CLINICAL OBSTETRICS AND GYNECOLOGY Volume 48, Number 2, 460477 2005, Lippincott Williams & Wilkins

Controversies With the Diagnosis and Management of HELLP Syndrome

JOHN M. OBRIEN, MD and JOHN R. BARTON, MD Perinatal Diagnostic Center, Central Baptist Hospital, Lexington, Kentucky

Introduction
The spectrum of disease resulting from the pathophysiology of preeclampsia continues to challenge the diagnostic acumen of clinicians. One of preeclampsias various manifestations includes the specic entity of HELLP syndrome. Recently, investigators have provided evidence some cases of HELLP syndrome represent a vasculopathy mediated by an abnormal concentration of vascular growth factors.1 However, until the underlying etiology for preeclampsia is better dened and testing for such factors is commonplace, controversies in the diagnosis and management of HELLP syndrome will persist as its numerous clinical ndings will lead to varied inpressions of severity and to varied thresholds for intervention.

Controversies in Diagnosis
The preeclamptic patient with the constellation of hemolysis, hepatic dysfunction, and
Correspondence: John M. OBrien, MD, Director, Perinatal Diagnostic Center, Central Baptist Hospital, 1740 Nicholasville Road, Lexington, KY 40503. E-mail: jobrien@bhsi.com
CLINICAL OBSTETRICS AND GYNECOLOGY /

low platelets has been described in the literature for decades with early accurate descriptions by Prichard et al and Chesley.2,3 It was not until 1982, however, when Weinstein coined the acronym HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) that clinicians could more easily recognize and discuss this group of patients with remarkable hepatic involvement by severe preeclampsia.4 Investigations into the pathophysiology of preeclampsia, and specically HELLP syndrome, have revealed a disorder characterized by hepatic endothelial disruption followed by platelet activation, aggregation, and consumption ultimately resulting in distal ischemia and hepatocyte death.5,6 This vasculopathy can be limited to a hepatic segment or occur diffusely throughout the liver. Most commonly, HELLP syndrome involves smaller terminal arterioles yielding a process with characteristic histologic features. The classic hepatic lesion associated with HELLP syndrome is periportal or focal parenchymal necrosis in which hyaline deposits of brin-like material can be seen
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Controversies With HELLP Syndrome in the sinusoids.79 Alternatively and less frequently, larger-vessel disease can impact wider vascular distributions in the liver with more catastrophic outcomes such as hepatic infarction or subcapsular hematoma. This rare large-vessel disease is more readily visible by imaging studies such as magnetic resonance imaging (MRI) or computed tomography (CT) scanning and is associated with worse laboratory values indicating more dramatic hepatic dysfunction.10 The greatest controversy involving HELLP syndrome is in the diagnosis of the condition. The syndrome outlined by Weinstein in the early 1980s provided a description of the disease process and gave clinicians an easier framework to understand the pathophysiology. Namely, his group of 29 patients with severe preeclampsia/eclampsia manifested more pronounced hepatic involvement rather than primarily cerebral or renal disease. Later, Sibai et al established laboratory criteria for the diagnosis and provided standards for subsequent discussions in the literature (see Table 1).11 In his classication, Sibai dened laboratory abnormalities sufcient for the diagnosis of each element of the syndrome: hemolysis by an abnormal peripheral smear, elevated bilirubin .1.2 mg/dL, or elevated lactate dehydrogenase (LDH) .600 U/L; elevated liver enzymes by an aspartate aminotransferase (AST) .70 IU/L (which was greater than 2 standard deviations of normal) and lactate dehydrogenase (LDH) .600 U/L; and low platelets dened as 100,000/mm3, as this value was standard in other elds of medicine.
TABLE 1.
11

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Martin et al also attempted to classify the disease noting an increase in untoward outcomes, including cardiopulmonary, central nervous system, and renal dysfunction, as the degree of thrombocytopenia worsened.12 In their retrospective review of 302 cases of HELLP syndrome, they dened class 1 HELLP syndrome as a platelet nadir below 50,000/mm3, whereas those with platelet nadirs between 51,000 and 100,000/mm3 were dened as class 2. Class 3 HELLP syndrome represented a newly classied group of patients with hepatocyte death but a higher platelet count nadir, 101,000 to 150,000/mm3. In this series, thrombocytopenia in women with HELLP syndrome was found to represent a marker for more extensive endothelial disruption and hepatocyte death as peak aminotransferase values correlated well with platelet nadirs. Still others have offered differing criteria for the diagnosis of HELLP syndrome to Sibais and Martins, each assessing varying degrees of hepatic involvement as evidenced by liver function test abnormalities to represent thresholds for diagnosis (see Table 1).13,14 Despite the best of intentions, these differing depictions of HELLP syndrome with differing criteria for platelet count and liver function test abnormalities have created a rationale for questioning ndings of individual reports and have likely confused clinicians. Compared with the 1980s, when Weinstein rst coined the term, HELLP syndrome and its variants are now more commonly recognized earlier when platelet consumption yields

Classications of HELLP Syndrome

Platelet Count AST $70 $40 .50 .30 U/L U/L U/L U/L LDH $600 U/L $600 U/L .600 U/L *
3

Sibai et al Martin et al12 van Pampus13 Visser and Wallenburg14

,100,000/mm ,150,000/mm3 ,100,000/mm3 ,100,000/mm3

* Not included in their criteria. Reprinted from Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol. 2004;103:981991. AST, aspartate aminotransferase; LDH, lactic dehydrogenase.

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OBrien and Barton For diagnostic criteria to be most useful, they should be based on objective criteria, testing should be readily available, and the results of these tests should not be subject to interpretation. These criteria should also attempt to identify earlier stages of the disease process rather than limiting the diagnosis to a small subset of only the most severe cases. Finally, the denitions should be easy to use for the clinician. The diagnosis of HELLP syndrome is made by laboratory parameters alone, although supporting typical ndings of preeclampsia, including hypertension and proteinuria, help rule out other potential imitators (see the next section on differential diagnosis). Laboratory evaluation should include a complete blood count with platelet count, a peripheral smear, coagulation studies, serum AST, creatinine, glucose, bilirubin, and LDH levels. Ideally, the laboratory parameters for HELLP syndrome should be intuitive,easytoremember,andconsistentbetween laboratories. Of the laboratory studies routinely obtained for diagnostic purposes, platelet count and liver function tests are the best standardized and can fulll these criteria. The platelet count historically used to diagnose thrombocytopenia is ,100,000/mm3 and is the threshold most consistent across all specialties of medicine. The liver function tests prole we use is that presented by Sibai as AST or ALT . 2 times the upper limit of normal or 70 U/L. To assess the degree of hemolysis, we do not evaluate peripheral smears ourselves or ask hematologists/pathologists to provide middle-of-thenight evaluations. We do use an LDH value to give an indication for hemolysis as suggested by Sibai. We are also cognizant, however, that an elevated LDH, most of the time, also reects hepatocyte destruction in addition to hemolysis. Therefore, in our opinion, a complete blood count and metabolic prole are readily available, rapidly performed tests, which allow recognition and denition of severe involvement of liver parenchyma by preeclampsia. The alphabet soup present

milder degrees of thrombocytopenia and elevated liver function tests document hepatic ischemia. It appears, however, the same pathophysiology is ongoing whether the patient has evidence of thrombocytopenia and elevated liver function tests alone or whether schistocytes are present in the peripheral smear, the serum bilirubin is elevated, or other abnormalities such as coagulopathy or renal insufciency have unfolded. With greater involvement of the endothelium of the liver by preeclampsia, more red blood cells are hemolyzed and more hepatic ischemia results with the combination yielding higher bilirubin levels and impaired coagulation studies. Thus, the primary controversy in the diagnosis of HELLP syndrome has been in precisely dening when in the spectrum of the hepatic involvement with preeclampsia does the true HELLP syndrome develop. Some patients have been termed as having partial HELLP syndrome, ELLP syndrome, or class 3 HELLP syndrome. These women are also at risk for significant maternal and fetal morbidity as a result of this same pathophysiology despite criticisms that elements of the true disease may be missing. In a study by Van Pampus et al, 10% of women with ELLP syndrome were identied as having serious complications, including eclampsia, cerebral ischemia, and abruptio placentae compared with a 24% rate for women with true HELLP.13 In a study by Abramovici et al, the rate of fetal distress (13% vs. 18%) and intrauterine growth restriction (28% vs. 31%) was lower in women with HELLP syndrome versus the partial HELLP group.15 These data do not demonstrate that a sufciently different outcome occurs in patients with hepatic involvement by preeclampsia to justify subdividing these patients into minute subclassications. Unfortunately, it appears once severe preeclampsia has manifested remarkable end-organ involvement, adverse renal, central nervous system, and pulmonary complications can arise and should be anticipated.

Controversies With HELLP Syndrome in the literature attempting to differentiate HELLP versus ELLP versus EL versus HEL syndrome, or partial HELLP versus HELLP, is of limited value when attempting to treat a patient identied with signicant hepatic involvement from severe preeclampsia. We anticipate that expert groups focused on the care for women with hypertensive disorders in pregnancy can better dene the clinical condition of hepatic involvement by preeclampsia and eliminate the current confusion and controversy.

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Differential Diagnosis
Sibai has noted that most patients with HELLP syndrome present preterm with hypertension, and proteinuria, and report epigastric or right upper quadrant pain.16 Unfortunately, however, other patients present with only nausea or vomiting, and still others may have nonspecic viral-like symptoms. In Weinsteins second report,17 nausea or vomiting and epigastric pain were the most common symptoms. A pregnant woman in the late second or early third trimester with right upper quadrant pain, epigastric pain, or identied hepatic dysfunction should be considered as having HELLP syndrome until other elements of the differential diagnosis are excluded (see Table 2). Epigastric pain may antedate the

TABLE 2.

Medical and Surgical Disorders Potentially Confused With HELLP Syndrome

Hyperemesis gravidarum Idiopathic thrombocytopenia Kidney stones Peptic ulcer Pyelonephritis Systemic lupus erythematosus Thrombotic thrombocytopenic purpura Viral hepatitis

Acute fatty liver or pregnancy Appendicitis Cholestasis of pregnancy Diabetes insipidus Gallbladder disease Gastroenteritis Glomerulonephritis Hemolytic uremic syndrome Hepatic encephalopathy

laboratory abnormalities of HELLP syndrome by several hours, leading clinicians to question initial impressions. Symptoms of upper quadrant pain without laboratory abnormalities may lead errantly to diagnoses of gastritis or gallbladder disease. Reevaluation of laboratory studies in 4 to 6 hours after onset of symptoms usually conrms an initial clinical suspicion of HELLP syndrome. Patients with HELLP syndrome frequently demonstrate signicant weight gain with generalized edema. However, severe hypertension (systolic blood pressure $160 mm Hg, diastolic blood pressure $110 mm Hg) is not a constant nding in HELLP syndrome. Although 69% of the 112 patients studied by Sibai et al had a diastolic blood pressure $110 mm Hg at admission to the hospital, 15% had a diastolic blood pressure of #90 mm Hg. In Weinsteins5 initial report, less than half (13) had an admission blood pressure $160/110 mm Hg. Thus, hypertension is not obligatory to diagnose HELLP syndrome. More signicant renal involvement by preeclampsia compared with hepatic disease appears better correlated with the severity of hypertension. Once laboratory abnormalities sufcient to diagnose HELLP syndrome are observed, other hepatopathies may be considered and eliminated as possibilities. Concomitant hypoglycemia, coagulopathy, elevated ammonia level, and renal dysfunction are associated with acute fatty liver of pregnancy. Cerebral dysfunction, fever, and rash may be part of thrombotic thrombocytopenic purpura. Hemolytic uremic syndrome is primarily a renal disease in children and is related to infection with Escherichia coli. In adults, almost all cases develop in the postpartum period. Exacerbation of systemic lupus erythematosus with nephritis can also mimic severe preeclampsia. The clinical manifestations and laboratory ndings of the various conditions presented in Table 2 can be differentiated from severe preeclampsia. Occasionally, however, the time course of the condition and prompt postpartum resolution of laboratory studies are the

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OBrien and Barton list for the management of the condition provides an orderly sequential approach. The clinical course of women with HELLP syndrome is usually characterized by progressive and sometimes sudden deterioration in maternal and fetal conditions. Therefore, patients with suspected diagnosis of HELLP syndrome should be hospitalized immediately and observed in a labor and delivery unit. The rst priority is to assess and stabilize the maternal condition, particularly coagulation abnormalities. Patients with HELLP syndrome who are remote from term should be referred to a tertiary care center. Such patients should be managed as having severe preeclampsia and should initially receive intravenous (IV) magnesium sulfate as prophylaxis against seizures and antihypertensive medications to keep systolic blood pressure below 160 mm Hg and/or diastolic blood pressure below 105 mm Hg.19 This can be achieved with a 5-mg bolus dose of hydralazine, to be repeated as needed every 15 to 20 minutes for a maximum dose of 20 mg per hour. Blood pressure is recorded every 15 minutes during therapy and every hour once the desired values are achieved. If hydralazine does not lower blood pressure adequately and/or if maternal side effects such as tachycardia or headaches develop, another drug such as labetalol or nifedipine can be used. The recommended dose of labetalol is 20 to 40 mg IV every 10 to 15 minutes for a maximum of 220 mg over 1 hour, and the dose of nifedipine is 10 to 20 mg orally every 30 minutes for a maximum dose of 50 mg over 1 hour. During the observation period, maternal and fetal conditions are assessed. The recommended regimen of magnesium sulfate is a loading dose of 6 g given over 20 minutes followed by a maintenance dose of 2 g per hour as a continuous IV solution. Magnesium sulfate is initiated at the beginning of the observation period and then continued during labor and for at least 24 hours postpartum. The next step is to evaluate fetal well-being using the nonstress

only means to determine the etiology for maternal disease. Finally, clinicians should be familiar with the various endothelial vascular organs that can be affected by preeclampsia. Although involvement in the renal and hepatic vessels is most common, other vessels potentially affected include the cerebral, cardiac, and pulmonary. Involvement by this vasculopathy of these organs can yield concomitant eclampsia, myocardial dysfunction, and pulmonary edema, and acute respiratory distress syndrome, adding to the diagnostic challenges.

Management Controversies
The diagnosis of HELLP syndrome has long been recognized as heralding the need for aggressive, standardized therapies, including magnesium sulfate administration, antihypertensive therapy, and delivery to reduce associated maternal morbidity and mortality (see Table 3).18 Several critical steps are involved in the management of these cases and are summarized in Figure 1. This check-

TABLE 3.

Serious Maternal Complications in 442 Patients With HELLP Syndrome

No. 92 69 33 32 26 26 4 4 4 4 3 4 Percent 21 16 8 8 6 6 1 1 1 1 1 1

Complication Disseminated intravascular coagulopathy Abruptio placentae Acute renal failure Severe ascites Pulmonary edema Pleural effusions Cerebral edema Retinal detachment Laryngeal edema Subcapsular liver hematoma Acute respiratory distress syndrome Death, maternal

Reprinted from Sibai BM. Diagnosis and management of gestational hypertension and preeclampsia. Obstet Gynecol. 2003; 102:181192.

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465

FIGURE 1.

Checklist in the management of HELLP syndrome.

test or biophysical prole, as well as to obtain ultrasonographic biometry for assessment of possible intrauterine growth retardation. Finally, a decision must be made as to whether immediate delivery is indicated.

Steroids and the Management of HELLP Syndrome

Several retrospective studies have demonstrated glucocorticoids can also impact the

maternal condition in patients with HELLP syndrome, thereby adding another newer intervention to this armementarium.2024 Five randomized trials comparing the use of high-dose dexamethasone with either no treatment21,22,25,26 or with betamethasone27 in women with presumed HELLP syndrome were summarized by Sibai28 and are presented in Table 4. The results of these studies demonstrate improved laboratory values and urine output in patients receiving

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OBrien and Barton

Randomized Trials of Corticosteroids In Women With ELLP Or HELLP Syndrome
Dexamethasone (no.)
21

TABLE 4.
Authors Magann et al

Control (no.) 13 20 17 15 21

Key Finding Improved platelet, ALT, LDH values in dexamethasone group Improved platelet, AST, LDH, urine output, MAP in dexamethasone group Improved platelet counts only with dexamethasone Improved platelet, AST, MAP, and urine output with dexamethasone Improved AST, LDH, MAP, and urine output with dexamethasone

12* 20 17 15 19*

Magann et al22 Vigil-De Gracia25 Yalcin et al26 Isler et al27

* Antepartum. Postpartum. Received intramuscular betamethasone. Reprinted from Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol. 2004;103:981991. ELLP, elevated liver enzymes and low platelets; AST, aspartate amino transferase; ALT, alanine amino transferase; LDH, lactic dehydrogenase; MAP, mean arterial pressure.

dexamethasone, but provide limited evidence of reduced maternal morbidity. However, because most of these trials were performed postpartum, the true extent glucocorticoids can inuence outcomes has yet to be determined. The mechanism of action of this drug is unknown but appears to alter the nal steps in endothelial cell disruption as evidenced by steroids having the ability to improve laboratory values postpartum when presumably the ability to synthesize new mediators of disease is limited after delivery of the placenta. Because HELLP syndrome is characterized by the endothelial damage within the liver, we can only surmise glucocorticoids act to minimize the degree of intravascular endothelial injury within the body, improve blood ow within the liver specically, and halt ongoing hepatocyte death and platelet consumption. Because glucocorticoids are the only known drugs to improve the maternal laboratory ndings in cases of severe preeclampsia, we use this observation in our management. Our dosing of the medication is directed not only to improve neonatal outcomes by lowering the incidence of such complications as respiratory distress syndrome and

intraventricular hemorrhage, but also to attempt to reduce maternal morbidity. The dose, route of administration, and duration of treatment of glucocorticoids is important and has varied between studies. These aspects of therapy still require further study with properly controlled trials, but some information is evident from the literature. First, intravenous glucocorticoids appear to have a more rapid onset of action compared with intramuscular dosing. The randomized trial by Isler et al demonstrated intravenous dosing was superior to intramuscular dosing for several outcome variables, including improving urine output and greater improvement in laboratory values.27 Second, glucocorticoids improve the maternal condition in a dose-dependent manner. In a review of data collected at our center, we observed maternal platelet count increased more dramatically before delivery with a high-dose protocol of glucocorticoids versus standard regimens used for enhancing lung maturity.24 We therefore use this high-dose protocol in our management of patients with severe maternal disease (see Table 5). Finally, the duration of action of this medication is limited and patients may experience a worsening of their laboratory

Controversies With HELLP Syndrome

TABLE 5. High-Dose Glucocorticoid Therpy to Improve Laboratory Abnormalities in Patients With HELLP Syndrome

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For most patients with HELLP syndrome, 10 mg intravenous dexamethasone every 6 hours for 2 doses followed by 6 mg intravenous dexamethasone every 6 hours for 2 additional doses. For select patients at highest risk, including those with profound thrombocytopenia (,20,000/mm3) or with central nervous system dysfunction (ie, blindness, paralysis), 20 mg intravenous dexamethasone every 6 hours for up to 4 doses.

studies 48 to 72 hours after dosing with glucocorticoids.23,24 We term this nding the rebound phenomenon. Steroid treatment, therefore, is not curative but may create a window of opportunity for intervention before the maternal condition may again deteriorate. During the period when the maternal status is being optimized, adequate but not excessive hydration of the patient is performed, laboratory studies are followed to observe the expected response, and the fetal status is intermittently reassessed. Because glucocorticoids do not appear to alter the underlying pathophysiology, delivery remains the only denitive therapy. We do not proceed with expectant management of HELLP syndrome beyond an appropriate interval to optimize the maternal status and obtain fetal exposure to the drug (2448 hours). Furthermore, if no improvement in the clinical or laboratory status is noted within 8 to 12 hours of administration of the medication, we reevaluate the diagnosis considering other conditions such as acute fatty liver, consider increasing the dose of glucocorticoid, consider transfusion, and expedite delivery. With this information, we have created owsheets for the management of antepartum and postpartum HELLP syndrome (see Figs. 2A and B). Understanding the goals of therapy are essential to optimal outcomes and are 2-fold: 1) to improve the ma-

ternal status immediately before and during delivery if needed, and 2) in women ,35 weeks, to provide glucocorticoid exposure to the fetus for enhancement of fetal lung maturation. We believe that glucocorticoids may be used for maternal benet even if the patient has previously received this medication for fetal lung maturity in the current pregnancy. We therefore attempt to delineate maternal versus fetal indications for the use of glucocorticoids in patients with HELLP syndrome. An increase in maternal platelet count before delivery can alter management by potentially minimizing bleeding complications. For instance, with treatment, we have observed a signicant increase in the use of regional anesthesia in those women with HELLP syndrome exposed to glucocorticoids for 24 hours compared with women who did not receive this therapy or achieve this latency period.29 We therefore coordinate our efforts with our anesthesiologists before effecting delivery, attempting to maximize the maternal platelet count and thereby increase the use of regional anesthesia. Regional anesthesia has been shown to avoid complications of exacerbated hypertension, aspiration, and failed intubation attributable to general anesthesia in this population. We have given glucocorticoids at any gestational age to address maternal disease because such a benet may exist in term gestations. However, the use of highdose dexamethasone to improve maternal outcome in women with HELLP syndrome beyond 34 weeks gestation and/or in the postpartum period remains experimental. A latency period before effecting delivery is not appropriate or necessary in all cases of HELLP syndrome but is required to expect a benet from glucocorticoid administration. If the gestational age is $35 weeks, the patient is asymptomatic, and the platelet count is sufcient to offer any type of anesthesia, we proceed promptly with delivery and do not suggest a latency period for glucocorticoids to impact the maternal status. Alternatively, the

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OBrien and Barton enhancing fetal maturity. Except for variables pertaining to HELLP syndrome, clinical and laboratory data and median prolongation of pregnancy did not differ between the groups. Perinatal mortality was 14.1% in patients with HELLP syndrome and 14.8% in patients without HELLP. Because the perinatal outcomes in this study are similar to studies performed in the United States where delivery was affected within 48 hours of the diagnosis of HELLP syndrome, the benet of temporizing management of HELLP syndrome remains questionable. Ultimately, only a well-designed randomized trial will resolve this management issue. The described conservative management techniques were often associated with the use of invasive procedures and numerous medical and surgical treatments. These confounding variables make it difcult to evaluate any treatment modality proposed for this syndrome. Occasionally, some patients without true HELLP syndrome may demonstrate antepartum reversal of hematologic abnormalities after bedrest, the use of steroids, or plasma volume expansion. However, in our experience, the majority of these patients demonstrate progressive deterioration in either maternal or fetal condition. The potential risks associated with conservative management of HELLP syndrome include abruptio placentae, pulmonary edema, acute renal failure, eclampsia, perinatal death, and maternal death. Therefore, because only a limited prolongation of pregnancy can be expected and because no difference in fetal survival with aggressive attempts at expectant management has been observed, we caution against expectant management beyond a 24- to 48-hour latency to optimize the maternal status for delivery. We should specically caution women with disseminated intravascular coagulation (DIC) should not be expectantly managed.

fetal status may not allow for expectant management and a sufcient latency period to optimize both the fetal and maternal condition. If a nonreassuring fetal assessment is observed, we consider initiating our steroid protocol when the maternal disease is severe. We proceed with delivery and expect the impact of our therapy to begin postpartum.

Conservative Management
Prolonging the latency period beyond 48 hours from the time of the diagnosis of HELLP syndrome to delivery is controversial. van Pampus et al described the clinical progress and maternal outcome of the HELLP and ELLP (ndings of HELLP syndrome but without evidence of hemolysis) syndrome in 127 patients managed in the Academic Medical Center in Amsterdam between 1984 and 1996 with a live fetus in utero.13 The patients were treated by temporizing management, including the use of antihypertensives and magnesium sulfate. The predominant indication for terminating pregnancy was fetal distress or fetal death and not maternal condition. All serious maternal complications occurred at the onset of the syndrome (24% of cases with HELLP syndrome vs. 10% with ELLP). Two mothers with HELLP syndrome died after a cerebral hemorrhage. Seventy-nine (62%) of women were not delivered after 3 days and 65 (51%) after 7 days. Although the authors noted it is unlikely that a more aggressive approach would have reduced maternal mortality or morbidity, their sample size was inadequate to evaluate rare serious maternal complications of HELLP or ELLP syndrome. In a study by Visser and Wallenburg,14 128 consecutive preeclamptic patients with HELLP syndrome and a gestational age less than 34 weeks gestation were matched for maternal and gestational age with 128 preeclamptic patients without HELLP syndrome. Both groups were treated with volume expansion and pharmacologic vasodilatation under invasive hemodynamic monitoring with the aim of prolonging gestation and

Transfusion
Platelet transfusions are indicated either before or after delivery in all patients with

Controversies With HELLP Syndrome

469

FIGURE 2. A, Flowchart for antepartum HELLP syndrome. B, Flowchart for postpartum management of HELLP syndrome.

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OBrien and Barton plications, including postpartum hemorrhage, vaginal/labial hematoma for vaginal delivery, wound hematomas/separation for cesarean delivery, and infection resulting from prolonged induction. The choice between attempted vaginal delivery versus cesarean section should be based on assessment of various predictors for success of an attempted induction, including 1) cervical status, 2) fetal heart rate tracing or biophysical prole, and 3) umbilical artery Doppler studies. We have observed a very poor success rate for attempted induction in the face of a preterm gestation with intrauterine growth restriction and markedly abnormal Doppler studies. We proceed directly to cesarean section under such circumstances.31 Briggs et al32 evaluated wound complications between patients with antepartum HELLP syndrome with primary closure versus delayed closure and Pfannenstiel versus midline skin incisions. A total of 104 patients were identied; 75 had a primary skin closure and 29 had a delayed closure 48 to 72 hours postoperatively. Immediate wound complications (wound infection, hematoma) occurred in 18 (26%) patients who had primary closure versus 8 (24%) who had a delayed closure (odds ratio, 1.13; 95% condence interval, 0.393.27). A late wound breakdown was seen in only 1 patient with primary closure but in none with delayed closure. No statistical difference in wound complication was found between midline (primary or delayed) and Pfannenstiel (primary, delayed) incisions (odds ratio, 0.65; 95% condence interval, 0.231.88). The authors concluded that for women with antepartum HELLP syndrome delivered by cesarean section, the frequency of wound complications is not inuenced by type of skin incision or time of skin closure (primary or delayed). Generalized oozing from any operative site is very common in thrombocytopenic patients. To minimize the risk of hematoma formation, the bladder ap should be left open and a subfascial drain may be used for 24 to 48 hours. A subcutaneous drain may also be considered if the skin is

HELLP syndrome in the presence of significant bleeding from puncture sites, wound, intraperitoneal, extensive ecchymosis, and so on. Furthermore, transfusion is indicated in all antepartum patients whose platelet count is less than 20,000/mm3. Correction of profound thrombocytopenia is particularly important before cesarean section. Repeated platelet transfusions, however, may not be necessary because consumption occurs rapidly and the effect is transient. Our policy is to administer 6 to 10 units of platelets in all patients with a platelet count less than 40,000/mm3 before intubating the patient for cesarean section. Platelets are the most commonly transfused blood component in patients with HELLP syndrome. However, red cells and fresh-frozen plasma may also be needed in patients with more severe coagulopathies. The need for transfusion may be reduced by optimizing the patients status before delivery and reducing the severity of thrombocytopenia. Martin et al have demonstrated a reduction in the rate for transfusion of both cellular components and plasma in patients exposed to dexamethasone over 2 epochs.30 The association between dexamethasone exposure and a reduced rate of transfusion has also been noted by our group. The decision to delay delivery to improve the maternal platelet count by steroid exposure is again dependent on several aspects of the clinical situation, including fetal status. A large, multicenter, placebo-controlled, randomized trial of patients with markedly thrombocytopenic, antepartum HELLP syndrome would be necessary to quantitate the potential benet of reduced need for transfusion after steroid exposure. Such a trial does not appear to be forthcoming, however, especially when considering the fetal benets to glucocorticoid administration for lowering the rate of complications of prematurity.

Delivery Controversies
Delivery of a patient with HELLP syndrome is associated with numerous potential com-

Controversies With HELLP Syndrome approximated attempting to minimize the incidence of wound complications. Subcutaneous tissues should be approximated with sutures as evidenced by randomized trials and metaanalysis for skin closure at cesarean delivery.33

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Controversies in Management of Subcapsular Hematoma

The most dramatic sequelae of hepatic involvement by preeclampsia is the development of segmental hepatic infarction, extensive parenchymal hemorrhage, or subcapsular hematoma. Hepatic imaging ndings in selected patients with HELLP syndrome can identify these abnormalities.10 Rupture of a subcapsular hematoma is particularly concerning because it can lead to death by exsanguination from the inability to control bleeding as a result of surgical difculties with repair of the liver and coagulopathy. Of the 34 patients evaluated by Barton and Sibai, 16 patients (47%) had abnormal hepatic imaging results. The most common CT abnormalities were subcapsular hematoma of the liver (n = 13) and intraparenchymal hemorrhage (n = 6). Comparison of the clinical characteristics and laboratory evaluations of patients with normal and abnormal hepatic imaging ndings demonstrated a signicant difference in platelet count nadir between the patients with normal and abnormal imaging ndings but failed to show any statistically signicant difference in gestational age, mean arterial pressure, or the other laboratory parameters studied. Of the 13 patients with severe thrombocytopenia (platelet count ,20,000/mm3), 10 (77%) had abnormal hepatic imaging ndings. Emergency intervention was needed for 6 patients on the basis of these imaging ndings. CT and MRI have excellent sensitivity for detecting acute liver hemorrhage, but because CT was more available, faster, and safer for potentially unstable patients, and hence was the imaging modality of choice.

The differential diagnosis of an unruptured subcapsular hematoma of the liver in pregnancy should include acute fatty liver of pregnancy, abruptio placentae with disseminated intravascular coagulation, ruptured uterus, or sepsis. Most patients with a subcapsular hematoma of the liver are seen in the late second or third trimester of pregnancy, although cases have been reported in the immediate postpartum period. Patients typically report right upper quadrant pain, but localized pain may be absent. Stimulation of the phrenic nerve at the diaphragm can produce referred pain along this nerves distribution to its origin in the C4C5 cervical plexus, including the pericardium, peritoneum, pleura, and shoulder. Physical examination ndings consistent with peritoneal irritation and hepatomegaly may be present. Surgical repair has been recommended for hepatic hemorrhage without liver rupture. More recent experience suggests, however, this complication should be managed conservatively in patients who remain hemodynamically stable.34,35 Management should include close monitoring of hemodynamics and coagulation status. Serial assessment of the subcapsular hematoma with ultrasound or CT is necessary with immediate intervention for rupture or worsening of maternal status. It is important with conservative management to avoid exogenous sources of trauma to the liver such as abdominal palpation, convulsions, or emesis, and to use care in transportation of the patient. Indeed, any sudden increase in intraabdominal pressure could potentially lead to rupture of the subcapsular hematoma.36 In most instances, rupture of a subcapsular hematoma involves the right lobe and is preceded by the development of a parenchymal hematoma. Patients frequently present with shoulder pain, shock, or evidence of massive ascites, respiratory difculty, or pleural effusions, and often with a dead fetus. An ultrasound or computed axial tomography of the liver should be performed to rule out the presence of subcapsular hematoma of the liver and assess for the presence of intraperitoneal

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OBrien and Barton nessee, Memphis, 4 patients with HELLP syndrome were complicated by a ruptured subcapsular hematoma.18 Three cases required transfusion of 22 to 40 units of packed red blood cells and multiple units of platelets and fresh-frozen plasma. Two of these 3 cases were complicated by pulmonary edema and acute renal failure, but all survived without any residual deciency. The fourth case was a patient who presented in profound shock and with disseminated intravascular coagulopathy. This patient subsequently died secondary to a ruptured pulmonary emphysematous bleb during management of adult respiratory distress syndrome.

bleeding. Paracentesis conrms the presence of intraperitoneal hemorrhage suspected by examination or hepatic imaging. The presence of ruptured subcapsular liver hematoma resulting in shock is a surgical emergency requiring acute multidisciplinary treatment. Resuscitation should consist of massive transfusions of blood, correction of coagulopathy with fresh-frozen plasma and platelets, and immediate laparotomy. Options at laparotomy include packing and drainage (preferred), surgical ligation of the hemorrhaging hepatic segments, embolization of the hepatic artery to the involved liver segment, and loosely suturing omentum or surgical mesh to the liver to improve integrity. Even with appropriate treatment, maternal and fetal mortality is over 50%. Mortality is most commonly associated with exsanguination and coagulopathy. Initial survivors are at increased risk for developing adult respiratory distress syndrome, pulmonary edema,37 and acute renal failure in the postoperative period.38 Smith et al39 reviewed their management of 7 patients with spontaneous rupture of the liver occurring during pregnancy. Of the 4 survivors, the mean gestational age was 32.8 weeks and the mean duration of hospitalization was 16 days. All the survivors managed with packing and drainage of the liver survived, whereas the 3 patients treated with hepatic lobectomy died. The authors also extracted 28 cases from the literature reported since 1976. From a total of 35 cases, 27 patients (82%) managed by packing and drainage survived, whereas only 25% of 8 patients undergoing hepatic lobectomy survived. The authors emphasized hepatic hemorrhage with persistent hypotension unresponsive to transfusion of blood products may be managed surgically with laparotomy, evacuation of the hematoma, packing of the damaged liver, and draining of the operative site. In certain cases in which the patient is stable enough to undergo angiography, transcatheter embolotherapy is a reasonable alternative to surgery.40 In a review of 442 cases of HELLP syndrome managed at the University of Ten-

TABLE 6.

Management of Patients With Subcapsular Hematoma of the Liver

General considerations: I. Have the blood bank aware of the potential need for large amounts of packed red blood cells, fresh-frozen plasma, and platelet concentrate (ie, 30 units of blood, 20 units of fresh-frozen plasma, 3050 units of platelets) II. Consultation of a general or vascular surgeon III. Avoid direct and indirect manipulation of the liver IV. Close monitoring of hemodynamic status V. Intravenous magnesium sulfate to prevent seizures If the hematoma is unruptured: I. Conservative management with serial computed tomography scans or ultrasound If the hematoma is ruptured and patient hemodynamically unstable: I. Massive transfusions II. Immediate laparotomy A. If bleeding is minimal: 1. Observation 2. Draining area with closed suction B. If bleeding is severe: 1. Application of laparotomy sponges as packs for pressure 2. Embolization of the hepatic artery to the involved liver segment

Controversies With HELLP Syndrome On the basis of review of the literature, an outline for the management of hepatic complications of HELLP syndrome was developed (Table 6). This outline emphasizes the potential for transfusion of large amounts of blood and blood products and the need for aggressive intervention if rupture of the hematoma is suspected and the patient is hemodynamically unstable. We recommend 30 units of packed red blood cells, 20 units of fresh-frozen plasma, 30 to 50 units of platelets, and 20 to 30 units of cryoprecipitate be available if rupture of a subcapsular hematoma is suspected. Our experience is in agreement with the recent observations of Smith et al39 in that a stable patient with an unruptured subcapsular hematoma should be conservatively managed. Constant monitoring must continue during this management, however, because patients can rapidly become unstable after rupture of the hematoma. Survival clearly is associated with rapid diagnosis and immediate medical or surgical stabilization. Coagulopathy must be aggressively managed. These patients should be managed in an intensive care unit with close monitoring of hemodynamic parameters and uid status to avoid pulmonary edema or respiratory compromise.

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Postpartum Management
The diagnostic criteria for HELLP syndrome may develop antepartum or postpartum. Sibai and associates18 revealed that 70% had evidence of the syndrome antepartum, and 30% developed the criteria postpartum. In the postpartum period, the time of onset ranged from a few hours to 7 days, with the majority developing within 48 hours after delivery. Patients in this group are at increased risk for the development of pulmonary edema with acute renal failure.37,38 HELLP syndrome may be diagnosed postpartum following 1 of 3 clinical scenarios: 1) worsening of antepartum severe preeclampsia with delivery not yet altering the time course of the disease, 2) new onset of severe preeclampsia postpartum, or 3) re-

bound deterioration of a patient with antepartum HELLP syndrome after exposure to corticosteroid antepartum. The goals of therapy postpartum differ compared with antepartum and are aimed solely at improving the maternal status. Management of seizure prophylaxis is similar to the antepartum patient with HELLP syndrome, including the need for magnesium sulfate. Hypertension control may be more aggressive, however, because there is no longer concern about compromising the uteroplacental circulation. Blood pressure goals of systolic blood pressure ,155 mm Hg and/or diastolic blood pressure ,105 mm Hg are suggested. After delivery, the patient should be monitored closely in an intensive care setting for 24 to 48 hours. Most patients show evidence of resolution of the disease process within 48 hours after delivery. The differential diagnosis of postpartum hypertension and proteinuria should include thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, and exacerbation of systemic lupus. These alternative diagnoses may be considered if resolution of the disease is prolonged. However, some patients with HELLP syndrome, especially those with DIC, may demonstrate delayed resolution or even deterioration. Such patients may require longer, intensive monitoring. These patients are at risk for developing pulmonary edema as a result of transfusions of blood and blood products, uid mobilization, and compromised renal function.38 As a result of the persistent potential for adverse outcomes postpartum, several reports have advocated the use of corticosteroids to more promptly restore vascular integrity. In a retrospective study, Martin et al41 reported the puerperal courses of 43 women with postpartum HELLP syndrome who were treated with dexamethasone and compared them with 237 similar patients who did not receive corticosteroids. Dexamethasone at a dosage of 10 mg IV at 12-hour intervals was given until disease remission was noted in treated patients, at which time

474

OBrien and Barton the 9 patients in group 1 responded rapidly to 1 or 2 plasma exchange procedures with few complications and no maternal deaths. In contrast, in the 9 patients in group 2 with HELLP syndrome presentations complicated by other end-organ disease, the response to plasma exchange was variable and there were 2 deaths in this group. This series details the postpartum application of plasma exchange therapy for unremitting HELLP syndrome, but reveals that a uniformly positive response to this therapy is not observed when there is additional single or multiple organ injury.44 Potential adverse effects of this plasma exchange include plasma-transmitted infections, anaphylaxis, volume overload, sepsis, and maternal death.

up to 2 additional 5-mg IV doses were given at 12-hour intervals. Patients who received dexamethasone for postpartum-onset HELLP syndrome experienced a shorter disease course, faster recovery, less morbidity, and less need for other interventionist therapy compared with a historical group of patients with HELLP syndrome who did not receive dexamethasone. Postpartum patients with delayed resolution of HELLP syndrome (including persistent severe thrombocytopenia) represent a management dilemma. Exchange plasmapheresis with fresh-frozen plasma has been advocated as a treatment by some authors.4244 Because the majority of these patients will have spontaneous resolution of their disease, early initiation of plasmapheresis may result in unnecessary treatment. Schwartz44 suggested serial studies indicating a progressive elevation of bilirubin or creatinine associated with hemolysis and thrombocytopenia may be an indication for plasmapheresis. Martin and coworkers42 reported the use of plasma exchange with fresh-frozen plasma in 7 women in the postpartum period with HELLP syndrome that persisted .72 hours after delivery. All patients had persistent thrombocytopenia, rising lactic dehydrogenase, and evidence of multiorgan dysfunction. The authors recommended that a trial of plasma exchange with fresh-frozen plasma be considered in HELLP syndrome that persists past 72 hours from delivery and in which there is evidence of a life-threatening microangiopathy. Since their publication, however, the Mississippi group has reviewed 18 patients with HELLP syndrome who were treated postpartum with single or multiple plasma exchange with fresh-frozen plasma.43 Each patient was entered into the clinical trial either because of persistent evidence of atypical preeclampsiaeclampsia as HELLP syndrome .72 hours after delivery (group 1) or with evidence of worsening HELLP syndrome at any time postpartum in association with single- or multiple-organ injury (group 2). In the absence of other disease conditions,

Maternal Counseling
Pregnancies complicated by HELLP syndrome are associated with life-threatening complications for both the mother and her infant. Therefore, clinicians should be able to answer questions regarding subsequent pregnancy outcome and long-term prognosis. Women with a history of HELLP syndrome are at increased risk of all forms of preeclampsia in subsequent pregnancies. In general, the rate of preeclampsia in subsequent pregnancies is approximately 20% with signicantly higher rates if the onset of HELLP syndrome was in the second trimester. The rate of recurrent HELLP syndrome ranges from 2% to 19%. We quote a recurrence risk of less than 5%.4547 Because of these risks, these women are informed that they are at increased risk for adverse pregnancy outcome (preterm delivery, fetal growth restriction, abruptio placentae, and fetal death) in subsequent pregnancies. Therefore, they require close monitoring during subsequent gestations. Currently, there is no preventive therapy for recurrent HELLP syndrome. Liver function tests were studied in 54 women at a median of 31 months (range, 3101 months) after pregnancies complicated by the HELLP syndrome.48 Serum levels of AST, LDH, and conjugated bilirubin

Controversies With HELLP Syndrome were found to be normal. Total bilirubin levels, however, were elevated in 11 (20%) of the studied women. The authors of this report suggested the possibility that a dysfunction of the bilirubin-conjugating mechanism represents a risk factor for the development of this syndrome.48 There are 2 reports describing longterm renal function after HELLP syndrome.38,49 One of the reports included 23 patients whose pregnancies were complicated by HELLP syndrome and acute renal failure; 8 of these women had 11 subsequent pregnancies with 9 resulting in term gestation.38 All 23 women also had normal blood pressures and renal function at an average follow up of 4.6 years (range, 0.511 years). The other study compared renal function after at least 5 years after HELLP syndrome in 10 patients with the respective ndings in 22 patients with previous normotensive gestation.49 There were no differences in renal function tests between the 2 groups. These ndings suggest that the development of HELLP syndrome with or without renal failure does not affect long-term renal function.

475

ing. Delivery is the ultimate cure, and optimizing the status of a seriously ill patient before delivery improves outcome.

References
1. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350:672683. 2. Pritchard JA, Weisman R, Ratnoff OD, et al. Intravascular hemolysis, thrombocytopenia and other hemologic abnormalities associated with severe toxemia of pregnancy. N Engl J Med. 1954;250:8998. 3. Chesley LC. Disseminated intravascular coagulation. In: Hypertensive Disorders in Pregnancy. New York: Appleton-CenturyCrofts; 1978:88118. 4. Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol. 1982;142: 159167. 5. Roberts JM, Cooper DW. Pathogenesis and genetics of pre-eclampsia. Lancet. 2001; 357:5356. 6. Roberts JM. Preeclampsia, what we know and what we do not know. Semin Perinatol. 2000;24:2428. 7. Barton JR, Riely CA, Adamel TA, et al. Hepatic histopathologic condition does not correlate with laboratory abnormalities in HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). Am J Obstet Gynecol. 1992;167:15381543. 8. Aarnoudse JG, Houthoff HF, Weits J, et al. A syndrome of liver damage and intravascular coagulation in the last trimester of normotensive pregnancy. A clinical and histopathological study. Br J Obstet Gynaecol. 1986;93: 145155. 9. Arias F, Mancilla-Jimenez R. Hepatic brinogen deposits in pre-eclampsia. Immunouorescent evidence. N Engl J Med. 1976;295: 578582. 10. Barton JR, Sibai BM. Hepatic imaging in HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). Am J Obstet Gynecol. 1996;174:18201827. 11. Sibai BM, Taslimi MM, El-Nazer A, et al. Maternal-perinatal outcome associated with the syndrome of hemolysis, elevated

Summary
Signicant hepatic involvement by preeclampsia leading to hepatocyte necrosis and thrombocytopenia should alarm the clinician regardless of whether criteria for HELLP syndrome have been fully achieved. Liver parenchyma is relatively unforgiving of the endovascular insult presented by severe preeclampsia. This vasculopathy can result in adverse maternal outcomes such as DIC, subcapsular hematoma, hepatic infarction, and death. The greatest challenges in caring for women with this disease are appreciating the diagnosis, instituting timely interventions, and avoiding associated complications. The addition of high-dose glucocorticoids to the armamentarium of therapy for HELLP syndrome may improve outcomes for both the mother and fetus, but denitive proof by randomized trials is lack-

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