Angiogenic Biomarkers as Predictive Tests for Early Onset Preeclampsia: A Population-Based Study

Preeclampsia is the most common of the serious complications of pregnancy. It is caused by a defect in the placenta and is symptomless in the early stages. It is currently only detectable by regular antenatal checks on the mother s blood pressure and urine. In its widest forms, preeclampsia affects about 1 in 10 pregnancies overall and 1 in 50 pregnancies severely. It is potentially life-threatening to mother and baby if allowed to develop and progress undetected. Preeclampsia is curable only by delivery, which puts some babies at risk if they have to be delivered prematurely. Recently, scientists have identified chemicals in the blood that appear to be associated with the onset of preeclampsia. However, it is not known how accurate these ?biomarkers? are at predicting preeclampsia, nor how early in the pregnancy the association can be detected. If the biomarkers could provide a warning that a pregnant woman was highly likely to develop symptoms, then preventative treatment could be given early. Furthermore, if women not at all at risk could be identified, then they could be spared repeated visits to the hospital for blood and urine tests. To determine the accuracy of these biomarkers, samples of blood and urine collected from pregnant women from three European countries will be brought to Birmingham for testing. These samples have been donated at three different time points in the pregnancy, to allow the investigators to determine when the best time to test is. The results from the samples will be anonymously linked to clinical information such as blood pressure to see if the biomarkers appear in women who develop preeclampsia. Statistical analysis of the tests and clinical information will provide doctors and midwives with information about the risk of preeclampsia if a women tests positive or negative for these biomarkers.

Preeclampsia (PE) is a systemic endothelial disease characterised by hypertension, proteinuria, exacerbated inflammation, dysregulated angiogenesis and can lead to end-organ failure. There are currently no reliable means to predict in early pregnancy who will go on to develop this condition, despite the many theories for the pathogenesis of PE. Also no definitive biomarker exists with the potential for risk stratification or delineation of the mechanism of action for potential therapeutic agents. The only effective treatment for PE resolution is delivery by Caesarean section. We and others have performed a variety of retrospective studies suggesting that specific angiogenic markers, placental growth factor (PlGF) and its antagonist soluble Flt-1 (sFlt1) and novel soluble endoglin (sEng) are promising screening tools capable of predicting PE prior to it?s clinical manifestations. These biomarkers are strongly rooted in the pathology of PE. It remains unknown, however, whether the test characteristics of these biomarkers are robust in a diverse European population and whether these tests perform well utilising high-throughput, highly sensitive assays. We hypothesise that a quantifiable increase in blood sEng and sFlt, and a decrease in blood and/or urine PlGF will antedate maternal clinical symptoms of early onset ( 32 weeks gestation) PE and differentiate it from late onset PE. To verify if changes in angiogenic and anti-angiogenic proteins can be used to accurately predict women at risk of developing early onset PE, we will test blood and urine samples collected longitudinally from over 40,000 pregnant women and assay for the blood sFlt1, and sEng and blood/urine PlGF levels screening for PE amongst asymptomatic women in early pregnancy at two time points (8-12 weeks gestation and 17-20 weeks gestation). To address these important aims, we have assembled a team with expertise in the biology of angiogenic markers and PE, clinical investigators with a track record of performing high-quality prospective studies in pregnancy, and medical device and immunoassay experts from industry. We believe this proposal will lead to the development of highly economical and robust testing strategies that will allow efficient assessment of potential therapeutic interventions, permit a targeted approach concentrating on women at the highest risk and also reduce NHS cost.