement by preeclampsia
to justify subdividing these patients into
minute subclassications. Unfortunately, it
appears once severe preeclampsia has man-
ifested remarkable end-organ involvement,
adverse renal, central nervous system, and
pulmonary complications can arise and should
be anticipated.
For diagnostic criteria to be most useful,
they should be based on objective criteria,
testing should be readily available, and the
results of these tests should not be subject
to interpretation. These criteria should also
attempt to identify earlier stages of the dis-
ease process rather than limiting the diagno-
sis to a small subset of only the most severe
cases. Finally, the denitions should be easy
to use for the clinician.
The diagnosis of HELLP syndrome is
made by laboratory parameters alone, al-
though supporting typical ndings of pre-
eclampsia, including hypertension and pro-
teinuria, help rule out other potential imita-
tors (see the next section on differential
diagnosis). Laboratory evaluation should in-
clude a complete blood count with platelet
count, a peripheral smear, coagulation stud-
ies, serum AST, creatinine, glucose, biliru-
bin, and LDH levels. Ideally, the laboratory
parameters for HELLP syndrome should be
intuitive, easytoremember, andconsistent be-
tween laboratories. Of the laboratory studies
routinely obtained for diagnostic purposes,
platelet count and liver function tests are
the best standardized and can fulll these
criteria.
The platelet count historically used to di-
agnose thrombocytopenia is ,100,000/mm
3
and is the threshold most consistent across
all specialties of medicine. The liver func-
tion tests prole we use is that presented
by Sibai as ASTor ALT .2 times the upper
limit of normal or 70 U/L. To assess the
degree of hemolysis, we do not evaluate
peripheral smears ourselves or ask hematol-
ogists/pathologists to provide middle-of-the-
night evaluations. We do use an LDH value
to give an indication for hemolysis as sug-
gested by Sibai. We are also cognizant, how-
ever, that an elevated LDH, most of the time,
also reects hepatocyte destruction in addi-
tion to hemolysis. Therefore, in our opinion,
a complete blood count and metabolic pro-
le are readily available, rapidly performed
tests, which allow recognition and denition
of severe involvement of liver parenchyma
by preeclampsia. The alphabet soup present
462 OBrien and Barton
in the literature attempting to differentiate
HELLP versus ELLP versus EL versus
HEL syndrome, or partial HELLP versus
HELLP, is of limited value when attempting
to treat a patient identied with signicant he-
patic involvement from severe preeclampsia.
We anticipate that expert groups focused on
the care for women with hypertensive disor-
ders in pregnancy can better dene the clinical
condition of hepatic involvement by pre-
eclampsia and eliminate the current confusion
and controversy.
Differential Diagnosis
Sibai has noted that most patients with
HELLP syndrome present preterm with
hypertension, and proteinuria, and report
epigastric or right upper quadrant pain.
16
Unfortunately, however, other patients pres-
ent with only nausea or vomiting, and still
others may have nonspecic viral-like
symptoms. In Weinsteins second report,
17
nausea or vomiting and epigastric pain were
the most common symptoms. A pregnant
woman in the late second or early third
trimester with right upper quadrant pain,
epigastric pain, or identied hepatic dys-
function should be considered as having
HELLP syndrome until other elements of
the differential diagnosis are excluded (see
Table 2). Epigastric pain may antedate the
laboratory abnormalities of HELLP syn-
drome by several hours, leading clinicians
to question initial impressions. Symptoms
of upper quadrant pain without laboratory
abnormalities may lead errantly to diagnoses
of gastritis or gallbladder disease. Reevalu-
ation of laboratory studies in 4 to 6 hours
after onset of symptoms usually conrms
an initial clinical suspicion of HELLP
syndrome.
Patients with HELLP syndrome frequently
demonstrate signicant weight gain with
generalized edema. However, severe hyper-
tension (systolic blood pressure $160 mmHg,
diastolic blood pressure $110 mm Hg) is
not a constant nding in HELLP syndrome.
Although 69% of the 112 patients studied by
Sibai et al had a diastolic blood pressure
$110 mm Hg at admission to the hospital,
15% had a diastolic blood pressure of
#90 mm Hg. In Weinsteins
5
initial report,
less than half (13) had an admission blood
pressure $160/110 mm Hg. Thus, hyperten-
sion is not obligatory to diagnose HELLP
syndrome. More signicant renal involve-
ment by preeclampsia compared with hepatic
disease appears better correlated with the se-
verity of hypertension.
Once laboratory abnormalities sufcient
to diagnose HELLP syndrome are observed,
other hepatopathies may be considered and
eliminated as possibilities. Concomitant hy-
poglycemia, coagulopathy, elevated ammo-
nia level, and renal dysfunction are associated
with acute fatty liver of pregnancy. Cerebral
dysfunction, fever, and rash may be part of
thrombotic thrombocytopenic purpura. He-
molytic uremic syndrome is primarily a renal
disease in children and is related to infection
with Escherichia coli. In adults, almost all
cases develop in the postpartum period. Exac-
erbation of systemic lupus erythematosus with
nephritis can also mimic severe preeclampsia.
The clinical manifestations and laboratory
ndings of the various conditions presented
in Table 2 can be differentiated from severe
preeclampsia. Occasionally, however, the time
course of the condition and prompt postpar-
tum resolution of laboratory studies are the
TABLE 2. Medical and Surgical
Disorders Potentially Confused
With HELLP Syndrome
Acute fatty liver
or pregnancy
Hyperemesis gravidarum
Idiopathic thrombocytopenia
Appendicitis
Cholestasis of
pregnancy
Kidney stones
Peptic ulcer
Pyelonephritis
Diabetes insipidus Systemic lupus erythematosus
Gallbladder disease
Gastroenteritis
Thrombotic
thrombocytopenic purpura
Glomerulonephritis Viral hepatitis
Hemolytic uremic
syndrome
Hepatic
encephalopathy
Controversies With HELLP Syndrome 463
only means to determine the etiology for ma-
ternal disease.
Finally, clinicians should be familiar with
the various endothelial vascular organs that
can be affected by preeclampsia. Although
involvement in the renal and hepatic vessels
is most common, other vessels potentially
affected include the cerebral, cardiac, and
pulmonary. Involvement by this vasculop-
athy of these organs can yield concomitant
eclampsia, myocardial dysfunction, and pul-
monary edema, and acute respiratory dis-
tress syndrome, adding to the diagnostic
challenges.
Management Controversies
The diagnosis of HELLP syndrome has long
been recognized as heralding the need for
aggressive, standardized therapies, includ-
ing magnesium sulfate administration, anti-
hypertensive therapy, and delivery to reduce
associated maternal morbidity and mortality
(see Table 3).
18
Several critical steps are in-
volved in the management of these cases
and are summarized in Figure 1. This check-
list for the management of the condition pro-
vides an orderly sequential approach.
The clinical course of women with
HELLP syndrome is usually characterized
by progressive and sometimes sudden dete-
rioration in maternal and fetal conditions.
Therefore, patients with suspected diagnosis
of HELLP syndrome should be hospitalized
immediately and observed in a labor and de-
livery unit. The rst priority is to assess and
stabilize the maternal condition, particularly
coagulation abnormalities. Patients with
HELLP syndrome who are remote from
term should be referred to a tertiary care
center.
Such patients should be managed as hav-
ing severe preeclampsia and should initially
receive intravenous (IV) magnesium sulfate
as prophylaxis against seizures and antihy-
pertensive medications to keep systolic
blood pressure below 160 mm Hg and/or di-
astolic blood pressure below 105 mm Hg.
19
This can be achieved with a 5-mg bolus dose
of hydralazine, to be repeated as needed
every 15 to 20 minutes for a maximum dose
of 20 mg per hour. Blood pressure is recorded
every 15 minutes during therapy and every
hour once the desired values are achieved.
If hydralazine does not lower blood pressure
adequately and/or if maternal side effects
such as tachycardia or headaches develop,
another drug such as labetalol or nifedipine
can be used. The recommended dose of
labetalol is 20 to 40 mg IV every 10 to 15
minutes for a maximum of 220 mg over
1 hour, and the dose of nifedipine is 10 to
20 mg orally every 30 minutes for a maxi-
mum dose of 50 mg over 1 hour. During the
observation period, maternal and fetal con-
ditions are assessed.
The recommended regimen of magne-
sium sulfate is a loading dose of 6 g given
over 20 minutes followed by a maintenance
dose of 2 g per hour as a continuous IV so-
lution. Magnesium sulfate is initiated at the
beginning of the observation period and
then continued during labor and for at least
24 hours postpartum. The next step is to
evaluate fetal well-being using the nonstress
TABLE 3. Serious Maternal Complications
in 442 Patients With
HELLP Syndrome
Complication No. Percent
Disseminated intravascular
coagulopathy 92 21
Abruptio placentae 69 16
Acute renal failure 33 8
Severe ascites 32 8
Pulmonary edema 26 6
Pleural effusions 26 6
Cerebral edema 4 1
Retinal detachment 4 1
Laryngeal edema 4 1
Subcapsular liver
hematoma 4 1
Acute respiratory distress
syndrome 3 1
Death, maternal 4 1
Reprinted from Sibai BM. Diagnosis and management of gesta-
tional hypertension and preeclampsia. Obstet Gynecol. 2003;
102:181192.
464 OBrien and Barton
test or biophysical prole, as well as to ob-
tain ultrasonographic biometry for assess-
ment of possible intrauterine growth retarda-
tion. Finally, a decision must be made as to
whether immediate delivery is indicated.
Steroids and the Management
of HELLP Syndrome
Several retrospective studies have demon-
strated glucocorticoids can also impact the
maternal condition in patients with HELLP
syndrome, thereby adding another newer
intervention to this armementarium.
2024
Five randomized trials comparing the use
of high-dose dexamethasone with either no
treatment
21,22,25,26
or with betamethasone
27
in women with presumed HELLP syndrome
were summarized by Sibai
28
and are pre-
sented in Table 4. The results of these stud-
ies demonstrate improved laboratory values
and urine output in patients receiving
FIGURE 1. Checklist in the management of HELLP syndrome.
Controversies With HELLP Syndrome 465
dexamethasone, but provide limited evi-
dence of reduced maternal morbidity. How-
ever, because most of these trials were
performed postpartum, the true extent
glucocorticoids can inuence outcomes
has yet to be determined.
The mechanism of action of this drug is
unknown but appears to alter the nal steps
in endothelial cell disruption as evidenced
by steroids having the ability to improve lab-
oratory values postpartum when presumably
the ability to synthesize new mediators of
disease is limited after delivery of the pla-
centa. Because HELLP syndrome is charac-
terized by the endothelial damage within the
liver, we can only surmise glucocorticoids
act to minimize the degree of intravascular
endothelial injury within the body, improve
blood ow within the liver specically, and
halt ongoing hepatocyte death and platelet
consumption.
Because glucocorticoids are the only known
drugs to improve the maternal laboratory
ndings in cases of severe preeclampsia, we
use this observation in our management.
Our dosing of the medication is directed
not only to improve neonatal outcomes by
lowering the incidence of such complica-
tions as respiratory distress syndrome and
intraventricular hemorrhage, but also to at-
tempt to reduce maternal morbidity. The
dose, route of administration, and duration
of treatment of glucocorticoids is important
and has varied between studies. These
aspects of therapy still require further study
with properly controlled trials, but some in-
formation is evident from the literature.
First, intravenous glucocorticoids appear
to have a more rapid onset of action com-
pared with intramuscular dosing. The ran-
domized trial by Isler et al demonstrated in-
travenous dosing was superior to intramus-
cular dosing for several outcome variables,
including improving urine output and greater
improvement in laboratory values.
27
Sec-
ond, glucocorticoids improve the maternal
condition in a dose-dependent manner.
In a review of data collected at our center,
we observed maternal platelet count in-
creased more dramatically before delivery
with a high-dose protocol of glucocorticoids
versus standard regimens used for enhanc-
ing lung maturity.
24
We therefore use this
high-dose protocol in our management of
patients with severe maternal disease (see
Table 5). Finally, the duration of action of
this medication is limited and patients may
experience a worsening of their laboratory
TABLE 4. Randomized Trials of Corticosteroids In Women With ELLP Or HELLP Syndrome
Authors
Dexamethasone
(no.)
Control
(no.) Key Finding
Magann et al
21
12* 13 Improved platelet, ALT, LDH values in
dexamethasone group
Magann et al
22
20 20 Improved platelet, AST, LDH, urine output,
MAP in dexamethasone group
Vigil-De Gracia
25
17 17 Improved platelet counts only with dexamethasone
Yalcin et al
26
15 15 Improved platelet, AST, MAP, and urine output
with dexamethasone
Isler et al
27
19* 21 Improved AST, LDH, MAP, and urine output
with dexamethasone
* Antepartum.
Postpartum.
Received intramuscular betamethasone.
Reprinted from Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low
platelet count. Obstet Gynecol. 2004;103:981991.
ELLP, elevated liver enzymes and low platelets; AST, aspartate amino transferase; ALT, alanine amino transferase; LDH, lactic dehy-
drogenase; MAP, mean arterial pressure.
466 OBrien and Barton
studies 48 to 72 hours after dosing with glu-
cocorticoids.
23,24
We term this nding the
rebound phenomenon. Steroid treatment,
therefore, is not curative but may create
a window of opportunity for intervention
before the maternal condition may again
deteriorate.
During the period when the maternal sta-
tus is being optimized, adequate but not
excessive hydration of the patient is per-
formed, laboratory studies are followed to
observe the expected response, and the fetal
status is intermittently reassessed. Because
glucocorticoids do not appear to alter the
underlying pathophysiology, delivery re-
mains the only denitive therapy. We do not
proceed with expectant management of
HELLP syndrome beyond an appropriate in-
terval to optimize the maternal status and
obtain fetal exposure to the drug (2448
hours). Furthermore, if no improvement in
the clinical or laboratory status is noted
within 8 to 12 hours of administration of
the medication, we reevaluate the diagnosis
considering other conditions such as acute
fatty liver, consider increasing the dose of
glucocorticoid, consider transfusion, and ex-
pedite delivery.
With this information, we have created
owsheets for the management of antepar-
tum and postpartum HELLP syndrome
(see Figs. 2A and B). Understanding the
goals of therapy are essential to optimal out-
comes and are 2-fold: 1) to improve the ma-
ternal status immediately before and during
delivery if needed, and 2) in women ,35
weeks, to provide glucocorticoid exposure
to the fetus for enhancement of fetal lung
maturation.
We believe that glucocorticoids may be
used for maternal benet even if the patient
has previously received this medication for
fetal lung maturity in the current pregnancy.
We therefore attempt to delineate mater-
nal versus fetal indications for the use of
glucocorticoids in patients with HELLP
syndrome.
An increase in maternal platelet count be-
fore delivery can alter management by
potentially minimizing bleeding complica-
tions. For instance, with treatment, we have
observed a signicant increase in the use of
regional anesthesia in those women with
HELLP syndrome exposed to glucocorti-
coids for 24 hours compared with women
who did not receive this therapy or achieve
this latency period.
29
We therefore coordi-
nate our efforts with our anesthesiologists
before effecting delivery, attempting to max-
imize the maternal platelet count and there-
by increase the use of regional anesthesia.
Regional anesthesia has been shown to
avoid complications of exacerbated hyper-
tension, aspiration, and failed intubation
attributable to general anesthesia in this pop-
ulation. We have given glucocorticoids at
any gestational age to address maternal dis-
ease because such a benet may exist in
term gestations. However, the use of high-
dose dexamethasone to improve maternal
outcome in women with HELLP syndrome
beyond 34 weeks gestation and/or in the
postpartum period remains experimental.
A latency period before effecting delivery
is not appropriate or necessary in all cases
of HELLP syndrome but is required to expect
a benet from glucocorticoid administration.
If the gestational age is $35 weeks, the patient
is asymptomatic, and the platelet count is suf-
cient to offer any type of anesthesia, we pro-
ceed promptly with delivery and do not sug-
gest a latency period for glucocorticoids to
impact the maternal status. Alternatively, the
TABLE 5. High-Dose Glucocorticoid
Therpy to Improve Laboratory
Abnormalities in Patients With
HELLP Syndrome
For most patients with HELLP syndrome, 10 mg
intravenous dexamethasone every 6 hours for 2
doses followed by 6 mg intravenous dexamethasone
every 6 hours for 2 additional doses.
For select patients at highest risk, including those
with profound thrombocytopenia (,20,000/mm
3
)
or with central nervous system dysfunction
(ie, blindness, paralysis), 20 mg intravenous
dexamethasone every 6 hours for up to 4 doses.
Controversies With HELLP Syndrome 467
fetal status may not allow for expectant man-
agement and a sufcient latency period to op-
timize both the fetal and maternal condition. If
a nonreassuring fetal assessment is observed,
we consider initiating our steroid protocol
when the maternal disease is severe. We pro-
ceed with delivery and expect the impact of
our therapy to begin postpartum.
Conservative Management
Prolonging the latency period beyond 48
hours from the time of the diagnosis of
HELLP syndrome to delivery is controver-
sial. van Pampus et al described the clinical
progress and maternal outcome of the
HELLP and ELLP (ndings of HELLP syn-
drome but without evidence of hemolysis)
syndrome in 127 patients managed in the
Academic Medical Center in Amsterdam
between 1984 and 1996 with a live fetus
in utero.
13
The patients were treated by tem-
porizing management, including the use of
antihypertensives and magnesium sulfate.
The predominant indication for terminating
pregnancy was fetal distress or fetal death
and not maternal condition. All serious ma-
ternal complications occurred at the onset of
the syndrome (24% of cases with HELLP
syndrome vs. 10%with ELLP). Two mothers
with HELLP syndrome died after a cerebral
hemorrhage. Seventy-nine (62%) of women
were not delivered after 3 days and 65 (51%)
after 7 days. Although the authors noted it is
unlikely that a more aggressive approach
would have reduced maternal mortality or
morbidity, their sample size was inadequate
to evaluate rare serious maternal complica-
tions of HELLP or ELLP syndrome.
In a study by Visser and Wallenburg,
14
128 consecutive preeclamptic patients with
HELLP syndrome and a gestational age less
than 34 weeks gestation were matched for
maternal and gestational age with 128
preeclamptic patients without HELLP syn-
drome. Both groups were treated with vol-
ume expansion and pharmacologic vasodila-
tation under invasive hemodynamic monitor-
ing with the aim of prolonging gestation and
enhancing fetal maturity. Except for variables
pertaining to HELLP syndrome, clinical and
laboratory data and median prolongation of
pregnancy did not differ between the groups.
Perinatal mortality was 14.1% in patients with
HELLP syndrome and 14.8%in patients with-
out HELLP. Because the perinatal outcomes
in this study are similar to studies performed
in the United States where delivery was af-
fected within 48 hours of the diagnosis of
HELLP syndrome, the benet of temporizing
management of HELLP syndrome remains
questionable. Ultimately, only a well-designed
randomized trial will resolve this management
issue.
The described conservative management
techniques were often associated with the
use of invasive procedures and numerous
medical and surgical treatments. These con-
founding variables make it difcult to eval-
uate any treatment modality proposed for
this syndrome. Occasionally, some patients
without true HELLP syndrome may demon-
strate antepartum reversal of hematologic
abnormalities after bedrest, the use of ste-
roids, or plasma volume expansion. How-
ever, in our experience, the majority of these
patients demonstrate progressive deteriora-
tion in either maternal or fetal condition.
The potential risks associated with conser-
vative management of HELLP syndrome in-
clude abruptio placentae, pulmonary edema,
acute renal failure, eclampsia, perinatal death,
and maternal death. Therefore, because only
a limited prolongation of pregnancy can
be expected and because no difference in
fetal survival with aggressive attempts at
expectant management has been observed,
we caution against expectant management
beyond a 24- to 48-hour latency to optimize
the maternal status for delivery. We should
specically caution women with dissemi-
nated intravascular coagulation (DIC) should
not be expectantly managed.
Transfusion
Platelet transfusions are indicated either be-
fore or after delivery in all patients with
468 OBrien and Barton
FIGURE 2. A, Flowchart for antepartum HELLP syndrome. B, Flow-
chart for postpartum management of HELLP syndrome.
Controversies With HELLP Syndrome 469
HELLP syndrome in the presence of signif-
icant bleeding from puncture sites, wound,
intraperitoneal, extensive ecchymosis, and
so on. Furthermore, transfusion is indicated
in all antepartum patients whose platelet
count is less than 20,000/mm
3
. Correction
of profound thrombocytopenia is particu-
larly important before cesarean section. Re-
peated platelet transfusions, however, may
not be necessary because consumption occurs
rapidly and the effect is transient. Our policy
is to administer 6 to 10 units of platelets in
all patients with a platelet count less than
40,000/mm
3
before intubating the patient
for cesarean section.
Platelets are the most commonly trans-
fused blood component in patients with
HELLP syndrome. However, red cells and
fresh-frozen plasma may also be needed in
patients with more severe coagulopathies.
The need for transfusion may be reduced
by optimizing the patients status before de-
livery and reducing the severity of thrombo-
cytopenia. Martin et al have demonstrated
a reduction in the rate for transfusion of both
cellular components and plasma in patients
exposed to dexamethasone over 2 epochs.
30
The association between dexamethasone ex-
posure and a reduced rate of transfusion has
also been noted by our group. The decision
to delay delivery to improve the maternal
platelet count by steroid exposure is again
dependent on several aspects of the clinical
situation, including fetal status. A large,
multicenter, placebo-controlled, randomized
trial of patients with markedly thrombocyto-
penic, antepartum HELLP syndrome would
be necessary to quantitate the potential ben-
et of reduced need for transfusion after ste-
roid exposure. Such a trial does not appear
to be forthcoming, however, especially when
considering the fetal benets to glucocorti-
coid administration for lowering the rate
of complications of prematurity.
Delivery Controversies
Delivery of a patient with HELLP syndrome
is associated with numerous potential com-
plications, including postpartum hemor-
rhage, vaginal/labial hematoma for vaginal
delivery, wound hematomas/separation for
cesarean delivery, and infection resulting
from prolonged induction. The choice be-
tween attempted vaginal delivery versus
cesarean section should be based on assess-
ment of various predictors for success of an
attempted induction, including 1) cervical
status, 2) fetal heart rate tracing or biophys-
ical prole, and 3) umbilical artery Doppler
studies. We have observed a very poor suc-
cess rate for attempted induction in the face
of a preterm gestation with intrauterine
growth restriction and markedly abnormal
Doppler studies. We proceed directly to
cesarean section under such circumstances.
31
Briggs et al
32
evaluated wound complica-
tions between patients with antepartum
HELLP syndrome with primary closure ver-
sus delayed closure and Pfannenstiel versus
midline skin incisions. A total of 104 patients
were identied; 75 had a primary skin closure
and 29 had a delayed closure 48 to 72 hours
postoperatively. Immediate wound complica-
tions (wound infection, hematoma) occurred
in 18 (26%) patients who had primary closure
versus 8 (24%) who had a delayed closure
(odds ratio, 1.13; 95% condence interval,
0.393.27). A late wound breakdown was
seen in only 1 patient with primary closure
but in none with delayed closure. No statisti-
cal difference in wound complication was
found between midline (primary or delayed)
and Pfannenstiel (primary, delayed) incisions
(odds ratio, 0.65; 95% condence interval,
0.231.88). The authors concluded that for
women with antepartum HELLP syndrome
delivered by cesarean section, the frequency
of wound complications is not inuenced by
type of skin incision or time of skin closure
(primary or delayed).
Generalized oozing from any operative
site is very common in thrombocyto-
penic patients. To minimize the risk of he-
matoma formation, the bladder ap should
be left open and a subfascial drain may be
used for 24 to 48 hours. A subcutaneous
drain may also be considered if the skin is
470 OBrien and Barton
approximated attempting to minimize the in-
cidence of wound complications. Subcutane-
ous tissues should be approximated with
sutures as evidenced by randomized trials
and metaanalysis for skin closure at cesarean
delivery.
33
Controversies in Management
of Subcapsular Hematoma
The most dramatic sequelae of hepatic in-
volvement by preeclampsia is the develop-
ment of segmental hepatic infarction, exten-
sive parenchymal hemorrhage, or subcapsu-
lar hematoma. Hepatic imaging ndings in
selected patients with HELLP syndrome
can identify these abnormalities.
10
Rupture
of a subcapsular hematoma is particularly
concerning because it can lead to death by
exsanguination from the inability to control
bleeding as a result of surgical difculties
with repair of the liver and coagulopathy.
Of the 34 patients evaluated by Barton
and Sibai, 16 patients (47%) had abnormal
hepatic imaging results. The most common
CT abnormalities were subcapsular hema-
toma of the liver (n = 13) and intraparenchy-
mal hemorrhage (n = 6).
Comparison of the clinical characteristics
and laboratory evaluations of patients with
normal and abnormal hepatic imaging nd-
ings demonstrated a signicant difference in
platelet count nadir between the patients
with normal and abnormal imaging ndings
but failed to show any statistically signi-
cant difference in gestational age, mean
arterial pressure, or the other laboratory
parameters studied. Of the 13 patients with
severe thrombocytopenia (platelet count
,20,000/mm
3
), 10 (77%) had abnormal
hepatic imaging ndings. Emergency inter-
vention was needed for 6 patients on the ba-
sis of these imaging ndings. CT and MRI
have excellent sensitivity for detecting acute
liver hemorrhage, but because CTwas more
available, faster, and safer for potentially un-
stable patients, and hence was the imaging
modality of choice.
The differential diagnosis of an unruptured
subcapsular hematoma of the liver in preg-
nancy should include acute fatty liver of
pregnancy, abruptio placentae with dissemi-
nated intravascular coagulation, ruptured
uterus, or sepsis. Most patients with a subcap-
sular hematoma of the liver are seen in the
late second or third trimester of pregnancy,
although cases have been reported in the im-
mediate postpartum period. Patients typically
report right upper quadrant pain, but local-
ized pain may be absent. Stimulation of the
phrenic nerve at the diaphragm can produce
referred pain along this nerves distribution to
its origin in the C4C5 cervical plexus, in-
cluding the pericardium, peritoneum, pleura,
and shoulder. Physical examination ndings
consistent with peritoneal irritation and hepa-
tomegaly may be present.
Surgical repair has been recommended
for hepatic hemorrhage without liver rup-
ture. More recent experience suggests, how-
ever, this complication should be managed
conservatively in patients who remain
hemodynamically stable.
34,35
Management
should include close monitoring of hemody-
namics and coagulation status. Serial assess-
ment of the subcapsular hematoma with ul-
trasound or CT is necessary with immediate
intervention for rupture or worsening of ma-
ternal status. It is important with conserva-
tive management to avoid exogenous sour-
ces of trauma to the liver such as abdominal
palpation, convulsions, or emesis, and to use
care in transportation of the patient. Indeed,
any sudden increase in intraabdominal pres-
sure could potentially lead to rupture of the
subcapsular hematoma.
36
In most instances, rupture of a subcapsular
hematoma involves the right lobe and is pre-
ceded by the development of a parenchymal
hematoma. Patients frequently present with
shoulder pain, shock, or evidence of massive
ascites, respiratory difculty, or pleural effu-
sions, and often with a dead fetus. An ultra-
sound or computed axial tomography of the
liver should be performed to rule out the pres-
ence of subcapsular hematoma of the liver
and assess for the presence of intraperitoneal
Controversies With HELLP Syndrome 471
bleeding. Paracentesis conrms the presence
of intraperitoneal hemorrhage suspected by
examination or hepatic imaging.
The presence of ruptured subcapsular liver
hematoma resulting in shock is a surgical
emergency requiring acute multidisciplinary
treatment. Resuscitation should consist of
massive transfusions of blood, correction of
coagulopathy with fresh-frozen plasma and
platelets, and immediate laparotomy. Options
at laparotomy include packing and drainage
(preferred), surgical ligation of the hemor-
rhaging hepatic segments, embolization of
the hepatic artery to the involved liver seg-
ment, and loosely suturing omentum or surgi-
cal mesh to the liver to improve integrity. Even
with appropriate treatment, maternal and fetal
mortality is over 50%. Mortality is most com-
monly associated with exsanguination and
coagulopathy. Initial survivors are at increased
risk for developing adult respiratory distress
syndrome, pulmonary edema,
37
and acute re-
nal failure in the postoperative period.
38
Smith et al
39
reviewed their management
of 7 patients with spontaneous rupture of the
liver occurring during pregnancy. Of the 4
survivors, the mean gestational age was
32.8 weeks and the mean duration of hospi-
talization was 16 days. All the survivors
managed with packing and drainage of the
liver survived, whereas the 3 patients treated
with hepatic lobectomy died. The authors al-
so extracted 28 cases from the literature
reported since 1976. From a total of 35
cases, 27 patients (82%) managed by pack-
ing and drainage survived, whereas only
25% of 8 patients undergoing hepatic lobec-
tomy survived. The authors emphasized he-
patic hemorrhage with persistent hypoten-
sion unresponsive to transfusion of blood
products may be managed surgically with
laparotomy, evacuation of the hematoma,
packing of the damaged liver, and draining
of the operative site. In certain cases in
which the patient is stable enough to under-
go angiography, transcatheter embolother-
apy is a reasonable alternative to surgery.
40
In a review of 442 cases of HELLP syn-
drome managed at the University of Ten-
nessee, Memphis, 4 patients with HELLP
syndrome were complicated by a ruptured
subcapsular hematoma.
18
Three cases re-
quired transfusion of 22 to 40 units of
packed red blood cells and multiple units
of platelets and fresh-frozen plasma. Two
of these 3 cases were complicated by pul-
monary edema and acute renal failure, but
all survived without any residual deciency.
The fourth case was a patient who presented
in profound shock and with disseminated
intravascular coagulopathy. This patient
subsequently died secondary to a ruptured
pulmonary emphysematous bleb during
management of adult respiratory distress
syndrome.
TABLE 6. Management of Patients With
Subcapsular Hematoma of
the Liver
General considerations:
I. Have the blood bank aware of the potential
need for large amounts of packed red blood
cells, fresh-frozen plasma, and platelet
concentrate (ie, 30 units of blood, 20 units of
fresh-frozen plasma, 3050 units of
platelets)
II. Consultation of a general or vascular surgeon
III. Avoid direct and indirect manipulation of the
liver
IV. Close monitoring of hemodynamic status
V. Intravenous magnesium sulfate to prevent
seizures
If the hematoma is unruptured:
I. Conservative management with serial
computed tomography scans or ultrasound
If the hematoma is ruptured and patient
hemodynamically unstable:
I. Massive transfusions
II. Immediate laparotomy
A. If bleeding is minimal:
1. Observation
2. Draining area with closed suction
B. If bleeding is severe:
1. Application of laparotomy sponges as
packs
for pressure
2. Embolization of the hepatic artery to
the
involved liver segment
472 OBrien and Barton
On the basis of reviewof the literature, an
outline for the management of hepatic com-
plications of HELLP syndrome was devel-
oped (Table 6). This outline emphasizes
the potential for transfusion of large amounts
of blood and blood products and the need for
aggressive intervention if rupture of the he-
matoma is suspected and the patient is he-
modynamically unstable. We recommend
30 units of packed red blood cells, 20 units
of fresh-frozen plasma, 30 to 50 units of
platelets, and 20 to 30 units of cryoprecipi-
tate be available if rupture of a subcapsular
hematoma is suspected. Our experience is
in agreement with the recent observations
of Smith et al
39
in that a stable patient
with an unruptured subcapsular hematoma
should be conservatively managed. Constant
monitoring must continue during this man-
agement, however, because patients can
rapidly become unstable after rupture of
the hematoma. Survival clearly is associated
with rapid diagnosis and immediate medical
or surgical stabilization. Coagulopathy must
be aggressively managed. These patients
should be managed in an intensive care unit
with close monitoring of hemodynamic
parameters and uid status to avoid pulmo-
nary edema or respiratory compromise.
Postpartum Management
The diagnostic criteria for HELLP syndrome
may develop antepartumor postpartum. Sibai
and associates
18
revealed that 70% had
evidence of the syndrome antepartum, and
30% developed the criteria postpartum. In
the postpartum period, the time of onset
ranged from a few hours to 7 days, with
the majority developing within 48 hours after
delivery. Patients in this group are at in-
creased risk for the development of pulmo-
nary edema with acute renal failure.
37,38
HELLP syndrome may be diagnosed post-
partum following 1 of 3 clinical scenarios:
1) worsening of antepartum severe pre-
eclampsia with delivery not yet altering the
time course of the disease, 2) new onset of
severe preeclampsia postpartum, or 3) re-
bound deterioration of a patient with antepar-
tum HELLP syndrome after exposure to cor-
ticosteroid antepartum.
The goals of therapy postpartum differ
compared with antepartum and are aimed
solely at improving the maternal status.
Management of seizure prophylaxis is sim-
ilar to the antepartum patient with HELLP
syndrome, including the need for magne-
sium sulfate. Hypertension control may be
more aggressive, however, because there is
no longer concern about compromising the
uteroplacental circulation. Blood pressure
goals of systolic blood pressure ,155 mm Hg
and/or diastolic blood pressure ,105 mm Hg
are suggested.
After delivery, the patient should be mon-
itored closely in an intensive care setting for
24 to 48 hours. Most patients show evidence
of resolution of the disease process within
48 hours after delivery. The differential diag-
nosis of postpartum hypertension and pro-
teinuria should include thrombotic throm-
bocytopenic purpura, hemolytic uremic
syndrome, and exacerbation of systemic lu-
pus. These alternative diagnoses may be con-
sidered if resolution of the disease is pro-
longed. However, some patients with HELLP
syndrome, especially those with DIC, may
demonstrate delayed resolution or even dete-
rioration. Such patients may require longer,
intensive monitoring. These patients are at
risk for developing pulmonary edema as a
result of transfusions of blood and blood
products, uid mobilization, and compro-
mised renal function.
38
As a result of the persistent potential for
adverse outcomes postpartum, several
reports have advocated the use of corticoste-
roids to more promptly restore vascular in-
tegrity. In a retrospective study, Martin et al
41
reported the puerperal courses of 43 women
with postpartum HELLP syndrome who
were treated with dexamethasone and com-
pared them with 237 similar patients who
did not receive corticosteroids. Dexametha-
sone at a dosage of 10 mg IV at 12-hour
intervals was given until disease remission
was noted in treated patients, at which time
Controversies With HELLP Syndrome 473
up to 2 additional 5-mg IV doses were given
at 12-hour intervals. Patients who received
dexamethasone for postpartum-onset HELLP
syndrome experienced a shorter disease
course, faster recovery, less morbidity, and
less need for other interventionist therapy
compared with a historical group of patients
with HELLP syndrome who did not receive
dexamethasone.
Postpartum patients with delayed resolu-
tion of HELLP syndrome (including persis-
tent severe thrombocytopenia) represent
a management dilemma. Exchange plas-
mapheresis with fresh-frozen plasma has
been advocated as a treatment by some
authors.
4244
Because the majority of these
patients will have spontaneous resolution
of their disease, early initiation of plasma-
pheresis may result in unnecessary treat-
ment. Schwartz
44
suggested serial studies
indicating a progressive elevation of biliru-
bin or creatinine associated with hemolysis
and thrombocytopenia may be an indication
for plasmapheresis. Martin and coworkers
42
reported the use of plasma exchange with
fresh-frozen plasma in 7 women in the post-
partum period with HELLP syndrome that
persisted .72 hours after delivery. All
patients had persistent thrombocytopenia,
rising lactic dehydrogenase, and evidence
of multiorgan dysfunction. The authors rec-
ommended that a trial of plasma exchange
with fresh-frozen plasma be considered in
HELLP syndrome that persists past 72 hours
from delivery and in which there is evidence
of a life-threatening microangiopathy.
Since their publication, however, the Mis-
sissippi group has reviewed 18 patients with
HELLP syndrome who were treated postpar-
tum with single or multiple plasma ex-
change with fresh-frozen plasma.
43
Each pa-
tient was entered into the clinical trial either
because of persistent evidence of atypical
preeclampsiaeclampsia as HELLP syn-
drome .72 hours after delivery (group 1)
or with evidence of worsening HELLP syn-
drome at any time postpartum in association
with single- or multiple-organ injury (group
2). In the absence of other disease conditions,
the 9 patients in group 1 responded rapidly to
1 or 2 plasma exchange procedures with few
complications and no maternal deaths. In con-
trast, in the 9 patients in group 2 with HELLP
syndrome presentations complicated by other
end-organ disease, the response to plasma ex-
change was variable and there were 2 deaths in
this group. This series details the postpartum
application of plasma exchange therapy for
unremitting HELLP syndrome, but reveals
that a uniformly positive response to this ther-
apy is not observed when there is additional
single or multiple organ injury.
44
Potential ad-
verse effects of this plasma exchange include
plasma-transmitted infections, anaphylaxis,
volume overload, sepsis, and maternal death.
Maternal Counseling
Pregnancies complicated by HELLP syn-
drome are associated with life-threatening
complications for both the mother and her in-
fant. Therefore, clinicians should be able to
answer questions regarding subsequent preg-
nancy outcome and long-term prognosis.
Women with a history of HELLP syndrome
are at increased risk of all forms of pre-
eclampsia in subsequent pregnancies. In gen-
eral, the rate of preeclampsia in subsequent
pregnancies is approximately 20% with
signicantly higher rates if the onset of
HELLP syndrome was in the second tri-
mester. The rate of recurrent HELLP syn-
drome ranges from 2% to 19%. We quote
a recurrence risk of less than 5%.
4547
Be-
cause of these risks, these women are
informed that they are at increased risk
for adverse pregnancy outcome (preterm
delivery, fetal growth restriction, abruptio
placentae, and fetal death) in subsequent
pregnancies. Therefore, they require close
monitoring during subsequent gestations.
Currently, there is no preventive therapy
for recurrent HELLP syndrome. Liver
function tests were studied in 54 women
at a median of 31 months (range, 3101
months) after pregnancies complicated
by the HELLP syndrome.
48
Serum levels
of AST, LDH, and conjugated bilirubin
474 OBrien and Barton
were found to be normal. Total bilirubin
levels, however, were elevated in 11
(20%) of the studied women. The authors
of this report suggested the possibility that
a dysfunction of the bilirubin-conjugating
mechanism represents a risk factor for the
development of this syndrome.
48
There are 2 reports describing long-
term renal function after HELLP syn-
drome.
38,49
One of the reports included
23 patients whose pregnancies were com-
plicated by HELLP syndrome and acute
renal failure; 8 of these women had 11 sub-
sequent pregnancies with 9 resulting in
term gestation.
38
All 23 women also had
normal blood pressures and renal function
at an average follow up of 4.6 years (range,
0.511 years). The other study compared
renal function after at least 5 years after
HELLP syndrome in 10 patients with the
respective ndings in 22 patients with pre-
vious normotensive gestation.
49
There
were no differences in renal function tests
between the 2 groups. These ndings sug-
gest that the development of HELLP syn-
drome with or without renal failure does
not affect long-term renal function.
Summary
Signicant hepatic involvement by pre-
eclampsia leading to hepatocyte necrosis
and thrombocytopenia should alarm the cli-
nician regardless of whether criteria for
HELLP syndrome have been fully achieved.
Liver parenchyma is relatively unforgiving
of the endovascular insult presented by se-
vere preeclampsia. This vasculopathy can
result in adverse maternal outcomes such
as DIC, subcapsular hematoma, hepatic in-
farction, and death. The greatest challenges
in caring for women with this disease are ap-
preciating the diagnosis, instituting timely
interventions, and avoiding associated com-
plications. The addition of high-dose gluco-
corticoids to the armamentarium of therapy
for HELLP syndrome may improve out-
comes for both the mother and fetus, but de-
nitive proof by randomized trials is lack-
ing. Delivery is the ultimate cure, and opti-
mizing the status of a seriously ill patient
before delivery improves outcome.
References
1. Levine RJ, Maynard SE, Qian C, et al. Circu-
lating angiogenic factors and the risk of pre-
eclampsia. N Engl J Med. 2004;350:672683.
2. Pritchard JA, Weisman R, Ratnoff OD, et al.
Intravascular hemolysis, thrombocytopenia
and other hemologic abnormalities associated
with severe toxemia of pregnancy. N Engl J
Med. 1954;250:8998.
3. Chesley LC. Disseminated intravascular co-
agulation. In: Hypertensive Disorders in
Pregnancy. New York: Appleton-Century-
Crofts; 1978:88118.
4. Weinstein L. Syndrome of hemolysis, elevat-
ed liver enzymes, and low platelet count: a
severe consequence of hypertension in preg-
nancy. Am J Obstet Gynecol. 1982;142:
159167.
5. Roberts JM, Cooper DW. Pathogenesis and
genetics of pre-eclampsia. Lancet. 2001;
357:5356.
6. Roberts JM. Preeclampsia, what we know
and what we do not know. Semin Perinatol.
2000;24:2428.
7. Barton JR, Riely CA, Adamel TA, et al. He-
patic histopathologic condition does not
correlate with laboratory abnormalities in
HELLP syndrome (hemolysis, elevated liver
enzymes, and low platelet count). Am J Ob-
stet Gynecol. 1992;167:15381543.
8. Aarnoudse JG, Houthoff HF, Weits J, et al. A
syndrome of liver damage and intravascular
coagulation in the last trimester of normoten-
sive pregnancy. Aclinical and histopatholog-
ical study. Br J Obstet Gynaecol. 1986;93:
145155.
9. Arias F, Mancilla-Jimenez R. Hepatic brin-
ogen deposits in pre-eclampsia. Immunou-
orescent evidence. N Engl J Med. 1976;295:
578582.
10. Barton JR, Sibai BM. Hepatic imaging in
HELLP syndrome (hemolysis, elevated liver
enzymes, and low platelet count). Am J
Obstet Gynecol. 1996;174:18201827.
11. Sibai BM, Taslimi MM, El-Nazer A, et al.
Maternal-perinatal outcome associated
with the syndrome of hemolysis, elevated
Controversies With HELLP Syndrome 475
liver enzymes, and low platelets in severe
preeclampsia-eclampsia. Am J Obstet Gyne-
col. 1986;155:501509.
12. Martin JN Jr, Rinehart B, May WL, et al. The
spectrumof severe preeclampsia: Comparative
analysis by HELLP syndrome classication.
Am J Obstet Gynecol. 1999;180:13731384.
13. VanPampus MG, Wolf H, Westenberg SM,
et al. Maternal and perinatal outcome after
expectant management of the HELLP syn-
drome compared with preeclampsia without
HELLP syndrome. Eur J Obstet Gynecol
Reprod Biol. 1998;76:3136.
14. Visser W, Wallenburg HCS. Temporising
management of severe pre-eclampsia with
and without the HELLP syndrome. Br J
Obstet Gynaecol. 1995;102:111117.
15. Abramovici D, Friedman SA, Mercer BM,
et al. Neonatal outcome in severe preeclamp-
sia at 24 to 36 weeks gestation: does the
HELLP (hemolysis, elevated liver enzymes,
and low platelet count) syndrome matter?
Am J Obstet Gynecol. 1999;180:221225.
16. Sibai BM. The HELLP syndrome (hemoly-
sis, elevated liver enzymes, and low plate-
lets): much ado about nothing? Am J Obstet
Gynecol. 1990;162:311316.
17. Weinstein L. Preeclampsia/eclampsia with
hemolysis, elevated liver enzymes and
thrombocytopenia. Obstet Gynecol. 1985;
66:657660.
18. Sibai BM, Ramadan MK, Usta I, et al.
Maternal morbidity and mortality in 442
pregnancies with hemolysis, elevated liver
enzymes, and low platelets (HELLP syn-
drome). Am J Obstet Gynecol. 1993;169:
10001006.
19. Sibai BM. Diagnosis and management of
gestational hypertension and preeclampsia.
Obstet Gynecol. 2003;102:181192.
20. Clark SL, Phelan JR, Allen SH, et al. Ante-
partum reversal of hematologic abnormali-
ties associated with the HELLP syndrome.
J Reprod Med. 1987;32:781784.
21. Magann EF, Bass D, Chauhan SP, et al. An-
tepartum corticosteroids: disease stabiliza-
tion in patients with the syndrome of
hemolysis, elevated liver enzymes, and low
platelets (HELLP). Am J Obstet Gynecol.
1994;171:11481153.
22. Magann EF, Perry KGJr, Meydrech EF, et al.
Postpartum corticosteroids: accelerated
recovery from the syndrome of hemolysis,
elevated liver enzymes, and low platelets
(HELLP). Am J Obstet Gynecol. 1994;171:
11541158.
23. Tompkins MJ, Thiagarajah S. HELLP (he-
molysis, elevated liver enzymes, and low
platelet count) syndrome: the benet of cor-
ticosteroids. Am J Obstet Gynecol. 1999;
181:304309.
24. OBrien JM, Milligan DA, Barton JR. Im-
pact of high-dose corticosteroid therapy for
patients with HELLP (hemolysis, elevated
liver enzymes, and low platelet count) syn-
drome. Am J Obstet Gynecol. 2000;183:
921924.
25. Vigil-DeGracia P, Garcia-Caceres E. Dexa-
methasone in the postpartum treatment of
HELLP syndrome. Int J Gynaecol Obstet.
1997;59:217221.
26. Yalcin OT, Sener T, Hassa H, et al. Effects of
postpartum corticosteroids in patients with
HELLP syndrome. Int J Gynaecol Obstet.
1998;61:141148.
27. Isler CM, Barrilleaux PS, Magann EF, et al.
A prospective, randomized trial comparing
the efcacy of dexamethasone and betame-
thasone for the treatment of antepartum
HELLP syndrome. Am J Obstet Gynecol.
2001;184:13321339.
28. Sibai BM. Diagnosis, controversies, and
management of the syndrome of hemolysis,
elevated liver enzymes, and low platelet
count. Obstet Gynecol. 2004;103:981991.
29. OBrien JM, Shumate SA, Satchwell SL,
et al. Maternal benet to corticosteroid
therapy in patients with HELLP (hemolysis,
elevated liver enzymes, and low platelets)
syndrome: impact on the rate of regional an-
esthesia. Am J Obstet Gynecol. 2002;186:
475479.
30. Martin JN Jr, Thigpen BD, Rose CH, et al.
Maternal benet of high-dose intravenous
corticosteroid therapy for HELLP syn-
drome. Am J Obstet Gynecol. 2003;189:
830834.
31. Bush K, OBrien JM, Milligan DA, et al. The
utility of umbilical artery Doppler in women
with the HELLP (hemolysis, elevated liver
enzymes, and low platelets) syndrome. Am
J Obstet Gynecol. 2001;184:10871089.
32. Briggs R, Chari RS, Mercer B, et al. Post-
operative incision complications after
cesarean section in patients with antepar-
tum syndrome of hemolysis, elevated liver
476 OBrien and Barton
enzymes, and low platelets (HELLP): does
delayed primary closure make a difference?
Am J Obstet Gynecol. 1996;175:893896.
33. Chelmow D, Rodriguez EJ, Sabatini MM.
Suture closure of subcutaneous fat and
wound disruption after cesarean delivery:
a meta-analysis. Obstet Gynecol. 2004;
103:974980.
34. Goodlin RC, Anderson JC, Hodgson PE.
Conservative treatment of liver hematoma
in the postpartum period. J Reprod Med.
1985;30:368370.
35. Manas KJ, Welsh JD, Rankin RA, et al.
Hepatic hemorrhage without rupture in
preeclampsia. N Engl J Med. 1985;312:
424426.
36. Neerhof MG, Zelman W, Sullivan T. Hepatic
rupture in pregnancy: a review. Obstet Gyne-
col Surv. 1989;44:407409.
37. Sibai BM, Mabie BC, Harvey CJ. Pulmonary
edema in severe preeclampsia-eclampsia:
analysis of 37 consecutive cases. Am J Obstet
Gynecol. 1987;156:11741179.
38. Sibai BM, Ramadan MK. Acute renal failure
in pregnancies complicated by hemolysis,
elevated liver enzymes, and low platelets.
AmJ Obstet Gynecol. 1993;168:16821687.
39. Smith LG Jr, Moise KJ Jr, Dildy GA, et al.
Spontaneous rupture of the liver during preg-
nancy: current therapy. Obstet Gynecol.
1991;77:171175.
40. Loevinger EH, Lee WM, Anderson MC.
Hepatic rupture associated with preg-
nancy: treatment with transcatheter
embolotherapy. Obstet Gynecol. 1985;65:
281284.
41. Martin JN Jr, Perry KG, Blake PG, et al.
Better maternal outcomes are achieved
with dexamethasone therapy for postpartum
HELLP (hemolysis, elevated liver enzymes,
and thrombocytopenia) syndrome. Am J
Obstet Gynecol. 1997;177:10111017.
42. Martin JN Jr, Files JC, Blake PG, et al.
Plasma exchange for preeclampsia: I. Post-
partum use for persistently severe pre-
eclampsia-eclampsia with HELLP syndrome.
Am J Obstet Gynecol. 1990;162:126137.
43. Martin JN Jr, Files JC, Blake PG, et al. Post-
partum plasma exchange for atypical pre-
eclampsia-eclampsia as HELLP syndrome.
AmJ Obstet Gynecol. 1995;172:11071127.
44. Schwartz ML. Possible role for exchange
plasmapheresis with fresh frozen plasma
for maternal indications in selected cases
of preeclampsia and eclampsia. Obstet
Gynecol. 1986;68:136139.
45. Sibai BM, Ramadan MK, Chari RS, et al.
Pregnancies complicated by HELLP syn-
drome (hemolysis, elevated liver enzymes,
and low platelets): Subsequent pregnancy
outcome and long-term prognosis. Am J
Obstet Gynecol. 1995;172:125129.
46. Van Pampus MG, Wolf H, Mayruhu G, et al.
Long-termfollow-up in patients with a histo-
ry of (H)ELLP syndrome. Hypertens Preg-
nancy. 2001;20:1523.
47. Chames MC, Haddad B, Barton JR, et al.
Subsequent pregnancy outcome in women
with a history of HELLP syndrome at #28
weeks of gestation. Am J Obstet Gynecol.
2003;188:15041508.
48. Knapen M, VanAltena A, Peters WHM, et
al. Liver function following pregnancy
complicated by the HELLP syndrome. Br
J Obstet Gynaecol. 1998;105:12081210.
49. Jacquemyn Y, Jochems L, Duiker E, et al.
Long-term renal function after HELLP
syndrome. Gynecol Obstet Invest. 2004;57:
117120.
Controversies With HELLP Syndrome 477