Obstetrics & Gynaecology - Doctoral Theses

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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.
Caesarean section and subsequent pregnancy outcome: a Danish register-based cohort study
(University College Cork, 2014) O'Neill, Sinéad M.; Agerbo, Esben; Kenny, Louise C.; Greene, Richard A.; Kearney, Patricia M.; Khashan, Ali S.; National Perinatal Epidemiology Centre, College of Medicine and Health, University College Cork; Health Research Board
Background and Aims: Caesarean section rates have increased in recent decades and the effects on subsequent pregnancy outcome are largely unknown. Prior research has hypothesised that Caesarean section delivery may lead to an increased risk of subsequent stillbirth, miscarriage, ectopic pregnancy and sub-fertility. Structure and Methods: Papers 1-3 are systematic reviews with meta-analyses. Papers 4-6 are findings from this thesis on the rate of subsequent stillbirth, miscarriage, ectopic pregnancy and live birth by mode of delivery. Results Systematic reviews and meta-analyses: A 23% increased odds of subsequent stillbirth; no increase in odds of subsequent ectopic pregnancy and a 10% reduction in the odds of subsequent live birth among women with a previous Caesarean section were found in the various meta-analyses. Danish cohorts: Results from the Danish Civil Registration System (CRS) cohort revealed a small increased rate of subsequent stillbirth and ectopic pregnancy among women with a primary Caesarean section, which remained in the analyses by type of Caesarean. No increased rate of miscarriage was found among women with a primary Caesarean section. In the CRS data, women with a primary Caesarean section had a significantly reduced rate of subsequent live birth particularly among women with primary elective and maternal-requested Caesarean sections. In the Aarhus Birth Cohort, overall the effect of mode of delivery on the rate and time to next live birth was minimal. Conclusions: Primary Caesarean section was associated with a small increased rate of stillbirth and ectopic pregnancy, which may be in part due to underlying medical conditions. No increased rate of miscarriage was found. A reduced rate of subsequent live birth was found among Caesarean section in the CRS data. In the smaller ABC cohort, a small reduction in rate of subsequent live birth was found among women with a primary Caesarean section and is most likely due to maternal choice rather than any ill effects of the Caesarean. The findings of this study, the largest and most comprehensive to date will be of significant interest to health care providers and women globally.
Caesarean section delivery and childhood obesity
(University College Cork, 2020-07-17) Masukume, Gwinyai; Khashan, Ali; McCarthy, Fergus; Kenny, Louise C.; O’Neill, Sinéad M.; Baker, Philip N.; Morton, Susan M.B.; Science Foundation Ireland
Background and aims: Caesarean section (CS) birth, in particular elective/planned CS, has been found to be associated with an increased risk of childhood obesity. Various mechanisms that differ by birth mode, including differences in the vaginal and faecal microflora and stress hormone concentration have been suggested to underpin this association. The literature describing this association, often derived from non-nationally representative cohorts has been inconsistent, limited by small sample size, often unable to distinguish between elective and emergency CS, have publication bias favouring positive effects and often unable to adjust for key confounders like maternal pre-pregnancy body mass index (BMI). Given the rising global use of CS with some countries having CS rates above 50%, the aim of this thesis was to critically evaluate the association between CS birth and childhood obesity and to use three large contemporary nationally representative prospective longitudinal cohort studies and one smaller cohort, with detailed phenotypic data, to investigate this association. Structure and methods: The existing published literature relating to CS birth and childhood obesity was critically evaluated and synthesised to identify major conceptual themes and research gaps (Chapter 1). Chapter 2 details and justifies the thesis’ methodological approach. The following four longitudinal birth cohort studies were utilised: Screening for Pregnancy Endpoints (SCOPE) and Babies After SCOPE: Evaluating the Longitudinal Impact on Neurological and Nutritional Endpoints (BASELINE); Growing Up in Ireland (GUI); Growing Up in New Zealand (GUiNZ) and the Millennium Cohort Study (MCS) cohorts. In order to facilitate comparison between different cohorts (Chapters 3 through to 7), children were classified, on the basis of their BMI, as obese, overweight, normal or underweight according to the sex and age specific International Obesity Task Force criteria. A range of statistical analytic approaches including linear, multinomial and mixed-effects regression were employed. Multiple imputation was used to handle substantial missing data. In addition to our primary outcome BMI, which was modeled as continuous or categorical variable, the association between our exposure CS birth and BF% was investigated in cohorts that had this data available. Where the sample size permitted, the association between CS birth and transition into or out of obesity was examined. The overall results in the context of the published literature were discussed including limitations and strengths and future research directions (Chapter 7). Results: SCOPE-BASELINE cohorts: At two months of age, children born by CS, had a similar BF% to those born vaginally. At age six months, children born by CS had a significantly higher BMI, adjusted mean difference=0.24; 95% confidence interval (CI) 0.06 to 0.41, but this did not persist into future childhood, at age five years. There was no evidence to support an association between mode of delivery and long-term risk of obesity in the child. GUI cohort: We found insufficient evidence to support a relationship between elective CS and childhood obesity at age three and five years. An increased risk of obesity in children born by emergency CS, adjusted relative risk ratio (aRRR) = 1.56; [95% CI 1.20 to 2.03], but not elective, suggests that the influence of vaginal microflora in developing childhood obesity was minimal. The association with emergency CS was likely due to its indications. GUiNZ cohort: Planned CS was an independent predictor of obesity in early childhood at age two years aRRR=1.59; [95% CI 1.09 to 2.33] but this association was not apparent by four and a half years This suggests that birth mode is associated with early growth, at least in the short term. This association occurred during a critical phase of human development, the first two years of life. Given the developmental origins of health and disease hypothesis this may lead to long-term detrimental cardiometabolic changes. MCS cohort: Infants born by planned CS did not have a significantly higher BMI at ages three, five, seven, eleven and fourteen years adjusted mean difference=0.00; [95% CI -0.10 to 0.10], or BF% at ages seven 0.13; [95% CI -0.23; 0.49] and fourteen compared to those born by normal VD. This may suggest that the association, described in the literature, could be due to the indications/reasons for CS birth or residual confounding. Conclusions: The hallmark finding of the thesis was an association between CS birth in general, elective CS in particular, and childhood obesity during the first two years of life. This association had dissipated by age three through to fourteen. Whether this association remerges in adulthood or is a risk factor for cardiometabolic disease is an area for future research. The association observed with emergency CS is possibly due to confounding by the underlying reasons for CS, confounding by indication. There is potential to improve consistency and robustness in this research field by better and standardised definition particularly of the exposure, CS birth. Better consistency in the timing of obesity assessment is also warranted.
Causes and consequences of pregnancy loss and perinatal death
(University College Cork, 2016) Meaney, Sarah; O'Donoghue, Keelin; Corcoran, Paul
There have been major advances in reproductive medicine, however there is still a considerable risk that a woman may experience pregnancy loss and/or perinatal death. It is acknowledged that pregnancy loss and perinatal death are traumatic events further emphasising the need for empathetic supportive care. However, there is still a dearth of research identifying not only the most appropriate bereavement care but also how best to support parents in subsequent pregnancies. The data from these studies revealed that the experiences of the bereaved parents were distinctly different depending on whether they experienced miscarriage, an ectopic pregnancy or perinatal death. These data further illustrated the profound impact that pregnancy loss and/or perinatal death has on both women and men, their relationships with each other as well as with their family and friends. Findings also indicate how the hospital environment can have a negative impact on parents when experiencing pregnancy loss and/or perinatal death. Parents emphasised the importance of dedicated clinics and wards within the hospital. These dedicated spaces give parents and couples privacy and dignity at the time of their loss. Pregnancy loss is often referred to as an ‘invisible loss’ as often the event may not publicly acknowledged. These data further illustrate the isolating effect of pregnancy loss as parents felt they could not discuss their pregnancy loss and/or perinatal death as it may create socially awkward situations. The qualitative data also indicated there is considerable misperception and misunderstanding in relation to pregnancy loss and perinatal death, which was not only evidenced in the individual interviews but also throughout social media. How society understands and responds to pregnancy loss and perinatal death can be influential on an individual’s experience. These data suggest there is a need for a better understanding of pregnancy loss and perinatal death throughout society.
The challenges facing recruitment and retention of doctors in obstetrics and gynaecology in Ireland
(University College Cork, 2020-09) O'Sullivan, Suzanne; Horgan, Mary (Medicine); Bennett, Deirdre
Obstetrics and gynaecology is a medical specialty which includes all aspects of sexual and reproductive health across the life course of a female. It is traditionally perceived as a “lifestyle unfriendly” specialty, and future specialist shortages have been identified internationally. Irish maternity services have low consultant numbers, understaffed units, predominantly female trainees and have been exposed to high levels of litigation and intense media scrutiny for years. Using a combination of quantitative and qualitative research, this thesis presents a detailed exploration of attitudes to and experience of obstetrics and gynaecology as a career from the perspectives of the following groups: 1. Medical students from an Irish medical school (University College Cork), 2. Current specialists in training across all levels of experience, and 3. Consultant obstetrician gynaecologists. The quantitative research involved detailed surveys of all penultimate year medical students in UCC (n=134, response rate 68.7%) and trainees in obstetrics and gynaecology (n=124, response rate 70.8%). The qualitative research involved semistructured interviews using deductive thematic analysis, of 17 consultant obstetrician gynaecologists from different ages, genders and geographical locations across the country. For medical students, factors that increased the attraction to the specialty were continuity of care (p= 0.002), delivering babies (p=0.004), female patients only (p=0.026), limited focus of disease (p=0.01), intellectual content (p=0.001), combination of obstetrics and gynaecology (p=0.014), predominance of female practitioners (p=0.002), career opportunities and interaction with consultants (p=0.016). Protection from litigation was deemed by 85% of students to moderately or strongly increase the appeal to the specialty. When trainees were asked how much they enjoyed working in the specialty on a scale of 1 to 10 with 1 representing no enjoyment at all and 10 representing immense enjoyment, 85.3% responded with a value of 7 or higher. When asked if they would recommend a career in obstetrics and gynaecology to their family member or child, only 3% strongly agreed. 86.7% of trainees felt that the media did not have a positive impact on patients and 94.1% felt that the media representation of obstetrics and gynaecology was fair and balanced. 82.3% felt that the media negatively influenced patients’ attitudes to doctors. 37.1% of trainees have been involved in a medico-legal case and 79.5% state that the medico-legal climate has a moderately or strongly negative impact on recruitment and retention, while 84.2% feel it has a moderately or strongly negative impact on patients. In terms of future workforce planning, female trainees are significantly more likely to consider job-sharing (p=0.006) and are less likely to do private practice in obstetrics and gynaecology (p=0.002). 50.4% of all trainees plan to take parental leave and 33.9% plan on taking a sabbatical. The qualitative part of the study reflected themes of gender imbalance, reduced experience of new consultants due to EWTD, increased patient demand and unrealistic expectation, harm due to negative media coverage and the litigation culture, new entrant consultant pay disparity and lack of advocacy for doctors from professional bodies and the Health Service Executive. Solutions to the problems raised included restoration of pay parity, increased consultant numbers, improved advocacy, formal mentorship, and tackling negative media coverage and the litigation culture. Robust workforce planning, flexibility in training and consultant posts, diversification of the specialty to include community gynaecology and interdisciplinary spread of clinical care were also recommended. The voice of the current and future physician was at the centre of this work and the opinions and perceptions of these doctors is what I wish to address in this thesis. Their knowledge of the particular problems facing obstetrics and gynaecology in terms of clinical need and medical recruitment is unparalleled. Policymakers would do well to partner with the professional and training bodies to ensure, practical, economical and evidence-based solutions to the problems facing recruitment and retention in maternity services.
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.
An exploration of miscarriage in the Republic of Ireland: incidence, management, risk factors, interventions, and populations’ knowledge
(University College Cork, 2019-08) San Lázaro Campillo, Indra; O'Donoghue, Keelin; Meaney, Sarah
Background: Miscarriage is one of the most common complications in early pregnancy. It is estimated that approximately one out of five women will have a miscarriage throughout their reproductive lives. Despite the high prevalence of miscarriage and the biopsychological burden associated with experiencing miscarriage, there are several gaps in the literature. For example, there is a lack of standardisation of definitions and types of miscarriage worldwide. This high heterogeneity in cut-offs for defining miscarriage is limiting international comparisons of the evidence available. This is distorting the recording of data related to miscarriage in national and international health databases. Furthermore, little is known about the trends of hospital admissions for miscarriage and the non-fatal complications associated with it. In fact, there is no sufficient evidence of the validity of diagnosis of miscarriage in routinely collected health databases. In addition, although approximately 50% of miscarriages are linked to chromosomal abnormalities, the underlying causes of miscarriage are still unclear for the remainer. Therefore, it is imperative to understand and identify causes and risk factors of unexplained miscarriage in order to develop effective treatments and promote healthy behaviours among the population. The most well-established risk factors for miscarriage are advanced maternal age, previous pregnancy loss and parity. However, there is a need to identify risk factors in order to be able to prevent the likelihood of experiencing miscarriage. It is accepted that women who experience miscarriage suffer from psychological morbidity after the loss and in subsequent pregnancies. Nevertheless, further research is needed in order to obtain robust evidence on what specific group of women are more susceptible to develop psychological morbidity after miscarriage, what are the psychological and emotional changes during pregnancy after a miscarriage, and what are the effective non-pharmacological interventions to improve psychological wellbeing as well as future pregnancy outcome. Outline and aims: In this thesis, I explored several dimensions surrounding the event of miscarriage. To do that, I firstly reviewed the published evidence to date about miscarriage in order to find gaps in the literature. This thesis encompassed a total of six research studies to contribute to the existing body of knowledge about miscarriage. The main objective of the first study was to determine national trends in incidence and management of inpatient admissions for early miscarriage in the Republic of Ireland. After this study, it was essential to validate the diagnosis of miscarriage in the national health system used to obtain these trends. Consequently, the aim of the second study was to compare agreement for the diagnosis of miscarriage between three types of routinely collected hospital-based health records. This thesis includes three research studies that explored several gaps in the literature about pregnant women with a history of miscarriage. The first study explored the risk factors associated with miscarriage among women attending an early pregnancy assessment unit (EPAU). The second study aimed to determine barriers and facilitators when designing large-scale longitudinal studies; and the third study was a systematic review, which aimed to identify randomised controlled trials that assessed the effect of interventions to reduce stress, anxiety and depression in pregnant women with a history of miscarriage. Finally, this thesis includes a cross-sectional study that was designed to assess university student’s knowledge of basic reproductive health information about miscarriage. Findings and clinical implications: This thesis provides additional evidence to the growing body of work focusing on miscarriage. This thesis highlights the need for unifying inpatient and outpatient data in order to estimate the total burden of miscarriage at a national level. Furthermore, it is crucial to standardise the diagnosis of the type of miscarriage at a national level. The results presented in this thesis also emphasise the misunderstanding of causes, signs and symptoms of miscarriage, which shows it is essential to inform the public about miscarriage in general, as well as its treatments and the scientific evidence available to date. In addition, reproductive health information about miscarriage should be disseminated to a younger stratum of the population, who are at early stages in their reproductive life. Indeed, this would enable better informed decision-making about their reproductive behaviour and lifestyle by helping them to be aware of risk factors for miscarriage, identifying signs and symptoms of miscarriage and learning what to expect when experiencing a miscarriage. Moreover, providing reproductive health information about miscarriage will help the population to be aware of when and where seek for help. In this thesis, I suggest University settings as the ideal scenario to reach and promote reproductive health information about miscarriage in this targeted group. Efforts to satisfy the population’s needs on reproductive health and pregnancy loss should be made by healthcare professionals and researchers, and should also include public health advocates and policymakers. As a result of the findings from this thesis, I suggest further research in the area of miscarriage, and I outline a number of recommendations in relation to clinical practice and public policy. It is essential to obtain robust evidence on the association of poor mental health and adverse pregnancy outcomes that may lead to targeted interventions for women who are at higher risk of developing stress or mental disorder before, during and after pregnancy. The need for targeted interventions to reduce stress and increase mental wellbeing among pregnant women with a history of miscarriage is also warranted. An effort should be made to design and implement high quality, appropriately powered, RCTs that can provide reliable and non-biased evidence on preventable risk factors and effective psychological and behavioural interventions that may improve outcomes in future pregnancies. To achieve this goal, research funders need to acknowledge the burden of miscarriage at national and international level and support well-designed and large-scale RCTs. Funding RCTs in this area will lead to increase the understanding of potential interventions that might improve women´s psychological wellbeing after pregnancy loss.
Exploring the role of mitochondrial dysfunction in the pathophysiology of pre-eclampsia
(Elsevier B.V., 2018-06-18) Williamson, Rachel D.; McCarthy, Fergus P.; Khashan, Ali S.; Totorika, Ainhoa; Kenny, Louise C.; McCarthy, Cathal
The impact of first pregnancy and delivery on pelvic floor dysfunction
(University College Cork, 2014) Durnea, Constantin M.; Khashan, Ali; O'Reilly, Barry A.; Kenny, Louise C.; Health Research Board; Science Foundation Ireland; Continence Foundation Ireland
Background: The first childbirth has the greatest impact on a woman’s pelvic floor when major changes occur. The aim of this study was to comprehensively describe pelvic floor dysfunction (PFD) in young nulliparous women, and its correlation with postnatal pathology. Methods: A prospective study was performed at Cork University Maternity Hospital, Ireland. Initially 1484 nulliparous women completed the validated Australian Pelvic Floor Questionnaire at 15 weeks’ gestation and repeatedly at one year postnatally (N=872). In the second phase, at least one year postnatally, 202 participants without subsequent pregnancies attended the clinical follow up which included: pelvic organ prolapse quantification, a 3D-Transperineal ultrasound scan and collagen level assessment. Results: A high pre-pregnancy prevalence of various types of PFD was detected, which in the majority of cases persisted postnatally and included multiple types of PFD. The first birth had a negative impact on severity of pre-pregnancy symptoms in <15% of cases. Apart from prolapse, vaginal delivery, including instrumental delivery did not increase the risk of PFD symptoms, where as Caesarean section was protective for all types of PFD. The first birth had a bigger impact on pre-existing symptoms of overactive bladder compared to stress urinary incontinence. Pelvic organ prolapse is extremely prevalent in young primiparous women, however usually it is low grade and asymptomatic. Congenital factors and high collagen type III levels play an important role in the aetiology of pelvic organs prolapse. Levator ani trauma is present in one in three women after the first pregnancy and delivery. Conclusion: The main damage to the pelvic floor most likely occurs due to an undiagnosed congenital intrinsic weakness of the pelvic floor structures. PFD is highly associated with first childbirth, however it seems that pregnancy and delivery are contributing factors only which unmask the congenital intrinsic weakness of the pelvic floor support.
The impact of intrapartum fetal death and other serious adverse perinatal events on healthcare professionals and the maternity services
(University College Cork, 2019) McNamara, Karen; O'Donoghue, Keelin; Greene, Richard A.
Obstetrics and midwifery are high risk specialties. Sometimes and even despite the provision of the best medical care possible, serious adverse events do occur. While patients and service users of the Irish maternity services bear the bulk of the burden of harm from these adverse events, the healthcare staff who are also involved in these cases can be substantially affected. Stillbirth, which encompasses both antenatal and intrapartum death, is one of the more serious adverse events or outcomes that can happen during a pregnancy. Existing research focuses largely on the impact that antenatal stillbirth has on obstetricians and midwives, with no research focusing specifically on the impact that intrapartum fetal death has on maternity service healthcare professionals. Much is also now known and acknowledged about the increasing levels of burnout and compassion fatigue that are affecting healthcare professionals. In fact, it has been recognised that healthcare professionals are more likely to experience burnout than the general workforce and it is now estimated that burnout affects 1 in 2 doctors. Healthcare professionals in the maternity services are not exempt from these issues. What is apparent, however, is that relative to the literature pertaining to the general medical specialties, there is a clear paucity of research investigating the effectiveness of available support strategies for maternity healthcare professionals to access either in the aftermath of an adverse event or to help them tackle burnout in the longer term. This thesis focuses on the specific impact that intrapartum death, and other serious perinatal adverse events have on healthcare professionals. I have utilised both quantitative and qualitative research methods to describe in detail the scale of the impact, both personally and professionally, that these events have on the involved healthcare professionals. Obstetricians and midwives are profoundly and negatively affected by a personal involvement in an intrapartum death. Following a review of the existing literature, I identified a substantial lack of effective support strategies for maternity healthcare professionals to access to help them with the impact of adverse events. This finding was echoed by my research with the cohort of obstetricians and midwives who participated in my studies. By and large they had received no training in dealing with intrapartum death nor had they received any education on self-care strategies. This thesis concludes with two studies, aimed at addressing this deficit and these studies are an evaluation of both local and national support strategies for maternity healthcare professionals to potentially utilise on an ongoing basis. Finally, I discuss the implications that my research has on clinical practice, and I discuss the possibilities for future research that may potentially improve the support that maternity healthcare professionals are given in the aftermath of these adverse events.
An international study of fear of childbirth and tocophobia with application in an Irish maternity setting
(University College Cork, 2019) O'Connell, Maeve A.; Khashan, Ali; Leahy-Warren, Patricia; O'Neill, Sinead; Kenny, Louise C.; Science Foundation Ireland; Health Research Board
It is normal for women to face childbirth with a degree of apprehension. Women can experience levels of fear from low to severe, phobic fear termed tocophobia. Tocophobia is a severe fear of childbirth which is debilitating for women during pregnancy and can impact their health and well-being. Most women with tocophobia request a Caesarean Section (CS) since they have a phobia of vaginal birth. The last three decades have seen an increased emphasis on fear of childbirth as an important women’s health issue both in research and clinical practice. However, to date, there has been little agreement on the concept and definition of what tocophobia is, how best to measure fear of childbirth and consequently, prevalence. Moreover, there is a dearth of research in relation to fear of childbirth in Ireland; with the majority of research performed in Scandinavia. Various interventions have been trialled, but there is little information about how women experienced the interventions and how the intervention could be improved. Thus, the objective of the present thesis is to provide an in-depth investigation of this (relatively new) research phenomenon and to add to what is known about interventions which have been trialled.
Monitoring behaviours and experiences before, during and after pregnancy in Ireland
(University College Cork, 2014) O'Keeffe, Linda M.; Kearney, Patricia M.; Greene, Richard A.; Health Research Board
Background: On-going surveillance of behaviours during pregnancy is an important but overlooked population health activity that is particularly lacking in Ireland. Few, if any, nationally representative estimates of most maternal behaviours and experiences are available. While on-going surveillance of maternal behaviours has not been a priority thus far in European countries including Ireland, on-going surveillance was identified as a key priority in the United States (US) during the 1980’s when the Pregnancy Risk Assessment Monitoring System (PRAMS), was established. Today, PRAMS is the only surveillance programme of maternal behaviours and experiences world-wide. Although on-going prevalence estimates are required in Ireland, studies which examine the offspring health effects of maternal behaviours are also required, since various questions regarding maternal exposures and their offspring health effects remain unanswered. Gestational alcohol consumption is one such important maternal exposure which is common in pregnancy, though its offspring health effects are unclear, particularly at lower or moderate levels. Thus, guidelines internationally have not reached consensus on safe alcohol recommendations for pregnant women. The aims of this thesis are to implement the PRAMS in Ireland (PRAMS Ireland), to describe the prevalence of health behaviours around the time of pregnancy in Ireland and to examine the effect of health behaviours on pregnancy and child outcomes (specifically the relationship between alcohol use during pregnancy and infant and child growth). Structure: In Chapter 1, a brief background and rationale for the work, as well as the thesis aims and objective is provided. A detailed description of the design and implementation of PRAMS Ireland is described in Chapter 2. Chapter 3 and Chapter 4 describe the methodological results of the implementation of the PRAMS Ireland pilot study and PRAMS Ireland main study. In Chapter 5, a comparison of alcohol prevalence in two Irish studies (PRAMS Ireland and Growing up in Ireland (GUI)) and one multi-centre prospective cohort study, Screening for Pregnancy Endpoints (SCOPE) Study is detailed. Chapter 6 describes findings on adherence to National Clinical Guidelines on health behaviours and nutrition around the time of pregnancy in PRAMS Ireland. Findings on exposure to alcohol use in pregnancy and infant growth outcomes are described in Chapter 7 and Chapter 8. The results of analysis conducted to examine the impact of gestational alcohol use on offspring growth trajectories to age ten are described in Chapter 9. Finally, a discussion of the findings, strengths and limitations of the thesis, direction for future research, policy, practice and public health implications are discussed in Chapter 10.Results: Implementation of PRAMS: PRAMS may be an effective system for the surveillance of health behaviours around the time of pregnancy in the Irish context. PRAMS Ireland had high response rates (67% and 61% response rates in the pilot and main study respectively), high item completion rates and valid prevalence estimates for many health behaviours. Examining prevalence of health behaviours: We found high levels of alcohol consumption before and during pregnancy, poor adherence to healthy diets and high levels of smoking before and during pregnancy among women in Ireland. Socially disadvantaged women had higher rates of deleterious health behaviours before pregnancy, although women with the most deleterious behaviour profiles before pregnancy appeared to experience the greatest gain in protective health behaviours during pregnancy. The impact of alcohol use on infant and offspring growth: We found that low and moderate levels of alcohol use did not impact on birth outcomes or offspring growth whereas heavy alcohol consumption resulted in reduced birth length and birth weight; however, this finding was not consistently observed across all studies. Selection, reporting and confounding biases which are common in observational research could be masking harmful effects. Conclusion: PRAMS is a valid and feasible method of surveillance of health behaviours around the time of pregnancy in Ireland. A surveillance program of maternal behaviours and experiences is immediately warranted due to high levels of deleterious health behaviours around the time of pregnancy in Ireland. Although our results do not indicate any evidence of harm, given the quality of evidence available, abstinence and advice of abstinence from alcohol may be the most prudent choice for patients and healthcare professionals respectively. Further studies of the effects of gestational alcohol use are required; particularly those which can reduce selection bias, reporting bias and confounding.
Placental growth factor; potential for its use in twin pregnancy and evaluation of its benefit in singletons with suspected preterm pre-eclampsia
(University College Cork, 2020) Hayes-Ryan, Deirdre; O'Donoghue, Keelin; Kenny, Louise C.
Hypertensive Disorders of Pregnancy are common and may result in increased maternal and neonatal morbidity and mortality. Twin pregnancies confer an increased risk of development of a hypertensive disorder of pregnancy. Placental growth factor is an angiogenic protein highly expressed during pregnancy. The pro-angiogenic/anti-angiogenic synergism of PlGF and its receptors is critical for successful placentation in early pregnancy. Circulating maternal levels of placental growth factor correlate well with placental function. Women presenting with suspected pre-eclampsia are currently triaged based on hypertension and dipstick proteinuria. Numerous studies advocate a role for placental growth factor testing as a useful adjunct in the management of women presenting with preterm pre-eclampsia. Several automated immunoassay platforms to quantify placental growth factor are currently available. Comparative studies of these immunoassays are limited. Current reference values and clinical cut-offs for PlGF were constructed from singleton pregnancy cohorts. Given the larger placental volume present in a twin pregnancy, separate reference ranges are likely required. Pregnant women are seldom included in randomised controlled trials and their attitudes and experiences of this are not often investigated. Gathering feedback of their experience is paramount for future trial design to facilitate participation. In this thesis, I reviewed nine years of clinical data in twin pregnancies from a single maternity unit to understand the impact of hypertensive disorders on maternal and neonatal outcomes. I examined cross sectional values from uncomplicated twin pregnancies to assess the potential for using PlGF in this population. I compared the PlGF results obtained from an ELISA to an automated immunoassay, to determine if clinical cut-offs developed for one platform were transferrable to another. I conducted a national multi-site randomised control trial; PARROT Ireland, to evaluate the impact of incorporation of PlGF testing into routine clinical care. Lastly, through one on one interviews with trial participants, I investigated the barriers and facilitators to pregnant women taking part in clinical research. The data from these studies revealed that maternal age >40 years, nulliparity, conception through use of a donor oocyte, and presence of obstetric cholestasis are all important risk factors for the development of a hypertensive disorder in a twin pregnancy. The incidence of iatrogenic late prematurity and neonatal hypoglycaemia are increased when a hypertensive disorder complicates a twin pregnancy. PlGF levels in twin pregnancy differ significantly between those women with a pregnancy that will later be complicated by preeclampsia and those that will not. The difference is present many weeks before clinical signs or symptoms are present, indicating that PlGF has potential to aid diagnosis of pre-eclampsia in twin pregnancies. A dichorionic twin pregnancy specific reference range for PlGF has been developed, which may be utilised for further interventional research on PlGF in twins. The findings also indicate that PlGF biomarker levels vary significantly between different immunoassay platforms, highlighting the importance of developing validated clinical cut-offs for any automated immunoassay before they can be clinically applied. The result of the interim analysis from the PARROT Ireland trial is of no significant reduction in either maternal or neonatal morbidity with the integration of point of care PlGF based testing. These are interim results only however and the final results may differ. Should the final trial results demonstrate a positive impact on maternal morbidity, without a negative impact on neonatal morbidity, it would indicate that PlGF testing should be incorporated into routine clinical investigations for women presenting with suspected pre-eclampsia before 37 weeks’ gestation. The final study of the thesis highlights that pregnant women are interested and willing to participate in research. Identifying the correct timepoint and location to approach women, as well as the manner and language used to communicate with them, are key elements in ensuring their participation. The findings from this thesis, though supportive of the current literature in relation to the potential of PlGF, highlight that there is more research required.
Predicting successful outcome of singleton and multiple pregnancies after assisted reproductive technologies (ART)
(University College Cork, 2020) Geisler, Minna; O'Donoghue, Keelin; Waterstone, John
Pregnancies conceived through ART are increasing in prevalence in maternity units in Ireland. This is due in a large part to the increasing age of women attempting to conceive for the first time but also due to the increasing success of ART. This thesis explores pre-pregnancy characteristics that may aid in predicting pregnancy outcome in women undergoing IVF treatment. The thesis includes three studies. The first is a retrospective study of the pregnancy outcomes of singleton and twin pregnancies conceived from ART. The study found that ART conceived twins had similar perinatal outcomes to spontaneously conceived twins. Overall, singleton pregnancy outcomes were very favourable. Singleton pregnancies, when compared to twin pregnancies, were more likely to result in a livebirth, while twin pregnancies were significantly more likely to result in miscarriage, preterm delivery and/or neonatal unit admission. The second study is a prospective cohort study of 142 nulliparous women at the outset of their IVF cycle. A 3D ultrasound of the uterine volume was performed. Women completed a survey on lifestyle and demographics. None of the interrogated demographics or lifestyle factors demonstrated a significant impact on conception nor on pregnancy loss. Neither uterine length nor volume impacted on pregnancy rates or on preterm delivery rates. The final study details the findings of a survey-based study of 320 women recruited prior to IVF treatment and followed for outcome (negative/positive pregnancy test, first trimester miscarriage). The survey focused on psychological stressors. The findings suggest that stressors do not impact greatly on conception rates from ART. Job-related stress is associated with higher chance of miscarriage. In the absence of any robust predictors of successful, or indeed adverse, pregnancy outcome it is preferable to aim for single embryo transfer and a singleton pregnancy.
Prediction and prevention of venous thrombosis in pregnancy
(University College Cork, 2013) Ismail, Siti Khadijah; Higgins, John R.; Norris, Lucy; ANU Research Centre, College of Medicine and Health, University College Cork
Venous thromboembolism (VTE) remains the leading cause of maternal mortality. Reports identified further research is required in obese and women post caesarean section (CS). Risk factors for VTE during pregnancy are periodically absent indicating the need for a simple and effective screening tool for pregnancy. Perturbation of the uteroplacental haemostasis has been implicated in placenta mediated pregnancy complications. This thesis had 4 main aims: 1) To investigate anticoagulant effects following a fixed thromboprophylaxis dose in healthy women post elective CS. 2) To evaluate the calibrated automated thrombogram (CAT) assay as a potential predictive tool for thrombosis in pregnancy. 3) To compare the anticoagulant effects of fixed versus weight adjusted thromboprophylaxis dose in morbidly obese pregnant women. 4) To investigate the LMWH effects on human haemostatic gene and antigen expression in placentae and plasma from the uteroplacental , maternal and fetal circulation. Tissue factor pathway inhibitor (TFPI), thrombin antithrombin (TAT), CAT and anti-Xa levels were analysed. Real-time PCR and ELISA were used to quantify mRNA and protein expression of TFPI and TF in placental tissue. In women post CS, anti-Xa levels do not reflect the full anticoagulant effects of LMWH. LMWH thromboprophylaxis in this healthy cohort of patients appears to have a sustained effect in reducing excess thrombin production post elective CS. The results of this study suggest that predicting VTE in pregnant women using CAT assay is not possible at present time. The prothrombotic state in pregnant morbidly obese women was substantially attenuated by weight adjusted but not at fixed LMWH doses. LMWH may be effective in reducing in- vivo thrombin production in the uteroplacental circulation of thrombophilic women. All these results collectively suggest that at appropriate dosage, LMWH is effective in attenuating excess thrombin generation, in low risk pregnant women post caesarean section or moderate to high risk pregnant women who are morbidly obese or tested positive for thrombophilia. The results of the studies provided data to inform evidence-based practice to improve the outcome for pregnant women at risk of thrombosis.
Prenatal stress, the placenta and maternal microbial transmission; implications for health and disease
(University College Cork, 2018) Togher, Katie L.; Clarke, Gerard; Khashan, Ali; O'Keeffe, Gerard W.; Kenny, Louise C.; Science Foundation Ireland; University College Cork
There is an extensive amount of epidemiological evidence showing that prenatal maternal distress (PNMD) is a risk factor for a wide range of poor obstetric and neonatal outcomes, as well as an increased risk for the development of metabolic, immune and nervous system disorders in affected children later in life. Whilst many epidemiology studies have supported these associations, the biological mechanisms linking maternal prenatal distress with adverse outcomes remains understudied, particularly in human cohorts. One potential mechanism, known as the glucocorticoid hypothesis proposes that fetal overexposure to stress-induced maternal cortisol during critical windows of development increases the risk of adverse outcomes in the offspring. At the core of this hypothesis is the placenta, which expresses the enzyme 11beta hydroxysteroid dehydrogenase type 2 (HSD11B2), which ultimately controls the amount of cortisol a fetus is exposed to. Prenatal stress has been shown to reduce the placental expression of this enzyme; however the molecular mechanisms through which this occurs have not been well examined. More recently, the transmission of a suboptimal stressed maternal microbiota is emerging as an alternative mechanism that may mediate the impact of prenatal stress on infant development. However this has not yet been examined in a clinical population. We first utilized an in vitro placenta model, JEG-3 cells, to examine the effects of stress on the placental expression of HSD11B2. JEG-3 cells were cultured with exogenous cortisol and interleukin-1 beta (IL-1β), two potential biological mediators of prenatal stress. This study showed both cortisol and IL-1β can reduce HSD11B2 expression, an effect that could be prevented by co-treatment with a histone deacetylase inhibitor. Having established that cortisol can directly affect the expression of HSD11B2, we moved on to our first clinical study to examine this question in a clinical population by examining the impact of prenatal distress on placental gene expression and infant outcomes. A cohort of 121 pregnant women receiving antenatal care at Cork University Maternity Hospital (CUMH) completed the Perceived stressed scale (PSS), State Trait Anxiety Inventory (STAI) and Edinburgh Postnatal Depression Scale (EPDS) in late pregnancy and donated placental biopsies at the time of birth. This study identified a significant reduction in HSD11B2 mRNA along with an increase in the glucocorticoid receptor (NR3C1) in placentae from high distressed pregnancies. Additionally prenatal distress was associated with a number of adverse outcomes including delivering via Caesarean section, reduced Apgar scores and reduced birth temperature, supporting a role for placental glucocorticoid signalling in the relationship between prenatal distress and adverse outcomes. Having reported that stress impacts molecular placental signals and birth outcomes, we moved on to complete the SMArTI (Stressed Microbial Transfer to the Infant) study, a more detailed pregnancy cohort to examine the impact prenatal distress on the maternal and infant microbiome. This study yielded a final cohort off 111 nulliparous pregnant women that were recruited from the IMPROvED consortium at CUMH. Women enrolled in SMArTI completed distress questionnaires and provided saliva and fecal samples in the second and/or third trimester of pregnancy. Vaginal swabs, placenta samples and newborn hair were acquired at birth and infant fecal samples were subsequently collected across the first 5 months of life. We first used this cohort to further examine and validate the relationship between prenatal distress, placental glucocorticoid genes and infant outcomes. We found this relationship to be dependent on the timing of distress, type of distress and infant sex. Most notably we observed second trimester maternal anxiety correlated with reduced birthweight in female infants, a relationship mediated by placental FK506-bind protein 51 (FKBP51) mRNA expression. We finally used the SMArTI cohort to examine, for the first time, the impact of PNMD on the maternal and infant microbiome, using 16S rRNA gene sequencing. Reduced diversity of the maternal gut microbiome in the second trimester was associated with second trimester distress, most substantially with maternal depressive symptoms, an effect that was no longer apparent by the third trimester. The third trimester gut microbiome appeared relatively resistant to change with only modest alterations observed in women who had high second trimester cortisol. Of interest, third trimester distress had no effect on the third trimester gut microbiome, highlighting the experience of distress specifically in the second trimester as an important window of vulnerability. Reduced diversity of the vaginal microbiome, just prior to delivery, was associated with second trimester cortisol, with no alterations linked third trimester distress. When examining the infant gut microbiome we found increased diversity across the first 5 months of life to be associated with second trimester stress with corresponding decreases to the important Bifidobacteriaceae and Lactobacillaceae family. In conclusion, this thesis indicates the experience of PNMD influences key placental genes involved in glucocorticoid signalling in the placentae. The timing of maternal distress and infant sex are important factors in this relationship. Of particular interest we find placental FKBP51 to mediate a relationship between maternal anxiety and infant birthweight, demonstrating a direct role for placental glucocorticoid signalling underlying the relationship between prenatal distress and infant outcomes. The work presented in this thesis is the first of its kind to prospectively examine the influence of PNMD on the maternal gut, vaginal and infant gut microbiome. Stress-induced alterations in the maternal gut microbiome may contribute to adverse obstetric and birth outcomes albeit via a mechanism other than transmission of a suboptimal maternal microbiota during birth. Taken together, our results identify the second trimester as an especially vulnerable period to stress exposures and implicate the placenta and microbiome in mediating these effects. Counteracting the impact of stress during this critical time window may have important obstetric implications. Additionally understanding the consequence of the altered infant gut microbiome as a result of prenatal distress warrants further investigation.
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.
The role of inflammatory mediators in the overactive and bladder pain syndromes
(University College Cork, 2015) Offiah, Ifeoma; O'Reilly, Barry A.; McMahon, Stephen B.; MedImmune, United Kingdom
The Overactive Bladder (OAB) and Bladder Pain Syndrome (BPS) are debilitating disorders for which the pathophysiological mechanisms are poorly understood. Injury or dysfunction of the protective urothelial barrier layer, specifically the proteoglycan composition and number, has been proposed as the primary pathological characteristic of BPS. For OAB, the myogenic theory with dysfunction of the muscarinic receptors is the most reiterated hypothesis. For both over activity of the inflammatory response has been posited to play a major role in these diseases. We hypothesise that BPS and OAB are peripheral sensory disorders, with an increase in inflammatory mediators, such as cytokines and chemokines, which are capable of activating, either directly or indirectly, sensory nerve activity causing the disease. The aim of the PhD is to identify potential new therapeutic targets for the treatment of BPS and OAB. We used medium throughput quantitative gene expression analysis of 96 inflammation associated mediators to measure gene expression levels in BPS and OAB bladder biopsies and compared them to control samples. Then we created a novel animal model of disease by specific proteoglycan deglycosylation of the bladder mucosal barrier, using the bacterial enzymes Chondroitinase ABC and Heparanase III. These enzymes specifically remove the glycosaminoglycan side chains from the urothelial proteoglycan molecules. We tested role of the identified mediators in this animal model. In addition, in order to determine on which patients peripheral treatment strategies may work, we assessed the effect of local anaesthetics on patients with bladder pain. Gene expression analysis did not reveal a difference in inflammatory genes in the OAB versus control biopsies. However, several genes were upregulated in BPS versus control samples, from which two genes, FGF7 and CLL21 were correlated with patient clinical phenotypes for ICS/PI symptom and problem indices respectively. In order to determine which patients are likely to respond to treatment, we sought to characterise the bladder pain in BPS patients. Using urodynamics and local anaesthetics, we differentiated patients with peripherally mediated pain and patients with central sensitisation of their pain. Finally to determine the role of these mediators in bladder pain, we created an animal model of disease, which specifically replicates the human pathology: namely disruption in the barrier proteoglycan molecules. CCL21 led to an increase in painrelated behaviour, while FGF7 attenuated this behaviour, as measured by cystometry, spinal c-fos expression and mechanical withdrawal threshold examination. In conclusion, we have identified CCL21 and FGF7 as potential targets for the treatment of BPS. Manipulation of these ligands or their receptors may prove to be valuable previously unexploited targets for the treatment of BPS.
The spiritual and professional impact of stillbirth
(University College Cork, 2016) Nuzum, Daniel; O'Donoghue, Keelin; Morris, Heather
Stillbirth is without question one of the most devastating experiences of grief for parents and families. The death of a baby is also a distressing experience for healthcare professionals who share hopes of a live healthy baby at the end of pregnancy. It is a sad reality however, that in Ireland one in 238 babies will die before birth. The creation and nurture of new life in pregnancy is a spiritual experience as a new baby is at the same time experienced and anticipated. There is little in the published literature concerning the spiritual impact of stillbirth on healthcare chaplains who are the main providers of spiritual care for parents and staff colleagues in Irish maternity units. In addition there are few qualitative studies that explore the impact of stillbirth on consultant obstetricians and no published studies on the spiritual impact of stillbirth on bereaved parents. This study explored the spiritual and professional impact of stillbirth on Irish maternity healthcare chaplains, consultant obstetricians and bereaved parents. Following an overall review of spiritual care provision following stillbirth in the Irish maternity services, thematic analysis was used in the first phase of the study following in-depth interviews with maternity healthcare chaplains. Interpretative Phenomenological Analysis was used in the second and third phases with consultant obstetricians and bereaved parents respectively. The data from both maternity healthcare chaplains and consultant obstetricians revealed that stillbirth posed immense personal, spiritual and professional challenges. Chaplains expressed the spiritual and professional impact of stillbirth in terms of perception of their role, suffering, doubt and presence as they provided care for bereaved parents. A review of spiritual care provision in the Irish maternity services revealed a diversity of practice. The data from consultant obstetricians identified considerable personal, professional and spiritual impact following stillbirth that was identified in superordinate themes of human response to stillbirth, weight of professional responsibility, conflict of personal faith and incongruence between personal faith and professional practice. Data from bereaved parents revealed that stillbirth was spiritually challenging and all parents expressed that stillbirth posed considerable challenge to their faith/ belief structure. The parents of only three babies felt that their spiritual needs were adequately addressed while in hospital. The data had six superordinate themes of searching for meaning, maintaining hope, importance of personhood, protective care, questioning core beliefs and relationships. Other findings from the data from bereaved parents outlined the importance of environment of care and communication. This study has revealed the immense impact of stillbirth on healthcare chaplains, consultant obstetricians and most especially the spiritual impact for bereaved parents. Recommendations are made for improvements in clinical and spiritual care for bereaved parents following stillbirth and for staff wellbeing and support initiatives. Further research areas are recommended in the areas of spiritual care, theological reflection, bereavement care, post-mortem consent procedures and staff wellbeing.
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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