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Placental dysfunction and pre-eclampsia

Mohamed SE Elmoursi and Nigel AB Simpson
2 June, 2014  
Pre-eclampsia prevention may be enhanced by combining antenatal risk and clinical factors and biochemical markers into a predictive strategy
Mohamed SE Elmoursi
Clinical Research Fellow 
Nigel AB Simpson
Senior Clinical Lecturer, 
Section of Obstetrics & Gynaecology, 
Leeds Institute of Molecular Medicine, 
St James’s University Hospital, Leeds UK
Pre-eclampsia (PE) is a multisystem disorder that complicates 8% of pregnancies. It typically manifests as new-onset hypertension (≥140/90 mm Hg) and proteinuria (≥300mg per 24h) after 20 weeks’ gestation.(1) PE is one of the main causes of maternal, foetal and neonatal morbidity and mortality in the world. It is estimated that more than 8 million women are affected each year, resulting in over 70,000 maternal deaths worldwide. Moreover, women who develop PE have an increased risk of hypertension, cardiovascular disease and cardiovascular-related death in later life.
On a global scale it is estimated that one woman dies every six minutes from complications of this condition.(1) Maternal deaths from PE primarily arise in those women developing eclampsia (seizures), uncontrolled hypertension, coagulopathy and renal and/or hepatic compromise. Problems are not restricted to the mother. Foetal and neonatal complications occurring as a consequence of PE include stillbirth, growth restriction and prematurity with concomittant adverse cognitive and motor neurodevelopmental outcomes, such as cerebral palsy. PE is responsible for a third of births before 35 weeks of gestation.(2) 
Prediction and prevention
The only treatment for PE is delivery – once diagnosed, the process cannot be reversed. As a consequence, there are ongoing efforts to develop different preventative strategies for PE. The most widely used preventive treatment is low-dose aspirin, which has been found to work through several mechanisms, most probably through improving placentation. In a recent meta-analysis used to investigate the benefits of low-dose aspirin started at or before 16 weeks of gestation, its administration led to a significant reduction in the risk of developing preterm PE (delivery before or at 37 weeks). By contrast, early use of aspirin was not associated with a significant reduction in the risk of term PE. Moreover, the risks of overall PE and severe PE, with a reduction in the relative risk by 90%, were significantly reduced, but not the risk for mild PE3. This remains the only effective intervention. Other putative strategies such as the use of vitamin C and E and calcium supplements are not successful in preventing PE.(4,5)
Predictive strategies
The availability of effective preventative options underlines the need for better prediction. It is becoming more evident that PE is unlikely to be detected early by a single predictive marker or test fulfilling World Health Organization criteria (easy to perform, inexpensive, high positive and low negative predictive values) for biomarker selection owing to its heterogeneity. However, the ability to predict PE may be enhanced by combining antenatal risk factors, clinical factors and biochemical markers into multivariate algorithms with performance levels that would enable clinical utility.(6)
One of the main problems facing researchers is that PE is a heterogeneous collection of disease manifestations with varying severity that share some common features, but also show fundamental discrepancies. A single mechanism cannot explain all presentations of PE.(7) Recent research has therefore focused on measurable indicators of placental and endothelial dysfunction, which are the most commonly encountered features of PE. 
Placental dysfunction is commonly associated with foetal growth restriction (FGR), especially in early onset PE. Ness and Roberts demonstrated that 30% of babies of pre-eclamptic women showed restricted growth in utero (defined as growth at or below the 10th percentile in weight for its gestational age) and that this was characteristic of early onset PE, not late onset PE.(8) 
Several factors are produced in the human placenta. The most important are placental growth factor (PlGF), vascular endothelial growth factor (VEGF) and its soluble receptor (sVEGFR-1; also known as soluble fms-like tyrosine kinase 1 (sFlt-1)). PlGF is an endothelial factor essential in stimulating angiogenesis and stabilising the endothelium in mature blood vessels, while VEGF is known to be structurally similar to PlGF and is known to be a potent angiogenic factor. On the other hand sVEGFR-1 is an antiangiogenic factor, acting as a sink receptor for VEGF and PlGF before their binding to their cell membrane receptors as part of systemic endothelial homeostasis.(9) sVEGFR-1 is released by pre-eclamptic placentas in greater quantities.
These novel biomarkers are being used not only to predict the later onset of PE and thus preventative strategies, but also to predict its severity and assist timing of delivery. In normal pregnancy, PlGF concentration increases during the first 30 weeks of gestation, and then decreases. Studies have shown that the concentration of PlGF in the second trimester of pregnancy is relatively low weeks before the onset of PE.
PlGF levels are even lower in women who develop early-onset PE compared with women who develop late-onset PE, and also identifies those mothers whose babies are at greater risk of stillbirth and growth restriction.(10) These studies suggest that PlGF, a marker of placental dysfunction, can be used successfully as a predictor of early onset PE.
At 30–33 weeks gestation, the detection rate of intermediate PE (requiring delivery at 34–37 weeks) and late PE (with delivery after 37 weeks) by combing maternal characteristics and serum PlGF, at a false-positive rate of 10%, was 85.7 and 52.8%, respectively.(11) Hence, most cases of clinically significant PE may be detected using maternal characteristics and PlGF.
PlGF can be measured using conventional laboratory-based assays, but point-of-care systems are already available offering the possibility of more ready access at the bedside or in the clinic. PlGF, being a small molecule (30kD), is freely filtered by the glomerulus, and thus can be found in the urine. A low concentration of PlGF in spot urine samples has been reported in PE. This finding may eventually lead to the design of a non-invasive urine spot test using the inexpensive dipstick technology similar to proteinuria.(12)
Other biomarkers such as soluble endoglin (sEng), a receptor for transforming growth factor beta (TGFβ) in endothelial cells, has also been shown to be increased to a greater extent in severe preterm PE than in those with mild preterm PE, suggesting that the increase in sEng could be used to predict the severity of the syndrome. Different combination ratios of placental markers have also been proposed as a way of further refining their predictive ability. PlGF/sEng ratio attained a sensitivity of 74% with a fixed false-positive rate of 15% for the identification of severe late PE, while a plasma concentration of PlGF/sVEGFR-1 <0.12MoM at 30–34 weeks of gestation had a sensitivity of 80%, with a specificity of 94%.(13)
Future strategies
Advances in chromatographic and mass spectrometric techniques, which ensure the identification and quantification of plasma proteins present in plasma at very low (ng/ml) concentrations, have identified several novel protein markers for PE: insulin-like growth factor binding protein (IGF-BP) and acid labile subunit (IGFALS), with comparable test performance in preliminary studies.(14) It is likely that emerging proteomic and metabolomic technologies will identify further candidate biomarkers that will improve screening strategies for PE.
The identification of biomarkers for the early detection of PE is essential for applying better surveillance and treatment protocols in pre-eclamptic patients. In addition, the use of dependable markers to correctly stratify women with PE according to its severity could help clinicians implement preventive strategies for PE. Moreover, such markers may also have a role in reducing the number of PE-related iatrogenic preterm deliveries. For now, more multicentre studies are required to explore the potential role of these markers for risk stratification in PE to influence the impact of clinical decisions on maternal and perinatal outcomes.
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