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Pre-eclampsia, Severe Pre-eclampsia and Hemolysis, Elevated Liver Enzymes and Low Platelets Syndrome What Is New? Etienne Ciantar; James J Walker Posted: 09/14/2011; Women's Health. 2011;7(5):555-569. © 2011 Future Medicine Ltd. Abstract and Introduction Abstract Pre-eclampsia 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 pre-eclampsia, 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 pre-eclampsia, 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. Introduction Hypertension in pregnancy remains a leading cause of maternal and fetal morbidity and mortality in the UK and worldwide. It is one of the most common medical disorders in pregnancy and the most frequent cause of iatrogenic prematurity. Pre-eclampsia occurs in 2–8% of all pregnancies,[1] with the incidence of severe pre-eclampsia being around 1%. Between February 2005 and February 2006 there were 214 confirmed cases of eclampsia in the UK, representing an estimated incidence of 2.7 per 10,000 births.[2] Pre-eclampsia 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 pre-eclampsia, 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 90 mmHg or more, taken on two occasions more than 4 h apart, or a single diastolic blood pressure of more than 110 mmHg. This can occur either in women who already have hypertension (which can be primary or secondary) and who become pregnant, or can manifest itself de novo in the second half of pregnancy in women who were previously normotensive, when it is called pregnancy-induced hypertension or gestational 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 contraceptive pill). However, since both groups are at an increased risk of developing pre-eclampsia, they need to be closely monitored.[3,4] Pre-eclampsia is a multisystem disorder characterized by hypertension, as described earlier, with the addition of proteinuria, defined as more than 300 mg of protein in a 24 h urine collection or more than 30 mg/mmol in a spot urinary protein:creatinine sample. It occurs after 20 weeks of gestation with the hypertension and proteinuria resolving postnatally. Occasionally women present with a severe complication of pre-eclampsia such as eclampsia, or hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. The risk of pre-eclampsia is 4.1% in women in their first pregnancy and 1.7% in later pregnancies overall. However, this risk rises to 14.7% in the second pregnancy in women who had pre-eclampsia in their first pregnancy and 31.9% in women who had pre-eclampsia in their previous two pregnancies.[5] In the most recent Confidential Enquiry into Maternal and Child Health in the UK (2003–2005), there were 18 reported deaths from preeclampsia and eclampsia, an increase of four deaths from the previous triennium. Ten of these deaths were caused by intracranial hemorrhage, highlighting the ineffective management of the systolic blood pressure in these women.[6] A study from the USA also demonstrated a significant 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 significant variation in practice around the UK in the management of pre-eclampsia, which may contribute to the substandard care of this potentially lethal condition. In a survey of 370 women who developed pre-eclampsia, 34% did not receive antihypertensive treatment with a systolic blood pressure of 160 mmHg 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 management of hypertensive disorders during pregnancy in order to standardize care and improve morbidity and mortality. This guideline contains recommendations on the diagnosis and management of hypertension in pregnancy during the antenatal, intrapartum and postnatal period. It also offers guidance on the management of women who suffer from chronic hypertension and wish to conceive as well as advice to women whose pregnancy was complicated by hypertension. [9] Pathophysiology The pathophysiology of pre-eclampsia 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 strategies. Apart from a few well documented exceptions, pre-eclampsia 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 trophoblastic invasion of the myometrium by the spiral arteries is inhibited in women with hypertension 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 lead to placental failure. There seems to be an interaction between uterine natural killer cells and trophoblastic cells, regulating trophoblastic invasion as well as macrophage-derived TNF-α.[11,12] The fetal–maternal immunological interaction at placentation involves maternal killer immunoglobulin-like receptors and fetal HLA-C molecules. This interaction seems to fail in pre-eclampsia, highlighting an immunological basis to trophoblastic invasion deficiency.[13] This immunological influence also explains the increased incidence of pre-eclampsia in primigravida and change in paternity,[14] as well as the reduced incidence of pre-eclampsia in women who received a blood transfusion.[15] While abnormal placentation leads to placental insufficiency and fetal growth restriction, the development of pre-eclampsia is not inevitable. Further systemic changes are required. Increased inflammatory activity leads to widespread damage to the vascular endothelium leading to capillary leak, vasoconstriction and intravascular hemolysis, and platelet activation.[16] This is further compounded by a heightening of the immunological state in pre-eclampsia, 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 inflammation and vascular dysfunction.[18] Therefore, the development of pre-eclampsia 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 pre-eclampsia 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 pre-eclampsia.[19] It is also postulated that pre-eclampsia occurs because of the elevation of circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which acts as a potent inhibitor of VEGF.[20] Studies have shown that by reducing the levels of free sFlt-1 the symptoms of pre-eclampsia 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 restriction (IUGR) and abruption, it reduces the risk of pre-eclampsia by a third.[23] There is currently growing interest in therapeutically reducing the elevated levels of sFlt-1 in pre-eclampsia to minimize its severity and prolong the pregnancy in early-onset disease. Statins, so far contraindicated in pregnancy, inhibit cytokine-mediated release of sFlt1.[24] Statins to Ameliorate Early Onset Pre-eclampsia (StAmP), the first randomized 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 pre-eclampsia, there have been various studies trying to identify preventive pharmaceutical agents, with a particular emphasis on the use of antiplatelet agents. A Cochrane systematic review of 59 trials including 37,560 women revealed a reduction in the risk of pre-eclampsia with the use of antiplatelet 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 pre-eclampsia associated with the use of antiplatelet drugs (46 trials; 32,891 women; relative risk: 0.83; 95% CI: 0.77–0.89, 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 baseline risk with those considered to be at high risk on entering the trial (previous pre-eclampsia, chronic hypertension, diabetes, renal disease and autoimmune disease) having a RR of 25% (95% CI: 34–15%). 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 pregnancies, family history of severe pre-eclampsia and being a teenager), antiplatelet agents were associated with a 14% reduction in pre-eclampsia risk (95% CI: 21–5% reduction). The NNT based on absolute RR was therefore 72 women (95% CI: 52–119 women). However, 19 high risk women are needed to treat to prevent one case of pre-eclampsia (95% CI: 13–34 women), while for moderate risk women this goes up to 119 (95% CI: 73–333 women).[26] Antiplatelet agents were also associated with an 8% reduction in the relative risk of preterm birth (29 trials, 31,151 women, relative risk: 0.92, 95% CI: 0.88–0.97); NNT 72 (52, 119), as well as a 14% reduction in fetal and neonatal death (40 trials, 33,098 women, relative risk 0.86, 95% CI: 0.76–0.98); 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: 0.83–0.98).[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 low-dose preparations. The moderate efficacy of low-dose aspirin in preventing pre-eclampsia 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 intervention makes the use of low-dose aspirin in preventing pre-eclampsia 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 pre-eclampsia should start low-dose aspirin (75 mg) from 12 weeks until the birth of the baby.[9] The women considered to be at high risk are the following: • Hypertensive disease in the previous pregnancy • Chronic kidney disease • Autoimmune disease such as systemic lupus erythematosus and antiphospholipid syndrome • Type 1 or Type 2 diabetes • Chronic hypertension In addition, the same recommendation holds for women with more than one moderate risk factor for developing pre-eclampsia. These include: • First pregnancy • Age 40 years or older • Pregnancy interval of more than 10 years • BMI of more than 35 kg/m2 or more at first visit • Family history of pre-eclampsia • Multiple pregnancies There have been other numerous studies to evaluate the effectiveness of other agents in the prevention of pre-eclampsia. A Cochrane systematic review evaluating the role of nitric oxide agents (i.e., glycerine trinitrate, L-arginine) showed that there is insufficient evidence to draw reliable conclusions in preventing pre-eclampsia and its complications.[27] Similarly, in another Cochrane review of two randomized controlled trials comparing progesterone with placebo in preventing pre-eclampsia 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 pre-eclampsia. 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 recognized that diuretics should not be used in pregnancy 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 pre-eclampsia to treat clinically significant pulmonary edema in women whose fluid balance is being closely monitored. One randomized controlled trial studied the role of low-molecular-weight heparin in preventing pre-eclampsia. The study involved 80 women with an angiotensin-converting enzyme DD genotype and a history of preeclampsia. A group of 41 women were assigned to receive dalteparin 5000 IU/day at the time of a positive pregnancy test, while 39 women did not receive treatment. The treatment group had a lower risk of developing pre-eclampsia compared with the control group (RR: 0.26; 95% CI: 0.08–0.86).[30] However, this was a poor quality trial although it did show a statistically and clinically significant reduction in preeclampsia but in a highly selected group of women with a particular genotype. Patients with systemic lupus erythematosus, whose risk of developing pre-eclampsia is as high as 32–50%, have been shown to improve their feto-maternal outcomes, especially their risk of developing pre-eclampsia, if treated with low-molecular-weight heparin.[31] The effect of nutritional supplements in preventing pre-eclampsia has also been extensively studied. Magnesium, folic acid, fish oils, algal oils, antioxidants and garlic do not seem to be effective in preventing the disease.[9] Interestingly, a Cochrane review of 12 randomized controlled trials involving 15,206 women has shown that women receiving calcium supplementation were half as likely to develop pre-eclampsia compared with placebo. Therefore, calcium supplementation appears to be beneficial for women at high risk of developing hypertension in pregnancy and in communities with low dietary calcium.[32] However, there does not seem to be any statistically significant RR in communities where dietary calcium intake is adequate. Management of Pre-eclampsia Proteinuria The association between proteinuria and pre-eclampsia 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. Pollak's work, published in 1960, revealed that the kidneys in preeclampsia underwent a series of unique pathological changes.[33] The glomeruli were found to be enlarged, swollen and ischemic. Glomerular involvement in pre-eclampsia is widespread, with all being affected to the same degree. The most prominent pathological feature seems to be the cellular edema of the glomerular tuft, affecting both endothelial and epithelial cells. The swollen endothelial cytoplasm encroaches upon the lumen of the glomerular capillaries, contributing to the tuft's ischemia. The changes were not found to occur in other diseases affecting the kidney. Therefore, these changes are diagnostic of pre-eclampsia, 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 associated 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 trepidation and delivery contemplated if significantly high levels are present. Historically, a 24 h urinary collection of >5 g mandated delivery. The trend now is to have a more rational approach towards proteinuria. In a study of 598 women with a previous history of pre-eclampsia, it was found that women who developed severe gestational hypertension (without proteinuria) were more likely to have a preterm delivery and a small-for-gestational-age baby compared with women with mild pre-eclampsia. 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 pre-eclampsia who delivered before 37 weeks were studied retrospectively.[38] These patients were divided into groups with mild (<5 g/24 h), severe (5–9.9 g/24 h) and massive (>10 g/24 h) proteinuria. 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 proteinuria did not seem to have any effect on neonatal outcomes. The authors concluded that neonatal morbidity is related to prematurity and not to proteinuria per se.[38] A systematic review of 16 primary articles involving 6749 women with pre-eclampsia and varying levels of proteinuria concluded that the estimations of levels of proteinuria in women with pre-eclampsia do not correlate with maternal and fetal outcomes. Urinary protein estimation was not found to be a clinically useful predictive 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 welldesigned prospective studies. Pre-eclampsia 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 pathological 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. Pre-eclamptic Toxemia Screen Since pre-eclampsia 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 hypertension 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 pre-eclampsia, it was found that uric acid is a poor predictor for complications.[40] The review showed that a positive result (uric acid level of 350 µmol/l or more) predicted progression to eclampsia with a pooled likelihood ratio (LR) of 2.1 (95% CI: 1.4–3.5), with a negative result having a pooled LR of 0.38 (95% CI: 0.18–0.81). A positive result predicted development of severe hypertension with a LR of 1.7 (95% CI: 1.3–2.2), with a negative result having a LR of 0.49 (95% CI: 0.38–0.64). The chance of requiring a Cesarean section was 2.4 (95% CI: 1.3–4.7) and 0.39 (95% CI: 0.20–0.76) for positive and negative results respectively. Stillbirth and neonatal death had respective LRs of 1.5 (95% CI: 0.91–2.6) and 0.51 (95% CI: 0.2–1.3), while for predicting small-for-gestational-age, the LR was 1.3 (95% CI: 1.1–1.7) for a positive result and 0.60 (95% CI: 0.43–0.83) 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 pre-eclampsia it was found that the only variable that significantly predicted maternal complications (HELLP syndrome, placental abruption, oliguria and eclampsia) was diastolic 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 100 × 109/l was associated with a statistically significant increased likelihood of adverse maternal and perinatal outcomes.[42] Similarly, elevated liver enzymes and creatinine levels greater than 110 µmol/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 pre-eclampsia, 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 above 100 × 109/l. Treatment Labetalol is a widely used, safe and effective antihypertensive agent that is licensed for use in pregnancy. It is now considered to be the firstline agent.[9] Alternative treatment may be necessary when labetalol is contraindicated, such as in patients with asthma. Additionally women of Afro–Caribbean origin seem to be resistant to β-blocker treatment. Safe alternatives to labetalol are methyldopa and nifedipine. The latter can be used safely in combination with either labetalol or methyldopa. In extreme circumstances all three can be used together, however, 80% of women with pre-eclampsia have their blood pressure controlled with oral labetalol only.[43] In a study of 200 primigravida women with mild pre-eclampsia at 26–35 weeks gestation, labetalol has been shown to reduce blood pressure 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 gestation in which fetal morbidity associated with prematurity is minimized. Commencing antihypertensive treatment in pre-eclampsia depends on the blood pressure readings. Mild hypertension (140/90 to 149/99 mmHg) does not require treatment. However, moderate hypertension (150/100 to 159/109 mmHg) would require commencement of labetalol with an aim to keep the diastolic blood pressure between 80–100 mmHg and the systolic blood pressure less than 150 mmHg. Similar ranges are aimed for with severe hypertension, which is defined as a blood pressure of 160/110 mmHg or higher.[9] Patients with preeclampsia should be admitted to hospital, have regular blood pressure readings (at least four times a day), testing for proteinuria and monitoring of blood parameters, namely 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 hypertension and three times weekly with moderate/severe hypertension. In addition, once proteinuria has been identified, quantification need not be repeated. Fetal Monitoring Fetal Biometry & Umbilical Artery Doppler Velocimetry Patients with pre-eclampsia have an increased risk of intrauterine growth restriction. Growth scans and fetal biometry are therefore useful in identifying and monitoring fetal growth in these patients. In patients with hypertensive disease of pregnancy, the absence of enddiastolic velocities on umbilical artery Dopplers is crucial as this is associated with increased neonatal morbidity and mortality. Therefore, the presence of end-diastolic 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 8633 participants looked into the use of umbilical artery Doppler velocimetry in high-risk pregnancies compared with no Doppler or with routine monitoring.[46] Perinatal mortality 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: 0.47–0.97) and they were less likely to have low Apgar scores at 5 min (OR: 0.89; 95% CI: 0.74–0.97). These women were also less likely to be admitted antenatally (OR: 0.56; 95% CI: 0.43–0.72) and to require an emergency Cesarean section (OR: 0.85; 95% CI: 0.74–0.97). Additionally, subgroup analysis of well defined studies showed that women monitored with umbilical artery Doppler velocimetry were less likely to be induced (OR: 0.78; 95% CI: 0.63–0.96) or to have elective delivery (OR: 0.73; 95% CI: 0.61–0.88) or Cesarean section (OR: 0.78; 95% CI: 0.65–0.94).[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 morbidity 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. Biophysical Profile There is no evidence to support the use of a biophysical profile (BPP) in pregnancies complicated by hypertension. A Cochrane systematic review assessing the use of the BPP compared with conventional monitoring (cardiotocography only or modified BPP) showed that there were no statistically significant differences in perinatal deaths or admission to neonatal special care between the two groups.[47] There were also no statistically significant differences amongst the two groups for the following parameters: Apgar scores less than 7 at or after 5 min, small for gestational age, meconium-stained liquor, respiratory distress syndrome and Cesarean section for fetal distress. Subgroup analysis 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 properties, protection of the umbilical cord and placenta, 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 single deepest vertical pocket measurement as a screening tool for decreased amniotic volume in the prevention of adverse pregnancy outcomes.[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 5 min or Cesarean section.[49] Uterine Artery Doppler Velocimetry Since pre-eclampsia is associated with a disturbance in utero–placental blood flow, assessing 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 12,994 patients to evaluate the clinical usefulness of Doppler analysis of the uterine artery velocity 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 pre-eclampsia with a pooled LR of 6.4 (95% CI: 5.7–7.1), while a negative result had a pooled LR of 0.7 (95% CI: 0.6–0.8). For IUGR the pooled LR for a positive result was 3.6 (95% CI: 3.2–4.0) and 0.8 for a negative result (95% CI: 0.8–0.9). Perinatal death had a pooled LR of 1.8 (95% CI: 1.2–2.9) for a positive result and 0.9 for a negative result (95% CI: 0.8–1.1). In the high-risk population a positive result predicted pre-eclampsia with a pooled LR of 2.8 (95% CI: 2.3–3.4), while a negative result hade a LR of 0.8 (95% CI: 0.7–0.9). IUGR was predicted with a ratio of 2.7 (95% CI: 2.1–3.4) with a positive result and 0.7 (95% CI: 0.6–0.9) for a negative result. In this population perinatal death was predicted with a pooled LR of 4.0 (95% CI: 2.4–6.6) for a positive result and 0.6 (95% CI: 0.4–0.9) for a negative result. Therefore, it was concluded that uterine artery Doppler studies had limited accuracy in predicting pre-eclampsia 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 management in women who are at a high risk of developing preeclampsia but have abnormal uterine artery Dopplers at 20–24 weeks.[9] Incidentally these women would already be on aspirin and closely monitored so it is debatable how this test would alter the patient's management. Timing of Delivery Ultimate treatment of pre-eclampsia is delivery, bearing in mind the neonatal risks associated with iatrogenic prematurity. Two randomized controlled trials investigated the maternal and neonatal outcome when adopting an early delivery approach against expectant management in women with severe pre-eclampsia at up to 34 weeks gestation.[51,52] In both trials patients were stabilized with magnesium sulfate and antihypertensives and given steroids for fetal lung maturation. If they continued 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 management with bed rest, oral antihypertensives and intensive antenatal fetal monitoring until they were delivered at 34 weeks, or earlier if maternal or fetal condition worsened. Neonates in the early delivery group showed a greater frequency of hyaline membrane disease (relative risk: 2.3; 95% CI: 1.39–3.81) and necrotizing enterocolitis (relative risk: 5.54; 95% CI: 1.04–29.56) with no statistically significant difference in rates of stillbirth or death after delivery (relative risk: 1.50; 95% CI: 0.42–5.41). There were 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 compromise. There is no evidence of any benefit in prolonging pregnancy beyond 34 weeks in severe pre-eclampsia. In addition, it is difficult to base timing of birth on single biochemical and hematological parameters (including level of proteinuria) 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 Pre-eclampsia Intervention Trial in the Almost Term patient (HYPITAT) showed that there was no maternal or immediate neonatal disadvantage with immediate birth after 37 weeks in women with pre-eclampsia and the NICE guideline recommends delivery after 37 weeks since there is no evidence of benefit in prolonging pregnancy.[9,53] Similar findings were seen for those with mildto-moderate hypertension but the NICE guideline states that delivery should be offered to women after 37 weeks as the evidence is less clear. The mode of birth for women with severe pre-eclampsia or eclampsia depends on the clinical circumstances and on the woman's preference. Magnesium Sulfate: Treatment 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 secondary to tetanus.[54] Its mode of action is not clearly understood. In a Cochrane review comparing it with diazepam, it was found that magnesium 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 7 days 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 magnesium sulfate follows the Collaborative Eclampsia Trial:[58] • Loading dose of 4 g given intravenously over 5 min, followed by an infusion of 1 g/h maintained for 24 h; • Recurrent seizures should be treated with a further dose of 2–4 g given over 5 min. Magnesium Sulfate: Prevention The Magnesium Sulphate for Prevention of Eclampsia (MAGPIE) Trial Collaborative Group evaluated the use of magnesium sulfate in the prevention of eclampsia in women with pre-eclampsia.[59] The study consisted of 10,141 women in the antenatal period or less than 24 h postpartum. They had a blood pressure of 140/90 mmHg or more and 1+ of proteinuria (30 mg/dl) on urinary dipstick. Women were randomized in 33 countries to either magnesium sulfate (n = 5071) or placebo (n = 5070). Women who were given magnesium sulfate had a 58% lower risk of developing eclampsia (95% CI: 40–71) than the placebo group (40, 0.8%, vs 96, 1.9%; 11 fewer women with eclampsia per 1000 women). Maternal mortality was also lower in the treatment group (relative risk 0.55; CI: 0.26–1.14). A total of 24% of women given magnesium sulfate reported side effects as opposed to 5% with placebo. Two follow-up studies investigating the long-term effects to the mother and baby following treatment with magnesium sulfate during pregnancy 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 pre-eclampsia 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 pre-eclampsia who are in a critical care setting if birth is planned within 24 h. Patients with severe pre-eclampsia 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 Papilledema Signs of clonus (three or more beats) Liver tenderness HELLP syndrome Platelet count falling to below 100 × 109/l Abnormal liver enzymes (alanine transaminase or aspartate transaminase rising to above 70 IU/l) Antihypertensives in Severe Pre-eclampsia Apart from treating and preventing convulsions, it is also important to lower the blood pressure in women with severe pre-eclampsia. 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 150/100 mmHg. 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 pre-eclampsia 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 mortality 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, vasoconstriction and increased osmolarity superimposed on the damaged endothelium found in pre-eclampsia.[63] There seems to be a predilection of the parieto-occipital and occipital lobes in hypertensive encephalopathy and eclampsia. Posterior reversible encephalopathy has been described in women with severe pre-eclampsia and eclampsia. 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 150/80–100 mmHg in women with severe hypertension who are in critical care. There is no evidence of any significant differences in efficacy between the different antihypertensive preparations (labetalol, nifedipine and hydralazine). A Cochrane review of all randomized 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 efficacy of the various drugs used in this setting.[66] In fact, more robust studies are needed to compare 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 hydralazine 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 intravenous one, owing to ease of administration and cost–effectiveness. Fluid Balance The Confidential Enquiry into Maternal and Child Health in the UK reported six deaths in the triennium 1994–1996 caused by adult respiratory distress syndrome, related to poor fluid management in women with pre-eclampsia or eclampsia.[67] This highlighted the importance of having senior medical involvement in managing the fluid balance of these patients. Subsequent reports showed a marked improvement in the number of deaths reported for the same complication, with no deaths in the last two triennia 2003–2005 and 2006–2008. 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 intravenous hydralazine. The Yorkshire Obstetric Critical Care Group developed a common guideline for the management of severe pre-eclampsia and eclampsia for the 16 units 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 80 ml/h in the peripartum period, leading to a low rate of fluid-related problems in the mothers. This is also related to the allowance of a relatively low urine output, allowing 8 h with the equivalent of less than 20 ml/h of urine output prior to intervening. In a 5-year prospective study on the risks of serious complications from severe pre-eclampsia and eclampsia in the region following the introduction of this guideline, it was found that amongst 1087 women diagnosed with pre-eclampsia 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 concluded that the guideline, which could be easily implemented in other regions, may contribute to lower rates of serious complications. There are strong similarities amongst pre-eclampsia guidelines from other countries. The American Congress of Obstetricians and Gynecologists recommends that severe pre-eclampsia should be managed in a tertiary center, while patients with mild disease who are still remote from term can be treated conservatively.[68] Treatment with labetalol or hydralazine is recommended if the diastolic blood pressure is 105 mmHg or more. Magnesium sulfate is also recommended for the prevention and treatment of seizures in women with pre-eclampsia or eclampsia.[68] The Society of Obstetricians and Gynaecologists of Canada recommend antihypertensive therapy when the blood pressure exceeds 160/100 mmHg using labetalol, nifedipine or hydralazine with magnesium sulfate also used for the prevention and treatment of seizures.[69] These guidelines recommend expectant management for women <34 weeks in centers capable to care for preterm infants, while for women between 34–36 weeks with nonsevere pre-eclampsia, there is insufficient evidence on the risks and benefits of expectant 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 170/110 mmHg 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 derangements. In gestations between 24–32 weeks, management should be restricted to centers with the appropriate expertise and before 34 weeks delivery should be delayed for 24–48 h if the 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 platelets syndrome is one of the serious complications of pre-eclampsia 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 hypertensive. Severe epigastric pain is a common presentation. 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 0.5–0.9% of all pregnancies and 10–20% of cases with severe pre-eclampsia.[73] Diagnosis requires the presence of microangiopathic hemolysis, thrombocytopenia and abnormalities of liver enzymes. There is still controversy on the biochemical thresholds required to diagnose the condition. Sibai uses the following criteria: hemolysis as evidenced by a peripheral smear, lactate dehydrogenase greater than 600 IU/l, or total bilirubin greater than 20.52 µmol/l; aspartate transaminase greater than 70 IU/l and platelets less than 100,000 cells/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 evidenced by an increased lactate dehydrogenase and progressive anemia; liver dysfunction as evidenced by an lactate dehydrogenase higher than 600 IU/l; aspartate transaminase greater than 40 IU/l and alanine transaminase greater than 40 IU/l, or both and a platelet count less than 150,000 cells/mm3.[76,77] The Mississippi HELLP Classification System classifies women based on the lowest perinatal platelet count: • Class one HELLP syndrome – platelet nadir less than or equal to 50,000 cells/mm3; • Class two – platelet nadir less than or equal to 100,000 cells/mm3; • Class three – platelet nadir less than or equal to 150,000 cells/mm3.[77] Hemolysis, elevated liver enzymes and low platelets syndrome is associated with severe maternal complications, including acute renal failure and liver failure, disseminated intravascular coagulopathy, pulmonary edema, cerebrovascular accident and sepsis.[74] It is also closely linked to complications associated with prematurity and growth restriction with a perinatal mortality of 14.1%.[78] It has also been shown that up to 70% of patients with HELLP syndrome will require preterm delivery with 15% occurring at extremely preterm gestational ages (less than 27 weeks).[79] Corticosteroids have been used in women with pre-eclampsia complicated by HELLP syndrome. A Cochrane review of 11 trials including 550 women 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 difference in risk of maternal death (risk ratio: 0.95, 95% CI: 0.28–3.21), maternal death or severe maternal morbidity (risk ratio: 0.27, 95% CI: 0.03–2.12) or perinatal/infant death (risk ratio 0.64, 95% CI: 0.21–1.97). The only difference was in improvement in platelet count in the treatment groups (standardized mean difference 0.67; 95% CI: 0.24–1.10), 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 pre-eclampsia not complicated by HELLP syndrome, this may require delivering at significantly preterm gestations. Neonatal outcomes in patients with HELLP syndrome is related to gestational age rather than the condition itself.[79] However, patients with this complication are at an increased risk of eclampsia or possibly intracerebral bleeding, which can lead to seizure activity and death. Therefore, preterm delivery is usually unavoidable in cases of established HELLP syndrome. Postnatal Management Up to 44% of eclamptic fits occur in the postnatal period. It is therefore important that medical and midwifery staff remain vigilant until the patient's 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 antihypertensive 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 pre-eclamptic toxemia screen should be repeated at 48–72 h postdelivery but not repeated if normal. The patient can be discharged and followed-up in the community when she has no symptoms of pre-eclampsia, blood pressure is less than 149/99 mmHg and her blood tests are stable or improving.[9] Women who developed pre-eclampsia 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 pre-eclampsia requiring delivery before 34 weeks the risk is 25%. This increases to 55% if the pre-eclampsia necessitated delivery before 28 weeks.[81] Optimizing the BMI will reduce the future risk. Conclusion Our knowledge of pre-eclampsia over the last few decades has evolved rapidly. We are now able to understand the disease process better while identifying the patients who are at a greater risk. Use of antihypertensive medication, 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 management strategies the maternal and fetal mortality 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 Currently, the mainstay of management of pre-eclampsia 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 baby at risk. Further improvement in prediction and prevention will follow. A better understanding of the systemic inflammatory changes will allow a moderation of these to reduce the risks to the mother and the baby, making 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. Sidebar 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 pre-eclampsia 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 pre-eclampsia. • Rising uric acid does not add any additional information to these tests. Treatment • Labetalol is now considered the first-line antihypertensive agent. • Patients with pre-eclampsia should be admitted to hospital, have regular blood pressure readings (at least four times 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 34 weeks in severe pre-eclampsia. 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 pre-eclampsia who are in a critical care setting if birth is planned within 24 h. 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 platelets syndrome. Postnatal Management • Women who developed severe pre-eclampsia requiring delivery before 34 weeks have a 25% risk of the condition recurring in the next pregnancy. 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