Gestational Hypertension

Hypertension may be present before pregnancy, or it may be diagnosed for the first time during pregnancy. In addition, in some women, hypertension may become evident only during labor or during the postpartum period. For clinical purposes, women with hypertension may be classified into one of the three categories listed above; these are described further in Table 31-1 . Recently, the diagnosis of PE and its subtypes have been expanded and revised by the members of the American College of Obstetricians and Gynecologists (ACOG) Task Force on Hypertension in Pregnancy :

• •
  

  Systolic BP greater than 140 mm Hg but less than 160 mm Hg or

  
  
• •
  

  Diastolic BP greater than 90 mm Hg but less than 110 mm Hg and

  
  
• •
  

  These pressures must be observed on at least two occasions 4 hours apart but no more than 7 days apart.

Severe Hypertension

Severe hypertension refers to sustained elevations in systolic BP to at least 160 mm Hg and/or in diastolic BP to at least 110 mm Hg for at least 4 hours or once if the patient is receiving oral antihypertensive agents or received intravenous (IV) antihypertensive medications prior to the 4-hour period.

Proteinuria

Proteinuria may also be present before pregnancy, or it may be newly diagnosed during pregnancy. The definition of proteinuria is the same no matter when it occurs:

• •
  

  Greater than 0.3 g in a 24-hour urine collection or protein/creatinine (P/C) ratio greater than 0.3. If it is not possible to measure 24-hour protein or P/C ratio, proteinuria can be defined as a dipstick measurement of at least 1+ on two occasions.

  
  
• •
  

  Protein excretion in the urine increases in normal pregnancy from approximately 5 mg/dL in the first and second trimesters to 15 mg/dL in the third trimester. These low levels are not detected by dipstick. The concentration of urinary protein is influenced by contamination with vaginal secretions, blood, bacteria, or amniotic fluid. It also varies with urine specific gravity and pH, exercise, and posture.

  
  
• •
  

  Proteinuria usually appears after hypertension in the course of the disease process, but in some women, it may appear before hypertension.

Edema

Edema is defined as excessive weight gain (>4 lb [1.8 kg] in 1 week) in the second or third trimester, and it may be the first sign of the potential development of PE. However, 39% of patients with eclampsia do not have edema.

Preeclampsia and Eclampsia

Preeclampsia is gestational hypertension (GH) plus proteinuria. Box 31-1 lists criteria for diagnosis of GH and PE. The ACOG Task Force on Hypertension in Pregnancy Group classifies PE based on whether it is has severe features. The term mild preeclampsia has been removed from the ACOG classification system and should not be used in clinical practice.

It is recognized that some women with GH may have undiagnosed chronic hypertension, whereas others will subsequently progress to develop the clinical syndrome of preeclampsia. In general, the likelihood of progression to PE depends on gestational age at time of diagnosis, with higher rates if the onset of hypertension is before 35 weeks’ gestation ( Fig. 31-1 ).

Rate of progression from gestational hypertension to preeclampsia by gestational age at diagnosis.

(Data from references .)

Chronic Hypertension

Chronic hypertension is defined as hypertension present prior to pregnancy or that is diagnosed before 20 weeks of gestation. Hypertension that persists for more than 3 months postpartum is also classified as chronic hypertension.

Gestational Hypertension

Gestational hypertension is the most frequent cause of hypertension during pregnancy. The incidence ranges between 6% and 29% in nulliparous women and between 2% and 4% in multiparous women. The incidence is markedly increased in patients with multiple gestations. In general, most cases of GH develop at or beyond 37 weeks’ gestation, and thus the overall pregnancy outcome is usually similar to that seen in women with normotensive pregnancies ( Table 31-3 ). However, women with mild GH have higher rates of induction of labor.

Maternal and perinatal morbidities are substantially increased in women with severe GH. Indeed, these women have increased risk for morbidity compared with women with mild PE. The rates of abruptio placentae, preterm delivery (at <37 and 35 weeks), and small-for-gestational-age (SGA) infants in these women are similar to those seen in women with PE and severe features. It remains unclear whether this increase in preterm delivery is secondary to scheduled early delivery according to physician preference or whether it occurs because of a disease process.

Atypical Preeclampsia

The criteria for atypical preeclampsia include gestational proteinuria or FGR plus one or more of the following symptoms of preeclampsia: hemolysis, thrombocytopenia, elevated liver enzymes, early signs and symptoms of preeclampsia-eclampsia earlier than 20 weeks, and late postpartum preeclampsia-eclampsia (>48 hours postpartum).

Capillary Leak Syndrome: Facial Edema, Ascites and Pulmonary Edema, and Gestational Proteinuria

Hypertension is considered to be the hallmark for the diagnosis of preeclampsia. However, in some patients with PE, the disease may manifest as either a capillary leak (proteinuria, facial and vulvar edema, ascites, pulmonary edema); excessive weight gain, particularly during the second and early third trimester; or a spectrum of abnormal hemostasis with multiple-organ dysfunction. These women usually present with clinical manifestations of atypical preeclampsia, such as proteinuria with or without facial edema, vulvar edema ( Fig. 31-4 ), excessive weight gain (>4 lb/wk), ascites, or pulmonary edema in association with abnormalities in laboratory values or presence of symptoms but without hypertension. Therefore we recommend that women with capillary leak syndrome with or without hypertension be evaluated for platelet, liver enzyme, and renal abnormalities. Those with symptoms such as new onset of unrelenting severe headache, severe visual disturbances, or abnormal blood tests should be considered to have PE.

Vulvar edema in severe preeclampsia.

Risk Factors for Preeclampsia

Several factors have been identified with increased risk for preeclampsia ( Box 31-2 ). Generally, PE is considered a disease of primigravid women. The risk increases in those who have limited sperm exposure with the same partner before conception. The protective effects of long-term sperm exposure with the same partner might provide an explanation for the high risk for PE in women younger than 20 years old. A previous abortion (spontaneous or induced) or a previous normal pregnancy with the same partner is associated with a lower risk for PE. However, this protective effect is lost with a change of partner or with prolonged interval between pregnancies.

Both Scandinavian and U.S. studies have confirmed the importance of paternal factors as a contributor to PE as well as an interpregnancy interval greater than 7 years. Using whole population data, Lie and colleagues demonstrated that men who fathered one preeclamptic pregnancy were nearly twice as likely to father a preeclamptic pregnancy with a different woman (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2 to 2.6 after adjustment for parity), regardless of whether the new partner had a history of a preeclamptic pregnancy. Thus mothers had a substantially increased risk in their second pregnancy (2.9%) if their partner had fathered a preeclamptic first pregnancy with another woman. This risk was nearly as high as the average risk among primigravid women.

Recent advances in assisted reproductive technology (ART) have been associated with an increased risk for preeclampsia. Among the factors cited are a greater proportion of women older than 40 years, infertile women during their first gestation, multifetal gestation, obese women with polycystic ovary syndrome (PCOS), and women who become pregnant with donated gametes or embryos. The use of donated gametes can influence the maternal-fetal immune interaction. In addition, infertile women with recurrent miscarriage are also reported to be at increased risk for PE.

Obesity reflected as increased body mass index (BMI) heightens the risk for preeclampsia. The worldwide increase in obesity is thus likely to lead to a rise in the frequency of PE. Obesity has a strong link to insulin resistance, which is also a risk factor for PE. The exact mechanism by which obesity or insulin resistance is associated with PE is not well understood.

Earlier studies found an overall higher rate of thrombophilia in women with PE compared with controls. Recently, a number of reports have failed to reproduce these findings. The disparity in results may reflect the heterogeneity of the women being studied. In the largest series of preeclamptic women with thrombophilia, women had increasing risk for very early onset, severe disease (delivery before 28 weeks) compared with those who did not have thrombophilia.

Pathophysiology

The etiology of preeclampsia remains unknown. Many theories have been suggested, but most of them have not withstood the test of time. Some of the theories still under consideration are listed in Box 31-3 .

During normal pregnancy, impressive physiologic changes occur in the uteroplacental vasculature and in the cardiovascular system. These changes are most likely induced by the interaction of the fetal (parental) allograft with maternal tissue. The development of mutual immunologic tolerance in the first trimester is thought to lead to important morphologic and biochemical changes in the systemic and uteroplacental maternal circulation.

Uterine Vascular Changes

The human placenta receives its blood supply from numerous uteroplacental arteries that are developed by the action of migratory interstitial and endovascular trophoblasts into the walls of the spiral arterioles . This transforms the uteroplacental arterial bed into a low-resistance, low-pressure, high-flow system. The conversion of the spiral arterioles of the nonpregnant uterus into the uteroplacental arteries has been termed physiologic changes . In a normal pregnancy, these trophoblast-induced vascular changes extend all the way from the intervillous space to the origin of the spiral arterioles that represent the radial arteries in the inner one third of the myometrium. It is suggested that these vascular changes are effected in two stages, “the conversion of the decidual segments of the spiral arterioles by a wave of endovascular trophoblast migration in the first trimester and the myometrial segments by a subsequent wave in the second trimester.” This process is reportedly associated with extensive fibrinoid formation and degeneration of the muscular layer in the arterial wall. These vascular changes result in the conversion of about 100 to 150 spiral arterioles into distended, tortuous, and funnel-shaped vessels that communicate through multiple openings into the intervillous space.

In contrast, pregnancies complicated by preeclampsia or by FGR demonstrate inadequate maternal vascular response to placentation. In these pregnancies, the previously mentioned vascular changes are usually found only in the decidual segments of the uteroplacental arteries. Hence the myometrial segments of the spiral arterioles continue to exhibit their characteristic musculoelastic architecture, thereby leaving them responsive to hormonal influences. Additionally, the number of well-developed arterioles is smaller than that found in normotensive pregnancies.

It has been postulated that this defective vascular response to placentation is due to inhibition of the second wave of endovascular trophoblast migration that normally occurs from about 16 weeks’ gestation onward. These pathologic changes may have the effect of curtailing the increased blood supply required by the fetoplacental unit in the later stages of pregnancy and may correlate with the decreased utero­placental blood flow seen in most cases of preeclampsia . Frusca and associates studied placental bed biopsy specimens obtained during cesarean delivery from normal pregnancies ( n = 14), preeclamptic pregnancies ( n = 24), and chronic hypertensive pregnancies only ( n = 5). Biopsy specimens from the preeclamptic group demonstrated abnormal vascular changes in every case, and 18 had acute atherosclerotic changes. In contrast, 13 of the 14 specimens from normotensive pregnancies had normal vascular physiologic changes. In addition, they found that the mean birthweight was significantly lower in the group with atherosclerosis than it was in the other group without such findings. It is important to note that these vascular changes may also be demonstrated in a significant proportion of normotensive pregnancies complicated by FGR. Meekins and associates demonstrated that endovascular trophoblast invasion is not an all-or-none phenomenon in normal and preeclamptic pregnancies. These authors observed that morphologic features found in one spiral artery may not be representative of all vessels in a placental bed.

Vascular Endothelial Activation and Inflammation

The mechanism by which placental ischemia leads to the clinical syndrome of PE is thought to be related to the production of placental factors that enter the maternal circulation and result in endothelial cell dysfunction. Soluble fms-like tyrosine kinase 1 (sFlt-1) is a protein produced by the placenta. It acts by binding to the receptor-binding domains of vascular endothelial growth factor (VEGF), and it also binds to placental-like growth factor (PLGF). Increased levels of this protein in the maternal circulation results in reduced levels of free VEGF and free PLGF with resultant endothelial cell dysfunction.

Maternal serum and placental levels of sFlt-1 are increased in pregnancies complicated by preeclampsia values above seen during normal pregnancies. Maynard and coworkers demonstrated that soluble placenta-derived VEGF receptor (sFlt-1)—an antagonist of VEGF and PLGF—is unregulated in PE, which leads to increased systemic levels of sFlt-1 that fall after delivery. Increased circulating sFlt-1 in PE is associated with decreased circulating levels of free VEGF and PLGF and results in endothelial dysfunction. The magnitude of increase in sFlt levels correlates with disease severity, which lends further support to VEGF–soluble Flt balance and represents one of the final common pathophysiologic pathways.

First-trimester PLGF levels are decreased in future preeclamptic pregnancies and in pregnancies complicated by FGR, whereas sFlt levels do not differ from controls. Again, these data are compatible with decidual angiogenic growth factors, in particular PLGF, as being essential for early placental development (PLGF is low in both FGR and preeclampsia), with a later involvement of sFlt as a fetal rescue signal steering the maternal response; that is, the degree of maternal systemic hypertension. This hypothesis is supported by Levine and colleagues, who demonstrated that during the last 2 months of pregnancy in normotensive controls, the level of sFlt-1 increased and the level of PLGF decreased.

Levine and associates investigated urinary PLGF levels in pregnant women with and without PE and found that among normotensive pregnant women, urinary PLGF increased during the first two trimesters, peaked at 29 to 32 weeks, and decreased thereafter. Among women who ultimately developed PE, the pattern of urinary PLGF was similar, but levels were significantly reduced beginning at 25 to 28 weeks. Particularly large differences were seen among those who subsequently developed early-onset PE and in those who delivered SGA infants. A similar study suggested that urinary angiogenic factors can identify women with severe PE.

During the past decade, our understanding of the molecular basis for the pathophysiologic abnormalities in preeclampsia has reached an unprecedented level. Clear appreciation now exists for the role of cell adhesion molecules (CAMs) and angiogenic proteins and for activation of the inflammatory system in the pathogenesis of microvascular dysfunction in women with PE. Evidence also suggests an exaggerated inflammatory response (abnormal cytokine production and neutrophil activation) in women with the clinical findings of PE. However, this enhanced inflammatory response is absent before the development of PE.

Recent studies that have confirmed increased levels of asymmetric dimethylarginine at 23 to 25 weeks in pregnant women who develop PE have emphasized the importance of the nitric oxide–cyclic guanosine monophosphate (cGMP) pathway. Endothelial dysfunction and inappropriate endothelial cell activation associated with alterations in nitric oxide levels in PE explains most typical clinical manifestations, including the increased endothelial cell permeability and increased platelet aggregation.

Genetics and Genetic Imprinting

According to the genetic conflict theory, fetal genes are selected to increase the transfer of nutrients to the fetus, whereas maternal genes are selected to limit transfer in excess of some optimal level. The phenomenon of genomic imprinting means that a similar conflict exists within fetal cells between genes that are maternally derived and those that are paternally derived. The conflict hypothesis suggests that placental factors (fetal genes) act to increase maternal BP, whereas maternal factors act to reduce BP. Endothelial cell dysfunction may have evolved as a fetal rescue strategy to increase nonplacental resistance when the uteroplacental blood supply is inadequate.

Nilsson and associates published a model that suggests a heritability estimate of 31% for PE and 20% for GH. It is unlikely that one major PE gene will be found because such a gene would be selected against through evolution, unless it also carried a major reproductive advantage. It is more likely that a rapidly growing number of susceptibility genes will be uncovered and that many of these will be found to interact with the maternal cardiovascular-hemostatic system or in the regulation of maternal inflammatory responses. These loci segregate with different populations, and it should be noted that these loci only explain a relatively small percentage of the overall cases of PE. In addition, although these linkage studies indicate maternal susceptibility, they do not exclude the additional involvement of fetal genes. Another important consideration regarding the genetics of PE is the confounding effect of the so-called fetal origins of adult disease hypothesis, which suggests that a hostile intrauterine environment for a female fetus would form the basis for the insulin resistance syndrome with its associated endothelial dysfunction and, as such, that it would lead to an increased risk for PE (see Chapter 5 ).

Epigenetic features and imprinting are also involved in the pathogenesis of PE. Further evidence of the role of imprinting was recently suggested by Oudejans and van Dijk and Nafee and associates.

Changes in Prostanoids

Several investigators have described levels of the various prostaglandins and their metabolites throughout pregnancy. They have measured the concentrations of these substances in plasma, serum, amniotic fluid, placental tissues, urine, and cord blood. The data have been inconsistent, which reflects differences in methodology. During pregnancy, prostanoid production increases in both maternal and fetoplacental tissues. Prostacyclin is produced by the vascular endothelium and in the renal cortex. It is a potent vasodilator and inhibitor of platelet aggregation. Thromboxane A ₂ (TXA ₂ ) is produced by the platelets and trophoblasts; it is a potent vasoconstrictor and platelet aggregator. Hence, these eicosanoids have opposite effects and play a major role in regulating vascular tone and vascular blood flow. An imbalance in prostanoid production or catabolism has been suggested as being responsible for the pathophysiologic changes in preeclampsia. However, the precise role by which prostaglandins are involved in the etiology of PE remains unclear.

Lipid Peroxide, Free Radicals, and Antioxidants

Evidence is accumulating that lipid peroxides and free radicals may be important in the pathogenesis of preeclampsia. Superoxide ions may be cytotoxic to the cell by changing the characteristics of the cellular membrane and producing membrane lipid peroxidation. Elevated plasma concentrations of free radical oxidation products precede the development of PE. In addition, some studies reported lower serum antioxidant activity in patients with PE than in those with normotensive pregnancies.

Much of the controversy about oxidative stress is related to the nonspecificity of the markers. A recent study by Moretti and associates measured oxidative stress “on line” in exhaled breath (not subjective to in vitro artifacts) and confirmed greater oxidative stress in women with PE compared with nonpregnant controls and those who had uncomplicated pregnancies.

Diagnosis of Preeclampsia

Preeclampsia is a clinical syndrome that embraces a wide spectrum of signs and symptoms that have been clinically observed to develop alone or in combination. Elevated BP is the traditional hallmark for diagnosis of the disease. The diagnosis of PE and the severity of the disease process are generally based on maternal BP. Many factors may influence the measurement of BP, including the accuracy of the equipment used, the size of the sphygmomanometer cuff, duration of the rest period before recording, posture of the patient, and the Korotkoff phase used (phase IV or phase V for diastolic BP measurement). It is recommended that all BP values be recorded with the woman in a sitting position for ambulatory patients or in a semireclining position for hospitalized patients. The right arm should be used consistently, and the arm should be in a roughly horizontal position at heart level. For diastolic BP measurements, both phases—muffling sound and disappearance sound—should be recorded. This is very important because the level measured at phase IV is about 5 to 10 mm Hg higher than that measured at phase V. A rise in BP has been used by several authors as a criterion for the diagnosis of hypertension in pregnancy. This definition is usually unreliable because a gradual increase in BP from the second to third trimester is seen in most normotensive pregnancies. Villar and Sibai prospectively studied BP changes during the course of pregnancy in 700 young primigravidas and found that 137 patients (19.6%) had PE. The sensitivity and positive predictive values for PE of a threshold increase in diastolic BP of at least 15 mm Hg on two occasions were 39% and 32%, respectively. The respective values for a threshold increase in systolic pressures were 22% and 33%.

Three recent studies from New Zealand, the United States, and Turkey investigated pregnancy outcomes in women with a rise in diastolic BP of more than 15 mm Hg but an absolute diastolic level below 90 mm Hg compared with gravidas who remained normotensive. The New Zealand report and a Turkish study included women with elevated BPs without proteinuria, whereas the American investigation included women with an increased diastolic pressure by 15 mm Hg or more plus proteinuria (≥300 mg/24 hours). Overall, pregnancy outcomes were similar among women who remained normotensive and those who demonstrated a rise in diastolic pressure of 15 mm Hg or higher but did not reach 90 mm Hg. The use of a specific rise in BP over baseline as a diagnostic criterion is principally influenced by two factors: gestational age at time of first observation and frequency of BP measurements. Thus a 15 mm Hg rise in diastolic BP is unreliable to diagnose PE.

Prediction of Preeclampsia

A review of the world literature reveals that more than 100 clinical, biophysical, and biochemical tests have been recommended to predict or identify the patient at risk for future development of preeclampsia. The results of the pooled data for the various tests and the lack of agreement among serial tests suggest that none of these clinical tests is sufficiently reliable for use as a screening test in clinical practice.

Numerous biochemical markers have been proposed to predict which women are destined to develop PE. These biochemical markers were generally chosen on the basis of specific pathophysiologic abnormalities that have been reported in association with PE. Thus these markers have included markers of placental dysfunction, endothelial and coagulation activation, angiogenesis, and markers of systemic inflammation. However, the results of various studies to evaluate the reliability of these markers in predicting PE have been inconsistent, and many of these markers suffer from poor specificity and predictive values that are too low for routine use in clinical practice.

During the past decade, several prospective and nested case-control studies have found that certain maternal risk factors, biophysical clinical factors, and serum biomarkers obtained in the first trimester are associated with subsequent development of hypertensive disorders of pregnancy (HDP), GH, or PE. These studies evaluated the use of these factors or markers alone or in combination, and they provided detection rates for various subtypes of hypertension and PE with a false-positive rate (FPR) of either 5% or 10%. Overall, neither the maternal factors nor the serum biomarkers, either alone or combined, had an adequate detection rate for either all HDPs or GH or PE developing at 37 weeks of gestation or later. In the same studies, using maternal factors and mean arterial pressure (MAP) in the first trimester, the detection rate for PE before 34 weeks was 73%, and for PE before 37 weeks, it was 60% with an FPR of 10%. Using data from the Maternal-Fetal Medicine Foundation, the use of combined maternal factors and biophysical and biochemical markers increased the detection rate to 95% for PE that required delivery before 34 weeks of gestation and 77% for PE that required delivery at before 37 weeks of gestation with an FPR of 10%. However, the positive predictive value (PPV) for such a screen remained less than 10%. In addition, these studies were conducted in a heterogeneous group of women at various risks for HDP and PE. A recent study by Giguère and colleagues evaluated combined maternal factors and serum markers measured in the first trimester in 7929 women who were at very low risk for GH (2.7%) and PE (1.8%). In those with PE, the incidence was 0.2% at less than 34 weeks and 1.2% at less than 37 weeks of gestation. They found that a clinical model that included maternal risk factors, BMI, and MAP had a detection rate of 54% and a PPV of 3% with an FPR of 10% for preeclampsia at less than 37 weeks of gestation, whereas a full model that also included serum biomarkers had a detection rate of 39% and a PPV of 2% for PE at less than 37 weeks of gestation.

Based on the results of this study and other reports in recent years, it is clear that evaluation of maternal clinical factors and other biophysical and biomarkers measured in the first trimester is useful only for the prediction of those who will ultimately progress to PE that will require delivery prior to 34 weeks of gestation. However, given the poor PPV for PE before 34 weeks and the poor detection rates for all cases of GH and PE, the clinical indications for a PE screening test in the first trimester remain unclear. Currently, no prospective studies or randomized trials have evaluated the benefits and risks of first-trimester screening for prediction of PE. Until then, the use of such tests for screening should remain investigational.

Doppler ultrasound is a useful method to assess uterine artery blood flow velocity in the second trimester. An abnormal uterine artery velocity waveform is characterized by a high resistance index or by the presence of an early diastolic notch (unilateral or bilateral). Pregnancies complicated by abnormal uterine artery Doppler findings in the second trimester are associated with more than a sixfold increase in the rate of PE . However, the sensitivity of an abnormal uterine artery Doppler for predicting PE ranges from 20% to 60% with a PPV of 6% to 40%. Current data do not support Doppler studies for routine screening of pregnant women for PE, but uterine artery Doppler could be beneficial as a screening test in women at very high risk for PE if an effective preventive treatment should become available.

The ACOG task force report on hypertension in pregnancy recommends only using risk factors for identifying women considered at increased risk for PE.

Prevention of Preeclampsia

Numerous clinical trials describe the use of various methods to prevent or reduce the incidence of preeclampsia. Because the etiology of the disease is unknown, these interventions have been used in an attempt to correct theoretic abnormalities in PE. A detailed review of these trials is beyond the scope of this chapter; however, the results of these studies have been the subject of several recent systemic reviews. In short, randomized trials have evaluated protein or salt restriction; zinc, magnesium, fish oil, or vitamin C or E supplementation; the use of diuretics and other antihypertensive agents; and the use of heparin to prevent PE in women with various risk factors. These trials have had limited sample sizes, and results have revealed minimal to no benefit. Some of the methods studied are summarized in Box 31-4 .

Laboratory Abnormalities in Preeclampsia

Women with preeclampsia may exhibit a symptom complex that ranges from minimal BP elevation to derangements of multiple-organ systems. The renal, hematologic, and hepatic systems are most likely to be involved.

Hemolysis, Elevated Liver Enzymes, and Low Platelets (HELLP) Syndrome

Considerable debate surrounds the definition, diagnosis, incidence, etiology, and management of HELLP syndrome. Patients with such findings were previously described by many investigators. Weinstein considered it a unique variant of PE and coined the term HELLP syndrome for this entity. Barton and associates performed liver biopsies in patients with PE and HELLP syndrome, and periportal necrosis and hemorrhage were the most common histopathologic findings. In addition, they found that the extent of the laboratory abnormalities in HELLP syndrome, including the platelet count and liver enzymes, did not correlate with hepatic histopathologic findings.

Laboratory Criteria for Diagnosis

Various diagnostic criteria have been used for HELLP. Hemolysis, defined as the presence of microangiopathic hemolytic anemia, is the hallmark of the triad of HELLP syndrome. The classic findings of microangiopathic hemolysis include an abnormal peripheral smear (schistocytes, burr cells, echinocytes), elevated serum bilirubin (indirect form), low serum haptoglobin levels, elevated lactate dehydrogenase (LDH) levels, and a significant drop in hemoglobin levels. A significant percentage of published reports included patients who had no evidence of hemolysis; hence, these patients will not fit the criteria for HELLP syndrome. In some studies in which hemolysis is described, the diagnosis is suspect because it has been based on the presence of an abnormal peripheral smear (no description of type or degree of abnormalities) or elevated LDH levels (threshold of 180 to 600 U/L).

No consensus exists in the literature regarding the liver function test to be used or the degree of elevation in these tests to diagnose elevated liver enzymes. In his original report, Weinstein mentioned abnormal serum levels of aspartate transaminase (AST), abnormal alanine transaminase (ALT), and abnormal bilirubin values; however, specific levels were not suggested. In subsequent studies in which elevated liver enzymes were described, either AST or ALT, the values considered to be abnormal ranged from 17 to 72 U/L. In clinical practice, many of these values are considered normal or slightly elevated.

Low platelet count is the third abnormality required to establish the diagnosis of HELLP syndrome; no consensus has been reached among various published reports regarding the diagnosis of thrombocytopenia. The reported cut-off values have ranged from 75,000/mm ³ to 279,000/mm ³ , and a level of less than 100,000/mm ³ is most often cited.

Many authors have used elevated total LDH (usually >600 U/L) as a diagnostic criteria for hemolysis. Of the five isoforms of LDH, only two of them—LDH ₁ and LDH ₂ —are released from ruptured red blood cells. In most women with severe preeclampsia-eclampsia, the elevation in total LDH is probably caused mostly by liver ischemia. Therefore many authors advocate that elevated bilirubin values (indirect form), abnormal peripheral smear, or a low serum haptoglobin level should be part of the diagnostic criteria for hemolysis.

Based on a retrospective review of 302 cases of HELLP syndrome, Martin and colleagues devised the following classification based on the nadir of the platelet count. Class 1 HELLP syndrome was defined as a platelet nadir below 50,000/mm ³ , class 2 as a platelet nadir between 50,000 and 100,000/mm ³ , and class 3 as a platelet nadir between 100,000 and 150,000/mm ³ . These classes have been used to predict the rapidity of recovery postpartum, maternal-perinatal outcome, and the need for plasmapheresis.

Hemolysis, defined as the presence of microangiopathic hemolytic anemia, is the hallmark of HELLP syndrome. The role of disseminated intravascular coagulation (DIC) in preeclampsia is controversial. Most authors do not regard HELLP syndrome to be a variant of DIC because coagulation parameters such as PT, PTT, and serum fibrinogen are normal. However, the diagnosis of DIC can be difficult to establish in clinical practice. When sensitive determinants of this condition are used—such as antithrombin III, fibrinopeptide A, fibrin monomer, D-dimer, α ₂ -antiplasmin, plasminogen, prekallikrein, and fibronectin—many patients have laboratory values consistent with DIC. Unfortunately, these tests are time consuming and are not suitable for routine monitoring. Consequently, less sensitive parameters are often used. Sibai and associates defined DIC as the presence of thrombocytopenia, low fibrinogen levels (plasma fibrinogen <300 mg/dL), and fibrin split products above 40 mg/mL. These authors noted the presence of coagulopathy in 21% of 442 patients with HELLP syndrome. They also found that most cases occurred in women who had antecedent placental abruption or peripartum hemorrhage, and it occurred in all four women in their study who had subcapsular liver hematomas. In the absence of these complications, the frequency of DIC was only 5%.

In view of the previously mentioned diagnostic problems, we recommended that uniform and standardized laboratory values be used to diagnose HELLP syndrome. Plasma haptoglobin and bilirubin values should be included in the diagnosis of hemolysis. In addition, the degree of abnormality of liver enzymes should be defined as a certain number of standard deviations (SDs) from the normal value for each hospital population. Our laboratory criteria to establish the diagnosis are presented in Box 31-5 .

Box 31-5

Criteria to Establish the Diagnosis of Hellp Syndrome

• 
  

  Hemolysis (as least two of these):

  
  
  
  
  • •
    

    Peripheral smear (schistocytes, burr cells)

    
    
  • •
    

    Serum bilirubin (≥1.2 mg/dL)

    
    
  • •
    

    Low serum haptoglobin

  
  
  
  
• 
  

  Severe anemia unrelated to blood loss

  
  
• 
  

  Elevated liver enzymes

  
  
  
  
  • •
    

    Aspartate transaminase or alanine transaminase at least twice the ULN

    
    
  • •
    

    Lactate dehydrogenase twice or more of the ULN

  
  
  
  
• 
  

  Low platelets (<100,000/mm ³ )

HELLP, hemolysis, elevated liver enzymes, and low platelets; ULN, upper limit of normal.

Clinical Findings

The reported incidence of HELLP syndrome in preeclampsia has been variable, which reflects the differences in diagnostic criteria. The syndrome appears to be more common in white women and is also more common in preeclamptic women who have been managed conservatively.

Early detection of HELLP syndrome can be a challenge in that many women present with nonspecific symptoms or subtle signs of PE. The various signs and symptoms reported are not diagnostic of PE and may also be found in women with severe preeclampsia-eclampsia without HELLP syndrome. Right upper quadrant or epigastric pain and nausea or vomiting have been reported with a frequency ranging from 30% to 90% ( Table 31-6 ). Most women gave a history of malaise typical of a nonspecific viral-like syndrome for several days before presentation, which led one investigator to suggest performing laboratory investigations (complete blood count [CBC] and liver enzymes) in all pregnant women with suspected PE who have these symptoms during the third trimester. Headaches are reported by 33% to 61% of the patients, whereas visual changes are reported in about 17%. A small subset of patients with HELLP syndrome may present with symptoms related to thrombocytopenia, such as bleeding from mucosal surfaces, hematuria, petechial hemorrhages, or ecchymosis.

TABLE 31-6

SIGNS AND SYMPTOMS IN WOMEN WITH HELLP SYNDROME

	WEINSTEIN ( n = 57) (%)	SIBAI ET AL ( n = 509) (%)	MARTIN ET AL ( n = 501) (%)	RATH ET AL ( n = 50) (%)
Right upper quadrant epigastric pain	86	63	40	90
Nausea, vomiting	84	36	29	52
Headache	NR	33	61	NR
Hypertension	NR	85	82	88
Proteinuria	96	87	86	100

 

HELLP, hemolysis, elevated liver enzymes, and low platelets; NR, not reported.

Modified from Sibai BM. Diagnosis, controversies, and management of HELLP syndrome. Obstet Gynecol. 2004;103:981.

Although most patients have hypertension (82% to 88%; see Table 31-6 ), it may be only mild in 15% to 50% of the cases and absent in 12% to 18%. Most of the patients (86% to 100%) have proteinuria by dipstick examination, although it has been reported to be absent in 13% of cases.

Differential Diagnosis

The presenting symptoms, clinical findings, and many of the laboratory findings in women with HELLP syndrome overlap with a number of medical syndromes, surgical conditions, and obstetric complications; therefore the differential diagnosis of HELLP syndrome should include any of the conditions listed in Box 31-6 . Because some women with HELLP syndrome may present with gastrointestinal, respiratory, or hematologic symptoms in association with elevated liver enzymes or low platelets in the absence of hypertension or proteinuria, many initially are misdiagnosed as having other conditions such as upper respiratory infection, hepatitis, cholecystitis, pancreatitis, acute fatty liver of pregnancy (AFLP), or immune thrombocytopenic purpura (ITP). Conversely, some women with other conditions—such as thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), systemic lupus erythematosus (SLE), sepsis, or catastrophic antiphospholipid antibody syndrome—may be erroneously diagnosed as having HELLP syndrome. In addition, PE may occasionally be superimposed on one of these disorders, which further contributes to the diagnostic difficulty. Because of the remarkably similar clinical and laboratory findings of these disease processes, even the most experienced clinician can face a difficult diagnostic challenge. Therefore efforts should be made to attempt to identify an accurate diagnosis, given that management strategies may be different among these conditions. It is important to emphasize that affected women may have a variety of unusual signs and symptoms, none of which are diagnostic of severe PE. Pregnant women with probable PE who present with atypical symptoms should have a CBC, a platelet count, and liver enzyme determinations irrespective of maternal BP findings.

Box 31-6

Medical and Surgical Disorders Often Confused with Hellp Syndrome

• •
  

  Acute fatty liver of pregnancy

  
  
• •
  

  Appendicitis

  
  
• •
  

  Gallbladder disease

  
  
• •
  

  Glomerulonephritis

  
  
• •
  

  Hemolytic uremic syndrome

  
  
• •
  

  Hepatic encephalopathy

  
  
• •
  

  Hyperemesis gravidarum

  
  
• •
  

  Idiopathic thrombocytopenia

  
  
• •
  

  Pyelonephritis

  
  
• •
  

  Systemic lupus erythematosus

  
  
• •
  

  Antiphospholipid antibody syndrome

  
  
• •
  

  Thrombotic thrombocytopenic purpura

  
  
• •
  

  Viral hepatitis

HELLP, hemolysis, elevated liver enzymes, and low platelets.

Occasionally, the presence of this syndrome is associated with hypoglycemia that leads to coma, severe hyponatremia, and cortical blindness. A rare but interesting complication of HELLP syndrome is transient nephrogenic diabetes insipidus. Unlike central diabetes insipidus, which results from the diminished or absent secretion of arginine vasopressin by the hypothalamus, transient nephrogenic diabetes insipidus is characterized by a resistance to arginine vasopressin mediated by excessive vasopressinase. It is postulated that elevated circulating vasopressinase may result from impaired hepatic metabolism of the enzyme.

Management of Hellp Syndrome

Management of preeclamptic women who present with HELLP syndrome is highly controversial. Consequently, several therapeutic modalities have been described in the literature to treat or reverse HELLP syndrome. Most of these modalities are similar to those used in the management of severe PE remote from term ( Box 31-7 ).

Box 31-7

Therapeutic Modalities Used to Treat or Reverse Hellp Syndrome

• 
  

  Plasma volume expansion

  
  
  
  
  • •
    

    Bed rest

    
    
  • •
    

    Crystalloids

    
    
  • •
    

    Albumin 5% to 25%

  
  
  
  
• 
  

  Antithrombotic agents

  
  
  
  
  • •
    

    Low-dose aspirin

    
    
  • •
    

    Dipyridamole

    
    
  • •
    

    Heparin

    
    
  • •
    

    Antithrombin III

  
  
  
  
• 
  

  Immunosuppressive agents

  
  
  
  
  • •
    

    Steroids

  
  
  
  
• 
  

  Miscellaneous

  
  
  
  
  • •
    

    Fresh-frozen plasma infusions

    
    
  • •
    

    Exchange plasmapheresis

    
    
  • •
    

    Dialysis

  
  

HELLP, hemolysis, elevated liver enzymes, and low platelets.

Modified from Sibai BM. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing? Am J Obstet Gynecol. 1990;162:311.

The clinical course of women with true HELLP syndrome is usually characterized by progressive and sometimes sudden deterioration in the maternal condition. Because the presence of this syndrome has been associated with increased rates of maternal morbidity and mortality, many authors consider its presence to be an indication for immediate delivery. There is also a consensus of opinion that prompt delivery is indicated if the syndrome develops beyond 34 weeks’ gestation or earlier if obvious multiorgan dysfunction, DIC, liver infarction or hemorrhage, renal failure, suspected abruption, or nonreassuring fetal status are apparent. Delivery is also indicated if the syndrome develops before 23 weeks’ gestation.

On the other hand, considerable disagreement exists about the management of women with HELLP syndrome at or before 34 weeks of gestation when the maternal condition is stable, except for mild to moderate abnormalities in blood tests, and fetal condition is reassuring. In such patients, some authors recommend the administration of corticosteroids to accelerate fetal lung maturity followed by delivery after 24 hours, whereas others recommend prolonging pregnancy until the development of maternal or fetal indications for delivery or until achievement of fetal lung maturity. Some of the measures used in these latter cases have included one or more of the following: bed rest, antihypertensive agents, antithrombotic agents (LDA, dipyridamole), plasma volume expanders (crystalloids, albumin, fresh frozen plasma [FFP]), and corticosteroids (prednisone, prednisolone, dexamethasone, or betamethasone).

Expectant Management of Hellp Syndrome

Few large case series describe expectant management of women with true HELLP, partial HELLP, or severe PE with isolated liver enzyme elevation. In general, these reports suggest that transient improvement in laboratory values or pregnancy prolongation from a few days to a few weeks is possible in a select group of women with HELLP syndrome. It is important to note that most of the patients included in these studies were ultimately delivered within 1 week of expectant management.

Investigators from the Netherlands have reported their experience with expectant management in women with HELLP syndrome before 34 weeks’ gestation. Visser and Wallenburg reported the use of plasma volume expansion using invasive hemodynamic monitoring and vasodilators in 128 women with HELLP syndrome before 34 weeks’ gestation. Magnesium sulfate and steroids were not used in such women. Twenty-two of the 128 patients were delivered within 48 hours; the remaining 102 patients had pregnancy prolongation for a median of 15 days (range, 3 to 62 days). Fifty-five of these 102 women had antepartum resolution of HELLP syndrome, with a median pregnancy prolongation in these women of 21 days (range, 7 to 62 days). No maternal deaths or serious maternal morbidity was reported. However, 11 of the 128 pregnancies (8.6%) resulted in fetal death at 25 to 34.4 weeks, and 7 neonatal deaths (5.5%) at 27 to 32 weeks’ gestation were reported.

Van Pampus and coworkers reported the use of bed rest, antihypertensive medication, and salt restriction in 41 women with HELLP syndrome before 35 weeks’ gestation. Fourteen women (34%) were delivered within 24 hours; in the remaining 27 women, pregnancy was prolonged a median of 3 days (range, 0 to 59 days). Fifteen of these 27 women showed complete normalization of the laboratory values. No serious maternal morbidities were noted, but 10 fetal deaths were reported at 27 to 35.7 weeks’ gestation.

The study by Ganzevoort and colleagues included 54 women with HELLP syndrome at the time of enrollment. In a subsequent publication, the same authors compared maternal and perinatal complications in these women to the respective outcomes in women without HELLP. They found that the median number of days of pregnancy prolongation and maternal and perinatal complications were similar between the two groups.

One randomized, double-blind trial compared prednisolone ( n = 15) to placebo ( n = 16) in patients with HELLP syndrome before 30 weeks’ gestation. Prednisolone was given intravenously twice a day. The primary outcome measures were the entry-to-delivery interval and the number of “recurrent HELLP” exacerbations in the antepartum period. The mean entry-to-delivery interval was similar between the two groups (6.9 days for prednisolone and 8 days for placebo). Three cases of liver hematoma or rupture were reported, along with one maternal death in the placebo group. The perinatal mortality rate was similar between the two groups (20% in the prednisolone group and 25% in the placebo group).

The results of these studies suggest that expectant man­agement is possible in a very select group of women with suspected HELLP syndrome before 34 weeks’ gestation. However, despite pregnancy prolongation in some of these cases, the overall perinatal outcome was not improved compared with fetuses at a similar gestational age who were delivered within 48 hours after the diagnosis of HELLP syndrome.

Confounding variables make it difficult to evaluate any treatment modality proposed for this syndrome. Occasionally, some patients without true HELLP syndrome may demonstrate antepartum reversal of hematologic abnormalities following bed rest, use of corticosteroids, or plasma volume expansion. However, most of these patients experienced deterioration in either maternal or fetal condition within 1 to 10 days after conservative management. It is doubtful that such limited pregnancy prolongation will result in improved perinatal outcome, and maternal and fetal risks are substantial.

In summary, the results of these studies suggest that expectant treatment is possible in a select group of women with HELLP syndrome before 34 weeks’ gestation. However, the number of women who were studied in these reports is inadequate to evaluate maternal safety; therefore such treatment should be considered experimental. In addition, most experts—including members of the ACOG Task Force—recommend delivery of such patients after completion of a course of corticosteroids for fetal lung maturity or if the gestational age is less than 24 weeks.

Corticosteroids to Improve Pregnancy Outcome in Women with Hellp Syndrome

It is well established that antenatal glucocorticoid therapy reduces neonatal complications and neonatal mortality in women with severe PE at 34 weeks’ gestation or less (see Chapter 29 ). The recommended regimens of corticosteroids for the enhancement of fetal maturity are betamethasone (12 mg intramuscularly every 24 hours, two doses) or dexamethasone (6 mg intramuscularly every 12 hours, four doses). These regimens have been identified as the most appropriate for this purpose because they readily cross the placenta and have minimal mineralocorticoid activity. However, it is unclear whether the same or different regimens are beneficial in women with HELLP syndrome.

Corticosteroids have been suggested as safe and effective drugs for improving maternal and neonatal outcome in women with HELLP or partial HELLP syndrome. A review of the literature reveals substantial differences in methodology, time of administration, and drug selection among investigators who advocate the use of corticosteroids in women with HELLP syndrome. Different regimens of steroids have been suggested for preventing respiratory distress syndrome (RDS) as well as to accelerate maternal recovery in the postpartum period. The regimens of steroids used included intramuscular betamethasone (12 mg/12 hr or 24 hours apart on two occasions) or IV dexamethasone (various doses at various time intervals) or a combination of the two. Some studies used steroids only in the antepartum period (for 24 hours, 48 hours, repeat regimens, or chronically for weeks until delivery). In other studies, steroids were given for 48 hours before delivery and then were continued for 24 to 48 hours postpartum, whereas others recommend their administration only in the postpartum period.

Some randomized trials have compared the use of high-dose dexamethasone to either no treatment or betamethasone in women with presumed HELLP syndrome. These studies were summarized in a review by Sibai. The results of these studies demonstrated improved laboratory values and urine output in patients receiving dexamethasone but found no differences in serious maternal morbidity. In addition, the number of patients studied was limited, and neither of these small studies used a placebo.

More recently, three randomized, double-blind placebo trials were conducted to evaluate dexamethasone versus placebo in women with antepartum and postpartum HELLP syndrome. Two of the trials were multicenter, and one was a single-center trial. The results of the two large, multicenter trials are summarized in Tables 31-7 and 31-8 . Overall, these trials revealed no maternal benefit of using dexamethasone in women with HELLP syndrome. It is my opinion that corticosteroids should only be used for 48 hours to accelerate fetal lung maturity in women who have reached 24 to 34 weeks’ gestation. In addition, it is recommended that dexamethasone not be used to treat maternal symptoms of HELLP syndrome either beyond 34 weeks or in the postpartum period.

TABLE 31-7

MATERNAL COMPLICATIONS WITH DEXAMETHASONE VERSUS PLACEBO IN HELLP SYNDROME

	NO. WITH PLACEBO (%)	NO. WITH DEXAMETHASONE (%)	CRUDE RELATIVE RISK (95% CI)
Acute renal failure *	8 (13)	6 (10)	0.8 (0.3-2.1)
Oliguria	4 (6)	5 (7.6)	1.3 (0.4-4.5)
Pulmonary edema *	1 (2)	3 (4.6)	3.1 (0.3-28)
Eclampsia	10 (15)	8 (14)	0.8 (0.3-1.9)
Infections	10 (15)	5(8)	0.5 (0.2-1.4)
Death	1 (2)	3 (5)	3.0 (0.3-28)
Platelet transfusion	10 (15)	12 (18)	1.2 (0.6-2.6)
Plasma transfusion	6 (9)	5 (8)	0.8 (0.3-2.6)

 

CI, confidence interval.

Modified from Fonseca JE, Mendez F, Catano C, Arias F. Dexamethasone treatment does not improve the outcome of women with HELLP syndrome: a double-blind, placebo-controlled, randomized clinical trial. Am J Obstet Gynecol. 2005;193:1591-1598.

* Only included patients without the event before randomization.

TABLE 31-8

MATERNAL COMPLICATIONS COMPARING DEXAMETHASONE VERSUS PLACEBO FOR POSTPARTUM HELLP SYNDROME

COMPLICATION *	DEXAMETHASONE ( n = 56)		PLACEBO ( n = 49)
	n	%	n	%
Pulmonary edema	2	3.6	5	10.2
Hemorrhagic manifestation	20	35.7	16	32.7
Acute renal failure	9	16.1	12	24.5
Oliguria	27	48.2	22	44.9
Blood transfusion	16	28.6	19	38.6
Any complication	37	66.1	25	51
Death	2	3.6	2	4.1

 

Modified from Katz L, de Amorim MM, Figueiroa JN, Pinto e Silva JL. Postpartum dexamethasone for women with hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome: a double-blind, placebo-controlled, randomized clinical trial. Am J Obstet Gynecol. 2008;198:283.

* Each patient may have more than one complication.

Maternal and Perinatal Outcome

The presence of HELLP syndrome is associated with an increased risk for maternal death (1%) and increased rates of maternal morbidities such as pulmonary edema (8%), acute renal failure (3%), DIC (15%), abruptio placentae (9%), liver hemorrhage or failure (1%), acute respiratory distress syndrome (ARDS), sepsis, and stroke (<1%). Pregnancies complicated by HELLP syndrome are also associated with increased rates of wound hematomas and the need for transfusion of blood and blood products. The rate of these complications depends on the population studied, the laboratory criteria used to establish the diagnosis, and the presence of associated preexisting medical conditions (chronic hypertension, lupus) or obstetric complications (abruptio placentae, peripartum hemorrhage, fetal demise, eclampsia). The development of HELLP syndrome in the postpartum period also increases the risk for renal failure and pulmonary edema. The presence of placental abruption increases the risk for DIC, pulmonary edema, and renal failure and also increases the need for blood transfusions. Patients who have a large volume of ascites appear to have a high rate of cardiopulmonary complications. Finally, women who meet all the criteria suggested for diagnosis will have higher rates of maternal complications than those who have partial HELLP or elevated liver enzymes only ( Table 31-9 ).

TABLE 31-9

MATERNAL COMPLICATIONS IN 316 PREGNANCIES WITH HELLP SYNDROME, PARTIAL HELLP SYNDROME, OR SEVERE PREECLAMPSIA WITH NORMAL LABORATORY VALUES

	HELLP ( n = 67)	PARTIAL HELLP ( n = 71)	SEVERE HELLP ( n = 178)
Blood products transfusion (%)	25 *	4	3
Disseminated intravascular coagulation (%)	15 *	0	0
Wound hematoma, infection (%) †	14 ‡	11 §	2 §
Pleural effusion (%)	6 ‡	0	1
Acute renal failure (%)	3 ‡	0	0
Eclampsia (%)	9	7	9
Abruptio placentae (%)	9	4	5
Pulmonary edema (%)	8	4	3
Subcapsular liver hematoma (%)	1.5	0	0
Intracerebral hemorrhage (%)	1.5	0	0
Death (%)	1.5	0	0

 

HELLP, hemolysis, elevated liver enzymes, and low platelets.

From Audibert F, Friedman SA, Frangieh AY, Sibai BM. Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol. 1996;175:460.

* P < .001, HELLP vs. partial and severe HELLP.

† Percentages of women who had cesarean delivery.

‡ P < .05, HELLP vs. severe HELLP.

§ P < .05, partial vs. severe HELLP.

It is generally agreed that perinatal mortality and morbidity are substantially increased in pregnancies complicated by the HELLP syndrome. The reported perinatal death rate in recent series ranged from 7.4% to 34%, and this high perinatal death rate is mainly experienced at a very early gestational age (<28 weeks) in association with severe FGR or placental abruption. It is important to emphasize that neonatal morbidities in these pregnancies are dependent on gestational age at time of delivery, and they are similar when corrected for gestational age to those in preeclamptic pregnancies without the HELLP syndrome. The rate of preterm delivery is about 70%, and 15% occur before 28 weeks’ gestation. As a result, these infants have a high rate of acute neonatal complications.

The HELLP syndrome may develop antepartum or postpartum. Analysis of 442 cases studied by Sibai and associates revealed that 309 (70%) had evidence of the syndrome antepartum, whereas 133 (30%) developed the condition postpartum. Four maternal deaths were reported, and morbidity was frequent ( Table 31-10 ).

TABLE 31-10

SERIOUS MATERNAL COMPLICATIONS IN 442 PATIENTS WITH HELLP SYNDROME

COMPLICATION	N (%)
Disseminated intravascular coagulation	92 (21)
Abruptio placentae	69 (16)
Acute renal failure	33 (8)
Severe ascites	32 (8)
Pulmonary edema	26 (6)
Pleural effusions	26 (6)
Cerebral edema	4 (1)
Retinal detachment	4 (1)
Laryngeal edema	4 (1)
Subcapsular liver hematoma	4 (1)
Adult respiratory distress syndrome	3 (1)
Death, maternal	4 (1)

 

HELLP, hemolysis, elevated liver enzymes, and low platelets.

From 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). Am J Obstet Gynecol. 1993;169:1000.

In the postpartum period, the time of onset of the manifestations can range from a few hours to 7 days, but most develop within 48 hours postpartum. Thus laboratory assessment for potential HELLP syndrome should be considered during the first 48 hours postpartum in women with significant hypertension or symptoms of severe PE. Eighty percent of the women who develop HELLP syndrome postpartum had PE before delivery, whereas 20% had no evidence of PE during either the antepartum or intrapartum periods. It is my experience that patients in this group are at increased risk for the development of pulmonary edema and acute renal failure ( Table 31-11 ). The differential diagnosis should include exacerbation of SLE, TTP, and HUS.

TABLE 31-11

OUTCOME AND COMPLICATIONS OF HELLP SYNDROME IN RELATION TO TIME OF ONSET

	ANTEPARTUM ONSET ( n = 309) (%)	POSTPARTUM ONSET ( n = 133) (%)	RELATIVE RISK	95% CI
Delivery at <27 wk *	15	3	4.84	2.0-11.6
Delivery at 37-42 wk †	15	25	0.61	0.41-0.91
Pulmonary edema	5	9	0.50	0.24-1.05
Acute renal failure †	5	12	0.46	0.24-0.87
Eclampsia	7	10	0.73	0.38-1.40
Abruptio placentae	16	15	1.05	0.65-1.70
DIC	21	20	1.09	0.73-1.64

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