INFANT Research Centre - Doctoral Theses

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    Multi-modal assessment of newborns at risk of neonatal hypoxic ischaemic encephalopathy – the MONItOr study
    (University College Cork, 2022) Garvey, Aisling A.; Dempsey, Eugene M.; Murray, Deirdre M.; Boylan, Geraldine B.; National Children’s Research Centre, Crumlin, Ireland
    Background: Hypoxic ischaemic encephalopathy (HIE) is the leading cause of acquired brain injury in term infants. At present, therapeutic hypothermia (TH) is the only approved therapy for infants with moderate-severe HIE. However, it must be commenced before 6 hours of age resulting in a clinical challenge to resuscitate, stabilize, identify and stratify infants in this narrow timeframe. Furthermore, a significant proportion of infants with mild HIE will have neurodevelopmental impairment. Improved, timely identification of infants at risk of brain injury is required. The aim of this study was to improve our knowledge of the early physiology of infants with HIE by describing the evolution of electroencephalography (EEG), near-infrared spectroscopy (NIRS) and non-invasive cardiac output monitoring (NICOM) in infants with all grades of HIE and to determine whether these markers may be helpful in the identification of infants at risk of brain injury. Methods: This prospective observational study was set in a tertiary neonatal unit (November 2017-March 2020). Infants with all grades of HIE had multi-modal monitoring, including EEG, NIRS and NICOM, commenced after delivery and continued for up to 84 hours. All infants had an MRI performed in the first week of life. Healthy term controls were recruited after delivery and had NICOM monitoring at 6 and 24 hours of age. In this thesis, I also included infants recruited previously as part of four historic prospective cohorts that had early EEG monitoring. These infants were combined with infants with mild HIE from the current prospective cohort to examine the difference in EEG features between infants with mild HIE and healthy term controls. Results: Eighty-two infants were recruited in the prospective cohort (30 mild HIE, 25 moderate, 6 severe, 21 controls) and 60 infants were included from the historic cohorts. This study identified significant differences between EEG features of infants with mild HIE and controls in the first 6 hours after birth. Seventy-two percent of infants with mild HIE had some abnormal features on their continuous EEG and quantitative analysis revealed significant differences in spectral shape between the groups. In our cohort, cSO2 increased and FTOE decreased over the first 24 hours in all grades of HIE regardless of TH status. Compared to the moderate group, infants with mild HIE had significantly higher cSO2 at 6 hours (p=0.003), 9 hours (p=0.009) and 12 hours (p=0.032) and lower FTOE at 6 hours (p=0.016) and 9 hours (0.029). Beyond 18 hours, no differences were seen between the groups. NICOM was assessed in infants with HIE and compared with controls. Infants with mild HIE have a significantly higher heart rate at 6 hours of age compared with controls (p=0.034). Infants with moderate HIE undergoing TH have a significantly lower cardiac output compared with mild HIE (p=0.046) and control groups (p=0.040). Heart rate is significantly reduced (p<0.001) but stroke volume is maintained and gradually increases from 6-72 hours despite TH. Finally, we assessed the ability of EEG, NIRS and NICOM to predict short-term outcome (abnormal MRI +/- death in the first week of life). At 6 hours, none of the EEG, NIRS or NICOM measures predicted short-term outcome. At 12 hours of age, both qualitative and quantitative EEG features significantly predicted abnormal short-term outcome. Conclusion: Identification of infants at risk of brain injury immediately after birth is challenging. Objective, early biomarkers are required. This is the first study to combine EEG, NIRS and NICOM in infants with all grades of HIE. Multi-modal monitoring is feasible and this thesis provides novel insights into the underlying physiology and evolution of injury in infants with HIE. Furthermore, it reaffirms the importance of early continuous EEG in HIE.
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    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 Arabia
    Background 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.
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    Attachment based early interventions: an examination of the impact on the attachment related behaviour of parents and caregivers
    (University College Cork, 2022-05) O'Byrne, Emma; Mccusker, Chris; Murray, Deirdre M.
    There were two research articles included in this thesis with two separate abstracts. Systematic Review: “Attachment and Biobehavioural Catch-Up” (ABC) is a 10 session home visiting programme, grounded in attachment theory. It aims to improve child emotion regulation, attachment and behavioural outcomes through changing caregivers’ attachment related behaviours. There is increasing evidence with respect to the efficacy of ABC, but the interventions direct effect on parent behaviour remains unclear. This review examined ABC’s association with parent behaviour (the putative mechanism of change). The PubMed, EMBASE, PyscINFO and SCOPUS databases were searched for relevant studies in August 2021, and again in April 2022. The eligibility criteria for included studies were (1) infants aged 0-27 months at time of the ABC intervention, (2) “at-risk” parents, (3) controlled trials published in peer-reviewed journals, and (4) measure of attachment related parent behaviour included. Eleven eligible studies were included, nine of which were rated as having good methodological quality. The findings showed ABC had a significant small to medium effect on a variety of attachment-related parent behaviours amongst parents’ with multiple psychosocial risk factors. “Sensitivity” was measured most frequently, with small to medium main effect sizes recorded at follow-up compared to controls. Implications for the clinical effectiveness of the ABC programme in community settings are discussed. Future research should clarify whom ABC is most effective for, and how it compares to similar attachment based interventions. Major Research Project: Infant massage has been shown to positively influence maternal wellbeing and the mother-child attachment in clinical samples and up to a 1 year follow-up period. The present study examined, in a longitudinal randomised controlled trial (RCT), whether such benefits may be accrued in non-clinical, community samples and across a 4 year period. Participants were recruited from a maternity hospital in Ireland. They were mostly educated to third level (93%), in employment (88%) and identified as Irish (88%). At baseline participants were randomised to an infant massage or control condition (N=269). Qualitatively mothers from the intervention group recalled their experience of infant massage from almost 4 years earlier in surprising detail. Four main themes emerged describing the infant massage experience as a positive opportunity for bonding and relaxing with a newborn. Quantitative data pertaining to maternal wellbeing and dyads attachment were collected at baseline, 4-months, 18-months and 48-months post-intervention. Overall, analyses showed no significant difference between groups with respect to maternal mental health or parent-child relationship factors at 4, 18 or 48-months. We concluded that, in a non-clinical sample, infant massage is (a) subjectively experienced in a positive way with personal and infant relationship benefits, yet (b) this did not translate into objective benefits on clinical scales related to maternal or relational outcomes in the short or long-term. Clinical implications and suggestions for research adaptations in this area are outlined.
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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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    Adverse pregnancy outcomes and the long-term risk of maternal kidney disease
    (University College Cork, 2021-01-06) Barrett, Peter M.; Khashan, Ali; McCarthy, Fergus; Kublickiene, Karolina; Wellcome Trust; Health Research Board
    Background: Adverse pregnancy outcomes, including hypertensive disorders of pregnancy (HDP), preterm delivery, foetal growth restriction, gestational diabetes (GDM), and pregnancy loss, have been associated with the risk of maternal chronic disease, particularly cardiovascular disease. Less is known about the long-term risk of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in women who have experienced pregnancy complications. This thesis aims to examine associations between adverse pregnancy outcomes and the risk of maternal CKD and ESKD in later life. Structure and methods: This thesis begins with an introductory chapter (Chapter 1) followed by a systematic review and meta-analysis of the published literature, based on a pre-specified protocol (Chapter 2). A detailed methods chapter outlines the data sources, study design, exposure and outcome variables, and statistical approach used in each of the original observational studies conducted for this research (Chapter 3). Four population-based cohort studies are presented, and they focus on the risk of maternal kidney disease following preterm delivery (Chapter 4), stillbirth (Chapter 5), HDP (preeclampsia and gestational hypertension) (Chapter 6) and GDM (Chapter 7) respectively. In each study, data from the Swedish national registers are used, and analyses are based on Cox proportional hazard regression models with time-dependent covariates, adjusted for a wide range of medical, obstetric, and socio-demographic factors. In Chapter 8, an updated systematic review and meta-analysis is presented to reflect newly published literature on this topic. This is followed by a discussion and interpretation of the key findings, including consideration of the public health implications arising from this work (Chapter 9). Finally, conclusions of the thesis are presented in Chapter 10. Results: (i) Updated systematic review and meta-analysis - Overall, the published literature on this topic was sparse and most meta-analyses were based on small numbers (<5) of original studies. HDP and preterm delivery were associated with higher risk of long-term kidney disease in parous women. Preeclampsia was associated with a strongly increased risk of ESKD (adjusted risk ratio (aRR) 4.90; 95% CI, 3.56-6.74) and a modest increased risk of CKD (aRR 1.73, 95% CI 1.42-2.12). Gestational hypertension was associated with a strongly increased risk of ESKD (aRR, 3.64, 95% CI, 2.34-5.66), and more modest increased risk of CKD (aRR 1.48, 95% CI 1.38-1.58). Preterm delivery was associated with an increased risk of ESKD (aRR 2.19, 95% CI 1.93-2.47), but there were too few studies to determine the risk of CKD, or to separate the effects of iatrogenic vs. spontaneous preterm deliveries. No significant association was observed between GDM and CKD (aRR 1.04, 95% CI 0.76-1.41), but this meta-analysis was based on pooled estimates from just two studies. (ii) Original population-based cohort studies - Preterm delivery was associated with increased risk of both CKD and ESKD in our study. This association was strongest in women who experienced iatrogenic preterm delivery (due to preeclampsia or small for gestational age (SGA)), but the risk persisted in women who only had spontaneous preterm deliveries compared to women who delivered at term (for CKD, aHR 1.32, 95% CI 1.25-1.39; for ESKD, aHR 1.99, 95% CI 1.67-2.38). Separately, stillbirth was alsoassociated with an increased risk of both CKD (aHR 1.26, 95% CI 1.09–1.45) and ESKD (aHR 2.25, 95% CI 1.55-3.25) compared to women who only experienced live births. These associations persisted independent of preeclampsia, SGA or congenital malformations. Preeclampsia was associated with a higher risk of CKD during follow-up (vs. no preeclampsia, aHR 1.92, 95% CI 1.83–2.03), but this risk differed by CKD subtype and was greater for hypertensive CKD, diabetic CKD, and glomerular/proteinuric CKD. Women who experienced preterm preeclampsia, recurrent preeclampsia, or preeclampsia complicated by antenatal obesity were at particularly high risk of CKD. There was also a modest risk of CKD among women who experienced gestational hypertension (vs. none, aHR 1.49, 95% CI 1.38–1.61). GDM-diagnosed women were at increased risk of CKD and ESKD overall. However, when GDM was stratified according to those who developed post-pregnancy type 2 diabetes (T2DM), the associations between GDM alone (without later T2DM) and maternal kidney disease were non-significant (for CKD, 1.11, 95% CI 0.89-1.38; for ESKD, aHR 1.58, 95% CI 0.70-3.60). By contrast, strong associations were observed with CKD and ESKD in those who had GDM followed by subsequent T2DM. Conclusion: Adverse pregnancy outcomes, specifically preeclampsia, gestational hypertension, preterm delivery and stillbirth, are associated with increased risk of maternal CKD and ESKD. These associations persisted in a nationwide cohort after controlling for a wide range of confounders. Although the relative risk of future kidney disease is highest for ESKD, associations with CKD are likely to be of greater importance from a population perspective, given the high prevalence of CKD. Women who experience adverse pregnancy outcomes may warrant systematic follow-up to prevent onset or progression of future kidney disease, but the optimal format and timing of this follow-up requires further research.