HELLP syndrome

HELLP syndrome is a clinical syndrome that develops in pregnancy characterized by the triad of:

• H       Haemolysis (with microangiopathic blood smear)
• EL      Elevated Liver enzymes
• LP      Low Platelets

Signs and symptoms typically develop between 28 and 36 weeks of gestation, however second trimester or postpartum onset can also occur.

There is no “typical” clinical presentation for patients with HELLP syndrome, and so its diagnosis is based upon the presence of all of the laboratory abnormalities comprising its name (hemolysis with a microangiopathic blood smear, elevated liver enzymes, and low platelet count) in a pregnant woman.

HELLP syndrome probably represents a severe form of preeclampsia however the exact relationship between the two disorders remains controversial.

As many as 15 – 20 % of patients with HELLP syndrome do not have antecedent hypertension or proteinuria, leading some authorities to believe that HELLP is a distinct disorder from preeclampsia.

Both preeclampsia with severe features and HELLP syndrome may be associated with serious complications including hepatic manifestations, such as infarction, hemorrhage, and rupture.

Following delivery, (the only definitive therapy) maternal symptoms and signs usually begin to improve within 48 hours, but a protracted course is possible.

The outcome for mothers with HELLP is generally good, however, serious complications are relatively common.

History

HELLP syndrome was first described as a distinct clinical entity (as opposed to severe pre-eclampsia) by Dr. Louis Weinstein in 1982

Epidemiology

• Affects up to 1% of pregnancies.
• Seen in 10–20% of severe preeclampsia/eclampsia cases.
• Maternal mortality rate: 1–2%.

Pathophysiology

HELLP syndrome probably represents a severe form of preeclampsia however the exact relationship between the two disorders remains controversial.

As many as 15 – 20 % of patients with HELLP syndrome do not have antecedent hypertension or proteinuria, leading some authorities to believe that HELLP is a distinct disorder from preeclampsia.

• Likely arises from aberrant placental development.
• May involve more hepatic inflammation and coagulation activation than preeclampsia.

Risk Factors:

• Previous HELLP syndrome
• Previous preeclampsia
• Genetic predisposition
• Multiparity (unlike preeclampsia

Of those women who develop HELLP, in a subsequent pregnancy:

• 7 % develop HELLP again.
• 18 % develop preeclampsia
• 18 % develop gestational hypertension.

Clinical features

There is no “typical” clinical presentation for patients with HELLP syndrome, and so the diagnosis of HELLP syndrome is based upon the presence of all of the laboratory abnormalities comprising its name (hemolysis with a microangiopathic blood smear, elevated liver enzymes, and low platelet count) in a pregnant woman.

Signs and symptoms typically develop between 28 and 36 weeks of gestation, however second trimester or postpartum onset can also occur.

In one illustrative series (of 442 patients) HELLP syndrome, occurred:

1. Prior to delivery (70 %):
   • Of these patients, approximately 80 % were diagnosed prior to 37 weeks of gestation
   • Fewer than 3 % developed the disease between 17 – 20 weeks of gestation.
2. Postpartum (30 %):
   • These cases were usually within 48 hours of delivery, but as long as 7 days after birth.

Symptoms

1. Headache (reported rates vary from 33 – 61 % of cases)
2. Nausea / vomiting (reported rates vary from 29 – 84 % of cases)
3. Malaise
4. Visual disturbances (reported rates vary from 10 – 20 % of cases)
5. Right upper quadrant pain / epigastric (reported rates vary from 40 – 90 % of cases)

Examination:

1. Hypertension (reported rates vary from 82 – 88 % of cases)
2. Right upper quadrant / epigastric tenderness (reported rates vary from 40 – 90 % of cases)
3. Jaundice (reported rates are around 5 % of cases)
4. Proteinuria (reported rates vary from 86 – 100 % of cases)

Diagnostic criteria

Diagnostic Criteria (Tennessee Classification)

• AST > 2x upper limit of normal (>70 IU/L)is that it is a single test that reflects both hepatocellular necrosis and red cell hemolysis.
• Microangiopathic hemolytic anemia: schistocytes on blood smear
• Platelets ≤ 100,000/μL
• Total bilirubin ≥ 20.52 μmol/L

Note that women who do not meet all of the above laboratory abnormalities are considered to have partial HELLP syndrome. These patients may however progress to a complete expression of the HELLP syndrome.

Complications

Serious maternal morbidity may be present at initial presentation or may develop shortly thereafter.

The risk of serious morbidity correlates with increasing severity of maternal symptoms and laboratory abnormalities

Serious complications can include:

1. Anaemia
2. Disseminated intravascular coagulation (DIC) (around 20%)
3. Abruptio placentae (around 16%)
4. Acute renal failure (around 8%).
5. Bleeding:
   • Subcapsular or intraparenchymal liver hematoma (around 1%).
   • Intracerebral hemorrhage
   • Bleeding related to thrombocytopenia, including severe postpartum haemorrhage
6. Pulmonary edema/ ARDS (around 6%).
7. Hepatic:
   • Liver impairment/ failure
   • Liver infarcts
   • Hepatic rupture / bleeding
8. Retinopathy:
   • Retinal detachment (around 1%).
9. Fetal:
   • Fetal/neonatal and long-term prognosis are most strongly associated with gestational age at delivery and birth weight.
   • Maternal laboratory parameters do not predict fetal mortality.
   • Adverse fetal effects include:
     • Premature delivery 
     • Intrauterine growth restriction / FDIU

Differential Diagnoses

The principle differential diagnoses will include: 

1. Pre-eclampsia / eclampsia (assuming that HELLP syndrome is a distinct entity from these)
2. Acute fatty liver of pregnancy:
   • Clinical presentation commonly includes nausea and vomiting, abdominal pain, malaise, polydipsia/polyuria, jaundice/dark urine, encephalopathy, and hypertension/preeclampsia.
   • Severe hypoglycaemia is also a characteristic feature
   • HELLP may be difficult to distinguish clinically from AFLP since both occur at the same time in gestation and share several clinical features. It is important to differentiate between the two disorders because women with AFLP can rapidly develop liver failure and encephalopathy.
   • Additional laboratory testing can be helpful: prolongation of the prothrombin (PT) and activated partial thromboplastin time (aPTT), severe hypoglycemia, and elevated creatinine concentration are more common in women with AFLP than in those with HELLP.
   • Hypertension is more common in HELLP than in AFLP
3. Acute viral hepatitis
4. Other liver disease unrelated to pregnancy.
5. Haematological conditions: 
   • HUS:
     • Severe renal insufficiency is suggestive of haemolytic uremic syndrome (HUS), which may be caused by a Shiga toxin-producing organism, complement regulatory defect (inherited or acquired), or a drug effect.
   • TTP (rare in pregnancy):
     • A high LDH level with only modest elevation of AST is more consistent with TTP than HELLP.
     • The percentage of schistocytes on peripheral smear is often higher in TTP (2 – 5 %) than in HELLP (< 1 %).
   • DIC: prolongation of the PT and aPTT, and reductions in the plasma concentrations of factors V and VIII.
6. Conditions causing Right upper quadrant / epigastric pain in general:
   • Right upper quadrant / epigastric pain may mimicmany common non- obstetric conditions such as biliary colic/ cholecystitis or lower lobe lung conditions (pneumonia or pulmonary embolism)
   • These can of course all occur in pregnancy, however in any pregnant patient there must always be high index of suspicion for a pregnancy related condition – such as abruption, splenic artery aneurysm rupture, preeclampsia / eclampsia or HELLP

A correct diagnosis is vital, as “empiric” treatments may be contraindicated and dangerous, anticoagulation for suspected PE for example is contraindicated and dangerous in all of these pregnancy related conditions.          

Investigations

Blood tests:

• FBE (anemia, thrombocytopenia, schistocytes)
• U&Es, glucose
• LFTs (AST, ALT, bilirubin)
• Coagulation profile (usually normal unless DIC)
• LDH >600 U/L
• Blood group & save/crossmatch

Imaging:

• CXR (respiratory symptoms)
• Abdominal ultrasound (fetal well-being, abruption, liver complications)
• CT/MRI (suspected liver hematoma/rupture)

Management

In general terms, management is along similar lines as for pre-eclampsia/ eclampsia.

Following delivery, maternal symptoms and signs usually begin to improve within 48 hours, but a protracted course is possible.

The outcome for mothers with HELLP is generally good, however, serious complications are relatively common.

From an ED perspective the major immediate life threats are:

• Hepatic hemorrhage / subcapsular hematoma / liver rupture
• Multi-organ failure

In general terms management involves the following:

1.  Immediate attention to any ABC issues

2. Hypertension, (if present):

• The approach to antihypertensive therapy is the same as that for preeclampsia
• Oral antihypertensive drugs:
  • Oral antihypertensive drugs are mandatory for systolic blood pressure ≥ 170 mm Hg or diastolic pressure ≥ 110 mm Hg, although lower thresholds are advisable if signs or symptoms are present.
  • Options include:
    • Labetolol
    • Methyldopa
    • Nifedipine SR
    • The two most commonly used IV options are:
      • IV labetalol: Intravenous labetalol is now considered to be the primary drug of choice for the urgent control of severe hypertension in pregnancy.
      • IV hydralazine: may be considered for women with a contraindication to IV beta blockers such as a history of significant asthma or congestive heart failure. Classified as class C during pregnancy.

3. MgSO4 IV for eclamptic seizure prophylaxis

4. Corticosteroids (IV)

• These have no clear benefit for HELLP syndrome itself.
• They may be given for enhancing fetal lung maturity from 24 – 34 weeks:
  • 2 doses of 12 mg betamethasone 24 hours apart
    Or
  • 6 mg dexamethasone 12 hours apart before delivery.

5. Blood products:

• Blood transfusion may be required for clinically significant anaemia or where there is intra-abdominal bleeding.   
• Platelets:
  • Actively bleeding patients with thrombocytopenia should be transfused with platelets.
  • Platelet transfusion may be indicated to prevent excessive bleeding during delivery if the platelet count is less than 20,000 cells/microL, but the threshold for prophylactic platelet transfusion in this setting is controversial and there should be haematology consultation. 

6. Liver haemorrhage:

• This is usually managed conservatively where possible.
• Correct any coagulopathy
• Surgical options include:
  • Drainage of the hematoma
  • Packing / oversewing of lacerations, or partial hepatectomy
• Arterial embolisation may also be considered in patients who are who are relatively hemodynamically stable

7. Delivery:

Delivery (either by vaginal delivery or cesarean section) is indicated if the HELLP syndrome occurs after the 34th gestational week or the foetal and/or maternal condition deteriorates.

At 24 – 34 weeks’ gestation and a stable mother and fetus, administration of steroids and a wait of 24 – 48 hours may be considered. After this time a re-evaluation is made for delivery based on the maternal-fetal condition.

Prevention

There is no current evidence that any therapy prevents recurrent HELLP syndrome.

Disposition

As soon as the diagnosis is suspected consultation/ referral should be made urgently to the Obstetric Unit.

Frequently these will be also be need for consultation with:

• Haematology Unit
• ICU
• Paediatrics

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References

FOAMed

• Nickson C. HELLP syndrome. CCC
• Nickson C. Hot Case #14 – I’m pregnant … HELLP! ICN

Publications

• Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. 1982. Am J Obstet Gynecol. 2005 Sep;193(3 Pt 1):859; discussion 860.
• Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues and management. A Review. BMC Pregnancy Childbirth. 2009 Feb 26;9:8.
• Lee NM, Brady CW. Liver disease in pregnancy. World J Gastroenterol. 2009 Feb 28;15(8):897-906.
• McCrae KR. Thrombocytopenia in pregnancy. Hematology Am Soc Hematol Educ Program. 2010;2010:397-402.
• Neligan PJ, Laffey JG. Clinical review: Special populations–critical illness and pregnancy. Crit Care. 2011 Aug 12;15(4):227.
• Shames BD, Fernandez LA, Sollinger HW, Chin LT, D’Alessandro AM, Knechtle SJ, Lucey MR, Hafez R, Musat AI, Kalayoglu M. Liver transplantation for HELLP syndrome. Liver Transpl. 2005