HELLP Syndrome

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HELLP syndrome, named for 3 features of the disease (hemolysis, elevated liver enzyme levels, and low platelet levels), is a life-threatening condition that can potentially complicate pregnancy. HELLP was once known as edema-proteinuria-hypertension gestosis type B in the early 20th century and was later renamed in 1982 by Louis Weinstein.

Although the idea is controversial, some propose that HELLP is a severe form of preeclampsia, which, in turn, is defined as gestational hypertension accompanied by proteinuria after the 20th week of gestation. Others believe that HELLP syndrome is an entity of its own. Although the cause of HELLP syndrome is unknown, certain risk factors, including a maternal age of older than 34 years, multiparity, and European descent, have been described. [1, 2, 3]

There is no known preventive management.

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

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

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

A study by Weiner et al reported that although severe preeclampsia and HELLP syndrome have similar placental histopathologic findings, HELLP syndrome was associated with higher rates of placental maternal vascular supply lesions and small-for-gestational-age. [10]

Another hypothesis proposes acute maternal immune rejection due to immunocompetent maternal cells coming into contact with a genetically distinct fetus, altering the maternal-fetal immune balance and causing endothelial dysfunction, platelet activation and aggregation, and arterial hypertension. [11]

Other theories include inborn errors of fatty acid oxidative metabolism secondary to long- and medium-chain fatty acid mutations, which cause liver damage secondary to insufficient mitochondrial oxidation of fatty acids required for ketogenesis. [12, 13]

Yet another theory suggests a placental-instigated acute inflammatory condition targeting the liver. [14]

In addition, dysfunction in the complement system via excessive activation or defective regulation for a given amount of endothelial injury has been proposed to cause damage to hepatic vessels in HELLP. [15]

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

 

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

Risk factors for HELLP syndrome include the following:

Maternal age older than 34 years

Multiparity

White race or European descent

History of poor pregnancy outcome [1, 16]

HELLP syndrome occurs in 0.1%-0.6% of all pregnancies and in 4%-12% of patients with preeclampsia. HELLP syndrome typically occurs between week 27 of gestation and delivery, or immediately postpartum in 15%-30% of cases. [17, 18, 19, 20]

The incidence of HELLP syndrome is significantly higher in whites and women of European descent. [19]

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

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

The recurrence rate is 2%-27% in subsequent pregnancies. [21, 22]

Patients are at increased risk of preeclampsia or pregnancy-induced hypertension, in addition to preterm delivery, fetal growth restriction, and placental abruption in future pregnancies. [21, 2]

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

Maternal mortality ranges from 1%-3%, with a perinatal mortality rate of 35%. [23] Class 1 or complete HELLP (see Stages) is associated with the highest incidence of perinatal morbidity and mortality. Sixty percent of deaths occur in patients with class 1 disease; cerebral hemorrhage is the most common autopsy finding. [24, 25] Morbidity includes the following:

Disseminated intravascular coagulation (DIC) (20%)

Placental abruption (16%)

Acute renal failure (7%)

Pulmonary edema (6%) [23]

Fetal morbidity and mortality rates range from 9%-24% [26] and usually result from placental abruption, intrauterine asphyxia, or prematurity. [27]

See Complications for a complete list of adverse maternal outcomes.

Patients with HELLP syndrome should be educated on the risk of maternal and fetal morbidity and mortality in future pregnancies.

Rahman TM, Wendon J. Severe hepatic dysfunction in pregnancy. Q J Med. 2002. 95:343:[Medline].

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Lichtman, M, Kipps T, Seligsohn U, Kaushansky K, Prchal J. Thrombocytopenia. Williams Hematology, Eighth Edition. 8. McGraw-Hill Companies; 2010. Chapter 119.

Knerr I, Beinder E, Rascher W. Syncytin, a novel human endogenous retroviral gene in human placenta: Evidence for its dysregulation in preeclampsia and HELLP syndrome. Am J Obstet Gynecol. 2002. 186:210. [Medline].

Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004. 350:672. [Medline].

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Widmer M, Villar J, Beniani A, et al. Mapping the theories of preeclampsia and the role of angiogenic factors: A systematic review. Obstet Gynecol 109:168, 2007. Obstet Gynecol. 2007. 109:168. [Medline].

Semenovskaya Z, Erogul M. Pregnancy, Preeclampsia. Medscape Reference. May 2010. [Full Text].

Weiner E, Schreiber L, Grinstein E, Feldstein O, Rymer-Haskel N, Bar J, et al. The placental component and obstetric outcome in severe preeclampsia with and without HELLP syndrome. Placenta. 2016 Nov. 47:99-104. [Medline].

Zhou Y, McMaster M, Woo K, et al. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol. 2002. 160:1405-23. [Medline].

Nelson J, Lewis B, Walters B. The HELLP syndrome associated with fetal medium chain acyl-CoA dehydrogenase deficiency. Journal of Inherited Metabolic Diseases. 2000. 23:518-519.

Ibdah JA, Bennet MJ, Rinaldo P, Zhao Y, Gibson B, Sims HF, et al. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. New England Journal of Medicine. 1999. 340:1723-1731.

Strand S, Strand D et al. Placenta-derived CD59 ligand causes liver damage in hemolysis, elevated liver enzymes and low platelet count syndrome. Gastroenterology. 2004. 126:849-858.

Fang C, Richards A et al. Advances in understanding of pathogenesis of aHUS and HELLP. BJH British Journal of Haematology. 2008. 143:336-348.

Ohara Padden, M. HELLP Syndrome: Recognition and Perinatal Management. The Academy of Family Physicians. Sept 1, 1999. [Full Text].

Martin JN Jr, Magann EF, Blake PG. Analysis of 454 pregnancies with severe preeclampsia/eclampsia/HELLP syndrome using the 3-class system of classification. Am J Obstret Gynecol 1993. 1993. 168:386.

Martin JN Jr, Magann EF. HELLP syndrome current principles and recommended practice. Curr Obstet Med. 1996. 4:129-75.

Sibai BM, Ramamdan MK, Usta I, Salama M, Mercer BM, Friedman SA. Maternal morbidity and mortality in 442 pregnancies with HELLP syndrome. Am J Obstet Gynecol. 1993. 169:1000-6.

Ukomadu C, Greenberger N, Blumberg R, Burakoff R. Hepatic Complications of Pregnancy. Current Diagnosis and Treatment: Gastroenterology, Hepatology and Endoscopy. McGraw Hills and Company; 2009. Chapter 8.

O’Brien JM, Barton JR. Controversies with the diagnosis and management of HELLP syndrome. Clinical Obstetrics and Gynecology. June 2005. 48:2:460-477.

Sullivan CA, Magann EF, Perry KG Jr, et al. The recurrence risk of the syndrome of hemolysis, elevated liver enzymes, and low platelets: Subsequent pregnancy outcome and long term prognosis. Am J Obstet Gynecol. 1995. 172:125.

Barton JR, Sibai BM. Diagnosis and management of hemolysis, elevated liver enzymes, and low platelets syndrome. Clin Perinatol. 2004. 31:807-33. [Medline].

Magann EF, Martin JN Jr. Twelve steps to optimal management of HELLP syndrome. Clin Obstet Gynecol. 1999. 42:532. [Medline].

Isler CM, Rinehart CK, Terrone DA, Martin RW, Magann EF, Martin JN Jr. Maternal mortality associated with HELLP syndrome. Am J Obstet Gynecol. 1999. 181:924-8.

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Sibai BM. Diagnosis, controversies and management of the syndrome of hemolysis, elevated liver enzymes and low platelet count. Obstet and Gynecol. 2004. 103:981-91.

Vigil-De Gracia P. Pregnancy complicated by pre-eclampsia-eclampsia with HELLP syndrome. Int J Gynecol Obstet. 2001. 72:17-23.

Martin JN Jr. Rinehart K, May WL, Magann EF, Terrone DA, Blake PG. The spectrum of severe preeclampsia: comparative analysis by HELLP syndrome classification. Am J Obstet Gynecol. 1999. 180:1373-84.

Sibai B. HELLP Syndrome. UptoDate. 2010. [Full Text].

Weinstein L. Preeclampsia/eclampsia with hemolysis, elevated liver enzymes and thrombocytopenia. Obstet Gynecol. 1985. 66:657- 60.

Roberts JM. Cooper DW. Pathogenesis and genetics of pre-eclampsia. Lancet. 2001. 357:53-56.

Aarnoudse JG, Houthhoff HF et al. A syndrome of liver damage and intravascular coagulation in the last trimester of normotensive pregnancy. A clinical and histopathological study. BR J Obstet Gynaecol. 1986. 93:145-155.

Arias F, Mancilla-Jimenez R. Hepatic fibrinogen deposits in pre-eclampsia. Immunofluorescent evidence. N Engl J Med. 1976. 295:578-582.

Barton JR, Riely CA, Adamel TA, et al. Hepatic histopathologic condition does not correlate with laboratory abnormalities in HELLP syndrome (hemolysis, elevated liver enzymes and low platelet count). Am J Obstet Gynecol. 1992. 167:1538-1543.

Barton JR, Sibai BM. Hepatic imaging in HELLP syndrome. Am J Obstet Gynecol. 1996. 174:1820-1827.

Martin JN Jr., Magann EF, Isler CM. HELLP Syndrome: the scope of disease and treatment. HELLP Syndrome: the scope of disease and treatment. Belfort MA. Thornton S, Saade GR. Hypertension in Pregnancy. Oxford:Marcel Dekker; 2003. Chapter 7 p 141-88.

Martin JN Jr. Rose C, Briery C. Understanding and managing HELLP syndrome: The integral role of aggressive glucocorticoids for mother and child. Am J of Obst & Gyn. 2006. 195:914-34.

Van Runnard Heimel PH, Juisjes AJM, Franx A, Koopman C, Bots ML, Bruinse HW. A randomized placebo-controlled trial of prolonged administration to patients with HELLP syndrome remote from term: maternal and neonatal complications. Am J Obstet Gynecol. 2004. 191:S41.

Isler CM, Barrilleaux PS, Magann EF et al. A prospective randomized trial comparing the efficacy of dexamethasone and betamethasone for the treatment of antepartum HELLP syndrome. Am J Obstet Gynecol. 2001. 184:1332-39.

O’Brien JM, Milligan DA, Barton JR. Impact of high-dose corticosteroid therapy for patients with HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome. Am J Obstet Gynecol. 2000. 183:921-4.

Briggs R, Chari RS, Mercer B, Sibai BM. Postoperative incision complications after cesareansection in patients with antepartum syndrome of hemolysis, elevated liver enzymes, and lowplatelets (HELLP): does delayed primary closure make a difference?. Am J Obstet Gynecol. 1996. 175:183-6.

Allen AM, Kim WR, Larson JJ, et al. The epidemiology of liver diseases unique to pregnancy in a US community: a population-based study. Clin Gastroenterol Hepatol. 2015 Aug 21. [Medline].

Morisawa H, Makino S, Takahashi H, Sorita M, Matsubara S. Retinal detachment in hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome: Color vision abnormality as the first and predominant manifestation. J Obstet Gynaecol Res. 2015 Nov. 41(11):1835-8. [Medline].

 

Class 1 (Severe)

Class 2 (Moderate)

Class 3 (Mild)

Platelets

≤50,000/µL

50,000-100,000/µL

100,000-150,000/µL

AST or ALT

≥70 IU/L

≥70 IU/L

≥40 IU/L

LDH

≥600 IU/L

≥600 IU/L

≥600 IU/L

Incidence of bleeding

13%

8%

No increased risk

Laboratory Test

Possible Result

Cause

Recovery to Baseline (in Number of Hours or Days Postpartum)

Haptoglobin

Hemolysis

24-30 hours

LDH

Hemolysis or liver dysfunction

3-5 days

AST or ALT

Liver dysfunction

3-5 days

Bilirubin

Hemolysis

Platelets (CBC)

Consumption

6-11 days

Hemoglobin/Hematocrit (CBC)

Hemolysis

PT

Normal

 

 

PTT

Liver dysfunction

D-dimer

Increased coagulation and secondary fibrinolysis

Fibrinogen

Huma Khan, MD Resident Physician, Department of Emergency Medicine, Northshore-Long Island Jewish Medical Center

Disclosure: Nothing to disclose.

Natalie B Meirowitz, MD Assistant Professor of Obstetrics and Gynecology, Albert Einstein College of Medicine; Chief of Maternal-Fetal Medicine, Director, Center for Maternal-Fetal Health, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Northshore-Long Island Jewish Medical Center

Natalie B Meirowitz, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald M Ramus, MD Professor of Obstetrics and Gynecology, Director, Division of Maternal-Fetal Medicine, Virginia Commonwealth University School of Medicine

Ronald M Ramus, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, Medical Society of Virginia, Society for Maternal-Fetal Medicine

Disclosure: Nothing to disclose.

Jordan G Pritzker, MD, MBA, FACOG Adjunct Professor of Obstetrics/Gynecology, Hofstra North Shore-LIJ School of Medicine at Hofstra University; Attending Physician, Department of Obstetrics and Gynecology, Long Island Jewish Medical Center; Medical Director, Aetna, Inc; Private Practice in Gynecology

Disclosure: Nothing to disclose.

HELLP Syndrome

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