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HELLP Syndrome

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Jul.18.2023

HELLP Syndrome

Synopsis

Key Points

  • HELLP syndrome is a rare, potentially life-threatening obstetric complication characterized by hemolysis, elevated liver enzyme concentrations, and low platelet count
  • Widely considered to represent a severe form of severe preeclampsia; however, relationship between disorders is controversial and some consider HELLP syndrome a separate disorder
  • Typically develops in the third trimester of pregnancy or early postpartum period and, in most cases, is preceded by hypertension and proteinuria
  • Presentation can be variable and symptoms are often nonspecific; right upper quadrant or epigastric pain, nausea, vomiting, and headache are common
  • Diagnosis is based on presence of microangiopathic hemolytic anemia on peripheral blood smear; elevated liver enzyme concentrations, specifically AST more than 2 times upper reference range for local laboratory (usually 70 units/L or higherr2); and thrombocytopenia (typical cutoff is less than 100,000/mm³); usually in conjunction with hypertension and proteinuria r1
  • Delivery is the only effective method of treatment; timing depends on gestational age and patient and fetal condition
  • Immediate delivery after maternal stabilization is indicated in pregnancies at 34 weeks of gestation or longer, less than 23 to 24 weeks gestation, and between 23 and 34 weeks of gestation if there is disseminated intravascular coagulation, liver infarction or hemorrhage, renal failure, pulmonary edema, suspected abruptio placentae, or nonreassuring fetal status r1
  • Delivery can be delayed for 24 to 48 hours to allow administration of corticosteroid to assist fetal lung maturation in pregnancies between 23 and 34 weeks of gestation, providing patient and fetal conditions remain stable
  • Route of delivery is selected on basis of gestational age, fetal presentation, cervical status, obstetric history, and patient and fetal condition
  • Prognosis for both patient and fetus is generally good, although serious complications are common; perinatal morbidity and mortality is primarily caused by early gestational age at delivery

Urgent Action

  • HELLP syndrome requires immediate obstetric consultation, patient stabilization, and delivery of fetus within 48 hours r2

Pitfalls

  • Not all patients with HELLP syndrome have hypertension and proteinuria
  • Nonspecific symptoms, such as abdominal pain, malaise, headache, and vomiting, can be mistaken for manifestations of a viral gastrointestinal syndrome

Terminology

Clinical Clarification

  • HELLP syndrome is a rare, potentially life-threatening obstetric complication; the acronym reflects that the syndrome is characterized by hemolysis, elevated liver enzyme concentrations, and a low platelet count r3
    • Occurs in 0.5% to 0.9% of all pregnancies and in 10% to 20% of patients with severe preeclampsia r2
    • Widely considered to represent an especially severe form of severe preeclampsia; however, relationship between disorders is controversial and some consider HELLP syndrome a separate disorder r4

Diagnosis

Clinical Presentation

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 and Risk Factors

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

Age
  • Mean age of patients with HELLP syndrome is usually higher than mean age of those with preeclampsia r2
  • Persons aged 25 years or older are at higher risk for HELLP syndrome than those who are younger than 25 years r7c27c28
Genetics
  • HELLP syndrome demonstrates a familial tendency like preeclampsia; however, may have different genetic basis than preeclampsia r8c29
  • No single genetic cause has been identified; multiple gene variants along with environmental factors may contribute r9c30
Ethnicity/race
  • No clear evidence indicates persons of a particular race are at increased risk for HELLP syndrome r10c31c32c33c34
    • However, higher rates of preeclampsia are seen in Black, American Indian, and Alaskan Native patients
      • Among those with preeclampsia, higher rates of severe morbidity and mortality for both the patient and the fetus are seen among non-Hispanic Black patients than any other race or ethnicity
    • Differences in prevalence and outcomes appear to be linked to racial inequities, with mixed results in research on biological differences r10
Other risk factors/associations
  • History of preeclampsia or HELLP syndrome r7c35c36
  • Unlike in preeclampsia, nulliparity is not a risk factor, as at least 50% of patients with HELLP syndrome are multiparous r5r11c37

Diagnostic Procedures

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)

Differential Diagnosis

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

Treatment

Goals

  • Stabilize patient and assess fetal condition
  • Deliver infant promptly

Disposition

Admission criteria

All patients require admission for immediate obstetric consultation and delivery r2

Criteria for ICU admission
  • Most patients with HELLP syndrome require admission to obstetric ICU; neonatal ICU is required for infant in most cases

Recommendations for specialist referral

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

Treatment Options

Promptly initiate antihypertensive therapy in patients who have persistent (15 minutes or more) hypertension with systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 110 mm Hg, or both r1

  • Optimal target has not been determined, but protocols recommend systolic blood pressure lower than 160 mm Hg and diastolic blood pressure lower than 100 mm Hg r14
  • Lowering blood pressure too much may be harmful; avoid systolic blood pressure lower than 120 mm Hg or diastolic blood pressure lower than 80 mm Hg r14
  • For treatment during pregnancy, use fetal surveillance during antihypertensive treatment if fetus is viable r14

Administer magnesium sulfate for seizure prophylaxis r1

Delivery is definitive treatment for cases during pregnancy (although postpartum cases occur)

  • Timing of delivery depends on gestational age and conditions of patient and fetus
    • Deliver immediately after patient stabilization in: r1
      • Pregnancies at 34 weeks of gestation or longer
      • Pregnancies shorter than 23 weeks of gestation or if fetus is nonviable
      • Pregnancies between 23 and 34 weeks of gestation if there is disseminated intravascular coagulation, liver infarction or hemorrhage, renal failure, pulmonary edema, suspected abruptio placentae, or nonreassuring fetal status
        • Administering corticosteroids for fetal lung maturation is recommended, but do not delay delivery to complete course r1
    • Deliver within 24 to 48 hours after patient stabilization in pregnancies between 23 and 34 weeks of gestation, provided patient and fetus remain stable r1
      • Administering corticosteroids for fetal lung maturation is recommended, but do not complete course if condition of pregnant patient or fetus deteriorates r2
  • Route of delivery is selected on basis of gestational age, fetal presentation, cervical status, obstetric history, and patient and fetal condition r1
    • Cesarean delivery is recommended for standard obstetric indications (eg, unfavorable cervix, oligohydramniosr2)
    • Platelet transfusion before vaginal delivery is recommended by some experts if platelet count is less than 20,000/mm³ and before cesarean delivery if less than 50,000/mm³; precise threshold is determined in consultation with hematologist r15r16r17
    • Spinal or epidural anesthesia is recommended if analgesia/anesthesia is required for delivery. r1
      • No definitive lower limit platelet count is known for neuraxial anesthesia; however, risk of epidural hematoma is exceptionally low in patients with stable platelet counts 70,000/mm³ without anticoagulants or coagulopathy r1
  • Expectant management is not typically recommended r2
    • Expectant management before completing 34 weeks of gestation may be an acceptable option in carefully selected patients if it is performed in tertiary care units under close surveillance; however, there is limited evidence that this is beneficial r2r18r19
    • Not recommended if neonate is not expected to survive r1
    • Deliver immediately if fetal or maternal condition deteriorates during expectant management r1

Corticosteroids do not appear to reduce mortality and morbidity r1r20r21

  • May improve maternal platelet counts, but no overall evidence of benefit exists r20r21
    • May be considered in settings in which improved platelet count is clinically important

Drug therapy

  • Antenatal corticosteroids c74
    • Betamethasone r2c75
      • Betamethasone Acetate, Betamethasone Sodium Phosphate Suspension for injection; Adults: 12 mg IM every 24 hours for 2 doses. Consider a repeat or rescue course when at risk of preterm delivery within the next 7 days and prior course 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
Procedures
Cesarean delivery c83
General explanation
  • Surgical delivery of the fetus through incisions in abdominal wall (laparotomy) and uterine wall (hysterotomy)
Indication
  • Indications for immediate delivery (requiring cesarean delivery if vaginal delivery is not imminent) include: r2
    • Blood pressure higher than 160/110 mm Hg despite treatment with antihypertensive drugs
    • Persisting or worsening clinical symptoms
    • Deteriorating renal function
    • Severe ascites
    • Abruptio placentae
    • Oliguria
    • Pulmonary edema
    • Eclampsia
    • Ruptured subcapsular liver hematoma r2
  • If delivery is required at less than 30 to 32 weeks gestation and cervix is unfavorable for induction, some experts recommend cesarean delivery to avoid risks to fetus associated with long labor r12
Contraindications
  • No absolute contraindications; however, vaginal delivery is preferred due to lower complications
  • Relative contraindications
    • Severe thrombocytopenia; platelet transfusions are required before procedure
Complications
  • Same as those with cesarean delivery for any cause
    • Uterine lacerations
    • Bladder lacerations
    • Ureter injury
    • Bowel injury
    • Uterine atony
    • Hemorrhage
    • Postoperative infection
Induction of labor r22c84
General explanation
  • Procedure to stimulate uterine contractions before development of spontaneous labor; may be preceded by measures to facilitate cervical ripening
  • Oxytocin is the most common medication used to induce labor c85
  • Other methods to induce labor include prostaglandin E analogues, mechanical cervix dilation, membrane stripping, and amniotomy
Indication
  • Indicated to initiate delivery before onset of spontaneous labor in patients with HELLP syndrome
Contraindications
  • General contraindications for induction of labor
    • Active genital HSV infection
    • Vasa previa or complete placenta previa
    • Transverse fetal lie
    • Umbilical cord prolapse
    • Previous classic cesarean delivery
    • Previous myomectomy
  • Specific contraindications in HELLP syndrome
    • Ruptured subcapsular liver hematoma r2
    • If the cervix is unfavorable for induction, some experts recommend against induction of labor at less than 30 to 32 weeks to avoid risks to fetus associated with long labor r12
Complications
  • Same as those associated with induction of labor for any cause
    • Uterine hyperstimulation
    • Uterine rupture
    • Fetal distress and fetal acidosis
    • Failed labor induction requiring cesarean delivery

Comorbidities c86

Monitoring

  • Maternal r1
    • Closely monitor vital signs, fluid intake, and urine output c87c88c89
    • Monitor for contractions, rupture of membranes, abdominal pain, or bleeding
    • Obtain CBC, platelet count, liver enzyme, and creatinine concentrations at least every 12 hours r1c90c91c92c93
  • Fetal r1
    • Continuous fetal monitoring in a labor and delivery unit is recommended c94

Complications and Prognosis

Complications

  • Maternal complications r2
    • Eclampsia c95
    • Abruptio placentae c96
    • Disseminated intravascular coagulation c97
    • Acute renal failure c98
    • Severe ascites c99
    • Cerebral edema c100
    • Pulmonary edema c101
    • Acute respiratory distress syndrome c102
    • Wound hematoma or infection after cesarean delivery c103c104
    • Subcapsular liver hematoma c105
    • Liver rupture c106
    • Hepatic infarction c107
    • Recurrent thrombosis c108
    • Cerebral hemorrhage c109
    • Retinal detachment c110
    • Cerebral infarction c111
  • Fetal complications r2
    • Intrauterine growth restriction c112
    • Preterm delivery and associated complications c113
    • Neonatal thrombocytopenia c114
    • Respiratory distress syndrome c115

Prognosis

  • Prompt diagnosis and delivery result in best outcome for patient and fetus
  • Maternal complications are relatively common
    • Mortality reported in 1% to 25% of patients r2
    • AST levels greater than 2000 units/L and lactate dehydrogenase levels greater than 3000 units/L are associated with increased risk of mortality r1
  • Patients with HELLP syndrome might have an increased risk of future cardiovascular and metabolic disease (eg, hypertension, elevated BMI, elevated glucose, metabolic syndrome, unfavorable lipid parameters) based on studies of patients with preeclampsia and eclampsia, some of which included those with HELLP syndrome r23
  • Fetal prognosis is strongly influenced by gestational age at delivery; prognosis is poorer with delivery at earlier gestational ages
    • Perinatal death reported in 7.4% to 34% of patients r2

Screening and Prevention

Screening

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

Prevention

  • No specific preventive therapy for HELLP syndrome; however, daily low-dose aspirin after 12 weeks of gestation is recommended to reduce risk of preeclampsia in those at high risk r16c117c118
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