Carty, David Martin
Pre-eclampsia: early prediction and long-term consequences.
PhD thesis, University of Glasgow.
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Approximately one in ten pregnant women will have their blood pressure recorded above normal at some point during their pregnancy. Pre-eclampsia, the most common hypertensive disorder of pregnancy, affects around 5% of all first time mothers, and is an important cause of foetal and maternal morbidity and mortality worldwide. Efforts to diagnose the condition have been hampered by inability to predict which women are likely to be affected. Multiple pathways are known to be involved in its pathogenesis, and several screening tests have been suggested for its early prediction. None, however, have been sensitive or specific enough to have come into routine medical practice.
The work contained in this thesis describes a study which was designed to detect biochemical and clinical markers that could improve ability to predict pre-eclampsia. Over 3900 women were recruited in early pregnancy at four maternity clinics across the West of Scotland; baseline characteristics and information on past medical and obstetric history were obtained. Women were followed up throughout their pregnancy, and information on deliveries obtained from hospital databases. One-hundred and eighty of these women, who had multiple risk factors for pre-eclampsia, attended for further sampling and vascular assessment at gestational weeks 16 and 28.
The primary aim of the overall study was to examine whether a proteomic strategy could be used to identify patterns of peptides in urine that detect pre-eclampsia in the first and second trimesters. Using samples from healthy pregnant and non-pregnant women I was able to describe the normal human urinary proteome in pregnancy. By comparing these pregnancy-associated peptides between women who went on to develop pre-eclampsia and matched controls, I was able to identify a pattern of peptides, characterised by collagen fragments, fibrinogen and uromodulin that accurately predicted pre-eclampsia at week 28. No such markers were identified in the first trimester samples.
A further aim of the overall study was to identify early pregnancy plasma markers that could help to identify women destined to develop pre-eclampsia. By examining samples from early pregnancy I was able to demonstrate that the angiogenic markers soluble endoglin and placental growth factor are already altered at week 12-16 in women who go on to develop pre-eclampsia. Using a multi-marker approach, I also showed that E-Selectin, an adhesion molecule expressed on endothelial cells which controls interaction between circulating leukocytes and the endothelium, is higher at week 12-16 in women who go on to develop pre-eclampsia. Experiments using samples from later pregnancy, alternative analysis techniques and samples from an independent study population all helped to confirm these novel findings.
Endothelial dysfunction is known to play a key role in the development of pre-eclampsia, contributing to the hypertension, proteinuria and oedema seen in affected women. In the risk factor cohort I used vascular function studies to examine whether they supplied additional information to aid in risk stratification. Peripheral arterial tonometry, a novel non-invasive tool for the assessment of microcirculatory endothelial function, was examined in 180 women at gestational weeks 16 and 28. Reactive hyperaemia index (RHI), a measure of endothelial dysfunction calculated from vascular response to arm blood-flow occlusion, did not correlate with maternal factors such as age, BMI and blood pressure. Further, RHI did not help to identify which women would go on to develop pre-eclampsia, when examined at either week 16 or 28. I found that PAT score was negatively correlated with baseline digital pulse amplitude, suggesting that in later pregnancy, when women are more vasodilated, PAT and other techniques which rely on flow-mediated dilatation are less likely to be reliable.
I used pulse wave analysis, a well-established method for measuring arterial stiffness and central pressures, to determine whether it supplied additional information about pre-eclampsia risk. This technique has been previously reported to predict pre-eclampsia in early pregnancy. In this cohort of high risk women, no difference was seen at either week 16 or 28 between those who would go on to develop pre-eclampsia and those who would have normotensive pregnancies.
Although blood pressure and proteinuria return to normal after pre-eclampsia, evidence has emerged the condition has long-lasting implications; women with a history of pre-eclampsia have an increased risk of cardiovascular disease later in life, suffering stroke or myocardial infarction more frequently than women who had a healthy pregnancy. Conventional risk factors are thought to contribute, but do not fully explain this increased risk. I carried out further vascular function studies in women after pre-eclamptic pregnancy, to examine whether they had ongoing detectable endothelial dysfunction and arterial stiffness. At 6-9 months post-natally, affected women had lower baseline digital pulse amplitude but no other evidence of persistent vascular dysfunction.
Taken together, these data provide information about a number of markers that may improve understanding of the pathophysiological mechanisms underlying pre-eclampsia. As well as potentially improving the early prediction of disease, this work represents a highly topical area for further studies. While vascular function analysis does not appear to provide additional information on top of risk factors, these studies also provide useful information on vascular physiology in high-risk pregnancies.
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