Obstetrics & Gynaecology - Doctoral Theses

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    Axis of placental ageing in adverse pregnancy outcomes
    (University College Cork, 2023) Manna, Samprikta; McCarthy, Fergus; McCarthy, Cathal; European Chiropractors' Union
    Background: Pre-eclampsia (PE), an adverse pregnancy outcome affects 2-5% pregnancies worldwide and significantly adversely impacts both maternal and fetal outcomes. Intrauterine growth restriction (IUGR) is defined as the inability of the fetus to reach normal growth potential within the uterus as a result of various genetic, environmental, or placental factors. Premature ageing of the placenta in pregnancy outcomes such as PE and IUGR is associated with the persistent presence of oxidative stress and placental insufficiency reducing its functional capacity. Placental proteomics has been instrumental in improving our understanding of molecular mechanisms involved in the pathophysiology of placental insufficiency as well as identifying biomarkers to predict and diagnose pregnancy outcomes. In this study, we investigated cellular senescence phenotypes of PE and IUGR pregnancies by simultaneously measuring several biomarkers of senescence, as well as the proteomic signature of the placenta in healthy and adverse pregnancy outcomes PE and IUGR. Method: Maternal plasma and placental samples were collected at term (>37 weeks) and preterm (<37 weeks) gestation from nulliparous women undergoing prelabour elective Caesarean section with PE without intrauterine growth restriction (PE; n=5), PE associated with intrauterine growth restriction (n=8), intrauterine growth restriction (IUGR <10th centile) (n=6) and age-matched controls (n=20) from Cork University Maternity Hospital, Cork, Ireland. To assess cellular senescence absolute telomere length (aTL) and senescence associated genes in the placentas was performed by RTqPCR. Cyclin-dependent kinase inhibitors (p21 and p16) expression were determined by Western blotting. Senescence Associated Secretory Phenotype (SASP) were evaluated in maternal plasma by multiplex ELISA assay. Proteomic analysis of placental samples dissected into 3 sub-anatomical regions (maternal, middle, fetal) taken from 3 nulliparous healthy placentas was performed by mass-spectrometry and pathway analysis was conducted. Based on the differentially expressed proteins (DEPs), a placenta specific disease map using NaviCenta focusing on functional analysis to include the placenta specific context for healthy (n=4) compared to PE affected (n=4) and IUGR affected (n=4) placentas. Results: Placental expression of senescence associated genes CHEK1, PCNA, PTEN, CDKN2A, CCNB-1 was significantly upregulated in PE, while TBX-2, PCNA, ATM and CCNB-1 expression were significantly decreased in IUGR compared to controls. Moreover, placental p16 protein expression was significantly decreased in PE only when compared to controls placentas. We also observed that IL-6 was significantly increased in maternal circulation in PE when compared to controls; while IFN-γ was significantly increased in maternal circulation in women affected with IUGR when compared to controls. Proteomic profiling of healthy placentas divided into three sub-anatomical regions identified 1081, 1086, and 1101 proteins in maternal, middle, and fetal sub-anatomical regions respectively. Depending on sample site location and sub-anatomical regions, 374 differentially expressed proteins (DEP) were identified. When we investigated the proteomic variations between PE and IUGR placentas when compared to controls we observed 314, 391, and 378 proteins in healthy control, PE, and IUGR placenta, respectively. We performed functional analysis by combining ClusterCompare and NaviCenta to analyse a placenta-centric context, and observed regulatory elements predominantly involved in the immune regulation, complement cascade and antioxidant activities in PE and IUGR compared to control placentas. Conclusion: This thesis provides evidence of premature senescence in IUGR, while in PE, evidence of activated cell cycle checkpoint regulators is suggestive of cellular repair and proliferation rather than progression to cellular senescence. The heterogeneity within senescence molecular markers of these phenotypes highlights the complexity and disparity between pathophysiological insults unique to each obstetric complication. Proteomic profiling of sub-anatomical placental regions highlighted the variabilities between regions particularly providing evidence of senescence in these regions. Placental proteomic mapping of healthy placentas compared to adverse pregnancy outcomes PE and IUGR revealed the importance of complement system, inflammatory response, and antioxidant activity in placental function in PE placentas. The identification of novel targets such as transcription factor activity and synergistic miRNAs elements within the core regulatory network, might enlighten future placental research within adverse pregnancy outcomes.
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    Rethinking stillbirth through behaviour change
    (University College Cork, 2022) Escañuela Sánchez, Tamara; O'Donoghue, Keelin; Matvienko-Sikar, Karen; Meaney, Sarah; Byrne, Molly; Science Foundation Ireland
    Background Worldwide, two million babies are stillborn every year. While the majority of stillbirths occur in low and middle-income countries, stillbirth is still one of the most common adverse pregnancy outcomes in high-income countries. In Ireland, the latest National Perinatal Mortality Clinical Audit report states a stillbirth rate of 4.20 per 1000 births for the year 2020, showing an increase compared to previous years. The belief that reduced stillbirth rates in high-income countries cannot be achieved is refuted by differences in stillbirth rates across different countries. Although not all stillbirths are preventable, there has been a call made in high-income countries to focus on risk factors for stillbirth, in order to reduce stillbirth rates. These risk factors include sociodemographic factors, medical factors, obstetric history-related factors, placental and fetal-related factors as well as behavioural and lifestyle-related factors. Some of these factors are modifiable through medical management or through behaviour change modification. This Thesis focuses on risk factors that have the potential to be modified through maternal behaviour change interventions: substance use (smoking, alcohol, and illicit drug use), high BMI, sleep position, and attendance at antenatal care. Strategies have been successfully implemented internationally to reduce stillbirth rates by designing and implementing care bundles that, amongst other elements, take into consideration the modifiable/behavioural risk factors for stillbirth. However, in Ireland, no such initiatives have been developed, although recommendations have been made that support their development. For behaviour change interventions or public health initiatives to have the best possible success in reducing the rates of stillbirth, they need to be designed with a solid evidence base. Hence, the overall objective of this Thesis was to build the evidence base to enhance the understanding of the modifiable behavioural risk factors for stillbirth and pregnancy. Further, this evidence base is needed to inform the future development of a behaviour change intervention that could be part of a care bundle with the objective of reducing stillbirth rates in Ireland. Methodology To address the Thesis´s aims, both qualitative and quantitative methods were utilised. Applying multiple methods to explore a phenomenon provides flexibility to analyse different aspects of it in the different studies. Initially, a non-systematic review of the literature was conducted to identify the target behavioural risk factors that this project was going to focus on (Chapter 2). A website quantitative content analysis was conducted to assess the availability of information related to stillbirth and behavioural risk factors for stillbirth in Irish and UK websites (Chapter 3). For this study, descriptive and inferential statistics were utilised. Further, three systematic qualitative meta-synthesis were conducted to identify facilitators and barriers to modify identified behavioural risk factors according to the pregnant women’s experience (Chapters 4-6). A meta-ethnographic approach as described by Noblit and Hare was adopted to conduct these qualitative meta-syntheses. Reflexive Thematic Analysis as described by Braun and Clarke, with a constructivist approach, was used to conduct a qualitative semi-structured interview study with postpartum women about their experiences of stillbirth information provision and behaviour change during their antenatal care (Chapter 7). Finally, a systematic review of interventions designed in the context of stillbirth prevention that targeted behavioural risk factors was conducted (Chapter 8). This systematic review had the objective of identifying which behaviour change techniques (BCTs) have been used to date. Results The findings of the literature review (Chapter 2) showed that the modifiable behavioural risk factors with the strongest evidence of associations with stillbirth were substance use, smoking, heavy drinking and illicit drug use, lack of attendance and compliance with antenatal care, weight-related risks, and sleep position. The quantitative content analysis of websites (Chapter 3) revealed that information about stillbirth and behavioural risk factors for stillbirths was scarce on websites directed at the pregnant population, with only one website containing all the information sought. Five main areas of concern were identified across the three meta-synthesis of qualitative research of facilitators and barriers influencing women’s prenatal health behaviours (Chapters 4-6), regardless of the behaviour explored: 1) health literacy, awareness of risks and benefits; 2) insufficient and overwhelming sources of information; 3) lack of opportunities and healthcare professionals attitudes interfering with communication & discussion; 4) social influence of environment, and 5) social judgement, stigmatisation of women and silence around stillbirth. Further, the qualitative study with postpartum women (Chapter 7) revealed that women perceived behaviour change during pregnancy as easy and natural, as they were focused on obtaining the best outcomes for their babies. Although women had high levels of awareness regarding health advice, their awareness about stillbirth was very limited. Women reported a lack of discussion about stillbirth and behavioural risk factors during their antenatal care; however, most women showed a positive disposition towards receiving this information because “knowledge is key”, as long as it is done in a “sensible manner”. The systematic review of interventions designed in the context of stillbirth prevention identified nine relevant interventions. From the BCT coding, it was established that the most common BCT used was “information about health consequences”, followed by “adding objects to the environment” (Chapter 8). Conclusion This research makes a valuable contribution to the understanding of the maternal behaviours associated with an increased risk of stillbirth, and it provides a necessary evidence-base to inform future prevention strategies to reduce rates of stillbirth in Ireland and in similar healthcare settings. This research sought to incorporate women’s voices and use research methods to produce high-quality results that meet the research objectives. The findings from the studies in this Thesis support four overarching topics and highlight issues related to 1) health literacy and sources of information, 2) relationships with healthcare professionals (HCPs), 3) healthcare systems and structural barriers, and 4) interpersonal, social and structural factors. In response to the research findings, several recommendations are made in relation to policy, practice and research which are grounded on women’s experiences during pregnancy. Regarding policy, these recommendations include improving education and information sources for women and HCPs, providing pregnancy-specific supports, utilising community services to support women with behaviour change, and developing a care bundle to tackle the behavioural risk factors for stillbirth. Furthermore, the work practice recommendations made include developing clinical guidelines to support HCPs in providing care to pregnant women, and prioritising health promotion during antenatal care. These priorities might also serve to help funders and researchers to design and conduct policy-relevant research. The key future research areas identified by this Thesis are in relation to the involvement of PPI representatives, the assessment of the quality of the available sources of information and the further exploration of potential facilitators and barriers to modifying pregnant women’s sleeping position from a qualitative perspective. In addition, this Thesis proposes a detailed process to continue building on the work set out in the different studies to develop a pregnancy-specific behaviour change intervention for the modifiable behavioural risk factors for stillbirth in the future.
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    Data quality in the evolving digitised health service
    (University College Cork, 2021) McKernan, Joye; Greene, Richard A.; Corcoran, Paul
    Background/Objective: The research undertaken for this thesis focussed on data quality in the evolving digitised health service. In Ireland we all need to have our details on an electronic healthcare record. We need to have fully integrated systems documenting our health information across our whole life. We as patients need to be central to our care and have access to our data. EHRs can change healthcare by saving money, improving communication, and reducing errors. The introduction of an EHR is a substantial change management project that needs to include all stakeholders to ensure success. It requires vision, dedication, time, and patience. The power and importance of data cannot be overemphasised; we need to analyse what is required from data, using robust standard approaches, and ensure data is of high quality so that it can be used to improve patient outcomes and improve staff working conditions. The aim of this research project was to focus on aspects of digitisation that go towards achieving a high-quality data repository. We aimed to investigate the development and use of an EHR in the Irish healthcare system with specific consideration to the elements that impact data quality. We examined the experiences of the development team, patients, staff, service culture and the data collected. Methods: We used both quantitative and qualitative methods; this mixed method approach allowed for a deeper understanding of the issues. A document analysis of the closure report of the implementation of the EHR (MN-CMS) from the national project team was supported with discussions with team members. Patients at antenatal booking visits in an Irish maternity unit were invited to participate and complete a survey with respect to digitization of their health data. The survey was divided into three distinctive sections; participant information, regarding the staff encounters on their visits and questions about the new system. To engage with staff a pre- EHR implementation survey, a post EHR implementation survey and a post-implementation EHR documentation audit was carried out. A four-step approach was required when applying a national framework to a national data set. The four steps included a literature review, using elements of a data quality framework to develop the planning of an audit tool, data quality assessment of the Major Obstetric Haemorrhage (MOH) audit dataset. The fourth step assessed the data quality using the five dimensions of quality: (1) relevance, (2) accuracy and reliability, (3) timeliness and punctuality, (4) coherence and comparability, and (5) accessibility and clarity. To explore data quality in an EHR two phases were used; initially we examined the data from year 1 (2018); following analysis of the data set we found data quality issues. We then enacted an intervention and assessed the effect of a new data quality process. The intervention was to introduce a data quality resource to assess the datapoints within 1-2 days after documentation of the care by the healthcare professional. We assessed clinical data extracted from the MN-CMS national database for missing data and then examined the significance of the data issues. An ethnographic study approach was used to explore service culture around shift clinical handover, the process was divided into three components: an observational study, a short staff survey and a cause-and-effect assessment. Results: This project showed that several factors, need to be explored to fully understand data quality in healthcare. There is a growing need for high quality clinical ‘Big Data’ to measure, enhance and evaluate healthcare; clinical data systems need to be producing high quality complete and accurate data for primary and secondary use. Patients want to have access to their records and want to engage with healthcare professionals in their care. This engagement will lead to patients having more control over their health outcomes. EHRs are now becoming more and more widespread globally; in Ireland the Maternal & Newborn Clinical Management System (MN-CMS) has been implemented for four maternity units and is a pathfinder EHR project. It is a clinically led, patient centred EHR. Staff engagement is required for the implementation phase; they are a vital component to ensure a successful implementation. Staff may require additional training to ensure their documentation positively impacts data quality. There is a requirement to standardise terminology in relation to data quality and use data quality frameworks to assess the dimension of data quality. It is meaningful and useful to apply national data quality frameworks to data sets to investigate where improvements may be made. Capturing and ensuring quality data from an EHR takes time and resources; the data needs to be examined for accuracy and completeness. Resources in the form of staff are required to achieve this impact on data quality. They can improve data directly and more importantly they can engage with staff regarding their documentation, identify need for further training, technical solution changes and indeed review of data points and the value of recording them. Following the implementation of an EHR, workflows and practices might not change when they should have; it is important to explore why these changes may not occur and address the issues to identify the barriers and allow enablers to achieve appropriate change, engaging with staff in the process. Conclusion: This project aimed to explore the impacts of digitizing healthcare documentation on the quality of that data, examining the impact through patients, staff, and processes. This thesis has shown a need to move towards standardised terminology and methodologies to achieve these goals and the projects involved took a practical solutions approach. We have shown the importance of staff members and their role in the success of the project implementation. We have highlighted the importance of the use of frameworks to robustly assess data quality. There is growing literature regarding EHRs and data quality with the rapid expansion in digitization of healthcare data. This thesis adds to that literature, but significantly more work is needed in the areas of standardisation of data quality frameworks, the importance of staff in data quality, and co-designed patient portals.
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    Study of methods, systems, recommendations and bereaved parents’ involvements in perinatal death reviews, inquiries and audits
    (University College Cork, 2021-12-10) Helps, Änne; O'Donoghue, Keelin; Leitao, Sara; Greene, Richard A.; National Perinatal Epidemiology Centre; University College Cork
    Background: An estimated 5.3 million perinatal deaths occur worldwide each year. In Ireland, there were 335 perinatal deaths reported in 2019. These deaths are devastating for the parents, families and, if unexpected, for the healthcare staff involved, with long-lasting emotional consequences. Some of these deaths are unavoidable, but many are preventable. To investigate these deaths and identify contributory factors, local hospital-based perinatal death reviews as well as national perinatal mortality audits are carried out. In certain circumstances, for example if a higher than expected intrapartum perinatal death rate is recorded, an external inquiry may be commissioned to investigate events of public concern. Reports with recommendations are published after local perinatal death reviews, perinatal audits and external inquiries. In Ireland, there is currently no standardised format to the recommendations or their implementation. Further, the involvement of bereaved parents in local maternity hospital-based perinatal death reviews is poorly explored. The aim of this thesis is to analyse the methodology and structure of perinatal mortality audits, local reviews and inquiries, as well as recurrent themes in the recommendations of the published reports and the inclusion of bereaved parents in reviews. Methodology: Both qualitative and quantitative methods were employed for this thesis. A topic can be explored with flexibility and in depth by using a mixed methods approach. An integrative literature search was carried out focussing on the types and evolution of perinatal mortality audits and reviews in high-income countries. Further, an integrative review using quantitative and qualitative methods to identify established national perinatal mortality audits in four high-income countries and national initiatives addressing recommendations from these audits was done. Content analysis of the audits’ recommendations was performed organising them into themes according to topics covered. Additionally, a service evaluation of the local maternity hospitals’ perinatal death reviews in Ireland was carried using an electronic survey. The quantitative and qualitative data collected from all 19 maternity units were analysed to identify and compare current local review processes. In the analyses of the ten Irish inquiry reports relating to perinatal deaths and pregnancy loss services in the maternity services quantitative and qualitative data were collected by two clinicians using a specifically designed review tool. Descriptive analyses of the main characteristics of the reports gave an overview of the terms of reference and inquiry review process, and identified recurring themes in the recommendations. Qualitative content analysis of the reports’ findings and recommendations was used to identify key domains. An inductive thematic analysis with a semantic approach following the steps of familiarising, coding, identifying, grouping and revising themes identified the main themes and subthemes for each domain. Lastly, purposeful sampling was used to recruit bereaved parents in Ireland to take part in semi-structured interviews to examine how parents may be appropriately involved in the local hospital-based review in a way that is beneficial to them and the review process itself. Reflexive thematic analysis using a five-phase process (familiarisation, open coding, generating themes, developing themes, refining themes) was carried out on the collected data by three researchers. Results: Internationally, differences in perinatal mortality classifications, audits and reviews, as well as barriers to the implementation of recommendations were noted. Common and recurrent themes of recommendations from four established national perinatal mortality audits suggested a lack of progression of recommendations that is shared between countries. These four countries have adopted varying national initiatives and programmes to address the audits’ recommendations. A lack of standardisation for the methods of local perinatal mortality reviews and external inquiries in Ireland was highlighted within this thesis. Recommendations from ten inquiry reports were numerous and repetitive suggesting a lack of clear ownership for the implementation process. An analysis of the findings of the ten inquiry reports showed that that elements of governance of Irish maternity services (workforce, leadership, management of risk, work environment) impacted negatively and directly on the management of perinatal deaths and bereavement services. Further, three elements (hospital oversight, national documents, data collection) identified from the inquiry reports in turn affected governance structures in the management of perinatal deaths. Examination of these inquiry reports highlighted shortcomings in the perinatal bereavement care and pregnancy loss services provided to families in the Irish maternity services and the short- and long-term effects this can have. Interviews with bereaved parents revealed that parents want a more inclusive and open process that allows them to be included in the local hospital perinatal mortality review. However, this parental involvement needs to be carefully considered, flexible and appropriately resourced. Conclusion: The culture in the maternity unit determines how bereaved families and hospital staff cope after an adverse event like an unexpected perinatal death. A lack of open disclosure can have negative effects on how bereaved parents process events and cope with their grief after the death of their baby. Recently many reports with multiple recommendations have been published to improve safety standards in the Irish maternity services; however, implementation thus far has been slow and incomplete. The focus is currently on collecting data and highlighting issues, and less on progressing recommendations to implement changes and prevent similar events recurring. To overcome barriers to successful recommendation implementation and advance perinatal mortality audits and reviews, suggestions based on examples from the international literature were identified and provided as part of this thesis. Perinatal mortality processes, including reviews, need to be standardised across the 19 maternity units. Suggestions to achieve this include the adaptation of the national Incident Management Framework specifically to the maternity setting, the implementation of an electronic review tool such as MERT (Maternity Event Review Tool) for perinatal deaths and an assessment of the feasibility of a national perinatal (and/or paediatric) Coroner for Ireland. The inclusion of parents in perinatal mortality reviews needs to be addressed urgently yet carefully considered and resourced, in order for it to be beneficial to them and the review process itself. A collaborative process between staff and parents can highlight clinical areas in need of change, enhance lessons learned, and may prevent future perinatal deaths.
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    Applications of metabolomics to study the pathophysiology of adverse pregnancy outcomes
    (University College Cork, 2020) Morillon, Aude-Claire; McCarthy, Fergus; English, Jane; Yakkundi, Shirish; Kenny, Louise; Baker, Philip; Science Foundation Ireland; Waters Corporation
    Background: Clinical metabolomics is a growing field of research aiming to use metabolomic techniques to gain further knowledge into diseases, the use of biomarkers to predict their onset, or the effect of a potential therapeutic agent on the metabolome. Adverse pregnancy outcomes, such as small for gestation age (or fetal growth restriction), spontaneous preterm birth, and pre-eclampsia, lead to high maternal and fetal mortality and morbidity rates. However, despite research efforts to date, their pathophysiology remains poorly understood. Aim: The aims of this thesis was to determine the accuracy of metabolomics to predict small for gestation age (SGA) babies, to explore the metabolic pathways involved in the pathophysiology of SGA and spontaneous preterm birth (sPTB), to identify potential predictive biomarkers of sPTB, and investigate the use of a potential therapeutic agent in an animal model of pre-eclampsia. Methods: Firstly, a systematic review was undertaken to examine the predictive accuracy of metabolomics for the prediction of small for gestational age babies. The original search was conducted in February 2018 and the results are presented in Chapter 2. Secondly, we investigated the metabolic pathways involved in the pathophysiology of small for gestation age (SGA) using untargeted ultra-performance liquid chromatography coupled to quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS). Plasma (Cork) and urine (Cork, Auckland) samples were collected at 20 weeks of gestation from pregnant women participating in the SCreening fOr Pregnancy Endpoints (SCOPE) study, an international study that recruited 5,628 nulliparous women, with a singleton low-risk pregnancy. Cases were women with SGA (customised birthweight ≤ 10th centile) matched to controls who had uncomplicated pregnancies, according to age (±5 years), body mass index (BMI, ±3.5 kg/m2), and ethnicity. All samples were analysed in untargeted positive and negative ion modes, using UPLC-Q-TOF-MS. Data were processed, features were ranked based on p-values from empirical Bayes analysis adjusted for multiple testing, and significant features (adjusted p-values <0.05 were searched for identification (HMDB, LipidMaps)). Thirdly, we aimed to decipher the lipidomics pathways involved in pathophysiology of spontaneous preterm birth (sPTB). Our analysis focused on plasma samples from SCOPE in Cork, collected at 20 weeks of gestation. Samples were profiled using semi-targeted liquid chromatography-mass spectrometry lipidomics, and lipids significantly altered between sPTB (n=16) and Control (n=32) groups were identified using empirical Bayes testing, adjusting for multiple comparisons. Significantly altered lipids (adj. p-values <0.05) were database searched for identifications (HMDB, LipidMaps). Fourthly, in Chapter 5, we performed a discovery lipidomics experiment to determine potential biomarkers of sPTB, in plasma samples taken at 15 weeks of gestation in women who participated in SCOPE in Cork and Auckland. Selected participants were women who has sPTB before 34 weeks of gestation (n=16 from Cork, and n=23 from Auckland), matched to women who had an uncomplicated pregnancy (n=39) according to age (±5 years) and BMI (± 3 kg/m2). Lipidomics analysis was performed using UPLC-Q-TOF-MS. Statistical analysis using empirical Bayes, adjusted for multiple testing was used to create a list of potential biomarkers. Five potential biomarkers were selected for validation based on statistical analysis, and their identification was validated using standard mix and UPLC coupled to triple quadrupole mass spectrometer (TQ-MS) analyses. Their prediction potential was tested using samples taken at 15 and 20 weeks of gestation from women from SCOPE Cork who had sPTB before 37 weeks of gestation (n=54) matched to women who had an uncomplicated pregnancy (controls, n=108). In addition, plasma collected at time of delivery (ToD) was also analysed for six cases and their 12 matching controls. Cases were matched to controls according to age (±5 years) and BMI (± 3 kg/m2). Samples were analysed using UPLC-TQ-MS, and statistical analysis was performed using independent T tests on normalised data. In addition, independent T tests were performed to determine if the levels of each target were significantly different between cases and controls at each time point (15 or 20 weeks). We defined significance as p-value <0.05. Finally, in chapter 6 we performed metabolomics analysis of plasma from experiments examining L-Ergothioneine treatment in the Reduced Uterine Perfusion Pressure (RUPP) rat model of pre-eclampsia. The effect of L-Ergothioneine (ET) treatment was explored using in vivo treatment in rats: Sham control (SC, n=5), RUPP control (RC, n=5), Sham + ET (ST, n=5), RUPP + ET (RT, n=5). Metabolic profiles of plasma samples were obtained using UPLC-Q-TOF-MS, and statistical analysis of the data was performed on normalised data, using independent T tests adjusted with false discovery rate (FDR) to compare RC to SC, RT to RC and RT to ST. Metabolites significantly altered (FDR <0.05) were putatively identified through database search (HMDB). Results: The systematic review presented in Chapter 2 examining the predictive accuracy of metabolomics for small for gestational age babies showed that to date no combination of metabolites are able to predict small for gestational age accurately. However, the review revealed the potential of investigating lipids pathways, their involvement in the pathophysiology of small for gestational age, and their high predictive potential. The metabolomic studies performed on urine samples and reported in Chapter 3, showed lower levels of 4 metabolites of interest (sulfolithocholic acid, estriol-16-Glucuronide, Neuromedin N (1-4), and 4-Hydroxybenzaldehyde) in Cork were associated with SGA at 20 weeks of gestation, but not in Auckland samples. These urinary metabolites are associated with detoxification, nutrient transport and absorption pathways. The lipidomics analysis performed on plasma samples showed that higher levels of several glycerophospholipids (3 phosphatidylethanolamines, 5 phosphatidylserines, 3 phosphatidylcholines, 1 lyso phosphatidylcholine, 1 phosphatidylglycerophosphate, 1 lyso phosphatidylglycerophosphate, 2 phosphatidylinositols, 2 phosphatidylglycerophosphates, and 3 phosphatidylglycerols) in at 20 weeks of gestation were associated with the development of SGA in the Cork participants of the SCOPE pregnancy cohort. Chapter 4 demonstrated that twenty-six lipids showed lower levels in sPTB compared to controls (adjusted p <0.05), including 20 glycerophospholipids (12 phosphatidylcholines, 7 phosphatidylethanolamines, 1 phosphatidylinositol) and 6 sphingolipids (2 ceramides and 4 sphingomyelines). In addition, a diaglyceride, DG (34:4), was detected in higher levels in sPTB compared to controls. In Chapter 4, we reported that reduced levels of phospholipids (glycerophospholipids and sphingolipids) are associated with the pathophysiology of sPTB. In the UPLC-Q-TOF-MS discovery phase of the study presented in Chapter 5, a list of 120 potential lipid biomarkers were reported. Most were tentatively identified as glycerophospholipids and detected in lower levels in sPTB. From this list of features, 5 potential biomarkers predictive of sPTB were selected and used in a targeted UPLC-TQ-MS analysis. The results obtained showed that two of the targets showed significant differences between cases and controls and over time (between 15 and 20 weeks of gestation), PC (15:0/22:6) and TG (18:3/18:2/18:3). In Chapter 6, using untargeted UPLC-Q-TOF-MS, we tested the effect of L-Ergothioneine (ET) as a potential therapeutic agent for the treatment of pre-eclampsia in the RUPP rat model. We reported significantly higher levels of L-palmitoylcarnitine, fatty acyl substrate involved in beta-oxidation in the mitochondria, in RUPP rats compared to Sham rats. When comparing plasma metabolic profiles of RUPP + ET rats to RUPP rats, we reported 10 metabolites associated with inflammation significantly altered (FDR <0.05, e.g. 20-COOH-leukotriene E4). Glutamylcysteine, a metabolite associated with oxidative stress, was detected at significantly higher levels (FDR <0.05) when comparing RUPP + ET rats to RUPP rats, and RUPP + ET rats to Sham + ET rats. These results show that the therapeutic properties of L-Ergothioneine might be related to mitochondrial function preservation, by attenuating inflammatory response evident in pre-eclampsia in addition to increasing antioxidant levels. Conclusions: Overall, these results show that glycerophospholipids appear to play a key role in the pathophysiology of SGA and sPTB, and dysregulated glycerophospholipids are potential makers of adverse pregnancy outcomes. Further research is needed to understand their precise associations, whether they are a cause or effect of SGA and sPTB, as well as to validate their potential as predictive biomarkers in independent pregnancy cohorts. In addition, we have shown that the use of L-Ergothioneine for the treatment of pre-eclampsia in the RUPP rat model reduces the oxidative stress induced by pre-eclampsia, via amino acid and glycerophospholipids metabolism pathways. Future work should focus on a testing L-Ergothioneine as a treatment for pre-eclampsia in a clinical trial. This thesis has demonstrated the potential for metabolomics to help understand the pathophysiology of adverse pregnancy outcomes and has explored its use in assessing biological pathways, predictive biomarkers and potential therapeutic pharmacological interventions. To date results are limited with significant further validation required.