Paediatrics (RCH) - Theses
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ItemCystic fibrosis cascade carrier testing in Victoria, Australia( 2010)When a child is diagnosed with cystic fibrosis (CF) the impact is far-reaching. Parents of the child are presented medical information about CF and have to adjust to the new life trajectory the diagnosis has given the family. The diagnosis of CF through newborn screening has implications for other relatives with regard to increased risk of being a CF carrier and potentially also having a child with CF. Relatives should have the opportunity to learn of their increased carrier risk, and to make a decision regarding having carrier testing to learn whether or not they are a CF carrier. In the literature there is a clearly defined mismatch between relatives’ positive attitudes towards CF carrier testing, and the low uptake rates of carrier testing. Surveys of attitudes have demonstrated that relatives are interested in carrier testing, intend to seek testing, are satisfied with their experience if they had sought testing, and would recommend carrier testing to others at similar risk. Despite this, consistently low levels of uptake of testing are reported from research studies. Exploration of this mismatch between positive attitudes and low uptake will inform clinical practice around offering carrier testing to relatives of a child with CF. There are no studies to date in which carrier testing of relatives is investigated following a child’s diagnosis of CF through newborn screening. The aim of this thesis was to explore CF carrier testing for relatives (also known as cascade carrier testing) of a child diagnosed with CF through newborn screening, using a mixed methods approach to data collection. More specifically, the uptake of testing, factors associated with cascade carrier testing, and the reasons behind relatives’ decisions were examined. Results revealed that the vast majority of relatives of a child with CF diagnosed through newborn screening in Victoria, Australia, have not had cascade carrier testing; nevertheless, positive attitudes were observed. Those who were tested were more likely to be female, more closely related to the child with CF, and had higher knowledge scores than relatives who had not been tested. Most relatives who were tested did so in the first twelve months after the child’s diagnosis however there was a trend for a low level of testing to persist among relatives in the years following the diagnosis. Qualitative data provided reasons for carrier testing including: “wanted to know”, to pass information on to others, was pregnant at the time, and for reproductive planning. Reasons for not having carrier testing included: already completed family, “never really thought about it”, information not relevant yet, “never been asked”, “haven’t got around to it”, barriers to accessing testing and risk clarified by another relative. Newborn screening for CF is now being offered in a number of settings around the world. Findings from this thesis provide insight into the experiences of parents and relatives with implications for the cascade testing process. Recommendations for clinical practice are made to enhance the way cascade testing is offered to relatives following newborn screening.
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ItemWhole-genome expression profiling of cord blood mononuclear cells from monozygotic twin pairs( 2010)Substantial variation in gene expression levels exists between individuals, within specific tissues or cell types. With gene expression being the primary mechanism through which genetic information is translated into phenotype, the extent, nature and sources of this variation constitutes an important aspect of human biology. Variation in gene expression levels reflects a complex interplay of genetic and environmental factors. Certain environmental factors and exposures can modify gene expression through epigenetic modifications of DNA and chromatin, thus regulating transcription in a manner largely independent of genetic variation. The sensitivity of epigenetic mechanisms to these factors offers a means through which the environment can modulate expression of the genotype, with effects upon gene expression and ultimately, the phenotype. Studies of variation in gene expression in monozygotic (genetically identical) twins support a substantial environmental contribution to variation in gene expression levels. It is known that the epigenetic and gene expression profiles of monozygotic twins diverge throughout life. Mounting evidence suggests that the period of pre-natal development represents a particularly sensitive one for the occurrence of environmentally induced changes to epigenetic status and gene activity. The current study forms part of a larger research program investigating epigenetic variation in twins and its association with birth weight, maternal nutrition and foetal genotype. The Peri-/Post-natal Epigenetic Twins Study (PETS) builds upon the ‘developmental origins of adult disease’ hypothesis, based on the association between low birth weight and increased risk of cardiovascular and metabolic disease in later life, and focuses on epigenetic changes occurring in utero as the basis of the ‘foetal programming’ phenomenon. The current study is based on the hypothesis that divergence of epigenetic and gene expression profiles occurs from conception in monozygotic twins, in response to differing environments as experienced in utero. This study investigates the gene expression profiles of the cord blood mononuclear cells (CBMCs) of twelve newborn monozygotic twin pairs, including six pairs with birth weight discordance at greater than 15%. Genome-wide expression profiling was performed using the Illumina® Human-6 v2 BeadChip system. Gene expression discordance within twin pairs was assessed using three measures. Of these, the measure of Euclidean distance was considered to be the most systematic and useful. Expression discordance was found to vary substantially across pairs in our sample, with expression discordance being generally lower within twin pairs than between unrelated individuals. A significant correlation was identified between expression discordance and chorionicity, with greater expression discordance in dichorionic pairs compared to monochorionic pairs. The measure of Euclidean distance was also applied to publicly available datasets from genome-wide expression profiling of comparable tissues from adult twin pairs, revealing higher levels of expression discordance within the adult pairs relative to the newborn pairs. All genes surveyed by the microarray analysis were ranked according to the degree of within-pair variation shown across twin pairs. This ranked gene list was subjected to gene ontology analysis to identify gene ontology (GO) terms for which the corresponding ranks were higher than expected. Of the 27 GO terms ranked significantly higher than expected, one third related to immune response or response to other external signals. This data supports our hypothesis that divergence of gene expression profiles occurs from conception in monozygotic twins, and is reflected in differential expression phenotypes detectable at birth. Taken together, these results highlight the role of environment in determining gene expression profiles, and the contribution of environmentally induced changes in gene expression to expression discordance within monozygotic twin pairs. The increased variation observed within dichorionic twin pairs, coupled with the prominence of genes involved in immune/external signal response amongst those showing increased variation across pairs, implies that this variation may arise in response to subtly differing environments experienced by co-twins in utero. Birth weight is a phenotype of particular interest in the Peri-/Post-natal Epigenetic Twins Study (PETS), due to the association of low birth weight with an elevated risk of cardiovascular and metabolic disease in later life. In this study, linear modelling identified 342 genes whose expression levels showed a significant association with birth weight in dichorionic twin pairs. Gene ontology analysis of these genes revealed significant over-representation of GO terms relating to protein dephosphorylation, a process intrinsic to many forms of signal transduction. These data imply a link between the environmental modulation of gene activity via signal response/transduction and the phenotype of birth weight. Due to the myriad number of signal transduction pathways and physiological processes regulated by protein phosphorylation and dephosphorylation, it is not possible to pinpoint with certainty those that may be linked to birth weight or implicated in the association between low birth weight and elevated disease risk from our data. However, these results do provide a basis for further investigation of the specific environmental factors involved in the determination of gene expression variants associated with birth weight. It is to be hoped that future analyses will assist in the identification of the mechanisms underlying the correlation between low birth weight and an elevated risk of cardiovascular and metabolic disease in later life.
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ItemThe role of androgen in testicular descent( 2010)Undescended testis is the most common male congenital abnormality, occurring between 2% - 8% of the population. The migration of the testes from the abdomen into the scrotum requires both an anatomical change in connecting structures and regulating signals to mediate this process. The gubernaculum is the principle structure in testicular descent. Its development appears to be controlled by insulin-like hormone 3 and androgen. This thesis is comprised of three experimental sections. The first section examined the current operation rates for undescended testes in the paediatric population of Victoria. The second section provided a detailed anatomical and histological assessment of testicular descent in a normal and antiandrogen-treated rat model. The third and final section observed the immunoreactivity of androgen receptors (AR) and two types of oestrogen receptors (alpha; ERA and beta; ERB) in key anatomical structures during testicular descent in a normal and antiandrogen-treated rat model. Analysis of orchidopexy operations in the State of Victoria found that there had been a significant decline in the number of orchidopexy operations done in the paediatric population. This may represent a true decline in the incidence of disease, a failure of diagnosis or a failure of management. Further investigation will be required to determine the cause of current trends as the outcome may have significant consequences on male reproductive health. Analysis of anatomy and histology during normal testicular descent found a direct link between the genitofemoral nerve, gubernaculum and inguinal breast bud. This suggested that the inguinal mammary bud may also be involved in gubernacular development. Furthermore, prenatal antiandrogen-treatment led to persistence and growth of inguinal mammary tissue. These findings indicate that the failure of gubernacular differentiation and migration may be because of the ongoing presence of mammary tissue in the region of the inguinal canal. Analysis of the immunoreactivity of AR found that during the critical time-window for androgen activity the inguinal mammary tissue was positive for AR, whereas staining was minimal in the gubernaculum and the neurons of the genitofemoral nerve. In addition anti-androgen treatment led to down-regulation of AR expression in the inguinal mammary mesenchyme. Analysis of ERA expression did not identify any immunoreactive cells in the gubernaculum, mammary mesenchyme or neurons of the genitofemoral nerve during the study period. This result was not affected by anti-androgen treatment. Analysis of ERB expression found that it was present in the gubernaculum, mammary mesenchyme and neurons of the genitofemoral nerve during the study period. However, staining density was not affected by anti-androgen treatment. The observed pattern of immunoreactivity of androgen receptors supports the earlier observation that the inguinal mammary tissue may have a significant role in the occurrence of cryptorchidism. The observations also support existing evidence of the major role of androgens in the descent of testes. This thesis demonstrates that cryptorchism continues to be a significant developmental abnormality in male infants. The recent decline in the number of surgical operations is of concern. However, the thesis also provides new insights into anatomy and embryology of testicular descent and the role of androgen.
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ItemA prospective study of the psychological impact, understanding and disclosure of gene test results for hypertrophic cardiomyopathy and long QT syndrome.( 2010)Hypertrophic cardiomyopathy (HCM) and Long QT syndrome (LQTS) are inherited cardiovascular conditions for which genetic testing has become more common in clinical practice. The most concerning feature of these conditions is sudden death which can be prevented if those at risk are identified. Research into the clinical and molecular aspects of these conditions has advanced rapidly but research on the psychosocial implications of genetic testing for these conditions has lagged behind. The present study aimed to add to the limited body of research about the impact of genetic testing for HCM and LQTS to guide genetic health professionals working with families who are considering genetic testing. A multi-centre prospective questionnaire-based study was conducted to examine the impact of diagnostic and predictive testing for HCM and LQTS. Understanding of test results, risk perception, motivations for and concerns about testing and psychological impact of result disclosure were examined as well as disclosure of gene test result to relatives. Participants were recruited from four Australian and one British site. Questionnaires were completed before testing and at two weeks and three months post-disclosure. Data from participants who underwent diagnostic testing (n=46, 15-76 years old, 40 (80%) tested positive) were analysed separately to those who had predictive testing (n=77, 14-67 years old, 29 (38%) tested positive). A high proportion of participants from both the diagnostic and predictive gene testing groups were pleased they had testing, recalled their result accurately and in the diagnostic group, understood the implications of their result for their own health and their relatives. In those who had predictive testing, perceptions of the likelihood of developing disease, level of worry, and the number of concerns about LQTS and HCM reported were consistent with gene test result. More than 90% of participants in both groups disclosed their gene test results to first‐degree relatives. Concerns about sudden death were evident in participants from both the diagnostic and predictive group, confirming anecdotal reports from clinical practice. Concerns about the possibility of at-risk relatives inheriting either LQTS or HCM and the unpredictable natural history of both conditions were also common concerns. For the predictive testing group, multivariable linear regression analysis adjusting for baseline psychological scores and potential confounders, and accounting for family clusters demonstrated a higher mean anxiety (p=0.005) and distress (p=0.003) score in gene positive compared to gene negative participants at 2 weeks, but these differences were less apparent at 3 months. There was no difference in depression scores at any time point in those who underwent predictive testing. The same analysis was performed in the diagnostic testing group and there were no statistically significant differences in adjusted mean anxiety, distress and depression scores when comparing participants with gene positive and gene negative results at any time point. Overall, high proportions of participants who underwent diagnostic and predictive testing were pleased to have undergone testing, understood the implications of their result and disclosed their result to relatives. There was no evidence for significant negative psychological sequelae three months after receipt of test result in participants who had either diagnostic or predictive testing. Implications for practice are presented.
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ItemLife on the front line: exploring personal and professional impacts on healthcare professionals working with fetal anomaly( 2010)It has been just over 2 decades since the establishment of the Human Genome project, which has served to significantly enhance the capabilities of prenatal screening and testing. Pregnant women are offered a number of antenatal screening and diagnostic tests which give them information about their fetus, and can identify potential anomalies before it is born. This has consequently led to increases in the number of fetal anomalies that are identified in the prenatal period, and each year in Victoria, Australia 4% of pregnancies will be affected with a fetal anomaly (Riley & Halliday, 2008). Given these rapid advances, it is important to explore the interface between prenatal testing technology and society. While there has been some research on women’s experiences of a diagnosis of a fetal anomaly in pregnancy, it is also important to explore the experiences of healthcare professionals working in this setting. Healthcare professionals are at the forefront of new technologies and play an integral role in administering prenatal tests and supporting patients through the process of diagnosis and thereafter. However, to date there has been very little research on how healthcare professionals experience being involved in this process and the potential impact this may have on them and their practice. This study sought to address this gap in the literature and aimed to explore whether working with fetal anomaly has an impact on healthcare professionals, and identify any supports used and/or needed. Due to the limited amount of research in this area, a qualitative approach was utilised to provide an in-depth exploration of a range of views and experiences. Interviews were conducted with 40 healthcare professionals working in fetal medicine settings in Melbourne, Victoria: 11 medical practitioners and 29 allied health professionals. Qualitative analysis identified a range of challenging situations and demonstrated that working with fetal anomaly had a substantial personal and professional impact on participants. Caring for patients in crisis, the urgency of the setting due to patients’ advancing pregnancy, and the difficulties with communicating ‘bad’ news were discussed as intrinsic factors contributing to the difficulty of the clinical environment. Participants also discussed, at length, the personal emotional impact of their work and believed this was instrumental in feeling burdened by caring for patients at this time of grief. Many reported that working with fetal anomaly had repercussions for their daily lives, particularly when they were pregnant themselves. The provision of termination of pregnancy services was described as an implicit aspect of the fetal medicine setting, and participants spoke about many challenges that were encountered due to their involvement with this process. Despite the difficult nature of working in this clinical environment, participants described their job as fulfilling. However, they also perceived being largely unsupported in their role, and many spoke about feeling as though they could not ask for, or seen to be needing, support, as they did not want to appear vulnerable. Many of the themes that were identified relate to phenomena of ‘burnout’ and compassion fatigue, which appear to be particularly relevant to participants in this study. These results reflect the complex issues inherent in this topic. Findings from this study will contribute to the evidence base, and suggest areas in which additional training, tailored support, and institutional changes could be implemented to mitigate this impact.
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ItemThe quality of life of young women with a menstrual problem and families attending a hospital-based gynaecological clinic in Melbourne, Australia( 2010)BACKGROUND: Menstrual disorders are very common among young women and have been shown to have negative effect on physical and psychosocial health. Despite high prevalence of menstrual dysfunction in young women, only small percentage seeks medical help. Very few papers have examined health related quality of life (HRQL) in younger population with menstrual problem. AIMS: The aim of the study was to assess young women’s and their parents’ perception on the impact of menstrual problem on the young women’s quality of life and identified factors that have impact on it. It was also aimed to describe the quality of life of parents of young women with menstrual problems and factors influencing their quality of life (QoL). METHOD: This was a descriptive, cross-sectional study conducted in Royal Children’s Hospital, Melbourne between 1st October 2008 till 30th June 2010. Research tools used for young women were PedsQL 4.0 generic module (Teen-report) and Parent Bonding Instrument whereas tools for parents include PedsQL 4.0 generic module (Parent-report), SF12v2 and Kessler Psychological Distress Scale. RESULTS: A hundred and eighty four young women and parents completed self-administered questionnaires. The most common menstrual problems seen in our gynaecological clinic were dysmenorrhoea (38.6%), followed by heavy menstrual bleeding (33.6%), oligomenorrhoea (19.6%) and amenorrhoea (8.2%). The mean overall score was 70.48+16.44 with 42.5% having a score below one standard deviation from the norms. Young women with dysmenorrhoea had the poorest score in physical function whereas those with amenorrhoea had the lowest score in psychosocial function. Higher body mass index, smoking, alcohol drinking, sexual activity, parental anxiety and parental overprotection were associated with poorerscore. Overall, parents rated lower QoL scores than young women themselves in all four domains (physical, emotional, social and school). Parent-child agreements were moderate to good with best agreement in school functioning. Parents’ of young women with menstrual problems reported lower QoL scores than the norm in all domains with worse scores in ‘role emotional’ and ‘mental health’ domain. Parental anxiety and medical illnesses were associated with poorer parental QoL. CONCLUSION: Although menstrual problems are not life threatening, they can pose a significant impact not only on the quality of life of these young women but also their parents. Identification of these impacts might lead to recognition of potential services or education to improve this. Understanding the characteristics that predict QoL may help clinician identify patients who are risk for poor QoL.
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ItemThe epidemiology of egg allergy and other IgE-mediated food allergies in infants( 2010)IgE-mediated food allergy often develops early in life and has a major impact on the quality of life of the child and its family. Recent increases in the prevalence of food allergy, which have occurred too rapidly to be explained by genetic factors alone, suggest that environmental factors may play an important role. Potential candidates include maternal and infant diet and infant microbial exposures. However, few studies to date have examined risk factors for food allergies. I investigated the prevalence and risk factors for egg allergy, the most common IgE-mediated food allergy in infants, within the HealthNuts study. HealthNuts is an ongoing population-based cross-sectional study of 12-month-old infants in Melbourne, Australia. As part of the study, parents reported on infant feeding and other environmental exposures. All infants subsequently received a skin prick test for four foods including egg white and those with a wheal size ≥ 1mm underwent an oral food challenge with raw egg white. This thesis includes data from the first 2,600 infants included in the study, which is due to complete recruitment in April 2011. Among infants participating in the HealthNuts study, there was a high prevalence of egg allergy (9.3%, 95% CI 8.2-10.5). There was no evidence that maternal dietary factors were associated with infant egg allergy. Of the infant dietary factors examined, only timing of egg introduction was associated with egg allergy risk. Introduction of cooked egg into the infant diet at 4-6 months of age was associated with a 3-fold decreased risk of egg allergy compared with introduction after 12 months of age. Other infant dietary factors previously suggested to be associated with general allergy risk, namely duration of breastfeeding and age at introduction of first solid foods, were not associated with egg allergy. Factors previously associated with increased microbial exposure, including siblings, childcare and pet ownership, were associated with a reduced risk of egg allergy. There was evidence of a dose-response effect for siblings and egg allergy, with an increasing number of siblings associated with a further reduction in egg allergy: one sibling, OR0.72 (95% CI 0.53-0.97), two siblings OR 0.57 (95% CI 0.35-0.92) and three or more siblings OR 0.47 (95% CI 0.20-1.09). Attending childcare before 7 months of age was associated with a reduced risk of egg allergy compared with never having attended childcare (OR 2.05, 95% CI 0.97-4.35), while there was no evidence of a protective effect of childcare attendance between 7-12 months of age. Having either a cat or dog at home at one year of age was associated with a reduced risk of egg allergy among infants with a history of eczema (OR 0.49, 95% CI 0.31-0.78) but not among those without a history of eczema (OR 1.01, 95% CI 0.62-1.62). My results show that egg allergy is common in infants and suggest several possible risk factors related to infant diet and potentially microbial exposures which may help to explain recent rise in food allergy prevalence. The protective effect of introduction of egg at 4-6 months of age has implications for infant feeding guidelines internationally and, if confirmed, suggests that changes in infant feeding practices could have the potential to reduce the prevalence of egg allergy.
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ItemAlternative pneumococcal vaccination schedules for infants in Fiji and pneumococcal epidemiology( 2010)This thesis documents the pneumococcal disease burden and the results of a Phase II pneumococcal vaccine trial in the low middle income country, Fiji. The overall objective was to gather sufficient evidence for the Fiji Ministry of Health to decide whether to introduce the pneumococcal vaccination into its national schedule and define an appropriate and affordable vaccination strategy. The nasopharynx is the main reservoir for pneumococci and plays an important role in the spread of the organism. Studies of nasopharyngeal carriage offer insights into the pneumococcal disease burden in a community, particularly for potential serotypes which may cause pneumonia, and are a convenient way of determining the level of antibiotic resistance among pneumococcal isolates circulating in a population. The first study, a cross-sectional pneumococcal nasopharyngeal carriage survey of healthy children aged 3-13 months, was undertaken to document the prevalence of pneumococcal nasopharyngeal carriage, risk factors for carriage, serotypes and antimicrobial susceptibility patterns of carried pneumococci in healthy young children in Fiji (Chapter 3). Pneumococcal nasopharyngeal carriage was common in Fijian children. Penicillin resistance was documented for the first time, and, as a result, first-line treatment for meningitis was altered. A low proportion of carriage serotypes were included in the 7-valent pneumococcal conjugate vaccine. Invasive pneumococcal disease is an important cause of morbidity and mortality, particularly in the very young and the elderly. The introduction of the 7-valent pneumococcal conjugate vaccine in the national immunisation schedule in the USA has resulted in an impressive reduction in infant invasive pneumococcal disease. In addition, the vaccine has had a more than expected herd immunity effect on invasive pneumococcal disease in the elderly and other age groups. Chapter 4 reports on a study that aimed to document age-specific burden of invasive pneumococcal disease including clinical syndromes, underlying conditions, serotype distribution, and the potential protection against invasive pneumococcal disease and chest X-ray confirmed pneumonia by 7-valent pneumococcal conjugate vaccine in Fiji. The annual invasive pneumococcal disease incidence was comparable to countries of similar socioeconomic status. Being indigenous Fijian was an independent risk factor for disease. Underlying conditions were common and the case fatality rate was high particularly in the elderly population. For every, 1.930 and 128 infants vaccinated, one death and one case respectively, would be prevented in those <5 years, by introduction of universal immunisation with the 7-valent conjugate vaccine. A Phase II vaccine trial was undertaken to document the safety, immunogenicity and impact on pneumococcal carriage of various pneumococcal vaccination regimens combining one, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine in infancy (Chapters 5 to 10). In order to broaden the serotype coverage, the additional benefit of a booster of 23-valent pneumococcal polysaccharide vaccine at 12 months of age was also assessed. To address the theoretical concerns of hyporesponsiveness to 23-valent pneumococcal polysaccharide vaccine following re-challenge, the immunological responses at 17 months of age to a small challenge dose of 20% of 23-valent pneumococcal polysaccharide vaccine (mPPS) in children who had or had not received the 23-valent pneumococcal polysaccharide vaccine at 12 months of age was undertaken. The immunogenicity following a 2 or 3 dose 7-valent pneumococcal conjugate vaccine primary series was similar for many serotypes. A single 7-valent pneumococcal conjugate vaccine dose would offer protection in the first 12 months of life for many serotypes. The one or 2 dose 7-valent pneumococcal conjugate vaccine schedules induced immunologic memory, with memory responses following 23-valent pneumococcal polysaccharide vaccine being most profound for children who had received only a single dose of 7-valent pneumococcal conjugate vaccine previously, compared with the 2 or 3 dose groups. Following the 23-valent pneumococcal polysaccharide vaccine booster, there were significant responses for all 23 serotypes which persisted for at least 5 months following vaccination. However despite higher antibody concentration at 17 months in children who had received 23-valent pneumococcal polysaccharide vaccine at 12 months, the response to a re-challenge was poor to all 23 serotypes compared to children who did not receive the 12 month 23-valent pneumococcal polysaccharide vaccine. This indicates immunological hyporesponsiveness or non-responsiveness. This effect occurred regardless of pre-mPPS antibody levels and prior 7-valent pneumococcal conjugate vaccine exposure. The addition of 23-valent pneumococcal polysaccharide vaccine at 12 months had no impact on carriage, despite the substantial boosts in antibody levels observed and despite significantly higher opsonophagocytic activity and antibody avidity comparing pre- and post-levels. In summary, a substantial burden of pneumococcal disease in Fiji was found. The 7-valent pneumococcal conjugate vaccine would provide limited coverage of invasive disease compared to its use in affluent countries. Two doses of 7-valent pneumococcal conjugate vaccine have similar immunogenicity as 3 doses although a single dose still provides some protection. The 23-valent polysaccharide vaccine booster was found to be immunogenic but re-challenge resulted in hyporesponsiveness. Further research evaluating the potential of reduced dose schedules using the newer conjugate vaccines with an early conjugate booster would be recommended.
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ItemThe incidence and timing of brain injury and its influence on neurodevelopmental outcome in infants undergoing surgery for congenital heart disease( 2010)INTRODUCTION: Brain injury is the most common complication amongst infants with congenital heart disease (CHD) who require surgery during the newborn period. Up to one half of children demonstrate impairment in neurodevelopment following cardiac surgery early in life. The developing brain of the newborn infant may be vulnerable to injury and impairment of normal development, due to abnormalities in cerebral blood flow related to the underlying cardiac abnormality in utero and following birth. Numerous peri-operative factors may also influence the risk of brain injury and development including interventions and management including surgical and perfusion techniques and intensive care factors, in addition to individual patient factors. Links between early detection of brain anomalies and later neurodevelopment in children following cardiac surgery have not previously been described. AIMS: The aim of this study was to determine the incidence and timing of brain injury and impaired brain development in young infants undergoing surgery for CHD, and to ascertain the impact of risk factors, associated with cardiac surgery and peri-operative intensive care during early infancy, on neurodevelopmental outcome at two years of age. METHODS: Seventy-five full-term infants undergoing surgery for CHD prior to two months of age were enrolled in a prospective study at the Royal Children’s Hospital, Melbourne. Infants were excluded if they were born prior to 36 weeks’ gestation, if they had a known genetic abnormality independently associated with impaired neurodevelopment, if they were considered too clinically unstable to be able to undergo a pre-operative magnetic resonance imaging (MRI) scan and if they were unlikely to be able to undergo a late MRI scan for geographic reasons. Study participants underwent a series of neurological investigations in the peri-operative period: 1) serial MRI scans before, at one week following surgery and at 2-3 months of age, and 2) amplitude-integrated electroencephalography (aEEG) before, during and for 72 hours following surgery. Surviving children were then assessed at two years of age using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) and a neurological evaluation. RESULTS: The enrolled cohort of 75 infants had a mean birth weight of 3.3 ± 0.5kg, head circumference 34.4 ± 2.2cm and gestational age at birth of 39.0 ± 1.4 weeks. They had a median age at surgery of seven days (IQR 3-14) and the surgical categories of participants were as follows: closed biventricular repair (6); open biventricular repair (26); open biventricular repair with arch repair (4); single ventricle palliation (25); isolated Blalock-Taussig shunt (14). Cardiopulmonary bypass (CPB) was utilised during surgery in 84% and antegrade cerebral perfusion (ACP) in 39% of infants. Recovery of a continuous background pattern on aEEG occurred at a median of 13 (IQR 3-25) post-operative hours and sleep-wake-cycling (SWC) returned at 27 (IQR 17-49) post-operative hours. A longer recovery time to a continuous background pattern following surgery increased the risk of neurological and motor impairment, and a longer recovery time to SWC increased the risk of cognitive and language impairment. Electrical seizures were identified in 29% of infants during the peri-operative period for a median cumulative time of six minutes. Intra-operative seizures occurred in 19% of infants during CPB, predominantly occurred during the institution of ACP and moderate hypothermia, and were strongly related to mortality (p<0.0001). Post-operative seizures also occurred in 19% of infants, predominantly during support with extra-corporeal membrane oxygenation, but were not related to subsequent outcome. Delay in brain maturation on MRI was common, with almost half the infants demonstrating up to four weeks delay in cortical folding pattern on their pre-operative scans. However, myelination impairment was most strongly related to subsequent impairment of neurodevelopment at two years. Punctate deep white matter and periventricular signal abnormalities occurred frequently, especially during the post-operative period, but tended to resolve spontaneously and did not relate to neurodevelopmental outcome. Stroke occurred rarely during peri-operative period and was unrelated to the performance of a balloon atrial septostomy. A complete neurodevelopmental evaluation was undertaken at 23.8 ± 1.6 months of age in 65 children. Two year mortality was 12%. The mean cognitive, language and motor composite scores were 90.2 ± 14.0, 91.1 ± 16.5 and 93.5 ± 13.5. Neurological deficits were identified in 26% of children at two years, most commonly hypotonia and eye abnormalities. The risk of cognitive function developing more than two standard deviations below the expected mean was three times that anticipated by test norms, whilst language function had an almost five-fold risk of significant delay compared with test norms. Peri-operative risk factors identified for mortality before two years of age were a higher serum lactate at six post-operative hours and the presence of white matter injury on the late MRI scan (p<0.0001). Patient-related risk factors for impairment in neurodevelopment at two years were a lower gestational age at birth, male gender and impaired myelination in the posterior limb of the internal capsule on pre-operative MRI. Peri-operative risk factors for impaired neurodevelopment were the absence of pre-operative vasoactive infusions, a higher serum lactate at the conclusion of surgery, a longer hospital length of stay and delayed recovery of the aEEG following surgery. The type of surgery undertaken and a variety of intra-operative surgical and perfusion techniques appeared to have little impact on subsequent outcome in survivors. CONCLUSIONS: Neurodevelopmental delay and neurological impairment is common in two-year-olds following cardiac surgery during early infancy. A relationship was found between early markers of brain maturation and subsequent neurodevelopment in this group of full-term infants. However, a clear-cut link between early injury, as evidenced by abnormalities on imaging or aEEG, and subsequent performance could not be demonstrated.
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ItemLongitudinal outcome of childhood asthma into adult life: outcome at 50 years( 2010)Asthma is one of the commonest conditions affecting the Australian and worldwide population and a significant level of knowledge about its natural progression from childhood into adulthood has been established from the Melbourne Epidemiological Study of Childhood Asthma (MESCA). This study randomly selected children who were born in Melbourne, Australia in1957 and has followed them up every 7 years to the current study whereby the participants are now 50 years of age. This study has provided a significant contribution to knowledge of the outcomes of childhood asthma into adult life. The hypothesis of the study was that children with severe asthma will have persistent symptoms into adult life and reduced lung function when compared to those who were healthy controls or had wheezy bronchitis, and that there was an association between children with severe asthma and adult chronic obstructive pulmonary disease in adult life. The first aim of the study was to describe the clinical outcome of childhood asthma at the age of 50 years and determine the factors that promote persistence or remission of asthma symptoms. The second aim was to monitor and track the change in lung function secondary to childhood asthma and examine the factors that may affect its rate of decline in adult life. Such factors include the severity of childhood asthma, sex, smoking history, asthma remission and bronchial hyperresponsiveness. There is also increasing evidence that childhood asthma may predispose subjects to the development of chronic airflow limitation in adult life. Lung function declines through adult years, and children with asthma, who may have deficits in lung function from early life, are likely to reach a threshold of symptomatic chronic airflow limitation at an earlier age than those without asthma. Therefore the final aim of the study was to assess for a possible relationship between childhood asthma and the subsequent development of adult chronic obstructive pulmonary disease (COPD). In this longitudinal study, 346 subjects participated from a cohort of 479 remaining survivors, representing a participation rate of 76%. Subjects underwent an interviewer-administered questionnaire, validated health-related quality of life questionnaires, objective lung function testing with bronchodilator response and skin prick testing as a means to measure atopy. The results of this study demonstrate that children who have more severe patterns of asthma in childhood will continue to have symptoms at the age of 50 years and reduced lung function when compared to children with intermittent asthma (wheezy bronchitis) or those without asthma (i.e. control group). Risk factors that determine the persistence of childhood asthma into adult life include severe asthma as a child, female sex and childhood hay fever. Children with severe asthma have established lower lung function from childhood years when compared to the controls and those with wheezy bronchitis and the deficits track throughout adult life. Importantly, there was no increase in the rate of decline in lung function in children with severe asthma compared to those with wheezy bronchitis or the control group despite the persistence of symptoms. The rate of decline in lung function was not affected by gender, history of smoking at the age of 21 or 50 years, asthma “clinical remission” status at age 50 years or bronchial hyperresponsiveness at the age of 28 years. Children with severe asthma are also at increased risk to developing chronic airflow limitation or chronic obstructive pulmonary disease by the age of 50 years, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Interestingly, a proportion of these children did not have a smoking history suggesting a phenotype of COPD which is related to childhood asthma. The children who developed COPD at age 50 had reduced lung function measurements from childhood years but again, there was no increase in the rate of decline in lung function throughout their adult years, when compared to those who were in the control group or had active asthma. The findings presented in this thesis confirm that lung function in adult life is determined in childhood and is reduced in children with asthma. This would suggest that airway remodeling, a process that occurs within the structural components of the airways in response to inflammation, begins in early life. Therefore, research into determining the factors that contribute to airway remodeling in infants and preschool children needs to be highlighted. Childhood risk factors that determine the persistence of asthma at the age of 50 years include childhood severe asthma, female sex and allergic rhinitis. Attention to the interplay of female gender and allergic rhinitis on the persistence of asthma is of interest as it will provide greater understanding towards asthma pathogenesis and highlight potential disease-modifying therapeutic options. There is also emerging evidence of a link between the outcomes of severe childhood asthma and adult chronic obstructive pulmonary disease, represented by fixed airflow obstruction. The absence of a smoking history supports the heterogenous nature and varying phenotype of this adult disease entity. To further define this relationship, longitudinal measurements of airway wall inflammation from childhood to adulthood, ideally by non-invasive techniques would be helpful. Clearly, if children with severe asthma are at risk of developing adult chronic obstructive pulmonary disease, longitudinal surveillance of these children needs to continue, especially if therapy with inhaled corticosteroids has been instituted.