Identification of first trimester maternal serum markers predictive of spontaneous preterm birth

Abstract

Preterm birth is the leading cause of perinatal morbidity and mortality worldwide. Despite considerable efforts, prediction and prevention of preterm birth continues to remain a challenge for obstetricians globally. Early identification of pregnancies at highest risk of preterm birth may enable the implementation of therapeutic strategies aiming to prevent preterm birth and/or the morbidities associated with early delivery. Screening for spontaneous preterm birth is made more complex due to the heterogeneity of this condition, which has a variety of underlying aetiologies and risk factors. Even though spontaneous preterm birth is caused by several aetiologies, there appears to be a final common pathway leading to the onset of labour. There may therefore be value either in developing screening tools that screen for multiple aetiological pathways or alternatively that identify common features that develop before women become symptomatic with the onset of spontaneous labour. Paper I reviews recent research findings related to first trimester prediction and prevention of adverse pregnancy outcomes. This thesis reports a body of work related to the development of a predictive test for spontaneous preterm labour. Paper II is focussed on the challenges of using current proteomic strategies to identify and quantify novel protein markers of disease in serum. I carried out various optimisation strategies to resolve protein species in maternal serum using a refined top-down two-dimensional gel electrophoresis method coupled with mass spectrometry. In addition to this, a process of deep imaging using third separation gel electrophoresis was adapted to effectively resolve protein species and isoforms that would not be recognised by traditional proteomic techniques as they would be masked by co-migrating protein species of higher abundance. These techniques were applied in Paper III where they were used to identify protein species and post translationally modified proteoforms (phosphorylation and glycosylation) in first trimester maternal serum banked from cohorts of women who delivered spontaneously before 37 weeks' gestation. These findings were compared to serum collected from a cohort of women who delivered at term (= 37 weeks' gestation). Paper IV utilised a western blot approach to determine serum concentrations of a select group of candidate protein species and proteoforms that were significantly altered in Paper II in a larger cohort of women that had delivered after spontaneous preterm labour (37 weeks) controls. A variant of Vitamin D-binding protein was found to be significantly decreased in women who delivered < 37 weeks spontaneously. This work has shown that there is evidence of change in protein abundance as early as 11-13 weeks of gestation in women who continue on to deliver preterm after the spontaneous onset of labour. Further work is needed to determine the strength of these findings in predicting risk of preterm birth. Further work should also examine how novel biomarkers can be combined with established screening tools in larger diverse patient cohorts to validate their potential use as candidates for prediction of spontaneous preterm birth.

Date of Award	2018
Original language	English