INFANT Research Centre - Doctoral Theses
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Item Evaluation of biomarkers for the diagnosis, management and follow-up of women with gestational trophoblastic disease(University College Cork, 2024) Joyce, Caroline Martha; O'Donoghue, Keelin; McCarthy, Tommie V.; Coulter, John; Irish Research CouncilGestational Trophoblastic Disease (GTD) describes a spectrum of disorders arising from the abnormal proliferation of trophoblastic tissue. Human chorionic gonadotrophin (hCG) is an excellent biomarker for most forms of this disease as its concentration accurately reflects trophoblastic activity. Hydatidiform mole (HM) or molar pregnancy is the most common form of GTD which may be suspected on ultrasound but requires pathological confirmation for diagnosis. Prognosis is generally excellent however close surveillance with hCG monitoring is imperative to detect cases progressing to malignant disease, referred to as gestational trophoblastic neoplasia (GTN). Clinical management and treatment of women with GTN in specialist centres achieves cure rates approaching 100%, emphasising the importance of accurate hCG monitoring for early detection of disease persistence to ensure optimal outcome. This thesis aims to evaluate pathological, genetic, and biochemical biomarkers used in the diagnosis, monitoring, and follow-up of women with GTD. In this thesis, a scoping review was performed to generate evidence and identify gaps in the GTD knowledge base to inform areas for future research. Key findings were the need to standardise hCG immunoassays for effective GTD surveillance, to improve diagnostic reporting pathways and to establish more accurate incidence rates. In order to identify patient priorities and inform initiatives to enhance the quality of care, a service evaluation was performed with women enrolled in the National GTD Registry invited to participate. Feedback revealed a knowledge gap regarding GTD amongst healthcare professionals outside GTD centres. This study also revealed shortcomings in psychological support and bereavement counselling offered to women after a molar pregnancy. To enhance the diagnostic accuracy of HM reporting, an in-situ hybridisation ploidy assay was developed with a customised scoring system to aid partial hydatidiform mole (PHM) diagnosis. This innovative technique provides a reliable adjunct to morphological assessment for PHM classification. The accuracy of this ploidy technique was confirmed by evaluation with molecular short tandem repeat genotyping. A national pathology questionnaire was performed to gather information on GTD diagnostic rates. Data collected was cross-referenced with cases documented in the National GTD Registry. This revealed a concerning under-enrolment of women with GTD (42%) onto the National GTD Registry by their clinicians. An audit of HM diagnostic rates over a 3-year period was performed following the Implementation of the new ploidy technique to aid diagnosis . This revealed a higher local PHM incidence rate (1 in 296 births) than reported nationally in the pathology audit (1 in 484 births). An electronic questionnaire was distributed to all European laboratories offering hCG for GTD management to gather insights on 5 key areas: hCG methodology, quality parameters, reporting and operational procedures, and use of hCG for non-GTD testing. This revealed considerable inter- and intra-laboratory variability in practice, emphasising the need to promote standardisation and harmonisation of immunoassays for GTD-derived hCG. A review of five challenging cases managed at the Irish GTD centre was conducted to evaluate the role of serum hCG and molecular genotyping in guiding management decisions, treatment strategies, and risk stratification for women with molar pregnancy, GTN and GTD mimics. These complex cases confirmed the pivotal role of serum hCG and molecular genotyping in monitoring disease persistence, prognostic stratification, and clinical management Novel strategies to measure hCG were pursued to address the lack of centralised hCG testing for GTD in Ireland. A proof-of-concept study for remote capillary blood collection was performed to evaluate the clinical efficacy and user acceptability of this method of collection for hCG monitoring in early pregnancy. The study confirmed the equivalence of capillary and venous blood hCG testing, demonstrated complete clinical concordance, thereby offering an alternative to venepuncture for hCG measurement. To explore the accessibility of hCG testing in the community, a point-of-care testing (POCT) device was evaluated for its suitability to triage women with pregnancy of unknown location (PUL) in the early pregnancy unit. The Abbott iSTAT®1 POCT instrument was chosen for this purpose and was clinically concordant with central laboratory hCG results facilitating the use of clinical decision thresholds for PUL. The research presented in this thesis provides valuable clinical insights through a series of nine research studies and has broadened the knowledge base in GTD. The findings offer an opportunity to positively impact diagnostic practices. The knowledge gap regarding GTD amongst healthcare professionals revealed in the patient survey points to a need for targeted educational initiatives in this area. Widespread integration of the HER2 ploidy technique to support morphology and standardise HM reporting could improve diagnostic accuracy, addressing a suspected underdiagnosis of PHM nationally and possibly internationally. It also suggests the need to re-evaluate incidence rates following the introduction of advanced diagnostic techniques such as ploidy assessment and molecular genotyping. This thesis identified an under-registration of women with GTD in Ireland supporting the need for initiatives such as mandatory registration or advocacy by professional organisations to increase registration rates. The inter and intra-laboratory variation in hCG immunoassays revealed in the European laboratory survey merits renewed harmonisation efforts through pilot external quality assurance and sample exchange programmes. The use of novel methods to enhance the accessibility of hCG monitoring for GTD in the community, through capillary blood collection or use of point-of-care analysis, warrants further study. The positive patient feedback indicated a preference for this approach, suggesting better compliance with serial test monitoring, a priority for GTD management.Item Axis of placental ageing in adverse pregnancy outcomes(University College Cork, 2023) Manna, Samprikta; McCarthy, Fergus; McCarthy, Cathal; European Chiropractors' UnionBackground: 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.Item The impact of maternal chronic hypertension and chronic kidney disease on the risk of adverse pregnancy outcomes and long-term cardiovascular disease: a population-based epidemiology study(University College Cork, 2022-08-31) Al Khalaf, Sukainah; Khashan, Ali; McCarthy, Fergus; O'Reilly, Eilis; Ministry of Health – Kingdom of Saudi ArabiaBackground and aims: The prevalence of chronic hypertension (CH) and chronic kidney disease (CKD) have increased among pregnant women in recent decades. Given the improvement in antenatal care over the last few decades, it is still unclear whether the risk of adverse pregnancy outcomes (APOs) among women with CH and/or CKD has decreased. There is limited evidence on the association between antihypertensive treatment and APOs in women with CH. Although there is evidence that women with a history of APOs have an increased risk of cardiovascular disease (CVD), it remains unclear whether pre-pregnancy hypertension and the occurrence of APOs would influence this association. The aim of this PhD project was to investigate the impact of maternal CH and/or CKD and antihypertensive treatment on the risk of APOs and long-term CVD. Structure and methods: This thesis includes eight chapters: Introduction, Methods, two systematic review articles on the impact of CH and CKD on APOs, three original research articles, and Discussion. Data from the Swedish National Registers were analysed to examine the associations between CH/CKD and the risk of APOs over the last three decades. Data from the UK CALIBER platform were used to investigate: i) the association between CH and APOs, with a focus on the role of antihypertensive treatment and control of hypertension, and ii) the associations between pre-pregnancy hypertension and subsequent diagnosis of 12 different CVDs, considering the role of APOs on these associations. Adverse pregnancy outcomes were pre-eclampsia, preterm birth, stillbirth, Caesarean section and small for gestational age (SGA). The statistical methods were done using logistic regression models for the Swedish data, logistic regression models with propensity score matching for the antihypertensive treatment analyses, while the associations between pre-pregnancy hypertension and CVD were analysed using stratified Cox models. All statistical models were adjusted for several potential confounders. Results: Systematic reviews and meta-analyses: CH was associated with 5-fold increased odds of pre-eclampsia and approximately 2-fold increased odds of stillbirth, preterm birth, and SGA, compared to women without CH. Women with treated CH (compared to untreated normotensive women) had higher odds of APOs. However, the results were inconsistent when outcomes were compared between treated and untreated women with CH; no increased odds of superimposed pre-eclampsia or other APOs were observed, except for 86% increased odds of SGA. Findings from the meta-analysis suggested that women with CKD had higher odds of pre-eclampsia, Caesarean section, preterm birth, very preterm birth, and SGA. All causes of CKD were associated with increased odds of pre-eclampsia, preterm birth, and SGA, with stronger associations in women with diabetic CKD, particularly for preterm birth [adjusted odds ratio (aOR): 4.76, (95% confidence interval (CI), 3.65–6.21)] and SGA [aOR: 4.50, (95% CI, 2.92–6.94)]. The findings according to the severity of kidney disease showed that later stages of CKD were associated with a greater odds of APOs than earlier stages. Swedish National Registers: The overall findings from this study suggested that the odds of APOs remain high in women with CH and/or CKD, and the odds persisted independent of parity, maternal age, and body mass index, among other potential confounders. No association was found between CKD and stillbirth. All causes of CKD were associated with higher odds of pre-eclampsia, emergency Caesarean section, and medically indicated preterm birth, and the ORs were higher in women with diabetic CKD, renovascular disease, and congenital kidney disease than other CKD subtypes. CALIBER studies: The results suggested a higher odds of APOs in women with CH (treated and untreated) compared to untreated normotensive women. In women with CH, those requiring treatment (versus untreated) had 17%, 25%, and 80% increased odds of superimposed pre-eclampsia, preterm birth, and fetal growth restriction (FGR), respectively. However, these results were mainly attributable to the level of blood pressure (BP) control among the treated group; as similar results were found between the untreated and treated women with CH who achieved tight control (BP<135/85 mmHg) for all assessed outcomes except for a 59% decreased odds of superimposed pre-eclampsia and a 55% increased odds of FGR. Pregnant women with CH who were prescribed methyldopa (versus β-blockers) had 43%, 59%, and 44% increased odds of superimposed pre-eclampsia, preterm birth, and very preterm birth, but 66% lower odds of FGR. No differences in outcomes were found in women who were prescribed calcium-channel-blockers (versus β-blockers) except for 94% increased odds of preterm birth. The magnitude of the associations increased with increasing BP, and the strongest associations were observed in women with severe hypertension (BP≥ 160/90 mmHg). In treated women with CH, less-tight (BP≥135/85 mmHg) versus tight (BP<135/85 mmHg) control was associated with almost 2-fold higher odds of superimposed pre-eclampsia, very preterm birth, and a 3-fold higher odds of severe hypertension. During the 20-year study period, 16,499 CVD incident were observed, of which two-thirds (66%) had occurred in young women (under 40 years). Pre-pregnancy hypertension (versus no pre-pregnancy hypertension) was associated with a 2-fold higher risk of any subsequent CVD. When the results were subclassified according to the presence of APOs, the strongest associations were found in women with pre-pregnancy hypertension and APOs across the 12 CVD; with almost a 3-fold increased risk to develop any subsequent CVD, an 8-fold increased risk of coronary heart disease, and a 10-fold increased risk of heart failure, compared to those who remained normotensive without APOs. Conclusions: This thesis indicated that CKD and CH were associated with a wide range of APOs than the general obstetric population. Therefore, multidisciplinary prenatal consultation and antenatal management should be provided for these women with close monitoring during pregnancy. If antihypertensive treatment is required, clinicians might consider tighter control during pregnancy as better outcomes were observed in women with tightly controlled hypertension. β-blockers might be superior in reducing APOs than methyldopa, with an exception for FGR, which was higher in the β-blockers group. Finally, the findings suggested strong associations between pre‐pregnancy hypertension with subsequent CVD, with a greater risk among women who had pre-pregnancy hypertension and APOs. Pre-pregnancy hypertension should be managed adequately during pregnancy to reduce the risk of APOs and subsequently reduce the risk of CVD, which emphasizes that a history of reproductive risk factors (including APOs) should be considered in screening tools for CVD beyond the postpartum period to optimize long-term cardiometabolic health in women.Item Portable acquisition and interpretation of EEG for neonatal healthcare applications(University College Cork, 2020) O'Sullivan, Mark; Popovici, Emanuel; Temko, Andriy; Irish Research CouncilNeonatal encephalopathy is a significant concern for both parents and medical staff. It results in the death or disability of over 2 million infants globally each year and accounts for 23% of all infant deaths. Early identification and treatment of brain injury is vital. Electroencephalography (EEG) is the gold standard for monitoring brain function. However, conventional EEG monitors are complex systems, which require specialised medical staff to configure and interpret the data. The equipment and expertise are limited to tertiary-care hospitals with neurology/neurophysiology facilities. Even in such hospitals, the process of diagnosing neonatal brain injuries suffers from long delays, making it difficult to intervene within the effective treatment window. In this thesis, a portable EEG acquisition and interpretation system for clinical use in the neonatal population is investigated. The acquisition system includes the design of a low-power and wireless electronic circuit for the acquisition, processing, and transmission of EEG signals. Existing state-of-the-art devices are reviewed and analysed. A custom solution, which offers eight channels of low-noise EEG acquisition and integration with a low-power microcontroller unit for on-board data processing and machine learning inference, is proposed. Novel signal processing and machine learning algorithms to support EEG data interpretation are optimised for use in resource-constrained applications and platforms. To date, minimal consideration is given to the regulatory and commercial requirements when developing medical devices in academia. This introduces a barrier to bringing academic innovation through to clinical adoption. A regulatory and commercial route-to-market is proposed herein for a cost-effective and time-efficient translation to clinical use.Item Experiences of pregnancy with major fetal anomalies(University College Cork, 2020-09-24) Power Walsh, Stacey; O'Donoghue, Keelin; Meaney, SarahBackground: Two to three percent of pregnancies will receive a diagnosis of a congenital anomaly, of which a proportion are fatal. While the prevalence of congenital anomalies is low it is the leading cause of fetal death and child mortality. More women are receiving a diagnosis of a fetal anomaly during their pregnancy as a result of advancements in technology. While there is no universally agreed definition, the term fatal fetal anomaly (FFA) is widely used to describe a condition likely to lead to death of the fetus in utero or within 28 days of birth. Delivering a diagnosis of a FFA is usually unexpected and is an unwanted and traumatic event for parents. Little is known about what conditions are most responsible for perinatal mortality. Following a FFA diagnosis, parents face multiple challenges, primarily whether to continue and avail of PPC or terminate the affected pregnancy. Regardless of the choice, the outcome is ultimately the same, ending in a fetal, neonatal or infant death. The need for the decision to be an informed one is paramount. Information is an essential factor to develop patient’s knowledge and empowers them in their decision-making. Media offers an insight into health-related information widely available to the public. FFA has generated international media attention as termination of pregnancy (TOP) for FFA was legislated for, for the first time in Ireland. However, it is identified that what the people voted for has not materialised in the legislation relating to practical terms of delivering abortion care. Following pregnancy loss or perinatal death, parents require various levels of support during their bereavement. There is an over reliance on voluntary organisations to provide peer support to families to meet their needs that often surpass that of standard maternity hospital provision. Education is essential in healthcare in order to keep up-to-date with best practice. This is of particular importance as TOP for FFA, without gestational limits, was provided for within legislation for the first time in Ireland from 2019. This change in legislation warrants an exploration into Volunteers experiences of supporting families, and Fetal Medicine Specialists’ (FMS) experiences of caring for parents following a FFA diagnosis. The overall aim of this thesis was to explore various aspects of pregnancies diagnosed with FFA, during this change in service provision. Methodology: To address the thesis’s aims, both qualitative and quantitative methods were employed. Employing a mixed methods approach to study a phenomenon allows for flexibility to explore different aspects in each of the studies. A secondary analysis was undertaken on anonymised data obtained from the National Perinatal Epidemiology Centre, pertaining to perinatal deaths from January 2011 to December 2016 in Ireland. A national cross-sectional telephone survey was undertaken to assess the public knowledge on FFA. For these quantitative studies, descriptive and inferential statistics were utilised to analyse data. A critical discourse analysis was undertaken to examine the relations between discourse and social and cultural phenomena. Habermasian’s framework facilitated an objective analysis of text in the Irish media, to facilitate interpretation and understanding of socially produced meanings. A modified Delphi study, involving two rounds and inclusive of free text, was undertaken to identify educational needs of Volunteers. Lastly, for two of the qualitative studies an interpretive descriptive approach facilitated the researcher to delve into Volunteers’ and FMS experiences of supporting and caring for parents who receive a diagnosis of a FFA at a time where TOP for FFA is being provided for, for the first time. This inductive approach represents a co-constructed truth, it moves beyond the level of description of the phenomenon and articulates a meaning of and explanation for these experiences, generating implications for practice and application of these. Both of these studies adopted a data analysis methodology based on the principles of thematic analysis. Results: A lack of accurate knowledge relating to FFA, its classification, diagnosis and supports available to parents experiencing a pregnancy affected by a FFA among the general public was illustrated within this thesis. Additionally, the data identified misrepresentations in the information relating to FFA delivered to the general public. Outlined by these findings, opportunistic politicians were found to utilise the media to highlight their party’s ideological perspective regarding FFA, to derive political advantage to gain popularity and power. This thesis identified that the uncertainty of what conditions were deemed fatal in accordance with the legislation was related to the ambiguity and restrictiveness of the Irish TOP legislation as long-term survivors are known to many of the conditions considered a FFA. The lack of a universal agreement of what constitutes as a FFA and a list of conditions that are associated with this term, adds additional challenges to diagnosing a congenital anomaly as fatal. On examination of perinatal deaths with a congenital anomaly as a main cause of death, reported between 2011 and 2016, only 42% could be deemed a FFA in accordance with the criteria implemented by the Irish legislation. Many of the conditions in isolation may not be a FFA however, when combined they have the potential to be fatal. The suitability of the Irish legislation for TOP for FFA generated further difficulties for FMS due to its rapid introduction into clinical practice. FMS reported the lack of organisational support, time to prepare and additional resources as challenges for the introduction of a new service. These challenges were exacerbated by FMS fear of criminalisation attached to the TOP legislation if a TOP was carried out for a condition not deemed to be fatal and the subsequent media scrutiny. The data from these studies also revealed the importance of education and keeping up to date in order to deliver the best evidence based peer support and healthcare. The need for information specific to TOP for FFA provision in the Republic of Ireland was highlighted. Both Volunteers and FMS emphasised the importance of collaborative working (Volunteers requiring the support of healthcare professionals and FMS requiring the support of their colleagues) to meet the needs of parents following a FFA diagnosis while also acknowledging the importance of teamwork in supporting them in their peer support or clinical role. Organisational and collegial support is essential to sustain the delivery of peer-to-peer support for Volunteers and to reduce the feeling of isolation and judgement for FMS providing TOP for FFA. Thus, assisting both Volunteers and FMS in their own self-care while working in an emotive environment involving pregnancy loss and perinatal death. Conclusion: These data suggest there is a need for better knowledge of FFA, particularly regarding the complexity relating to the presentation of infants with a fetal anomaly that leads to them being fatal. These studies acknowledge the need for a universal term and definition that represents fetuses/infants with conditions that cause perinatal death to ensure a standard of care for women and their partners following a FFA diagnosis. It promotes the need for a universal database designed to collect essential epidemiologic information on congenital anomalies within the Republic of Ireland to support the labelling of a condition as a FFA. Additionally, the importance of education and the need to provide support and care to parents following FFA that reflects best practice and responds to their needs. FMS providing TOP for FFA services require organisational and collegial support to effectively deliver this new service. Furthermore, this thesis promotes the need to support both Volunteers and healthcare professionals involved in the delivery of care for parents following a FFA diagnosis through a collaborative approach, one that values and respects all members. The findings of these data outline several recommendations for the Irish TOP legislation, healthcare policy and clinical practice. It argues the need to reform the TOP legislation by removing the retained criminalisation, amending Section 11 and remove the restrictive 28 days. Furthermore, it is recommended that the Act refers to clinical practice guidelines informed by FMS and those healthcare professionals working within the abortion services. Finally, it identifies areas that warrant further research, such as the exploration of parents’ experiences of care and support received following a FFA diagnosis, to inform future intervention and improve care delivered to parents following a FFA diagnosis.