Preeclampsia is a disorder of widespread vascular endothelial malfunction and vasospasm that occurs after 20 weeks.docx

Preeclampsia is a disorder of widespread vascular endothelial malfunction and vasospasm that occurs after 20 weeks' gestation and can present as late as 4-6 weeks postpartum. It is clinically defined by hypertension andproteinuria, with or without pathologic edema.The incidence of preeclampsia in the United States is estimated to range from 2% to 6% in healthy, nulliparous women.[1, 2, 3]Among all cases of the preeclampsia, 10% occur in pregnancies of less than 34 weeks' gestation. The global incidence of preeclampsia has been estimated at 5-14% of all pregnancies.In developing nations, the incidence of the disease is reported to be 4-18%,[4, 5]with hypertensive disorders being the second most common obstetric cause of stillbirths and early neonatal deaths in these countries.[6]Medical consensus is lacking regarding the values that define preeclampsia, but reasonable criteria in a woman who was normotensive before 20 weeks' gestation include a systolic blood pressure (SBP) greater than 140 mm Hg and a diastolic BP (DBP) greater than 90 mm Hg on 2 successive measurements, 4-6 hours apart. Preeclampsia in a patient with preexisting essential hypertension is diagnosed if SBP has increased by 30 mm Hg or if DBP has increased by 15 mm Hg.Mild and severe preeclampsiaPreeclampsia is mild in 75% of cases and severe in 25% of them.[7]In its extreme, the disease may lead to liver and renal failure, disseminated intravascular coagulopathy (DIC), and central nervous system (CNS) abnormalities. If preeclampsia-associated seizures develop, the disorder has developed into the condition calledeclampsia.Mild preeclampsia is defined as the presence of hypertension (BP 140/90 mm Hg) on 2 occasions, at least 6 hours apart, but without evidence of end-organ damage in the patient.Severe preeclampsia is defined as the presence of 1 of the following symptoms or signs in the presence of preeclampsia: SBP of 160 mm Hg or higher or DBP of 110 mm Hg or higher on 2 occasions at least 6 hours apart Proteinuria of more than 5 g in a 24-hour collection or more than 3+ on 2 random urine samples collected at least 4 hours apart Pulmonary edema or cyanosis Oliguria (< 400 mL in 24 h) Persistent headaches Epigastric pain and/or impaired liver function Thrombocytopenia Oligohydramnios, decreased fetal growth, or placental abruptionClassification and Characteristics of Hypertensive DisordersPreeclampsia is part of a spectrum of hypertensive disorders that complicate pregnancy. As specified by the National High Blood Pressure Education Program (NHBPEP) Working Group, the classification is as follows[8]: Gestational hypertension Chronic hypertension Preeclampsia/eclampsia Superimposed preeclampsia (on chronic hypertension)Although each of these disorders can appear in isolation, they are thought of as progressive manifestations of a single process and are believed to share a common etiology.Gestational hypertensionThe characteristics of gestational hypertension are as follows: BP of 140/90 mm Hg or greater for the first time during pregnancy No proteinuria BP returns to normal less than 12 weeks' postpartum Final diagnosis made only postpartumChronic hypertensionChronic hypertension is characterized by either (1) a BP 140/90 mm Hg or greater before pregnancy or diagnosed before 20 weeks' gestation; not attributable to gestational trophoblastic disease or (2) hypertension first diagnosed after 20 weeks' gestation and persistent after 12 weeks postpartum.Preexisting chronic hypertension may present with superimposed preeclampsia presenting as new-onset proteinuria after 20 weeks' gestation.Preeclampsia/eclampsiaPreeclampsia/eclampsia is characterized by a BP of 140/90 mm Hg or greater after 20 weeks' gestation in a women with previously normal BP and who have proteinuria ( 0.3 g protein in 24-h urine specimen).Eclampsia is defined as seizures that cannot be attributable to other causes, in a woman with preeclampsiaSuperimposed preeclampsiaSuperimposed preeclampsia (on chronic hypertension) is characterized by (1) new onset proteinuria ( 300 mg/24 h) in a woman with hypertension but no proteinuria before 20 weeks' gestation and (2) a sudden increase in proteinuria or BP, or a platelet count of less than 100,000/mm3, in a woman with hypertension and proteinuria before 20 weeks' gestation.HELLP syndromeHELLP syndrome (hemolysis, elevated liver enzyme, low platelets) may be an outcome of severe preeclampsia, although some authors believe it to have an unrelated etiology. The syndrome has been associated with particularly high maternal and perinatal morbidity and mortality rates and may be present without hypertension or, in some cases, without proteinuria.ProteinuriaProteinuria is defined as the presence of at least 300 mg of protein in a 24-hour urine collection. Some investigators and clinicians have accepted a urine protein-creatinine ratio of at least 0.3 as a criterion for proteinuria, but the American College of Obstetricians and Gynecologists (ACOG) has not yet incorporated this into their definition.[9]In the emergency department, a urine protein-to-creatinine ratio of 0.19 or greater is somewhat predictive of significant proteinuria (negative predictive value [NPV], 87%).[10]Serial confirmations 6 hours apart increase the predictive value. Although more convenient, a urine dipstick value of 1+ or more (30 mg/dL) is not reliable in the diagnosis of proteinuria.PathophysiologyIn the fetus, preeclampsia can lead to ischemic encephalopathy, growth retardation, and the various sequelae of premature birth.Eclampsia is estimated to occur in 1 in 200 cases of preeclampsia when magnesium prophylaxis in not administered. (See Seizure Prophylaxis.)[11, 12]Cardiovascular diseaseAs previously mentioned, preeclampsia is characterized by endothelial dysfunction in pregnant women. Therefore, the possibility exists that preeclampsia may be a contributor to future cardiovascular disease. In a meta-analysis, several associations were observed between an increased risk of cardiovascular disease and a pregnancy complicated by preeclampsia. These associations included an approximately 4-fold increase in the risk of subsequent development of hypertension and an approximately 2-fold increase in the risk of ischemic heart disease, venous thromboembolism, and stroke.[13]Moreover, women who had recurrent preeclampsia were more likely to suffer from hypertension later in life.[13]In a review of population-based studies, Harskamp and Zeeman noted a relationship between preeclampsia and an increased risk of later chronic hypertension and cardiovascular morbidity/mortality, compared with normotensive pregnancy. Moreover, women who develop preeclampsia before 36 weeks' gestation or who have multiple hypertensive pregnancies were at highest risk.[14]Harskamp and Zeeman also found that the underlying mechanism for the remote effects of preeclampsia is complex and probably multifactorial. The risk factors that are shared by cardiovascular disease and preeclampsia are as follows: Endothelial dysfunction Obesity Hypertension Hyperglycemia Insulin resistance Dyslipidemia

Metabolic syndrome, the investigators noted, may be a possible underlying mechanism common to cardiovascular disease and preeclampsia.Mechanisms behind preeclampsiaAlthough hypertension may be the most common presenting symptom of preeclampsia, it should not be viewed as the initial pathogenic process.The mechanisms by which preeclampsia occurs is not certain, and numerous maternal, paternal, and fetal factors have been implicated in its development. The factors currently considered to be the most important include the following[15]: Maternal immunologic intolerance Abnormal placental implantation Genetic, nutritional, and environmental factors Cardiovascular and inflammatory changes Immunologic factors have long been considered to be key players in preeclampsia. One important component is a poorly understood dysregulation of maternal tolerance to paternally derived placental and fetal antigens.[16]This maternal-fetal immune maladaptation is characterized by defective cooperation between uterine natural killer(NK) cells and fetal human leukocyte antigen (HLA)-C, and results in histologic changes similar to those seen in acute graft rejection. The endothelial cell dysfunction that is characteristic of preeclampsia may be partially due to an extreme activation of leukocytes in the maternal circulation, as evidenced by an upregulation of type 1 helper T cells.Placentation in PreeclampsiaPlacental implantation with abnormal trophoblastic invasion of uterine vessels is a major cause of hypertension associated with preeclampsia syndrome.[17, 18]In fact, studies have shown that the degree of incomplete trophoblastic invasion of the spiral arteries is directly correlated with the severity of subsequent maternal hypertension. This is because the placental hypoperfusion resulting from the incomplete invasion leads by an unclear pathway to the release of systemic vasoactive compounds that cause an exaggerated inflammatory response, vasoconstriction, endothelial damage, capillary leak, hypercoagulability, and platelet dysfunction, all of which contribute to organ dysfunction and the various clinical features of the disease.Normal placentation and pseudovascularizationIn normal pregnancies, a subset of cytotrophoblasts called invasive cytotrophoblasts migrate through the implantation site and invade decidua tunica media of maternal spiral arteries and replace its endothelium in a process called pseudovascularization.[19]The trophoblast differentiation along the invasive pathway involves alteration in the expression of a number of different classes of molecules, including cytokines, adhesion molecules, extracellular matrix, metalloproteinases, and the class Ib major histocompatibility complex (MHC) molecule, HLA-G.[20, 21]For example, during normal differentiation, invading trophoblasts alter their adhesion molecule expression from those that are characteristic of epithelial cells (integrins alpha 6/beta 1, alpha V/beta 5, and E-cadherin) to those of endothelial cells (integrins alpha 1/beta 1, alpha V/beta 3, and VE-cadherin).As a result of these changes, the maternal spiral arteries undergo transformation from small, muscular arterioles to large capacitance, low-resistance vessels. This allows increased blood flow to the maternal-fetal interface. Remodeling of these arterioles probably begins in the first trimester and ends by 18-20 weeks' gestation. However, the exact gestational age at which the invasion stops is unknown.Failure of pseudovascularization in preeclampsiaThe shallow placentation noted in preeclampsia results from the fact that the invasion of the decidual arterioles by cytotrophoblasts is incomplete. This is due to a failure in the alterations in molecular expression necessary for the differentiation of the cytotrophoblasts, as required for pseudovascularization. For example, the upregulation of matrix metalloproteinase-9 (MMP-9) and HLA-G, 2 molecules noted in normally invading cytotrophoblasts, does not occur.The invasive cytotrophoblasts therefore fail to replace tunica media, which means that mostly intact arterioles, which are capable of vasoconstriction, remain. Histologic evaluation of the placental bed demonstrates few cytotrophoblasts beyond the decidual layer.The primary cause for the failure of these invasive cytotrophoblasts to undergo pseudovascularization and invade maternal blood vessels is not clear. However, immunologic and genetic factors have been proposed. Early hypoxic insult to differentiating cytotrophoblasts has also been proposed as a contributing factor.Endothelial DysfunctionData show that an imbalance of proangiogenic and antiangiogenic factors produced by the placenta may play a major role in mediating endothelial dysfunction. Angiogenesis is critical for successful placentation and the normal interaction between trophoblasts and endothelium. (See Angiogenic Factors in Preeclampsia, below.)Several circulating markers of endothelial cell injury have been shown to be elevated in women who develop preeclampsia before they became symptomatic. These include endothelin, cellular fibronectin, and plasminogen activator inhibitor-1, with an altered prostacyclin/thromboxane profile also present.[22, 23]Evidence also suggests that oxidative stress, circulatory maladaptation, inflammation, and humoral, mineral, and metabolic abnormalities contribute to the endothelial dysfunction and pathogenesis of preeclampsia.Angiogenic Factors in PreeclampsiaThe circulating proangiogenic factors secreted by the placenta include vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). The antiangiogenic factors include soluble fms-like tyrosine kinase I receptor (sFlt-1) (otherwise known as soluble VEGF receptor type I) and soluble endoglin (sEng).VEGF and PlGFVEGF and PlGF promote angiogenesis by interacting with the VEGF receptor family. Although both growth factors are produced by placenta, the serum level of PlGF rises much more significantly in pregnancy. In a study, Taylor et al demonstrated that the serum level of PlGF decreased in women who later developed preeclampsia.[24]The fall in serum level was notable as early as the second trimester in women who developed preeclampsia and intrauterine growth restriction.In another investigation, Maynard et al observed that the serum levels of VEGF and PlGF were decreased in women with preeclampsia.[25]However, the magnitude of decrease was less pronounced for VEGF, as its serum level was not as high as that of PlGF, even in normal pregnancy. Other investigators have confirmed this finding and have shown that the serum level of PlGF decreased in women before they developed preeclampsia.[26, 27]Bills et al suggest that circulating VEGF-A levels in preeclampsia are biologically active because of a loss of repression of VEGF-receptor 1 signaling by PlGF-1, and VEGF165b may be involved in the increased vascular permeability of preeclampsia.[28]Soluble fms-like tyrosine kinase 1 receptorThe receptor sFlt-1 is a soluble isoform of Flt-1, which is a transmembrane receptor for VEGF. Although sFlt-1 lacks the transmembrane domain, it contains the ligand-binding region and is capable of binding circulating VEGF and PlGF, preventing these growth factors from binding to transmembrane receptors. Thus, sFlt-1 has an antiangiogenic effect.In addition to angiogenesis, VEGF and PlGF are important in maintaining endothelial homeostasis. Selective knockout of the glomerular VEGF gene has been shown to be lethal in rats, whereas the heterozygotes were born with glomerular endotheliosis (the renal lesion characteristic of preeclampsia) and eventually renal failure. Furthermore, sFlt-1, when injected into pregnant rats, produced hypertension and proteinuria along with glomerular endotheliosis.[25]In addition to animal studies, multiple studies in humans have demonstrated that excess production of sFlt-1 is associated with an increased risk of preeclampsia. In a case-control study that measured levels of sFlt-1, VEGF, and PlGF, investigators found an earlier and greater increase in the serum level of sFlt-1 in women who developed preeclampsia (21-24 wk) than in women who did not develop preeclampsia (33-36 wk), whereas the serum levels of VEGF and PlGF deceased. Furthermore, the serum level of sFlt-1 was higher in women who developed severe preeclampsia or early preeclampsia (< 34 wk) than it was in women who developed mild preeclampsia at term.[26]Soluble endoglinsEng is a soluble isoform of co-receptor for transforming growth factor beta (TGF-beta). Endoglin binds to TGF-beta in association with the TGF-beta receptor. Because the soluble isoform contains the TGF-beta binding domain, it can bind to circulating TGF-beta and decrease circulating levels. In addition, TGF-beta is a proangiogenic molecule, so the net effect of high levels of sEng is anti-angiogenic.Several observations support the role of sEng in the pathogenesis of preeclampsia. It is found in the blood of women with preeclampsia up to 3 months before the clinical signs of the condition, its level in maternal blood correlates with disease severity, and the level of sEng in the blood drops after delivery.[29]In studies on pregnant rats, administration of sEng results in vascular permeability and causes hypertension. There is also evidence that it has a synergistic relationship with sFlt-1, because it increases the effects of sFlt-1 in pregnant rats; this results in HELLP syndrome, as evidenced by hepatic necrosis, hemolysis, and placental infarction.[30]Moreover, sEng inhibits TGF-beta in endothelial cells and also inhibits TGF-beta-1 activation of nitric oxide mediated vasodilatation.Genetic Factors in PreeclampsiaPreeclampsia has been shown to involve multiple genes. Over 100 maternal and paternal genes have been studied for their association with preeclampsia, including those known to play a role in vascular diseases, BP regulation, diabetes, and immunologic functions.Importantly, the risk of preeclampsia is positively correlated between close relatives; a study showed that 20-40% of daughters and 11-37% of sisters of women with preeclampsia also developed the disease.[16]Twin studies have shown a high correlation as well, approaching 40%.Because preeclampsia is a genetically and phenotypically complex disease, it is unlikely that any single gene will be shown to play a dominant role in its development.Additional Factors in PreeclampsiaOther substances that have been proposed, but not proven, to contribute to preeclampsia include tumor necrosis factor, interleukins, various lipid molecules, and syncytial knots.[31]Risk Factors for PreeclampsiaThe incidence of preeclampsia is higher in women with a history of preeclampsia, multiple gestations, and chronic hypertension or underlying renal disease. In addition, Lykke et al found that preeclampsia, spontaneous preterm delivery, or fetal growth deviation in a first singleton pregnancy predisposes women to those complications in their second pregnancy, especially if the complications were severe.[32]Gestational ageIn a registry-based cohort study of 536,419 Danish women, delivery between 32 and 36 weeks gestation increased the risk of preterm delivery in the second pregnancy from 2.7% to 14.7% and increased the risk of preeclampsia from 1.1% to 1.8%. A first delivery before 28 weeks increased the risk of a second preterm delivery to 26% and increased the risk of preeclampsia to 3.2%.Preeclampsia in a first pregnancy, with delivery between 32 and 36 weeks' gestation, increased the risk of preeclampsia in a second pregnancy from 14.1% to 25.3%. Fetal growth 2-3 standard deviations below the mean in a first pregnancy increased the risk of preeclampsia from 1.1% to 1.8% in the second pregnancy.[32]Primigravid patients in particular seem to be predisposed to preeclampsia.Maternal ageWomen aged 35 years and older have a markedly increased risk of preeclampsia.RaceIn the United States, the incidence of preeclampsia is 1.8% among white women and 3% in black women.Additional risk factorsSome risk factors contribute to poor placentation, whereas others contribute to increased placental mass and poor placental perfusion secondary to vascular abnormalities.[33]In addition to those discussed above, preeclampsia risk factors also include the following: Hydatidiform mole Obesity Thrombophilia Oocyte donation or donor insemination Urinary tract infection Diabetes Collagen vascular disease Periodontal disease[34]One literature review suggests that maternal vitamin D deficiency may increase the risk of preeclampsia and fetal growth restriction. Another study determined that vitamin D deficiency/insufficiency was common in a group of women at high risk for preeclampsia. However, it was not associated with the subsequent risk of an adverse pregnancy outcome.[35]Studies have suggested that smoking during pregnancy is associated with a reduced risk of gestational hypertension and preeclampsia; however, this is controversial.[21]Placenta previa has also been correlated with a reduced risk of preeclampsia.Body weight is strongly correlated with progressively increased preeclampsia risk, ranging from 4.3% for women with a body mass index (BMI) < 20 kg/m2 to 13.3% in those with a BMI >35 kg/m2. A United Kingdom study on obesity showed that 9% of extremely obese women were preeclamptic, compared with 2% of matched controls.[36]Table 1 lists the risk factors and their odds ratios for preeclampsia.[33]Table 1. Risk Factors for Preeclampsia*(Open Table in a new window)Nulliparity3:1

Age >40 y3:1

Black race1.5:1

Family history5:1

Chronic renal disease20:1

Chronic hypertension10:1

Antiphospholipid syndrome10:1

Diabetes mellitus2:1

Twin gestation (but unaffected by zygosity)4:1

High body mass index3:1

Angiotensinogen gene T235

Homozygous20:1

Heterozygous4:1

*Adapted from ACOG Technical Bulletin 219, Washington, DC 1996.[9]

Evaluation of PreeclampsiaBecause the clinical manifestations of preeclampsia can be heterogeneous, diagnosing preeclampsia may not be straightforward. In particular, because the final diagnosis of gestational hypertension can only be made in retrospect, a clinician may be forced to treat some women with gestational hypertension as if they have preeclampsia. In addition, if a woman has underlying renal or cardiovascular disease, the diagnosis of preeclampsia may not become clear until the disease becomes severe.Mild to moderate preeclampsia may be asymptomatic. Many cases are detected through routine prenatal screening.Preeclampsia in a previous pregnancy is strongly associated with recurrence in subsequent pregnancies. A history of gestational hypertension or preeclampsia should strongly raise clinical suspicion.Physical findingsPatients with severe preeclampsia display end-organ effects and may complain of the following: Headache Visual disturbances - Blurred, scintillating scotomata Altered mental status Blindness - May be cortical[22]or retinal Dyspnea Edema Epigastric or right upper quadrant abdominal pain Weakness or malaise - May be evidence of hemolytic anemiaEdema exists in many pregnant women, but a sudden increase in edema or facial edema is suggestive of preeclampsia. The edema of preeclampsia occurs by a distinct mechanism that is similar to that of angioneurotic edema.Hepatic involvement occurs in 10% of women with severe preeclampsia. The resulting pain (epigastric or right upper quadrant abdominal pain) is frequently accompanied by elevated serum hepatic transaminase levels.The presence of clonus may indicate an increased risk of convulsions.A study by Cooray et al found that the most common symptoms that immediately precede eclamptic seizures are neurologic symptoms (ie, headache, with or without visual disturbance), regardless of degree of hypertension. This suggests that closely monitoring patients with these symptoms may provide an early warning for eclampsia.[37]Recurrence of preeclampsiaUncommonly, patients have antepartum preeclampsia that is treated with delivery but that recurs in the postpartum period.[38]Recurrent preeclampsia should be considered in postpartum patients who present with hypertension and proteinuria. (See Prognosis.)In patients who are suffering a recurrence of preeclampsia, findings on physical examination may include the following (see Prognosis): Altered mental status Decreased vision or scotomas Papilledema Epigastric or right upper quadrant abdominal tenderness Peripheral edema Hyperreflexia or clonus: Although deep tendon reflexes are more useful in assessing magnesium toxicity, the presence of clonus may indicate an increased risk of convulsions. Seizures Focal neurologic deficit

Measurement of HypertensionHypertension is diagnosed when 2 BP readings of 140/90 mm Hg or greater are noted 6 hours apart within a 1-week period. Measuring BP with an appropriate-sized cuff placed on the right arm at the same level as the heart is important. The patient must be sitting and, ideally, have had a chance to rest for at least 10 minutes before the BP measurement. She should not be lying down in a lateral decubitus position, as the arm often used to measure the pressure in this position will be above the right atrium.The Korotkoff V sound should be used for the diastolic pressure. In cases in which the Korotkoff V sound is not present, the Korotkoff IV sound may be used, but it should be noted as such. The difference between the Korotkoff IV and V sounds may be as much as 10 mm Hg. When an automated cuff is used, it must be able to record the Korotkoff V sound. When serial readings are obtained during an observational period, the higher values should be used to make the diagnosis.Lack of hypertension on examinationAlthough hypertension is an important characteristic of preeclampsia, because the underlying pathophysiology of preeclampsia is a diffuse endothelial cell disorder influencing multiple organs, hypertension does not necessarily need to precede other preeclamptic symptoms or laboratory abnormalities. Presenting symptoms other than hypertension may include, as previously mentioned, edema, visual disturbances, headache, and epigastric or right upper quadrant tenderness.Diagnostic ConsiderationsGestational hypertensionDuring diagnosis, preeclampsia must be differentiated from gestational hypertension; although gestational hypertension is more common and may present with symptoms similar to those of preeclampsia, including epigastric discomfort or thrombocytopenia, it is which is not characterized by proteinuria. (See Classification and Characteristics of Hypertensive Disorders.)Placental hypoperfusionPlacental hypoperfusion or ischemia in preeclampsia has many causes. Preexisting vascular disorders, such as hypertension and connective tissue disorders, can result in poor placental circulation. In cases of multiple gestation or increased placental mass, it is not surprising for the placenta to become underperfused. However, most women who develop preeclampsia are healthy and do not have underlying medical conditions. In this group of women, abnormally shallow placentation has been shown to be responsible for placental hypoperfusion. (See Placentation in Preeclampsia.)Differential diagnosisAbdominal Trauma, BluntAbruptio PlacentaeAneurysm, AbdominalAppendicitis, AcuteCholecystitis and Biliary ColicCholelithiasisCongestive Heart Failure and Pulmonary EdemaDomestic ViolenceEarly Pregnancy LossEncephalitisHeadache, TensionHypertensive EmergenciesHyperthyroidism, Thyroid Storm, and Graves DiseaseMigraine HeadacheOvarian TorsionPregnancy, EclampsiaStatus EpilepticusStroke, HemorrhagicStroke, IschemicSubarachnoid HemorrhageSubdural HematomaThrombotic Thrombocytopenic PurpuraToxicity, AmphetamineToxicity, SympathomimeticToxicity, Thyroid HormoneTransient Ischemic AttackUrinary Tract Infection, FemaleWithdrawal SyndromesCerebrovascular accidentsSeizure disordersBrain tumorsMetabolic diseasesMetastaticgestational trophoblastic diseaseThrombotic thrombocytopenic purpuraRoutine StudiesAll women who present with new-onset hypertension should have the following laboratory tests: Complete blood cell (CBC) count Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels Serum creatinine Uric acidIn addition, a peripheral smear should be performed, serum lactate dehydrogenase (LDH) levels should be measured, and an indirect bilirubin should be carried out if HELLP syndrome is suspected. Although a coagulation profile (prothrombin time [PT], activated partial [aPTT], and fibrinogen) should also be evaluated, the clinical use of routine evaluation is unclear when the platelet count is 100,000/mm3 or more with no evidence of bleeding.[39]Laboratory values for preeclampsia and HELLP syndrome [8, 40]Renal values are as follows: Proteinuria of >300 mg/24 h Urine dipstick >1+ Protein/creatinine ratio >0.3* Serum uric acid >5.6 mg/dL* Serum creatinine >1.2 mg/dLPlatelet/coagulopathy-related results are as follows: Platelet count < 100,000/mm3 Elevated PT or aPTT* Decreased fibrinogen* Increased d-dimer*Hemolysis-related results are as follows: Abnormal peripheral smear* Indirect bilirubin >1.2 mg/dL* Lactate dehydrogenase >600 U/L*In addition, elevated liver enzymes (serum AST >70 U/L) are found in preeclampsia and HELLP syndrome.[19]Urine testsTo diagnose proteinuria, a 24-hour urine collection for protein and creatinine should be obtained whenever possible. Up to 30% of women with gestational hypertension who have trace protein noted on random urine samples may have 300 mg of protein in a 24-hour urine collection.[41]Thus, a 24-hour urine protein analysis remains the criterion standard for proteinuria diagnosis. Alternatively, greater than 1+ protein on a dipstick analysis on a random sample is sufficient to make the diagnosis of proteinuria.Random urine samples can be used to calculate the protein-creatinine ratio. Thresholds of 0.14-0.3 have been proposed for diagnosing proteinuria.[42]However, there is no agreement yet as to the best threshold for identifying pregnant women with significant proteinuria. Moreover, up to 10% of patients with preeclampsia and 20% of patients with eclampsia may not have proteinuria.[43, 44](HELLP syndrome has been known to occur without hypertension or proteinuria.)Hyperuricemia is one of the earliest laboratory manifestations of preeclampsia. It has a low sensitivity, ranging from 0% to 55%, but a relatively high specificity of 77-95%.[45]Serial levels may be useful to indicate disease progression.Baweja et al suggest that when measuring urinary albumin using high-performance liquid chromatography in an early and uncomplicated pregnancy, spot urinary albumin:creatinine ratio (ACR) values are higher. If measured early in the second trimester, an ACR of 35.5 mg/mmol or higher may predict preeclampsia before symptoms arise.[46]Congo red dyeA study at Yale University has shown preliminary results that Congo red, a dye currently used to locate atypical amyloid aggregates in Alzheimer disease, may also be effective in the early diagnosis of preeclampsia.[45]This finding may lead to a spot urine test that can be used in emergency departments and internationally, especially in resource-poor countries where preeclampsia continues to be underdiagnosed and accounts for a large percentage of maternal and fetal mortality.Liver enzymesAlthough controversy exists over the threshold for elevated liver enzyme, the values proposed by Sibai et al (AST of >70 U/L and LDH of >600 U/L) appear to be the most widely accepted. Alternatively, values that are 3 standard deviations away from the mean for each laboratory value may be used for AST.[40]HistologyThe presence of schistocytes, burr cells, or echinocytes on peripheral smears, or elevated indirect bilirubin and low serum heptoglobin levels, may be used as evidence of hemolysis in diagnosing HELLP syndrome. The differential diagnosis for HELLP syndrome must include various causes for thrombocytopenia and liver failure such as acute fatty liver of pregnancy,hemolytic uremic syndrome,acute pancreatitis, fulminant hepatitis,systemic lupus erythematosus,cholecystitis, and thrombotic thrombocytopenic purpura.Additional laboratory testsOther laboratory values suggestive of preeclampsia include an elevation in hematocrit and a rise in serum creatinine and/or uric acid. Although these laboratory abnormalities increase the suspicion for preeclampsia, none of these laboratory tests should be used to diagnose preeclampsia.CT Scanning and MRIComputed tomography (CT) scanning and magnetic resonance imaging (MRI) scans have revealed numerous abnormalities in patients with eclampsia, such as cerebral edema, focal infarction, intracranial hemorrhage, and posterior leukoencephalopathy.[47]Currently, however, there is no pathognomonic CT scan or MRI finding for eclampsia. Furthermore, cerebral imaging is not necessary for the conditions diagnosis and management. However, head CT scanning is used to detect intracranial hemorrhage in selected patients with sudden severe headaches, focal neurologic deficits, seizures with a prolonged postictal state, or atypical presentation for eclampsia.UltrasonographyUltrasonography is used to assess the status of the fetus as well as to evaluate for growth restriction (typically asymmetricaluse abdominal circumference). Aside from transabdominal ultrasonography, umbilical artery Doppler ultrasonography should be performed to assess blood flow. The value of Doppler ultrasonography in other fetal vessels has not been demonstrated.CardiotocographyCardiotocography is the standard fetal nonstress test and the mainstay of fetal monitoring. Although it gives continuing information about fetal well being, it has little predictive value.Management of PreeclampsiaThe optimal management of a woman with preeclampsia depends on gestational age and disease severity. Because delivery is the only cure for preeclampsia, clinicians must try to minimize maternal risk while maximizing fetal maturity. The primary objective is the safety of the mother and then the delivery of a healthy newborn. Obstetric consultation should be sought early to coordinate transfer to an obstetric floor, as appropriate.[48]Patients with mild preeclampsia are often induced after 37 weeks' gestation. Before this, the immature fetus is treated with expectant management with corticosteroids to accelerate lung maturity in preparation for early delivery.In patients with severe preeclampsia, induction of delivery should be considered after 34 weeks' gestation. In these cases, the severity of disease must be weighed against the risks of infant prematurity. In the emergency setting, control of BP and seizures should be priorities. In general, the further the pregnancy is from term, the greater the impetus to manage the patient medically.Prehospital TreatmentPrehospital care for pregnant patients with suspected preeclampsia includes the following: Oxygen via face mask Intravenous access Cardiac monitoring Transportation of patient in left lateral decubitus position Seizure precautionsCare in Mild PreeclampsiaBefore 37 weeks, expectant management is appropriate. In most cases, patients should be hospitalized and monitored carefully for the development of worsening preeclampsia or complications of preeclampsia. Although randomized trials in women with gestational hypertension and mild preeclampsia demonstrate the safety of outpatient management with frequent maternal and fetal evaluations, most of the patients in these studies had mild gestational hypertension.[49]Therefore, the safety of managing a woman with mild preeclampsia as an outpatient still needs to be investigated.Although bedrest has been recommended in women with preeclampsia, little evidence supports its benefit. In fact, prolonged bed rest during pregnancy increases the risk of thromboembolism.A pregnancy complicated by mild preeclampsia at or beyond 37 weeks should be delivered. Although the pregnancy outcome is similar in these women as it is in women with a normotensive pregnancy, the risk of placental abruption and progression to severe disease is slightly increased.[50, 51]Thus, regardless of cervical status, induction of labor should be recommended. Cesarean section may be performed based on standard obstetric criteria.Antepartum testing is generally indicated during expectant management of patients with mild preeclampsia. However, there is little consensus regarding the types of tests to be used and the frequency of testing. Most clinicians offer a nonstress test (NST) and a biophysical profile (BPP) at the time of the diagnosis and usually twice per week until delivery.[33, 9]If a patient is at 34 weeks' gestation or more and has ruptured membranes, abnormal fetal testing, progressive labor, or fetal growth restriction in the setting of mild preeclampsia, delivery is recommended.Care in Severe PreeclampsiaWhen severe preeclampsia is diagnosed after 34 weeks' gestation, delivery is most appropriate. The mode of delivery should depend on the severity of the disease and the likelihood of a successful induction. Whenever possible, however, vaginal delivery should be attempted and cesarean section should be reserved for routine obstetric indications.Women with severe preeclampsia who have nonreassuring fetal status, ruptured membranes, labor, or maternal distress should be delivered regardless of gestational age. If a woman with severe preeclampsia is at 32 weeks' gestation or more and has received a course of steroid, she should be delivered as well.Patients presenting with severe, unremitting headache, visual disturbance, and right upper quadrant tenderness in the presence of hypertension and/or proteinuria should be treated with utmost caution.Expectant management of severe preeclampsiaIf a patient presents with severe preeclampsia before 34 weeks' gestation but appears to be stable, and if the fetal condition is reassuring, expectant management may be considered, provided that the patient meets the strict criteria set by Sibai et al (see Laboratory values for preeclampsia and HELLP syndrome).[52]This type of management should be considered only in a tertiary center. In addition, because delivery is always appropriate for the mother, some authorities consider delivery as the definitive treatment regardless of gestational age. However, delivery may not be optimal for a fetus that is extremely premature. Therefore, in a carefully chosen population, expectant management may benefit the fetus without greatly compromising maternal health.All of these patients must be evaluated in a labor and delivery unit for 24 hours before a decision for expectant management can be made. During this period, maternal and fetal evaluation must show that the fetus does not have severe growth restriction or fetal distress. In addition, maternal urine output must be adequate. The woman must have essentially normal laboratory values (with the exclusive exception of mildly elevated liver function test results that are less than twice the normal value) and hypertension that can be controlled.Fetal monitoring should include daily nonstress testing and ultrasonography performed to monitor for the development of oligohydramnios and decreased fetal movement. In addition, fetal growth determination at 2-week intervals must be performed to document adequate fetal growth. A 24-hour urine collection for protein may be repeated. Corticosteroids for fetal lung maturity should be administered prior to 34 weeks.Daily blood tests should be performed for liver function tests (LFTs), CBC count, uric acid, and LDH. Patients should be instructed to report any headache, visual changes, epigastric pain, or decreased fetal movement.Criteria for deliveryWomen with severe preeclampsia who are managed expectantly must be delivered under the following circumstances: Nonreassuring fetal heart status Uncontrollable BP Oligohydramnios, with amniotic fluid index (AFI) of less than 5 cm Severe intrauterine growth restriction in which the estimated fetal weight is less than 5% Oliguria (< 500 mL/24 h) Serum creatinine level of at least 1.5 mg/dL Pulmonary edema Shortness of breath or chest pain with pulse oximetry of < 94% on room air Headache that is persistent and severe Right upper quadrant tenderness Development of HELLP syndromeSeizure Treatment and Prophylaxis With Magnesium SulfateThe basic principles of airway, breathing, and circulation (ABC) should always be followed as a general principle of seizure management.Magnesium sulfate is the first-line treatment for the prevention of primary and recurrent eclamptic seizures. For eclamptic seizures that are refractory to magnesium sulfate, lorazepam and phenytoin may be used as second-line agents.Active seizures should be treated with intravenous magnesium sulfate as a first-line agent.[7]A loading dose of 4 g should be given by an infusion pump over 5-10 minutes, followed by an infusion of 1 g/h maintained for 24 hours after the last seizure. Recurrent seizures should be treated with an additional bolus of 2 g or an increase in the infusion rate to 1.5 g or 2 g per hour.Prophylactic treatment with magnesium sulfate is indicated for all patients with severe preeclampsia. However, no consensus exists as to whether patients with mild preeclampsia need magnesium seizure prophylaxis. Although ACOG recommends magnesium sulfate in severe preeclampsia, it has not recommended this therapy in all cases of mild preeclampsia.Some practitioners withhold magnesium sulfate if BP is stable and/or mildly elevated and if the laboratory values for LFTs and platelets are mildly abnormal and/or stable. Other physicians feel that even patients with gestational hypertension should receive magnesium, as a small percentage of these patients may either have preeclampsia or may develop it. The ultimate decision should depend on the comfort level of the labor and delivery staff in administering intravenous (IV) magnesium sulfate. An estimated 100 patients need to be treated with magnesium sulfate therapy to prevent 1 case of eclampsia.[53, 7, 54]Acute Treatment of Severe Hypertension in PregnancyIn the setting of severe hypertension (SBP >160 mm Hg; DBP >110 mm Hg), antihypertensive treatment is recommended. The goal of hypertension treatment is to lower BP to prevent cerebrovascular and cardiac complications while maintaining uteroplacental blood flow (ie, maintain BP around 140/90 mm Hg). However, although antihypertensive treatment decreases the incidence of cerebrovascular problems, it does not alter the progression of preeclampsia. Control of mildly increased BP does not appear to improve perinatal morbidity or mortality, and it may, in fact, reduce birth weight.HydralazineHydralazine is a direct peripheral arteriolar vasodilator and, in the past, was widely used as the first-line treatment for acute hypertension in pregnancy.[55, 56]This agent has a slow onset of action (10-20 min) and peaks approximately 20 minutes after administration. Hydralazine should be given as an IV bolus at a dose of 5-10 mg, depending on the severity of hypertension, and may be administered every 20 minutes up to a maximum dose of 30 mg.The side effects of hydralazine are headache, nausea, and vomiting. Importantly, hydralazine may result in maternal hypotension, which can subsequently result in a nonreassuring fetal heart rate tracing in the fetus.[8]In a meta-analysis, Magee et al pointed out that hydralazine was associated with worse maternal and perinatal outcomes than were labetalol and nifedipine. Furthermore, hydralazine was associated with more maternal side effects than were labetalol and nifedipine.[55]LabetalolLabetalol is a selective alpha blocker and a nonselective beta blocker that produces vasodilatation and results in a decrease in systemic vascular resistance. The dosage for labetalol is 20 mg IV with repeat doses (40, 80, 80, and 80 mg) every 10 minutes up to a maximum dose of 300 mg. Decreases in BP are observed after 5 minutes (in contrast to the slower onset of action of hydralazine), and the drug results in less overshoot hypertension than does hydralazine.Labetalol decreases supraventricular rhythm and slows the heart rate, reducing myocardial oxygen consumption. No change in afterload is observed after treatment with labetalol. The side effects of labetalol are dizziness, nausea, and headaches. After satisfactory control with IV administration has been achieved, an oral maintenance dose can be started.[8, 55]NifedipineCalcium channel blockers act on arteriolar smooth muscle and induce vasodilatation by blocking calcium entry into the cells. Nifedipine is the oral calcium channel blocker that is used in the management of hypertension in pregnancy. The dosage of nifedipine is 10 mg PO every 15-30 minutes, with a maximum of 3 doses. The side effects of calcium channel blockers include tachycardia, palpitations, and headaches. Concomitant use of calcium channel blockers and magnesium sulfate is to be avoided. Nifedipine is commonly used postpartum in patients with preeclampsia, for BP control.[8, 55]Sodium nitroprussideIn a severe hypertensive emergency, when the above-mentioned medications have failed to lower BP, sodium nitroprusside may be given. Nitroprusside results in the release of nitric oxide, which in turn causes significant vasodilation. Preload and afterload are then greatly decreased. The onset of action is rapid, and severe rebound hypertension may result. Cyanide poisoning may occur subsequent to its use in the fetus. Therefore, sodium nitroprusside should be reserved for use in postpartum care or for administration just before the delivery of the fetus.[8]Fluid ManagementLittle clinical evidence exists in the published literature on which to base decisions regarding the management of fluids during preeclampsia. Currently, no prospective studies on this topic are available, and guidelines are largely based on consensus and retrospective review.Despite the presence of peripheral edema, patients with preeclampsia are intravascularly volume depleted, with high peripheral vascular resistance. Diuretics should be avoided.Aggressive volume resuscitation may lead to pulmonary edema, which is a common cause of maternal morbidity and mortality. Pulmonary edema occurs most frequently 48-72 hours postpartum, probably due to mobilization of extravascular fluid. Because volume expansion has no demonstrated benefit, patients should be fluid restricted when possible, at least until the period of postpartum diuresis.Volume expansion has not been shown to reduce the incidence of fetal distress and should be used judiciously.Central venous or pulmonary artery pressure monitoring may be indicated in critical cases. A central venous pressure (CVP) of 5 mm Hg in women with no heart disease indicates sufficient intravascular volume, and maintenance fluids alone are sufficient. Total fluids should generally be limited to 80 mL/h or 1 mL/kg/h.Careful measurement of fluid input and output is advisable, particularly in the immediate postpartum period. Many patients will have a brief (up to 6 h) period of oliguria following delivery; this should be anticipated and not overcorrected.Postpartum ManagementPreeclampsia resolves after delivery. However, patients may still have an elevated BP postpartum. Liver function tests and platelet counts must be performed to document decreasing values prior to hospital discharge. In addition, one third of seizures occur in the postpartum period, most within 24 hours of delivery, and almost all within 48 hours.[57]Therefore, magnesium sulfate seizure prophylaxis is continued for 24 hours postpartum. (See Seizure Treatment and Prophylaxis With Magnesium Sulfate.)Rarely, a patient may have elevated liver enzymes, thrombocytopenia, and renal insufficiency more than 72 hours after delivery. In these cases, the possibility of hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP) must be considered. In such situations, plasmapheresis, along with corticosteroid therapy, may be of some benefit to such patients and must be discussed with renal and hematology consultants.In addition, the use of dexamethasone (10 mg IV q6-12h for 2 doses followed by 5 mg IV q6-12h for 2 doses) has been proposed in the postpartum period to restore platelet count to normal range in patients with persistent thrombocytopenia.[58, 59]The effectiveness of this therapy in preventing severe hemorrhage or ameliorating the disease course needs further investigation.Elevated BP may be controlled with nifedipine or labetalol postpartum. If a patient is discharged with BP medication, reassessment and a BP check should be performed, at the latest, 1 week after discharge. Unless a woman has undiagnosed chronic hypertension, in most cases of preeclampsia, the BP returns to baseline by 12 weeks postpartum.Eclampsia is common after delivery and has occurred up to 6 weeks after delivery. Al-Safi et al suggest that the first week after discharge is the most critical period for the development of postpartum eclampsia. Discussing the risks and educating patients about the possibility of delayed postpartum preeclampsia is important, regardless of whether they develop hypertensive disease prior to discharge.[60]Patients at risk for eclampsia should be carefully monitored postpartum.[61]Additionally, patients with preeclampsia who were successfully treated with delivery may present with recurrent preeclampsia up to 4 weeks postpartum.Prevention and Prediction of PreeclampsiaEfforts to prevent preeclampsia have been disappointing.[62]AspirinA systematic review of 14 trials using low-dose aspirin (60-150 mg/d) in women with risk factors for preeclampsia concluded that aspirin reduced the risk of preeclampsia and perinatal death, although it did not significantly affect birth weight or the risk of abruption.[63]Low-dose aspirin in unselected nulliparous women seems to reduce the incidence of preeclampsia only slightly.[64]For women with risk factors for preeclampsia, starting low-dose aspirin (commonly, 1 tablet of baby aspirin per day), beginning at 12-14 weeks' gestation, is reasonable. The safety of low-dose aspirin use in the second and third trimesters is well established.[63, 65]HeparinThe use of lowmolecular weight heparin in women with thrombophilia who have a history of adverse outcome has been investigated. To date, however, no data suggest that the use of heparin prophylaxis lowers the incidence of preeclampsia.Calcium and vitamin supplementsResearch into the use of calcium and vitamin C and E supplementations in low-risk populations did not find a reduction in the incidence of preeclampsia.[66, 67, 68]In a multicenter, randomized, controlled trial, Villar et al found that at the doses used for supplementation, vitamins C and E were not associated with a reduction of preeclampsia, eclampsia, gestational hypertension, or any other maternal outcome. Low birthweight, small for gestational age, and perinatal deaths were also unaffected.[69]A study by Vadillo-Ortega et al suggests that in a high-risk population, supplementation during pregnancy with a special food (eg, bars) containing L-arginine and antioxidant vitamins may reduce the risk of preeclampsia. However, antioxidant vitamins alone do not protect against preeclampsia. More studies performed on low-risk populations are needed.[70]Results from the Norwegian Mother and Child Cohort Study suggest that supplementation of milk-based probiotics may reduce the risk of preeclampsia in primiparous women. A prospective randomized trial has not yet been done to evaluate this intervention.[71]Screening TestsPreeclampsia is an appropriate disease to screen, as it is common, important, and increases maternal and perinatal mortality. However, although numerous screening tests for preeclampsia have been proposed over the past few decades, no test has so far been shown to appropriately screen for the disease.[72](Measurement of urinary kallikrein was shown to have a high predictive value, but it was not reproducible.[73, 74])Although work on sFlt-1, PlGF, and VEGF have been promising, their positive predictive value in predicting preeclampsia have yet to be evaluated in a prospective fashion.Currently, the clinical value of an accurate predictive test for preeclampsia is not clear, as effective prevention is still lacking. Intensive monitoring in women who are at increased risk for developing preeclampsia, when identified by a predictive test, may lower the incidence of adverse outcome for the mother and the neonate. However, the effectiveness of such a strategy must be rigorously investigated.PrognosisMorbidity and mortalityWorldwide, preeclampsia and eclampsia are estimated to be responsible for approximately 14% of maternal deaths per year (50,000-75,000).[16]Morbidity and mortality in preeclampsia and eclampsia are related to the following conditions: Systemic endothelial dysfunction Vasospasm and small-vessel thrombosis leading to tissue and organ ischemia CNS events, such as seizures, strokes, and hemorrhage Acute tubular necrosis Coagulopathies Placental abruption in the motherRecurrenceIn general, the recurrence risk of preeclampsia in a woman whose previous pregnancy was complicated by preeclampsia near term is approximately 10%.[43]If a woman has previously suffered from severe preeclampsia (including HELLP syndrome and/or eclampsia), she has a 20% risk of developing preeclampsia sometime in her subsequent pregnancy.[75, 76, 77, 78, 79, 80]If a woman has had HELLP syndrome or eclampsia, the recurrence risk of HELLP syndrome is 5%[76]and of eclampsia it is 2%.[78, 79, 80]The earlier the disease manifests during the index pregnancy, the higher the chance of recurrence rises. If preeclampsia presented clinically before 30 weeks' gestation, the chance of recurrence may be as high as 40%.[81]The fullPIERS model has been validated and was successful in predicting adverse outcomes in advance; therefore, it is potentially able to influence treatment choices before complications arise.[82]