Introduction
HELLP syndrome, an acronym for Hemolysis, Elevated Liver enzymes, and Low Platelet count, represents a severe and life-threatening complication primarily occurring in pregnant and postpartum women. While historically considered a variant or progression of severe preeclampsia, contemporary research suggests HELLP syndrome may possess distinct underlying etiologies. Characterized by a microangiopathic hemolytic anemia, liver dysfunction, and thrombocytopenia, prompt recognition and accurate diagnosis based on established Hellp Diagnosis Criteria are crucial for effective management and improved maternal and neonatal outcomes. This article provides an in-depth review of HELLP syndrome, emphasizing the diagnostic criteria, evaluation, and differential diagnosis necessary for timely and appropriate clinical intervention.
Etiology of HELLP Syndrome
The precise cause of HELLP syndrome remains elusive, but current understanding points towards a systemic inflammatory process potentially triggered by an aberrant complement cascade activation. While sharing some pathophysiological overlaps with preeclampsia, notably poor placentation, HELLP syndrome appears to involve a more pronounced activation of the complement system and more significant hepatic inflammation. This divergence may explain why a subset of HELLP syndrome cases presents without preceding hypertension or proteinuria, challenging the traditional view of HELLP as solely a complication of preeclampsia.
Furthermore, complement dysregulation leading to thrombotic microangiopathy can underlie certain HELLP syndrome presentations, particularly pregnancy-related hemolytic uremic syndrome (HUS). While fetal long-chain 3-hydroxy acyl CoA dehydrogenase deficiency (LCHAD) has been investigated as a potential contributor, routine screening for these genetic variants is not currently recommended due to the lack of direct impact on clinical management strategies. Emerging evidence also suggests a potential link between SARS-CoV-2 infection during pregnancy and an increased risk of developing HELLP syndrome and preeclampsia, highlighting the evolving understanding of risk factors.
Epidemiology of HELLP Syndrome
HELLP syndrome affects approximately 0.5% to 0.9% of all pregnancies. The majority of cases, around 70%, manifest during the third trimester, while the remaining cases occur within 48 hours postpartum. This postpartum presentation underscores the importance of vigilance even after delivery. The severity of HELLP syndrome is reflected in its significant maternal mortality rate, ranging from 0% to 24%, and a perinatal mortality rate that can reach up to 37%. These statistics emphasize the critical need for timely diagnosis and effective management guided by clear HELLP diagnosis criteria.
Pathophysiology of HELLP Syndrome
The pathophysiological cascade in HELLP syndrome is initiated by ischemic-reperfusion injury. Inadequate trophoblast invasion or defective endothelial apoptosis leads to failed remodeling of spiral arteries, resulting in placental ischemia. This placental ischemia triggers endothelial activation and the release of antiangiogenic factors, culminating in widespread microvascular injury across multiple organs.
Abnormal fetal fatty acid oxidation and the subsequent release of metabolic intermediates into the maternal circulation further contribute to liver and vascular dysfunction, particularly in cases involving inherited defects in mitochondrial fatty acid oxidation in the fetus. The inflammatory component of HELLP syndrome is characterized by an increase in leukocytes and pro-inflammatory cytokines, coupled with a decrease in anti-inflammatory cytokines, exacerbating systemic damage.
Platelet activation and adhesion to damaged endothelium initiate the coagulation cascade. The release of thromboxane A2 and serotonin from platelets induces vasospasm, platelet aggregation, and further endothelial damage. This process leads to platelet consumption and subsequent thrombocytopenia, a key component of HELLP diagnosis criteria. As red blood cells traverse through these capillaries obstructed by platelet-fibrin complexes, they undergo fragmentation, resulting in microangiopathic hemolytic anemia, another crucial diagnostic feature. The culmination of multiorgan microvascular injury and hepatic necrosis defines the clinical manifestation of HELLP syndrome. Delivery of the fetus is the definitive resolution, interrupting the cascade of events.
Histopathology of HELLP Syndrome
Microscopic examination of peripheral blood smears plays a vital role in HELLP diagnosis criteria, revealing schistocytes or helmet cells, which are pathognomonic for microangiopathic hemolytic anemia. Liver biopsies, though rarely performed clinically, demonstrate characteristic histopathological changes including fatty infiltration, intravascular fibrin deposition, neutrophilic infiltration, sinusoidal obstruction, intrahepatic vascular congestion, hepatic necrosis, and periportal hemorrhage. In severe cases, these changes can progress to intraparenchymal or subcapsular hemorrhage and potentially life-threatening capsular rupture.
History and Physical Examination in HELLP Syndrome
Patients who develop HELLP syndrome are often multiparous and over 35 years of age. The typical gestational age at presentation is between 28 and 37 weeks, during the third trimester, or within the first seven days postpartum. The clinical presentation of HELLP syndrome can be variable, which underscores the importance of considering HELLP diagnosis criteria even with atypical symptoms.
Common presenting symptoms include colicky mid-epigastric and/or right upper quadrant pain, often accompanied by nausea, vomiting, and fatigue. Associated signs and symptoms may include jaundice, increased abdominal girth due to ascites, lower extremity edema, headache, and visual disturbances. In severe cases, patients may present with dramatic complications such as severe bleeding, placental abruption, acute kidney injury, liver hematoma, or retinal detachment.
Physical examination findings may include hypertension (blood pressure >140/90 mmHg), ascites, and pedal edema. Right upper quadrant or epigastric tenderness is a frequently observed sign. Jaundice and visual disturbances may also be present. A thorough physical examination is essential, particularly when any of the aforementioned complications are suspected, to guide the diagnostic workup based on HELLP diagnosis criteria.
Evaluation and HELLP Diagnosis Criteria
Prompt and accurate evaluation is paramount when HELLP syndrome is suspected in a pregnant patient in the third trimester or in the immediate postpartum period. The initial diagnostic workup should include:
- Complete Blood Count (CBC): To assess platelet count and detect hemolysis.
- Peripheral Blood Smear: To identify schistocytes and burr cells, indicative of microangiopathic hemolytic anemia.
- Liver Function Tests (LFTs): Including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels to evaluate liver enzyme elevation.
- Serum Creatinine: To assess renal function.
Elevated liver function tests warrant further investigation, including:
- Haptoglobin: To assess for hemolysis (low haptoglobin levels).
- Lactate Dehydrogenase (LDH): Elevated in hemolytic anemia and liver injury.
- Coagulation Studies: Including fibrinogen, prothrombin time (PT), and activated partial thromboplastin time (PTT) to rule out disseminated intravascular coagulation (DIC) and assess overall coagulation status.
Tennessee and Mississippi Classifications for HELLP Syndrome
The Tennessee classification is a widely used set of HELLP diagnosis criteria requiring the presence of all three components: Hemolysis, Elevated Liver enzymes, and Low Platelets. Specifically, the Tennessee criteria are:
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Hemolysis: Confirmed by at least two of the following:
- Peripheral smear demonstrating schistocytes and burr cells.
- Serum bilirubin >1.2 mg/dL.
- Low serum haptoglobin (below the normal range).
- Elevated Lactate Dehydrogenase (LDH)
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Elevated Liver Enzymes: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 times the upper limit of normal.
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Low Platelets: Platelet count < 100,000 cells/microL.
The Mississippi classification further sub-classifies HELLP syndrome based on the severity of thrombocytopenia, providing a more granular assessment of disease severity. This classification is as follows:
| Class | Platelet Count (cells/microL) |
|---|---|
| Class 1 | ≤ 50,000 |
| Class 2 | > 50,000 to ≤ 100,000 |
| Class 3 | > 100,000 to ≤ 150,000 |
Patients who meet some but not all of the Tennessee HELLP diagnosis criteria are considered to have partial HELLP syndrome. These patients require close monitoring as they may progress to full HELLP syndrome.
It is important to note that in classic HELLP syndrome, platelet activation is the primary hematological abnormality, and clotting factors are typically not significantly affected. Therefore, PT, PTT, and fibrinogen levels are usually normal. However, disseminated intravascular coagulation (DIC) can coexist with HELLP syndrome, particularly in severe cases, and should be suspected if PT and PTT are prolonged or fibrinogen is low. In such cases, the clinical picture becomes more complex, and management strategies need to address both HELLP syndrome and DIC.
Image: Microscopic view of a peripheral blood smear illustrating schistocytes, a key diagnostic feature for hemolysis in HELLP syndrome evaluation.
Treatment and Management of HELLP Syndrome
The cornerstone of HELLP syndrome management is supportive care and prompt delivery of the fetus. Medical management is primarily focused on stabilizing the patient and mitigating complications. Given the potential for rapid deterioration, patients with HELLP syndrome are best managed in tertiary care centers equipped with maternal and neonatal intensive care units. Immediate transfer to such facilities should be considered for patients initially evaluated at centers lacking these resources.
Initial management steps include patient stabilization and fetal status assessment using nonstress tests and ultrasound with biophysical profile. Multidisciplinary consultation is essential, involving intensivists, hepatologists, nephrologists, hematologists, surgeons, obstetricians, and neonatologists to ensure comprehensive and coordinated care.
Severe hypertension should be promptly managed with intravenous antihypertensive agents such as labetalol, hydralazine, or nifedipine. Patients presenting with severe right upper quadrant or epigastric pain and elevated liver function tests require urgent bedside ultrasound to rule out liver rupture, fulminant liver failure, or hepatic bleeding. Further imaging with CT or MRI may be necessary for confirmation. Surgical intervention, including liver transplantation in rare cases, may be required for liver rupture. Less invasive procedures like percutaneous embolization of hepatic arteries may be considered in stable patients with hepatic hemorrhage.
Management of associated complications such as DIC, pulmonary edema, acute respiratory failure, and acute kidney injury is primarily supportive and should adhere to established clinical guidelines. Massive transfusions may be necessary to address severe anemia or coagulopathy. Red blood cell transfusion should be considered if hemoglobin levels fall below critical thresholds. In cases of HELLP syndrome coexisting with thrombotic thrombocytopenic purpura (TTP), therapeutic plasma exchange can be beneficial.
Referral to an obstetrician for prompt delivery is crucial as it remains the only definitive treatment for HELLP syndrome. Betamethasone administration for fetal lung maturity is recommended when gestational age is less than 34 weeks to improve neonatal outcomes, balancing the risks and benefits based on gestational age and maternal condition.
Differential Diagnosis of HELLP Syndrome
Accurate HELLP diagnosis criteria are essential to differentiate HELLP syndrome from other pregnancy-related disorders that may present with similar clinical features. Key differential diagnoses include:
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Preeclampsia with DIC: While sharing similar third-trimester presentation, hypertension, and proteinuria with HELLP syndrome, preeclampsia with DIC involves significant clotting factor consumption, leading to prolonged PT and PTT, unlike typical HELLP syndrome.
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Acute Fatty Liver of Pregnancy (AFLP): AFLP also presents in the third trimester but typically exhibits an obstructive pattern of liver injury with elevated direct bilirubin and ammonia levels, features less common in HELLP syndrome. Hypoglycemia is also more characteristic of AFLP.
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Thrombotic Thrombocytopenic Purpura (TTP): TTP more commonly presents in the first trimester and is characterized by a pentad of fever, altered mental status, acute kidney injury/hematuria, hemolytic anemia, and thrombocytopenia. Unlike HELLP, clotting factors are usually normal, and patients are often normotensive without proteinuria. ADAMTS-13 deficiency is a hallmark of TTP.
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Pregnancy-Related Hemolytic-Uremic Syndrome (HUS): This condition can mimic TTP but typically lacks fever and altered mental status. ADAMTS 13 levels are normal. It is often associated with complement dysregulation and may require eculizumab treatment.
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Systemic Lupus Erythematosus (SLE) Flare: SLE flares can present with thrombocytopenia and hemolytic anemia, but liver function tests are usually normal, and jaundice is absent. While hypertension and proteinuria may occur, other typical SLE features like malar rash, serositis, and arthritis help differentiate it from HELLP syndrome.
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Antiphospholipid Syndrome (APS): APS can also cause hemolysis and thrombocytopenia, and may present with hypertension and proteinuria. However, liver function tests are typically normal. Recurrent arterial/venous thrombosis and recurrent pregnancy loss are dominant features of APS.
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Fulminant Viral Hepatitis: Viral hepatitis should be considered in the differential diagnosis, especially in cases with prominent jaundice and liver dysfunction. Appropriate viral serology and clinical history are crucial for differentiation.
Prognosis of HELLP Syndrome
HELLP syndrome is a severe condition with significant maternal and perinatal morbidity and mortality. Maternal mortality rates range from 0% to 24%, and perinatal mortality can reach up to 37%. Maternal deaths are often attributed to complications such as DIC, placental abruption, postpartum hemorrhage, and acute renal failure. DIC occurs in a substantial proportion of cases (15% to 62.5%), placental abruption in 11% to 25%, postpartum hemorrhage in 12.5% to 40%, and acute renal failure in 36% to 50%. Poor perinatal prognosis is linked to placental abruption, intrauterine hypoxia, asphyxia, prematurity, and low birth weight.
Women with a history of HELLP syndrome have a 19% to 27% risk of recurrence in subsequent pregnancies. Recurrent cases tend to occur later in gestation and may be less severe after two prior episodes. However, the risk of recurrence underscores the need for careful monitoring in subsequent pregnancies.
Complications of HELLP Syndrome
HELLP syndrome can lead to a wide range of severe maternal and fetal complications, contributing to its high mortality rates.
Maternal complications include:
- Eclampsia
- Placental abruption
- Cesarean section
- DIC
- Recurrent thrombosis
- Liver rupture/hematoma
- Fulminant liver failure
- Cerebral infarction
- Cerebral hemorrhage
- Pulmonary/cerebral edema
- Cardiovascular instability
- Acute kidney injury
- Infection/sepsis
- Retinal detachment
- Severe peripartum bleeding
- Maternal death
Fetal complications include:
- Perinatal death
- Intrauterine growth restriction (IUGR)
- Preterm birth
- Neonatal thrombocytopenia, leukopenia, neutropenia
- Respiratory distress syndrome
Consultations in HELLP Syndrome Management
Effective management of HELLP syndrome necessitates a multidisciplinary approach involving consultations from various specialties:
- Intensive Care
- Anesthesiology
- Pediatrics/Neonatology
- Maternal-Fetal Medicine
- Hepatology
- Surgery
- Nephrology
- Hematology
- Ophthalmology
Deterrence and Patient Education for HELLP Syndrome
Patient education is crucial for women with HELLP syndrome and those at risk. Patients should be thoroughly informed about the disease course, potential maternal and perinatal complications, and mortality risks. For women with a history of HELLP syndrome, counseling regarding the risk of recurrence in subsequent pregnancies is essential. Lifestyle modifications, such as maintaining a healthy weight, regular exercise, and managing pre-existing conditions like hypertension and diabetes, may help mitigate the risk. Early and consistent prenatal care, including routine laboratory testing, is vital in subsequent pregnancies to facilitate early detection and management of potential complications.
Enhancing Healthcare Team Outcomes in HELLP Syndrome
Optimal outcomes in HELLP syndrome management rely on effective interprofessional team collaboration. In addition to obstetricians, various specialists, including hospitalists, intensivists, hematologists, nephrologists, hepatologists, surgeons, ophthalmologists, and neonatologists, play critical roles. Nurses and pharmacists are also integral team members, contributing to monitoring, medication management, and overall patient care. Effective communication, shared decision-making, and clear documentation among all team members are essential to ensure timely interventions, minimize complications, and improve maternal and neonatal outcomes in this complex and high-risk condition. Regular team meetings and debriefings can further enhance team performance and optimize patient care pathways for HELLP syndrome management.
Review Questions
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References
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Disclosure: Farhan Khalid declares no relevant financial relationships with ineligible companies.
Disclosure: Neetu Mahendraker declares no relevant financial relationships with ineligible companies.
Disclosure: Tiffany Tonismae declares no relevant financial relationships with ineligible companies.
