History

• Typically develops in the third trimester of pregnancy or early postpartum period
  • About 70% of cases develop before delivery ^r2c1c2c3
    • Of those, about 70% occur between 27 and 36 weeks of gestation
    • Almost 20% of cases develop beyond 37 weeks of gestation ^r2c4
  • About 30% of cases develop postpartum ^r2r5c5
    • Most postpartum cases develop within the first 48 hours but may occur as late as 7 days after delivery
    • In 80% of cases, evidence of preeclampsia is present before delivery
• Onset is usually rapid and, in most cases, preceded by hypertension and proteinuria ^c6c7
• Presentation can be variable and symptoms are often nonspecific, leading to missed or delayed diagnosis ^r6
• Typical symptoms are similar to those of preeclampsia and include: ^r2
  • Abdominal pain ^c8
    • Right upper quadrant or epigastric pain ^c9c10
    • May be fluctuating and colicky ^c11c12
  • Nausea and vomiting ^c13c14
  • Malaise ^c15
  • Headache (30%-60% of cases) ^r2c16
  • Visual changes (20% of cases) ^r2c17
  • Nonspecific viral syndrome–like symptoms, without fever ^c18

Physical examination

• Physical findings are similar to those of preeclampsia and include:
  • Hypertension ^c19
    • Systolic 140 mm Hg or higher or diastolic 90 mm Hg or higher ^r1
      • Diagnosis of hypertension is based on 2 blood pressure measurements made at least 4 hours apart ^r1
    • Severe hypertension: Systolic 160 mm Hg or higher or diastolic 110 mm Hg or higher ^r1c20
      • Diagnosis can be based on 2 blood pressure measurements within a short interval (to initiate prompt treatment) ^r1
    • Hypertension may be absent in 10% to 20% of patients ^r2c21
  • Excessive weight gain ^r2c22
  • Generalized edema ^r2c23
  • Jaundice (rarely) ^c24

Causes

• Pathogenesis is unclear; may represent a severe form of preeclampsia associated with abnormal placental development and function ^c25
  • Develops in 10% to 20% of patients with preeclampsia ^r5c26
  • Patients with preeclampsia are at higher risk of developing HELLP syndrome than those without preeclampsia

Risk factors and/or associations

Primary diagnostic tools

• Initial evaluation includes a thorough history, physical examination, blood pressure measurements, and blood and urine testing to detect presence of proteinuria and/or end-organ involvement ^c38
• Obtain CBC, peripheral blood smear, and hepatic function panel (including AST, ALT, and bilirubin levels) and lactate dehydrogenase in everyone with suspected preeclampsia or HELLP syndrome based on clinical presentation (typical symptoms, usually in association with hypertension and proteinuria) ^r2c39c40c41
  • Two methods of diagnosis are commonly used: ^c42
    • Tennessee classification ^r2
      • Hemolysis, indicated by 2 or more of the following: evidence of microangiopathic hemolysis on peripheral smear (schistocytes, burr cells); serum bilirubin 1.2 mg/dL or greater; serum haptoglobin 25 mg/dL or less or lactate dehydrogenase 2 or more times the upper level of normal; severe anemia not due to blood loss (hemoglobin 8-10 g/dL, depending on gestation)
      • Elevated liver enzymes, indicated by AST or ALT 2 or more times the upper level of normal
      • Low platelets, indicated by platelet count less than 100,000/mm³
    • American College of Obstetricians and Gynecologists criteria ^r1
      • Lactate dehydrogenase 600 IU/L or greater
      • AST and ALT two or more times the upper level of normal
      • Platelet count less than 100,000/mm³
• Obtain comprehensive metabolic panel, including creatinine concentration, disseminated intravascular coagulation panel, and urine protein concentration (24-hour urine collection or protein-creatinine ratio) ^c43c44c45c46
• Assess fetal well-being with nonstress test and ultrasonographic evaluation to estimate fetal weight and amniotic fluid index; biophysical profile is indicated if nonstress test is nonreactive ^{r1c47c48c49c50c51}
  • In potentially unstable situations, fetal monitoring is always performed first using bedside ultrasonography
• Determine if patient is in labor and evaluate cervix with Bishop score ^r2

Laboratory ^{c52c53c54c55c56c57}

• CBC ^r2c58
  • Platelet count less than 100,000/mm³ is necessary to diagnose HELLP syndrome ^r1
    • Platelet counts can decrease to as low as 6000/mm³ (6 × 10⁹/L), but any platelet count less than 150,000/mm³ (150 × 10⁹/L) warrants attention ^r7c59
    • Mississippi subclassification assigns severity by nadir of thrombocytopenia but is not widely used clinically ^r2
      • Class I: Platelet count less than 50,000/mm³, AST or ALT 70 IU/L or higher, and lactate dehydrogenase 600 IU/L or higher
      • Class II: Platelet count between 50,000/mm³ and 100,000/mm³, AST or ALT 70 IU/L or higher, and lactate dehydrogenase 600 IU/L or higher
      • Class III: Platelet count between 100,000/mm³ and 150,000/mm³, AST or ALT 40 IU/L or higher, and lactate dehydrogenase 600 IU/L or higher
        • Note that Class III levels do not meet commonly used diagnostic criteria
  • Reticulocyte count can be increased ^c60
  • Hematocrit may be decreased or within reference range and is typically the last of the abnormalities to appear; finding of decreased serum haptoglobin concentration may confirm ongoing hemolysis when hematocrit is within reference range ^r2
• Peripheral blood smear ^r2c61
  • Microangiopathic hemolysis is suggested by presence of fragmented RBCs (schistocytes) or contracted, spiculated RBCs (Burr cells) in peripheral blood smear
• Hepatic function panel ^c62c63c64c65
  • AST or ALT concentration of 70 units/L or higher is typical in HELLP syndrome ^r2
    • Laboratory thresholds vary; diagnosis is based on AST and/or ALT more than 2 times the upper reference range for local laboratory ^r1
  • Intravascular hemolysis is supported by elevated serum bilirubin concentration (at least 20.5 μmol/L or at least 1.2 mg/100 mL) and elevated lactate dehydrogenase concentration greater than 600 units/L (or at least 2 times the upper level of normal for laboratory range ^r2
• Serum haptoglobin level ^c66
  • Decrease is useful to corroborate presence of intravascular hemolysis in conjunction with minimal microangiopathic changes in RBC morphology ^r12
• Urine protein to creatinine ratio ^r1c67
  • Proteinuria is defined by ratio 0.3 or greater (or protein of 300 mg or more in a 24-hour urine collection)

Most common

• Pregnancy-related conditions
  • Preeclampsia ^c68d1
    • Complication of pregnancy characterized by hypertension and proteinuria or, in the absence of proteinuria, by new onset of organ dysfunction
    • HELLP syndrome may represent a severe form of preeclampsia, and there is significant overlap in clinical and biochemical features
    • Like HELLP syndrome, preeclampsia may manifest with hypertension, proteinuria, epigastric pain, headache, and visual symptoms
    • Unlike HELLP syndrome, preeclampsia is more common in nulliparous females, and hypertension and proteinuria are always present
    • May be differentiated on basis of the following laboratory findings:
      • No evidence of microangiopathic hemolysis on peripheral blood smear
      • Platelet count may be within reference range (may be decreased in severe cases)
  • Acute fatty liver of pregnancy ^c69
    • Rare complication of pregnancy caused by disordered maternal metabolism of fatty acids occurring in third trimester
    • Clinical signs are variable, and in severe cases there is significant overlap in clinical and biochemical features with HELLP syndrome ^r2
    • Like HELLP syndrome, acute fatty liver of pregnancy typically occurs in third trimester of pregnancy and manifests as malaise, anorexia, nausea, vomiting, mid-epigastric or right upper abdominal pain, and headache
    • Unlike most cases of HELLP syndrome, may be associated with jaundice and low-grade fever, and hypertension and proteinuria are usually absent
    • May be differentiated on basis of the following laboratory findings: ^r13
      • Platelet count within reference range at presentation
      • Elevated WBC count, creatinine concentration, and bilirubin concentration
      • Prolonged prothrombin time or activated partial thromboplastin time
      • Antithrombin III activity reduced below 65%
      • Hypoglycemia
• Non–pregnancy-related conditions
  • Conditions such as gastroenteritis, acute cholecystitis, appendicitis, and acute hepatitis may have similar clinical presentation with abdominal pain, malaise, nausea, and vomiting ^c70c71c72c73
    • Unlike HELLP, presenting symptoms are not associated with hypertension or proteinuria
    • Differentiated on basis of history, clinical features, and laboratory findings
      • No evidence of microangiopathic hemolysis on peripheral blood smear; platelet count within reference range
  • Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome also have hemolysis, thrombocytopenia, and may have similar clinical presentation (eg, nausea, vomiting, abdominal pain, headache) ^r2
    • Unlike HELLP, elevation of AST and ALT is usually mild and anemia is more prominent

Admission criteria

All patients require admission for immediate obstetric consultation and delivery ^r2

Recommendations for specialist referral

• All patients are managed by obstetrician in consultation with maternal-fetal medicine specialist, hematologist, and anesthesiologist as necessary

Drug therapy

• Antenatal corticosteroids ^c74
  • Betamethasone ^r2c75
    • Betamethasone Acetate, Betamethasone Sodium Phosphate Suspension for injection; Pregnant females: 12 mg IM every 24 hours for 2 doses in all pregnant women between 24 and 34 weeks gestation who are at risk for preterm delivery within 7 days; administer first dose even if ability to administer second dose is unlikely. Consider therapy starting at 23 weeks gestation for pregnant women who are at risk of preterm delivery within 7 days. Consider a repeat or rescue course in women who are less than 34 weeks gestation, at risk of preterm delivery within the next 7 days, and prior course of antenatal corticosteroids was administered more than 14 days previously. Rescue course could be provided as early as 7 days from the prior dose if indicated by clinical situation.
• Magnesium sulfate ^r1c76
  • Magnesium Sulfate Solution for injection; Adults: 4 to 6 g IV loading dose followed by a maintenance dose of 1 to 2 g/hour IV for at least 24 hours. Max: 30 to 40 g/day.
• Antihypertensive drugs ^r2r14c77
  • Labetalol ^c78
    • Labetalol Hydrochloride Solution for injection; Adults females: 20 mg IV over more than 2 minutes for persistent SBP of 160 mm Hg or higher, or DBP of 110 mm Hg or higher. Repeat BP in 10 minutes and if either BP threshold is exceeded, give 40 mg IV over more than 2 minutes. Repeat BP in 10 minutes and if either BP threshold is exceeded, give 80 mg IV over more than 2 minutes. Repeat BP in 10 minutes and if either BP threshold is exceeded, switch to hydralazine 10 mg IV over more than 2 minutes. Repeat BP in 20 minutes. If either BP threshold is still exceeded, obtain emergency consultation from maternal–fetal medicine, internal medicine, anesthesia, or critical care subspecialists and give additional antihypertensive medication per specific order. Once SBP is less than 160 and DBP is less than 110, check BP every 10 minutes for 1 hour, then every 15 minutes for 1 hour, then every 30 minutes for 1 hour, and then every hour for 4 hours.
  • Hydralazine ^c79
    • Hydralazine Hydrochloride Solution for injection; Adult females: 5 to 10 mg IV over 2 minutes for SBP of 160 or more or DBP of 110 or more mmHg. Check BP in 20 minutes and if either BP threshold is exceeded, give 10 mg IV over 2 minutes. Check BP in 20 minutes and if either threshold is exceeded, switch to labetalol 20 mg IV over 2 minutes and check BP in 10 minutes. If either BP threshold is exceeded, give labetalol 40 mg IV over 2 minutes, obtain emergency consultation, and give additional antihypertensive medication per specific order. Once SBP is less than 160 and DBP is less than 110, check BP every 10 minutes for 1 hour, then every 15 minutes for 1 hour, then every 30 minutes for 1 hour, and then every hour for 4 hours.
  • Nifedipine ^c80
    • Nifedipine Oral immediate release capsule; Adults females: 10 mg PO for persistent SBP of 160 mm Hg or higher, or DBP of 110 mm Hg or higher. Check BP in 20 minutes and if either BP threshold is exceeded, give 20 mg PO. Check BP in 20 minutes and if either BP threshold is exceeded, give 20 mg PO. Check BP in 20 minutes and if either BP threshold is still exceeded, switch to labetalol 20 mg IV for more than 2 minutes. Obtain emergency consultation from maternal–fetal medicine, internal medicine, anesthesia, or critical care subspecialists and give additional antihypertensive medication per specific order. Once SBP is less than 160 and DBP is less than 110, check BP every 10 minutes for 1 hour, then every 15 minutes for 1 hour, then every 30 minutes for 1 hour, and then every hour for 4 hours.

Nondrug and supportive care

Administer IV fluids ^r2c81

Closely monitor vital signs and fluid balance

Consider platelet transfusion in actively bleeding patients with platelet count less than 50,000/mm³, before vaginal delivery in those with platelet count less than 20,000/mm³, and before cesarean delivery in those with platelet count less than 40,000 to 50,000/mm³. ^{r12r15r16r17c82}

• Because evidence is limited regarding indications for platelet transfusion, consult hematology and anesthesiology specialists to determine thresholds

Comorbidities ^c86

At-risk populations

• Patients with HELLP syndrome in previous pregnancies are at risk in subsequent pregnancies ^r2

Screening tests

• No specific screening tests; early antenatal care and more frequent antenatal monitoring are required ^c116