Elsevier

The Lancet

Volume 387, Issue 10022, 5–11 March 2016, Pages 999-1011
The Lancet

Seminar
Pre-eclampsia

https://doi.org/10.1016/S0140-6736(15)00070-7Get rights and content

Summary

Pre-eclampsia affects 3–5% of pregnancies and is traditionally diagnosed by the combined presentation of high blood pressure and proteinuria. New definitions also include maternal organ dysfunction, such as renal insufficiency, liver involvement, neurological or haematological complications, uteroplacental dysfunction, or fetal growth restriction. When left untreated, pre-eclampsia can be lethal, and in low-resource settings, this disorder is one of the main causes of maternal and child mortality. In the absence of curative treatment, the management of pre-eclampsia involves stabilisation of the mother and fetus, followed by delivery at an optimal time. Although algorithms to predict pre-eclampsia are promising, they have yet to become validated. Simple preventive measures, such as low-dose aspirin, calcium, and diet and lifestyle interventions, show potential but small benefit. Because pre-eclampsia predisposes mothers to cardiovascular disease later in life, pregnancy is also a window for future health. A collaborative approach to discovery and assessment of the available treatments will hasten our understanding of pre-eclampsia and is an effort much needed by the women and babies affected by its complications.

Introduction

Pre-eclampsia is a pregnancy-specific syndrome that affects 3–5% of pregnancies and is traditionally diagnosed when a pregnant woman presents with increased blood pressure and proteinuria.1 Pre-eclampsia is one of the main causes of maternal, fetal, and neonatal mortality, especially in low-income and middle-income countries.2 In this Seminar, we describe the current management of pre-eclampsia in terms of prediction, prevention, diagnosis, treatment, and long-term consequences. Our aim is to provide a guide for the optimal management of pre-eclampsia, both in low-resource and high-resource settings.

The acute clinical importance of pre-eclampsia lies in its relation to maternal and neonatal mortality and morbidity. When left untreated, pregnant women with pre-eclampsia have severe complications such as eclampsia, liver rupture, stroke, pulmonary oedema, or kidney failure, which can all be lethal.3 Pre-eclampsia is also related to fetal growth restriction and preterm birth, either spontaneous or through iatrogenic delivery. Children born to mothers with pre-eclampsia have an increased risk of bronchopulmonary dysplasia and cerebral palsy, caused by preterm birth and being small for gestational age.4, 5 Pre-eclampsia decreases health-related quality of life and increases the risk of post-partum depression.6, 7

The cause of pre-eclampsia is unclear. Some women are genetically predisposed to developing the disease which may run in families.8 Robust associations have been identified between pre-eclampsia and gene variants involved in thrombophilia, inflammation, oxidative stress and the renin angiotensin system.9, 10 In a meta-analysis of studies to identify gene variants associated with pre-eclampsia, 22 variants were reproducible across studies with 7 remaining significant upon meta-analysis. However, thrombophillic gene variants in F2 and F5 have been consistently associated with the disease.11, 12, 13 Interactions between maternal gene variants and genes encoding fetal HLA-C have been shown to predispose pregnancies to pre-eclampsia in white people, sub-Saharan Africans, and the Chinese Han population, suggesting a role of an impaired immune tolerance in the pathogenesis of pre-eclampsia.14, 15, 16 In women with pre-eclampsia, placental antiangiogenic factors are upregulated and disrupt the maternal endothelium, leading to an antiangiogenic state that can result in clinical signs of pre-eclampsia.17

Section snippets

Definition of pre-eclampsia

The diagnostic criteria for pre-eclampsia were changed by the International Society for the Study of Hypertension in Pregnancy (ISSHP) in 2014.18 ISSHP defines pre-eclampsia as de-novo hypertension present after 20 weeks of gestation combined with proteinuria (>300 mg/day), other maternal organ dysfunction, such as renal insufficiency, liver involvement, neurological or haematological complications, uteroplacental dysfunction, or fetal growth restriction. As proteinuria is no longer required in

Prediction of pre-eclampsia

Although perfect prediction of pre-eclampsia has been a noble but hitherto elusive goal, distinction between women who are at low risk and high risk is possible. Strong risk factors are previous pre-eclampsia or hypertension in pregnancy, chronic kidney disease, hypertension, diabetes (type 1 or type 2), and autoimmune disorders, including systemic lupus erythematosus or antiphospholipid syndrome.20, 26 Moderate risk factors are first pregnancy, age 40 years or more, a pregnancy interval

Prevention of pre-eclampsia

With reliable risk prediction for pre-eclampsia on the horizon, interventions to prevent pre-eclampsia become more important (table 1). Aspirin is the drug of choice for the prevention of pre-eclampsia, based on the findings of an individual patient data (IPD) meta-analysis that showed moderate benefit of aspirin (RR 0·90, 95% CI 0·84–0·97).41 Other pharmacological drugs, such as heparin and dalteparin, show promising effects in women who are at increased risk for pre-eclampsia, but unlike

Clinical presentation of pre-eclampsia

The clinical presentation of pre-eclampsia is varied.1 Women are mostly asymptomatic, and the disease is often diagnosed during routine antenatal care. Maternal adverse outcomes are recorded in 10% of women with pre-eclampsia, whereas this risk increases to 15% in women with early-onset disease.62

The clinical presentation and findings could be indicative of the underlying multisystem morbidity. Women with severe pre-eclampsia might present with symptoms such as headache, visual disturbances

Signs and symptoms

Clinicians routinely obtain information on the presence of symptoms associated with progression to severe disease. However, individual symptoms of pre-eclampsia such as headache (AUC 0·58, 95% CI 0·24–0·86), epigastric pain (0·70, 0·30–0·93), and visual disturbances (0·74, 0·33–0·94) do not adequately predict adverse maternal outcomes.64 Chest pain and dyspnoea also have limited predictive value (0·64, 0·54–0·74) for composite adverse maternal outcomes.62 Authors of a systematic review reported

Laboratory tests

The maternal spot urine estimate of the protein:creatinine ratio is promising for the detection of proteinuria in women with suspected pre-eclampsia. There is insufficient knowledge of how the protein:creatinine ratio should be used in clinical practice because test accuracy and prevalence across studies are heterogeneous.71 The degree of proteinuria is not predictive for placental abruption or HELLP syndrome, whereas data on the capacity of proteinuria to predict eclampsia are conflicting.67,

Prediction models

Because all the above-mentioned tests have limited accuracy individually to predict complications, attempts have been made to integrate these tests into multivariable models. The full pre-eclampsia integrated estimate of risk (PIERS) multivariable model predicts composite adverse maternal outcome within 48 h in women admitted to hospital for pre-eclampsia (AUC ROC 0·88, 95% CI 0·84–0·92). In PIERS, the predictive factors are gestational age, platelet count, chest pain or dyspnoea, oxygen

Clinical management of women diagnosed with pre-eclampsia

Novel therapies for pre-eclampsia target various aspects of pre-eclampsia pathogenesis and are in development, yet the only cure for pre-eclampsia is delivery of the placenta (panel 1).86 On the basis of consensus, severe hypertension or end-organ complications should be managed in an inpatient setting. Subspecialty consultation is advised to address underappreciation of the risks of pre-eclampsia. An early epidural catheter will attenuate pain-induced hypertension and enable neuraxial

When to deliver the woman with pre-eclampsia

Because delivery of the placenta is the only cure for pre-eclampsia, optimal timing of delivery is crucial. The decision to deliver is based on the balance between the maternal and fetal risks of continuing the pregnancy and the neonatal risks of ending the pregnancy. In pre-eclampsia, the main driver is an assessment of the risk to the mother, but sometimes a growth-restricted child can become compromised and necessitate induction.

In a study that compared induction of labour and expectant

Cardiovascular risk after pre-eclampsia

In 1964, Epstein showed that women with pre-eclampsia were at increased risk of developing cardiovascular disease later in life.108 Until recently, women who have had a pregnancy complicated by hypertensive disorders, including pre-eclampsia, were not offered preventive measures. Evidence now overwhelmingly suggests that women who had pregnancy-related complications such as hypertensive disorders, gestational diabetes, intrauterine growth restriction, or preterm delivery have increased risk of

Management of pre-eclampsia in low-resource settings

Pre-eclampsia and its serious consequences, including death, are many times more common in low-resource settings than in well resourced settings.20, 127 This epidemiological finding provides a model for seeking clues to the cause of pre-eclampsia and an obligation to direct global efforts to reduce mortality and morbidity from pre-eclampsia towards low-resource settings. Demographic risk factors for pre-eclampsia include young or advanced maternal age, family or personal history of hypertensive

Future research

Despite the scientific efforts (>17 000 PubMed citations on pre-eclampsia since 2010) to increase knowledge of the aetiological and clinical aspects of pre-eclampsia, the incidence of the disease is not decreasing138 and is still the main cause of maternal mortality, with significant adverse effects mainly in low-income and middle-income countries. Standardisation and collaboration in research will probably improve the use of resources. The Core Outcome Measures in Effectiveness Trials (COMET)

Search strategy and selection criteria

We searched PubMed and the Cochrane Library with the terms “pre-eclampsia” and “hypertension and pregnancy”, and cross-referenced them with the following terms: “epidemiology”, “definition”, “prediction”, “prevention”, “management”, “clinical trials”, “preconception care”, and “thrombophilia”. We restricted the search to studies done in humans and published in English. We limited our search to publications between January, 2010, and January, 2015, with a focus on publications after 2012. We

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