|Year : 2013 | Volume
| Issue : 2 | Page : 75-85
Preeclampsia: A review of the evidence
TA Jido, IA Yakasai
Department of Obstetrics and Gynaecology, Bayero University/Aminu Kano Teaching Hospital, Kano, Nigeria
|Date of Web Publication||22-May-2013|
T A Jido
Department of Obstetrics and Gynaecology, Aminu Kano Teaching Hospital, Zaria Road, Kano
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Preeclampsia is a common complication of pregnancy associated with high maternal and perinatal morbidity and mortality especially in developing countries. There is considerable progress in the understanding of the pathophysiology and the management of the diseases, although the aetiology and primary pathology remained elusive. Integration of current evidence in the clinical management of the condition has witnessed improved maternal and fetal outcomes in many societies. In developing countries variations in management often not based on current evidence accounts for comparatively higher morbidity and mortality. This article aims to provide an overview of our present understanding of preeclampsia help care providers and our managers focus practice and policy to reflect existing evidence.
| Abstract in French|| |
La prééclampsie est une complication commune des grossesses associées à de forts taux de morbidité et mortalité périnatales, particulièrement dans les pays en voie de développement. Des progrès considérables ont été réalisés dans la compréhension de la pathophysiologie et la gestion de cette maladie, bien que l'étiologie et la pathologie primaire en restent encore difficilement cernables. L'intégration des preuves cliniques actuelles dans la gestion de cette maladie a démontré une amélioration des résultats foeto-maternaux dans de nombreuses sociétés. Toutefois dans les pays en voie de développement on dénote une morbidité et mortalité comparativement plus hautes - ceci étant dû aux variations et différences de gestion de ce problème, gestion peu basée sur les résultats cliniques actuels, Cet article a pour but de proposer une vue d'ensemble de notre compréhension actuelle de la prééclampsie afin d'encourager les prestataires et dirigeants médicaux à adopter une pratique plus ciblée et à prendre les décisions qui vont intégrer les résultats des tests cliniques actuels.
Mots clés: Preuve clinique, gestion, prééclampsie
Keywords: Evidence, management, preeclampsia
|How to cite this article:|
Jido T A, Yakasai I A. Preeclampsia: A review of the evidence. Ann Afr Med 2013;12:75-85
| Introduction|| |
Despite lack of complete understanding, preeclampsia and eclampsia have been recognised and described many centuries ago. Hippocrates noted that headaches, convulsions and drowsiness are ominous signs in association with pregnancy. In his treatise on gynaecology Varandeous coined the term eclampsia in 1619.  Evidence exist that ancient civilisations of China, Egypt and India have all recognised and described this disease as well as the bleak maternal and foetal prognosis it portends. Association with hypertension and proteinuria, the two cardinal features were noted in mid to late 19 th century (hypertension) and the early 20 th century proteinuria. Delivery was further identified as the key feature of management in the 20 th century. Notwithstanding the extensive literature and progress in our understanding, these facts still remains the basis of our management of preeclampsia and eclampsia.
Hypertension in pregnancy is defined as diastolic blood pressure (DBP) of 90 mmHg or more on two occasions at least four hours apart or a single DBP of 110 mmHg or more. This may occur in a patient known to be hypertensive called chronic hypertension or may arise de novo in an otherwise normotensive patient often in the second half of pregnancy in which case it is called pregnancy induced hypertension or gestational hypertension. The association of hypertension with significant protein in the urine constitute preeclampsia. Significant proteinuria is the presence of 300 mg of protein in the urine collected over 24 hours or 30 mg/mmol on spot protein: Creatinine ratio. In semi-quantitative assay this correlates with 2+ or more of protein in the urine. When convulsions occur in the presence of preeclampsia in a patient with no known seizure disorder the term eclampsia is ascribed. HELLP syndrome is an acronym for haemolysis, elevated liver enzymes and low platelets often seen in association with severe preeclampsia for which it implies poor prognosis. ,
Ten per cent of all pregnancies are complicated by hypertension. The incidence of preeclampsia is 3-7% in the nulliparous and 1-3% in the multiparous.  The risk of developing preeclampsia is 4.1% in the first pregnancy. This however, rises to 14.7% in the second and 31.9% in the third pregnancy amongst women with preeclampsia in all preceding pregnancies.  The incidence of eclampsia on the other hand varies between developed and developing countries and is in a way a reflection of the availability, utilisation and effectiveness of maternity care. In most of Western Europe and North America the incidence is 2-3 per 10000 deliveries , compared to 13 per 1000 deliveries in developing countries. 
Classification of preeclampsia
The Yorkshire series of severe preeclampsia serve as a guide for the classification of preeclampsia.  A simplified version of the inclusion criteria is presented in [Table 1]. It is important to bear in mind that the criteria is subjective and events may progress rapidly such that women should be managed based on careful assessment rather than a set criteria.
The Cochrane library and the Cochrane register of controlled trials, PUBMED and Medscape were searched for relevant meta-analyses, systematic reviews, randomised controlled trials and articles as appropriate. Search terms used include: Preeclampsia, hypertensive disorders of pregnancy, pregnancy toxaemia, pregnancy induced hypertension, eclampsia, eclampsia in resource poor countries.
Aetiology and risk factors
The aetiology of preeclampsia is not known. Various risk factors have been impugned mostly bordering on genetic, immunologic factors. Mechanisms through which these factors cause preeclampsia are the subjects of many studies and will be considered in detail under pathophysiology. Risk factors can be broadly classified into general, pregnancy related and underlying medical conditions [Table 2] and [Table 3].
Although the primary pathology leading to preeclampsia is still to be defined, complex pathophysiologic pathways and mechanisms have been described. These are closely intertwined and appear to be triggered by the presence of placental tissue. Women with hydatidiform mole present with preeclampsia in the absence of fetus. Placental studies consistently showed aberrant uterovascular development of the placental bed. At the core of this is a complete or partial failure of trophoblastic invasion of the myometrium and the spiral arteries resulting in muscular vasculature in the placental bed that is responsive to vasoactive substances.
This deficiency in trophoblastic invasion is now known to be as a result of a defective interaction between trophoblastic cells and uterine natural killer cells. The same mechanism also releases tumour necrosis factor alpha (TNFα) into the circulation. Other factors involved in this immunologic pathway at the level of the placenta are maternal killer immunoglobulin like receptors and fetal HLA-C molecules.  In vitro placental studies using metallopeptidase ADAM 17 led to increase production of TNFα in preeclamptic placentae compared to normotensive women.  Interactions between these factors seem to fail in preeclampsia resulting in deficiency in trophoblastic invasion of the myometrium and high pressure narrow calibre vessels. 
This in turn leads to microtrauma at the level of the placenta with release in to the circulation of placental fragments. These fragments causes systemic inflammatory reaction, activation of leucocytes and platelets which further increases the inflammation, releases free radicals and causes vascular endothelial damage and vascular dysfunction.  Thus defective trophoblastic invasion causes placental insufficiency, abnormal fetal growth and placental damage leading to systemic inflammatory response.  This in turn causes vascular endothelial dysfunction and damage which clinically manifest as hypertension, proteinuria and other systemic responses.
Recent molecular studies attributed vascular endothelial dysfunction in preeclampsia to the loss of vascular endothelial growth factor (VEGF). Cancer patients on treatment with VEGF inhibitors elicit symptoms of preeclampsia like syndrome in the absence of trophoblast. The mechanism through which production of VEGF is inhibited in preeclampsia is mediated through the elevated levels of fms-like tyrosine kinase 1 (sFlt-1), a potent VEGF inhibitor. ,, Cigarette smokers who are known to have elevated levels of sFlt-1 have incidence of preeclampsia which is a third lower than general population. However adverse effects of smoking like preterm labour, intrauterine growth restriction and placental abruption more than compensated for this benefit. 
On its own vascular endothelial dysfunction causes proteinuria, increase capillary permeability and oedema. Resulting cerebral hypoxia and oedema leads to eclamptic seizures. In the liver periportal necrosis and parenchymal damage result in elevated enzymes and haemolysis. Autopsy findings in eclamptic patients support the model of cerebral oedema, ischaemia, fibrinoid necrosis and encephalopathy. 
| Diagnosis and prognosis|| |
The diagnosis and prediction of outcome for mother and fetus are most of the time taken in a single breath and will be discussed hand in hand with specific emphasis on the present evidence.
Proteinuria is a specific feature of preeclampsia and in the presence of hypertension it is the criterion standard upon which the diagnosis hinges. It is a result of characteristic pathological changes in the glomeruli that are consistent in all patients with preeclampsia.  Here there is swelling of the glomerulus due to glomerular cellular tuft oedema which encroaches on the lumen of glomerular capillaries resulting in ischaemia and increase in permeability to protein.
Standard urine dipstick is used for screening of proteinuria. Quantification of protein in 24 hour urine collection or spot protein: Creatinine ratio confirms the diagnosis. The degree of proteinuria and maternal age correlates with adverse maternal outcome, increase obstetrics interventions and low birth weight. Intrapartum fetal distress and recurrent late decelarations are also increased with rising proteinuria. Similarly massive proteinuria defined as protein >10 g/24 h is associated with early onset preeclampsia, early gestational age at delivery, and prematurity.  However in terms of fetal outcome once this is controlled for prematurity there are no associated adverse events seen with proteinuria hence it is the prematurity that is the cause of all adverse events and not the degree of proteinuria. A recent systematic review concluded that the level of proteinuria does not correlate with maternal and fetal outcome.  The national institute of health and clinical excellence (NICE), recommend that once proteinuria is diagnosed there is no benefit in repeating the test.  This certainly seems to fly the face of present clinical practice. Data from the preeclampsia integrated estimate of risk study (PIERS) concluded that urine dipstick test perform as well as protein: Creatinine ratio and 24 urine collection in predicting maternal outcome  with similar cautioned that proteinuria should not be used in isolation for decision making in women with preeclampsia.
Preeclamptic toxaemia screen refers to a panel of blood test carried out once the diagnosis is suspected with a view to assess the multi-organ nature of the condition. These include full blood count in particular platelets count, renal function test, liver function test and coagulation screen. It is pertinent to bear in mind that the clinical value of these tests in assessing maternal fetal outcome or progression to eclampsia remains very little in the absence of proteinuria.
Like proteinuria, uric acid is a specific feature of preeclampsia, but its value in predicting maternal and fetal outcome remains very tenuous. A systematic review involving 2000 patients from 23 studies using a threshold of 360 μmol/l or more showed that the likelihood ratio of disease progression to eclampsia was 2.1, severe hypertension 1.7, caesarean section 2.4, stillbirth and neonatal death 1.5 and small for gestational age 1.3 leading to the conclusion that the use of therapeutic measures such as planning delivery or magnesium sulphate on this basis is not to be justified. 
Similarly serial blood sampling had no predictive value on disease progression. However, low platelets count less than 100 × 10 9 /L, raised liver transaminases and creatinine >110 mcmol/L are each associated with adverse maternal outcome. , The PIERS study enrolled 2008 women with preeclampsia, 1053 had abnormal liver function test. The odds of having adverse maternal outcome were higher in women with any abnormal liver function test than in those with normal results. Similarly when results were stratified into quartiles, there was positive correlation with the higher quartiles for aspartate and alanine transaminases as well as lactate dehydrogenase and the lower quartiles for albumin.  However neither change of LFT result within 48 hrs of admission or from admission to delivery nor the rate of change was predictive of adverse outcome.
The odds of abnormal coagulation were increased in women with platelet count less than 50 × 10 9 /L (OR 7.78, 95% CI 3.36-18.03) and 50-99 × 10 9 /L (OR 2.69, 95% CI 1.44-5.01) compared to counts 150 × 10 9 /L. Platelets count less than 100 × 10 9 /L has good specificity 92% but low sensitivity 22% for predicting adverse maternal out come and should therefore not be used in isolation for decision making in patients with preeclampsia.  In the presence of normal platelets count coagulation screen does not add any value to these parameters.
A retrospective analysis of 111 preeclamptics in Sweden shows correlation of diastolic blood pressure with HELLP syndrome, Oliguria, eclampsia and placental abruption. Furthermore the last CEMACH report supports the association of systolic hypertension with cerebrovascular haemorrhage. 
The PIERS was recently commissioned to develop a model to identify the risks of fatal or life threatening complications in women with preeclampsia admitted to tertiary institutions within 48 hours of admission in Australia, New Zealand and Canada. The main outcomes are maternal mortality and other serious complications. Of the total 2023 women enrolled in the study, 261 had adverse maternal outcomes (106 or 5% within 48 hrs of admission). The predictors of adverse outcome included: Gestational age at admission, chest pain or dyspnoea, low oxygen saturation, low platelet count, creatinine and aspartate transaminase concentrations. 
Pharmacological treatment of preeclampsia is limited to symptomatic control of blood pressure and seizure prophylaxis. In treating blood pressure extensive evidence has accumulated over the years on the safety and efficacy of the β-blocker labetalol, presently considered first choice and with which effective control can be achieved in 80% of preeclamptic patients. , Labetalol however is contraindicated in severe asthma and has tendency for resistance among Afro-Caribbean women. Alternatives in the form of calcium channel blocker nifedipine and alpha methyldopa are safe and effective. There is consistent evidence on the efficacy of antihypertensives in reducing blood pressure to a significant level. In preeclampsia this is not paralleled with improved perinatal outcome. Maternal morbidity and mortality as well as gestational age at delivery are improved. Sibai et al. in a study of 200 primigravidae with mild-moderate preeclampsia showed that labetalol reduces the blood pressure, prolonged gestational age at delivery but no improvement in perinatal outcome. 
Commencing antihypertensive treatment in severe hypertension is an established norm in clinical practice and it is for this much of the evidence in improved maternal morbidity and the gestation at delivery benefits exist. , The objective of therapy is DBP 80-100 mmHg and SBP less than 150 mmHg.  Treatment of moderate hypertension (DBP 100-109 mmHg, SBP 150-159 mmHg) has recently been shown to reduce progression to severe preeclampsia, reduce maternal morbidity and prolonged gestational age at delivery. Perinatal outcome remained the same after controlling for prematurity with increased risk of impaired fetal growth.  Despite the agreement on the need for no treatment in mild preeclampsia in clinical parlance the evidence base for this recommendation remains sparse.
The tradition that based antihypertensive treatment in pregnancy on the diastolic blood pressure is still prevalent. The centre for maternal and child enquiries latest report is however instructive that the most consistent failing in the clinical care for women with severe preeclampsia is the inadequate treatment of systolic hypertension on the erroneous notion that diastolic hypertension correlates more with maternal morbidity and mortality. Ten of the 18 deaths related to preeclampsia in the last triennium had fatal intracranial haemorrhage. This type of haemorrhage and aortic dissection are known to correlate more with systolic hypertension. Furthermore evidence from pregnant women with stroke is supportive of this hypothesis regardless of ischaemic or haemorrhagic nature of the stroke.  Current recommendation is for treatment of systolic hypertension of 150 mmHg or more.
NICE recommend the admission of patients for blood pressure control and monitoring, testing for proteinuria and preeclamptic toxaemia screen. Blood pressure should be monitored at least four times in 24 h and treatment will depend on the severity. Once proteinuria is identified further quantification is not recommended. The frequency of blood test in mild preeclampsia is twice a week and three times in moderate to severe disease. 
Seizure prophylaxis and control
The role of magnesium sulphate in control and prophylaxis of eclamptic seizures is well established. , Its long term safety for mother and baby is also proven.  So far the evidence for prophylaxis is based on data among patients with severe preeclampsia.  The evidence for the efficacy of magnesium sulphate in seizure control dates back to the 1920s in tetanus patients. Its widespread use in obstetrics practice followed the publication of the collaborative eclampsia trial in 1995. The magpie trial examined its efficacy in seizure prophylaxis among patients with preeclampsia. Recent Cochrane review established its superiority over other anticonvulsants with reference to control, prevention, recurrence of seizure as well as maternal and fetal morbidity and mortality. , Mechanism of action for this effect is not known. The regimen for its administration has been the subject of many researches but evidence and experience are based mostly on the regimen used in the collaborative eclampsia trial.  In this a loading dose of 4 g intravenously over 5-10 minutes is followed with maintenance dose of 1 g/hr for 24 hrs. Recurrent seizures are treated with a further bolus of 2 g or increasing the infusion rate to 2 g/hr.
The magnesium sulphate for prevention of eclampsia (MAGPIE) trial involved 10 141 patients with preeclampsia from 33 countries randomised to magnesium or placebo in an intension to treat randomised control trial (RCT) designed with eclamptic convulsion as its main outcome. The women in the magnesium arm had 58% lower risk of progressing to eclampsia (95% CI = 40-71) compared to the placebo group.
Safety of magnesium sulphate in the treatment of preeclampsia and eclampsia is reported by the Magpie study group 18 months and 2 years after.  At two years of follow up there were on clear differences between the randomised groups in child's behaviour, women's fertility and use of health care services. 
Fluid and electrolyte management
This is the aspect of preeclampsia where limited clinical evidence exists in the literature. Much of existing guidance and recommendation are based on consensus and retrospective reports. Despite high rates of oedema preeclamptics have contracted intravascular volume and high peripheral resistance, poor fluid management is a recognised factor in the death of women with severe preeclampsia and eclampsia mostly resulting from pulmonary oedema. These lead to the recommendation for early senior obstetrician and anaesthetist involvement in the management of these patients.  The implementation of this has lead to marked improvement in mortality from this cause in the succeeding triennia 2003-2005 and 2006-2008.  Current recommendation is for total intake of fluid of not more than 1 ml/kg/hr or 80 ml per hour. Input and output should be carefully monitored and patients with complications should have central venous pressure (CVP) monitoring where possible to allow for optimal volume replacement. A CVP of 5 mmHg indicate sufficient intravascular volume in the absence of heart disease. Most patients on this treatment will have transient postpartum oliguria. The recommendation is to allow for urine output less than 20 ml/hr for up to 8 hrs before instituting interventions. Volume expansion to improve urine output is to be very carefully considered in women with severe preeclampsia. This guideline has been shown to be effective in temperate climes, whether the same protocol will benefit patients in the tropics remains to be tested and forms an area for further research.
| Fetal monitoring|| |
The association of preeclampsia with adverse fetal outcome, increased perinatal morbidity and mortality is responsible for the evaluation and employment of various biometric and biophysical parameters to select fetuses that would benefit from early delivery, intrauterine intervention or further monitoring. Growth monitoring identifies the fetus whose growth is impaired. Assessment of liquor volume to assess fetal well-being  can be achieved by amniotic fluid index or measurement of single deepest vertical pool. Comparison between these measures showed no difference with respect to neonatal intensive care admission, caesarean section, meconium staining of the liquor amnii, Apgar score less than 7 at 5 minutes, arterial cord pH less than 7.1 or perinatal death. 
Biophysical profile assessment showed no significant difference in terms of neonatal care unit admission or perinatal death when compared to cardiotocography. There is tendency towards an increase caesarean section. 
In a systematic review of RCTs Westergaad et al. assessed the role of uterine artery Doppler in women with high risk pregnancy compared to no Doppler or routine monitoring. The use of Doppler was associated with significantly less perinatal morbidity and mortality, helps in deciding the time for delivery, reduce rates of induction of labour, emergency caesarean section, antenatal admission and low apgar scores in 5 minutes. The absence or reversal of endiastolic flow correlated with neonatal morbidity and mortality. 
As delivery remained the definite treatment for preeclampsia its timing in relation to the gestational age is the critical consideration if increased foetal morbidity and mortality due to prematurity is not to be traded for maternal safety. Naturally two groups of patients emerge on the basis of this consideration, the early onset severe preeclampsia prior to 34 completed weeks and those thereafter. In both cases the primary goal of treatment involves the stabilisation of patients with antihypertensive therapy, seizure prophylaxis and in the early cases administration of steroids to enhance lung maturity.
The hypertension and preeclampsia intervention trial in the almost term patient (HYPITAT) addressed the timing of delivery in preeclampsia after 36 weeks  where a policy of induction of labour is favoured to reduce maternal morbidity and caesarean section rate without a compromise to neonatal outcome. There is no statistically significant increase in maternal morbidity or immediate neonatal morbidity with immediate delivery after 37 weeks. This approach is adopted by NICE who recommend delivery after 37 weeks in severe preeclampsia. A similar trend is observed in practice with mild-moderate preeclampsia although the evidence base is less robust. 
Sibai et al. randomised patients with early onset severe preeclampsia in to early delivery and expectant management. The early delivery groups are stabilised as described above and delivery is planned for 48 hours after steroids. In the expectant group patients are conservatively managed and delivery planned for after 34 weeks except in the event of deteriorating maternal or fetal condition.  The early delivery group show significant increase in respiratory distress syndrome and necrotising enterocolitis. There was no difference in stillbirth, neonatal death or caesarean section rates. Expectant management is therefore justifiable to 34 weeks in severe preeclampsia, however beyond this gestation there is no benefit seen. The gestation window between 34 weeks and 36 completed weeks is the subject of current HYPITAT-II, the outcome of which is eagerly awaited. 
Mode of delivery depends on clinical and obstetrics circumstances and patient's preference.
| Postpartum management|| |
Although delivery is the definitive treatment of preeclampsia more eclamptic convulsions are seen in the postpartum than before or during labour in many countries in the world. Careful monitoring of blood pressure in the immediate postpartum is recommended by NICE in patients with preeclampsia.  For some patients the postpartum period is when antihypertensives are required. Delivery brings about large volume shift, vasoconstriction, increase osmolality and hypercoagulability to aid the rapid physiologic changes characteristic of the period. Most eclamptic seizure occurs in the first 24-48 hours of delivery, seizure prophylaxis should therefore continue for up to 24 hours postpartum.  Antihypertensive treatment is commenced with blood pressure of 150/100 mmHg and the goal remains the same as in the prepartum period. Toxaemia screening may be required for up to 72 hours, there is no benefit in repeating it if it is normal. Rarely elevated liver enzymes, thrombocytopenia persists beyond this period with renal insufficiency. These should herald the consideration for haemolytic ureamic syndrome (HUS) and/or thrombotic thrombocytopenic purpura (TTP) and inform treatment with corticosteroids and plasmapheresis.  Once the blood pressure is maintained below 150/100 mmHg for 24 hours patients that are not symptomatic who have acceptable toxaemia screen can be discharged to community care.
A debriefing with the team leading in her care is recommended in the case of eclampsia, severe preeclampsia, delivery before 34 weeks, HELLP syndrome or adverse perinatal outcome. The focus of this should address the main event that has occurred as well as advise the patient on her risk in subsequent pregnancy. Women with high BMI should be advised to optimise this before the next pregnancy. Where delivery was necessitated before 34 weeks the risk of recurrence of preeclampsia is 25% and risk increases to over 50% if delivery before 28 weeks.  Prepregnancy care and low dose aspirin in early pregnancy is recommended. In patients with background chronic hypertension eventual discharge to general practice at 6 weeks is the normative practice.
The limitation in our understanding of the pathophysiology of preeclampsia means that its prevention has been the subject of many studies. The evidence so far seems to favour antiplatelet agents of which most relates to low dose aspirin. A Cochrane systematic review of 59 trials including 37 560 women concluded that antiplatelet agents reduce the risk of preeclampsia by 17% (RR 0.83; 95% CI: 0.77-0.89; NNT 72) with increasing benefit in the higher risk group.  In high risk women (previous preeclampsia, chronic hypertension, diabetes mellitus, chronic renal disease, autoimmune diseases including antiphospholipid antibodies) the risk reduction increases to 25%, with 19 needed to treat (95% CI 34-15%). A hundred and nineteen women needed to be treated in moderate risk group to achieve a risk reduction of 14% (95% CI 21%-5%). Patients in this category are primigravidae, aproteinuric mild hypertension, positive roll over test, abnormal uterine artery Doppler, multiple pregnancy, teenage and family history of preeclampsia.
Recent systematic review by Trivedi which included 19 trials showed no benefit with low dose aspirin in 16550 low risk women (RR 0.86; 95% CI: 0.64-1.17) and 21% risk reduction in 11687 high risk women (RR 0.79; 95% CI: 0.65-0.97).  Rossi et al. on the other hand showed no benefit in both high risk (P = 0.05; OR: 0.72; 95% CI: 0.51-1.0) and low risk group P = 0.10; OR: 0.82; 95% CI: 0.63-1.12). 
Antiplatelet agents also reduce the risk of preterm birth in preeclampsia (RR: 0.92; 95% CI: 0.88-0.97; NNT 119); fetal and neonatal death (RR: 0.86; 95% CI: 0.76-0.98; NNT 243) and small for gestational age (RR: 0.90; 95% CI: 0.83-0.98).  Antiplatelet agents are safe and cheap and therefore cost effective.
The NICE recommend their use from 12 weeks until delivery in high risk women (previous preeclampsia, chronic renal disease, autoimmune diseases including APS, diabetes mellitus and chronic renal disease and chronic hypertension). They further recommend the prophylaxis in patients with BMI >35, first pregnancy, interpregnancy interval >10 years, those over 40 years, family history and multiple pregnancy. An audit of this practice will guide future recommendations on antiplatelet agents.
There is large body of research on nutritional supplements for the prevention of preeclampsia. Supplements that have been evaluated are folic acid, antioxidant vitamins, fish oil, garlic, magnesium and calcium.  A Cochrane review of 12 RCT involving 15206 patients confirm the ineffectiveness of all except calcium which show some benefit in high risk patients and those from communities with low dietary calcium.  Overall women receiving calcium supplementation had 50% reduction in incidence of preeclampsia compared to a placebo group (RR 0.48; 95% CI 0.35-0.69). Further subgroup analysis showed a 32% risk reduction amongst low risk women n = 14619; (RR 0.68; 95% CI 0.49-0.94) and 78% risk reduction among high risk women n = 587; (RR 0.22 95% CI 0.12-0.42). Thus the evidence support supplementation amongst high risk women in areas with low dietary calcium but no statistical benefit is elicited in low risk women with adequate dietary calcium intake. 
A single small RCT evaluated the role of low molecular weight heparin which is shown to be beneficial in patients with systemic lupus erythematosus and APS in observational studies. This showed a risk reduction (RR: 0.26; 95% CI: 0.08-0.86) which is impressive. This trial was however criticised on its very high selectivity. The patients were selected on the basis of history of preeclampsia and possession of angiotensin converting enzyme DD genotype. 
Historically diuretics were tried without success with potential hazard of blood volume reduction and adverse pregnancy outcome. Their role today is limited to the treatment of severe pulmonary oedema. Similarly Cochrane concluded that there is no clear evidence for progesterone and the evidence for nitric oxide agents (L-arginine and glycerine trinitrate) is insufficient for recommendation. 
| Eclampsia|| |
Eclampsia, the occurrence of new onset grand mal seizures or unexplained coma in association with signs and symptoms of preeclampsia is the most serious complication of preeclampsia for which high rates of maternal and perinatal morbidity and mortality are reported. Rarely eclampsia occurs without proteinuria (38%) and hypertension in 16%. The incidence of eclampsia in the Netherlands was 6.2 per 10000 deliveries compared to 1.3% of deliveries in parts of Nigeria. Similarly the case fatality is higher in developing compared to developed countries. Of the 63 000 maternal deaths annually attributed to preeclampsia and eclampsia worldwide most are in the developing world. Of 112 maternal deaths reported from Northern Nigeria 46.4% were in eclamptic patients. 
Like the precursor preeclampsia the pathophysiology of eclampsia remains speculative. However the convulsions are attributed to diffuse cerebral oedema, ischaemia and infarction based on CT scan and autopsy findings. 
Eclamptic seizures last 60-75 seconds are grand mal in nature. Starts with distortion of the face, protrusion of the eyes and foaming of the mouth, the respiration ceases and the body is rigid. This is followed by generalised muscular contraction that commences from the jaws, face and the eyelids and spreads to the whole body in a sequence of strong contractions alternating with relaxation. The patient eventually lapsed into coma or unconsciousness for variable period and has no recollection of the preceding events.
Events leading to eclamptic convulsions have been studied with a view to predicting and preventing the seizures. Headache is the most consistent symptom in 83% of patients, visual disturbance and right upper quadrant or epigastric pain are noted in 44% and 19% of patients respectively.
Hypereflexia was seen in 52% of patients while others contend that the presence of ankle clonus is more predictive of eclamptic seizures. , It is not surprising that present strategy for prevention of seizures seek to treat all cases of severe preeclampsia with magnesium sulphate since the efficacy of the drug was elicited in the MAGPIE trial.
Clinical management of eclampsia to avert maternal mortality should be based on a drill that prevent the patient from injury during convulsions while maintaining a patent airway, suction of vomits and/or excess secretions, administration of oxygen, control of convulsions with magnesium sulphate, control of hypertension, fluid management, monitoring and the delivery of the patient when stable. These measures can easily be achieved in the hospital setting where skill, facilities and consumables are available. In most instances in developing countries however, eclamptic convulsions occur out with the health facility and no skilled attendance is at hand to administer established interventions. Details of treatment of eclamptic convulsions including recurrent seizures and blood pressure have been covered under treatment. When seizures persist despite repeat dose of magnesium sulphate the next line of action is diazepam in a slow intravenous dose of 10 mg and status eclampticus warrants treatment with sodium thiopentone. This last measure will require intubation and airway management and should be decided in concert with the anaesthetist. 
| HELLP syndrome|| |
The occurrence of microangiopathic haemolysis, elevated liver enzymes and low platelets is a serious complication of pregnancy associated with statistically significant increase in maternal and fetal morbidity and mortality. The syndrome is seen in 0.5%-0.9% of pregnancies and 10%-20% of patients with severe preeclampsia.  Hypertensive patients with the condition tend to be parous with relatively mild to moderate hypertension. Diagnosis is based on evidence of haemolysis, raised liver enzymes and low platelets. However respective thresholds for these parameters vary between reports. Martin define haemolysis on the basis of progressive anaemia, raised lactate dehydrogenase >600 IU/L; alanine transaminase and aspartate transaminase >40 IU/L and platelets count less than 150000/mm.  Sibai  employed LDH of 700 IU/L, AST >70 IU/l and platelets less than 100000/mm 3 . The Mississipi classification recognised three classes based on platelet counts of 50000/mm 3 , 100000/mm, and 150000/mm 3 respectively. 
Acute fatty liver is the main differential diagnosis. In addition to the features of HELLP syndrome hypoglycaemia, hyperammonaemia, hypofibrigenaemia and prolonged partial thromboplastin time points to acute fatty liver. If in doubt the application of the Swansea criteria aids the identification of the later condition. ,
Corticosteroids used in the treatment of HELLP syndrome improve the platelets count but have no clear effect on maternal and foetal outcomes.  Cochrane review of 550 patients from 11 trials showed no clear effect in reduction of maternal death (RR: 0.95; 95% CI: 0.28-3.21), maternal death and severe maternal morbidity (RR: 0.27; 95% CI: 0.03-2.12) and perinatal or infant death (RR: 0.64; 95% CI: 0.21-1.97).  Routine use of steroids is not recommended for the treatment of this condition. Delivery remained the definitive treatment. This may be at a very preterm gestation where the fetal role for steroids still remained valid.
Maternal complications include acute renal failure, hepatic failure, disseminated intravascular coagulation, pulmonary oedema, cerebrovascular haemorrhage and infection. Preterm delivery may be seen in up to 70% of cases and is at less than 28 weeks in 15%. Prematurity is therefore common and perinatal mortality is in the region of 14.1%. 
Challenges in the management of preeclampsia in resource poor setting
Developing countries, where resource constraints in maternity care abound correspond with areas of high incidences of preeclampsia and eclampsia. Relatively high incidences are attributed to biological factors among the negroid population but more importantly epidemiologic determinants such as high rates of early child bearing, inadequate antenatal care services and gross underutilisation of available ones contributes to the high morbidity and mortality associated with the disease. , Reports of eclampsia from developing countries universally concur on the absence of antenatal care attendance among the patients. , Although doubts have been expressed with regards to the capacity of antenatal screening to adequately sieve out all cases of preeclampsia and treat them before any complications. Assuming similar incidences of preeclampsia the variations in the rates of eclampsia can only be attributed to the differences in early detection and management of preeclampsia.
Factors responsible for non utilisation of services are well enunciated and varying strategies proposed, yet the most impact is seen where user fees are abrogated. , The improved attendance witnessed is not matched by reduction morbidity and mortality. These partly is because of late presentation often in the wake of complications like eclampsia, inadequate resource allocation, poor and non programmatic application of the limited resources and maldistribution of expertise with most concentrated in teaching and tertiary centres away from where the vast majority of maternities occur. The poor state of midwifery services means that care is often medically driven with associated cost and accessibility implications.
At institutional level comprehensive care of preeclampsia demands multidisciplinary approach which is not readily available in developing countries owing to dearth of trained personnel. Where the requisite skill is on hand lack of or timely availability of consumables and supplies may be the differences in the patient care.
Where resources are limited the expectation is for a policy favouring cost effectiveness and targeted application of resource on a need basis. In developing countries systemic weaknesses undermines policy leadership and in turn clinical effectiveness. As a result there is lack of uniformity in the standard of care that is provided such that the impact of scientific and clinical advances are incoordinated and often takes a long time to translate clinical care. We concur with others that improvement in maternal and perinatal outcomes in preeclampsia demands the multidisciplinary management of the disease based on clearly designed protocols that integrate current evidence in the context of resource availability. ,
| Conclusion|| |
Over the years knowledge and understanding of preeclampsia have progressed considerably. The evolution in clinical management of the disease has positively impacted on the maternal and fetal morbidity and mortality. However, the gap in unravelling its pathophysiology means that treatment is still symptomatic; delivery remained the main therapy and screening and preventive measures elusive. Standardisation of management offers the benefit in improving maternal outcome especially in the developing world. Future focus at more precise prediction and prevention of disease should form the basis of research. Specific measures in improving fetal growth dysfunction and preventing prematurity would positively impact on perinatal outcome.
| Acknowledgement|| |
Miss Leila M for French translation of abstract.
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[Table 1], [Table 2], [Table 3]
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