HELLP Syndrome

Overview

HELLP syndrome is a life-threatening microangiopathic condition that usually occurs after the 20 week of pregnancy or in the postpartum period; it is defined by the triad of hemolysis, elevated liver enzymes, and low platelets. According to the International Society for the Study of Hypertension in Pregnancy (ISSHP) 2021 classification, HELLP is not considered a separate disease, but a manifestation of severe preeclampsia; therefore, in every patient diagnosed with HELLP, other signs of preeclampsia (proteinuria, target organ involvement) should also be assessed.

The syndrome occurs in approximately 0.5-0.9% of all pregnancies and in 10-20% of severe preeclampsia cases. About 70% of cases start before delivery (the majority in the third trimester), and 30% after delivery (usually within the first 48 hours); the patient is typically multiparous and over 35 years old.

In pathophysiology, placental ischemia due to abnormal trophoblast invasion, antiangiogenic factor (soluble fms-like tyrosine kinase-1, sFlt-1) release and diffuse endothelial damage are the initiators; Complement activation and platelet adhesion by thromboxane A2 lead to serotonin release, which leads to vasospasm and platelet depletion. Erythrocytes passing through narrowed, fibrin-platelet-occluded capillaries break down and microangiopathic hemolytic anemia occurs; Fibrin accumulation in the liver sinusoids causes periportal necrosis, elevated transaminase and subcapsular hematoma in severe cases.

Since this chain ends only with the delivery of the placenta, the definitive treatment is birth. The most common clinical warning complaints are right upper quadrant or epigastric pain, nausea-vomiting and malaise; Since hypertension and proteinuria may be mild or absent in some cases, these nonspecific complaints are easily missed.

Diagnosis is based on the laboratory. Tennessee (full HELLP) criteria are platelet <=100,000/μL, AST >=70 IU/L (or AST/ALT value greater than twice the upper limit of normal), and LDH >=600 IU/L; In peripheral smear of hemolysis, schistocytes support low haptoglobin (<25 mg/dL) and increased indirect bilirubin (>=1.2 mg/dL).

The Mississippi classification grades the severity of the disease according to platelet rare: Platelet <=50,000 in Class 1, 50,000-100,000 in Class 2, 100,000-150,000/μL in Class 3.

In partial HELLP, only a part of the criteria is met; this picture requires close monitoring as it can progress to the full HELLP. In the differential diagnosis, LDH above 1000 U/L and serum creatinine exceeding twice normal are not expected in HELLP and these values are in favor of atypical hemolytic uremic syndrome (aHUS); in contrast, hemoglobin can remain normal (>11 g/dL) in HELLP due to hemoconcentration.

The classification terminology has also changed over time: the American Association of Obstetricians (ACOG) has abandoned dividing preeclampsia into "mild" and "severe"; because the picture can suddenly become severe at any stage and this binary distinction has been found misleading. Instead, the phrase "preeclampsia with/without severe trait" is used, and HELLP is considered severe trait by definition.

Note: threshold and dose values may vary slightly between sources; Institution protocol and up-to-date guide are essential.

Key considerations

• HELLP largely overlaps with severe preeclampsia and eclampsia; HELLP is considered the laboratory phenotype at the severe end of this disease spectrum, and the diagnosis cannot be excluded even if hypertension-proteinuria is mild or absent.
• Acute fatty liver of pregnancy (AFLP) is very similar to HELLP but stands out with hypoglycemia, marked hyperbilirubinemia, prolonged prothrombin time, and hypofibrinogenemia; Swansea criteria assist in differentiation, and treatment is again urgent delivery.
• Thrombotic thrombocytopenic purpura (TTP) is distinguished by ADAMTS13 levels dropping below 10%, prominent neurological findings, and a picture that does not resolve with delivery; it is the most dangerous mimic because plasma exchange is fatal if delayed.
• Atypical hemolytic uremic syndrome (aHUS) differs from HELLP with predominant renal failure, lactate dehydrogenase rising above 1000 U/L, and the condition often worsening postpartum, and requires complement inhibition (eculizumab).
• Acute viral or autoimmune hepatitis raises transaminases to much higher levels than HELLP but typically does not involve hemolysis and consumptive thrombocytopenia.
• Acute cholecystitis, choledocholithiasis, and biliary tract pathologies mimic right upper quadrant pain; imaging shows gallbladder-duct findings, and hemolysis-thrombocytopenia do not accompany.
• Non-pregnancy-specific thrombocytopenias, especially immune thrombocytopenic purpura (ITP) and gestational thrombocytopenia, run with isolated platelet decrease without hemolysis and liver enzyme elevation.
• Antiphospholipid syndrome and catastrophic antiphospholipid syndrome can cause microangiopathy and thrombocytopenia; a history of thrombosis, antibody positivity, and multiple organ thrombosis help distinguish.
• Disseminated intravascular coagulation developing in the context of sepsis occurs with an infection focus and systemic inflammatory response; fever, positive cultures, and hemodynamic disturbance differentiate the picture from HELLP.

Why it matters

The pathophysiology of HELLP involves placental-origin endothelial damage and microangiopathic hemolysis, which it shares with preeclampsia; therefore, the definitive treatment is delivery, and diagnosis should not delay stabilization. MgSO4 is the first-line treatment in preventing/repeating eclamptic seizures (superior to phenytoin/diazepam); since toxicity depends on dose and renal excretion, it is managed by clinical monitoring of DTR, respiration, and urine output, and the antidote calcium gluconate is kept ready.

Reducing severe HT within 30-60 minutes decreases maternal cerebral hemorrhage/stroke risk; labetalol, hydralazine, and oral nifedipine have comparable effectiveness. Platelet thresholds are based on bleeding risk: since surgery (cesarean) is always possible, a target >=50,000/µL is aimed for before delivery, while a lower threshold (around 20,000-25,000/µL) is usually sufficient for vaginal delivery; in active bleeding/DIC, early and multiple product support is provided regardless of these thresholds.

Although corticosteroids provide temporary biochemical improvement in platelet count, randomized evidence has not shown benefit in maternal mortality and morbidity; therefore, they are not routinely recommended for maternal indication, and are used <34 weeks only for fetal lung maturation. Routine cesarean is not enforced in the birth route; cesarean is chosen only for obstetric indications because the risk of surgical bleeding and abdominal-wall/intra-abdominal hematoma is high in the setting of severe thrombocytopenia and coagulopathy.

Critical complications

• Disseminated intravascular coagulation (DIC) develops in approximately 15-62.5% of HELLP cases and is recognized by prolonged prothrombin/activated partial thromboplastin time, falling fibrinogen, and rising D-dimer; management is based on target-oriented replacement with fresh frozen plasma, cryoprecipitate (if fibrinogen <150-200 mg/dL), red blood cell and platelet suspension, and acceleration of delivery.
• Placental abruption is seen in about 11-25% of cases and presents with painful vaginal bleeding, uterine hypertonicity-tenderness, and non-reassuring fetal heart rate pattern; management involves urgent delivery, blood product replacement, and correction of DIC.
• Subcapsular liver hematoma and rupture is a rare but fatal complication seen in less than 2% of HELLP pregnancies; sudden severe epigastric or right shoulder pain along with sudden hypotension-shock suggests rupture, which is confirmed by emergency ultrasonography or computed tomography. A stable, unruptured hematoma is usually managed conservatively; in case of rupture, hepatobiliary surgery, hepatic artery embolization, and massive transfusion protocol are employed, and liver transplantation may be considered in resistant cases.
• Acute kidney injury is recognized by oliguria-anuria, rising creatinine, and electrolyte imbalance; management involves careful monitoring of fluid balance, avoidance of nephrotoxic drugs, reduction of magnesium sulfate maintenance, monitoring of serum magnesium, and temporary hemodialysis if necessary. Predominant kidney failure should prompt re-evaluation of the diagnosis in favor of aHUS.
• Acute pulmonary edema develops in approximately 8-11% of cases; it is recognized by dyspnea, hypoxemia, and bilateral crackles, and is managed by avoiding fluid overload, providing oxygen, diuretics, and noninvasive or invasive ventilation if needed.
• Eclamptic seizure and cerebral complications (cerebral hemorrhage, posterior reversible encephalopathy syndrome, ischemic stroke) present with persistent headache, visual impairment, and altered consciousness; seizure prophylaxis and treatment with magnesium sulfate and rapid control of severe hypertension are critical in preventing cerebral hemorrhage. Cerebral hemorrhage is the main cause of maternal death due to HELLP.
• Postpartum hemorrhage occurs in approximately 12.5-40% of cases; it can be massive when combined with uterine atony on a background of thrombocytopenia and coagulopathy, and is managed with uterotonic agents, blood product replacement, and surgical-radiological intervention if necessary.
• Magnesium sulfate toxicity is an iatrogenic complication; it is recognized by loss of deep tendon reflexes, respiratory rate falling below 12/min, and decreased urine output, the infusion is stopped, and calcium gluconate 1 g is administered intravenously slowly as an antidote. Kidney involvement decreases magnesium excretion, significantly increasing the risk of toxicity in HELLP.

Special considerations

• Postpartum-onset HELLP accounts for approximately 30% of cases and mostly appears within the first 48 hours; in this group, since the placenta has already been delivered, treatment is supportive care and close monitoring rather than delivery, and also the condition that does not improve or worsens after birth necessitates distinguishing between thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome.
• The main drugs used in treatment for breastfeeding mothers (labetalol, nifedipine, magnesium sulfate) pass into breast milk in negligible amounts, so breastfeeding is generally sustainable; methyldopa is not preferred during lactation due to concerns about postpartum depression and is switched to an alternative as soon as the mother stabilizes.
• In a patient with renal failure, magnesium is excreted by the kidneys, so the risk of toxicity is high; the loading dose is generally maintained, but the maintenance dose is reduced or stopped, and serum magnesium level along with clinical signs of toxicity are closely monitored.
• Advanced maternal age (over 35) and multiparous women are the typical risk group for HELLP; this profile should lower the threshold for considering isolated thrombocytopenia as pathological rather than gestational.
• In pregnancies under 34 weeks where the mother and fetus are stable, in selected cases, it is possible to wait 24-48 hours in a well-equipped center and mature the fetal lungs with antenatal corticosteroid (betamethasone 12 mg intramuscularly, 2 doses 24 hours apart); however, in the presence of DIC, liver hematoma-rupture, abruption, renal failure, pulmonary edema, eclampsia, or fetal danger, this wait is abandoned and delivery is performed immediately regardless of gestational age.
• In women planning subsequent pregnancies, to reduce the risk of recurrent preeclampsia-HELLP, ACOG recommends starting low-dose aspirin (81 mg/day) from the end of the first trimester (optimally before the 16 week, between 12-28 weeks); a history of HELLP alone is considered high risk.

Follow-up plan

Refer red cases without delay to a center with obstetrics + intensive care (and hepatobiliary surgery/interventional radiology if necessary). Postpartum close monitoring for at least 48 hours:

HELLP often peaks at 24-48 hours postpartum or may begin postpartum. Serial complete blood count, liver/kidney function tests, LDH, coagulation (PT/aPTT, fibrinogen, D-dimer); improvement in platelet and LDH trends is a sign of recovery.

Continue MgSO4 for 24 hours after delivery/last seizure; monitor BP, reflexes, respiration, urine output. If right upper quadrant pain persists/worsens, rule out hematoma with liver imaging (USG/CT).

In worsening/atypical cases, re-evaluate the TTP-HUS differentiation (ADAMTS13, kidney). In most cases, platelet count rarely drops on postpartum day 3-4 and then starts to rise, and lactate dehydrogenase decreases; if this trend does not reverse by day 4, reconsider the diagnosis.

For discharge, platelet counts should show a significant rising trend, hypertension should be under control, and liver-kidney function should be improving. The patient should be informed of warning signs such as persistent headache, vision changes, right upper quadrant pain, shortness of breath, decreased urine, and bleeding; it should be emphasized that postpartum preeclampsia-HELLP can also start after discharge.

Blood pressure should be monitored for several days postpartum and around 1-2 weeks, and antihypertensives should be adjusted if necessary. In the long term, a history of HELLP increases the risk of chronic hypertension, cardiovascular and cerebrovascular disease, kidney disease, and diabetes; the patient should be advised on lifestyle changes, regular blood pressure monitoring, and cardiovascular risk assessment.

Counseling should be provided regarding the risk of recurrence in subsequent pregnancy (HELLP recurrence according to sources is about 13-27%, with additionally increased risk of preeclampsia, preterm birth, growth restriction, and abruption), and low-dose aspirin should be planned early in the new pregnancy.