Elsevier

The Lancet

Volume 365, Issue 9461, 26 February–4 March 2005, Pages 785-799
The Lancet

Seminar
Pre-eclampsia

https://doi.org/10.1016/S0140-6736(05)17987-2Get rights and content

Summary

Pre-eclampsia is a major cause of maternal mortality (15–20% in developed countries) and morbidities (acute and long-term), perinatal deaths, preterm birth, and intrauterine growth restriction. Key findings support a causal or pathogenetic model of superficial placentation driven by immune maladaptation, with subsequently reduced concentrations of angiogenic growth factors and increased placental debris in the maternal circulation resulting in a (mainly hypertensive) maternal inflammatory response. The final phenotype, maternal pre-eclamptic syndrome, is further modulated by pre-existing maternal cardiovascular or metabolic fitness. Currently, women at risk are identified on the basis of epidemiological and clinical risk factors, but the diagnostic criteria of pre-eclampsia remain unclear, with no known biomarkers. Treatment is still prenatal care, timely diagnosis, proper management, and timely delivery. Many interventions to lengthen pregnancy (eg, treatment for mild hypertension, plasma-volume expansion, and corticosteroid use) have a poor evidence base. We review findings on the diagnosis, risk factors, and pathogenesis of pre-eclampsia and the present status of its prediction, prevention, and management.

Section snippets

Maternal and perinatal outcome

Pre-eclampsia is a major obstetric problem leading to substantial maternal and perinatal morbidity and mortality worldwide, especially in developing countries.1, 12 Maternal and perinatal outcomes in pre-eclampsia depend on one or more of the following: gestational age at time of disease onset, severity of disease, quality of management, and presence or absence of pre-existing medical disorders.1, 2, 12, 13, 14, 15, 16, 17, 18, 19, 20 In general, maternal and perinatal outcomes are usually

Diagnosis

Pre-eclampsia is usually diagnosed in the presence of hypertension associated with proteinuria.1, 2, 10 Hypertension is defined as a blood pressure of at least 140 mm Hg (systolic) or at least 90 mm Hg (diastolic) on at least two occasions and at least 4–6 h apart after the 20th week of gestation in women known to be normotensive beforehand.1, 2, 10 Blood-pressure recordings to establish the diagnosis should be no more than 7 days apart.1, 2, 7 Hypertension is regarded as severe if there are

Epidemiology and risk factors

Frequency of pre-eclampsia ranges between 2% and 7% in healthy nulliparous women.2, 4, 7 In these women, the disease is mostly mild, the onset mostly near term or intrapartum (75% of cases), and only conveys a negligible increased risk for adverse pregnancy outcome.2, 4, 7 By contrast, frequency and severity of the disease are substantially higher in women with multifetal gestation,13, 33, 34 chronic hypertension,13, 14 previous pre-eclampsia,13, 15 pregestational diabetes mellitus,13 and

Pathophysiology

It should be emphasised that the causes of pre-eclampsia remain unknown. Therefore, the current attempt to distil recent pathophysiological data in one causal framework represents another one of the many hypotheses proposed to explain the pathogenesis of pre-eclampsia. Typically, progress of any new theory starts with a flurry of studies bolstering one hypothesis and leading to tremendous excitement and interest, which then is invariably followed by studies that do not confirm such a hypothesis

Placentation and the immune theory of pre-eclampsia

Epidemiological studies support the concept of maternal–fetal (paternal) immune maladaptation being centrally implicated in the causation of pre-eclampsia.6, 36, 38 Deposition of semen in the female genital tract provokes a cascade of cellular and molecular events that resemble a classic inflammatory response. The critical seminal factor seems to be seminal-vesicle-derived transforming growth factor β1 (TGFβ1)—it initiates a postmating inflammatory reaction, allowing an increased ability to

Placental debris hypothesis—syncytiotrophoblast shedding

Shedding of syncytiotrophoblasts, a feature of healthy pregnancy, is increased in pre-eclampsia. This shedding is now viewed as part of syncytial renewal.72 Enhanced deportation of microvillous membrane particles of syncytiotrophoblasts73 and raised concentrations of free fetal DNA and cytokeratin in the maternal circulation have been recorded in pre-eclampsia.74, 75 Increased cell-free fetal DNA was noted at 16–18 weeks in future pre-eclamptic women, but these concentrations did not correlate

Endothelial activation and inflammation

It is still uncertain whether pre-eclampsia is caused by the damaged ischaemic or reperfused placenta or by the inappropriate or exaggerated maternal inflammatory response towards the presence of the trophoblast, although the endothelium is associated with the pathophysiology of disease. Many endothelial studies have focused on the importance of prostacyclin and thromboxane A2 imbalance in women with pre-eclampsia.70 Recent studies confirming increased concentrations of asymmetric

Genes, the genetic-conflict hypothesis, and genetic imprinting

According to the genetic-conflict theory,100 fetal genes will be selected to increase the transfer of nutrients to the fetus, and maternal genes will be selected to restrict transfer exceeding a specific maternal optimum. With genomic imprinting, a similar conflict exists within fetal cells between genes that are maternally derived and those that are paternally derived. The conflict hypothesis predicts that placental factors (fetal genes) will act to raise maternal blood pressure, whereas

Prediction of pre-eclampsia

Many biochemical markers have been proposed to predict which women are likely to develop pre-eclampsia.8, 106 These markers were generally chosen on the basis of specific pathophysiological abnormalities that have been reported in association with pre-eclampsia—ie, those of placental dysfunction,8, 103 endothelial and coagulation activation,8, 90, 106 and systemic inflammation.73, 75, 107 Maternal concentrations of these biomarkers have been reported to be either increased or reduced early in

Prevention of pre-eclampsia

During the past decade, several randomised trials reported the use of various methods to reduce the rate or severity (or both) of pre-eclampsia (table). Results of these studies have been the subject of several systemic reviews.5, 6, 112, 113, 114, 115, 119 In summary, there have been few trials assessing protein or salt restriction; zinc, magnesium, fish oil, or vitamins C and E supplementation; the use of diuretics and other antihypertensive drugs; or heparin to prevent pre-eclampsia in women

Calcium supplementation

In a Cochrane review,114 calcium supplementation was associated with reduced hypertension and pre-eclampsia, particularly for those at high risk of the disease and with a low baseline dietary calcium intake (for those with an adequate calcium intake the difference was not significant). No side-effects of calcium supplementation were recorded in the trials reviewed.113 However, the reduction was not indicated in any overall effect on stillbirths or neonatal deaths. The data lend support to

Aspirin and other antiplatelet drugs

Most randomised trials investigating the prevention of pre-eclampsia have used low doses of aspirin (500–1500 mg/L).114 The rationale for recommending low-dose aspirin prophylaxis is that the vasospasm and coagulation abnormalities in the disorder are caused partly by an imbalance in the thromboxane-A2-to-prostacyclin ratio. Low-dose aspirin treatment in pregnancy inhibits biosynthesis of platelet thromboxane A2 with little effect on vascular prostacyclin production, thus altering the balance

Management of pre-eclampsia

Adequate and proper prenatal care is most important in the management of pre-eclampsia.1, 2, 10, 28 Maternal antenatal monitoring includes identification of women at high risk, early detection by the recognition of clinical signs and symptoms, and progression of the condition to severe state.1, 2, 10, 28 After diagnosis, subsequent treatment will depend on the results of initial maternal and fetal assessment. The main objective of management of pre-eclampsia must always be the safety of the

Expectant management of severe pre-eclampsia

The clinical course of severe pre-eclampsia can be characterised by progressive deterioration in both maternal and fetal conditions.124 Because these pregnancies have been associated with raised rates of maternal morbidity and mortality and with pronounced risks for the fetus, such patients should be delivered if the disease develops after 34 weeks' gestation.1, 124 Delivery is also clearly indicated when there is imminent eclampsia (persistent, severe symptoms), multiorgan dysfunction, severe

Antihypertensive treatment

Treatment of acute hypertension should prevent potential cerebrovascular and cardiovascular complications, which are the most common cause of maternal mortality and morbidity in developed countries.21, 128 Although the use of antihypertensive drugs in women with pre-eclampsia and severe rises in blood pressure have been shown to prevent cerebrovascular problems, such treatment does not prevent or alter the natural course of the disease in women with mild pre-eclampsia.2, 129

The most recent

Use of corticosteroids to improve pregnancy outcome in women with severe pre-eclampsia or HELLP syndrome

There has been uncertainty regarding the effectiveness and safety of corticosteroids in women with severe pre-eclampsia with or without HELLP syndrome.2 A prospective, double-blind, randomised trial133 of 218 women with severe pre-eclampsia and gestational age between 26 and 34 weeks were assigned either betamethasone or placebo. A significant reduction in the rate of respiratory distress syndrome in the steroids group was recorded. Corticosteroid use also was associated with reduced risks of

Plasma-volume expansion

Some women with severe pre-eclampsia have a restricted circulating plasma volume and are haemoconcentrated.1 This has led to the recommendation that plasma volume should be expanded with either colloid or crystalloid solutions, to improve maternal systemic and uteroplacental circulation.135 However, intravascular volume expansion carries a serious risk of volume overload, which could lead to pulmonary or cerebral oedema. Also, large volume expansion often requires invasive monitoring of

Prevention of convulsions and control of acute convulsions

Eclampsia is defined as the onset of convulsions in women who have either gestational hypertension or pre-eclampsia. Several randomised trials have compared the efficacy of magnesium sulphate with other anticonvulsants in women with eclampsia.138 These trials compared magnesium sulphate with diazepam, phenytoin, or a lytic cocktail. Magnesium sulphate was associated with a significantly reduced rate of recurrent seizures and maternal death than that seen with other anticonvulsants.138

Postpartum pre-eclampsia

In general, pre-eclampsia is cured by delivery of the placenta, although in some women the disease process could worsen during the first 48 h after delivery. Such women might be at risk for pulmonary oedema, renal failure, HELLP syndrome, postpartum eclampsia, and stroke.2, 20 Therefore, women with diagnosed hypertension or pre-eclampsia (or both) need very close monitoring of blood pressure, maternal symptoms, and measurements of fluid intake and urine output.2, 20

Severe hypertension or

Future directions

Many challenges remain regarding the prediction, prevention, and management of pre-eclampsia. Future research should expand our knowledge of biomarkers for early prediction of severe pre-eclampsia and aim to reduce the prevalence of the disorder that is associated with adverse pregnancy outcome (severe disease and onset before 33 weeks' gestation). However, the lack of universal criteria to diagnose pre-eclampsia has hampered basic research into the cause, identifying biomarkers for prediction,

Search strategy and selection criteria

We searched MEDLINE, PubMed, and the Cochrane Library for published work relevant to this Seminar with the search words: “preeclampsia”, “epidemiology”, “definition”, “pathophysiology”, “prediction”, “prevention”, and “management”. This search was updated from 2000, to November, 2004. Publications were selected for review based on original research, randomised controlled trials, and meta-analyses and evidence-based reviews of assessment of interventions. We also included highly regarded

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