Download M GovenderWhere is HELLP

17 August 2012
No.27
Some Help with HELLP
M Govender
Commentator: A Ganaw
Department of Anaesthetics
Moderator: S Reddy
CONTENTS
WHY IS IT IMPORTANT? IS IT COMMON? ..........................................3
DEFINITION OF HAEMOLYSIS .............................................................5
DEFINITION OF ELEVATED LIVER ENZYMES ....................................7
DEFINITION OF THROMBOCYTOPENIA..............................................8
PRESENTING SYMPTOMS ...................................................................9
CLINICAL FINDINGS .............................................................................9
PATHOGENESIS ................................................................................. 10
CLASSIFICATION ................................................................................12
SHORT COMINGS ...............................................................................12
Differential Diagnosis ......................................................................13
Morbidity........................................................................................... 14
Management ..................................................................................... 15
Anaemia ............................................................................................ 17
Magnesium Sulphate .......................................................................19
Other Options ................................................................................... 19
Mode of Delivery ..............................................................................19
Anaesthesia and Analgesia ............................................................. 20
Hepatic Complications ....................................................................20
Post-partum Course.........................................................................21
CONCLUSION...................................................................................... 22
REFERENCES ..................................................................................... 24
2
SOME HELP WITH HELLP
WHY IS IT IMPORTANT? IS IT COMMON?
 1/1000 pregnancies.(7)
 15% in second trimester, 50% third trimester.
 Remainder within 48 hours after delivery, some up to 6 days after.
 Pre-eclampsia is complicated by HELLP in 4-12% of the cases.
 Eclampsia is complicated in 10% of cases.
 Weinstein etal described in a study that 29 pregnancies were
found to have a “severe subset of pre-eclampsia and eclampsia” in
1982.(8)
3
 Since then there has been an increase in research to accurately
define this entity and to further investigate the impact of what
correct management has on morbidity as well as mortality.
 There seems to be an ethnic, age and parity variance; with
increased incidence in multiparous and older aged groups.
 Sullivan etal found that, of those pregnancies previously affected
by HELLP, that there was a recurrence of at least 19% in
subsequent pregnancies. (6)
 Although Sibai etal described only a recurrence of 3%. (7)
 Mortalities are as high as 25%.
 It has been associated with poor fetal outcome, with perinatal
mortality rates between 7-60%.
 However it is possible that these rates are related more with
gestational age and prematurity rather than HELLP alone.
 It is well known that HELLP stands for Haemolysis, Elevated Liver
Enzymes, and Low Platelets; but the question remains what does
each aspect mean?
 Whilst no consensus still exists as to the exact definitions, a
guideline is possible to direct us towards a possible diagnosis and
hence management.
4
DEFINITION OF HAEMOLYSIS
 It is evident that in order to confirm HELLP, lab diagnostic tests are
necessary.
 The
possible
pathogenesis
may
MicroangiopathicHaemolyticAnaemia.
be
secondary
to
 Red cell fragmentation due to flow through damaged blood vessels
from endothelial dysfunction results in the production of
shistocytes (fragmented red cells) some with spicula known as
Burr cells.
 The increase in production of a new line of red blood cells to
compensate for the loss is reflected by the increase in the number
of reticulocytes.
 The liberated haemoglobin may then be converted to
unconjugated bilirubin in the spleen or even complex with
haptoglobin in the plasma.
 The liver immediately removes this complex thus resulting in low
haptoglobin levels.
The Presence of Haemolysis is the presence of :
5
(MRCP: polycythemia)
 Peripheral Blood Smear – fragmented red cells and increased
reticulocyte count.
 Spherocytes, Schistocytes, Burr Cells.
 Haptoglobin - <0.4g/l - <1g/l.
 Elevated LDH - >600.
 Anaemia – Microangiopathic Haemolytic.
 Elevated Unconjugated Bilirubin.
 Presence of Abnormal Blood Smear, Elevated Bilirubin, Elevated
LDH – confirms the Diagnosis.(8)
 Wilke etal found an abnormal peripheral smear in 11 out of 25
patients.(8)
 Paternoster etal found that only 25% of their patients had elevated
LDH and Bilirubin.(8)
 Unfortunately these are non-specific tests and it must be noted
that only elevated unconjugated bilirubin indicates haemolysis.
 And the most sensitive marker is in fact haptoglobin levels.
6
DEFINITION OF ELEVATED LIVER ENZYMES
 AST > 2000 or possibly >4000.
 Elevated ALT may also be seen.
 An associated elevation in LDH may also be indicative of liver
injury.
 Glutathione-s-transferase alpha deficiency could be a better
indicated than transaminases but limited studies are present to
confirm this.
 It is postulated that liver injury occurs from fibrin deposits thus
causing obstruction in hepatic blood flow and eventually
necrosis.(2)
 A new discussion has occurred concerning CD95L–believed to
mediate hepatocyte apoptosis.
 Strand etal postulates that CD95L, a placental derived humoral
factor, is released into maternal circulation, thus becoming
possibly important in pathogenesis of HELLP.(2)
 It seems that there is a correlation with increasing levels of serum
CD95 and HELLP severity.
 Hence it may be possible to predict liver damage with CD95 levels
as well as the above blood parameters, however this is still under
investigation.
 In severe cases there may be formation of Intrahepatic
Haemorrhage, Subcapsular Haematomas and Hepatic Rupture.
 Further radiographical evidence can confirm the presence of liver
damage and it may be necessary to use both ultrasound as well as
blood tests to diagnose this.
 Liver biopsies support cellular necrosis.(2)
 They also point to similarities with acute fatty liver of pregnancy as
findings of microvesicular fatty deposits are confirmed.(2)
7
(imaging of nontraumatic hemorrhagic hepatic lesions, Radiographics
March 2000 vol. 20 no. 2 367-378)
DEFINITION OF THROMBOCYTOPENIA
 “HELLP syndrome should be suspected in any patient who
shows a significant drop in the platelet count during the
antenatal period” (1)
 It is possibly the first indicator of the presence of HELLP.
 A number less than 100,000/µL.
 Severity can be ascertained using platelet numbers however and it
is found to be the basis of the classification of HELLP.
 Of note being the Nadir classification as postulated by Martin etal
who were able to create separate groups based on platelet count
nadir. (1)










From this we find that:
Those in Class 1 have a count of 50,000/µL.
Those in Class 2 a count of 50,000 – 100,000/µL.
And finally Class 3 a count of 100,000 – 150,000/µL.(6)
It may be further considered that those with a count less than
150,000/µL can be classified as Mild.
Moderate severity with counts of 50,000 – 100,000/µL.
Severe with counts <50,000/µL.(6)
PTT and Fibrinogen levels are often found to be normal.
Fibrinogen levels only fall below 300mg/dL if DIC develops.
DIC considered if there are any other laboratory findings present.
which correlate with diagnosis. (2)
8
PRESENTING SYMPTOMS
 If all of the laboratory tests are considered then it does seem
simple to diagnose HELLP.
 So why then does it still seem to be proving such an elusive entity?
 It is noted that it is one of the obstetric complications most
frequently misdiagnosed. (6)
 Well perhaps the answer lies in firstly the presenting symptoms.
 They are unfortunately non-specific.
 90% have general malaise.
 65% epigastric pain.
 30% have vomiting and headache.
 Most have vague flu-like symptoms.
 Others may have GIT bleeding and Haematuria.(2)
 Hence it is often found that most physicians miss HELLP and thus
miss the chance for diagnostic tests and early management.
 A further confounder may be the clinical findings.
CLINICAL FINDINGS
 90% have right upper quadrant pain.
 30% having some form of oedema.
 Interesting to note that hypertension and proteinuria are
uncommon findings with only 30% having them, but as HELLP
syndrome increases in severity it is found that higher blood
pressures and more proteinuria are present.
9
 Several have normal clinical findings.
 For this alone it is found that many diagnoses have been delayed
by up to 8 days and often some are never diagnosed at all. (6)
 Martin etal state that it is safest to consider any pregnant patient,
in the second or third trimester, with right upper quadrant pain
especially if with associated nausea and vomiting, to have HELLP
until it is excluded. (2)
 Further more if any patient with pre-eclampsia presents with
severe epigastric pain, it should then be assumed that she may
have hepatic rupture or hemorrhage, and now should
be
(8)
considered an obstetrical emergency.
 Taking both clinical findings and presenting symptoms into
consideration it does become clear as to why HELLP syndrome is
often missed These are all extremely non-specific, and without
experience or knowledge patients can be easily misdiagnosed,
and often mistreated.
PATHOGENESIS
 Evidence present suggests a possible connection with immune
mediated reactions.(2)
 Cytokine mediated response may cause endothelial damage at a
cellular level.
 HELLP syndrome may indeed have its beginnings in altered
ischemic placental tissue, function as well altered development.
 This in turn results in platelet, and vasoconstrictor activated or
even deranged vascular relaxation related endothelial breakdown.
 Several indicators promote an inflammatory association.
10
Figure 1
 Further investigation seems to promote the possibility that the liver
may be play a pivotal role in pathogenesis.(3)
 As previously noted CD95L is a possible cause of cellular
apoptosis.
 Proteins of placental origin may result in hepatocellular damage.
 Spontaneous rupture and resultant hemorrhage may be a leading
cause of death.
 HELLP does seem to be a multi-organ disease finding possible
origins associated with vascular damage and increased platelet
activity.
 The eventual downward spiral begins with thromboxane A and
serotonin release activating the platelet cascade with further
endothelial damage which may only be resolved once delivery or
termination of pregnancy has occurred .(6)
 As noted before haemolysis may be due to passage of blood cells
through the damaged vessels.
 Haeger etal reported increases in tumor necrosis factor α. (8)
 Investigations show that TNF-α effect on endothelial cells as well as
coagulation may play a role in HELLP.
11
CLASSIFICATION
Figure 2
 The basis of classifying HELLP is the platelet count nadir.
 Further assessment
transaminases.
is
brought
about
by
looking
at
liver
 All to direct and plan management.
 The concept of partial or incomplete HELLP was coined by Martin
etal for those HELLP patients who don’t present with or conform to
all of the parameters.(2)
 “True” HELLP or complete if all parameters are met. (2)
SHORT COMINGS
 While the classification is helpful, it does fall short in several areas.
 Class 1 and 2 combined in Tennessee – unable to discriminate
between groups.
 Mississippi – no place for incomplete or partial forms.
 Inadequate description of several clinical presentations.
 Despite this it is difficult to manage HELLP without classifying
severity therefore the above classification is necessary.
12
Differential Diagnosis
 Of concern is the concept that both clinical findings as well as
laboratory diagnosis can be found in several other disorders.
 These so called “mimics” are most likely the reason behind
misdiagnosis and mistreatment of HELLP.
 Commonest amongst these are viral hepatitis and cholangitis.
 Others include ITP, TTP and even acute fatty liver of pregnancy as
well as SLE and Haemolytic Uraemic Syndrome.
 Acute fatty liver presents in the third trimester with the same signs
and symptoms as HELLP.
 Blood tests show thrombocytopenia, acute liver failure as well as
presence of DIC.
 It does have Hypoglycaemia and prolonged PT unlike HELLP.
 Radiology may show similar liver changes as that found in HELLP.
 Biopsy is the gold standard for confirming diagnosis.
 Idiopathic Thrombocytopenic Purpura(ITP) presents clinically with
purpura and petechiae due to the presence of thrombocytopenia
 Interesting to note however that pregnancy is not a reason for
increased risk.
 Thrombocytic Thrombocytopenic Purpura(TTP) shares injury of the
endothelium, aggregation of platelets, as well as anaemia, with
HELLP.
 A possible differential factor is the presence of neurology such as
seizures, headache, confusion and weakness.
 Haemolytic Uraemic Syndrome (HUS)presents post-partum with
renal failure.
 SLE is a multi-organ autoimmune disorder.
 40% with thrombocytopenia, 20% with anaemia.
 Hepatitis presents with the same symptoms and often blood results
parallel that of HELLP with elevated transaminases.
 Cholangitis has right upper quadrant pain in common.
 With all these pathologies having overlap with HELLP it does
present a difficult dilemma for medical personnel as HELLP is found
to be the last possibility on the list.
 Hence I have reason to hypothesize the possibility that the previous
epidemiology may be underestimating the prevalence of HELLP,
and in fact it may be found that HELLP is more common than we
believe it to be.
13
Morbidity
 2 broad categories can be formed, namely that of the mother and
that of the foetus.
For the mother:
 The most significant complication has been found to be acute renal
failure, a result of acute tubular necrosis due to vascular damage
and altered blood flow.
 Eclampsia occurs earlier in the pregnancy if associated with HELLP,
severity depending on HELLP severity.
 Spontaneous rupture of liver haematoma, however rare, is a serious
life threatening condition.
 Diagnosis confirmed with radiology and clinical symptoms of severe
epigastric pain and hypotension.
 The most common is AbruptioPlacantae and DIC.
 The 2 seem interrelated as Abruptio increases the occurrence of
DIC.
 Audibertetal reported an occurrence of atleast 1.5% of HELLP
syndrome patients complicated by cerebral haemorrhage (11)
 Others have found less numbers complicated with stroke and
brainstem thrombosis.
For the Foetus
 Foetal outcome is poor if delivery is indicated early, but steroid
therapy may help.
 The risk of IUGR still remains high with some authors believing that
risk for SGA may also be increased.
 About 15 – 30% of pregnancies may be at risk of thrombocytopenia
and thus increasing the risk of intraventricular haemorrhage. (8)
 Some may even have persistent PDA’s.
 Most, I have noted, seem to believe that the risk of foetal
abnormalities are the same as those of normal healthy pregnancies.
 Whether or not this is true however remains controversial.
 Consensus is present however that, whether or not abnormalities do
occur, is dependent on gestational age.
14
Management
 Once HELLP is confirmed then what do we do?
 We need an accurate plan of action.
 I believe that in my readings these are probably the better methods
to treat HELLP Syndrome.
figure 3
 Stabilize mother, Assess fetal condition, decide indication for
prompt delivery.
 Immediate delivery at 34 weeks' gestation or later -> Caesar.
 Within 48 hours after evaluation, stabilization of the maternal
condition at 27 to 34 weeks gestation.
 Conservative management for more than 48–72 hoursat ? 27
weeks' gestation -> Caesar along with corticosteroids.
 This seems to be the cornerstone of guided management when
HELLP is diagnosed.
15
 Once again we are presented with broader categories concerning
management.
 As HELLP represents several deranged parameters and complicate
multiple organ systems we must focus on a management program
that not only concerns foetal health in terms of gestational age, but
also assists in treating the mother and each of the most severe
complications that ails her.
Firstly there is the Conservative Approach:
 Expectant management before 34 weeks possible if in a tertiary
care unit with close maternal and foetal surveillance.
 Advantages due to prolongation of pregnancy weighed against the
increased risks for maternal and foetal complications.
 As directed from the previous flow diagram it may be possible to
decide on whether to wait the course of pregnancy or take an active
more aggressive approach, all of which hangs on gestational age.
Next Anti-Hypertensives:
 Whilst hypertension has been found to be uncommon, it is still
important to have a plan in place to treat it, as it is simple to treat
and assists in the prevention of any cerebro-vascular and cardiovascular as well as renal and even hepatic dysfunction.
 So what is our definition of hypertension in pregnancy?
 Frishmanetal states that any systolic pressure increase of 30mmHg
or a diastolic increase of 15mmHg requires observation. (18)
 Hypertension after 20 weeks gestation in the previously
Normotensive is Gestational Hypertension.
 Add Proteinuria and Pre-eclampsia occurs.
 So what are the drug choices available to us?
‘Oral Labetalol as a first-line antihypertensive, if this fails to control blood
pressure it should be given intravenously.’ (1)
 20mg iv then after 10 minutes 40mg.
 Then 80mg every 10-15 minutes. (18)
Failing this the next line seems to be:
 Nifedipine orally- 5-10mg, repeat in 30 minutes if necessary
- then 10-20mg every 3-6 hours(18)
careful with concurrent use of magnesium
sulphate
 Sodium nitroprusside–0.5-10 mcg/kg/min IV infusion (18)
 The end goal is diastolic blood pressures between 90-100 mmHg.
16
Treatment of Coagulopathy:
 It is necessary to assess the possibility of significant maternal
bleeding.
 Roberts etal speak of a count <40 as a predictor of haemorrhage.
(17)
 ‘Prior to caesarean section, or other surgical intervention, correction
of platelet numbers and coagulation defects is important. This
should include fresh frozen plasma and/or cryoprecipitate’. (1)
Platelet transfusion if
 Count < 20.
 Pre caesarean count of 40-50.
 Although platelet transfusion is contra-indicated in TTP and HUS
due to the consumption of these platelets.
 Most believe that prophylactic platelet transfusion has no value in
HELLP. (17)
Anaemia:
 The indications for transfusion seem to be directed by clinical
evaluation more than absolute laboratory counts.
 Signs include severe hypotension and pallor along with
compensatory tachycardia.
 Many do think that routine transfusions are unnecessary however
17
Use Of Corticosteroids:
 promote fetal lung maturity
 high-dose dexamethasone
 treatment with repeated doses
The Pros:
 It Accelerates maturation of the fetal lungs.
 Favourable maternal effects - diminished oedema, prevention of
thrombotic microangiopathic anaemia.
 Antenatal - reduce the risk of IVH and NEC – 24 to 34 weeks
gestation with associated platelet count of greater than 50.
High-Dose:
 10 mg dexamethasone every12 hours – reduction of maternal
morbidity as well rapid platelet count recovery.
 Martin et al. (2006).
 Recommends for short-term intervention.
 Advocates continuation of pregnancy for more than 48 hours after maternal and fetal morbidity and mortality.(2)
The Controversy:
 Fonseca et al.
 Found no support for the routine use of high-dose dexamethasone.
 May be necessary to consider Preterm delivery –greater benefit for
the fetusand the mother.
 Effective in severe preeclampsia, ? Of less benefit in HELLP
syndrome.(2)
 Sibaiet al.
 States that high-dose is Not for routine use.
 Promotes regime of 2 doses of betamethasone every 12 hours
intramuscularly, or 6 mg dexamethasone intravenously every 12
hours.
 For delivery 24 hours after the last dose.(7)
18
Magnesium Sulphate:
 Prophylaxis seems to be advocated, even in the absence of
hypertension. (3)
 It is the primary drug of choice to prevent seizures.
 4-6 gram of a 20 percent solution as a bolus.
 Then a maintenance infusion of 2 grams per hour.
 Close attention to be paid to urine output and blood magnesium
levels.
Other Options:
 It has been postulated that anti-thrombin might a possible treatment
alternative, but this is still under investigation.(2)
 No current data has been found to support or prove its use in
HELLP, but some show benefit in pre-eclampsia.
 Newer studies have shown a reduction in glutathione levels in
HELLP.(2)
 Some benefit may be found in replacing glutathione and reducing
intracellular damage.
 Again further investigation is needed.
Mode of Delivery:
 class 3 – term then spontaneous delivery.
 class 2 or class 1 –34 weeks delivered immediately after pressure
control.
 obstetric indications – cervical status, obstetric history, the
maternal and the fetal condition.
 < 34 weeks, worsening uncontrollable maternal condition or foetal
distress.
 Maternal indications – pressure > 160/110 mmHg, worsening
renal function, ascites, 19 bruption placentae, oliguria, pulmonary
oedema or eclampsia - Caesar.
 24 and 34 weeks– Corticosteroids then delivery induction 24 hours
later.
 Caesar before 30 weeks.
 Close monitoring after 48 hours.
19
Anaesthesia and Analgesia:
 IVI Opioids are proposed with bleeding risk.
 Neuraxial technique still remains a go to method not only for
analgesia during labour but as anaesthesia for caesarean section
as well – Epidural, however controversial, is the one of choice.(1)
 Nerve blocks are useful second choice to epidurals.
 Perineal infiltration for episiotomy and perineal repair.
 Regional with Platelets >100 is considered safe.
 Contraindicated if the Platelets <75.
 Of course a general anaesthetic is the next choice if a regional is
contra-indicated.
 As an anaesthetic provider it may be important to recognize that our
involvement does not begin or even stop at providing just
anaesthesia and analgesia.
 We must consider optimisation of pregnant mothers with HELLP
prior to any procedure, whether it may be normal vaginal delivery or
caesarean.
 Hence we must play an active role in every part of management
from the previous possible guidelines till eventually anaesthesia if
required.
 Careful consideration must be given to those who are complicated
with Hepatic complications as below, as well as other complications
to guide our plan for anaesthesia and analgesia.
Hepatic Complications:
 INFARCTION – found to resolve spontaneously after delivery.\
 HAEMATOMA OR RUPTURE – require volume replacement and
transfuse as needed.
 If severe then Percutaneous embolization of the hepatic artery.
 May take Months to resolve.
 SURGERY – if there is haemodynamic instability or persistent
bleeding or increased pain or haematoma expansion.
 Then Packing and drainage.
20
Post-partum Course:
 Many note that most HELLP Syndrome resolves, at a graded pace,
post-delivery.
 Some however persist post delivery and at least 30% develop after
birth.(8)
 As before groups are divided as to the benefit of corticosteroid
therapy.
 Plasma exchange with fresh frozen plasma has been put forward as
therapy for those who continue to have increasing bilirubin and
creatinine at least 72 hours post delivery.
 If haemolysis, thrombocytopenia and hypoproteinaemia persist,
replacement of red blood cell concentrate and platelets, and
albumin supplementation may be necessary – once again
controversy is present as there is no consensus as to benefit of this
regime.(1)
 It was considered that those with reduced urine output due to
possible renal injury may benefit from the use of furosemide. (19)
 Further investigation has proved this incorrect.
 Newer management protocols seem to advocate a fluid bolus of
250-500 mls.(19)
 Finally, since some suffer from DIC and have a delayed resolution,
it was proposed that heparin may play a role in management.(2)
 Recent studies have shown a high risk of post-partum haemorrhage
and as a result heparin has been excluded as a viable treatment
option.(2)
21
CONCLUSION
 HELLP may be more common than previously stated.
 The difficulties involved in not only accurately confirming diagnosis,
but also making the diagnosis seems to show that there is a definite
necessity to create a standardized definition.
 The trouble arises due to the presence of other common
pathologies who ‘mimic’ HELLP.
 Hence consensus still remains out of our grasp.
 The articles available so show that there are certain parameters
which we can look for to better define HELLP and, in so doing,
further prevent morbidity.
 Hopefully these have shown some clarity as to what HELLP is and
how to treat it.
 Despite these short comings we are able to create a classification
and from there a possible management protocol.
 Once again consensus is required, but most agree that gestational
age as well as HELLP severity is an important factor.
 Gestational age guides us as to whether immediate delivery is
required, and also provides a platform to assess foetal prognosis
post delivery.
 The severity of thrombocytopenia provides us with a possible
classification and thus an assessment of severity.
 From this we can assess the urgency for intervention and whether
any intervention is beneficial.
 It does seem that most advocate looking at each parameter as well
as clinical findings and treat each with a specific goal and with
specific management.
 There seems to be a short fall in stating whether the mother or
foetus takes precedence, but understanding is that perhaps the
22
mother is our number one patient and if she is stabilized then the
foetus will be too.
 The anaesthetic team plays an important and active role in every
aspect of this disease from the beginning, ending with analgesia
and anaesthesia when delivery is warranted or surgical intervention
is required for the possible complications.
 Questions still do present themselves however:
 Firstly there are no reference to whether any of the patients in these
studies were normotensive or hypertensive pre-pregnancy.
 Thus the question is, will that change our goals and whether HELLP
is at increased risk or commoner in these patients.
 Second most of these studies were done in first world countries.
 Do they translate as well in our hospitals?
 How accurate are the diagnosis in KZN?
 How useful are the interventions in our Hospitals, and therefore
what are the outcomes?
 With these questions in mind HELLP can be diagnosed and
properly treated.
 Further investigation may be required to answer the previous
questions.
 Hopefully the answers may be found in the near future.
 Until then, the take home message is that HELLP means
Haemolysis, Elevated Liver Enzymes, and Low Platelets.
 That each of these has a specific definition which can be confirmed
in the lab.
 That HELLP requires a multifactorial approach
anaesthetics can play an active role in management.
23
and
that
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