Obstetrics and Gynaecology - Theses
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ItemDefining abnormal fetal size in pregnancy to help identify infants at risk of size related complications( 2023-03)A key component of antenatal care centres on ensuring that fetal size is appropriate for gestational age. Most attention is focused on detecting small infants because they are known to be at increased risk of perinatal mortality and many short and long-term complications. This is because small fetal size often reflects a pregnancy affected by placental insufficiency- resulting in pathological growth- or true fetal growth restriction. Despite the fact that all international guidelines agree on the need to detect and monitor small fetuses, the decision about which obstetric growth standard best identifies the fetus at increased risk of adverse outcome remains a subject of fierce debate. There are many different published obstetric growth standards. Even within Australia, many institutions and states use different growth charts. The centile thresholds applied can thus be quite discrepant. This means that the chart used can have a significant impact on detection of the small (‘at-risk’) fetus and subsequent management decisions regarding surveillance and timing of birth. Therefore, the first aim of this thesis was to clarify which growth standards perform best in identifying the fetus at risk in an Australian obstetric population. To answer this question, we used a variety of epidemiological methods to examine the association of fetal size with adverse perinatal outcomes. We sourced large datasets in order to use rare primary endpoints of high clinical significance, such as stillbirth. The first dataset available included all women that delivered at a single tertiary centre (Mercy Hospital for Women) from 1994 to 2016 (101,309 births). The second dataset included all births within Victoria from 2005 – 2015 (735,591 births), obtained from the Consultative Council on Obstetric and Paediatric Mortality and Morbidity (CCOPMM). The third dataset, available in the latter part of the candidature, also from CCOPMM, included all births within Victoria from 2009 – 2019 (853,191 births). At each point throughout this thesis, the largest and most contemporary dataset available was used to answer our research questions. The size of our datasets enabled us to assess rare perinatal outcomes known to be associated with placental insufficiency, including stillbirth and major neonatal morbidity, as well as assess rare outcomes associated with large infants, such as shoulder dystocia. Our first project compared the classification of infants as <10th centile by the recently published INTERGROWTH-21st birthweight charts or by customised growth centiles. INTERGROWTH-21st growth charts were derived from a prospective international cohort of healthy mothers and infants. Such charts are considered ‘prescriptive’, capturing fetal growth and birthweight under optimal conditions. Customised fetal growth centiles were adjusted for fetal and maternal characteristics known to impact birthweight. INTERGROWTH-21st charts classified only 4.6% of infants below their 10th centile cutoff, compared with 10.6% by customised charts. This means that many fetuses currently considered high risk would be reclassified as healthy, using INTERGROWTH-21st charts. Therefore, we considered that INTERGROWTH-21st charts were not suitable for immediate adoption into Australian clinical practice. Our second project examined which growth standards were best to detect small fetuses at risk of perinatal morbidity and mortality in a preterm population. The impact that fetal size assessment has on informing surveillance and management decisions is particularly significant in the preterm period. We found that a growth standard derived from the estimated fetal weight of an in-utero population (a ‘fetal’ chart), had the best ability to identify fetuses at-risk in a preterm setting. This is because it identifies fetuses who are small compared with healthy fetuses in ongoing pregnancies, rather than fetuses that have been born prematurely for pathological conditions that may have adversely impacted fetal growth. Next, we compared sex-specific growth standards with those unadjusted for fetal sex, given male infants are known to be larger on average. We found that classifying infants as small by sex-specific standards better correlated with perinatal outcomes, indicating true fetal growth restriction. We then examined the impact of a growth standard that provided a single set of centiles for each gestational week, with one for each gestational day. We found that using a gestational day-specific growth chart was beneficial, as a week-based chart artificially distorted the centile classifications (and hence risk categorisation) for infants born at the beginning or end of a week. We then examined the impact of maternal size on the classification of infant size. Maternal obesity can affect fetal size, and we investigated whether infants experienced growth restriction, or failed to meet their growth potential, at a correspondingly higher birthweight centile in the setting of maternal obesity. We identified that the same stillbirth risk seen in <10th centile infants born from healthy weight mothers exists at a higher birthweight centile among infants born to mothers with higher body mass index. Finally, we examined the optimal assessment of fetal size among large for gestational age infants (>90th birthweight centile). Pathological overgrowth is more likely to be associated with intrapartum complications such as emergency caesarean section, so we investigated whether adjusting fetal centile according to maternal height alone, or height and weight, improved the prediction of emergency caesarean section. We found that adjusting for maternal height, but not both maternal height and weight, improved the prediction of emergency caesarean section risk. The findings of this thesis have helped clarify which aspects of growth charts may best identify the small, or large, infants at greatest risk of experiencing growth-related complications. These findings provide important guidance for future adoption, or creation, of improved obstetric growth standards to better identify fetuses at increased risk of adverse outcome, and will provide greater clarity for clinicians around the use of currently available charts.
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ItemMaternal morbidity, maternal mortality, and stillbirth in the Asia-Pacific region( 2023-01)The Asia-Pacific region hosts many low-middle-income countries with significant barriers to achieving health equity. The Solomon Islands is a Pacific nation with high levels of preventable maternal mortality, morbidity and stillbirth. This thesis investigated rates and causes of maternal morbidity in the region; maternal mortality, maternal morbidity and stillbirth in the Solomon Islands; and the role of betel nut on adverse pregnancy outcomes and hypertensive disorders in pregnancy. These findings can guide future research and health policy in the region.
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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.