Obstetrics and Gynaecology - Theses
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ItemUnderstanding placental and cardiovascular adaptations in pregnancy: implications for therapeutic development for fetal growth restriction and preeclampsia.( 2021)Preeclampsia and fetal growth restriction are among the most serious obstetric conditions worldwide. Though they affect so many, we still do not completely understand their pathogenesis, nor have good ways to detect or treat them. In this thesis, I aimed to: improve our understanding of placental and vascular adaptations in preeclampsia and growth restriction, assess the ability of candidate therapeutics to mediate vascular dysfunction associated with preeclampsia, and to explore new models of preeclampsia and the long-term impacts on maternal cardiovascular health. DAAM2 and NR4A2 transcripts are elevated in the circulation of individuals whose pregnancies are complicated by fetal growth restriction (with or without preeclampsia). In Chapters 2 and 3 of this thesis, I identified these transcripts are expressed in the placenta, but their expression in either growth restricted or preeclamptic placenta does not mirror the increased expression of DAAM2 and NR4A2 in the maternal circulation. Thus, they are unlikely to originate from the dysfunctional placenta. However, their expression in the placenta throughout gestation, and clear regulation under hypoxia suggest they have roles in normal placental development and placental dysfunction. LOX-1 is elevated in the maternal vasculature in preeclampsia. In contrast to this, I identified in Chapter 4 that LOX-1 expression is reduced in the preeclamptic placenta. Furthermore, its expression is reduced in trophoblast under hypoxia. Treatment of trophoblasts with candidate preeclampsia therapeutics, esomeprazole and lansoprazole, (proton pump inhibitors) increased LOX-1 expression. These findings suggest that LOX-1 has a distinct role in the placenta compared to the vasculature. In Chapters 5 and 6, I assessed the ability of statins and new generation antiplatelets to mitigate preeclampsia-associated vascular dysfunction. In a model of endothelial dysfunction, pravastatin and simvastatin reduced secretion of vasoconstrictor, endothelin-1 and anti-angiogenic factor, sFLT-1. The new generation antiplatelet agents clopidogrel, prasugrel and ticagrelor reduced vasoconstriction of pregnant human omental (healthy and preeclamptic) and mouse mesenteric arteries through three different vasoconstrictors. Therefore, these candidate therapeutics can mitigate a key aspect of the pathogenesis driving preeclampsia. In Chapter 7, we established a model of preeclampsia in our laboratory through the blockade of nitric oxide synthesis (using L-NAME) to induce vasoconstriction. This led to elevated blood pressure, impaired fetal growth and elevated circulating levels of ‘toxic’ factors associated with preeclampsia. We were able to use this model to assess the effects of the new generation antiplatelet prasugrel, as a therapeutic, finding that prasugrel administration alongside L-NAME could reduce maternal blood pressure. I followed the dams post-delivery to investigate whether this model could simulate the long-term effects of preeclampsia on maternal cardiovascular health. I found that blood pressure and circulating toxic factors recovered as soon as 1 week post-delivery. At 10 weeks post-delivery, mice administered L-NAME during pregnancy demonstrated altered vascular reactivity, and increased expression of genes associated with inflammation in both the heart and kidney. However, these changes did not model the breadth of effects we anticipated, based on what is seen clinically post-preeclampsia. Overall, this thesis has added critical new knowledge regarding placental development, placental dysfunction, and vascular dysfunction. It provides further insight into the capability of novel candidate therapies for the prevention and treatment of preeclampsia, and provides new models of preeclampsia that can be used to enhance both our understanding of disease, and to assess future therapeutic potential.
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ItemImpact of new criteria for the diagnosis of gestational diabetes: a maternal and neonatal health outcome and economic analysis in a large tertiary level maternity centre( 2017)Background: The development of diabetes mellitus during pregnancy, referred to as gestational diabetes (GDM), is associated with adverse maternal and fetal outcomes. Routine screening for this condition is therefore undertaken in all pregnant women. In 2014, gestational diabetes underwent a more liberal diagnostic update, which has been widely adopted in Australia but not universally accepted internationally. Concerns around a rapidly increasing annual incidence and implications for costs and workloads have been raised, but they are assumed to have been offset by improvements in clinical outcomes. As one of the only large Western countries to have adopted universal screening under the new criteria, Australia is uniquely poised to assess the value of such a system change. Hypothesis: That the change in diagnostic criteria for gestational diabetes has resulted in improved clinical outcomes and equitable health economics. Aim: To compare an entire cohort of women and babies diagnosed with gestational diabetes in 2014 (under the original criteria) with those diagnosed in 2016 (under the updated criteria) and, in particular, to assess any improvements in outcomes, to attribute costs to the increased incidence and to assess any overall economic benefit. Methods: All women diagnosed with gestational diabetes in 2014 and in 2016 were included as cases. Control groups in each year were defined as those who underwent screening and had a negative test (pre-existing diabetes was thus an exclusion criteria). Women with multiple pregnancies were excluded from both cases and controls. Demographic data were collected from all groups. Maternal outcomes and fetal outcomes were selected to represent those reported in the studies upon which the new criteria are based. Three broad groups of outcome analyses were undertaken. Firstly, all women in 2014 were compared to all women in 2016 to determine whether the change in policy has caused a hospital-wide improvement in outcomes. Secondly, women with GDM in 2014 were compared to controls in 2014 and women with GDM in 2016 were compared to controls in 2016. Finally, women with GDM in 2014 were compared to women with GDM in 2016. In each analysis, women with GDM were examined as a whole and subdivided into diet-controlled and insulin-controlled. For the economic analysis, models of care for routine pregnancy, GDM diet-controlled and GDM-insulin controlled were costed using average-occasions-of-service for clinical reviews, pharmacy fees for medications and consumables, and Medicare Benefits Schedule item numbers for ultrasound services. Cost-savings were assessed using modelling of adverse outcome avoided based on relative-risk reductions published in the studies upon which the new criteria were based. Results: There was an increase in annual incidence for GDM from 6.0% to 10.4% with gross costs of care increasing by approximately $900 000 and nett costs of care by approximately $560 000. There was a small hospital-wide reduction in very large babies (>95% for birth weight) from4.31% to 3.61% with no other significant differences between 2014 and 2016. Women with GDM remain a higher risk cohort in both demographics and outcomes than those without GDM, but in 2016 women with GDM that is controlled by dietary measures alone represent a cohort with similar outcomes to women without GDM. Modelling for adverse outcomes avoided by the change in criteria did not reveal a cost-saving in the short-term. Conclusions: The new criteria for diagnosing GDM has resulted in a marked increase in annual incidence (73% relative, 4.4% absolute) without a significant improvement in maternal and neonatal outcomes. While small numbers of adverse outcomes are likely avoided, it is unlikely the potential short-term savings would outweigh the increase in costs if applying a high-risk model of care to all women with GDM. The new criteria may lead to long-term improvements in health of the mother and/or baby that are cost-effective but further research is required to substantiate this possibility. Future randomized controlled trials into different systems of diagnosis and less expensive models of care for mothers with GDM and their babies are also warranted.
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ItemCharacterisation of maternal pre-eclampsia susceptibility genes( 2015)Introduction: Pre-eclampsia (PE) has affected pregnant women throughout human history and remains a leading cause of maternal and fetal mortality and morbidity worldwide today. PE is clinically characterised by de novo hypertension and proteinuria developing after 20 weeks’ gestation that resolves with delivery of the fetus and placenta. Up to 8% of all pregnant women are afflicted with the disorder, which may necessitate premature delivery of the fetus in severe cases. The aetiology of the disorder remains unknown, although the placenta is widely accepted to be central to the pathogenesis of PE, as PE can occur in women with molar pregnancies, where there is no viable fetus. A family history of PE is a major risk factor, with heritability estimates of up to 54%. Genetic linkage and association studies in the Australian/New Zealand population previously identified susceptibility loci on chromosomes 2, 5 and 13 for PE. Bioinformatic analyses of these loci yielded the following candidate maternal PE susceptibility genes from various functional groups: ACVR1, ACVR1C, ACVR2A, INHA and INHBB from the activin/inhibin signalling group; ERAP1, ERAP2 and LNPEP from the M1 aminopeptidase family; and COL4A1 and COL4A2 from the connective tissue components group. The main aim of this thesis was to characterise the expression and determine the functional significance of these genes in the development of PE. Main findings: The bulk of the findings of this thesis has been published or is accepted for publication in multiple international peer-reviewed journals. The first Placenta paper in Chapter 3, demonstrated significantly increased mRNA expression of the candidate genes – ACVR1, INHBB, ERAP1, ERAP2, LNPEP, COL4A1 and COL4A2, in the pre-eclamptic maternal decidual tissue, which correlated with greater clinical severity of PE. The second Placenta paper in Chapter 4, examined the levels of arresten and canstatin fragments, which are derived from the COL4A1 and COL4A2 genes respectively, in the plasma from pre-eclamptic women and gestational age matched normotensive controls. Arresten levels were significantly increased as early as 16 weeks’ gestation in pre-eclamptic plasma. The subsequent two results chapters examined the functional roles of the activin A receptor, ACVR2A, in decidual stromal cells and endothelial cells. In Chapter 5, modelling the decreased expression observed in pre-eclamptic decidua, using an in vitro cell culture model, showed that decidual stromal cells had an impaired ability to decidualise and caused abnormal regulation of multiple extravillous trophoblast functions. Chapter 6, which forms the basis of the Pregnancy Hypertension paper, revealed that the higher baseline concentrations of activin A observed in PE resulted in vascular endothelial dysfunction, which was further exacerbated by a reduction in ACVR2A expression. Finally in Chapter 7, which was published in PLoS One, shared biological pathways of the susceptibility genes from the different functional group were identified through bioinformatics analyses. These shared pathways provide an insight as to the cumulative contribution of the different genes in the development of PE. Conclusions: The overall findings of the thesis provide evidence to support a causative, functional role of these maternal susceptibility genes in the pathogenesis of PE. The altered expression of genes, which are detectable before the onset of clinical disease, suggests the potential for the development of novel predictive biomarkers. Given how a single gene can affect the functions of multiple cell types present at the maternal-fetal interface, it is likely that the multiple gene alterations would have cumulative functional effects that ultimately influence the onset and severity of PE.