HELLP Syndrome

HELLP is a syndrome characterized by thrombocytopenia, hemolytic anemia, and liver dysfunction believed to result from microvascular endothelial activation and cell injury.

The pathophysiology of HELLP syndrome is ill-defined. Some theorize that, because HELLP is a variant of preeclampsia, the pathophysiology stems from a common source. In preeclampsia, defective placental vascular remodeling during weeks 16-22 of pregnancy with the second wave of trophoblastic invasion into the decidua results in inadequate placental perfusion. The hypoxic placenta then releases various placental factors such as soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), which then binds vascular endothelial growth factor (VEGF) and placental growth factor (PGF), causing endothelial cell and placental dysfunction by preventing them from binding endothelial cell receptors. The result is hypertension, proteinuria, and increased platelet activation and aggregation.

Furthermore, activation of the coagulation cascade causes consumption of platelets due to adhesion onto a damaged and activated endothelium, in addition to microangiopathic hemolysis caused by shearing of erythrocytes as they traverse through capillaries laden with platelet-fibrin deposits. Multiorgan microvascular injury and hepatic necrosis causing liver dysfunction contribute to the development of HELLP.[4, 1, 5, 5, 6, 7, 8, 9]

A study by Weiner et al reported that although severe preeclampsia and HELLP syndrome have similar placental histopathologic findings, HELLP syndrome was associated with higher rates of placental maternal vascular supply lesions and small-for-gestational-age.[10]  In addition, a review by Stojanovska and Zenclussen noted that the HELLP syndrome is associated with hypertension and/or proteinuria in only 80% of patients and exhibits different cytokine activation.[11]

Another hypothesis proposes acute maternal immune rejection due to immunocompetent maternal cells coming into contact with a genetically distinct fetus, altering the maternal-fetal immune balance and causing endothelial dysfunction, platelet activation and aggregation, and arterial hypertension.[12]

Other theories include inborn errors of fatty acid oxidative metabolism secondary to long- and medium-chain fatty acid mutations, which cause liver damage secondary to insufficient mitochondrial oxidation of fatty acids required for ketogenesis.[13, 14]

Yet another theory suggests a placental-instigated acute inflammatory condition targeting the liver.[15]

In addition, dysfunction in the complement system via excessive activation or defective regulation for a given amount of endothelial injury has been proposed to cause damage to hepatic vessels in HELLP.[16]

Many hypotheses attempt to define the pathogenesis of HELLP syndrome, but the true pathology remains a mystery.

 

The cause of HELLP syndrome is currently unknown, although theories as described in Pathophysiology have been proposed.

Risk factors for HELLP syndrome include the following:

• Maternal age older than 34 years

• Multiparity

• White race or European descent

• History of poor pregnancy outcome[1, 17]

HELLP syndrome occurs in 0.1%-0.6% of all pregnancies and in 4%-12% of patients with preeclampsia. HELLP syndrome typically occurs between week 27 of gestation and delivery, or immediately postpartum in 15%-30% of cases.[18, 19, 20, 21]

The incidence of HELLP syndrome is significantly higher in whites and women of European descent.[20]

HELLP has been shown to occur in older maternal age groups, with a mean age of 25 years. In contrast, preeclampsia is most common in younger patients (mean age, 19 years).[20]

Most patients with HELLP syndrome stabilize within 24-48 hours, with the most protracted postpartum recovery time in patients with class 1 disease.[2]

The recurrence rate is 2%-27% in subsequent pregnancies.[22, 23]

Patients are at increased risk of preeclampsia or pregnancy-induced hypertension, in addition to preterm delivery, fetal growth restriction, and placental abruption in future pregnancies.[22, 2]

Women with HELLP syndrome are also at increased risk of developing hypertension and cardiovascular disease.[7]

Maternal morbidity/mortality

Maternal mortality ranges from 1%-3%, with a perinatal mortality rate of 35%.[24]  Class 1 or complete HELLP (see Stages) is associated with the highest incidence of perinatal morbidity and mortality. Sixty percent of deaths occur in patients with class 1 disease; cerebral hemorrhage is the most common autopsy finding.[25, 26]  Morbidity includes the following:

• Disseminated intravascular coagulation (DIC) (20%)

• Placental abruption (16%)

• Acute renal failure (7%)

• Pulmonary edema (6%)[24]

Neonatal morbidity/mortality

Fetal morbidity and mortality rates range from 9%-24%[27]  and usually result from placental abruption, intrauterine asphyxia, or prematurity.[28]

Complications

Maternal complications of HELLP syndrome may include the following:

• Hematologic: DIC, bleeding, hematoma

• Cardiac: Cardiac arrest, myocardial ischemia

• Pulmonary: Pulmonary edema, respiratory failure, pulmonary embolism, adult respiratory distress syndrome (ARDS)

• CNS: Hemorrhage/stroke, cerebral edema, central venous thrombosis, seizures, retinal detachment

• Renal: Acute renal failure, chronic renal failure requiring dialysis

• Hepatic: Hepatic (usually subcapsular) hematoma with possible rupture,[29]  ascites, nephrogenic diabetes insipidus

• Infection[18, 2]

Neonatal complications of HELLP syndrome may include the following:

• Prematurity

• Intrauterine growth retardation (39%)[2]

• Thrombocytopenia (one third of neonates born to patients with HELLP; 4% of these infants will have intraventricular hemorrhage[28] )

HELLP syndrome typically occurs between 27 weeks’ gestation and delivery in women with a mean age of 25 years.

A complete review of systems may reveal malaise, nausea, vomiting, weight gain, and various other nonspecific symptoms.

A wide range of symptoms, none of which are diagnostic, may be present in persons with HELLP syndrome. For instance, nausea, vomiting, and epigastric and right upper quadrant pain has been reported in 30%-90%[20, 30, 31] of patients, headache in 33%-68%,[32, 30] visual changes in 10%-20%,[33] and jaundice in 5%.[24]

In a series by Sibai et al, most patients with HELLP syndrome presented preterm with complaints of epigastric or right upper quadrant pain and nonspecific viral syndrome types of symptoms.[20] In earlier studies by Weinstein, nausea, vomiting, and epigastric pain were found to be the most common symptoms in patients with HELLP symptoms.[34, 3]

Common history findings are as follows:

• Malaise

• Nausea and vomiting

• Edema with secondary weight gain

• Epigastric or right upper quadrant pain

• Dyspnea (if pulmonary edema present)

A complete physical examination may reveal signs of dehydration, including dry mucous membranes, sunken eyes, weakness, and imbalance secondary to dizziness from excessive vomiting. Vital signs may reveal tachycardia, tachypnea, and hypertension.

Patients with HELLP syndrome show various signs and symptoms, many of which are synonymous with preeclampsia. Proteinuria is shown to be present in 86%-100% of patients and hypertension in 80%.[24] However, it should be noted that 15% of patients do not present with either.[20, 18, 33]

In addition, 55%-67% of patients present with nondependent edema, which can be periorbital or in the upper and lower extremities.[2] Right upper quadrant tenderness is found in 65%-90% of patients, while jaundice is evident in 5% of patients.[24] A lung examination may reveal crackles if pulmonary edema is present.

Vital signs may include the following:

• Hypertension

• Tachycardia

• Tachypnea

Generalized findings may include the following:

• Fatigue or weakness

• Distress due to pain

• Jaundice

Head, ears, eyes, nose and throat (HEENT) findings may include the following:

• Signs of dehydration including sunken eyes

• Edema leading to puffy eyes

• Dry mucous membranes

Pulmonary findings may include crackles secondary to noncardiogenic pulmonary edema.

Abdominal findings may include right upper quadrant to epigastric tenderness.

Extremities findings may include edema.

Although rare, large-vessel vasculopathy could result in hepatic infarction or subcapsular hematomas. If suspected (usually correlated with worsening hepatic function test results), CT scanning or MRI should be obtained. Hepatic ultrasonography may reveal increased echogenicity in irregular, well-demarcated areas of the liver.[22, 2]

Hepatic endothelial disruption and subsequent platelet activation, aggregation, and consumption lead to distal ischemia and hepatocyte death, which can be segmental or apparent diffusely throughout the liver.[35] Since HELLP tends to involve smaller terminal arterioles, characteristic histiologic features are periportal or focal parenchymal necrosis with hyaline deposits of fibrinlike material in the sinusoids.[36, 37, 38] If larger-vessel vasculopathy occurs, hepatic infarction or subcapsular hematomas may result, both of which would require imaging studies such as MRI or CT scanning.[39]

Two common classifications used to predict maternal morbidity and mortality were described in and are known as the Mississippi and the Tennessee classifications.

The two methods of classification, while useful, should not be regarded as a hard and fast rule. Partial HELLP syndrome, as per the Tennessee classification, can progress to the complete form. In addition, increased eclampsia and higher perinatal morbidity and mortality have been demonstrated in patients with HELLP syndrome,[40] while those with Mississippi class 3 disease have been shown to exhibit hepatic rupture.[41, 42]

Mississippi classification

The Mississippi classification divides HELLP syndrome into 3 classes based on platelet count, AST or ALT levels, and LDH levels.

Class 1, which has an approximately 13% incidence of bleeding, is associated with the highest maternal morbidity and mortality rates and longest recovery time. Patients in this class have a platelet count less than 50,000/µL, liver dysfunction with AST or ALT levels greater than 70 IU/L, and hemolysis as evidenced by an LDH level greater than 600 IU/L.

Class 2 includes platelet counts from 50,000-100,000/µL with AST, ALT, and LDH levels similar to those in class 1. Class 2 has an 8% incidence of bleeding.

The mild form of HELLP, class 3, has a platelet count from 100,000-150,000/µL, AST and ALT greater than 40 IU/L, and LDH greater than 600 IU/L, with no increased risk of bleeding.

The more severe the class, the longer the recovery time postpartum.[25, 41]

Table 2: Mississippi Classification of HELLP Syndrome (Open Table in a new window)

 

Tennessee classification

The Tennessee classification describes HELLP as either complete or partial.

Complete HELLP is defined as hemolysis with an abnormal peripheral smear finding and an LDH level greater than 600 IU/L or bilirubin level greater than 1.2 mg/dL. Patients with complete HELLP have platelet counts less than 100,000/µL and AST levels over 70 IU/L.

Partial HELLP describes severe preeclampsia plus some features of HELLP. These features are further defined as LP, or low platelet syndrome (slightly thrombocytopenic but no hemolysis or liver dysfunction); EL, or elevated liver enzyme syndrome (mildly elevated liver enzymes but no hemolysis or thrombocytopenia); HEL syndrome (hemolysis, elevated liver enzyme levels, but no thrombocytopenia); and ELLP syndrome (elevated liver enzyme levels and low platelet counts, no hemolysis).[41]

Complete HELLP syndrome is characterized by the following:

• Platelet count of 100,000/μL or less

• AST or ALT levels of 70 IU/L or more

• LDH (or bilirubin) (with hemolysis as evidenced on abnormal peripheral smear) levels of 600 IU/L (≥0.2 mg/dL) or more

Partial HELLP syndrome is characterized by severe preeclampsia plus one of the following:

• ELLP: Elevated liver enzyme levels, thrombocytopenia, no hemolysis

• EL: Mildly elevated liver enzyme levels, no thrombocytopenia, no hemolysis

• LP: Thrombocytopenia, no hemolysis, normal liver enzyme levels

• HEL: Hemolysis, liver dysfunction, no thrombocytopenia

Laboratory evaluation should include the following:

• Type and screen

• Complete blood cell (CBC) count: Thrombocytopenia, anemia with possible reticulocytosis

• Coagulation studies: Normal prothrombin time, 50% may have prolonged activated partial thromboplastin time

• Peripheral smear: Schistocytes, helmet cells, and burr cells secondary to microangiopathic hemolytic anemia

• Serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels: Elevated secondary to liver dysfunction

• Lactate dehydrogenase (LDH) level: Elevated secondary to liver dysfunction or hemolysis

• Complete metabolic panel (CMP): Elevated blood urea nitrogen (BUN)/creatinine with acute renal failure

• Bilirubin level: Increased secondary to hemolysis

• Haptoglobin level: Decreased secondary to hemolysis

• Fibrinogen levels: Low secondary to increased coagulation

• D-dimer: Increased due to fibrinolysis/DIC

Laboratory abnormalities apparent in HELLP syndrome and the recovery time postpartum required for normalization of these findings are summarized in Table 1.[24, 2]

Table 1: Laboratory Findings in HELLP Syndrome (Open Table in a new window)

The chart below illustrates an overview of the management of HELLP syndrome:

Management of HELLP syndrome begins with early and immediate recognition of the diagnosis. Stabilization of the patient begins in the prehospital setting. If seizures and hypertension are present, both should be controlled en route to the hospital.

Early recognition of HELLP syndrome begins with a close look at the history, vital signs, and physical examination findings. Emergency department management includes seizure prophylaxis, hypertension control, repletion of blood products, as indicated, and general stabilization of patient condition. See section Medications for a more complete pharmacologic guide.

Intravenous fluids should be given cautiously. Patients with HELLP syndrome may be volume overloaded and present with edema but are in fact intravascularly depleted.

Intravenous magnesium sulfate is given until 24 hours after delivery, at which point it can be stopped if the maternal condition is improved. The dosage for magnesium sulfate IV is a 6-g loading dose over 20 minutes with a 2-g per hour maintenance dose.[18, 9]

Hypertension is managed similarly to hypertension in preeclampsia. The blood pressure (BP) goal is to keep the systolic at 160 or less and the diastolic at 105 or less. Labetalol and hydralazine are the recommended drugs to treat a hypertensive crisis.[18, 9]

Although controversial, corticosteroids can be given as a treatment regimen for antepartum and postpartum management in patients with HELLP. Steroids are theorized to alter the degree of intravascular endothelial injury and prevent further hepatocyte death and platelet activation.[22] While evidence of maternal improvement is limited, studies have demonstrated improved laboratory findings, including improved platelet counts, liver function, blood pressure, and urine output with the use of high-dose dexamethasone.[30] Intravenous glucocorticoids appear superior to intramuscular steroids[43] and are dose-dependent.[44] Therefore, aggressive therapy with high-dose dexamethasone has been recommended over the standard regimens used for enhancing fetal lung maturity. Steroids are also believed to improve fetal morbidity by reducing the incidence of respiratory distress syndrome and intraventricular hemorrhage, as well as maternal morbidity.[22]

Dosing for high-risk patients with severe disease (platelet count < 20,000 or CNS dysfunction): 20 mg IV dexamethasone every 6 hours for up to 4 doses

Dosing for all other patients with HELLP syndrome: 10 mg IV dexamethasone every 6 hours for 2 doses then 6 mg IV dexamethasone every 6 hours for 2 doses

If no clinical or laboratory improvement, expedite delivery.[22]

Steroids can be initiated in the emergency department and continued on an inpatient basis.

Once stabilized, the patient should be transferred to a labor and delivery unit under an obstetrician’s care, where she can be closely monitored.

Delivery: Delivery (either vaginal delivery or cesarean section) is indicated if HELLP syndrome occurs close to 34 weeks’ gestation, in the setting of fetal lung maturity, or upon evidence of significant maternal or fetal distress before 34 weeks’ gestation. Steroids administered antenatally may increase the platelet count so that regional anesthesia can be given. General guidelines are as follows:

• If at 34 weeks’ gestation or later and unstable, deliver immediately

• If at 34 weeks’ gestation or later and stable, consider administration of steroids; evaluate over 24-48 hours and deliver

• If at 24-34 weeks’ gestation and stable, consider administration of steroids; wait 24-48 hours and evaluate for delivery based on the maternal-fetal condition

• If 34 weeks’ gestation or earlier with evidence of maternal or fetal distress, deliver immediately[24]

Cesarean versus vaginal delivery should be determined based on the following:

• Cervical ripening

• Fetal nonstress test or biophysical profile results

• Umbilical artery Doppler study

If there is a preterm gestation with intrauterine growth restriction or significantly abnormal Doppler test results, cesarean section should be performed.[22]

Cesarean section

Prior to performing a cesarean section, severe thrombocytopenia should be corrected. While platelets should be transfused, caution is advised owing to increased consumption of these platelets. A recommended dose is 6-10 U of platelets with thrombocytopenia of less than 40,000/µL. General anesthesia should be performed for thrombocytopenia of less than 75,000/µL.[24] The type of skin incision and primary versus secondary skin closure do not affect wound complications.[45] Hematoma formation at the operative site occurs in 20% of cases. To reduce this risk, an open bladder flap is recommended, and a subfascial drain can be used for 24-48 hours.[24, 22]

Postpartum curettage lowers the mean arterial pressure and improves oliguria and thrombocytopenia.[2]

Hepatic hematoma usually manifests as a subcapsular hematoma.

If it is not ruptured, it may be managed conservatively with close hemodynamic and coagulation status monitoring. Avoid any increase in intraabdominal pressure, including emesis, palpation, or trauma in transport. Serial CT scans or careful ultrasonography should guide management.

Rupture most often involves the anterior superior portion of the right upper lobe. Patients may present with shoulder pain, ascites, respiratory distress, shock, or fetal demise. Immediate intervention is mandated for a ruptured hematoma. Treatment considerations are as follows:

• Resuscitate: Transfuse and correct any coagulopathy with fresh frozen plasma or platelets

• Emergent laparotomy by general or vascular surgeon: Based on extent of bleeding, may pack and drain or surgically ligate hepatic segments that are bleeding, embolize the hepatic artery to the affected hepatic segment, and loosely suture the omentum or surgical mesh to the liver; hepatic lobectomy or liver transplantation in patients with total hepatic necrosis may also be indicated in some cases[24, 2]

• Owing to exsanguination and coagulopathy, maternal and fetal mortality rates are close to 50%, even with treatment[24, 22]

Patients should be on bedrest. If hepatic hematoma is present, the risk of trauma should be minimized.

Consider consultations with the following:

• Surgeon

• Hematologist

• Renal specialist

Maternal and fetal conditions can deteriorate rapidly, necessitating a closely monitored unit under an experienced obstetrician’s care. Patients, once stabilized and if remote from term, should be transferred to a tertiary care facility, where such monitoring can be provided.

Repeat laboratory tests every 6-12 hours until improvement noted. Monitor for remission.[22]

Consider steroids for up to 2 days postpartum to prevent rebound of liver dysfunction, thrombocytopenia, and oliguria.[2]

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Class Summary

These agents reduce blood pressure through various mechanisms.

Labetalol (Trandate)

Combined alpha- and beta-adrenergic blocking agent widely used in treating hypertension during pregnancy. Not associated with mild fetal growth restriction (unlike some other beta-blockers).

Intravenous and oral forms are used as an alternative to hydralazine in severe preeclampsia/eclampsia.

Hydralazine

Decreases systemic resistance through direct vasodilation of arterioles.

Nifedipine (Adalat, Afeditab, Nifediac, Procardia, Procardia XL)

Relaxes coronary smooth muscle and produces coronary vasodilation, which in turn improves myocardial oxygen delivery. Sublingual administration is generally safe, despite theoretical concerns.

Class Summary

Magnesium can terminate ongoing eclamptic seizures and prevent further seizures.

Magnesium sulfate

Several studies have revealed that it is the drug of choice for treating eclamptic seizures. Successful in controlling seizures in >95% of cases. Agent gives physiologic advantages to fetus by increasing uterine blood flow.

Inhibits the release of acetylcholine at motor endplate. In addition, magnesium has direct effect on skeletal muscle by virtue of competitive antagonistic effects with calcium.

Exclusively by kidneys and has little antihypertensive effect. Effective anticonvulsant and helps prevent recurrent seizures and maintain uterine and fetal blood flow.

Can be administered both IV and IM. Intravenous route is preferred over IM route because administration is controlled more easily and time to therapeutic levels is shorter. Intramuscular administration of magnesium sulfate tends to be more painful and less convenient. If IV access or close patient monitoring is unavailable, this is an effective therapy.

Goals of magnesium therapy are to terminate ongoing seizures and prevent further seizures. Patient should be evaluated qh to assure that deep tendon reflexes are present, respirations are at least 12 breaths per min, and urine output is at least 100 mL during the preceding 4 h.

When using magnesium sulfate IV, close monitoring of patient and fetus is necessary.

Magnesium therapy usually is continued for 12-24 h following delivery and may be stopped when hypertension resolves and patient has shown adequate diuresis.

Renally compromised patients should be monitored with magnesium levels, with aggressive adjustments made to facilitate levels at 6-8 mg/dL. Patients with increased urine output may need maintenance dose increased to 3 g/h to maintain therapeutic levels. Monitor patient for signs of worsening condition and magnesium toxicity.

The Parkland IM protocol is as follows:

Magnesium sulfate 4 g IV over 5 min, plus magnesium sulfate 10 g deep IM (3-in needle) divided in both buttocks and mixed with 1 mL 2% lidocaine. If a seizure persists more than 15 min after above dose, administer an additional 2 g of magnesium sulfate IV over 3-5 min.

Magnesium sulfate 5 g IM q4h, starting 4 h later unless patellar reflexes are absent, respiratory depression occurs, or urine output is < 100 mL in the prior 4 h. Therapeutic levels are 4.8-8.4 mg/dL. With the above protocol, serum magnesium levels usually are 4-7 mg/dL in a patient with an average volume of distribution and normal renal function.

Actual serum magnesium levels are monitored only in patients with symptomatic magnesium toxicity or renal compromise.

Patients may have seizures while receiving magnesium sulfate. If seizure occurs in first 20 min after loading dose, the convulsion usually is short, and no additional treatment is indicated. If seizure occurs >20 min after the loading dose, an additional 2-4 g of magnesium may be administered.

In adults, 60-180 mEq of potassium, 10-30 mEq of magnesium, and 10-40 mM of phosphate per day may be necessary for optimum metabolic response.

Give IV/IM for seizure prophylaxis in preeclampsia. Use IV route for quicker onset of action in true eclampsia.

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Dexamethasone (Baycadron, Maxidex, Ozurdex, Dexamethasone Intensol)

Has many pharmacologic benefits but significant adverse effects. Stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, inhibits prostaglandin and proinflammatory cytokines (eg, TNF-alpha, IL-6, IL-2, and IFN-gamma). The inhibition of chemotactic factors and factors that increase capillary permeability inhibits recruitment of inflammatory cells into affected areas. Suppresses lymphocyte proliferation through direct cytolysis and inhibits mitosis. Breaks down granulocyte aggregates, and improves pulmonary microcirculation. Adverse effects are hyperglycemia, hypertension, weight loss, GI bleeding or perforation synthesis, cerebral palsy, adrenal suppression, and death. Most of the adverse effects of corticosteroids are dose-dependent or duration-dependent.

Readily absorbed via the GI tract and metabolized in the liver. Inactive metabolites are excreted via the kidneys. Lacks salt-retaining property of hydrocortisone.

Patients can be switched from an IV to PO regimen in a 1:1 ratio.