HELLP SYNDROME

Prof. M.C.BansalMBBS., MS., FICOG., MICOG.Founder Principal & Controller,Jhalawar Medical College & Hospital Jjalawar.MGMC & Hospital , sitapura ., Jaipur

INDRODUCTION

The spectrum of disease resulting from pathophysiology of pre-eclampsia continues to challenge diagnostic accuracy of clinicians.

Out of pre- eclampsia’s various manifestations, a specific entity is HELLP syndrome.

The acronym HELLP was coined by Weinstein in 1982 to describe a syndrome consisting of Hemolysis, Elevated liver enzymes and Low platelet count.

DEFINITION

It is a syndrome that is characterized by hepatic endothelial disruption followed by platelet activation, aggregation and consumption, ultimately resulting in ischemia and hepatocyte death.

INCIDENCE HELLP Syndrome - 0.2 to 0.6% of

all pregnancies. Pre Eclampsia – 5 to 7% of all

pregnancies. Sibai et al reporetd 20%

incidence of HELLP in women with pre eclampsia.

70% cases diagnosed in antenatal period while 30% after delivery.

PATHOGENESIS The findings of this multisystem disease

are attributed to-› Abnormal vascular tone› Vasospasm › Coagulation defects

This vasculopathy either limited to hepatic segment or diffusely throughout liver.

More commonly involves smaller terminal arterioles yielding a characteristic histological features

1)Classical histological lesion in LIVER

Periportal or focal parenchymal necrosis in which hyaline deposits of fibrin like material

↓ Obstruction of hepatic blood flow ↓ Periportal necrosis Intra hepatic hemorrhage Subcapsular hematoma Eventual rupture of Glisson’s capsule

2) HEMOLYSIS

Hemolysis is due to a microangiopathic haemolytic anaemia (MAHA).

The term is now commonly described as thrombotic thrombocytopenic purpura.

More recently the term thrombotic microangiopathy is used to describe the syndrome charecterized by› Hemolytic anemia› RBC fragmentation› Thrombocytopenia › Thrombotic lesions in small blood vessels

Red cell fragmentation caused by high-velocity passage through damaged endothelium appears to represent the extent of small vessel involvement with intima damage, endothelial dysfunction and fibrin deposition.

Presence of fragmented (schizocytes) or contracted red cells with spicula (Burr cells) in the peripheral blood smear reflects the haemolytic process and strongly suggests the development of MAHA.

Peripheral smear shows-› Spherocytosis › Schizocytes› Reticulocytosis› Anisocytosis› Triangular cells› Helmet cells› Burr cells› Polychromasia

Destruction of red blood cells by haemolysis causes increased serum lactate dehydrogenase (LDH) levels and decreased haemoglobin concentrations.

Haemoglobinaemia or haemoglobinuria is macroscopically recognizable in about 10% of the women.

Liberated haemoglobin is converted to unconjugated bilirubin in the spleen or may be bound in the plasma by haptoglobin.

The haemoglobin-haptoglobin complex is cleared quickly by the liver, leading to low or undetectable haptoglobin levels in the blood, even with moderate haemolysis.

Low haptoglobin concentration can be used to diagnose haemolysis and is the preferred marker of haemolysis.

Thus, the diagnosis of haemolysis is supported by high LDH concentration and the presence of unconjugated bilirubin, but the demonstration of low or undetectable haptoglobin concentration is a more specific indicator.

3) THROMBOCYTOPENIA

Platelets (PLTs) < 150·109/L) in pregnancy may be caused by- › Gestational thrombocytopenia (GT)

(59%), › Immune thrombocytopenic

purpura (ITP) (11%), › Preeclampsia (10%), › HELLP syndrome (12%)

PLTs < 100·109/L are relatively rare in preeclampsia and gestational thrombocytopenia, frequent in ITP and obligatory in the HELLP syndrome (according to the Sibai definition).

Decreased Platelet count in the HELLP syndrome is due to their increased consumption.

Platelets are activated, and adhere to damaged vascular endothelial cells, resulting in increased platelet turnover with shorter lifespan.

DIC is the primary process in HELLP syndrome as suggested by some investigators but most patients show no abnormality on coagulation studies.

Patient who develop DIC generally are having well developed HELLP syndrome.

Immune system disorder theory The diffuse systemic nature & aetiopathology

of HELLP syndrome explained by possibility that Pre eclampsia intrinsically is an immunologically mediated systemic disorder.

Abnormal T & B lymphocyte function observed in patient with HELLP Syndrome .

There is an increased neutrophil- endothelial adhesiveness in pre- eclamptic patients

↓ Explains diffuse vascular implication of

disease process

RISK FACTORSHELLP Syndrome

Pre Eclampsia

Parity Multiparous Nulliparous

Age > 25yrs < 20yrs or > 45 yrs

Other relevant history

•White race•H/O Poor pregnancy outcome

•Family history of PIH•Chronic hypertension•Diabetes mellitus•Multifetal gestation•Less Antenatal visit

CLASSIFICATIONTENNESSEE CLASSIFICATION Based on laboratory criteria

1. Platelet count < 100,000/µL2. AST ≥ 70 IU/L & LDH ≥ 600 IU/L3. Hemolysis on peripheral smear

Partial HELLP Full HELLP

Any 2 of 3 criteria All of 3 criteria

MISSISSIPI CLASIFICATION (2006)

CLASS I › Platelet ≤ 50,000/µL(severe

thrombocytopenia)› AST ≥ 70 IU/L› LDH ≥ 600 IU/L› Hemolysis on smear

CLASS II› Platelet 50,000/µL to100,000/µL (moderate

thrombocytopenia)› AST ≥ 70 IU/L› LDH ≥ 600 IU/L› Hemolysis on smear

CLASS III› Platelet 100,000/µL to150,000/µL (mild

thrombocytopenia)› AST ≥ 40 IU/L› LDH ≥ 600 IU/L› Hemolysis on smear

Patients with FULL HELLP syndrome – › Are at higher risk for complication like DIC.› Should be considered delivery within 48

hrs. Patients with PARTIAL HELLP syndrome –

› Candidates for conservative management Patients with CLASS-I HELLP are at

higher risk for maternal morbidity and mortality than CLASS-II & III.

Class III HELLP syndrome is considered as a clinical significant transition stage or a phase of the HELLP syndrome which has the ability of progression.

DIAGNOSISCLINICAL FEATURES The clinical presentation in most

cases is vague & may be missed completely if higher degree of suspicion is not maintained.

About 7% of cases presents before 27 weeks, 46% cases before 37 weeks and 14% presents at term

With postpartum presentation, the onset is typically within first 48 hrs of delivery.

Symptoms Right sided upper abdominal pain or pain

around stomach 86-90%

Nausea 45-85% Headache 50% Malaise 80-90%

Signs Right upper quadrant tenderness 86% Increased blood pressure

67% Protenuria 85-90% Edema 55-65%

Typical patient Young, White woman ≥25yrs Multiparous Heavy with severe generalized edema 2nd or 3rd trimester c/o Rt. Upper quadrant pain since few days

for which she might be taking antacids. c/o malaise since few days, which may be

out of proportion to the discomfort expected by the stage of pregnency

Blood pressure is only slightly raised. Edema & proteinuria may or may not be

present

So, any pregnant woman presenting in OPD with malaise or viral like illness in 2nd or 3rd trimester should be evaluated with CBC and Liver function tests

Laboratory findings Thrombocytopenia occurs first followed

by raised liver enzymes and last is hemolysis.

Laboratory criteria for diagnosis —1. Low platelets - < 100,000/µL2. Elevated liver enzymes – AST > 70

IU/L - LDH > 600 IU/L

3. Hemolysis – Abnormal peripheral smear

- Total bilirubin > 1.2mg%

Leukocytosis Coagulation factors

› If DIC is not present – PT , aPPT, S. Fibrinogen will be normal

› If fibrinogen < 300 mg/dl along with other lab abnormality – DIC is suspected

› Positive D-dimer test is more sensitive indicator of sub clinical coagulopathy and may be positive before other coagulation studies are abnormal.

› Proteinuria S. uric acid – raised Hypogycemia- persistent, profound

hypoglycemia inspite of repeated glucose transfusion is peculiar to advanced HELLP syndrome.

Differential Diagnosis1. Diseases related to pregnancy

›      Benign thrombocytopenia of pregnancy›      Acute fatty liver of pregnancy (AFLP)

2. Infectious and inflammatory diseases, not specifically related to pregnancy:›      Virus hepatitis›      Cholangitis›      Cholecystitis›      Upper urinary tract infection›      Gastritis›      Gastric ulcer›      Acute pancreatitis

3. Thrombocytopenia›      Immunologic thrombocytopenia (ITP)›      Folate deficiency›      Systemic lupus erythematosus (SLE)›      Antiphospholipid syndrome (APS)

4. Rare diseases that may mimic HELLP syndrome›      Thrombotic thrombocytopenic

purpura (TTP)›      Haemolytic uremic syndrome (HUS)

Complications Maternal complications Eclampsia Abruptio placentae DIC Acute renal failure Severe ascites Cerebral oedema Pulmonary oedema Wound hematoma/infection

Maternal complications

Subcapsular liver hematoma Liver rupture Hepatic infarction Recurrent thrombosis Retinal detachment Cerebral infarction Cerebral Haemorrhage Maternal death

Fetal/neonatal complications

Perinatal death IUGR Preterm delivery Neonatal thrombocytopenia RDS

Spontaneous rupture of a Subcapsular liver haematoma in pregnancy is a rare, but life threatening complication.

Occurs 1 in 40,000 to 1 in 250,000 deliveries and about 1% to < 2% of the cases with the HELLP syndrome. Rupture most often occurs in the right liver lobe. The symptoms are sudden-onset severe pain in the epigastric and right upper abdominal quadrant radiating to the back, right shoulder pain, anaemia and

hypotension. The condition may be diagnosed by ultrasound,

CT or magnetic resonance imaging (MRI) examination.

Hepatic rupture may also occur in the post-partum period.

MANAGEMENT PLAN

Identification - clinical features - lab findings - D/D from other condition

Admission to hospital Stabilization•IV line ,Cross match•Catheterization•Respi assessment

Fetal assessment(NST,BPP,Color doppler )

Transport to tertiary care centre or latency for 24-48 hrs

Termination of pregnancy

Conservative approach for 48-72 hrs (<32wks POG, Partial HELLP,Tertiary health cenre)

Rebound / Resolution

●Monitor by lab Ix ●Stop MgSO4 24 hrs of delivery ●Continue antihypertensive & steroid

MANAGEMENT

In general, there are three major options for the management of women with severe preeclampsia and HELLP syndrome

These include: 1) Immediate delivery which is the primary choice at 34

weeks' gestation or later.2) Delivery within 48 hours after evaluation, stabilization

of the maternal clinical condition and Steroid treatment. At 27 to 34 weeks of gestation, this option appears appropriate and rational for the majority of cases.

3) Expectant (conservative) management for more than 48–72 hours may be considered in pregnant women before 27 weeks' gestation. In this situation, Steroid treatment is often used, but the regimens vary considerably.

Decision making in management

<32 wks 32-34wks >34wks

↓ ↓ ↓

Admit & conservative Mx Steroids Deliver

↓ ↓ No

Manage Pt based on Is pt eligible for conservative Mx ?

Clinical response during ↓ Yes

Period of observation Counsel pt abt benefit of continuing of

pregnency for ≥2 wks for lung maturity

↓

Worsens Stable Transfer pt to tertiary care centre

↓ ↓

Deliver Monitor pt in tertiary care centre

Role of steroids Whereas delivery is the mainstay of

treatment for the HELLP syndrome, Steroid treatment is a possible addendum. Present alternatives for Steroid treatment are:

1) Standard steroid treatment on maternal HELLP.

2) High-dose dexamethasone treatment of the mother.

3) Treatment with repeated doses to reduce maternal morbidity and hastening recovery.

Benefit of steroid treatment for the HELLP syndrome was first reported in 1984.

Mech. Of Action- Unknown Proposed mech - diminish oedema,

inhibit endothelial activation and reduce endothelial dysfunction

↓ Prevention of thrombotic microangiopathic anaemia, Inhibition of cytokine production

↓ induce anti-inflammatory effects in the HELLP syndrome

In fetus Benefit from steroid treatment of the

HELLP syndrome was reported in a publication from 1993 where less frequent grade III and IV IVH, necrotizing enterocolitis (NEC), retrolental fibroplasia and fewer neonatal deaths were observed.

In addition to accelerate foetal lung maturity, antenatal steroid has been used to reduce the risk of IVH and NEC in selected cases of the HELLP syndrome.

Effect of steroid depends on- Dose, Route & Duration of treatment

IV steroid- appear to have more rapid onset of action than IM better outcome in improving urine output & laboratory values.

Dose –increases platelet count when given in high doses

Duration –Duration of action of this medication is limited.

Patient may experience a worsening of their laboratory studies 48-72 hrs after dosing with steroid .– REBOUND PHENOMENON

Dosing schedule For most of patient with HELLP syndrome-10mg IV dexamethasone every 12 hrs until

delivery & then 10 mg IV dexamethasone every 12 hrs for

additional 3 doses post partum. For selected high risk cases with profound

thrombocytopenia with CNS dysfunction.20mg IV dexamethasone every 6hrs up to 4

doses

Recent evidence about the value of steroid treatment on maternal HELLP

In first largest randomized double blind, placebo controlled (dexamethasone versus placebo) study of 132 women by Fonseca et al. reported shorter mean hospitalization but no significant differences were found in recovery of platelet counts or liver enzymes.

A Cochrane analysis from 2004 concluded that steroid treatment did not affect maternal mortality and outcomes such as placental abruption, pulmonary oedema and liver complications.

Steroid is not curative but may create a WINDOW OF OPPORTUNITY for intervention before maternal condition may again deteriorate.

Role of trasfusion Platelet transfusion – is required eithr

before or after delivery, in presence of bleeding from puncture site, wound and intra peritoneal bleeding.

If platelet count <40,000/µL, 6 – 10 U of platelet is required.

PCV and FFP – required if coagulopathy is present.

Antithrombin III transfusion- correct hypercoagulability, stimulate prostacyclin production, regulate thrombin-induced vasoconstriction, improve foetal status.

In contrast to the use of heparin, antithrombin has not been shown to increase the risk of bleeding.

The potential benefit from antithrombin treatment of women with HELLP syndrome might be a reasonable objective to be tested in future well designed multicenter studies.

Management of post-partum HELLP syndrome

In most women with a HELLP syndrome, the maternal PLT counts continue to decrease immediately post-partum with an increasing trend on the third day.

About 30% of the HELLP syndromes develop after birth.

The time of onset ranged from few hrs to 7 days; the majority within the first 48 hoursafter delivery.

In post-partum HELLP syndrome, risk of renal failure and pulmonary oedema is significantly increased.

Since early post-partum administration of high-dose CS might accelerate recovery , its routine administration is highly advocated (10 mg of dexamethasone every 12 hours)

However, a randomized study showed that adjunctive use of intravenous dexamethasone for postpartum patients with severe preeclampsia did not reduce disease severity or duration.

There was no difference in maternal morbidity, duration of hospital stay, need for rescue scheme or the use of blood products between the groups.

These findings did not support the use of dexamethasone in the puerperium for recovery of women with HELLP .

Women with a HELLP syndrome who demonstrate progressive elevation of bilirubin or creatinine for more than 72 hours after delivery may benefit from plasma exchange with fresh frozen plasma.

In the case of continuing haemolysis, persistent thrombocytopenia and hypoproteinaemia, post-partum erythrocyte and thrombocyte substitution, as well as albumin supplementation, are standard treatment regimens

Risk of recurrence and pre-conceptional counselling

Sibai has shown that oral contraceptives are safe in women with a prior HELLP syndrome.

Women with a history of the HELLP syndrome carry an increased risk of at least 20% (range 5–52%) that some form of gestational hypertension will recur in a subsequent gestation

Women with a history of HELLP syndrome at or before 28 weeks' gestation during the index pregnancy are at increased risk for several obstetric complications (preterm birth, pregnancy-induced hypertension and increased neonatal mortality) in a subsequent pregnancy.

Conclusions

HELLP Syndrome and its management still poses a problem in modern obstetrics

Precise diagnosis and early treatment with non-mineral corticosteroides such as Dexamethasone may help achieve favorable maternal and perinatal results.

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