Obstetrics and Gynaecology - Theses
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ItemIdentification of novel biomarkers in the cervicovaginal fluid to predict preterm birth( 2013)INTRODUCTION: Preterm birth is associated with major perinatal morbidity and mortality. Despite the many advances in modern obstetrics the rate of preterm birth is increasing. The discovery of novel biomarkers that could reliably identify women who will subsequently deliver preterm may allow for timely medical intervention and therapeutic treatments aimed at improving maternal and fetal outcomes. The cervicovaginal fluid (CVF) provides a rich source for the discovery of putative biomarkers of pathophysiological disorders of pregnancy. It is hypothesised that the biochemical alterations that occur in the cervix and the overlying fetal membranes with labour may be reflected in the CVF proteome. Given the multifactorial aetiology of preterm birth, women may present with different clinical presentations that lead to preterm birth. This thesis has investigated the CVF proteome of three clinical groups of women in order to discover putative novel biomarkers of preterm birth in: (i) asymptomatic women at risk of preterm labour (PTL); (ii) women with symptoms of threatened PTL; and (iii) asymptomatic women who subsequently experienced preterm premature rupture of the fetal membranes (preterm PROM). A functional proteomic approach was used to detect putative novel biomarkers of PTL or preterm PROM using two-dimensional gel electrophoresis (2DE) coupled with mass spectrometry. Validation of these differentially expressed proteins was performed using enzyme-linked immunosorbant assay (ELISA) or Western blot on an independent cohort. MAIN FINDINGS: Chapter 3 contains work that has been published in Reproduction. IL-1ra and thioredoxin were significantly decreased in asymptomatic women with subsequent PTL and predictive modelling found these biomarkers to be effective predictors of spontaneous preterm birth. Chapter 4 contains work that has been published in PLoS One. This study investigated the temporal changes in vitamin D binding protein (VDBP) in the CVF with approaching term and PTL. VDBP was increased in the CVF with approaching term and PTL. Predictive modelling analysis also found VDBP to be a reliable predictor of spontaneous term and PTL. The study presented in Chapter 5 identified a number differentially expressed protein in the CVF proteome of women presenting with threatened PTL. IL-1ra, IL-1α, IL-1β, VDBP, thioredoxin and albumin were significantly altered in the CVF of symptomatic women in threatened PTL with subsequent preterm birth. Modelling analysis using albumin & VDBP was superior to fetal fibronectin in predicting preterm birth. The study presented in Chapter 6 has been published in Reproduction and describes the proteomic analysis of CVF samples collected from asymptomatic women who subsequently experienced preterm PROM. Western blot analysis confirmed IL-1ra, annexin A3 and cystatin A to be significantly altered in the women who later experienced spontaneous preterm PROM. CONCLUSION: This thesis has identified a number of novel biomarkers for the prediction of preterm birth and has demonstrated that multi-marker models have improved predictive utility compared to individual biomarkers alone (Chapters 3 and 5). The proteomic analysis of the CVF has confirmed that labour is a complex physiological process involving tissue remodelling, oxidative stress and inflammation. The discovery of IL-1ra, thioredoxin and VDBP to be differentially expressed with preterm labour in both asymptomatic and symptomatic women supports the theory of a final common pathway of labour.