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Due to advances in prenatal and neonatal medicine, there has been an improved survival rate of premature children over the past decades. Unfortunately, the most premature children have poor neurological and cognitive prognoses. The aetiology for the high proportion of learning disabilities in very premature children, is however often unknown (Grunau, Whitfield, & Davis, 2002; Litt, Taylor, Klein, & Hack, 2005). There has been increased awareness of visual problems in premature children, and of visual problems related to learning and reading. The studies reported in this thesis address the development of visual function as well as reading ability in premature children. A series of visual functions, cognitive- and reading ability were evaluated in a group of typical Norwegian children (n= 87) in order to provide developmental trajectories for these functions. This group acted as the control group for a group of premature children (n= 37), of whom the majority (n= 25) came from an established cohort of extremely premature children from the National Hospital in Oslo. Finally, an intervention study for treatment of binocular visual problems for a subgroup of premature and typical children (n= 27) was executed. Even when controlling for age, gender and cognitive ability, visual functions were generally weaker in the premature group. Deficiencies found in this group showed patterns that can be related to close work in one plane; a Planar component, and to focusing and binocular abilities; a Depth component. We have shown that convergence and fusion at close distances, which might interfere with near work, can be trained. There is also a possible improvement in ability to detect coherent motion as a result of this training. This ability might relate to learning and reading (Sigmundsson, Anholt, & Talcott, 2010; Stein, 2001). Thus more comprehensive visual examinations and treatment of deficiencies could lead to improved learning abilities in premature children.

Intrauterine growth restriction (IUGR) contributes significantly to neonatal mortality and morbidity, as well as increased incidence of severe adult disease, being characterised by an estimated fetal weight below the 10th percentile for gestational weight and an abdominal circumference below the 2.5th percentile. Fetal wellbeing is critically dependent on adequate development of placental villi as well as the maternal and fetal vasculatures and in approximately 60% of cases of pure IUGR (those not associated with pre-eclampsia), excessive perivillous fibrinoid material has been associated with poor villous growth. In the present study we used stereological analysis to analyse villous components and found decreased stem, intermediate and terminal villi as well as a reduced intervillous space in placenta from IUGR compared with controls, confirming analyses performed in previous studies. As the fibrinolytic pathway is hyper-activated in IUGR, we hypothesised that anqiostatiru, (AS4.5: an anti-angiogenic 52kDa proteolytic cleavage product of plasminogen), a potent endothelial apoptosis inducing agent produced during fibrinolysis may be involved in the pathophysiology of IUGR. We describe for the first time, that in addition to its' known effects on endothelial cells (which we confirmed), AS4.5 also induces dose-dependent apoptosis in 2 trophoblast cell lines and inhibits cell migration and "wound healing" in trophoblast cultures, while having no such effect on tumour cell lines. Although no definitive antibody for detection of AS4.5 exists, we show that conditions within villi from IUGR placental samples are permissive for generation of AS4.5, as co-immunolabelling for B-actin/plasminogen and B-actin/uPAR are both increased in IUGR samples from placental compared with matched controls. This increased propensity for AS4.5 generation on the villi of IUGR placenta correlates with a 2-3 fold increase in the rate of villous apoptosis within placental samples from cases of I UGR. Thus, generation of an endothelial/trophoblast apoptosis-inducing agent occurs at the site where villous turnover is greatest and is known to contribute to the pathophysiology of IUGR. Taken together, these data support the hypothesis that cell surface generated AS4.5 may contribute to the increased apoptosis observed during thrombophilic- type IUGR and warrants further investigation of placental and serum AS4.5 in a larger cohort of pure I UGR cases as a direct contributor to the pathogenesis of IUGR.

Late preterm infants (born at 34-36 weeks gestation) have increasingly been regarded as 'at risk' rather than 'Iow risk' infants. The impact of neonatal morbidity and admission for neonatal care, on the longer term outcomes of LPls has not been fully explored. This thesis has sought to bridge an identified gap in the literature relating to this significant group of neonatal care graduates. The overall aim of this thesis was to consider the significant population of LPls who require admission for neonatal care. Firstly, maternal and perinatal risk factors and neonatal outcomes were considered through a descriptive analysis of neonatal data from the Neonatal Intensive Care Outcomes Research and Evaluation (NICORE) database. The second component of the thesis then considered specifically the early childhood development (cognition, language, motor development, physical health and growth) at three years of age of LPls who required neonatal Intensive Care (lC) compared with infants of the same gestational age who did not require Intensive Care. LPls who required neonatal care were identified as a unique group, with distinct characteristics and outcomes in the neonatal period when compared to other admitted infants. LPls requiring Intensive Care (IC) had increased maternal and perinatal risk factors and increased adverse neonatal outcomes compared to LPls who required Special Care Only (SCO). Findings from the follow-up study revealed that despite increased maternal and perinatal risk factors and neonatal morbidity, LPls who required admission to IC had similar cognitive, language and motor abilities and growth, compared with their peers, who were not admitted for le. However, LPls who required IC had increased health service usage compared to the non-IC infants. Having considered, for the first time, the neonatal outcomes and early childhood development of LPls on the basis of their requirement for neonatal Intensive Care, this thesis has provided a novel insight into the outcomes of this under-researched group of children.

Preterm births are becoming more common worldwide, leading to an increase in the complications of prematurity. Preterm babies are specifically at risk of infection, defined as late onset sepsis after the third day of life. Ideally, infection should be prevented but if this is not possible rapid and accurate detection is necessary so that treatment can be started early_ Symptoms of infection in term and preterm infants are non-specific. Current methods of diagnosis are dependent on culturing organisms in blood, but this can be problematic and diagnostic performance in neonates is not good. Alternative methods may prove to be more efficient. The aim of this study was to determine if molecular methods can improve the diagnosis of infection in neonates. Success of the molecular assay was judged based on comparison with blood culture and CRP. ability to quantify bacterial copy number and to specifically identify pathogens. Infants whom clinicians thought were infected had additional blood sampled at the time of routine investigations for infection. Clinical and routine laboratory data were also recorded. Molecular analysis of the samples was performed using a reverse transcriptase real~ time PCR 16S rRNA assay. 16S rRNA is a universal sequence present in all bacteria. Infants were judged to be infected based on a previously validated culture~ independent clinical scoring system. Eighty four infants were included in the analysis. 16S reran proved to be more sensitive and specific than blood culture and CRP. The assay could quantify the number of bacteria present in the infection ("bacterial load"). A number of less common bacteria and Human Parechovirus were identified and further correlation is required to determine the pathogenicity of these organisms . In summary. molecular methods can enhance the diagnosis of late onset neonatal sepsis, provide quantitative information, on bacterial load and provide insights into the nature of bacteria causing the disease process.

The survival rate of premature infants is increasing. As such protective factors against cognitive and behavioural developmental impairments associated with prematurity need to be identified and understood in order to promote healthy infant development. Quality of parent-infant interaction may be a protective factor over and above other mediators such as sociodemographic and neonatal medical risks. Most research has considered the mothers' experience of having a premature infant and the quality of mother-infant interaction on infant outcomes. Evidence suggests that father involvement and interaction with the infant is also associated with improved developmental outcomes in later childhood. More research is needed of fathers' experiences of interactions with premature infants in order to promote early positive interactions, fostering healthy relationship and infant development. The current study used a qualitative design to investigate fathers' experiences of interacting with their premature infants on UK neonatal intensive care units and after discharge home. Telephone interviews were conducted with ten fathers from across the UK about their experiences of interacting with their premature infants. Thematic analysis identified six themes affecting fathers' experiences of interactions with their infant: i) Fragility of the infant - fathers were nervous and unsure about how to interact with their fragile babies, being scared of hurting them; ii) From self-conscious to self-confident interactions - fathers described the lack of privacy in the hospital contributing to them feeling self-conscious about attempting interactions with their infant, whereas they built confidence in interaction over time and felt interactions were more natural once in the freedom of their own home; iii) Medical equipment as barrier to interaction - the incubator and monitors around the infants acted as physical and emotional barriers to interaction, though the fathers recognised it was needed to keep their babies safe; iv) Passivity of baby - fathers struggled with interacting with their unresponsive infants and adapted their interactions to those which the passive infant did not need to participate in, such as singing to them; v) Not having the envisaged experience of fatherhood - fathers had to readjust their preconceived expectations of what the early days of fatherhood would be like had their infant been born full-term, to the new reality 0809, RES, Research Project, UofN: 4093405, UofL: 08127476 Pageiiof197 of having a premature baby; vi) Nature of information - although staff actively involved fathers in care-giving tasks and provided information about the infants' medical needs, little information was provided about non-care-giving interactions and fathers often had to ask what they could do with their baby. Fathers in this study described facing many challenges and barriers to interacting with their premature infants, and that these resulted in a delay in feeling like a father to the infant and in the development of the father-infant relationship. The findings have implications for the development of father- infant attachment which may influence infant development. The fathers described neonatal staff as excellent and supportive, though there appears to be a lack consistency of information to encourage fathers to interact with their premature infants from the earliest possible stages. Given the importance of this for positive infant outcomes, the experiences reported in this study may help inform support for fathers on UK NICUs to promote early interactions with their infant and foster healthy relationship and infant development.

The thesis explored the phenomenon of catch-up, a term used in relation to the development of children born prematurely. I considered how the term catch-up and the associated practice of corrected age influenced the mothering of children born prematurely at or before 32 weeks of gestational age. Initially, I considered the ways in which the notion of catch-up has drifted from its original specific meaning and highlighted theconfusion around the use of the practice of corrected age. A thematic analysis associated with theterm catch-up was developed from internet based discussion boards and email groups which support families with children born prematurely; these themes were then tested in interviews with 17 mothers whose children were aged 3, 5 or 7 years of age and who live in five primary care trusts in the South West of England. The central theme from the analysis interpreted catch-up as hope which either supports the mothers' hopes and dreams for their children or is regarded as a myth that can lead to the promotion of false hopes and expectation, a double-edged sword, where mothers see their children through the mediated gaze of catch-up. This paradox of hope was explored referencing the French existentialist Gabriel Marcel. I considered the notion of catch-up as a trial with characteristics of captivity, duration, endurance and fluidity before then considering whether mothers were altered by their experience of having children born prematurely.

This study aims to identify in the non-pregnant rat and pregnant dam those tissues with the greatest methionine cycle activity and those that are most sensitive to methyl group deficiency.  In addition, as human studies rely heavily on the plasma measurements, this study also aims to investigate whether plasma metabolites of homocysteine and methionine reflect tissue metabolism. This study investigated the kinetics of methionine metabolism in the rat using an L-[1-¹³C, ²H₃] methionine tracer that is converted to [1-¹³C] homocysteine and [1-¹³C] methionine by passage through the methionine cycle.  The effect of the methionine, folate and choline content in the diet was studied by measuring the conversion of homocysteine to methionine within tissue of the pregnant and non-pregnant rat.  Tissue homocysteine methylation was estimated from the ratio of [1-¹³C] methionine to [1-¹³C, ²H₃] methionine in comparison with the same ratio in the plasma. The main findings of this study were that the liver and the pancreas were the main sites of homocysteine methylation within the rat, with the pancreas also emerging as the major contributor to plasma homocysteine and synthesised methionine.  Additionally, it was observed that ht e fetus was able to compensate for a reduction in homocysteine methylation as a consequence of folate and choline deficiency within the dam until day 19 of gestation. After this time, however, the fetus cannot increase the conversion of homocysteine to methionine to compensate.  This study also indicated that as gestation progresses maternal methionine synthesis was reduced to conserve folate and choline for use within the fetus.

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No description available.