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Preeclampsia, severe preeclampsia and hemolysis, elevated liver enzymes and lowplatelets syndrome: whatisnew?
Etienne Ciantar & James J Walker1
Preeclampsia and eclampsia have been known to us for centuries. Significant improvements have been made in our knowledge of the disease, however, delivery remains the only effective form of treatment. There is widespread variation of practice in the management of hypertensive disease in pregnancy, which may lead to substandard care. The use of aspirin in preventing preeclampsia, the lack of correlation between urinary protein and adverse outcome, and the ineffectiveness of corticosteroids in the management of hemolysis and elevated liver enzymes and low platelets syndrome are a few of the developments that will alter the way this condition is managed. This article aims to provide a general overview of preeclampsia, eclampsia and hemolysis, hemolysis and elevated liver enzymes and low platelets syndrome supported by the latest evidence, which will help the care provider adopt a focused approach and use the latest knowledge to understand and manage this old condition.

Hypertension in pregnancy remains a lead ing cause of maternal and fetal morbidity and mortality in the UK and worldwide. It is one of the most common medical disorders in preg nancy and the most frequent cause of iatrogenic prematurity. Preeclampsia occurs in 28% of all pregnancies [1] , with the incidence of severe preeclampsia being around 1%. Between February 2005 and February 2006 there were 214confirmed cases of eclampsia in the UK, representing an estimated incidence of 2.7 per 10,000 births [2] . Preeclampsia and eclampsia have been known to the ancient civilizations of Egypt, China and India. However, it was only in the mid to late 19 and early 20th century that hypertension and proteinuria, the two key features of preeclamp sia, were recognized. It was also identified that delivery was the only effective treatment for this enigmatic condition. Although advances in management have been made, this still remains the case today. Hypertension in pregnancy is defined as a diastolic blood pressure of 90mmHg or more, taken on two occasions more than 4h apart, or a single diastolic blood pressure of more than 110mmHg. This can occur either in women who already have hypertension (which can be primary or secondary) and who become preg nant, or can manifest itself denovo in the sec ond half of pregnancy in women who were previously normotensive, when it is called pregnancy-induced hypertension or gestational
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hypertension. It can be difficult to differentiate between those with chronic hypertension and those with pregnancy induced hypertension in the latter half of pregnancy. However, women who are chronically hypertensive will have a high blood pressure at their first antenatal booking visit or are known to be hypertensive prior to pregnancy (e.g., while taking the oral contracep tive pill). However, since both groups are at an increased risk of developing preeclampsia, they need to be closely monitored [3,4] . Preeclampsia is a multisystem disorder char acterized by hypertension, as described earlier, with the addition of proteinuria, defined as more than 300mg of protein in a 24h urine collec tion or more than 30mg/mmol in a spot uri nary protein:creatinine sample. It occurs after 20weeks of gestation with the hypertension and proteinuria resolving postnatally. Occasionally women present with a severe complication of preeclampsia such as eclampsia, or hemo lysis, elevated liver enzymes and low platelets (HELLP) syndrome. The risk of preeclampsia is 4.1% in women in their first pregnancy and 1.7% in later preg nancies overall. However, this risk rises to 14.7% in the second pregnancy in women who had preeclampsia in their first pregnancy and 31.9% in women who had preeclampsia in their previous two pregnancies [5] . In the most recent Confidential Enquiry into Maternal and Child Health in the UK (20032005), there were 18 reported deaths
Women's Health (2011) 7 (5), 555569

Department of Obstetrics &Gynaecology, Leeds Institute of Molecular Medicine, Level 8, Clinical Science Building, St James University Hospital, Beckett Street, Leeds, LS97TL, UK Author for correspondence: Academic Unit of Obstetrics & Gynaecology, D Floor, Clarendon Wing, Leeds General Infirmary, Belmont Grove, Leeds LS2 9NS, UK
1

Tel.: +44 113 392 3901 Fax: +44 113 392 3902 e.ciantar@leeds.ac.uk

Keywords
Doppler velocimetry eclampsia hemolysis, elevated liver enzymes and low platelets syndrome low-dose aspirin magnesium sulfate preeclampsia pre-eclamptic toxemia screen proteinuria umbilical artery

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from preeclampsia and eclampsia, an increase of four deaths from the previous triennium. Ten of these deaths were caused by intracranial hemor rhage, highlighting the ineffective management of the systolic blood pressure in these women[6] . A study from the USA also demonstrated a sig nificant rise in the prevalence of hypertensive disorders amongst hospitalized pregnant women, from 67.2 per 1000 in 1998 to 81.4 per 1000 in 2006 [7] . It has been shown that there is still signifi cant variation in practice around the UK in the management of preeclampsia, which may con tribute to the substandard care of this potentially lethal condition. In a survey of 370women who developed preeclampsia, 34% did not receive antihypertensive treatment with a systolic blood pressure of 160mmHg or more, while only 17% of these women received magnesium sulfate prophylactically [8] . In view of this, the NICE has recently launched a new clinical guideline on the man agement of hypertensive disorders during preg nancy in order to standardize care and improve morbidity and mortality. This guideline con tains recommendations on the diagnosis and management of hypertension in pregnancy during the antenatal, intrapartum and postnatal period. It also offers guidance on the manage ment of women who suffer from chronic hyper tension and wish to conceive as well as advice to women whose pregnancy was complicated by hypertension [9] .
Pathophysiology

The pathophysiology of preeclampsia is complex and involves various pathways and mechanisms that are interlinked. There is ongoing research to help us further understand this condition and try to identify preventive and therapeutic strate gies. Apart from a few well documented excep tions, preeclampsia appears to be triggered by the placenta as it can occur in molar pregnancies where the fetus is absent. Histopathological placental studies from hypertensive women have established that tro phoblastic invasion of the myometrium by the spiral arteries is inhibited in women with hyper tension in pregnancy. However, this may be partial or incomplete, implying that the lack of trophoblastic invasion in hypertensive pregnant women is not an all or none phenomenon [10] . Interestingly, recent studies have identified the importance of immunological factors in guaranteeing implantation success and how an imbalance in the immunological milieu can
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lead to placental failure. There seems to be an interaction between uterine natural killer cells and trophoblastic cells, regulating tropho blastic invasion as well as macrophage-derived TNF- a. [11,12] The fetalmaternal immunologi cal interaction at placentation involves maternal killer immunoglobulin-like receptors and fetal HLA-C molecules. This interaction seems to fail in preeclampsia, highlighting an immuno logical basis to trophoblastic invasion defi ciency [13] . This immunological influence also explains the increased incidence of preeclampsia in primigravida and change in paternity [14] , as well as the reduced incidence of preeclampsia in women who received a blood transfusion [15] . While abnormal placentation leads to placen tal insufficiency and fetal growth restriction, the development of preeclampsia is not inevitable. Further systemic changes are required. Increased inflammatory activity leads to widespread dam age to the vascular endothelium leading to cap illary leak, vasoconstriction and intravascular hemolysis, and platelet activation [16] . This is further compounded by a heightening of the immunological state in preeclampsia, through activation of circulating leucocytes, which is similar to sepsis [17] . This inflammatory response may be caused by placental debris, where the damaged placenta releases fragments into the maternal circulation leading to systemic inflam mation and vascular dysfunction [18] . Therefore, the development of preeclampsia is mediated through the degree of placental pathology and the maternal inflammatory response to the results of damage. One of the recognized functional changes in preeclampsia is the dysfunction of the vascular endothelium. Although numerous mechanisms have been suggested, recent studies show that the loss of VEGF contributes towards these changes. It has been shown that cancer patients receiving anti-VEGF therapy exhibit symptoms similar to preeclampsia [19] . It is also postu lated that preeclampsia occurs because of the elevation of circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which acts as a potent inhibi tor of VEGF [20] . Studies have shown that by reducing the levels of free sFlt-1 the symptoms of preeclampsia have alleviated [21] . Cigarette smokers are known to have reduced levels of circulating sFLT-1 and increased PGF [22] . Clinically, whereas smoking increases the risk of preterm labor, intra-uterine growth restric tion (IUGR) and abruption, it reduces the risk of preeclampsia by a third [23] . There is currently growing interest in therapeutically reducing the
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elevated levels of sFlt-1 in preeclampsia to mini mize its severity and prolong the pregnancy in early-onset disease. Statins, so far contraindi cated in pregnancy, inhibit cytokine-mediated release of sFlt-1 [24] . Statins to Ameliorate Early Onset Preeclampsia (StAmP), the first random ized placebo-controlled trial for the use of statins in early pregnancy, is currently underway and the obstetric community is eager to find out whether statins have a role in the treatment of preeclampsia [25] .
Prevention

In view of the potential severity of preeclamp sia, there have been various studies trying to identify preventive pharmaceutical agents, with a particular emphasis on the use of antiplateletagents. A Cochrane systematic review of 59 trials including 37,560 women revealed a reduction in the risk of preeclampsia with the use of anti platelet drugs, mainly low-dose aspirin. The participants were all pregnant women at risk of developing the disease. There was found to be a 17% reduction in the risk of preeclampsia associated with the use of antiplatelet drugs (46trials; 32,891women; relative risk: 0.83; 95%CI: 0.770.89, numbers needed to treat [NNT]: 72). This confidence interval implies that the risk reduction (RR) could vary from a high of 23% to a low of 11%. However, the RR was increased in women with an increased base line risk with those considered to be at high risk on entering the trial (previous preeclampsia, chronic hypertension, diabetes, renal disease and autoimmune disease) having a RR of 25% (95%CI: 3415%). For moderate risk women (first pregnancy, mild rise in blood pressure and no proteinuria, abnormal uterine artery Doppler wave-forms, positive roll-over test, multiple preg nancies, family history of severe preeclampsia and being a teenager), antiplatelet agents were associated with a 14% reduction in preeclampsia risk (95% CI: 215% reduction). The NNT based on absolute RR was therefore 72 women (95%CI: 52119women). However, 19high risk women are needed to treat to prevent one case of preeclampsia (95%CI: 1334women), while for moderate risk women this goes up to 119 (95%CI: 73333women) [26] . Antiplatelet agents were also associated with an 8% reduction in the relative risk of preterm birth (29trials, 31,151women, relative risk:0.92, 95%CI: 0.880.97); NNT 72 (52, 119), as well as a 14% reduction in fetal and neonatal death (40 trials, 33,098 women, relative risk 0.86,
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95% CI: 0.760.98); NNT 243 (131, 1666) and a 10% reduction in small-for-gestational age babies (36 trials, 23,638 women, relative risk:0.90; 95%CI: 0.830.98) [26] . There also seems to be evidence that RR improves with higher doses of aspirin with a concurrent increased risk of adverse effects. Therefore, the safety profile is limited to lowdose preparations. The moderate efficacy of low-dose aspirin in preventing preeclampsia is perhaps not as promising as one would expect. The NNT are relatively high, although they are much lower for high-risk women [26] . However, the safety and low cost of the inter vention makes the use of low-dose aspirin in preventing preeclampsia a cost-effective tool, albeit of moderate efficacy. Further information is required to define the target group of patients and the effective dose of aspirin. The new NICE guideline on the management of hypertensive disorders during pregnancy therefore recommends that all women with a high risk of developing preeclampsia should start low-dose aspirin (75mg) from 12weeks until the birth of the baby [9] . The women considered to be at high risk are thefollowing: Hypertensive disease in the previous preg nancy Chronic kidney disease Autoimmune disease such as systemic lupus erythematosus and antiphospholipid syn drome Type1 or Type2 diabetes Chronic hypertension In addition, the same recommendation holds for women with more than one moder ate risk factor for developing preeclampsia. Theseinclude: First pregnancy Age 40years or older Pregnancy interval of more than 10years BMI of more than 35 kg/m2 or more at firstvisit Family history of preeclampsia Multiple pregnancies There have been other numerous studies to evaluate the effectiveness of other agents in the prevention of preeclampsia. A Cochrane sys tematic review evaluating the role of nitric oxide agents (i.e., glycerine trinitrate, l -arginine)
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showed that there is insufficient evidence to draw reliable conclusions in preventing preeclampsia and its complications [27] . Similarly, in another Cochrane review of two randomized controlled trials comparing proges terone with placebo in preventing preeclampsia and its complications, results showed that there was no clear evidence on its role in preventing the disease [28] . Diuretics have been used in the past to prevent or delay the onset of preeclampsia. However, four trials investigating the role of diuretics compared with placebo or no treatment in the prevention of preeclampsia did not show any benefit in terms of RR [29] . Since it is now recog nized that diuretics should not be used in preg nancy as they can reduce the plasma volume with deleterious consequences, there is limited evidence to support their use for the prevention of the disease. However, diuretics may only be used cautiously in preeclampsia to treat clini cally significant pulmonary edema in women whose fluid balance is being closelymonitored. One randomized controlled trial studied the role of low-molecular-weight heparin in prevent ing preeclampsia. The study involved 80women with an angiotensin-converting enzyme DD genotype and a history of preeclampsia. A group of 41women were assigned to receive dalteparin 5000IU/day at the time of a positive pregnancy test, while 39 women did not receive treatment. The treatment group had a lower risk of develop ing preeclampsia compared with the control group (RR: 0.26; 95% CI: 0.080.86) [30] . However, this was a poor quality trial although it did show a statistically and clinically signifi cant reduction in preeclampsia but in a highly selected group of women with a particular geno type. Patients with systemic lupus erythemato sus, whose risk of developing preeclampsia is as high as 3250%, have been shown to improve their feto-maternal outcomes, especially their risk of developing preeclampsia, if treated with low-molecular-weight heparin [31] . The effect of nutritional supplements in preventing preeclampsia has also been exten sively studied. Magnesium, folic acid, fish oils, algal oils, antioxidants and garlic do not seem to be effective in preventing the dis ease [9] . Interestingly, a Cochrane review of 12 randomized controlled trials involving 15,206women has shown that women receiv ing calcium supplementation were half as likely to develop preeclampsia compared with pla cebo. Therefore, calcium supplementation appears to be beneficial for women at high risk
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of developing hypertension in pregnancy and in communities with low dietary calcium [32] . However, there does not seem to be any sta tistically significant RR in communities where dietary calcium intake is adequate.
Management of preeclampsia Proteinuria

The association between proteinuria and preeclampsia has long been established and its presence is diagnostic of the disease and is indicative of its multisystem nature leading to maternal and fetal morbidity and mortality. Pollaks work, published in 1960, revealed that the kidneys in preeclampsia underwent a series of unique pathological changes [33] . The glomer uli were found to be enlarged, swollen and isch emic. Glomerular involvement in preeclampsia is widespread, with all being affected to the same degree. The most prominent pathological feature seems to be the cellular edema of the glomeru lar tuft, affecting both endothelial and epithe lial cells. The swollen endothelial cytoplasm encroaches upon the lumen of the glomerular capillaries, contributing to the tufts ischemia. The changes were not found to occur in other diseases affecting the kidney. Therefore, these changes are diagnostic of preeclampsia, which can be tested for by the presence of proteinuria. Proteinuria is screened for by using a urinary dipstick test and can be easily performed on the ward, clinic or in the community. Quantitative measurements can be obtained using a 24 h collection or a spot urine protein:creatinine ratio. Studies have linked the severity of the proteinuria with maternal and fetal outcomes. In women with preeclampsia, the probability of an adverse maternal outcome increases with increasing age and with higher spot urinary protein:creatinine ratios. Therefore, there is a reduction of spot urine threshold values with increasing age [34] . The extent of severity of proteinuria is asso ciated with higher obstetric intervention rates (induction of labor and predelivery Cesarean sections), as well as low birth weights [35] . The extent of proteinuria may also be linked to the severity of fetal distress in labor, with high levels of proteinuria being associated with an increased risk of recurrent late decelerations on the cardio-tocograph [36] . Owing to these findings, high levels of urinary protein have always been looked upon with trepi dation and delivery contemplated if significantly high levels are present. Historically, a 24h uri nary collection of >5g mandated delivery. The
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trend now is to have a more rational approach towards proteinuria. In a study of 598women with a previous history of preeclampsia, it was found that women who developed severe gesta tional hypertension (without proteinuria) were more likely to have a preterm delivery and a small-for-gestational-age baby compared with women with mild preeclampsia. In addition, in the presence of severe hypertension, proteinuria did not increase the rates of preterm delivery and small-for-gestational-age babies [37] . Similarly, in an interesting study by Newman et al., 299 patients with preeclampsia who delivered before 37weeks were studied retro spectively [38] . These patients were divided into groups with mild (<5 g/24 h), severe (59.9g/24h) and massive (>10g/24h) pro teinuria. Massive proteinuria was associated with an earlier onset of preeclampsia, earlier gestational age at delivery and increased risk of complications related to prematurity. However, after correction for prematurity, massive protein uria did not seem to have any effect on neonatal outcomes. The authors concluded that neonatal morbidity is related to prematurity and not to proteinuria perse [38] . A systematic review of 16 primary articles involving 6749women with preeclampsia and varying levels of proteinuria concluded that the estimations of levels of proteinuria in women with preeclampsia do not correlate with mater nal and fetal outcomes. Urinary protein estima tion was not found to be a clinically useful pre dictive test, disputing the practice of deciding on delivery based on the severity of proteinuria[39] . The new NICE guideline confers with the evidence highlighted in this systematic review in that there does not seem to be a direct link between changing urinary protein levels and adverse outcome [9] . Therefore, contrary to the standard practice so far, it recommends that once proteinuria has been diagnosed there is no benefit in repeating the test. However, this important issue needs further investigation by well-designed prospective studies. Preeclampsia is a multisystem disorder with hypertension being one of its manifestations and main clinical risks. Therefore, although lowering the blood pressure has no effect on the patho logical process of the condition, controlling blood pressure is necessary to avoid maternal risks such as maternal cerebrovascular accidents. Monitoring of the blood parameters, often referred to as a pre-eclamptic toxemia screen or hypertensive bloods, gives an indication on the severity and progress of the disease.
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Pre-eclamptic toxemia screen

Since preeclampsia is a multisystem disorder, this screen has traditionally consisted of a group of blood tests that study different organs and physiological systems such as a full blood count, particularly the platelet count, kidney function tests, liver function tests and a coagulation screen. In women with gestational hyperten sion without proteinuria, there is little evidence that these blood parameters have any link with disease progression and subsequent development to preeclampsia.
Uric acid

In a systematic quantitative review of a uric acid test to determine the accuracy by which it predicts maternal and fetal complications in women with preeclampsia, it was found that uric acid is a poor predictor for compli cations [40] . The review showed that a positive result (uric acid level of 350mol/l or more) predicted progression to eclampsia with a pooled likelihood ratio (LR) of 2.1 (95%CI:1.43.5), with a negative result having a pooled LR of 0.38 (95% CI: 0.180.81). A positive result predicted development of severe hyperten sion with a LR of 1.7 (95% CI: 1.32.2), with a negative result having a LR of 0.49 (95%CI: 0.380.64). The chance of requiring a Cesarean section was 2.4 (95%CI:1.34.7) and 0.39 (95% CI: 0.200.76) for positive and negative results respectively. Stillbirth and neonatal death had respective LRs of 1.5 (95%CI:0.912.6) and 0.51 (95%CI: 0.21.3), while for predicting small-for-gestational-age, the LR was 1.3 (95%CI: 1.11.7) for a posi tive result and 0.60 (95%CI: 0.430.83) for a negative result. It was therefore concluded that use of therapeutic measures such as magnesium sulfate or planning early delivery should not be based on uric acid levels [40] .
Renal function tests, liver function tests & platelet count

In a Swedish study of 111 patients with preeclampsia it was found that the only vari able that significantly predicted maternal complications (HELLP syndrome, placental abruption, oliguria and eclampsia) was dia stolic blood pressure [41] . Interestingly, serial blood sampling did not have any predictive value on disease progression [41] . In another cohort study conducted in Canada, the UK, Australia and New Zealand, a platelet count of less than 100109 /l was associated with a statistically significant increased likelihood of
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adverse maternal and perinatal outcomes [42] . Similarly, elevated liver enzymes and creatinine levels greater than 110mol/l were associated with adverse maternal outcomes[42] . Therefore, it can be inferred that platelet count, transaminases and serum creatinine are good predictors of disease progression in women who already have preeclampsia, while rising uric acid does not add any additional information to these tests. In addition, coagulation studies are of limited value when the platelet count is above100109/l.
Treatment

kidney function, electrolytes, full blood count, transaminases and bilirubin. The frequency of these investigations depends on the severity of the condition twice weekly with mild hyper tension and three times weekly with moderate/ severe hypertension. In addition, once protein uria has been identified, quantification need not be repeated.
Fetal monitoring Fetal biometry & umbilical artery Doppler velocimetry

Labetalol is a widely used, safe and effective antihypertensive agent that is licensed for use in pregnancy. It is now considered to be the first-line agent [9] . Alternative treatment may be necessary when labetalol is contraindicated, such as in patients with asthma. Additionally women of AfroCaribbean origin seem to be resistant to b-blocker treatment. Safe alternatives to labetalol are methyldopa and nifedipine. The latter can be used safely in combination with either labet alol or methyldopa. In extreme circumstances all three can be used together, however, 80% of women with preeclampsia have their blood pressure controlled with oral labetalol only [43] . In a study of 200primigravida women with mild preeclampsia at 2635weeks gestation, labetalol has been shown to reduce blood pres sure to statistically significant levels compared with hospitalization only [44] . The reduction in blood pressure was not associated with an improvement in perinatal outcome. This highlights the fact that the principal aim of decreasing blood pressure is to reduce maternal morbidity and to prolong the pregnancy to a ges tation in which fetal morbidity associated with prematurity is minimized. Commencing antihypertensive treatment in preeclampsia depends on the blood pres sure readings. Mild hypertension (140/90 to 149/99 mmHg) does not require treatment. However, moderate hypertension (150/100 to 159/109mmHg) would require commencement of labetalol with an aim to keep the diastolic blood pressure between 80100mmHg and the systolic blood pressure less than 150 mmHg. Similar ranges are aimed for with severe hyper tension, which is defined as a blood pressure of 160/110mmHg or higher [9] . Patients with preeclampsia should be admitted to hospi tal, have regular blood pressure readings (at least four times a day), testing for proteinuria and monitoring of blood parameters, namely
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Patients with preeclampsia have an increased risk of intrauterine growth restriction. Growth scans and fetal biometry are therefore useful in identifying and monitoring fetal growth in thesepatients. In patients with hypertensive disease of preg nancy, the absence of end-diastolic velocities on umbilical artery Dopplers is crucial as this is associated with increased neonatal morbidity and mortality. Therefore, the presence of enddiastolic flow is generally reassuring, while its absence indicates that delivery will be required in the near future [45] . A systematic review of 13 randomized controlled trials with a total number of 8633participants looked into the use of umbilical artery Doppler velocimetry in highrisk pregnancies compared with no Doppler or with routine monitoring [46] . Perinatal mortal ity was statistically significantly less in babies born to high-risk women who were monitored with umbilical artery Doppler velocimetry (OR [odds ratio]: 0.67; 95% CI: 0.470.97) and they were less likely to have low Apgar scores at 5min (OR: 0.89; 95%CI: 0.740.97). These women were also less likely to be admitted antenatally (OR: 0.56; 95% CI: 0.430.72) and to require an emergency Cesarean section (OR:0.85; 95%CI: 0.740.97). Additionally, subgroup ana lysis of well defined studies showed that women monitored with umbilical artery Doppler velocimetry were less likely to be induced (OR: 0.78; 95% CI: 0.630.96) or to have elective delivery (OR: 0.73; 95%CI: 0.610.88) or Cesarean section (OR: 0.78; 95%CI: 0.650.94) [46] . Therefore, it can be concluded that in studies of high-risk pregnancies, of which hypertension was a component, the use of umbilical artery Doppler velocimetry reduces perinatal morbid ity and mortality and helps in deciding timing of delivery, especially when absent end-diastolic flow was seen. However, there is little evidence on when the investigation should be performed and subsequently repeated.
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Biophysical profile

There is no evidence to support the use of a biophysical profile (BPP) in pregnancies compli cated by hypertension. A Cochrane systematic review assessing the use of the BPP compared with conventional monitoring (cardiotocogra phy only or modified BPP) showed that there were no statistically significant differences in perinatal deaths or admission to neonatal spe cial care between the two groups [47] . There were also no statistically significant differ ences amongst the two groups for the follow ing parameters: Apgar scores less than 7 at or after 5min, small for gestational age, meco nium-stained liquor, respiratory distress syn drome and Cesarean section for fetal distress. Subgroup ana lysis of the high-quality trials showed a statistically significantly higher level of Cesarean section in the BPP group [47] .
Liquor volume

Amniotic fluid is maintained at an equilibrium and has various important functions, including protection from trauma, bacteriostatic proper ties, protection of the umbilical cord and pla centa, and aiding in the development of the musculoskeletal system. It is also an important measure of fetal well-being [48] . A Cochrane review compared the use of the amniotic fluid index with the use of the sin gle deepest vertical pocket measurement as a screening tool for decreased amniotic volume in the prevention of adverse pregnancy out comes [49] . It showed that there is no evidence that one method is better than the other. There were no differences in admission to neonatal special care, perinatal death, umbilical artery pH less than 7.1, meconium, Apgar score less than seven at 5min or Cesarean section [49] .
Uterine artery Doppler velocimetry

had a pooled LR of 0.7 (95%CI: 0.60.8). For IUGR the pooled LR for a positive result was 3.6 (95%CI: 3.24.0) and 0.8 for a negative result (95%CI: 0.80.9). Perinatal death had a pooled LR of 1.8 (95%CI:1.22.9) for a positive result and 0.9 for a negative result (95%CI:0.81.1). In the high-risk population a positive result pre dicted preeclampsia with a pooled LR of 2.8 (95%CI: 2.33.4), while a negative result hade a LR of 0.8 (95%CI:0.70.9). IUGR was pre dicted with a ratio of 2.7 (95%CI: 2.13.4) with a positive result and 0.7 (95%CI: 0.60.9) for a negative result. In this population peri natal death was predicted with a pooled LR of 4.0 (95%CI: 2.46.6) for a positive result and 0.6 (95% CI: 0.40.9) for a negative result. Therefore, it was concluded that uterine artery Doppler studies had limited accuracy in predicting preeclampsia and its complications. The NICE guideline states that the negative predictive ability and sensitivity of the test is not sufficient to allow clinicians to alter their man agement in women who are at a high risk of devel oping preeclampsia but have abnormal uterine artery Dopplers at 2024weeks [9] . Incidentally these women would already be on aspirin and closely monitored so it is debatable how this test would alter the patientsmanagement.
Timing of delivery

Since preeclampsia is associated with a dis turbance in uteroplacental blood flow, assess ing uterine blood flow in the second trimester should help predict development of the disease. Chien et al. conducted a quantitative systematic review of 27 studies involving 12,994patients to evaluate the clinical usefulness of Doppler ana lysis of the uterine artery veloc ity waveform in the prediction of preeclampsia and its associated complications of IUGR and perinatal death [50] . The results showed that a positive result (flow velocity waveform ratio diastolic notch) in the low-risk population predicted preeclampsia with a pooled LR of 6.4 (95%CI:5.77.1), while a negative result
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Ultimate treatment of preeclampsia is delivery, bearing in mind the neonatal risks associated with iatrogenic prematurity. Two randomized controlled trials investi gated the maternal and neonatal outcome when adopting an early delivery approach against expectant management in women with severe preeclampsia at up to 34weeks gestation [51,52] . In both trials patients were stabilized with mag nesium sulfate and antihypertensives and given steroids for fetal lung maturation. If they con tinued to meet the eligibility criteria they were randomized into two groups early delivery by Cesarean section or induction 48 h after steroid administration and expectant manage ment with bed rest, oral antihypertensives and intensive antenatal fetal monitoring until they were delivered at 34weeks, or earlier if mater nal or fetal condition worsened. Neonates in the early delivery group showed a greater frequency of hyaline membrane disease (relative risk:2.3; 95% CI: 1.393.81) and necrotizing entero colitis (relative risk:5.54; 95%CI: 1.0429.56) with no statistically significant difference in rates of stillbirth or death after delivery (rela tive risk:1.50; 95% CI: 0.425.41). There were
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also no statistically significant differences in maternal complications (placental abruption and Cesarean section). It seems sensible to adopt an expectant approach and aim for delivery at 34 weeks unless there is clear maternal or fetal compro mise. There is no evidence of any benefit in pro longing pregnancy beyond 34weeks in severe preeclampsia. In addition, it is difficult to base timing of birth on single biochemical and hema tological parameters (including level of protein uria) as they are poor predictors of maternal and fetal outcome. Therefore, it is imperative that the decision on timing of delivery is knowledge by a senior obstetrician with an taken of the whole clinical picture. The Hypertension and Preeclampsia Intervention Trial in the Almost Term patient (HYPITAT) showed that there was no mater nal or immediate neonatal disadvantage with immediate birth after 37weeks in women with preeclampsia and the NICE guideline recom mends delivery after 37weeks since there is no evidence of benefit in prolonging pregnancy [9,53] . Similar findings were seen for those with mild-tomoderate hypertension but the NICE guideline states that delivery should be offered to women after 37weeks as the evidence is lessclear. The mode of birth for women with severe preeclampsia or eclampsia depends on the clinical circumstances and on the womanspreference.
Magnesium sulfate:treatment

Loading dose of 4g given intravenously over 5 min, followed by an infusion of 1 g/h maintained for 24h; Recurrent seizures should be treated with a further dose of 24g given over 5min.
Magnesium sulfate:prevention

Magnesium sulfate is the anticonvulsant of choice in the treatment of eclampsia. The drug has been used since the 1920s when it was found to be effective in the control of convulsions sec ondary to tetanus [54] . Its mode of action is not clearly understood. In a Cochrane review com paring it with diazepam, it was found that mag nesium sulfate was associated with less maternal death and recurrence of convulsions[55] . Babies of women treated with magnesium sulfate were also less likely to stay in special care for longer than 7days and were less likely to have Apgar sores less than seven at 1 and 5 min when compared with diazepam. Similar Cochrane reviews have demonstrated that magnesium sulfate is superior to phenytoin and to a lytic cocktail (a combination of drugs consisting of chlorpromazine, promethazine and pethidine) [56,57] . The regimen for administration of magne sium sulfate follows the Collaborative Eclampsia Trial[58] :
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The Magnesium Sulphate for Prevention of Eclampsia (MAGPIE) Trial Collaborative Group evaluated the use of magnesium sul fate in the prevention of eclampsia in women with preeclampsia [59] . The study consisted of 10,141women in the antenatal period or less than 24h postpartum. They had a blood pres sure of 140/90mmHg or more and 1+ of pro teinuria (30mg/dl) on urinary dipstick. Women were randomized in 33countries to either mag nesium sulfate (n=5071) or placebo (n=5070). Women who were given magnesium sulfate had a 58% lower risk of developing eclamp sia (95%CI: 4071) than the placebo group (40, 0.8%, vs 96, 1.9%; 11fewer women with eclampsia per 1000women). Maternal mortal ity was also lower in the treatment group (rela tive risk 0.55; CI: 0.261.14). A total of 24% of women given magnesium sulfate reported side effects as opposed to 5% with placebo. Two follow-up studies investigating the longterm effects to the mother and baby following treatment with magnesium sulfate during preg nancy showed that there were no statistically significant differences in the primary outcomes studied between the treatment and placebo group [60,61] . The primary outcomes were death and serious morbidity related to preeclampsia for the mother and death and noncongenital neurosensory disability for the baby. Magnesium sulfate has also been found to be cost effective in preventing eclampsia, with the benefit increasing with the severity of the disease [62] . Therefore, it should be considered in women with severe preeclampsia who are in a critical care setting if birth is planned within 24h. Patients with severe preeclampsia who would benefit from magnesium sulfate are those with severe hypertension and proteinuria or mild or moderate hypertension and proteinuria with one or more of the following [9] : Symptoms of severe headache Problems with vision, such as blurring or flashing before the eyes Severe pain just below the ribs or vomiting
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Preeclampsia, severe preeclampsia & HELLP syndrome

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Papilledema Signs of clonus (three or more beats) Liver tenderness HELLP syndrome Platelet count falling to below 100109/l Abnormal liver enzymes (alanine transami nase or aspartate transaminase rising to above 70IU/l)
Antihypertensives in severe preeclampsia

Apart from treating and preventing convulsions, it is also important to lower the blood pressure in women with severe preeclampsia. However, the blood pressure should not be reduced too quickly and too aggressively. The main aim is to stop the rise and maintain a stepwise downward trend to levels below 150/100mmHg. The Centre for Maternal and Child Enquiries latest report has shown that that the single most serious failing in the clinical care of women with preeclampsia is the inadequate treatment of the systolic blood pressure [6] . There still seems to be an erroneous understanding that the diastolic reading is more associated with maternal morbidity and mortal ity than the systolic. However, it is the latter that can lead to fatal intracranial hemorrhage or aortic dissection. In a study of strokes in women during pregnancy and the puerperium, it was found that hypertensive disorders are a common comorbid condition, being present in 45% of patients with an ischemic stroke and in 64% of patients with a hemorrhagic stroke. In addition, strokes are more likely to occur in the third trimester and the first week postpartum, possibly related to the large volume shifts, hypercoagulability, vasoconstric tion and increased osmolarity superimposed on the damaged endothelium found in preeclamp sia [63] . There seems to be a predilection of the parieto-occipital and occipital lobes in hyper tensive encephalopathy and eclampsia. Posterior reversible encephalo pathy has been described in women with severe preeclampsia and eclamp sia. It manifests itself as seizures, headaches, visual disturbances and characteristic imaging abnormalities on CT scans and MRI, associated with a sudden rise in blood pressure that leads to vasogenic edema owing to loss of the cerebral vasculature autoregulatory capacity [64,65] . It is therefore recommended by NICE that the maternal blood pressure should be brought down to a level of 150/80100mmHg in women with severe hypertension who are in critical care.
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There is no evidence of any significant dif ferences in efficacy between the different anti hypertensive preparations (labetalol, nifedipine and hydralazine). A Cochrane review of all ran domized trials looking at different drugs for the treatment of very high blood pressure during pregnancy concluded that there was insufficient data for reliable conclusions to compare the effi cacy of the various drugs used in this setting [66] . In fact, more robust studies are needed to com pare and evaluate the different antihypertensive treatments. Labetalol is the only drug licensed for the treatment of hypertension in pregnancy and has a very low side-effect profile. It can be given both orally and intravenously, in contrast to nifedipine, which is given orally and hydrala zine intravenously. The latter may cause sudden severe hypotension. Smaller more frequent doses of hydralazine can be used, but labetalol either orally or intravenously is generally considered to be a superior drug. The oral route is preferred to the intrave nous one, owing to ease of administration and costeffectiveness.
Fluid balance

The Confidential Enquiry into Maternal and Child Health in the UK reported six deaths in the triennium 19941996 caused by adult respiratory distress syndrome, related to poor fluid management in women with preeclampsia or eclampsia [67] . This highlighted the impor tance of having senior medical involvement in managing the fluid balance of these patients. Subsequent reports showed a marked improve ment in the number of deaths reported for the same complication, with no deaths in the last two triennia 20032005 and 20062008. Volume expansion should not be used in women with severe preeclampsia. The only exception is the preloading of no more than 500 ml of intravenous crystalloid fluid prior to birth in women being treated with intravenoushydralazine. The Yorkshire Obstetric Critical Care Group developed a common guideline for the manage ment of severe preeclampsia and eclampsia for the 16units within Yorkshire (UK) [43] . This guideline ensures a uniform standard of care amongst all units. It helps clinicians decide appropriate management, especially in the more challenging aspects of the disease such as fluid management. This guideline restricts fluids to 80ml/h in the peripartum period, leading to a low rate of fluid-related problems in the moth ers. This is also related to the allowance of a
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relatively low urine output, allowing 8h with the equivalent of less than 20ml/h of urine out put prior to intervening. In a 5-year prospective study on the risks of serious complications from severe preeclampsia and eclampsia in the region following the introduction of this guideline, it was found that amongst 1087women diagnosed with preeclampsia or eclampsia during the study period, 82 (3.9 per 10,000 deliveries) had eclamptic fits and 49 (2.3 per 10,000 deliveries) required intensive care admission. A total of 25 women (2.3%) developed pulmonary edema and six required renal dialysis (0.55%). It was con cluded that the guideline, which could be easily implemented in other regions, may contribute to lower rates of serious complications. There are strong similarities amongst preeclampsia guidelines from other countries. The American Congress of Obstetricians and Gynecologists recommends that severe preeclampsia should be managed in a tertiary cen ter, while patients with mild disease who are still remote from term can be treated conserva tively [68] . Treatment with labetalol or hydrala zine is recommended if the diastolic blood pres sure is 105mmHg or more. Magnesium sulfate is also recommended for the prevention and treatment of seizures in women with preeclamp sia or eclampsia [68] . The Society of Obstetricians and Gynaecologists of Canada recommend anti hypertensive therapy when the blood pressure exceeds 160/100mmHg using labetalol, nife dipine or hydralazine with magnesium sulfate also used for the prevention and treatment of seizures [69] . These guidelines recommend expectant management for women <34weeks in centers capable to care for preterm infants, while for women between 3436 weeks with nonsevere preeclampsia, there is insufficient evidence on the risks and benefits of expect ant management [69] . For women >37 weeks, immediate delivery is advised [69] . The Society of Obstetric Medicine of Australia and New Zealand recommend treating blood pressures exceeding 170/110mmHg using methyldopa, labetalol or oxprenolol. Hydralazine, nifedipine and prazosin are considered second-line drugs. Magnesium sulfate is used for the treatment of eclampsia with arrangements for delivery once the patient is stable. At mature gestational ages, delivery should not be delayed after controlling the maternal blood pressure and other derange ments. In gestations between 2432 weeks, management should be restricted to centers with the appropriate expertise and before 34weeks delivery should be delayed for 2448h if the
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maternal and fetal conditions permits, to allow administration of corticosteroids [70] . The Finnish Medical Society also recommends labetalol and nifedipine for the treatment of hypertension in preeclampsia [71] .
HELLP syndrome

Hemolysis, elevated liver enzymes and low plate lets syndrome is one of the serious complications of preeclampsia requiring level two critical care and is associated with significant maternal and fetal morbidity and mortality. Most women are usually parous and are often not very hyperten sive. Severe epigastric pain is a common presen tation. The main differential diagnosis is fatty liver which, in contrast to HELLP syndrome, is associated with hypoglycemia, high ammonia, low fibrinogen and a prolonged activated partial thromboplastin time[72] . Hemolysis, elevated liver enzymes and low platelets syndrome complicates 0.50.9% of all pregnancies and 1020% of cases with severe preeclampsia [73] . Diagnosis requires the pres ence of microangiopathic hemolysis, thrombo cytopenia and abnormalities of liver enzymes. There is still controversy on the biochemical thresholds required to diagnose the condi tion. Sibai uses the following criteria: hemoly sis as evidenced by a peripheral smear, lactate dehydrogenase greater than 600IU/l, or total bilirubin greater than 20.52mol/l; aspartate transaminase greater than 70IU/l and platelets less than 100,000cells/mm3 [74,75] . Women who do not have all these parameters are considered to have partial HELLP syndrome. Martin et al. define the condition as follows: hemolysis evi denced by an increased lactate dehydrogenase and progressive anemia; liver dysfunction as evidenced by an lactate dehydrogenase higher than 600IU/l; aspartate transaminase greater than 40IU/l and alanine transaminase greater than 40IU/l, or both and a platelet count less than 150,000cells/mm3 [76,77] . The Mississippi HELLP Classification System classifies women based on the lowest perinatal platelet count: Class one HELLP syndromeplatelet nadir less than or equal to 50,000cells/mm3 ; Class twoplatelet nadir less than or equal to 100,000cells/mm3 ; Class threeplatelet nadir less than or equal to 150,000cells/mm3 [77] . Hemolysis, elevated liver enzymes and low platelets syndrome is associated with severe maternal complications, including acute renal
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Preeclampsia, severe preeclampsia & HELLP syndrome

Review

failure and liver failure, disseminated intravas cular coagulopathy, pulmonary edema, cerebro vascular accident and sepsis [74] . It is also closely linked to complications associated with prema turity and growth restriction with a perinatal mortality of 14.1% [78] . It has also been shown that up to 70% of patients with HELLP syn drome will require preterm delivery with 15% occurring at extremely preterm gestational ages (less than 27weeks) [79] . Corticosteroids have been used in women with preeclampsia complicated by HELLP syn drome. A Cochrane review of 11trials includ ing 550women comparing steroids with placebo or no treatment in the management of women with HELLP syndrome showed that there was no clear evidence of any effect of corticosteroids on clinical outcomes [80] . There was no differ ence in risk of maternal death (risk ratio:0.95, 95%CI: 0.283.21), maternal death or severe maternal morbidity (risk ratio:0.27, 95%CI: 0.032.12) or perinatal/infant death (risk ratio0.64, 95%CI: 0.211.97). The only differ ence was in improvement in platelet count in the treatment groups (standardized mean difference 0.67; 95%CI: 0.241.10), especially in women who started their treatment in the antenatal period. Corticosteroids should therefore not be used in the management of HELLP syndrome. The definitive treatment of HELLP syndrome is delivery. Unlike severe preeclampsia not com plicated by HELLP syndrome, this may require delivering at significantly preterm gestations. Neonatal outcomes in patients with HELLP syn drome is related to gestational age rather than the condition itself [79] . However, patients with this complication are at an increased risk of eclamp sia or possibly intracerebral bleeding, which can lead to seizure activity and death. Therefore, pre term delivery is usually unavoidable in cases of established HELLP syndrome.
Postnatal management

pre-eclamptic toxemia screen should be repeated at 4872h postdelivery but not repeated if nor mal. The patient can be discharged and fol lowed-up in the community when she has no symptoms of preeclampsia, blood pressure is less than 149/99mmHg and her blood tests are stable or improving [9] . Women who developed preeclampsia will require debriefing during the postnatal period. Patients need to be reassured that the condition will improve postnatally, with an increased risk of it redeveloping in subsequent pregnancies. In women with severe preeclampsia requiring delivery before 34weeks the risk is 25%. This increases to 55% if the preeclampsia necessi tated delivery before 28weeks [81] . Optimizing the BMI will reduce the future risk.
Conclusion

Our knowledge of preeclampsia over the last few decades has evolved rapidly. We are now able to understand the disease process bet ter while identifying the patients who are at a greater risk. Use of antihypertensive medica tion, relevant investigations and treatment has improved the outcome of pre-eclamptic patients [82] . Unfortunately we still do not understand the pathophysiology well enough to devise effective screening tools and in the 21st century delivery remains the only effective treatment. However, with our more targeted investigations and man agement strategies the maternal and fetal mor tality is at its lowest. Applying evidence-based medicine for the management of preeclampsia will ensure that the standards will be maintained and improved.
Future perspective

Up to 44% of eclamptic fits occur in the postna tal period. It is therefore important that medical and midwifery staff remain vigilant until the patients overall clinical picture improves. Some patients will require antihypertensives for the first time in the postnatal period. Treatment needs to be started if the blood pressure exceeds 150/100 mmHg. Women on antenatal anti hypertensive therapy will continue the same treatment postnatally, however, methyldopa is contraindicated owing to the increased risk of depression. Treatment is reduced when the blood pressure falls below 130/80 mmHg. A
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Currently, the mainstay of management of preeclampsia is screening through antenatal care, close monitoring of those at risk, treatment of signs and symptoms and then delivering on the best day in the best way. The future lies in prediction and prevention with improvements in management preventing growth restriction and premature delivery. Early studies suggest that blood markers that increase the risk of development of disease are present as early as the first trimester, and the use of aspirin is known to reduce the incidence of disease development by 15%. Obviously the combination of these two approaches will both reduce the number of women requiring close monitoring and admission to hospital as well as the number that develop the more dangerous forms of disease that put the mother and her
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baby at risk. Further improvement in prediction and prevention willfollow. A better understanding of the systemic inflam matory changes will allow a moderation of these to reduce the risks to the mother and the baby, mak ing prolongation of the pregnancy more possible for the benefit of the baby without increasing the maternal risk. This builds on the improvements in maternal care that we have seen in recent years.
Executive summary
Pathophysiology Abnormal placentation leads to placental insufficiency and fetal growth restriction. Increased inflammatory activity gives rise to widespread damage to the vascular endothelium. This is compounded by a heightening of the immunological state through circulating leucocytes, similar to sepsis. This inflammatory response is probably caused by placental debris leading to systemic inflammation and vascular dysfunction. Prevention Low-dose aspirin is a cost-effective tool in the prevention of preeclampsia and should be recommended for use in moderate to high risk women in early pregnancy. Proteinuria Estimations of levels of proteinuria in women with preeclampsia do not correlate with maternal and fetal outcomes. Once proteinuria has been diagnosed there is no benefit in repeating the test. Pre-eclamptic toxemia screen Platelet count, transaminases and serum creatinine are good predictors of disease progression in women who already have preeclampsia. Rising uric acid does not add any additional information to these tests. Treatment Labetalol is now considered the first-line antihypertensive agent. Patients with preeclampsia should be admitted to hospital, have regular blood pressure readings (at least fourtimes a day), testing for proteinuria and monitoring of blood parameters, namely kidney function, electrolytes, full blood count, transaminases and bilirubin. Umbilical artery Doppler velocimetry In high-risk pregnancies, including those complicated by hypertensive disease, the use of umbilical artery Doppler velocimetry reduces perinatal morbidity and mortality. It helps in deciding timing of delivery, especially when end-diastolic flow is absent. Timing of delivery There is no evidence of any benefit in prolonging pregnancy beyond 34weeks in severe preeclampsia. Magnesium sulfate Magnesium sulfate is the anticonvulsant of choice in the treatment of eclampsia. It also prevents eclampsia and should also be considered in women with severe preeclampsia who are in a critical care setting if birth is planned within 24h. Fluid balance Volume expansion should not be used in women with severe preeclampsia. Hemolysis, elevated liver enzymes & low platelets syndrome Corticosteroids have no beneficial effect on the clinical outcome of patients with hemolysis, elevated liver enzymes and low plateletssyndrome. Postnatal management Women who developed severe preeclampsia requiring delivery before 34weeks have a 25% risk of the condition recurring in the next pregnancy. Conclusions Use of antihypertensives, relevant investigations and treatment has improved the outcome of pre-eclamptic patients. Blood markers that increase the risk of development of the disease are already present in the first trimester. The use of aspirin, in conjunction with the use of the first trimester blood markers, will help reduce the number of women requiring close monitoring, hospitalization and development of the more severe forms of the disease. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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