HELLP Syndrome

CHIEF EDITORS NOTE: This article is part of a series of continuing education activities in this Journal through which a totalof 36 AMA/PRA category 1 credit hours can be earned in 2004. Instructions for how CME credits can be earned appear onthe last page of the Table of Contents.

HELLP Syndrome:The State of the Art

Jason K. Baxter, MD,* and Louis Weinstein, MD*Clinical Instructor, Department of Obstetrics and Gynecology, Fellow, Division of MaternalFetal Medicine,Paul A. and Eloise B. Bowers Professor and Chairman of Obstetrics and Gynecology, Thomas Jefferson

University, Philadelphia, Pennsylvania

Preeclampsia/eclampsia has been recognized for centuries and continues to plague both thepatient and the obstetrician. A severe variant, the syndrome of hemolysis, elevated liver enzymes,and low platelets (HELLP), has been recognized for 50 years. Although much new data has beenelucidated about the condition, only several observations have withstood the test of time. Theseare the uniqueness of the disease to humans, the progressive nature of the disease, and the factthat delivery is the sole therapy.Target Audience: Obstetricians & Gynecologists, Family PhysiciansLearning Objectives: After completion of this article, the reader should be able to outline the history of

HELLP syndrome and describe the pathophysiology of HELLP syndrome, to summarize the clinicalpresentation and differential diagnosis of HELLP syndrome, and to list the various management options.

The association between hemolysis, thrombocyto-penia, and liver dysfunction was first described inassociation with a severe form of preeclampsia 50years ago. In 1954, Pritchard and colleagues de-scribed 3 cases of eclampsia associated with intra-vascular hemolysis, thrombocytopenia, and clottingdefects, including evidence of hepatic dysfunction in2, with only 1 survivor (1). In 1972, McKay re-viewed 4 cases of the syndrome occurring in eclamp-tic patients, including 2 liver ruptures and 1 maternaldeath (2). Kitzmiller et al.s review of the coagula-tion system in 31 patients with preeclampsia notedsignificant thrombocytopenia in 4 patients, 3 ofwhom had evidence of microangiopathic hemolyticanemia (3). In 1975, Killam et al. reported 5 cases ofpreeclampsia with classic hemolysis, elevated liverenzymes, and low platelet syndrome. They con-

cluded that the entity was more common than real-ized, prompt delivery is mandated regardless of ges-tational age, and hypertension does not have to besevere to see the hemolysis, elevated liver enzymes,and low platelet syndrome (4). Pritchard et al.s 1976report of 95 cases of eclampsia noted that 29% hadthrombocytopenia and 2% had overt hemolysis. Theyconcluded that the coagulation changes in these pa-tients were markedly different than that seen in pa-tients who experience a thromboplastin release (5).Goodlin has reported 16 patients with severe pre-eclampsia, thrombocytopenia, and abnormal liver en-zymes. He called severe preeclampsia another greatimitator, because all of those patients were misdi-agnosed as having disorders unrelated to pregnancy(6). In a later report, Goodlin et al. described 8patients with thrombocytopenia and abnormal liverenzymes with a perinatal mortality rate of 44% (7).

The term HELLP syndrome, an acronym for he-molysis, elevated liver enzymes, and low platelets,was first coined by Weinstein in 1982 (8). He ini-tially presented a series of 29 patients evaluated over

Address correspondence to: Jason K. Baxter, MD, Suite 400,834 Chestnut Street, Philadelphia, PA 19107. E-mail: [email protected] authors have disclosed no significant financial or other

relationship with any commercial entity.

CME REVIEWARTICLE Volume 59, Number 12OBSTETRICAL AND GYNECOLOGICAL SURVEYCopyright 2004by Lippincott Williams & Wilkins36

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30 months with the disorder, and then followed upwith a series of 57 patients who presented with thesyndrome at a single center over 5 years (9). HELLPsyndrome was initially proposed as the sixth criterionthat independently constituted a diagnosis of severepreeclampsia. HELLP syndrome was termed a severevariant of preeclampsia, part of the spectrum of thedisease process involved in preeclampsia/eclampsia.Although others have argued against the existence ofsuch an entity as HELLP syndrome, that it is onlypreeclampsia associated with a coexisting medical orsurgical condition (10,11), it is now widely acceptedthat HELLP syndrome is a clinical entity that obste-tricians must know how to recognize and treat in asimilar manner to severe preeclampsia.

PATHOPHYSIOLOGYPreeclampsia has been called the disease of theo-

ries, and as a severe variant of that disease, theetiology of HELLP syndrome remains elusive. Pre-eclampsia is a disease whose clinical findings usuallymanifest in the second half of pregnancy and isassociated with incomplete trophoblastic invasion ofthe maternal vessels early in pregnancy. Preeclamp-sia and HELLP syndrome are associated with endo-thelial injury, fibrin deposition in the vessel lumen,and increased platelet activation with platelet con-sumption. Platelet activation results in the release ofthromboxane A2 and serotonin, both vasoconstric-tors. Platelet aggregation damages the endotheliumand impairs the production of prostacyclin, a potentvasodilator. The alteration of the prostacyclin/throm-boxane A2 ratio is present in preeclampsia and isaltered by delivery.

HemolysisHemolysis, defined as the presence of microangio-

pathic hemolytic anemia, is a hallmark of HELLPsyndrome. It is confirmed by the sensitive, but notspecific, observation of burr cells (crenated, con-tracted, distorted red blood cells with spiny projec-tions along the periphery), schistocytes (small, irreg-ularly shaped red blood cell fragments), andpolychromasia on peripheral blood smear examina-tion. Red blood cell fragmentation occurs secondaryto passage through small blood vessels with intimaldamage and fibrin deposition. Hemolysis is morecommon than realized, as automated technology hasresulted in a decrease of manual examination ofperipheral smears. Lactic dehydrogenase levels andmeasurements of indirect bilirubin have also been

used as additional markers of evidence for hemoly-sis.

LiverThe classic hepatic lesion associated with HELLP

syndrome is periportal or focal parenchymal necro-sis, in which hyaline deposits of fibrin-like materialcan be seen in the hepatic sinusoids. The fibrin ob-struction of the hepatic sinusoids causes hepatocel-lular injury, which is manifested by elevated liverenzymes and pain localized to the right upper quad-rant or midepigastric region. Swelling of the liverwith distension of Glissons capsule causes pain.With a continued increase in intrahepatic pressureand the presence of subcapsular hematomas, the abil-ity of Glissons capsule to distend is exceeded andthe patient experiences rupture of the liver.

A debate has ensued regarding the differences be-tween HELLP syndrome and acute fatty liver ofpregnancy (AFLP). Minakami et al. reviewed 41liver specimens taken from 41 preeclamptic womenand showed the importance of staining with oil red Oto show microvesicular fat droplets in the hepato-cytes that do not show with the usual hematoxylineosin stain. The authors concluded that it was impos-sible to differentiate histologically among AFLP,HELLP syndrome, and preeclampsia, suggesting thatthey are all variants of the same disorder (12). Bartonand colleagues studied liver biopsies taken at thetime of cesarean section from 11 patients withHELLP syndrome. They showed no correlation be-tween the severity of the histologic findings and theclinical laboratory findings (13).

PlateletsThe decrease in circulating platelets is secondary to

an increased rate of consumption at the sites of thedamaged vascular endothelium. Often this is an earlyfinding in the development of preeclampsia (14).Bone marrow aspiration demonstrates an increasednumber of megakaryocytes and circulatingmegakaryocytes are noted. The resultant thrombocy-topenia is secondary to increased platelet turnover,reduced mean platelet lifespan, and adherence ofplatelets to exposed collagen at damaged vascularsites. These patients do not have clinical dissemi-nated intravascular dissemination (DIC), and coagu-lation studies are not needed for clinical managementof the patient with severe preeclampsia unless anabruption or other complicated clinical condition ispresent.

HELLP Syndrome Y CME Review Article 839

DIAGNOSISIncidence

The incidence of HELLP syndrome among patientswith severe preeclampsia or eclampsia has a range of10% to 20% (15). When preeclampsia is present, theincidence of HELLP syndrome varies from 2% to12% (16).

Clinical PresentationIn the 2 largest series from the Universities of

Tennessee and Mississippi, the majority of patientswith HELLP syndrome were black, young, and nul-liparous (15,17). A higher percentage were white,multiparous, and older (25 years old vs. 19 years old)when compared with the baseline population of pa-tients with severe preeclampsia (18). The onset ofsymptoms occurs in the majority (67%) of patientsduring the early third trimester (2737 weeks). Ap-proximately 25% of patients demonstrate the diseasefor the first time in the postpartum period, many ofwhom (79%) have had an antepartum diagnosis ofpreeclampsia.

The clinical presentation is variable with symp-toms of malaise, fatigue, and nonspecific complaintsreported by 90% of patients. Each of the individualsymptoms of nausea with or without vomiting, head-aches, abdominal pain, and edema are seen in morethan half of the patients presenting with HELLPsyndrome. Although approximately two thirds of pa-tients with HELLP syndrome present with bloodpressure 160/110 mm Hg, others have blood pres-sures in the range of 140160/90110 mm Hg, and aminority (15%) have diastolic blood pressure 90.Proteinuria of 2 or more on dipstick is present in85% of patients with 1 proteinuria seen in 9% andnone in 6% (18). Clinicians must be aware thatHELLP syndrome can occur in patients with normalor minimally elevated blood pressures and no pro-teinuria. It has been suggested to check a completeblood with platelet count and liver enzymes in anypregnant patient presenting with right upper quadrantor epigastric pain (18).

Laboratory PresentationVarious investigators have defined HELLP syn-

drome differently. Confusion regarding terminologyand diagnosis, and a lack of consensus regardingwhich liver function tests and what extremes of di-vergence from normal should be used to diagnose thesyndrome, hampered earlier study of the syndrome.

Martin et al. defined hemolysis as evidenced by afalling hematocrit, lactic dehydrogenase (LDH)164, or a bleeding diathesis, elevated liver enzymesas evidenced by an AST 48 and ALT 24, andthrombocytopenia as platelets 100 K (17). Theseinvestigators at the University of Mississippi havealso divided the diagnosis of HELLP syndrome intoclasses based on the severity of the thrombocytope-nia (19). Platelets less than or equal to 50 K consti-tutes class 1, between 50 and 100 K class 2, andgreater than 100 K class 3. We do not agree with thisclassification because class 3 (platelets over 100 K)is not consistent with most definitions of HELLPsyndrome. The definition used at the University ofTennessee in Memphis defined HELLP syndrome ashemolytic anemia (LDH 600 U/L), elevated liverenzymes (AST 70 U/L), and thrombocytopenia(PLTS 100 K) (18). The level of abnormal liverenzymes was set at 3 standard deviations over thelaboratorys mean.

PARTIAL HELLP SYNDROMEPatients that have manifested 1 or 2, but not all 3,

of the components of HELLP syndrome test thedecision-making ability of the clinician. Audibert etal. have demonstrated that the prognosis and out-come for partial, or evolving, HELLP syndrome isbetter than that seen with complete HELLP syn-drome (20). The evolving picture of HELLP syn-drome follows that of preeclampsia, whereby thenatural progression of the disease is to worsen overtime. Although conservative management of pre-eclampsia may be appropriate, the diagnosis of se-vere preeclampsia should prompt efforts toward anexpeditious delivery.

DIFFERENTIAL DIAGNOSISPreeclampsia and HELLP syndrome have been

misdiagnosed as other disease processes. The con-cept of preeclampsia as another great imitator waspresented in 1975. Preeclampsia and probableHELLP syndrome were misdiagnosed as viral hepa-titis, cholangitis, systemic lupus erythematous, im-mune thrombocytopenic purpura (ITP), detached ret-ina, and gastric ulcer (6). Since the term HELLPsyndrome has been coined and recognized as a clin-ical entity, it continues to be both over- and under-diagnosed. Goodlin presented 11 case histories ofsignificant medical and surgical problems initiallydiagnosed as HELLP syndrome or preeclampsia.These included misdiagnosed cases of actual cardio-

840 Obstetrical and Gynecological Survey

myopathy, dissecting aortic aneurysm, cocaineabuse, chronic renal disease, acute fatty liver, gan-grenous gallbladder, ruptured bile duct, glomerulo-nephritis, immune thrombocytopenia, systemic lupuserythematous, and pheochromocytoma (21). In thesecases, delivery may actually aggravate the clinicalcourse of the patients illness, and appropriate ther-apy may be delayed while dealing with the maternalcondition.

It has been suggested that severe preeclampsia,HELLP syndrome, pregnancy-associated hemolyticuremic syndrome (HUS), thrombotic thrombocyto-penic purpura (TTP), acute fatty liver of pregnancy(AFLP), and postpartum acute renal failure are dis-eases that are part of a spectrum of the same illness.Endothelial cell injury, with subsequent vasospasm,platelet activation, altered prostacyclinthromboxaneratio, and decreased release of endothelium-derivedrelaxing factor, play a central role in the pathogenesisof each of these conditions (22). A full discussion ofhow to differentiate amongst these disorders is be-yond the scope of this review.

MORTALITY AND MORBIDITYMortality rates vary from 0% to 24%. In a review

of 54 maternal deaths associated with HELLP syn-drome, a delay in diagnosis was noted in 51% withone third the result of patient delay, and the other twothirds resulting from delay in physician diagnosis.The delay in physician diagnosis was secondary tolack of recognition of the severity of the patientscondition. Events associated with maternal death in-clude cerebral hemorrhage (45%), cardiopulmonaryarrest (40%), DIC (39%), adult respiratory distresssyndrome (28%), renal failure (28%), sepsis (23%),hepatic hemorrhage (20%), and hypoxic ischemicencephalopathy (16%) (23). Persistent hypoglycemiain a patient with possible HELLP syndrome is anindication of severe liver failure. Although it may berelated to the differential diagnosis of AFLP, it is anindication for immediate delivery.

In addition, mothers with HELLP syndrome are atincreased risk for preterm delivery, DIC, placentalabruption, acute renal failure, pulmonary edema, andsubcapsular hepatic hematoma (18). Barton and Sibaireported findings of liver hematomas and hemor-rhage in women with HELLP syndrome who under-went hepatic imaging. Although liver function testabnormalities did not accurately reflect the presenceof abnormal hepatic imaging findings, the severity ofthe thrombocytopenia did correlate, especially whenthe platelet count was under 20 K (24). Patients with

HELLP syndrome having complaints of right upperquadrant pain along with neck pain, shoulder pain, orrelapsing hypotension should undergo imaging of theliver. Ultrasound imaging has the specific advantageof giving a bedside diagnosis without having to mo-bilize the patient away from the labor and deliverysuite. The usual sonographic appearance of an acutesubcapsular hepatic hematoma is a crescent-shapedcollection of echogenic fluid just beneath the capsuleof the liver (25).

Sibai and Ramadan reported acute renal failure in7.4% of their 435 patients with HELLP syndrome(26). This unusually high rate was usually associatedwith multiple obstetric complications such as placen-tal abruption, fetal death, DIC, postpartum hemor-rhage, and sepsis. Pulmonary edema complicated 6%of the patients courses in the University of Tennes-see series and was correlated with the presence ofacute renal failure (15).

EFFECT ON THE NEONATEPerinatal mortality associated with HELLP syn-

drome has been reported as high as 37% (27), butmore recent figures estimate an 11% perinatalmortality rate (28). Eeltink et al. reported the fetaland neonatal effects in 87 pregnancies withHELLP syndrome. They reported a stillbirth rateof approximately 10%, with another 10% of neo-natal deaths occurring within the first week of life.The average gestational age and birthweight was32 weeks and 1576 g, respectively, with a 44%incidence of small-for-gestational-age infants.Neonatal complications included respiratory dis-ease (43%), hyperbilirubinemia (45%), perinatalasphyxia (21.6%), patent ductus arteriosus (16%),neonatal thrombocytopenia (34%), and hypoglyce-mia (16%). No specific neonatal pathology result-ing from maternal HELLP syndrome was found(29). Most of the perinatal complications seemedto be the result of prematurity and placental insuf-ficiency. A review of the neonatal charts of 269consecutive pregnancies complicated by HELLPsyndrome, partial HELLP syndrome, or severepreeclampsia noted no differences in neonatal out-comes among the 3 groups at each gestational age(30). These studies confirm that in severe pre-eclampsia, neonatal morbidity and mortality aremainly related to gestational age at delivery ratherthan the presence or absence of the HELLP syn-drome.


MANAGEMENTDelivery

The optimal treatment for maternal safety in con-firmed cases of severe preeclampsia or HELLP syn-drome is delivery. Unfortunately, at early gestationalages, the neonatal risk of prematurity must be bal-anced against the maternal and fetal risks of expect-ant management. No large randomized trials havecompared conservative versus aggressive manage-ment of women with HELLP syndrome. Expectantmanagement before 32 weeks should only be consid-ered in tertiary care centers or as part of randomized,controlled trials with appropriate safeguards and con-sent (31). Although expectant management of severepreeclampsia remote from term may be arguable inselect instances, the diagnosis of HELLP syndromeis a harbinger that the fetal and maternal risks exceedthe benefits to be gained with pregnancy prolonga-tion.

Although many patients with HELLP syndrome donot require antihypertensive therapy, drug manage-ment is similar to that used for severe preeclampsia.Antihypertensive agents such as hydralazine, labeto-lol, nifedipine, or nitroprusside drip may be used tocontrol stroke range blood pressures over 180/110mm Hg (31). Intravenous magnesium sulfate shouldbe administered to lower the risk of seizure, regard-less of blood pressure. Intravenous fluid administra-tion and urine output must be meticulously moni-tored until the patients complete recovery. Pretermpatients should be transferred to a tertiary care centeronce the mother is stabilized hemodynamically (32).

The route of delivery should be based on obstetricindications. Labor may be induced at any gestationalage, and cervical-ripening agents may be helpful inpatients with an unfavorable cervix. Labor inductionattempts in a nulliparous patient with an unfavorablecervix before 30 weeks gestation often results in aprolonged induction. Many clinicians opt to performa cesarean delivery outright in these patients becausethe risk of eventually requiring a cesarean section ishigh. Intra- and postoperative oozing is common inpatients with HELLP syndrome undergoing cesareansection. The surgeon must consider leaving sub-and/or suprafascial closed drains in place to mini-mize the need for a repeat laparotomy to drain clotsor collections. Alternatively, the wound may be leftopen to the fascia and closed within the first 96hours, thus allowing ascites, weeping, and oozing todrain. Rarely will patients need a platelet transfusion,even with a platelet count of 25,000. Packed red

blood cell transfusion is often necessary postpartumsecondary to continued hemolysis.

The choice of anesthesia is dependent on the co-agulation status of the patient and the experience ofthe anesthesiologist. Regional anesthesia, whetherfor vaginal or cesarean delivery, is contraindicated ifa coagulopathy is present. Thrombocytopenia itselfdoes not constitute a coagulopathy, and one can useregional anesthesia even in the face of thrombocyto-penia (without DIC), because the incidence of epi-dural hematoma is exceedingly rare.

The liver should not be biopsied or aggressivelypalpated at the time of cesarean section. Undiag-nosed intraperitoneal blood deserves exploration fora source. If there is evidence of liver rupture, packingshould be performed and supportive measures insti-tuted. It is very difficult to resect a ruptured liver. In24 to 48 hours, the patient can return to the operatingroom to remove the packs. Subcapsular hematomasshould be managed conservatively.

Role of SteroidsAlthough the diagnosis of preterm HELLP syn-

drome necessitates delivery, allowing 48 hours afterinitial steroid administration may improve fetal out-comes with minimal risk to the mother. Any tempo-rizing measure must be weighed against the potentialrisks to the mother and baby associated with theprogression of the HELLP syndrome. Historically,therapies for HELLP syndrome or severe preeclamp-sia included transfer to a tertiary care center, controlof hypertension, and seizure prophylaxis while pro-ceeding toward delivery of the fetus. Case reportshave mentioned transient improvements in laboratoryvalues with bedrest and steroid treatment, originallygiven to improve fetal lung maturity in the prematurepregnancy (6,33). Magann et al. simultaneously pub-lished the findings of 2 separate nonblinded, random-ized, controlled trials demonstrating the effects ofdexamethasone on HELLP syndrome given antepar-tum (34) and postpartum (35). They demonstratedimproved blood pressures, urinary output, plateletcounts, and liver function tests with 10 mg dexa-methasone intravenously every 12 hours. A recentprospective, randomized trial from the University ofMississippi showed that intravenous dexamethasoneis more effective than intramuscular betamethasonefor improving these same laboratory values (36).Two retrospective analyses of data from the sameinstitution further suggest that antepartum and/orpostpartum treatment with high-dose dexamethasonewas associated with a lessening of the acuity ofillness, leading to a reduction of indicated therapy


interventions and a quicker recovery (37,38). Otherretrospective studies using high-dose steroids havesuggested a greater likelihood of attaining 24- to48-hour latency from treatment to delivery, de-creased need for blood product transfusion, and im-proved likelihood of regional anesthesia (3941). Ithas been theorized that high-dose steroids act sys-tematically to restore microvascular integrity andprevent plateletendothelial dysfunction and red celldestruction. They may act as an immunosuppressant,dampening an abnormal immune response associatedwith the pathophysiology of HELLP syndrome (42).Until randomized, prospective studies demonstrate adifference in outcome or clinical (rather than labora-tory) benefit of steroid treatment for HELLP syn-drome, we cannot recommend routine use of steroidsfor maternal benefit.

PostpartumEclamptic seizure prophylaxis with magnesium

sulfate should be continued for an undefined periodpostpartum, except in cases complicated by acuterenal failure. In contrast to preeclampsia/eclampsia,which is associated with an improvement in symp-toms and laboratory values immediately after deliv-ery, the clinical course of HELLP syndrome typicallyhas a nadir of platelets and peak of LDH 24 to 48hours postpartum (17). Therefore, we recommendcontinued close monitoring of the postpartum patientwith HELLP syndrome in a labor and delivery orintensive-care setting until an improvement in labo-ratory values is documented. Patients sometimes re-quire repeated, delayed transfusions of packed redblood cells as a result of continued hemolysis. Plas-mapheresis is indicated in cases with persistent he-molysis or platelets continuing to decrease more than72 hours postpartum (17).

COUNSELING FOR THE FUTURERecurrence Risk

Sullivan and colleagues at the University of Mis-sissippi studied 81 subsequent pregnancies in womenwith prior pregnancies complicated by HELLP syn-drome. They found that 23% of the subsequent preg-nancies were complicated by preeclampsia/eclampsiawithout HELLP syndrome and 19% were compli-cated by recurrent HELLP syndrome. HELLP syn-drome recurred an average of 2 weeks later than inthe index pregnancy (43). Sibai et al. reported thecomplication rates of 212 pregnancies in 152 womensubsequent to a prior pregnancy complicated by

HELLP syndrome (44). They reported elevated com-plication rates of preeclampsia, preterm delivery, in-trauterine growth restriction, abruption, and perinataldeath with significantly worse outcomes in thewomen with preexisting chronic hypertension. Over-all, the risk for preeclampsia in a subsequent preg-nancy was 21%, but the recurrence rate of HELLPsyndrome was only 4%. Two of the women withprior ruptured liver hematomas associated withHELLP syndrome had 3 subsequent normotensive,term pregnancies without complications. Chames etal. recently reported a descriptive study of 62 preg-nancies in 48 women with a history of HELLP syn-drome for which delivery occurred at less than orequal to 28 weeks gestation. They reported increasedrisks for obstetric complications: preeclampsia(55%), severe preeclampsia (44%), preterm delivery(53%), small for gestational age (27%), abruption(5%), and perinatal mortality (11%). The incidenceof recurrent HELLP syndrome was only 6% with all4 of the cases occurring at less than 30 weeks ges-tation (45). Similarly, van Pampas reported a 2% rateof recurrence for HELLP syndrome among 92 preg-nancies in The Netherlands (46). Although the recur-rence risk of HELLP syndrome appears low, thismay not accurately reflect the natural history of apregnancy in a woman who previously had HELLPsyndrome. Many of these pregnancies are watchedclosely, monitored for the development of HELLPsyndrome, possibly contributing to their delivery be-fore HELLP syndrome is allowed to fully develop.Therefore, these estimates and those from any poten-tial study of recurrent HELLP syndrome may beartificially lower than what would be seen if the truenatural history of the entity were allowed to developwithout intervention.

EFFECT ON MATERNAL FUTUREIn women without evidence of chronic hyperten-

sion before HELLP syndrome, 6% had chronic hy-pertension after more than 5 years of follow up.There were no complications reported in women whoreceived oral contraceptive pills after HELLP syn-drome, suggesting that they are not contraindicatedin these patients (44).

Dekker et al. suggested that patients with a historyof severe early-onset preeclampsia be screened forprotein S deficiency, activated protein C (aPC) resis-tance, hyperhomocystinemia, and anticardiolipin an-tibodies (47). A high prevalence of aPC resistanceand the factor V Leiden mutation was reported in 21German women with a history of HELLP syndrome


(48). In contrast, testing of 18 Italian women re-vealed no association of aPC resistance or factor VLeiden mutation with HELLP syndrome (49). Lee etal. did not find an association between anticardiolipinantibodies and preeclampsia or HELLP syndrome(50). We do not believe that a thrombophilia orantiphospholipid antibody workup is indicated basedon a history of HELLP.

Wilken et al. suggested screening babies from moth-ers with AFLP or HELLP syndrome for fatty acidoxidation disorders, based on their findings of an in-creased prevalence of babies with long-chain 3-hy-droxyacyl coenzyme A dehydrogenase (LCHAD) defi-ciency in pregnancies complicated by these 2 disorders(51). In a study of 113 Dutch women who had HELLPsyndrome, researchers found only 1 with the most com-mon LCHAD mutation, therefore testing of womenwith HELLP syndrome for LCHAD deficiency is notjustified (52). Because there is no intervention or treat-ment to prevent the disorder, we cannot recommendany form of screening for women with a history ofHELLP syndrome.

FUTURE DIRECTIONSPreeclampsia has been dubbed the disease of the-

ories. Until we elucidate the pathophysiology ofpreeclampsia, it is doubtful that we will find thera-pies to prevent it. As an atypical variant of severepreeclampsia, the pathophysiology and prevention ofHELLP syndrome will probably remain just as elu-sive. Recent research focusing on thromboblast dys-function and endothelial dysfunction has offeredpromising insights into the pathophysiology of pre-eclampsia. High serum inhibin A levels in the firsttrimester of pregnancy have been associated with analmost 5 times higher odds ratio for the subsequentdevelopment of severe preeclampsia (53). Increasedlevels of circulating soluble fms-like tyrosine kinase1 (SFlt-1) and decreased levels of placental growthfactor (PlGF) may precede the clinical diagnosis ofpreeclampsia by 5 weeks (54). The decrease in serumaldosterone levels and plasma rennin activity associ-ated with severe preeclampsia were not seen in pa-tients with HELLP syndrome (55). Levels of midtri-mester human chorionic gonadotropin (hCG) werehigher and unconjugated estriol were lower inwomen with HELLP syndrome when compared withcontrol subjects who had only severe preeclampsia(56). Eventually, these insights into the similaritiesand differences of preeclampsia and HELLP syn-drome may shed light on the pathophysiology andprevention of each.

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HELLP Syndrome