Obstetrics and Gynaecology - Theses
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ItemAgeing of the placenta: potential prognostics, diagnostics and therapeutics( 2022)Abstract Ageing effects on human organs are most notable in the elderly. However, the placenta is exceptional because it shows signs of ageing in a short time span. Healthy ageing of the placenta is the process of developing and maintaining the functional ability of the placenta until term and is a feature of uncomplicated pregnancies. However, recent studies show unhealthy ageing of the placenta is a common feature of important human pregnancy disorders. Unhealthy premature ageing of the placenta is associated with pregnancy complications of preeclampsia (PE) and fetal growth restriction (FGR), whereas unhealthy placental ageing at term is associated with stillbirth. Given the emerging importance of placental ageing, the general aim of the work was to investigate potential prognostics, diagnostics and therapeutics for ageing of the placenta. Regarding prognostics and diagnostics, the sFlt-1/PlGF ratio test used to predict the risk of PE was investigated in a retrospective clinical study. The sFlt-1/PlGF ratio increased with the healthy ageing of the placenta at term. In addition, the total extracellular vesicle population isolated from the maternal peripheral blood during second trimester increased in pregnancies with a late onset PE outcome compared to a gestation matched normotensive control outcome and showed an association with the sFlt-1 concentration. These results suggest that the sFlt-1/PlGF ratio and EV population size are potential prognostic or diagnostic markers for unhealthy placental ageing-associated pathologies such as PE and stillbirth. A hallmark of ageing is damage to stem cells, which prevents them from replenishing cells in ageing organs and tissues. Pharmaceutical drugs and extracellular vesicles (EV) with anti-ageing properties secreted by healthy ageing early term decidual mesenchymal stem cells (ET-DMSC) were used to treat unhealthy premature-ageing PE-DMSC and ageing late term DMSC (LT-DMSC). As well, a microRNA present in high levels in ET-DMSC (miR-516b-5p) was also analysed. Drugs with anti-ageing properties and EV from ET-DMSC delayed the ageing phenotype of both PE-DMSC and LT-DMSC. In addition, miR-516b-5p affected stem cell survival. ET-DMSC with elevated levels of miR-516b-5p had better survivability. Finally, as described above, the total EV population size in maternal blood is a potential prognostic or diagnostic marker for unhealthy placental ageing-associated pathologies. However, many cell types, including stem cells, secrete EV into maternal blood. The final aim was to determine whether EV secreted from DMSC into maternal blood could be enriched from maternal blood. In order to achieve this, unique DMSC-EV cell surface markers need to be identified. When compared with chorionic mesenchymal stem cell derived EV (CMSC-EV), mass spectrometry analyses showed DMSC-EV and CMSC-EV have unique combinations of lipids and proteins on their surface, which could potentially facilitate the isolation of DMSC-EV and CMSC-EV from maternal blood. In addition, studies in the literature showed that changes in the levels of candidate lipids and proteins are associated with healthy ageing and in some cases with unhealthy placental ageing-associates pathologies such as PE and FGR, where the placenta shows signs of premature ageing.
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ItemMaternal ophthalmic ultrasound in the assessment of preeclampsia( 2021)The neurological complications of preeclampsia, including eclampsia and intracerebral haemorrhage, are responsible for most of its maternal morbidity and mortality. Treatments are aimed at preventing these cerebral sequelae, and include antihypertensive agents (to prevent intracranial haemorrhage) and magnesium sulphate (for seizure prophylaxis). It is likely that these agents have a direct effect on the maternal cerebrovasculature, although their precise mechanisms of action remain incompletely understood. Ophthalmic ultrasound makes use of the eye’s direct connection to the brain: the ophthalmic artery, which is similar in size and embryological origin to smaller calibre intracerebral vessels, can undergo Doppler interrogation, while the optic nerve sheath diameter (ONSD) can be measured as a marker of intracranial pressure. This thesis aims to assess the utility of ophthalmic ultrasound in the assessment and prediction of preeclampsia, which hitherto has not been performed in an Australian population. In so doing, sonographic assessment of the optic nerve sheath diameter and Doppler variables of the ophthalmic artery was performed in three discrete cohorts: healthy pregnant women (n = 51), pregnant women with suspected but excluded preeclampsia (n = 50), and women with established preeclampsia receiving treatment with the antihypertensive agent labetalol (n = 20) and the anticonvulsant magnesium sulphate (n = 1). In the cohort of healthy pregnant women, the ocular sonographic variables demonstrated no relationship with maternal mean arterial pressure (MAP), gestational age, or each other. Postpartum analysis identified an apparent increase in cerebrovascular resistance – a novel finding. In the cohort of women with suspected but excluded preeclampsia, ocular sonographic variables were not found to differ between those with transient and gestational hypertension on the day of assessment. In contrast to the first cohort, a positive relationship was identified between maternal MAP and the ophthalmic artery peak ratio, and a negative relationship between MAP and the ophthalmic artery pulsatility index. This novel finding is suggestive of greater cerebrovascular susceptibility to changes in systemic blood pressure in women with hypertensive disorders of pregnancy. These two cohorts were combined to assess the utility of ocular sonographic variables in predicting pregnancy outcome. Univariate analysis identified the ophthalmic artery pulsatility/resistive indices and peak ratio as being significantly different in those who went on to develop a sustained hypertensive disorder, whereas the ONSD performed better in multivariate analysis. This was the first study to examine the utility of the ONSD in predicting preeclampsia. Finally, women with established preeclampsia had lower pulsatility indices and higher peak ratios in the ophthalmic artery, and greater dimensions of the optic nerve sheath, than either healthy pregnant women or those with other hypertensive disorders of pregnancy. In a novel finding, administration of labetalol resulted in a shift in the ONSD and Doppler variables of the ophthalmic artery toward those exhibited by healthy pregnant women, which appeared to be independent of labetalol’s effect on systemic blood pressure. Magnesium sulphate appeared to have a similar effect. These observations may permit more precise and individualised care of women with preeclampsia, and thus a reduction in the neurological burden of this disease.