Document Type

Theses, Ph.D


Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence



Publication Details

Successfully submitted for the award of Doctor of Philosophy (Ph.D) to the Technological University Dublin 2005.


Obstetrical complications including recurrent miscarriage, pre-eclampsia and intrauterine growth restriction (IUGR) affect 1%-5% of pregnant women (Younis and Samueloff 2003). Dysfunctional trophoblasts, impaired development of spiral arteries, imbalance in systems controlling the dilation and contraction of spiral arteries, placental fibrin clots and intervillous thrombosis are all possible factors that can result in an insufficient placental circulation. The combination of the hypercoagulable state of pregnancy and presence of genetic thrombophilic markets has the potential to induce placental thrombosis and cause placental insufficiency with subsequent obstetrical complications. The initial part of the research work involved examining the relationship between four common genetic risk factors for thrombosis in a recurrent miscarriage cohort using multiplex ARMS PCR. The result of phenotypic assays (activated protein C resistance, protein C levels, protein S levels, FVIII levels) for the recurrent miscarriage cohort were examined. There was no increased prevalence of any of the four genetic risk factors for thrombosis in our recurrent miscarriage cohort. Following examination of phenotypic assay results there was no concise link to recurrent miscarriage. The next phase of the work required the application of the multiplex ARMS PCR to cohorts IUGR and normal pregnancy placental samples. Our results indicated that none of the four genetic risk factors for thrombosis had an increased prevalence in the IUGR cohort compared with the normal pregnancy cohort. These results imply that for our two cohorts of obstetric complications, genetic risk factors predisposing to thrombosis, do not increase the risk of developing obstetrical complications. In our second set of experiments we investigated if inflammation is a potential contributor to placental insufficiency by disrupting the homeostasis of the uteroplacental circulation. A selection of inflammatory and haemostatic markers in IUGR and normal pregnancy cohorts were assessed using immunohistochemistry. Our results indicated no difference in expression of either inflammatory or haemostatic markets between the two cohorts. We also evaluated the proliferative and apoptotic status in both normal and IUGR cohorts. These results indicated a decrease in proliferation and an increase in apoptosis in the IUGR cohort compared to the normal cohort, suggesting a decline in the quality of functional trophoblasts in the IUGR placentas. The main aim of the final portion of the research was to examine the molecular aetiology of IUGR using microarray technology. This technology allows the evaluation of expression of thousands of genes on one single microarray chip. Following microarray analysis 293 genes had a two-fold difference in expression between a normal pregnancy cohort and an IUGR cohort. This list was reduced to the ten most significantly expressed genes between the two cohorts. Leptin and sFlt-1 receptor are two of the genes involved, these genes are associated with appetite control, angiogenesis and vessel growth. Until now our understanding of the various factors involved in defective placentation resulting in obstetrical complications has been limited. The findings of this thesis have determined the status of certain factors in obstetric complications while also discovering potentially novel components and mechanisms involved in the pathogenesis of IUGR.