HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)

INTRODUCTION — HELLP is an acronym that refers to a syndrome in pregnant and postpartum individuals characterized by hemolysis with a microangiopathic blood smear, elevated liver enzymes, and a low platelet count. It probably represents a severe form of preeclampsia (table 1A-B), but the relationship between the two disorders remains controversial. HELLP may be a separate disorder from preeclampsia because as many as 15 to 20 percent of patients with HELLP do not have antecedent hypertension or proteinuria [1-3].

Birth eventually leads to resolution of signs and symptoms of HELLP. Maternal complications are primarily related to bleeding, which can include hepatic hemorrhage. Neonatal complications are primarily related to the gestational age at birth, which is commonly preterm.

This topic will focus on the clinical presentation, diagnosis, differential diagnosis, and management of HELLP syndrome. Preeclampsia is reviewed in detail separately.

●(See "Preeclampsia: Clinical features and diagnosis".)

●(See "Preeclampsia: Antepartum management and timing of delivery".)

●(See "Preeclampsia with severe features: Delaying delivery in pregnancies remote from term".)

PREVALENCE — Prevalence ranges from 0.1 of normotensive pregnancies to 1 percent of pregnant people with preeclampsia without severe features, depending on the diagnostic criteria used.

RISK FACTORS

●Previous history of HELLP. (See 'Recurrence in subsequent pregnancies' below.)

●Several genetic variants have been associated with an increased risk for HELLP in research studies [4]. (See 'Pathogenesis' below.)

In contrast to preeclampsia, nulliparity is not a risk factor for HELLP [5]. Multiparous individuals account for ≥50 percent of affected patients.

PATHOGENESIS — The pathogenesis of HELLP is unclear. If it is a severe form of preeclampsia, it likely has the same origin (see "Preeclampsia: Pathogenesis"). If it is a separate entity, it can still have a similar origin (eg, shallow placentation), but for unknown reasons it may then diverge along a different pathway in which hepatic inflammation and activation of the coagulation system exceeds that in preeclampsia [4,6,7].

A subset of HELLP may be related to thrombotic microangiopathy caused by complement dysregulation (ie, complement-mediated thrombotic microangiopathy [CM-TMA]), which may be treatable without prompt fetal delivery. In a case report of a patient with severe early HELLP, treatment with eculizumab, a targeted inhibitor of complement protein C5, was associated with marked clinical improvement and complete normalization of laboratory parameters for 16 days, after which HELLP recurred [8]. The authors chose this intervention based on the hypothesis that preeclampsia with severe features/HELLP is a systemic inflammatory disorder mediated by the complement cascade and the observation that pregnant individuals with pathogenic variants in complement regulatory proteins appear to be at increased risk for developing preeclampsia with severe features [9]. Further research of possible benefits and harms is needed before such a clinical approach becomes advisable [10].

In less than 2 percent of patients with HELLP, the underlying etiology appears to be related to fetal long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency [11,12]. In one case series, all six pregnancies with fetal LCHAD deficiency developed severe maternal liver disease (HELLP or acute fatty liver of pregnancy [AFLP]) [13]. These complications probably were not due to chance or maternal heterozygosity for LCHAD deficiency alone because three other pregnancies with unaffected fetuses among these mothers were uncomplicated. In another case series in which 19 fetuses had LCHAD deficiency, 15 mothers (79 percent) developed AFLP or HELLP syndrome during their pregnancies [14]. Although these findings inform theories about the pathogenesis of HELLP, evaluation for genetic variants associated with LCHAD deficiency has no role in clinical management of patients with HELLP. (See "Acute fatty liver of pregnancy", section on 'Fetal long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency'.)

PATHOPHYSIOLOGY — Microangiopathy and activation of intravascular coagulation can account for all of the laboratory findings in HELLP syndrome (see 'Laboratory criteria for diagnosis' below). Hepatic histology may show microvascular fibrin deposition, neutrophilic infiltrate, fatty infiltration, lobular necrosis, and periportal hemorrhage (picture 1) [15]. Although kidney dysfunction is not an essential diagnostic criterion, microvascular dysfunction may also occur in the kidney and may increase its vulnerability to an ischemic insult [16].

PATIENT PRESENTATION

Signs and symptoms — HELLP has a variable presentation; the frequency of typical signs and symptoms is shown in the table (table 2) [17]. Symptoms typically present over a short period of time and progressively worsen.

Most patients have upper abdominal pain, which is probably the most common symptom. It may be localized to the midepigastrium, right upper quadrant, or below the sternum and the area may be tender on physical examination [18]. The pain is often severe and usually constant but may be fluctuating and colicky. Many patients also have nausea, vomiting, and generalized malaise, which may be mistaken for a nonspecific viral illness or viral hepatitis, particularly if the serum aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels are markedly elevated. The median AST level was 249 (range 70 to 6200) and the median LDH level was 853 units/L (range 560 to over 23,000) in one large series [18].

On physical examination, hypertension (defined as blood pressure ≥140/90 mmHg) and proteinuria are present in approximately 85 percent of cases, but it is important to note that either or both may be absent in patients with HELLP [17].

Thrombocytopenia-related bleeding (mucosal, hematuria, petechial hemorrhages, ecchymosis) is an unusual presentation [17]. The median platelet count was 57,000 cells/microL (range 7000 to 99,000) in one large series [18].

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

Substantial hepatic bleeding (subcapsular or intraparenchymal liver hematoma) and rupture may lead to very severe pain, hypotension and tachycardia; shoulder, chest, back, or neck pain; dyspnea or pain on inspiration; nausea/vomiting; and/or abdominal distention beyond that expected for the pregnant state [19-21]. In the overall population of patients with HELLP, the incidence of subcapsular hematoma is estimated to be 0.9 to 1.6 percent [18,22]. The aminotransferases in patients with hepatic bleeding are usually modestly elevated, but values of 4000 to 6000 international units/L can occasionally be seen.

Some HELLP cases are complicated by eclampsia [18,23]. Other severe manifestations include placental abruption, acute kidney injury, pulmonary edema, and retinal detachment [18]. Disseminated intravascular coagulation (DIC), if present, is usually associated with abruption, severe peripartum bleeding, or fulminant liver failure. (See 'Maternal outcome' below.)

Gestational age at onset — Symptoms typically develop between 28 and 37 weeks of gestation, but onset in the late second trimester or at term/postpartum is also common. In a series including over 440 pregnancies complicated by HELLP, 70 percent of cases occurred before birth, approximately 80 percent of these occurred before <37 weeks, approximately 20 percent occurred before 28 weeks, and <3 percent occurred at 17 to 20 weeks [18].

In the 30 percent of cases that occurred postpartum, most were diagnosed within 48 hours after birth, but occasionally as long as seven days; 80 percent had evidence of preeclampsia before birth. Why some cases of HELLP and preeclampsia develop postpartum is unknown and confusing since expulsion of the placenta initiates resolution of the disease in most patients.

DIAGNOSTIC EVALUATION — In pregnant individuals with characteristic symptoms of HELLP (eg, right upper quadrant/midepigastric pain, nausea, vomiting, malaise) and/or new-onset hypertension in the second half of pregnancy or first postpartum week, we order the laboratory tests needed to establish/exclude the diagnosis of HELLP. Because in rare cases of preeclampsia severe persistent upper abdominal pain may precede laboratory abnormalities by several hours, repeating the laboratory tests in four to six hours may be helpful unless another cause for the pain has been determined [24].

Laboratory work-up includes [17]:

●Complete blood count

●Peripheral smear

●Aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin

●Creatinine

A lactate dehydrogenase (LDH) level (as a marker for hemolysis) is needed to make a diagnosis of HELLP in some diagnostic protocols, thus it should be obtained at the same time as the initial laboratory work-up or secondarily in patients with elevated aminotransferases. In patients with elevated aminotransferases, the author of this topic obtains haptoglobin and LDH levels and coagulation studies (fibrinogen, prothrombin time, activated partial thromboplastin time). The coagulation studies are obtained to rule out acute fatty liver of pregnancy (AFLP) in the absence of abruption and severe thrombocytopenia.

DIAGNOSIS — The diagnosis of HELLP is based upon the presence of all of the laboratory abnormalities comprising its name (hemolysis with a microangiopathic blood smear [fragmented red blood cells; ie, schistocytes, burr cells], elevated liver enzymes, and low platelet count) in a pregnant/postpartum patient.

Pregnant/postpartum patients who have some of the typical laboratory abnormalities but do not have all of the laboratory criteria described below are considered to have partial HELLP (eg, cases without hemolysis have been termed ELLP) [5]. These patients may progress and eventually meet all laboratory criteria.

Laboratory criteria for diagnosis

Tennessee classification — The author of this topic requires the presence of all the following criteria to diagnose HELLP (called Tennessee classification) [25]:

●Hemolysis, established by at least two of the following:

•Peripheral smear with schistocytes and burr cells (picture 2).

•Serum bilirubin ≥1.2 mg/dL (20.52 micromol/L).

•Low serum haptoglobin (≤25 mg/dL) or lactate dehydrogenase (LDH) ≥2 times the upper level of normal (based on laboratory-specific reference ranges).

•Severe anemia unrelated to blood loss. (Severe anemia in pregnancy can be defined as hemoglobin level <8 to 10 g/dL, depending on the trimester). (See "Anemia in pregnancy", section on 'Definition of anemia'.)

●Elevated liver enzymes:

•Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2 times the upper level of normal (based on laboratory-specific reference ranges). (The use of twice the upper limit of normal threshold was chosen, in part, to avoid problems related to differences in assays, which may result in an elevated absolute value in one hospital that is considered near normal in another).

●Low platelets: <100,000 cells/microL

In HELLP, an elevated LDH level is a nonspecific marker that can be associated with severe hemolysis, acute hepatocellular injury, or both. The total bilirubin level is increased as a result of an increase in the indirect (unconjugated) fraction from hemolysis. Haptoglobin level is a specific marker of hemolysis: 25 mg/dL provides the best cutoff between hemolytic and nonhemolytic disorders. (See "Diagnosis of hemolytic anemia in adults", section on 'High LDH and bilirubin; low haptoglobin'.)

Other diagnostic criteria

●ACOG – The American College of Obstetricians and Gynecologists (ACOG) suggests slightly different diagnostic criteria and acknowledges the absence of clinical consensus among experts [26]. ACOG requires all of the following for diagnosis of HELLP:

•LDH ≥600 international units/L

•AST and ALT elevated more than twice the upper limit of normal

•Platelet count <100,000 cells/microL

●Mississippi classification – Some clinicians use the Mississippi classification system, which is based on severity of thrombocytopenia [27]:

•Class 1 – Platelet count ≤50,000 cells/microL plus LDH >600 international units/L and AST or ALT ≥70 international units/L

•Class 2 – Platelet count >50,000 but ≤100,000 cells/microL plus LDH >600 international units/L and AST or ALT ≥70 international units/L

•Class 3 – Platelet count >100,000 but ≤150,000 cells/microL plus LDH >600 international units/L and AST or ALT ≥40 international units/L

DIFFERENTIAL DIAGNOSIS — Differential diagnosis is discussed in detail separately. (See "Hypertensive disorders in pregnancy: Approach to differential diagnosis".)

A few key points: The four major disorders in differential diagnosis are acute fatty liver of pregnancy (AFLP), thrombotic thrombocytopenic purpura (TTP), pregnancy-related complement-mediated thrombotic microangiopathy (CM-TMA), and systemic lupus erythematosus. Distinguishing features of HELLP and these other disorders are shown in the tables (table 3A-B). There is also overlap with preeclampsia with severe features, which may not be a separate disease [28,29]. In HELLP, angiopathy (including thrombotic microangiopathy and microangiopathic hemolytic anemia) and liver dysfunction are marked, and the magnitude of hypertension is not highly correlated with the level of angiopathy and liver dysfunction. By contrast, most cases of severe preeclampsia have severe hypertension; thrombocytopenia and liver dysfunction, although present, are not as markedly abnormal as in HELLP. However, the clinical and histologic features are so similar that establishing the correct diagnosis may not be possible; furthermore, HELLP can occur concurrently with these disorders. Likewise, SARS-CoV-2 infection during pregnancy has been associated with a significant increase in the odds of preeclampsia with severe features, eclampsia, and HELLP [30]. The laboratory abnormalities of COVID-19 and HELLP can overlap, making diagnosis of HELLP difficult in infected patients. (See "COVID-19: Overview of pregnancy issues", section on 'Risk of preeclampsia'.)

MANAGEMENT — Our general approach is shown in the algorithm (algorithm 1).

Site of care — Because of the potential for life-threatening maternal complications (eg, liver rupture, acute kidney injury, disseminated intravascular coagulation [DIC]), which can develop rapidly and necessitate preterm birth, patients with HELLP should be managed at a tertiary care center with appropriate levels of maternal and neonatal intensive care, when possible. (See 'Maternal outcome' below and 'Fetal/neonatal outcome' below.)

The risk for serious morbidity correlates with increasing severity of maternal symptoms and laboratory abnormalities [27,31]. In a report of four patients with aspartate aminotransferase (AST) levels >2000 international units/L and lactate dehydrogenase (LDH) levels >3000 international units/L, all had disordered mental status, jaundice, intense hemolysis, and severe hypertension; one had multiorgan failure; and two died [31].

Treatment of severe hypertension — Severe hypertension, if present, requires prompt administration of one or more of the antihypertensive medications in this table (table 4) to reduce the risk of stroke. The approach to antihypertensive therapy is the same as that for preeclampsia (algorithm 2). (See "Treatment of hypertension in pregnant and postpartum patients", section on 'Acute therapy of severe hypertension'.)

In hemodynamically stable patients, intravenous fluids are administered conservatively, as in patients with preeclampsia. (See "Preeclampsia: Intrapartum and postpartum management and long-term prognosis", section on 'Fluids'.)

Hepatic imaging in patients with severe right upper quadrant/epigastric pain — Because of the poor correlation between the magnitude of laboratory abnormalities and liver histology [15], patients with severe symptoms (eg, persistent severe midepigastric pain not responding to opioids, tenderness on liver palpation, shoulder or neck pain, pain on inspiration) should undergo an appropriate imaging study expeditiously to look for hepatic bleeding, even if liver enzymes are not severalfold above the normal range, and to assess for other pathology [19,20,25]. Bedside ultrasound screening (focused assessment with sonography for trauma [FAST]) is a good initial study, followed by formal ultrasound examination and computed tomography (CT) or magnetic resonance imaging (MRI), when needed for clinical decision making. Imaging using CT (image 1 and image 2) or MRI (image 3 and image 4) is more accurate than ultrasound for detecting a liver hematoma and rupture but may not be as readily available and CT exposes the fetus to ionizing radiation. This is not an issue with noncontrast MRI, which is felt to be safe for the fetus. Issues regarding CT, MRI, and contrast in pregnant and lactating patients are discussed in more detail separately. (See "Diagnostic imaging in pregnant and lactating patients".)

Management of hepatic bleeding — Hepatic bleeding may remain contained or the liver may rupture, resulting in hemorrhage into the peritoneal cavity. Rupture is a life-threatening complication for both the mother and fetus, especially if diagnosis and treatment are delayed.

●The patient should be supported with volume replacement and transfusion of blood and blood products, as needed.

•We transfuse red blood cells if the hemoglobin is <7 g/dL and/or if the patient has ecchymosis, severe hematuria, or suspected abruption.

•Actively bleeding patients with thrombocytopenia should be transfused with platelets. Platelet transfusion may be indicated to prevent excessive bleeding during birth if the platelet count is less than 20,000 cells/microL, but the threshold for prophylactic platelet transfusion in this setting is controversial. The decision depends on patient-specific factors; consultation with the hematology service may be helpful. It is also useful to notify the blood bank that platelet transfusions may be required.

If cesarean birth is planned, platelet transfusion may be required. Some experts recommend platelet transfusion to achieve a preoperative platelet count greater than 40,000 to 50,000 cells/microL [17], but the minimum count before a neuraxial procedure is controversial and depends on factors in addition to platelet concentration. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Preparation for an invasive procedure' and "Adverse effects of neuraxial analgesia and anesthesia for obstetrics", section on 'Neuraxial analgesia and low platelets'.)

●Prompt cesarean birth is indicated when the patient is hemodynamically stable and severe anemia and coagulopathy, if present, have been corrected. We stabilize the patient before the cesarean, even in cases with nonreassuring fetal heart rate patterns or a low biophysical profile score. A team experienced in liver trauma surgery should be consulted during maternal stabilization and prior to delivery [32].

A hematoma that is unruptured and not expanding on initial imaging may be managed conservatively. The appearance of the hematoma depends on the age of the hematoma and the duration of and extension of the bleed. Subacute blood on ultrasound is echogenic.

Repeat ultrasound evaluation of the liver is performed 48 hours after the delivery. If liver findings remain stable, repeat imaging is performed again in one week and at six weeks postpartum. It may take months for a hematoma to resolve completely [19,25]. Patients with resolving laboratory abnormalities may be discharged home with outpatient follow-up.

●An expanding or ruptured hematoma requires operative management, which includes packing, drainage, hepatic artery ligation, and/or resection of affected areas of the liver. For patients with intractable hemorrhage despite these interventions, administration of recombinant factor VIIa has been successful in case reports [33]. Liver transplantation because of massive spontaneous hepatic rupture or acute liver failure has been life-saving in case reports [34-37].

●Similar considerations apply to postpartum patients with hepatic bleeding. Surgical intervention is always required for those with hemodynamic instability and generally required for those with persistent bleeding, increasing pain, or continued expansion of the hematoma on serial ultrasound examinations [38]; however, percutaneous embolization of the hepatic arteries is a reasonable first-line therapy in patients who are hemodynamically stable [39,40].

DIC, pulmonary edema, or acute kidney injury — Patients with disseminated intravascular coagulation (DIC), pulmonary edema, or acute kidney injury should be stabilized using standard therapies.

●(See "Disseminated intravascular coagulation (DIC) during pregnancy: Clinical findings, etiology, and diagnosis" and "Disseminated intravascular coagulation (DIC) during pregnancy: Management and prognosis".)

●(See "Acute respiratory failure during pregnancy and the peripartum period", section on 'Pulmonary edema'.)

●(See "Acute kidney injury in pregnancy".)

Magnesium sulfate — Magnesium sulfate is initiated at the time of admission to the labor and delivery unit and continued for 24 hours postpartum to prevent maternal seizures. (See "Preeclampsia: Intrapartum and postpartum management and long-term prognosis", section on 'Seizure prophylaxis'.)

It also provides fetal/neonatal neuroprotection when administered to pregnancies <32 weeks of gestation. (See "Neuroprotective effects of in utero exposure to magnesium sulfate".)

Role of therapeutic plasma exchange — Therapeutic plasma exchange has no benefit in patients with HELLP, but is the mainstay of treatment for patients with thrombotic thrombocytopenic purpura (TTP). Because patients with HELLP and those with TTP have both microangiopathic hemolysis and thrombocytopenia, making the correct diagnosis and, in turn, initiating the appropriate treatment can be challenging. Differential diagnosis is discussed in more detail separately. (See "Hypertensive disorders in pregnancy: Approach to differential diagnosis", section on 'Thrombotic microangiopathy: TTP and HUS'.) 

Delivery timing

Prompt delivery (preferred approach for most patients) — Delivery is the cornerstone of therapy for HELLP and is the only effective treatment. After maternal stabilization, the consensus among experts is that prompt delivery is indicated for pregnancies ≥34 weeks of gestation and pregnancies <34 weeks with severe complications (eg, abruption, hepatic bleeding, DIC, acute kidney injury, nonreassuring fetal status, pulmonary edema, fetal death, seizure, stroke) [17,41]. In pregnancies <34 weeks without severe complications, delivery can be delayed for 48 hours for antenatal corticosteroid administration (see 'Delayed delivery for up to 48 hours in selected pregnancies <34 weeks' below). However, pregnancies that have not reached a stage of fetal maturity that ensures a reasonable chance of extrauterine survival after a course of steroids are delivered promptly since expectant management is associated with a high risk of developing maternal complications without significant improvement in perinatal prognosis. (See 'Maternal outcome' below and 'Fetal/neonatal outcome' below.)

We do not manage patients with HELLP syndrome expectantly at any gestational age and consider delaying delivery for more than 48 hours investigational. There are few studies on the outcome of expectant management of HELLP syndrome. In these studies, the laboratory abnormalities of HELLP syndrome reversed in a subset of patients managed expectantly, and serious maternal complications were uncommon with careful maternal monitoring and timely intervention. However, the aim of expectant management is to improve neonatal morbidity and mortality. There is no evidence demonstrating improvement in overall perinatal outcome with expectant management compared with pregnancies delivered after a course of antenatal corticosteroids and no maternal benefits from expectant management. The following studies support our approach:

●In a study that treated 128 patients with HELLP <34 weeks of gestation with volume expansion and pharmacologic vasodilation under invasive hemodynamic monitoring, delivery was necessitated in 22 out of 128 (17 percent) of patients within 48 hours; the remaining patients had a median prolongation of pregnancy of 15 days [42]. Although there was no maternal mortality or serious maternal morbidity and more than one-half (55 out of 102) of the patients had complete reversal of their laboratory abnormalities with expectant management, 11 fetal and 7 neonatal deaths occurred.

●In another series, 41 patients with HELLP <35 weeks of gestation were managed expectantly [43]. Delivery was required within 48 hours in 14 out of 41 (34 percent), the remaining patients had a median prolongation of pregnancy of three days, and more than one-half (15 out of 27) had compete reversal of their laboratory abnormalities [43]. However, there were 10 fetal deaths.

Delayed delivery for up to 48 hours in selected pregnancies <34 weeks — Delaying delivery for up to 48 hours for administration of a course of antenatal corticosteroids can improve neonatal outcome in pregnancies <34 weeks that have reached a stage of fetal maturity that ensures a reasonable chance of extrauterine survival, but this benefit must be balanced against the maternal risk of developing complications in an ongoing pregnancy [17,41]. Although a short delay in delivery for betamethasone administration does not appear to increase maternal or fetal morbidity or mortality [44], we advise not attempting to delay delivery beyond 48 hours because disease progression usually occurs, sometimes with rapid maternal deterioration. Evidence of the efficacy of antenatal corticosteroids is reviewed separately. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on 'Evidence of efficacy'.)

We do not give betamethasone for fetal lung maturity in pregnancies with gestational age ≥34 weeks since no patients with HELLP were enrolled in randomized trials of the efficacy of steroids after 34 weeks. Furthermore, the marginal fetal benefit of steroids beyond 34 weeks is likely less than the maternal risk of expectant management. During administration of betamethasone, all patients are kept in the labor and delivery unit with continuous fetal monitoring. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on 'Long-term harms'.)

The author of this topic repeats the complete blood count (including platelet count) at 24 and 48 hours after administering steroids and more often if clinical deterioration is suspected. The American College of Obstetricians and Gynecologists (ACOG) recommends laboratory testing at least at 12-hour intervals until birth and in the postpartum period [26]. This information is useful when considering whether to administer red blood cell transfusions, whether neuraxial anesthesia can be performed safely (see "Adverse effects of neuraxial analgesia and anesthesia for obstetrics", section on 'Neuraxial analgesia and low platelets'), and whether platelet transfusion is indicated (See 'Management of hepatic bleeding' above.).

Choosing the route of birth — Vaginal birth is desirable in the absence of standard indications for cesarean birth (eg, breech, nonreassuring fetal status) and hepatic bleeding.

We induce patients with HELLP uncomplicated by hepatic bleeding regardless of gestational age when the cervix is favorable. When the cervix is unfavorable, we believe cesarean birth is probably preferable to induction in pregnancies less than 30 to 32 weeks of gestation, especially if signs of fetal compromise (growth restriction, oligohydramnios) are present. Induction of these pregnancies, even with use of cervical ripening agents, generally has a high failure rate and is often prolonged, thereby potentially exposing the mother and fetus to a higher risk of complications from severe HELLP syndrome [17]. (See "Induction of labor with oxytocin" and "Induction of labor: Techniques for preinduction cervical ripening".)

In patients with HELLP complicated by hepatic bleeding, we suggest cesarean birth because the increased intrabdominal pressure during vomiting and pushing can lead to further hepatic bleeding, even in patients who have undergone embolization by interventional radiology. Performing cesarean avoids this and allows visual evaluation of the source and amount of bleeding. Although the consequences of vaginal birth in patients with liver hematoma has not been studied, cesarean birth has been recommended for patients with esophageal varices as most cases of maternal mortality due to variceal hemorrhage occurred during vaginal birth [45].

Anesthesia/analgesia — Thrombocytopenia and coagulation abnormalities may preclude use of neuraxial anesthesia for labor and birth. The minimum platelet count necessary to safely perform neuraxial anesthesia is unknown, and practice varies. Use of neuraxial and general anesthesia for these patients is reviewed separately. (See "Anesthesia for the patient with preeclampsia", section on 'Coagulation'.)

Opioids administered intravenously provide some pain relief without risk of maternal bleeding, which may occur with intramuscular administration or with placement of neuraxial anesthesia, removal of a neuraxial catheter, or placement of a pudendal nerve block. However, there is no contraindication to perineal infiltration of an anesthetic for performing an episiotomy or repairing the perineum. (See "Pharmacologic management of pain during labor and delivery".)

Performing cesarean birth and exploring the abdomen — Management of thrombocytopenia at delivery is the same as in patients with thrombocytopenia related to preeclampsia with severe features, and reviewed separately. (See "Preeclampsia: Intrapartum and postpartum management and long-term prognosis", section on 'Management of thrombocytopenia'.)

If preoperative imaging was not performed in a patient with findings suggestive of liver hematoma, we perform a midline skin incision and very gently palpate the liver to assess for the presence of an unruptured hematoma, after extracting the fetus and placenta.

Because of the increased risk of subfascial and wound hematoma in patients with thrombocytopenia who undergo cesarean birth, the author of this topic places a subfascial drain and leaves the skin incision open for the first 48 postoperative hours [3]. Some surgeons place a subfascial and/or suprafascial drain and close the incision with staples, so it is easy to open partially if a hematoma develops. The management of the abdominal wall incision after cesarean should be individualized, depending on the surgeon's assessment of risk of hematoma/seroma development.

Is there a role for dexamethasone in treatment of HELLP? — We do not treat patients with HELLP syndrome with dexamethasone. The two largest, randomized, double-blind, placebo-controlled trials evaluating the use of dexamethasone to improve maternal outcome in patients with HELLP syndrome did not establish a benefit [46,47], in contrast to initial observational studies and small randomized trials that suggested more rapid improvement in maternal laboratory and clinical parameters [48-51].

In a meta-analysis of 11 trials (550 participants) comparing corticosteroid treatment with placebo/no treatment in HELLP, steroid administration did not lead to a convincing reduction in maternal death (risk ratio [RR] 0.95, 95% CI 0.28-3.21), maternal death or severe maternal morbidity (RR 0.27, 95% CI 0.03-2.12), or perinatal/infant death (RR 0.64, 95% CI 0.21-1.97), but the standardized mean difference in platelet count favored the steroid group (0.67, 95% CI 0.26-1.10) [52]. A subsequent randomized trial with an additional 132 patients assigned to dexamethasone or placebo reported no significant differences in the time to recovery of platelet counts and  and aspartate aminotransferase levels or frequency of complications [46]. 

The use of dexamethasone rather than betamethasone to promote fetal pulmonary maturity is a separate issue. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on 'Betamethasone or dexamethasone?'.)

POSTPARTUM — All of the signs and symptoms of HELLP, including subcapsular hematoma and liver rupture, can initially appear in the postpartum period [53]. Management is similar to that of HELLP diagnosed before birth, except fetal status no longer needs to be considered.

Maternal care — Patients who are critically ill or at substantial risk for developing serious complications can benefit from transfer to an intensive care setting, rather than a postpartum unit. Potential indications for intensive monitoring include threatened or actual liver rupture or fulminant liver failure, disseminated intravascular coagulation (DIC), acute kidney injury, massive transfusion, transfusion-related acute lung injury, and cardiac ischemia or cardiomyopathy.

Supportive care may involve oxygenation and ventilation (ie, supplemental oxygen or mechanical ventilation), sedation, pain control, hemodynamic support (ie, vasopressors), intensive monitoring, volume management (ie, intravenous fluids or diuretics), nutritional support, stress ulcer prophylaxis, and venous thromboembolism prophylaxis. (See "Critical illness during pregnancy and the peripartum period".)

Laboratory monitoring — Laboratory results may initially worsen in the 48 hours following birth (eg, platelet count usually decreases by 40 percent/day, hematocrit falls, and liver enzymes increase) [54], which is the reason that the American College of Obstetricians and Gynecologists (ACOG) recommends laboratory testing at least at 12-hour intervals in the postpartum period [26]. We stop checking laboratory values once they are clearly beginning to stabilize. In the absence of bleeding or complications related to HELLP, there is no benefit for further serial evaluation of platelet counts or liver enzymes. Although liver enzymes return to normal or substantially decrease by the fourth postpartum day [46,47,54,55], in one report, total bilirubin levels were elevated in 20 percent of patients who had liver function tests checked 3 to 101 months after giving birth [56].

An upward trend in platelet count and a downward trend in lactate dehydrogenase (LDH) concentration are usually seen by the fourth postpartum day in the absence of complications. In a series of 158 patients with HELLP syndrome, platelet counts decreased until 24 to 48 hours after birth, while serum LDH concentration usually peaked at this time [54]. In all patients who recovered, a platelet count greater than 100,000 cells/microL was achieved by the sixth postpartum day or within 72 hours of the platelet nadir. Others have reported similar findings [55]. The platelet count rebound can overshoot; one group reported values of 413,000 to 871,000 cells/microL [57].

If the platelet count continues to fall and LDH continues to rise after the fourth postpartum day, then diagnoses other than HELLP syndrome (eg, primary thrombotic microangiopathy) should be considered [26]. However, recovery can be delayed in patients with particularly severe HELLP, such as those with DIC, platelet count less than 20,000 cells/microL, renal dysfunction, or ascites [17,58]. These patients are at risk of developing pulmonary edema and acute kidney injury.

OUTCOME AND PROGNOSIS

Maternal outcome — The outcome for patients with HELLP is generally good; however, serious complications are relatively common. In the author's series of 437 patients with HELLP syndrome at a tertiary care facility, the following complications were observed [18]. Many complications are interdependent (eg, abruption is a common obstetric etiology of DIC, which, in turn, may induce acute kidney injury, which may lead to pulmonary edema; massive bleeding from the liver, postpartum uterine atony, or lacerations could also lead to DIC).

●Bleeding – 55 percent required transfusions with blood or blood products; 2 percent required laparotomies for major intraabdominal bleeding

●Disseminated intravascular coagulation (DIC) – 21 percent

●Placental abruption – 16 percent

●Acute kidney injury – 8 percent

●Pulmonary edema – 6 percent

●Subcapsular liver hematoma (or hepatic rupture) – 1 percent

●Retinal detachment – 1 percent

●Intracerebral hemorrhage – <1 percent

●Death – 1 percent

Serious maternal complications were observed in 25 of 56 cases of early-onset HELLP syndrome (<23 weeks) in a systematic review [59]. The most common were hepatic (13 in 56), central-nervous-system-related (11 in 56), and respiratory (11 in 56), with one maternal death. A systematic review of pregnant patients with spontaneous liver hematomas reported maternal mortality in 15 percent of cases [60].

Additional complications that have been reported in other series include adult respiratory distress syndrome, sepsis, stroke, cerebral hemorrhage and edema, and hepatic infarction (in patients with antiphospholipid syndrome, which has been diagnosed in nearly 50 percent of early-onset cases [59]) [5,61,62]. Wound complications secondary to bleeding and hematomas are common in patients with thrombocytopenia.

HELLP with or without acute kidney injury does not affect long-term kidney function [63,64]. Similarly, there are no ongoing hepatic sequelae following recovery from hepatic bleeding with/without rupture.

Fetal/neonatal outcome — The neonatal and long-term prognoses are most strongly associated with gestational age at birth and birth weight [65-73]. Preterm birth is common (70 percent; with 15 percent of births before 27 weeks) [65]. Leukopenia, neutropenia, and thrombocytopenia may be observed in the neonate but appear to be related to fetal growth restriction, preterm birth, and maternal hypertension rather than HELLP [67]. Maternal HELLP does not affect fetal/neonatal liver function.

The overall perinatal mortality rate is 7 to 20 percent; complications of preterm birth, fetal growth restriction, and abruption are the leading causes of perinatal death [17,66]. The severity of hemolysis, liver disfunction, and thrombocytopenia does not correlate with the risk of fetal demise, except in cases of liver hematoma or rupture where fetal mortality was 40 percent in a systematic review [60].

Early-onset HELLP syndrome has a very poor prognosis. In a systematic review including 57 pregnancies with HELLP syndrome before 23 weeks of gestation and known outcome, 36 (63 percent) were terminated and of the 21 continued pregnancies, there were 10 fetal demises before 20 weeks, six stillbirths, two neonatal deaths, and three living neonates (all born at 23 weeks) [59].

Recurrence in subsequent pregnancies — The risk of recurrent HELLP was about 4 percent for patients who were normotensive before onset of the syndrome, in a long-term study of 139 patients with subsequent pregnancies [74]. However, these patients were at increased risk for other placenta-mediated obstetric complications. In a meta-analysis of individual patient data from 512 patients with HELLP who became pregnant again, 7 percent developed HELLP, 18 percent developed preeclampsia, and 18 percent developed gestational hypertension in a subsequent pregnancy [75].

In a subsequent Norwegian registry-based study of 577 patients with HELLP in their first pregnancy and then a second pregnancy, 24 percent developed hypertensive disorders of pregnancy that included either HELLP syndrome, preeclampsia, pregnancy-induced hypertension, or eclampsia in the second pregnancy compared with 3.6 percent of patients with no HELLP in their first pregnancy [76]. The study did not provide results for recurrent HELLP syndrome alone. The risk of recurrence of hypertensive disorders of pregnancy was higher in patients with preterm versus term HELLP in the first pregnancy (30.3 versus 16.5 percent).

Prevention — There is no evidence that any therapy prevents recurrent HELLP syndrome, but data are limited. The author considers HELLP syndrome a form of severe preeclampsia and prescribes low-dose aspirin during the second and third trimesters in future pregnancies to reduce the risk of preeclampsia. Evidence for use of low-dose aspirin for prevention of preeclampsia is discussed separately. (See "Preeclampsia: Prevention", section on 'Low-dose aspirin'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertensive disorders of pregnancy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: HELLP syndrome (The Basics)" and "Patient education: High blood pressure and pregnancy (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – The most common clinical presentation of HELLP syndrome (hemolysis with a microangiopathic blood smear, elevated liver enzymes, and low platelet count) is abdominal pain and tenderness in the midepigastrium, right upper quadrant, or below the sternum (table 2). Most cases are diagnosed between 28 and 36 weeks of gestation, but signs/symptoms may present up to seven days postpartum. (See 'Patient presentation' above.)

●Diagnosis – The diagnosis of HELLP is based on the presence of all of the following criteria (Tennessee classification) (see 'Diagnosis' above):

•Hemolysis, established by at least two of the following:

-Peripheral smear with schistocytes and burr cells (picture 2)

-Serum bilirubin ≥1.2 mg/dL (20.52 micromol)

-Low serum haptoglobin or lactate dehydrogenase (LDH) ≥2 times the upper level of normal (based on laboratory-specific reference ranges)

-Severe anemia, unrelated to blood loss

•Elevated liver enzymes:

-Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2 times the upper level of normal (based on laboratory-specific reference ranges)

•Low platelets: <100,000 cells/microL

●Differential diagnosis – The four major disorders in differential diagnosis are acute fatty liver of pregnancy (AFLP), thrombotic thrombocytopenic purpura (TTP), pregnancy-related hemolytic-uremic syndrome, and systemic lupus erythematosus. All have features that overlap with HELLP (table 3A-B). (See 'Differential diagnosis' above.)

●Management – Because of the potential for life-threatening maternal complications, which can develop rapidly and necessitate preterm birth, patients with HELLP should be managed at a tertiary care center with appropriate levels of maternal and neonatal intensive care. Our general approach to management is shown in the algorithm (algorithm 1). (See 'Management' above.)

•Severe hypertension – Severe hypertension, if present, requires prompt administration of one or more of the antihypertensive medications in this table (table 4) to reduce the risk of stroke. The approach to antihypertensive therapy is the same as that for preeclampsia (algorithm 2). This approach and supporting evidence is available separately. (See "Treatment of hypertension in pregnant and postpartum patients", section on 'Acute therapy of severe hypertension'.)

•Hepatic imaging and management of hepatic bleeding – Patients with severe right upper quadrant/epigastric pain should undergo hepatic imaging as the pain may be due to hepatic bleeding, which may remain contained or rupture the liver capsule. Management of hepatic bleeding involves volume replacement and transfusion of blood and blood products, as needed. Prompt cesarean birth is indicated once the patient is hemodynamically stable and severe anemia and coagulopathy, if present, have been corrected.

A hematoma that is unruptured and not expanding may be managed conservatively. An expanding or ruptured hematoma requires operative management, which includes packing, drainage, hepatic artery ligation, and/or resection of affected areas of the liver. A team experienced in liver trauma surgery should be consulted during maternal stabilization and prior to delivery. (See 'Hepatic imaging in patients with severe right upper quadrant/epigastric pain' above.)

•Magnesium sulfate – Magnesium sulfate is initiated at the time of admission to the labor and delivery unit and continued for 24 to 48 hours postpartum to prevent maternal seizures. It also provides fetal/neonatal neuroprotection. The use of magnesium sulfate for these indications and evidence of efficacy of magnesium sulfate are available separately. (See "Preeclampsia: Intrapartum and postpartum management and long-term prognosis", section on 'Seizure prophylaxis' and "Neuroprotective effects of in utero exposure to magnesium sulfate".)

●Timing of delivery

•Pregnancies with serious complications – Pregnancies with serious maternal or fetal complications (eg, abruption, hepatic bleeding, disseminated intravascular coagulation [DIC], acute kidney injury, nonreassuring fetal status, pulmonary edema) require prompt delivery regardless of gestational age. (See 'Prompt delivery (preferred approach for most patients)' above.)

•Pregnancies ≥34 weeks without serious complication – For pregnancies ≥34 weeks of gestation without serious maternal or fetal complications, we suggest prompt delivery rather expectant management (Grade 2C). In this population, the potential risks of preterm birth or iatrogenic term birth are outweighed by the risk of developing serious complications associated with HELLP syndrome. (See 'Prompt delivery (preferred approach for most patients)' above.)

•Pregnancies <34 weeks without serious complications

-For pregnancies <34 weeks without serious maternal or fetal complications and at a stage of fetal maturity that ensures a reasonable chance of extrauterine survival, we suggest delaying delivery for 48 hours for administration of a course of antenatal corticosteroids rather than prompt delivery (Grade 2C). (See 'Delayed delivery for up to 48 hours in selected pregnancies <34 weeks' above and 'Prompt delivery (preferred approach for most patients)' above.)

-For preterm pregnancies that have not reached a stage of fetal maturity that ensures a reasonable chance of extrauterine survival, we suggest prompt delivery (Grade 2C). Expectant management is associated with a high risk of developing maternal complications without significant improvement in perinatal prognosis. (See 'Prompt delivery (preferred approach for most patients)' above.)

•Route of birth – Vaginal birth is desirable in the absence of standard indications for cesarean birth and hepatic bleeding (see 'Choosing the route of birth' above and 'Performing cesarean birth and exploring the abdomen' above). However:

-For pregnancies less than 30 to 32 weeks with an unfavorable cervix, we suggest cesarean birth (Grade 2C). These patients are likely to have a prolonged induction if vaginal birth is attempted.

-For patients with hepatic bleeding, we suggest cesarean birth (Grade 2C). The intrabdominal pressure during vomiting and pushing can lead to further hepatic bleeding.

Management of thrombocytopenia at delivery is the same as in patients with thrombocytopenia related to preeclampsia with severe features, and reviewed separately. (See "Preeclampsia: Intrapartum and postpartum management and long-term prognosis", section on 'Management of thrombocytopenia'.)

●Postpartum course – Most patients have an upward trend in platelet count and a downward trend in lactate dehydrogenase concentration by the fourth postpartum day. We stop checking laboratory values once the patient is clearly beginning to stabilize. (See 'Postpartum' above.)

●Outcome/prognosis

•Maternal – The outcome for mothers with HELLP syndrome is generally good, but serious complications such as abruption, acute kidney injury, subcapsular liver hematoma or hepatic rupture, pulmonary edema, hemorrhage, retinal detachment, and death may occur. (See 'Maternal outcome' above.)

Future pregnancies are at increased risk for developing HELLP, preeclampsia, and gestational hypertension. (See 'Recurrence in subsequent pregnancies' above.)

•Pediatric – The short-term and long-term pediatric prognoses are primarily related to the gestational age at delivery and birth weight. Maternal HELLP does not affect fetal/neonatal liver function. (See 'Fetal/neonatal outcome' above.)