Diagnosis, Controversies, And Management of the Hellp Syndrom, Sibai

HIGH-RISK PREGNANCY SERIES: AN EXPERT’S VIEW

Diagnosis, Controversies, and Management of theSyndrome of Hemolysis, Elevated Liver Enzymes, andLow Platelet Count

Baha M. Sibai, MD

Hemolysis, elevated liver enzymes, and low platelets(HELLP) syndrome has been recognized as a complicationof preeclampsia–eclampsia for decades. Recognition of thissyndrome in women with preeclampsia is increasing be-cause of the frequency of blood test results that revealunexpected thrombocytopenia or elevated liver enzymes.The diagnosis of HELLP syndrome requires the presenceof hemolysis based on examination of the peripheralsmear, elevated indirect bilirubin levels, or low serumhaptoglobin levels in association with significant elevationin liver enzymes and a platelet count below 100,000/mm3

after ruling out other causes of hemolysis and thrombocy-topenia. The presence of this syndrome is associated withincreased risk of adverse outcome for both mother andfetus. During the past 15 years, several retrospective andobservational studies and a few randomized trials havebeen published in an attempt to refine the diagnostic crite-ria, to identify risk factors for adverse pregnancy outcome,and to treat women with this syndrome. Despite the volu-minous literature, the diagnosis and management of thissyndrome remain controversial. Recent studies suggestthat some women with partial HELLP syndrome may betreated with expectant management or corticosteroid ther-apy. This review will emphasize the controversies sur-rounding the diagnosis and management of this syndrome.Recommendation for diagnosis, management, and coun-seling of these women is also provided based on results ofrecent studies and my own clinical experience. (ObstetGynecol 2004;103:981–91. © 2004 by The American Col-lege of Obstetricians and Gynecologists.)

We have invited select authorities to present backgroundinformation on challenging clinical problems and practi-cal information on diagnosis and treatment for use bypractitioners.

Intravascular hemolysis, elevated liver function tests,and thrombocytopenia have been described in womenwith severe preeclampsia–eclampsia for many decades.1

In addition, physicians have recognized that the presenceof these abnormalities is associated with adverse maternal

outcome for the past 50 years.2–4 In 1982, Weinstein5

described 29 cases of severe preeclampsia–eclampsia com-plicated by thrombocytopenia, abnormal peripheral bloodsmear, and abnormal liver function test results. He sug-gested that this collection of laboratory abnormalities con-stituted an entity separate from traditional severe pre-eclampsia and coined the term HELLP syndrome (H �hemolysis; EL � elevated liver enzymes; and LP � lowplatelets). Since then, numerous reports claiming to de-scribe this syndrome have appeared in the medical litera-ture. In 1990, Sibai1 reported that there is considerabledisagreement in the medical literature regarding the termi-nology, incidence, diagnosis, and management of theHELLP syndrome During the past 15 years, numerousretrospective and observational studies as well as few ran-domized trials have been published in an attempt to refinethe diagnostic criteria for this syndrome, to identify riskfactors for adverse pregnancy outcome, and to reducematernal and perinatal outcomes in women with this syn-drome. Despite this recent literature, the diagnosis, man-agement, and pregnancy outcome of HELLP syndromeremain controversial. In this review, I will describe thepathogenesis, diagnosis, and management of this syndromebased on data derived from the literature and from my ownexperience of treating more than 700 women with severepreeclampsia and eclampsia complicated by the HELLPsyndrome.6–8

LABORATORY CRITERIA FOR DIAGNOSIS

The diagnostic criteria used for HELLP syndrome arevariable and inconsistent. Hemolysis, defined as the pres-ence of microangiopathic hemolytic anemia, is the hallmarkof the triad of HELLP syndrome.1 The classic findings ofmicroangiopathic hemolysis include abnormal peripheralsmear (schistocytes, burr cells, echinocytes), elevated serumbilirubin (indirect form), low serum haptoglobin levels,elevated lactate dehydrogenase (LDH) levels, and signifi-cant drop in hemoglobin levels. A significant percentage ofpublished reports included patients who had no evidence of

From the Department of Obstetrics and Gynecology, University of Cincinnati,Cincinnati, Ohio.

VOL. 103, NO. 5, PART 1, MAY 2004981© 2004 by The American College of Obstetricians and Gynecologists. 0029-7844/04/$30.00

Published by Lippincott Williams & Wilkins. doi:10.1097/01.AOG.0000126245.35811.2a

hemolysis; hence, these patients will fit the criteria for ELLPsyndrome.9–15 Even in studies in which hemolysis wasmentioned, the diagnosis was based on the presence ofabnormal peripheral smear (no description of type or de-gree of abnormalities)16,17 or elevated LDH levels (thresh-old of 180–600 U/L).18–23

There is no consensus in the literature regardingwhether the liver function test should be used or whatdegree of elevation in these test results should be used todiagnose elevated liver enzymes.1 In the original reportby Weinstein,5 he mentioned abnormal serum levels ofaspartate transaminase (AST), abnormal alanine trans-ferase (ALT), and abnormal bilirubin values; however,levels were not stated. In addition, he made no mentionof LDH as a diagnostic test of liver involvement. Insubsequent studies in which elevated liver enzymes werementioned (either AST or ALT), the values consideredabnormal ranged from 17 to 72 U/L.1 In clinical practice,many of these values are considered normal or slightlyelevated. In essence, some of these studies includedwomen with low platelets syndrome. Some of thesewomen may have had severe preeclampsia with throm-bocytopenia, gestational thrombocytopenia, or immunethrombocytopenic purpura.

Low platelet count is the third abnormality required toestablish the diagnosis of HELLP syndrome. There is noconsensus among various published reports regardingthe diagnosis of thrombocytopenia. The reported cutoffvalues range from 75,000/mm3 to 279,000/mm3.9–18

Therefore, some of the patients included in these studieswill fit the criteria for “EL” (elevated liver enzymes)syndrome. In essence, these women had severe pre-eclampsia with mild elevation in liver enzymes.10,12

Despite well-intentioned efforts at making laboratorydiagnosis of HELLP syndrome based on elevations inAST, ALT, LDH, and the presence of hemolysis, sub-stantial interlaboratory differences remain a major prob-lem. This is due in part to the different number of assaysused to measure these tests as well as to the cutoff used toestablish an abnormal test. Some studies used the upperlimit for a particular test at their hospital laboratory, someused 2 standard deviations above the mean for that labora-tory, whereas others used more than 2 times the upper limitin their laboratory. Therefore, clinicians should be familiarwith the upper limit value for liver enzyme tests in their ownlaboratory when making the diagnosis of HELLP syn-drome. For example, the upper limit for an LDH mayrange from 180 to 618 U/L depending on the assay beingused. This is particularly important for patients referredfrom level I hospitals to tertiary care facilities where differ-ent assays are used to measure these tests.

Many authors13–15,18–23 have used elevated totalLDH (usually more than 600 U/L) as a diagnostic crite-

rion for hemolysis. There are 5 different isoforms ofLDH, and only 2 of them, LDH1 and LDH2, are releasedfrom ruptured red blood cells. In the majority of womenwith severe preeclampsia–eclampsia, the elevation intotal LDH is probably caused mostly by liver ischemia.Therefore, many authors advocate that elevated biliru-bin values (indirect form), abnormal peripheral smear,or a low serum haptoglobin level should be part of thediagnostic criteria for hemolysis.1,5,24–27

Time of Onset and Maternal Condition at Diagnosis

Another point of confusion includes the time of onsetand the clinical condition of the patient at the time ofdiagnosis of the syndrome. Some studies included pa-tients who had the abnormalities on admission,1–6,24–26

others included patients who developed the abnormali-ties during expectant management of preeclampsia re-mote from term,10–12,16 and others included patientswho developed the abnormalities in the postpartum pe-riod.6,20–23,28–30 Even among the latter group, some hadpreeclampsia before delivery, some had no clinical evi-dence of preeclampsia before delivery, some were diag-nosed during the first 48 hours postpartum,20–23,29,30

and others were diagnosed for the first time at or beyond3 days postpartum.6,28 It is important to recognize thatmaternal and perinatal outcomes of women who arereferred to a tertiary care facility because of HELLPsyndrome (usually remote from term or complicatedcases) are expected to be different from the respectiveoutcome in women who had the diagnosis made becauseof serial evaluation of liver enzymes and platelet countduring expectant management of preeclampsia. In addi-tion, both maternal and perinatal outcomes are expectedto be substantially worse in those patients in whomHELLP syndrome develops in the second trimester andwho require emergency cesarean delivery because ofnonreassuring fetal testing than in women in whomsevere preeclampsia develops at term and have sponta-neous vaginal delivery and subsequently had the diag-nosis of HELLP syndrome made because of frequentevaluation of liver enzymes and platelet count duringlabor and immediately postpartum.

CLINICAL FINDINGS

One of the major problems with early detection ofHELLP syndrome lies in its clinical presentation, be-cause patients may present with nonspecific symptomsor subtle signs of preeclampsia. Patients with this syn-drome may present with various signs and symptoms,none of which are diagnostic of preeclampsia and all ofwhich may be found in patients with severe preeclamp-sia–eclampsia without HELLP syndrome.1,5,9,21,24 Pa-

982 Sibai Diagnosis and Management of HELLP Syndrome OBSTETRICS & GYNECOLOGY

tients frequently will have right upper quadrant or epigas-tric pain, nausea, or vomiting ranging in frequency from30% to 90% (Table 1).6,7,17,21,26 Most patients will give ahistory of malaise for the past few days before presentation,and some will have nonspecific viral-syndrome–like symp-toms,1 which led one investigator to suggest performinglaboratory investigation (completed blood count and liverenzymes) in all pregnant women with suspected preeclamp-sia having these symptoms during the third trimester.1

Headaches are reported by 33–61%6,7,21 of the patientswhereas visual changes are reported in approximately17%.7 A subset of patients with HELLP syndrome maypresent with symptoms related to thrombocytopenia suchas bleeding from mucosal surfaces, hematuria, petechialhemorrhages, or ecchymosis.

Although the majority of patients will have hyperten-sion (82–88%, Table 1), it may be only mild in 15–50%of the cases,1–5 and absent in 12–18% (Table 1). Themajority of the patients (86–100%) will have proteinuriaby dipstick examination; however, it was reported to beabsent in 13% of cases in the 2 largest series.6,7,21

DIFFERENTIAL DIAGNOSIS

The presenting symptoms, clinical findings, and many ofthe laboratory findings in women with HELLP syn-drome overlap with a number of medical syndromes,surgical conditions, and obstetric complications. There-fore, the differential diagnosis of HELLP syndromeshould include any of the conditions listed in the Box.Because some patients with HELLP syndrome maypresent with gastrointestinal, respiratory, or hematologicsymptoms in association with elevated liver enzymes orlow platelets in the absence of hypertension or protein-uria, many cases of HELLP syndrome will initially bemisdiagnosed as upper respiratory infection, hepatitis,cholecystitis, pancreatitis, acute fatty liver of pregnancy,or immune thrombocytopenic purpura.1 Conversely,some conditions such as thrombotic thrombocytopenicpurpura, hemolytic uremic syndrome, systemic lupuserythematosus sepsis, or catastrophic antiphospholipid

antibody syndrome may be erroneously diagnosed asHELLP syndrome.

In addition, in some patients preeclampsia may be super-imposed on one of these disorders, further contributing tothe diagnostic difficulty. Because of the remarkably similarclinical and laboratory findings of these disease processes,even the most experienced physician will face a difficultdiagnostic challenge. Therefore, an effort should be madeto attempt to identify an accurate diagnosis given thatmanagement strategies may differ among these conditions.The clinical and laboratory findings, as well as the manage-ment of the conditions that mimic the HELLP syndrome,are beyond the scope of this report. For detailed discussionof differential diagnosis and management of these syn-dromes, several recent reviews have been written (Eger-man RS, Sibai BM. Recognizing and managing HELLPsyndrome and its imitators. Contemp Ob Gyn 1997;October:129–49).31–34

Differential Diagnosis in Women With HELLPSyndrome

Acute fatty liver of pregnancy (AFLP)Thrombotic thrombocytopenic purpura (TTP)Hemolytic uremic syndrome (HUS)Immune thrombocytopenic purpura (ITP)Systemic lupus erythematosus (SLE)Antiphospholipid syndrome (APS)CholecystitisFulminant viral hepatitisAcute pancreatitisDisseminated herpes simplexHemorrhagic or septic shock

MATERNAL AND PERINATAL OUTCOME

The presence of HELLP syndrome is associated with anincreased risk of maternal death (1%)6,7,23 and increasedrates of maternal morbidities such as pulmonary edema

Table 1. Signs and Symptoms in Women With HELLP Syndrome

Weinstein17Sibai et al6 andAudibert et al7 Martin et al21 Rath et al26

(n � 57) (n � 509) (n � 501) (n � 50)

Right upper quadrant or epigastric pain 86 63 40 90Nausea or vomiting 84 36 29 52Headache Not reported 33 61 Not reportedHypertension Not reported 85 82 88Proteinuria 96 87 86 100HELLP � hemolysis, elevated liver enzymes, and low platelets.

Data are presented as percentage.

983VOL. 103, NO. 5, PART 1, MAY 2004 Sibai Diagnosis and Management of HELLP Syndrome

(8%),7,21 acute renal failure (3%),7,21 disseminated intra-vascular coagulopathy (DIC, 15%),7 abruptio placentae(9%),7 liver hemorrhage or failure (1%), adult res-piratory distress syndrome (ARDS), sepsis, and stroke(� 1%).7,21 Pregnancies complicated by HELLP syn-drome are also associated with increased rates of woundhematomas and the need for transfusion of blood andblood products.1–8,21,23 The rate of these complicationswill depend on the population studied, the laboratorycriteria used to establish the diagnosis, and the presenceof associated preexisting medical conditions (chronichypertension, lupus) or obstetric complications (abrup-tio placentae, peripartum hemorrhage, fetal demise,eclampsia). The development of HELLP syndrome inthe postpartum period also increases the risk of renalfailure and pulmonary edema.35,36 The presence ofabruptio placentae increases the risk of DIC, need forblood transfusions, pulmonary edema, and renal fail-ure.6,8,35,36 Patients who have large volume ascites willhave a high rate of cardiopulmonary complications.37

Finally, patients who meet all the criteria reported by theauthor will have higher rates of maternal complicationsthan those who have partial HELLP or elevated liverenzymes only.7

There is general agreement that perinatal mortalityand morbidities are substantially increased in pregnan-cies complicated by the HELLP syndrome. The re-ported perinatal death rate in recent series ranged from7.4% to 20.4%.21,25,38–40 This high perinatal death rate ismainly experienced at very early gestational age (lessthan 28 weeks), in association with severe fetal growthrestriction or abruptio placentae.38–40 It is important toemphasize that neonatal morbidities in these pregnanciesare dependent on gestational age at time of delivery andthey are similar to those in preeclamptic pregnancieswithout the HELLP syndrome.25,38–40 The rate of pre-term delivery is approximately 70%, with 15% occurringbefore 28 weeks of gestation.6,25,33,39 As a result, theseinfants have a high rate of acute neonatal complicationssuch as respiratory distress syndrome, bronchopulmo-nary dysplasia, intracerebral hemorrhage, and necrotiz-ing enterocolitis.38

EXPECTANT MANAGEMENT OF (H)ELLP SYNDROME

The clinical course of women with true HELLP syn-drome is usually characterized by progressive and some-times sudden deterioration in the maternal condition.6,21

Because the presence of this syndrome has been associ-ated with increased rates of maternal morbidity andmortality, some authors consider its presence an indica-tion for immediate delivery.5,26 There is also a consensusof opinion that prompt delivery is indicated if the syn-

drome develops beyond 34 weeks of gestation, or earlierif there is multiorgan dysfunction, DIC, liver infarctionor hemorrhage, renal failure, suspected abruptio placen-tae, or nonreassuring fetal status.6,8

However, there is considerable disagreement aboutthe treatment of women with HELLP syndrome at orbefore 34 weeks of gestation when the maternal condi-tion is stable except for mild-to-moderate abnormalitiesin blood test results and a reassuring fetal condition. Insuch patients, some authors recommend the administra-tion of corticosteroids to accelerate fetal lung maturityfollowed by delivery after 24 hours,1,13,14,19 whereasothers recommend prolonging pregnancy until the de-velopment of maternal or fetal indications for delivery oruntil achievement of fetal lung maturity or 34 weeks ofgestation.11,12,16,25,40 Some of the measures used in theselatter cases have included one or more of the following:bed rest, antihypertensive agents, chronic parenteralmagnesium sulfate, antithrombotic agents (low-dose as-pirin, dipyridamole), plasma volume expanders (crystal-loids, albumin, fresh frozen plasma), and steroids (pred-nisone, dexamethasone, or betamethasone).

There are few case reports and few large case seriesdescribing expectant management of women with trueHELLP, partial HELLP, or severe preeclampsia withelevated liver enzymes only.9–12,16,25,40 In general, thesereports suggest that transient improvement in laboratoryvalues or pregnancy prolongation from a few days to afew weeks is possible in a select group of women with“HELLP” syndrome. It is important to note that most ofthe patients included in these studies were deliveredwithin a week after expectant management.

Recently, investigators from the Netherlands reportedthat expectant management is possible in women with“HELLP” syndrome before 34 weeks of gestation. Vis-ser and Wallenburg25 reported the use of plasma volumeexpansion utilizing invasive hemodynamic monitoringand vasodilators in 128 women with HELLP syndromebefore 34 weeks of gestation. Magnesium sulfate andsteroids were not used in such women. Twenty-two ofthe 128 patients were delivered within 48 hours; theremaining 102 patients had pregnancy prolongation fora median of 15 days (range, 3–62 days). Fifty-five ofthese 102 women had antepartum resolution of HELLPsyndrome with a median pregnancy prolongation of 21days (range, 7–62 days). There were no maternal deathsor serious maternal morbidity; however, 11 pregnancies(8.6%) resulted in fetal death at 25–34.4 weeks ofgestaion, and there were 7 (5.5%) neonatal deaths at27–32 weeks of gestation.25

Van Pampus et al39 reported the use of bed rest,antihypertensive medication, and salt restriction in 41women with HELLP syndrome before 35 weeks of


gestation. Fourteen women (34%) were delivered within24 hours; in the remaining 27 women, pregnancy wasprolonged a median of 3 days (range, 0–59 days). Fifteenof these 27 women showed complete normalization ofthe laboratory abnormalities. There were no seriousmaternal morbidities; however, there were 10 fetaldeaths at 27–35.7 weeks of gestation.

The results of these studies suggest that expectantmanagement is possible in a very select group of patientswith alleged HELLP syndrome before 34 weeks of ges-tation. However, despite pregnancy prolongation insome of these cases, the overall perinatal outcome wasnot improved compared with cases at similar gestationalage who were delivered within 48 hours after the diag-nosis of HELLP syndrome.38 Therefore, such manage-ment remains experimental in absence of randomizedtrials.

USE OF CORTICOSTEROIDS TO IMPROVE PREGNANCYOUTCOME IN WOMEN WITH HELLP SYNDROME

It is well established that antenatal glucocorticoid ther-apy reduces neonatal complications and neonatal mor-tality in women with severe preeclampsia at or before 34weeks of gestation.41 The recommended regimens ofcorticosteroids for the enhancement of fetal maturity arebetamethasone (12 mg intramuscularly every 24 hours,2 doses) or dexamethasone (6 mg intramuscularly every12 hours, 4 doses).42 These regimens have been identi-fied as the most appropriate for this purpose becausethey readily cross the placenta and have minimal miner-alocorticoid activity. However, it is unclear whether thesame or different regimens are safe and effective inwomen with HELLP syndrome.

Corticosteroids have been suggested as safe and effec-tive drugs for improving maternal and neonatal outcomein women with HELLP or partial HELLP syn-drome.18–23 A review of the literature reveals substantialdifferences in methodology, time of administration, anddrug selection among investigators who advocate the useof corticosteroids in women with HELLP syndrome.Different regimens of steroids have been suggested forpreventing respiratory distress syndrome as well as toaccelerate maternal recovery in the postpartum period.The regimens of steroids used included intramuscularbetamethasone (12 mg/12 hours or 24 hours apart on 2occasions) or intravenous dexamethasone (variousdoses at various time intervals) or a combination of thetwo.13–15,18–23 Some studies used steroids in the antepar-tum period only (for 24 hours, 48 hours, repeat regi-mens, or chronically for weeks until delivery).11,15,18,19

Those who used steroids for long intervals recommendtapering them over 4–6 weeks.11,12 In other studies,

steroids were given for 48 hours before delivery and thencontinued for 24–48 hours postpartum,14,15,22,23

whereas others recommend their administration in thepostpartum period only.29,30

There are few case reports describing the potentialmaternal–neonatal benefit of antenatal corticosteroidtherapy in women with (H)ELLP syndrome. Heyborneet al11 described 5 cases of HELLP syndrome at 24–30weeks of gestation in which temporary reversal of theHELLP syndrome was achieved with low-dose aspirinand corticosteroids. However, only 1 of the 5 womenhad true HELLP syndrome when dexamethasone wasused, and she was delivered within 48 hours of dexa-methasone administration. Two of the remaining 4women had ELLP syndrome, and the other 2 had ele-vated liver enzymes only (platelet counts of more than100,000). Eclampsia with DIC developed in 1 of these 4women, and 2 of the 5 neonates died.

Heller and Elliott12 described 4 women with high-order multiple pregnancies complicated by ELLP syn-drome who were treated with long-term corticosteroids.None of these women had hemolysis, 3 had elevatedliver enzymes only (platelet count more than 100,000),and 1 had thrombocytopenia only when steroids wereallegedly used to treat HELLP syndrome. Two of thesewomen developed pulmonary edema with such therapy.The authors reported that dexamethasone resulted instabilization of laboratory values and prolongation ofgestation by 6–41 days.12

There are 5 randomized trials comparing the use ofhigh-dose dexamethasone with either no treat-ment19,20,29,30 or with betamethasone43 in women whohad presumed HELLP syndrome (Table 2). The resultsof these studies demonstrated improved laboratory val-ues and urine output in patients receiving dexametha-sone, but no differences in serious maternal morbidity.In addition, the number of patients studied was limited,and neither of these studies used a placebo.

In summary, the available evidence suggests that stan-dard-dose corticosteroids (as recommended by the Na-tional Institutes of Health Consensus DevelopmentPanel) improve perinatal outcome when used in womenwith HELLP syndrome before 34 weeks of gesta-tion.14,19,38 In addition, in some of these women, there istransient improvement in maternal platelet counts,which makes them eligible to receive epidural anesthe-sia.13,15 There is also some evidence suggesting im-proved laboratory values with the use of higher doses ofdexamethasone in women with postpartum “HELLP”syndrome.14,22,23,29,30 The doses of dexamethasone con-sidered “high dose” in these reports was 10 mg of dexa-methasone administered intravenously every 6 to 12hours for 2 doses followed by 5–6-mg intravenous doses


given 6 to 12 hours later for 2 additional dos-es.14,22,23,29,30 However, it must be emphasized that mostof the patients included in these studies had partialHELLP only. In addition, none of these studies reportedimprovement in clinically important maternal morbiditysuch as the need for platelet transfusion or pulmonary,renal, or hepatic complications. Therefore, there is adefinite need for placebo-controlled, randomized trials inwomen with postpartum HELLP syndrome. Until then,the use of high-dose dexamethasone to improve mater-nal outcome in women with HELLP syndrome beyond34 weeks of gestation or in the postpartum period re-mains experimental.

RECOMMENDED MANAGEMENT

The clinical course of women with HELLP syndrome isusually characterized by progressive and sometimes sud-den deterioration in maternal and fetal conditions.Therefore, patients in whom HELLP syndrome is sus-pected should be hospitalized immediately and observedin a labor and delivery unit. Such patients should betreated for severe preeclampsia and should initially re-ceive intravenous magnesium sulfate as prophylaxisagainst convulsions and antihypertensive medications tokeep systolic blood pressure below 160 mm Hg or dia-stolic blood pressure below 105 mm Hg or both.44 Thiscan be achieved with a 5-mg bolus dose of hydralazine, tobe repeated as needed every 15–20 minutes for a maxi-mum dose of 20 mg per hour. Blood pressure is recordedevery 15 minutes during therapy and every hour oncethe desired values are achieved. If hydralazine does notlower blood pressure adequately or if maternal sideeffects such as tachycardia or headaches develop, an-other drug such as labetalol or nifedipine can be used.

The recommended dose of labetalol is 20–40 mgintravenously every 10–15 minutes for an hourly maxi-

mum of 220 mg, and the dose of nifedipine is 10–20 mgorally every 30 minutes for an hourly maximum dose of50 mg. During the observation period, maternal and fetalconditions are then assessed.

The recommended regimen of magnesium sulfate is aloading dose of 6 g given over 20 minutes, followed by amaintenance dose of 2 g per hour as a continuousintravenous solution. Magnesium sulfate is initiated atthe beginning of the observation period and then contin-ued during labor and for at least 24 hours postpartum.

The next step in management is to confirm or excludethe diagnosis of HELLP syndrome from other condi-tions listed in the Box. Blood tests should include acomplete blood count with platelet count, a peripheralsmear, coagulation studies, serum AST, creatinine, glu-cose, bilirubin, and LDH levels. My diagnosis of HELLPsyndrome requires the presence of all the following:platelet count less than 100,000/mm3, an AST levelgreater than 70 IU/L (more than 2 times the upper limitof normal values), abnormal peripheral smear, and anLDH level greater 600 IU/L (more than 2 times theupper limit of normal), or bilirubin (more than 1.2mg/dL). Those who do not have all these parameters areconsidered to have partial HELLP syndrome.7

In its early presentation, acute fatty liver of pregnancymay be difficult to differentiate from HELLP syndrome.Patients with acute fatty liver of pregnancy typicallypresent with nausea, vomiting, abdominal pain, andjaundice; however, hypertension and proteinuria areusually absent.31 In addition, most patients with acutefatty liver of pregnancy will have prolonged prothrom-bin and partial thromboplastin times with low fibrinogenand low serum glucose values (Egerman RS, et al. Con-temp Ob Gyn 1997;October:129–49). These latter ab-normalities (other than low glucose values) are rarelypresent in patients with HELLP syndrome without ab-

Table 2. Randomized Trials of Corticosteroids in Women With ELLP or HELLP Syndrome

AuthorsDexamethasone

(n)Control

(n) Key finding

Magann et al19 12* 13 Improved platelet, ALT, LDH values in dexamethasone groupMagann et al20 20† 20 Improved platelet, AST, LDH, urine output, mean arterial pressure

in dexamethasone groupVigil-De Gracia29 17† 17 Improved platelet counts only with dexamethasoneYalcin et al30 15† 15 Improved platelet, AST, mean arterial pressure and urine output

with dexamethasoneIsler et al43 19* 21‡ Improved AST, LDH, mean arterial pressure and urine output with

dexamethasoneELLP � elevated liver enzymes and low platelets; HELLP � hemolysis, elevated liver enzymes, and low platelets; ALT � alanine aminotransferase; LDH � lactic dehydrogenase; AST � aspartate amino transferase.

* Antepartum.† Postpartum.‡ Received intramuscular betamethasone.


ruptio placentae (Egerman RS, et al. Contemp Ob Gyn1997;October:129–49). Thrombotic thrombocytopenicpurpura is an extremely rare condition during preg-nancy characterized by neurological dysfunction, fever,severe thrombocytopenia, and severe hemolysis. Thesepatients will usually have very low hematocrit, markedlyabnormal peripheral smear, and normal or slightly ele-vated liver enzymes (Egerman RS, et al. Contemp ObGyn 1997;October:129–49). In contrast, patients withHELLP syndrome and acute fatty liver of pregnancyusually have normal-to-elevated hematocrit values andsignificantly higher liver enzymes values. Patients withhemolytic uremic syndrome usually present with renalfailure, and most cases (95%) develop in the postpartumperiod (Egerman RS, et al. Contemp Ob Gyn 1997;October:129–49). Patients with immune thrombocyto-penic purpura will have thrombocytopenia but rarelyassociated with hypertension or abnormal liver enzymes.

Once the diagnosis of HELLP syndrome is confirmed, adecision is made regarding the need for delivery (Figure 1).Patients with HELLP syndrome who are at less than 35weeks of gestation should be referred to a tertiary carefacility if the maternal condition is stable. The first priorityis to assess and stabilize the maternal condition, particularlyblood pressure and coagulation abnormalities. The nextstep is to evaluate fetal status with the use of fetal heart ratetesting, biophysical profile, or Doppler assessment of fetalvessels. Finally, a decision must be made as to whether

delivery should be initiated or delivery could be delayed for48 hours for corticosteroid benefit. It is my policy to initiatedelivery in all patients with true HELLP syndrome exceptin those with a gestational age between 24 to 34 weeks withstable maternal and fetal conditions. These latter patientsare given 2 doses of either betamethasone 12 mg intramus-cularly every 12 hours or dexamethasone 12 mg intrave-nously every 12 hours, and then delivered within 24 hoursafter the last dose of corticosteroids. Maternal and fetalconditions are assessed continuously during this time pe-riod. In some of these patients, there may be transientimprovement in maternal laboratory tests; however, deliv-ery is still indicated despite such improvement.

INTRAPARTUM MANAGEMENT

The presence of HELLP syndrome is not an indicationfor immediate cesarean delivery. Such an approachmight prove detrimental for both mother and fetus. Thedecision to perform cesarean delivery should be basedon fetal gestational age, fetal conditions, presence oflabor, and cervical Bishop score. My policy is to recom-mend elective cesarean delivery for all women withHELLP syndrome before 30 weeks of gestation who arenot in labor and whose Bishop score is below 5. I alsorecommend elective cesarean delivery to those withHELLP syndrome plus fetal growth restriction and/oroligohydramnios if the gestational age is below 32 weeksin the presence of an unfavorable cervical Bishop score.

Patients having labor or rupture of membranes areallowed to deliver vaginally in the absence of obstetriccomplications. When labor is indicated, it is initiatedwith either oxytocin infusions or prostaglandins in allpatients with a gestational age at or above 30 weeks,irrespective of the extent of cervical dilatation or efface-ment. A similar approach is used for those at or before 30weeks of gestation if the cervical Bishop score is at least 5.

Maternal pain relief during labor and delivery can beprovided by intermittent use of small doses of systemicopioids. Local infiltration anesthesia can be used for allvaginal deliveries in case of episiotomy or lacerationrepair. The use of pudendal block is contraindicated inthese patients because of the risk of bleeding and hema-toma formation into this area. Epidural anesthesia is alsocontraindicated, particularly if the platelet count is lessthan 75,000/mm3. Therefore, general anesthesia is themethod of choice for cesarean delivery in such patients.O’Brien et al15 assessed the impact of glucocorticoidadministration on the rate of epidural anesthesia use in37 women with partial HELLP syndrome who had aplatelet count below 90,000/mm3 before steroid admin-istration. The authors found that administration of cor-ticosteroids in these patients increased the rate of epi-

Figure 1. Management of HELLP (hemolysis, elevated liverenzymes, and low platelets) syndrome.Sibai. Diagnosis and Management of HELLP syndrome. Obstet Gynecol 2004.


dural anesthesia use, particularly in those who achieveda latency period of 24 hours before delivery (8 of 14 insteroid group versus 0 of 10 in no steroids, P � .006).15

Platelet transfusions are indicated either before orafter delivery in all patients with HELLP syndrome inthe presence of significant bleeding (ecchymosis, bleed-ing from gums, oozing from puncture sites, wound,intraperitoneal, etc.), and in all those with a platelet countof less than 20,000/mm3. Repeated platelet transfusionsare not necessary because of the short half-life of thetransfused platelets in such patients. Correction ofthrombocytopenia is also important before any surgery.My policy is to administer 6 U of platelets in all patientswith a platelet count less than 40,000/mm3 before intu-bation if cesarean delivery is needed. Generalized oozingfrom the surgical site can occur during surgery or in theimmediate postpartum period because of the continueddrop in platelet count in some of these patients. The riskof hematoma formation at these sites is approximately20%. Therefore, my policy is to use a subfascial drainand to keep the skin incision open for at least 48 hours inall patients requiring cesarean delivery.1

POSTPARTUM MANAGEMENT

After delivery, patients with HELLP syndrome shouldreceive close monitoring of vital signs, fluid intake andoutput, laboratory values, and pulse oximetry for at least48 hours. My policy is to continue intravenous magne-sium sulfate prophylaxis for 48 hours, and to use antihy-pertensive drugs if the systolic blood pressure is at least155 mm Hg or if the diastolic pressure is at least 105 mmHg. In general, the majority of patients will show evi-dence of resolution of the disease process within 48hours after delivery. However, some patients, especiallythose with abruptio placentae plus DIC, those with se-vere thrombocytopenia (platelet count less than 20,000/mm3), and those with severe ascites or significant renaldysfunction may show delayed resolution or even dete-rioration in their clinical condition.35–37 Such patients areat risk of the development of pulmonary edema fromtransfusion of blood and blood products, fluid mobiliza-

tion, and compromised renal function. These patientsare also at risk of acute tubular necrosis and need fordialysis,35,36 and may require intensive monitoring forseveral days. Some authors suggested that such patientsmight benefit from plasmapheresis or plasma transfu-sions.28 However, my experience indicates that thesepatients will recover with supportive therapy only.

The clinical and laboratory findings of HELLP syn-drome may develop for the first time in the postpartumperiod.6,22,23 In these patients, the time of onset of themanifestations ranges from a few hours to 7 days, withthe majority developing within 48 hours postpartum.6

Hence, all postpartum women and health care providersshould be educated and be aware of the signs andsymptoms of HELLP syndrome. The treatment of pa-tients with postpartum HELLP syndrome should besimilar to that in the antepartum period, including theuse of magnesium sulfate. The differential diagnosis inthese patients should include many of the conditionslisted in the Box.

Some authors recommend the administration of high-dose dexamethasone for patients with postpartumHELLP syndrome.22,23,29,30 These authors suggest thatsuch therapy results in accelerated recovery and shorterhospital stay as compared with a historical group notreceiving such therapy. My policy is not to give dexa-methasone to such patients because such therapy re-mains experimental.

SUBSEQUENT PREGNANCY OUTCOME AND REMOTEPROGNOSIS

Pregnancies complicated by HELLP syndrome may beassociated with life-threatening complications for boththe mother and her infant. Therefore, clinicians shouldbe able to answer questions regarding subsequent preg-nancy outcome and long-term prognosis. Women with ahistory of HELLP syndrome are at increased risk of allforms of preeclampsia in subsequent pregnancies (Table3). In general, the rate of preeclampsia in subsequentpregnancies is approximately 20%, with significantlyhigher rates if the onset of HELLP syndrome was in the

Table 3. Pregnancy Outcome After HELLP

Normotensive women

Women(n)

Pregnancies(n)

HELLP(%)

Preeclampsia(%)

Sibai et al47 139 192 3 19Sullivan et al45 122 161 19 23Van Pampus et al49 77 92 2 16Chames et al50* 40 42 6 52HELLP, hemolysis, elevated liver enzymes, and low platelets.

* HELLP at or before 28 weeks of gestation in a previous pregnancy.


second trimester. The rate of recurrent HELLP syn-drome ranges from 2% to 19%. My policy is to give thesewomen a recurrence risk of less than 5%.46–48 Because ofthese risks, these women are informed that they are atincreased risk for adverse pregnancy outcome (pretermdelivery, fetal growth restriction, abruptio placentae, andfetal death) in subsequent pregnancies. Therefore, theyrequire close monitoring during subsequent gestations.Currently, there is no preventive therapy for recurrentHELLP syndrome. Liver function tests were studied in54 women at a median of 31 months (range 3–101months) after pregnancies complicated by HELLP syn-drome.49 Serum levels of AST, LDH, and conjugatedbilirubin were found to be normal. However, total bili-rubin levels were elevated in 11 (20%) of the studiedwomen. The authors of this report suggested the possi-bility that a dysfunction of the bilirubin-conjugatingmechanism represents a risk factor for the developmentof this syndrome.49

There are 2 reports describing long-term renal func-tion after HELLP syndrome.36,50 One of the reportsincluded 23 patients whose pregnancies were compli-cated by HELLP syndrome and acute renal failure: 8 ofthese women had 11 subsequent pregnancies, with 9resulting in term gestation.35 All 23 women also hadnormal blood pressures and renal function at an averagefollow-up of 4.6 years (range 0.5–11 years). The otherstudy compared renal function after at least 5 years afterHELLP syndrome in 10 patients with the respectivefindings in 22 patients with previous normotensive ges-tation.50 There were no differences in renal function testsbetween the 2 groups. These findings suggest that thedevelopment of HELLP syndrome with or without renalfailure does not affect long-term renal function.

SUMMARY

The presence of HELLP syndrome is associated withlife-threatening maternal and fetal complications. De-spite the voluminous literature on this subject, there is anurgent need for a uniform definition and diagnosticcriteria for this syndrome. Pregnancies complicated bythis syndrome require a well-formulated managementplan. The potential benefits of expectant management inthose remote from term and the use of corticosteroids toimprove maternal outcome remain experimental.

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and low platelets) syndrome: impact on the rate of regionalanesthesia. Am J Obstet Gynecol 2002;186:475–9.

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Address reprint requests to: Baha M. Sibai, MD, University ofCincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267:e-mail: [email protected] January 22, 2004. Received in revised form February 23,2004. Accepted March 4, 2004.

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Diagnosis, Controversies, And Management of the Hellp Syndrom, Sibai

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