Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome: a review of diagnosis and management

Hemolysis, Elevated Liver Enzymes, and Low Platelets (HELLP) Syndrome: A Review of Diagnosis and Management CarlJ. Saphier and John T. Repke Hemolysis, elevated liver enzymes, and low platelet (HEI J .P) syndrome is a form of severe preeclampsia that threatens the gravida and her fetus. In this report, the diagnostic criteria and maternal and fetal risks of HEI.LP are defined. Prompt recognition and treatment in tertiary centers is emphasized, because the prognosis can be adversely affected by delayed or less than optimal diagnosis and treatment. Management guidelines are offered for treating this disorder. The potential roles of corticosteroids, plasmapheresis, and expectant management are critically evaluated. Subsequent pregnancy outcome, contraception, and preventative strategies are considered. Copyright 9 1998 by W.B. Saunders Company ne of the severe forms of preeclampsia in-

O cludes the syndrome named for its primary

laboratory abnormalities--hemolysis, elevated liver enzymes~ and low platelets (HELLP). It has become evident that in the setting of this disorder the gravida and her fetus are both at increased risk for significant morbidity and mortality. A clear understanding of how to recognize and treat HELLP is important for the primary and consultant obstetrician. M t h o u g h investigators have long recognized the potential risks associated with the developm e n t of liver dysfunction and coagulopathy with preeclampsia, it is recent work that has defined more clearly the subset of patients that have HELLP syndrome. Chesley' described the long-standing recognition that preeclampsia was associated with microthrombi and platelet consumption and that the overt development of a coagulopathy carried a poor prognosis. Kitzmiller et al 2 identified significant thrombocytopenia in a group of patients with severe preeclampsia. Early case series reported the association between hypertension, liver disease, and coagulopathy with poor maternal-fetal outcomes. 3-5 Goodlin et al6,7 suggested dichotomizFrom the Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA and the University of Nebraska Medical Center, Omaha, NE. Address reprint requests toJohn T. Repke, MD, Departmentof Obstetrics, Gynecology, Universityof Nebraska Medical Center, 600 S 42nd St, Omaha, NE 68198-3255. Copyright 9 1998 by W.B. Saunders Company O146-0005/98/2202-0005508. 00/0

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ing the severe forms of edema-proteinuria-hypertension (EPH) into two entities: one group at risk for experiencing seizures and another at risk for multiple organ failure, including significant liver abnormalities and thrombocytopenia. Weinstein 8'9 began, with the description of his original 29 patients with HELLP, the process that has led him and others to provide a better understanding of the entity he named.

Clinical Presentation One of the difficulties of the proper treatment of HELLP syndrome lies in its recognition, because patients frequently present with nonspecific symptoms or subtle signs. Patients most frequently complain of nausea, epigastric pain, or right upper quadrant pain, ranging in frequency from 36% to 86%.9'a~ A subset of patients found to have HELLP present with symptoms of severe preeclampsia, including headache in approximately one third of the cases and visual changes (eg, blurred and double vision) in 10%. '0 Mthough many patients present with hypertension, it may be only mild in 16% of the cases, and it is absent in another 15% of the patients, al Similarly, the degree of proteinuria may not reflect the severity of disease because it is only " 1 + " on dipstick in 9% of the cases or absent altogether in another 6%. 11 The majority of patients do have more significant hypertension and proteinuria. Physical examination may elicit the additional findings of right upper quadrant tenderness, n o n d e p e n d e n t edema, and hyper-

Seminars in Perinatology,Vol 22, No 2 (April), 1998: pp 118-133

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Table 1. Comparison of Diagnostic Criteria for Hemolysis, Elevated Liver Function Enzymes, and Low Platelets (HEIJ P) Syndrome Weinsteins

Sibai et aL n

Hemolysis

NS

Elevated Liver enzymes Low platelets

NS

Abnormal peripheral Smear, LDH >600, or TB >1.2 AST >70

< lO0,O00/mm 3

< lO0,O00/mm s

Martin et aL 13

Falling hematocrit LDH >164, or bleeding diathesis AST >48 ALT >24 < lO0,O00/mm s

Abbreviations: NS, not specified; LDH, lactate dehydrogenase; TB, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

reflexia. T h e insidious presentation of H E I J . P and its grave prognosis has appropriately led o n e investigator to suggest a high level of vigilance in excluding the diagnosis in the large n u m b e r of pregnant patients manifesting potential symptoms o r signs. 12 HELLP syndrome has been defined differently by various investigators. Although authorities agree that hemolysis, liver dysfunction, and thrombocytopenia must all be present for the diagnosis, they disagree over specific criteria. Table 1 summarizes the three most p r o m i n e n t criteria suggested by Weinstein, s Sibai et al la and Martin et al. 13 Although each of these investigators requires a platelet count be less than 100,000/ram 3, they differ on their criteria for hemolysis and liver enzyme abnormalities. All o f Weinstein's patients in his original and exp a n d e d series had evidence for hemolysis and abnormal liver enzymes, but the degree of abnormalities and actual laboratory tests were not specified, s'9 In defining hemolysis, Sibai et all0.n use an abnormal peripheral smear with characteristic red blood cell morphology (eg, schistocytes, burr cells) and either an elevated lactate dehydrogenase (LDH) or elevated total bilirubin (TB). Martin et alli,13-15u s e a falling hematocrit level without an alternative etiology in the setting o f an elevated LDH or clinical bleeding diathesis. Martin et al n'a~'15 do not require as high an LDH level or liver enzyme level as does Sibai et al 1~Although this discrepancy in criteria may be important when comparing the series o f patients reported by these and other investigators, the most relevant aspect for the individual practitioner is the p r o m p t recognition of hemolysis, liver abnormality, and thrombocytopenia existing together. T h e degree of abnormality required for diagnosis can be tailored to the individual physician's laboratory reference values,

allowing for an appropriate sensitivity and specificity. T h e presentation o f HEI J.P differs from classic preeclampsia in several important regards, although the two are closely related. HELLP occurs before term in over 80% o f the cases, with 11% of the cases occurring before 27 weeks) ~ HELLP presents at a significantly earlier gestational age than preeclampsia without HELLP. 16 Although the majority o f HELLP becomes evid e n t before delivery, approximately one third of the cases manifest first during the postpartum period, a~ In contrast to the classic profile of preeclampsia, HEI.I.P more frequently afflicts whites and multiparas) ~ HELLP and preeclampsia do overlap, with 4% to 12% o f the hypertensive diseases o f pregnancy complicated by H E L L P ) ~ In Sibai et al's ~~ series, HELLP occurred in 20% o f cases o f severe preeclampsia and in 10% of cases of eclampsia. It has also been discussed that even though the hypertension and proteinuria may be mild, the majority o f HELLP patients do present with cardinal signs of preeclampsia.

Differential Diagnosis Because misdiagnosis and less than optimal treatment is not u n c o m m o n with HELLP, p r o p e r m a n a g e m e n t relies on a thorough understanding of its differential diagnosis. T h e nonspecifc, mostly gastrointestinal symptoms o f HELLP lead many to consider gastrointestinal diseases, including hepatitis, gastritis, pancreatitis, cholecystitis, and appendicitis. When considering these diagnoses in p r e g n a n t patients, the physician should obtain liver function enzyme values and a platelet c o u n t ) 2 Supportive signs of preeclampsia, such as even mild hypertension or edema, should influence the physician to

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Table 2. Clinical Characteristics of HELLP Syndrome, TTP, HUS, and AFLP

Primary organ involved Gestational age Platelets PT/PTT Hemolysis Glucose Fibrinogen Creatinine

HELLP

TIP

HUS

Liver 2nd and 3rd trimester + N1 + N1 N1 N1/I'

Neurologic 2nd Trimester + Nl + N1 N1 1"

Renal Postpartum ,~ NI + N1 N1 1"1"

AFLP

Liver 3rd Trimester N1/+ 1' -/+ +~ 1'

Abbreviations: $, decreased; 1", increased; N1, normal value; +, present, -, absent; PT, prothrombin time; PTT, partial thromboplastin time.

strongly consider HELLP and preeclampsia. Hepatitis often presents with a higher liver enzyme level and rarely with the significant thrombocytopenia o f HELLP. For further discussion of liver disease in pregnancy, several recent reviews have been written. 18-2~ Rarely idopathic thrombocytopenia p u r p u r a (ITP) and systemic lupus erythematosis (SLE) present in pregnancy as a diagnostic dilemma. Although ITP manifests thrombocytopenia, it is rarely associated with liver enzyme abnormalities. Further, HELLP rarely presents first as a bleeding diathesis, whereas ITP occasionally does. An SLE flare may develop in a patient for the first time during pregnancy, and the patient may present with a clinical course similar to preeclampsia and HELLP. Ways of differentiating SLE from preeclampsia and HELLP include the presence of pancytopenia and depressed complement levels associated with SLE. In contrast, patients with HELLP and preeclampsia may have thrombocytopenia but normal white blood cell and c o m p l e m e n t levels. In addition, the presence o f autoantibodies would make SLE more likely. Renal biopsy to confirm the glomerular pathology consistent with SLE can be considered, but in the setting of significant thrombocyopenia, this may be relatively contraindicated. Neither ITP n o r SLE generally responds to delivery as HELLP does. T h e physician needs to differentiate thrombotic thrombocytopenia p u r p u r a (TTP), hemolytic uremic syndrome (HUS), and acute fatty liver o f pregnancy (AFLP) from HELLP because the), have different prognoses and treatments. Table 2 compares the clinical features of HELLP, TTP, HUS, and AFLP. Although HELLP primarily affects liver function, TTP manifests as neuro-

logical dysfunction and HUS as renal failure. Both TTP and HUS occur m u c h less frequently than HELLP and most likely represent a continuum, referred to as TTP-HUS. HUS classically refers to the clinical entity o f thrombocytopenic purpura, hemolytic anemia, and renal failure; TTP adds fever and neurological involvement to complete a pentad o f signs. Weiner's 21 review o f the reported cases of TTP and HUS in pregnancy showed some important differentiating aspects. TTP occurs frequently antepartum, but 58% of the cases occurred before 24 weeks' gestation. In contrast, 94% o f HUS related to pregnancy was f o u n d in the puerperium, as postpartum renal failure. Between 10% and 15% of the reported cases o f TTP and HUS are associated with signs of preeclampsia. T h e mortality of T T P and HUS may be significantly higher than with HELLP, as high as 58% to 68% in patients with TTP-HUS not receiving plasmapheresis therapy. Egerman et a122reviewed their institutional experience with TTP-HUS and confirmed the array of associated medical and obstetric complications, including fetal loss and preterm delivery for preterm labor and nonreassuring fetal status. In contrast to Weiner's ~1 review, Egerman et a122 f o u n d that TTP-HUS was often difficult to distinguish from preeclampsia, and that the correct diagnosis of TTP-HUS was frequently made after delivery, when patients had an atypical postpartum course with prolonged recovery. Plasmapheresis appears to greatly benefit TFP-HUS related to pregnancy, and Weiner did not identify in his series a mortality after receiving therapy. 21 T h e dramatic improvement in outcome associated with plasma exchange in patients with TTP-HUS has been reported outside of pregnancy. 2~-2~ In one randomized trial plasma ex-

I-1ELLP Syndrome: Diagnosis and Management

change was found to be superior to plasma infusion alone in nonpregnant patients with TFP. 26 Although corticosteroids can result in a favorable response in mild TI'P-HUS cases, the mainstay of therapy remains plasma exchange instituted as early as possible. Other treatments, including aspirin, dipyridamole, vincristine, imm u n e globulin, and splenectomy, have at best a secondary role and offer little benefit according to most authorities. ~4'~5 Similarly in pregnancy, plasma exchange, not delivery, appears to considerably impact the outcome of TTP-HUS. This is in contrast to HELLP, which predictably improves with delivery, and which has an unclear benefit from plasmapheresis. Patients who are delivered for presumed HELLP and preeclampsia and do not improve within the anticipated time period should be evaluated for TrP-HUS. HELLP and AFLP both affect the liver but differ in the magnitude of hepatic damage. AFLP is much more likely to profoundly impact hepatic synthesis resulting in marked hypoglycemia, hyperammonemia, and increased clotting times than is HELLP. The liver enzyme abnormalities are usually more pronounced in patients with HELLP than in AFLP. 27 AFLP also appears to occur later in gestation than HELLP, the majority of AFLP cases being reported late in the third trimester. 28'~ Disseminated intravascular coagulation (DIC) is common to both HELLP and AFLP, and is nearly universal in AFLP. 3~ AFLP is less common than HELLP, with AFLP having an overall incidence between 1 in 5,000 to 16,000 deliveries. ~'3~ Although the differential diagnosis of HELLP includes gastrointestinal, hematologic, and immunologic diseases, HELLP usually has graver consequences. Elevated liver enzyme levels and thrombocytopenia in pregnancy must be considered to be HELLP or preeclampsia first and foremost. The physician is therefore obligated to exclude HELLP syndrome in women with even subtle signs for a wide spectrum of diseases. Only after a complete evaluation can a physician be sure that the process is likely not HELLP or preeclampsia.

Maternal and Perinatal Morbidity The seriousness of HELLP syndrome is evident in the frequency and spectrum of maternal morbidity. The hematologic risks of spontaneous

12 1

and postpartum hemorrhage, need for blood product transfusion, and the development of superimposed DIC rank first. The reported incidence of requiring blood products in the form of red blood cells or platelets varies among the reported series, ranging from 10% t o 5 5 % . 9'10'17 Although a lower platelet count has been associated with a higher rate of postpartum hemorrhage, prophylactic platelet transfusion does not appear to prevent its occurrence? ~Other materhal complications commonly seen in HELLP include severe hypertension, eclampsia, pulmonary edema, and acute renal failure. Sibai et all0 observed eclampsia in 8% of the patients with HELLP. Miles et a132diagnosed HELLP in almost one third of the patients with postpartum eclampsia. The development of abruptio placentae places the patient at higher risk for pulmonary edema, renal failure, and DIC) ~ Those patients in whom postpartum HELLP develops may represent a subset of patients at particular risk for serious morbidity and have been found to be at substantial risk of renal failure and pulmonary edema) ~ Hepatic rupture occurs with HELLP occasionally and can herald profound hemorrhage and shock as well as present a difficult surgical emergency. Sibai et al~0 encountered ruptured livers in the setting of abruptio placentae with four patients, or 1% of his series, three of whom survived after receiving massive transfusions and surgical treatment. In the face of acute hemorrhage or shock, appropriate surgical exploration with packing, suturing, and the use of other hemostatic techniques, in addition to blood product transfusion, must not be delayed. Hepatic intraparenchymal hemorrhage, infarction, and subcapsular hematomas without rupture may occur, and they can be selectively managed conservatively with blood product transfusion as needed. HEI.I.P carries a significant risk of maternal mortality. Although the maternal mortality rate varies significantly among the reported series, the rate most likely approaches 1.0% to 3.5%. 9'1~ Review of the reported mortalities shows that these patients often suffered multiple-system orgala failure in association with eclampsia, DIC, hepatic rupture, adult respiratory distress syndrome, sepsis, or difficulty in establishing an airway. The patient with HEI.I .P requires a tertiary care setting capable of supporting her potential

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critical care needs, including readily available blood products and the support o f tertiary nursing, anesthetic, and surgical support. The fetus is similarly placed at increased risk for mortality and morbidity in the setting o f HELLP. As has been discussed, HELLP frequently occurs before term, and prematurity itself significantly contributes to its perinatal morbidity and mortality. T h e perinatat mortality rate ranges from 56 to 367 per 1,000 births. 9'n'~7'33'34 Perinatal death is most commonly experienced at very early gestational ages near the limit o f viability, in the setting o f severe growth restriction or abruptio placentae, and in patients who present to the hospital with an intrauterine fetal demise. Intrauterine growth restriction may be seen in over one third of the fetuses. 9'n'33'34 T h e r e also exists a significant risk for low umbilical artery pH and 5-minute Apgar sores. Emphasizing the significance of gestational age at delivery, Harms et al as f o u n d no difference in comparing the perinatal mortality of the group o f neonates delivered from mothers with HELLP to their population o f very low birth weight neonates. Gauging

Prognosis

Investigators have attempted to identify those patients with HELLP who are at particular risk of its serious morbidity. Such investigation has focused on whether the full diagnostic criteria are met, the platelet c o u n t nadir, the development of superimposed DIC, and the degree o f liver enzyme abnormality. Incomplete expression o f the diagnostic criteria may not carry the same risks as frank HELLP syndrome. Audibert et a116 c o m p a r e d the outcomes of patients who met the full criteria for HELLP as defined by Sibai et al, met some but not all criteria for HELLP, and met criteria only for severe preeclampsia without additional HELLP signs. They f o u n d that the patients with completely expressed HELLP syndrome appeared to have a worse outcome than the o t h e r two groups, as manifest by an earlier gestational age at delivery, higher cesarean section rate, more frequent use o f blood products, and more serious maternal morbidity. Patients with one or two o f the criteria for HELLP also had p o o r outcomes, apparently in the intermediary range between full HELLP and severe preeclampsia. This

may explain the range of outcomes reported in the literature for HELLP, because uniform criteria have not always been applied. It also suggests that those who meet all HELLP criteria manifest a more severe disease process than incomplete HELLP or severe preeclampsia without HELLP. Martin et al ls-15 have proposed a classification system for HELLP syndrome based on the platelet c o u n t nadir. T h e lowest ptatelet c o u n t is used to stratify patients into three categories: class 1 represented by a nadir with less than or equal to 50,000/ram3; class 2 by a nadir of 50,000 to 100,000/mma; and, class 3 by a nadir greater than or equal to 100,000 to 150,000/mm 3. Because class 3 has a platelet c o u n t greater than what is usually accepted by other authorities, Martin has concentrated on patients with class 1 or 2 HELLP. In their institution, Martin et al le'15 have reported a relationship with a lower platelet c o u n t nadir and a higher risk for postpartum h e m o r r h a g e and a longer and m o r e complicated recovery. In addition, they have reported that those patients with class 1 HELLP delivered sooner after the diagnosis than did patients with class 2 HELLP. As previously discussed, prophylactic platelet transfusion did not appear to alter risk for hemorrhage. 31 Others have reported an inverse correlation between the platelet nadir and peak liver enzyme abnormalities. 35 T h e utility o f the platelet count in prospectively predicting outcome has not been studied yet in HELLP. Furthermore, most studies have used the platelet count nadir, which may occur postpartum or after the development of an additional complication such as abruptio placentae. Patients with HELLP in whom superimposed DIC develops have been identified as being at particular risk for additional complications. T h e clinical diagnosis o f DIC in the setting o f HELLP is accomplished by establishing in addition to a platelet count o f less than 100,000/mm 3, a fibrinogen level o f less than 300 m g / d L , positive fibrin split products 40 /zg/dL or greater, and p r o l o n g e d p r o t h r o m b i n and partial thromboplastin times greater than or equal to 14 seconds and greater than or equal to 40 seconds, respectively. 1~ O t h e r laboratory tests that can be used to diagnose DIC, such as antithrombin III activity, are limited in their availability. DIC often develops as a further complication in patients with subcapsular liver hematomas, peripartum hemorrhage, and abruptio placentae. Those pa-

HELLP Syndrome: Diagnosis and Management

tients with DIC have been found to be at significant risk for renal failure, pulmonary edema, and death. 1~ Van Dam et ala6 prospectively studied the relationship of DIC and outcome in 18 patients with HELLP by applying a DIC score. In their series, fully expressed DIC developed in all of the patients who had a life-threatening complication, and no patient without DIC experienced a life-threatening complication. DIC often had developed in their patients well before the clinical presentation of their complications. Outside of extreme laboratory values, the degree of liver dysfunction does not correlate well with outcome in HEI J.P. A number of maternal mortalities have been linked to hepatic rupture, central liver necrosis, and extreme elevations of liver function enzymes.9'1~ Because the occurrence of hepatic rupture and mortality are rare, establishing a useful method of using liver enzyme level to screen HEI,I,P patients for risk of mortality would be difficult. Barton et al,~s and Barton and Sibaia9 in two studies investigated the relationship between liver histology and liver imaging with clinicai outcome. Findings from these studies showed a lack of strong association between overall laboratory abnormality and severity of hepatic histology and hepatic radiological findings. Those patients with severe thrombocytopenia, less than 20,000/ mm a, were found to be at particular risk for subcapsular hematoma and other radiological findings, which is consistent with the platelet and clotting factor consumption that often follows the development of these findings.39 Although the platelet count and liver enzyme level may be markedly abnormal in those patients in whom life-threatening complications develop, their use is limited in prospectively assigning risk to the patient with HELLP. DIC has been found in the majority of patients with lifethreatening complications, often as a result of other morbidity such as abruptio placentae or subcapsular liver hematoma. Those patients with markedly abnormal platelet counts, liver function values, or the development of DIC should be evaluated closely for other life-threatening complications, and may form a group that is undergoing or is at higher risk for acquiring the associated complications of HELLP.

Natural H i s t o r y The natural history of I-IELLP closely resembles that of severe preeclampsia, with a resolution of

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the disease process after delivery. The paradigm is that the patient with HELLP becomes progressively sicker until ultimate maternal and fetal deterioration, unless the process is interrupted by delivery. Experience from patients expectantly treated with severe preeclampsia and HEIJ,P, which will be reviewed in detail later, challenges this concept and suggests that a proportion of patients with these diseases may remain stable for a considerable length of time, or even temporarily improve before deteriorating. 17'4~ The platelet count and liver enzyme abnormalities correlate with each other, reaching their worst values together, a5 There are few studies characterizing the period before delivery in patients with HEI.I.P, because most authorities have in the past advocated delivery once the diagnosis is confirmed. After delivery, the majority of patients initially worsen followed by clinical improvement, with platelets and liver enzyme levels gradually returning to normal. In a study of 158 patients with HEI .l.P, Martin et ala4 found that the platelet count reached its nadir generally 24 to 48 hours postpartum and that recovery took 48 to 72 hours longer than the nadir. Only 7 of 158 patients did not recover within 72 hours of delivery. Similarly, Chandrin et al as found in 30 patients that the mean time from delivery to clinical resolution was 67 hours, with the nadir in platelet count also occurring in the majority of patients after delivery. Patients therefore warrant close observation and serial laboratory evaluation after delivery, a period during which their condition may first deteriorate before improving.

Investigational Therapies The most active areas of dialogue in HELLP center on plasmapheresis, corticosteroids, and expectant management. Experience with these potentially adjuvant therapies has been limited, and results vary. As will be presented, further research is needed to confirm their efficacy in HE1.1 .P. Unlike its role in T I P and HUS, treating HEI J.P with plasmapheresis remains investigational. The proponents of plasmapheresis most often have used this modality to remove the patient's plasma and exchange it with fresh frozen plasma. It is hypothesized that this process may

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work through several mechanisms: removing circulating toxins and free radicals, removing immunoglobulin complexes, replacing platelet aggregation inhibitors, stabilizing endothelial damage, and decreasing blood viscosity. Several case series have reported varying success with plasmapheresis in pregnancy, used for refractory HELLP or preeclampsia and for "I-TP-HUS. 47-5~ Martin et all3,a5 have had substantial experience with postpartum HELLP and plasmapheresis. They have treated 18 postpartum patients for HELLP that either persisted beyond 72 hours or was complicated by multisystem organ involvement. A favorable response was usually seen within 48 hours of instituting once daily exchange treatments in those patients treated for otherwise uncomplicated, persistent HELLP. In contrast, the group treated for HELLP with multisystem organ involvement did not show a strong positive effect to the plasmapheresis, in spite of generally receiving a greater number of exchanges. Of the nine patients in the latter group, four did not appear to benefit from the treatment. Two patients died of multiorgan failure, DIC, and adult respiratory distress syndrome (ARDS). Among both groups, patients frequently suffered adverse events possibly related to therapy, including pulmonary edema, blood and platelet transfusion, infection and sepsis, and eclampsia. Martin concluded that given the positive response in the group with uncomplicated persistent HELLP, plasmapheresis can be considered in similar patients. A clear benefit of plasma exchange in patients with HELLP complicated by multisystem organ involvement, DIC, and ARDS remains, in his opinion, to be established. In a report from the same institution, seven antepartum patients were treated unsuccessfully with plasmapheresis in attempts to prolong pregnancies complicated by HELLP or severe preeclampsia, resulting in poor maternal and fetal outcomes. 5~ Plasmapheresis has been associated with an array of proceduralrelated morbidities and mortality, as reviewed elsewhere. 49 Because the studies to date have been uncontrolled and have had mixed results, further investigation is needed before routinely implementing plasmapheresis in HELLP. The existing literature does not, in our opinion, currently support the use of plasmapheresis as a means of prolonging pregnancies with HELLP or severe preeclampsia. Plasmapheresis may ben-

efit patients delivered for HELLP who may have alternative diagnoses such as TTP-HUS, clinically expressed as an incomplete or prolonged postpartum recovery. Corticosteroids have been used in HELLP to accelerate fetal maturity and stabilize the maternal condition. Since the release of the National Institutes of Health consensus statement on antepartum corticosteroids, the emphasis has been to administer corticosteroids in pregnancies at risk for delivering between 24 to 34 weeks, including those complicated by hypertension.5~ In patients with HELLP syndrome, the results of a retrospective study comparing the perinatal outcomes of 27 fetuses exposed to corticosteroids with 27 controls without corticosteroids found a significantly reduced incidence of respiratory distress requiring ventilation.53Although limited in sample size, there were no additional significant benefits found in the incidence of other serious perinatal morbidity. Early reports noted that in some patients the maternal condition stabilized or improved after receiving corticosteroids for fetal indications, n'36'4~ In a reanalysis of maternal outcomes, a retrospective controlled study of 27 patients with HELLP who received corticosteroids for fetal indications found that the maternal platelet count, LDH, and liver function values more frequently improved or stabilized in patients who were exposed to steroids. 41 In two separate prospective, randomized studies, Magann et a142investigated the utility of corticosteroids in antepartum stabilization and in postpartum recovery. Of the 25 patients who were selected randomly to receiving antepartum treatment, the 12 who received double-dose, intravenous dexamethasone (10 mg every 12 hours) until delivery had a significant improvement in platelet count, liver function enzymes, urine output, and LDH when compared with the 13 controls. Further, the steroid patients had a significantly longer study entry-to-delivery time interval compared with control, 41 hours versus 15 hours, respectively. In their study of 20 postpartum HELLP patients selected randomly to a tapered regimen of intravenous dexamethasone (10 mg for two doses followed by 5 mg for two doses every 12 hours) and 20 controls with no additional therapy, Magann et a154 showed that patients who received steroids more rapidly improved their platelet count, liver function values, LDH, blood pressure, and urinary output. Nei-

t-IELLPSyndrome:Diagnosis and Management

ther study used a placebo, and maternal outcome did not reportedly differ outside of laboratory values and urinary output. Larger studies may confirm the maternal benefit seen in these two preliminary studies, and may reveal further clinically relevant differences. We are awaiting further studies in this area before adopting the use of high-dose corticosteroids antepartum or postpartum. Because there is no apparent detrimental effect in the mother or fetus, we consider giving antepartum corticosteroids in doses for fetal maturation to those patients with pregnancies that would qualify based on gestational age. Although expectant management is gaining popularity in the treatment of severe preeclampsia remote from term, the role of prolonging the pregnancy with HELLP remains controversial. Expectant management has been shown in severe preeclampsia to improve perinatal outcomes, including survival and major morbidity, in both randomized and nonrandomized studies. 4s'44`Ss These studies have specifically excluded patients with HEI J.P. Anecdotal and limited experience with expectant m a n a g e m e n t in HELLP has led to varying opinions to the timing of delivery, ranging from immediate delivery, to delivery after corticosteroids, and to attempted prolonged expectant management. 9,~6'4~ The main reason for this controversy is that some patients with HELLP may temporarily improve or remain stable for some period before delivery, whereas other patients deteriorate rapidly and suffer significant morbidity. In a retrospective controlled analysis of 128 consecutive patients with HELLP, Visser and Wallenburg 4~found that intensive maternal and fetal management without corticosteroids can achieve significant pregnancy prolongation with reasonable risk and outcome. They reported that the median prolongation was 10 days, that 83% of the patients were undelivered 48 hours after admission, and that 43% of the patients had at least a temporary reversal of the HELLP serological abnormalities. Their patients experienced a 14.1% perinatal mortality rate, with all of the fetal deaths caused by IUGR and extreme prematurity and six of eight neonatal deaths caused by hyaline membrane disease. Further, they did not find any significant differences in the maternal outcomes of pregnancies with HELLP compared with 128 controls with severe preeclampsia without HELLP. We believe that the favorable outcomes

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associated with the expectant management of HELLP indicate that immediate delivery may not be mandatory in cases in which the maternal condition is stable and the fetus may benefit from attempts to achieve maturation. An opportunity to administer corticosteroids for the acceleration of fetal maturation may exist. We await the results of further studies to help answer several important questions: Which patients are the most appropriate candidates, how long a delay is safe, at what gestational ages do patients benefit, and what criteria should be used for delivery? Until these questions are answered and the preliminary findings are confirmed, we continue to r e c o m m e n d delivery soon after the diagnosis of HELLP is confirmed. We believe that delaying delivery in HELLP should be considered only in select cases managed in tertiary perinatal centers by personnel experienced in the treatment of such patients, most usually individuals trained in maternal and fetal medicine.

Management Principles The management goals of HELLP center on optimizing the maternal condition while weighing the perinatal risks of premature delivery. Care is primarily supportive and anticipatory with the focus on determining the safest timing and route of delivery. The first task is to confirm or exclude HEI J.P or preeclampsia from the other diseases included in the differential diagnosis. A chemistry panel including blood urea nitrogen (BUN), creatinine, liver function enzymes including alanine and aspartate aminotransferases, LDH, glucose, and uric acid should be obtained. Complete hematologic evaluation needs to be accomplished through a complete blood count with platelets and peripheral smear, PT and PTT, and fibrinogen. ~'1~ Additional laboratory data discussed previously in the section on differential diagnosis may be used as needed. HELLP must remain the primary diagnosis to exclude, and its treatment should not be unnecessarily delayed. Serial serology tests and a period of maternal observation may be required to confirm the diagnosis of HELLP. Fetal evaluation should be undertaken early in the evaluation to rule out placental insufficiency and intrauterine growth restriction. Continuous fetal heart rate monitoring as well as ultrasound examination for anatomic survey, amniotic fluid

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Suspect HELLP Vs. Severe Preeclampsia Maternal and Fetal Evaluation

HELLP

Severe Preeclampsia Without HELLP

24

< Recommend Delivery

24-34 Steroids Expectant

> 34 Delivery

< 24 ~ / 2 8 ~ - 3 2 "~> 32-34 RDCelivemmr~ nd ~r Deiivlry Delivery 24-28

After Steroids

Steroids ? Expectant

Figure 1. Suggested management of HELLP syndrome and severe preeclampsia by gestational age in weeks. volume, estimated fetal weight, biophysical profile, and umbilical artery Doppler velocimetry would help accomplish this initial fetal evaluation. 57"5s Fetal testing, including fetal heart rate monitoring and biophysical profile with umbilical artery Doppler velocimetry is p e r f o r m e d at least daily until delivery. The gestational age is a major determinant to our approach of the pregnancy complicated by HELLP, as summarized in Fig 1. In contrast to patients we believe have severe preeclampsia without HELLP, we have a lower gestational age threshold for delivery with HELLP. At our institution, we administer corticosteroids in doses for the acceleration of fetal maturation to all pat e n t s initially being evaluated for HELLP or severe preeclampsia between 24 to 34 weeks. Once the diagnosis of HELLP syndrome is confirmed, we weigh the maternal risks o f delaying delivery with the fetal benefit of prolonging the pregnancy. In pregnancies with gestational ages between 28 and 32 weeks in which the maternal condition remains stable, we move to delivery after a complete course o f steroids, 48 hours after the first dose is administered. In pregnancies between 24 and 28 weeks' gestation, we administer corticosteroids and consider further expectant m a n a g e m e n t with very close maternal and fetal surveillance if the maternal condition

is stable. In pregnancies further than 32 to 34 weeks or with d o c u m e n t e d fetal lung maturity, we move directly to delivery. The patient plays an active role in the decision process, and informed consent is obtained if any delay in delivery is entertained. We immediately undertake delivery in patients for a deterioration o f maternal or fetal status. Given the controversy surrounding this issue, we believe that policies should be made on an individual patient basis, weighing institutional experience with HELLP syndrome and neonatal outcomes by gestational age. Because pregnancies before 24 weeks with severe preeclampsia or HELLP have been associated with a dismal perinatal survival, we do not recomm e n d prolonging the pregnancy and risking further maternal morbidity and mortality, a~176 The goal remains maternal safety, and we consider delaying delivery only in those circumstances we believe it would have substantial perinatal impact with reasonable maternal risk. T h e potential for serious maternal morbidity and mortality mandates appropriate supportive care. T h e care for the remainder o f the pregnancy should occur at a tertiary facility able to provide the services potentially required by the m o t h e r and neonate. Severe hypertension should be treated using appropriate anfihypertensives. We often choose the parenteral forms

HELLP Syndrome:Diagnosis and Management

Goal: Maintain BP 140-150/90-100 mm Hg

Labetalol 5-15 rng IV

OR Hydralazine -"

~

5 mg IV

Repeat 5 mg IV in 10.minutes J.

Repeat Every 10-20 minutes Double Dose to 300 mg Total As Needed

Repeat 10 mg IV Every 20 minutes As Needed Maximum 300 mg IV

/

Goal Not Obtained

,l

Consider Alternative Medications: Nitroglycerin (arterial line required) Sodium Nitroprusside Postpartum (arterial line required) Nifedipine Postpartum Figure 2. Parenteral HELLP syndrome.

antihypertensives used

in

of labetalol or hydralazine as a first line to titrate the maternal blood pressure in a safe range below a systolic of 160 m m Hg and diastolic of 110 m m Hg. We maintain the systolic blood pressure between 140 and 150 m m Hg and the diastolic blood pressure between 90 and 100 m m Hg according to Fig 2. Both drugs are effective in lowering blood pressure acutely, with labetalol having a faster onset and hydralazine possibly having a greater impact. 61 Alternatives include sodium nitroprnsside, nitroglycerine, and nifedipine for the treatment of refractory severe hypertension. Patients with HELLP are at increased risk for eclampsia and require seizure prophylaxis. T h e results of recent randomized controlled studies have confirmed the efficacy o f magnesium sulfate in preventing eclamptic seizures. 69'63 We start magnesium sulfate according to our protocol in Fig 3 during the initial evaluation and continue it until the patient shows signs o f recovery postpartum, usually between 24 and 48 hours after delivery. In the setting of significant thrombocytopenia we believe the intravenous route to be preferable to the intramuscular method, be-

127

cause o f the potential for h e m a t o m a formation at the injection site. Close attention to fluid status and parenteral fluids may help prevent pulmonary edema. Central hemodynamic monitoring with a pulmonary artery catheter may be required in the setting of refractory pulmonary e d e m a or oliguria, c'4 One series reported successful pulmonary artery catheter placement in 128 patients with HELLP without complication. 46 T h e n e e d for central monitoring should be made on an individual basis and is not routinely used in our institution. Blood p r o d u c t availability, in the form o f red blood cells, platelets, and clotting factors, must be ensured because the patient may require these emergently. Because prophylactic platelet transfusion was not found to be beneficial in preventing postpartum h e m o r r h a g e and because no study has directly addressed when platelet transfusion is beneficial, we reserve the use o f platelet transfusion for signs o f active bleeding. We have platelets readily available in the operating r o o m for rapid infusion at the time o f all surgical procedures. Fresh frozen plasma, cryoprecipitate, and packed red blood cells are available for immediate release as indicated. Ad-

Bolus Magnesium Sulfate 6 g IV over 15 minutes May be mixed in 100 ml crystalloid (Alternative IV push 20% solution at maximum rate 1 g/min)

Maintenance Magnesium Sulfate 1-3 g/hr IV continuous 40 g MgSO4 9 7H20 in 1,000 ml Ringers Lactate Rate 25-75 ml/hr

Maintain: Reflexes > 1 +

Respiratory Rate > 12/rain Serum Mg Levels 4 - 8 mEq/L if obtained Figure 3. Magnesium sulfate administration in HELLP syndrome.

128

Saphier and Repke

ditional supportive therapy, such as dialysis, may be needed. Amniocentesis has been p e r f o r m e d successfully and routinely by some investigators. 11'17'4~ In this limited experience, there does not appear to be a significantly increased risk associated with amniocentesis, and if an indication exists, one can perform the p r o c e d u r e with apparent safety. We have not used amniocentesis routinely in the setting of HELLP, because we often base our decision on the timing of delivery on the maternal and fetal status rather than on fetal lung indices. We administer corticosteroids for the acceleration of fetal maturation usually based on gestational age, weighing the potential fetal benefits of receiving the medication with the maternal risks o f delaying delivery. Although the optimal route of anesthesia has not been directly studied in HELLP, there is an apparently increased risk for complications associated with epidural anesthesia. In Sibai et al's 11 earlier series o f HELLP syndrome, 1 of 16 patients receiving epidural anesthesia suffered epidural bleeding in the setting o f a platelet count of 93,000/mm 3 and a bleeding time greater than 15 minutes. Although the bleeding stopped spontaneously after 24 hours, and the patient did not suffer long term sequelae, Sibai et al H r e c o m m e n d that epidural anesthesia be avoided in HELLP. Alternative forms of pain control include intrapartum narcotics and general endotracheal anesthesia for cesarean section. Occasionally we consider epidural anesthesia in patients with platelet counts greater than 75,000/mm s and normal clotting and bleeding time studies. The risk of laryngeal e d e m a leading to a difficult or a failed intubation may outweigh the risks of epidural or intrathecal bleeding in such patients. Without further study, definitive recommendations regarding platelet count and the optimal anesthetic cannot be offered. T h e optimal route o f delivery depends on the fetal status, gestational age, and cervical examination findings. The cesarean delivery rate in HELLP syndrome is expectedly high, ranging 30% to 80%. 9'10'45'46'65 Because there is a high rate of growth restriction, placental insufficiency, and abruptio placentae, cesarean sections are p e r f o r m e d frequently for a nonreassuring fetal status. T h e premature gestational age at delivery and the frequency o f an unripe cervix further make a successful induction difficult. Ma-

g a n n e t a165 f o u n d a gestational age before 30 weeks and a Bishop score of less than 2 associated with a significantly higher cesarean section rate, with over three-quarters of the patients with these risk factors undergoing surgical delivery. In this study, a lower platelet count was not associated with a higher cesarean section rate. Until a recent study, Sibai 12 r e c o m m e n d e d a vertical skin incision, liberal use o f drains, and delayed primary skin closure in cesarean section o f patients with HELLP. A study from Sibai's institution found, in their retrospective analysis, no benefit to this specific surgical approach. 66 Their rate o f wound complications was expectedly high, f o u n d to be 25% regardless of incision, use o f drains, or timing of skin closure. In our institution, generally we r e c o m m e n d primary cesarean section for nulliparas with premature gestations before 34 weeks with an unfavorable cervix or in the setting o f suspected growth restriction or placental insufficiency. We determine individually the type of incision and the n e e d for drains, while not routinely delaying the closure o f the incision. As discussed previously, the role of adjuvant therapy for patients with HELLP in the puerperium remains investigational. O u r experience is similar to Sibai et al's 1~ with the majority o f HELLP patients recovering with only supportive therapy. The patient who presents with persistent HELLP or multiple organ system failure requires further evaluation for alternative diagnoses, such as TTP, HUS, and SLE. The use of corticosteroids and plasmapheresis may be considered in these circumstances.

Future Pregnancy Outcome, Contraception, and Preventative Strategies After a pregnancy with HELLP the physician and patient often consider the prospects of future pregnancy outcome, contraceptive options, and potential for prevention. Patients with a history o f HELLP do appear at increased risk for HELLP and preeclampsia recurrence but have several contraceptive choices, and may benefit from preventative strategies in future pregnancies. T h e patient who has completed a pregnancy with HELLP faces the prospect of r e c u r r e n t HELLP in a future pregnancy. Two series have investigated the recurrence o f HELLP, and their

HELLP Syndrome: Diagnosis and Management

Table 3. Subsequent Pregnancy Outcome of HELLP Syndrome Sibai et a167 No Chronic HTN

No. of patients Recurrent HELLP (%) Preeclampsia (%) Preterm delivery (%) IUGR (%)

Sibai et a167 Chronic Sullivan HTN a al ns

192

20

64

3 19

5 75

19 21

21 12

80 45

NS NS

Abbreviations: HTN, hypertension; IUGR, intrauterine growth restriction; NS, not specified. results are summarized in Table 3. 67'68Results of both studies showed an increased risk of recurrent hypertension and preeclampsia in subseq u e n t pregnancies, with a rate approaching 20%. Although Sibai et a167f o u n d a risk of recurrent HELLP to be lower than Sullivan et al's 68 risk, many patients will find the rate acceptably reassuring, between 3% and 19%. Sibai et a167 f o u n d an increased risk of premature delivery and intrauterine growth restriction related to hypertensive disease complicating pregnancy, which was f o u n d to be significantly higher in the group of patients f o u n d to have chronic hypertension. This risk for r e c u r r e n t hypertensive disease in pregnancy resembles the predilection for recurrent preeclampsia in women who have had pregnancies complicated by severe preeclampsia in primigravidas, in the second trimester, or by eclampsia. 69-71Although the risk for recurrence in patients who have had HELLP is increased, the disease often manifests as a milder form if it develops. Although contraception has not been extensively studied after HELLP, the patient and her physician have several options. Barrier methods, such as condoms, diaphragms, and spermicidal foam and jellies are not contraindicated in patients who have had HELLP, because there is no biologic basis for an increased risk in this setting. One study suggested an increased risk of preeclampsia in patients using barrier methods, but did not particularly address multiparous patients with a history o f preeclampsia or HELLP. r2 T h e intrauterine device (IUD) offers long-term, reversible contraception to those patients who are appropriate candidates. P e r m a n e n t sterilization

129

o f the patient or her partner can be offered to those who are certain they have completed their child bearing. T h e limited experience with h o r m o n a l contraceptive methods indicates that oral contraceptives are safe after HELLP. A n u m b e r of case reports have identified patients who developed TTP-HUS while receiving oral contraceptives. 73-76 N o n e of these studies were cohort or case-controlled studies, so the incidence of TTPHUS in users of oral contraceptives has yet to be ascertained. Recurrent HELLP does not appear to occur frequently in oral contraceptive users with a history of HELLP, according to a study by Sullivan et al, 68 which reported oral contraceptive use in 98 such women without any complication. Oral contraceptives do not appear to increase the risk for preeclampsia in subsequent pregnancy. 77 With appropriate monitoring of blood pressure and signs o f other complications, oral contraceptive use appears an acceptable contraceptive choice for the patient with a history of HELLP. T h e r e is little published experience using other h o r m o n a l contraceptive methods in women with a history of HEI J.P. Previously, the estrogen c o m p o n e n t o f oral contraceptives had been thought to be responsible for the possible association with TrP-HUS. Recently, one progestational contraceptive, levonorgestrel implants (Norplant system; Wyeth-Ayerst Laboratories, Philadelphia, PA), has b e e n linked to TI'P-HUS. Norplant has been associated with three cases of T I P and several other cases o f thrombocyopenia reported to the Food and Drug Administration through 1993. 78'79 Although the true incidence o f occurrence or relative risk of T F P occurring a m o n g Norplant users remains unknown, an association may exist. No study to date has investigated the presence o f an association between TI"P-HUS or HELLP with Depot-Medroxyprogesterone (Depo-Provera; Upjohn Company, Kalamazoo, MI), a n o t h e r long-acting progestin marketed in the United States. Until there are valid cohort or case-controlled studies, physicians should exercise caution in prescribing and following up with patients who receive Norplant or Depo-Provera who have a history of HELLP. Although further investigation is n e e d e d to confirm the safety o f h o r m o n a l contraceptive opt.ions, barring any future study causally implicating adverse outcomes from their use, the

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physician and patient can reasonably choose them with close supervision. Efforts to prevent the occurrence and recurrence of preeclampsia and HELLP have been mostly unsuccessful as shown in large randomized trials. The theoretical basis and efficacy of several preventative regimens against preeclampsia have been reviewed,s~ Since this review, several studies have emerged. Attempts at preventing preeclampsia in healthy, nulliparous women have not proven successful in large randomized, placebo-controlled trials using lowdose aspirin and calcium supplements. 81,s9 Although initial reports supported using low-dose aspirin in patients at risk for preeclampsia, recent large randomized, placebo-controlled trials have not confirmed a strong benefit in preventing preeclampsia in those at risk, including a history of past preeclampsia, s~s The lack of benefit has been further confirmed in high-risk patients, including a history of preeclampsia, chronic hypertension, diabetes, and multiple gestation, in a large multicenter, randomized placebo-controlled trial to be published soon by the National Institute of Child Health and Human Development network. The value of lowdose aspirin in preventing recurrent HELLP or preeclampsia in a patient with a history of HELLP remains yet unproven. The efficacy of calcium in high-risk patients remains controversial, although most studies have suggested a beneficial effect. Recent metaanalyses of randomized, placebo-controlled trials using calcium have shown a consistent and significant effect of calcium supplementation (elemental calcium in doses 1.5 to 2.0 g/d) in lowering blood pressure in pregnancy and decreasing the incidence of preeclampsia. 86's7 The discrepancy in results between these previous studies showing benefit and the recent study of healthy, nulliparous patients that did not show benefit, may be explained in patient selection. The studies that show benefit have been generally performed in patients at risk for preeclampsia. For example, calcium supplementation has been successful in significantly decreasing preeclampsia in two recent studies, one study using nulliparous adolescents from Ecuador with deficient baseline dietary calcium intake and the other study in nuUiparous patients in the United States with positive roll-over and angiotension II infusion tests. 88'89 The multicenter study by Le-

vine et als~ showing no benefit was performed in women at low risk for preeclampsia with adequate calcium intake. Importantly, results of this study did not show a significant risk for maternal urolithiasis or neonatal hypocalcemia. We believe that further study isjustified to better clarify the role of calcium supplementation in patients at increased risk for preeclampsia. Until such a benefit is confirmed, we believe that physicians may reasonably consider calcium supplementation in women with a history of HELLP, or otherwise at risk for HELLP or preeclampsia, because calcium supplementation has not been shown to have significant risk.

Conclusion HELLP syndrome has significant maternal and fetal risk of morbidity and mortality. Prompt diagnosis and appropriate treatment is crucial to optimize outcome. Patients with HELLP should be treated in tertiary centers that are prepared to handle the multitude of associated maternal and fetal complications. Because HELLP occurs frequently at premature gestational ages, the obstetrician is faced with deciding the optimal timing and route for delivery. Guidelines for the supportive care before delivery and postpartum have been suggested. Review of the recurrence risk, selection of effective contraception, and consideration of preventative strategies completes the care of a patient who has had HELLP.

References 1. Chesley L: Hypertensive Disorders in Pregnancy (ed 1). New York, NY, Appleton-Century-Crofts, 1978 2. Kitzmiller JL, LangJE, Yelenosky PF, et al: Hematologic assays in pre-eclampsia. Am J Obstet Gynecol 118:362367, 1974 3. Killam AP, Dillard SH, Patton RC, et al: Pregnancy-induced hypertension complicated by acute liver disease and disseminated intravascular coagulation: Five case reports. Am J Obstet Gynecol 123:823-828, 1975 4. Schwartz ML, Brenner WE: Pregnancy-induced hypertension presenting with life-threatening thrombocytopenia. Am J Obstet Gynecol 146:756-759, 1983 5. McKayDG: Hematologic evidence of disseminated intravascular coagulation in eclampsia. Obstet Gynecol Surv 27:399-417, 1972 6. Goodlin RC: Severe pre-eclampsia: Another great imitator. Am J Obstet Gynecol 125:747-753, 1976 7. Goodlin RC, Cotton DB, Haesslein HC: Severe edemaproteinuria-hypertension gestosis. Am J Obstet Gynecol 132:595-598, 1978

ItELLP Syndrome:Diagnosis and Management

8. Weinstein L: Syndrome of hemolysis, elevated liver enzymes, and low platelet count: A severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 142:159-167, 1982 9. Weinstein L: Preeclampsia/eclampsia with hemolysis, elevated liver enzymes, and thrombocytopenia. Obstet Gynecol 66:657-660, 1985 10. Sibai BM, Ramadan MK, Usta I, et al: Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). A m J Obstet Gynecol 169:1000-1006, 1993 11. Sibai BM, Taslimi MM, eI-Nazer A, et al: Maternal-perinatai outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia-eclampsia. Am J Obstet Gynecol 155:501-509, 1986 12. Sibai BM: The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): Much ado about nothing? A m J Obstet Gynecol 162:311-316, 1990 13. MartinJr. JN, FilesJC, Blake PG, et al: Plasma exchange for preeclampsia. I. Postpartum use for persistently severe pre-eclampsia with HELLP syndrome. Am J Obstet Gynecol 162:126-137, 1990 14. Martin JNJr, Blake PG, Perry KGJr, et al: The natural history of HELLP syndrome: Patterns of disease progression and regression. Am J Obstet Gynecol 164:1500-1509, 1991 15. MartinJNJr, FilesJC, Blake PC,, et al: Postpartum plasma exchange for atypical preeclampsia-eclampsia as HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. A m J Obstet Gynecol 172:1107-1125, 1995 16. Audibert F, Friedman SA, Frangieh AY, et al: Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. A m J Obstet Gynecol 175:460-464, 1996 17. MacKennaJ, Dover NL, Brame RG: Preeclampsia associated with hemolysis, elevated liver enzymes, and low platelets-an obstetric emergency? Obstet Gyneco162:751754, 1983 18. Knox TA, Olans LB: Liver disease in pregnancy. N Engl J Med 335:569-576, 1996 19. Samuels P, Cohen AW: Pregnancies complicated by liver diesease and liver dysfunction. Obstet Gynecol Clin North Am 19:745-761, t992 20. Rustgi VK: Liver disease in pregnancy. Med Clin North Am 73:1041-1046, 1989 21. Weiner C: Thrombotic microangiopathy in pregnancy and the postpartum period. Semin Hematol 24:119-129, 1987 22. Egerman RS, Witlin AG, Friedman SA, et al: Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome in pregnancy: Review of 11 cases. Am J Obstet Gynecol 175:950-956, 1996 23. Caggiano V, Fernando LP, SchneiderJM, et al: Thromboric thrombocytopenic purpura: Report of fourteen cases-occurence during pregnancy and response to plasma exchange. J Clin Apheresis 1:71-85, 1983 24. Hayward CP, Sutton DM, Carter WHJr, et al: Treatment outcomes in patients with adult thrombotic thrombocytopenic purpura-hemolyric uremic syndrome. Arch Intern Med 154:982-987, 1994 25. Bell WR, Braine HG, Ness PM, et al: Improved survival

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HELLP Syndrome:Diagnosis and Management

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