BACKGROUND: Prenatal maternal stress has been implicated in having a role in adverse health outcomes across the life span. Despite its potentially pervasive effects and population health significance, research examining the determinants of prenatal maternal stress is limited and inconclusive. One particularly intractable outcome, preterm birth, has shown inconsistent associations with prenatal maternal stress. In addition, few measures of childhood perceived stress and perceived stress in pregnancy exist. OBJECTIVE: The purpose of these papers is to: present the theoretical foundation, conceptualization, and evidence base for the Life Course Stress and Preterm Birth Model; test and refine the Life Course Stress and Preterm Birth Model by evaluating the fit of the proposed model of stressors related to socioeconomic position (SEP) and family environment during childhood and pregnancy, perceived stress in pregnancy, and preterm birth; and conceptualize and measure perceived stress in pregnancy and childhood perceived stress, and to evaluate the validity and reliability of these two measures. METHOD: We used a prospective cohort design to collect data for structural equation analysis. All women who attended pre-birth clinics at two hospitals in different communities in south-western Ontario were invited to participate; women (N = 421) completed questionnaires following their pre-birth clinic visit. RESULTS: The mean gestational age at the time of questionnaire completion was 28.2 (SD = 5.3) weeks. Questionnaire return rate was 74%. Perceived childhood stress was moderately associated with perceived stress in pregnancy(β= .54). Adult subjective SEP had a moderate effect on stress-reduction in pregnancy (β = -.44). The main influence of childhood subjective SEP on prenatal stress was indirect by increasing adult subjective SEP and reducing childhood stress. Family cohesion in childhood and pregnancy had small, direct effects on prenatal stress, but played a greater role in increasing subjective SEP and adult family cohesion and reducing stress in childhood. Findings related to our stress measurement analysis demonstrated that perceived childhood stress and prenatal maternal stress were each conceptualized as a single, latent variable. The childhood perceived stress measure was comprised of one item related to perceived family stress and three global perceived stress items. The construct of perceived stress in pregnancy differed from childhood. Perceived stress in pregnancy encompassed items of perceived financial and family stress and global measures of recent and more distant past perceived stress, suggesting that it reflected chronic stress. Initial analyses provide evidence of reliability and validity in this sample. CONCLUSIONS: Perceived childhood stress had a persistent effect on stress in pregnancy after adjustment for other child and adult factors. Childhood factors played important direct and indirect roles on stress in pregnancy. Adult subjective SEP constituted the main adult contribution. The childhood and pregnancy measures of perceived stress contribute to our understanding of the construct of perceived childhood and prenatal maternal stress and inform the timing and nature of effective prevention and intervention approaches. The Life Course Model of Stress and Preterm Birth can be used as a framework to (a) direct clinical risk assessment, (b) guide research on preconception psychosocial influences on perinatal health, (c) direct perinatal surveillance approaches, (d) influence policy and program development to include determinants of perinatal health across the life course, and (e) inform population health approaches to preconception and prenatal care. / Thesis / Doctor of Philosophy (PhD)

BACKGROUND: The DoHAD hypothesis suggests that preterm infants should achieve similar growth and body composition to healthy term-born infants in order to minimize disease risk. Postnatal growth of preterm infants is not fully understood and requires additional characterization, particularly in terms of differences to and transition from intrauterine growth. The period of postnatal adaptation to extrauterine life has been described in preterm infants by Rochow et al., 2016 and was seen to last 21 days. During these first 21 days of life, preterm infants experience a physiological, one-time, permanent contraction of extracellular water spaces (water loss), which causes a downward shift in the growth trajectories. This period of adaptation/water loss and the transition to extrauterine growth rates to achieve WHOGS target trajectories need to be incorporated into individual reference curves for preterm infants. OBJECTIVES: To develop and evaluate approaches to establish individualized growth trajectories for preterm infants to achieve growth similar to the WHO growth standards (WHOGS) for healthy infants at term, using recently published data about the physiological postnatal adaptation. METHODS: Two approaches were compared: 1) Postnatal-Percentile Approach: growth following the percentile at day of life (DOL) 21 until term; 2) Growth-Velocity Approach: using day-specific Fenton median growth velocities between DOL 21 and term. The impact of these approaches were compared using body compositions of 57 healthy preterm infants obtained before discharge (36+0/7 to 42+6/7 weeks PMA). The main outcome was the weight difference between the predicted trajectory and WHOGS target at 42+0/7 weeks PMA for the infants’ birth weight percentile. RESULTS: Postnatal-Percentile Approach: Trajectories deviated by up to 930g and did not match with WHOGS. Growth-Velocity Approach: Trajectories converged with term WHOGS after adjusting growth velocities with a factor of 1.0017 (approximately 10% increase in daily growth velocities). The validation of the Growth-Velocity Approach in preterm infants with minimal medical interventions revealed little deviation between predicted and actual weights. Infants were symmetrically distributed around zero deviation with a mean deviation of -10±370g and an average of 20% fat mass. In contrast, the Postnatal-Percentile Approach showed large deviations between predicted and actual weights and a skewed distribution around zero deviation with a mean deviation of -310±380g or 70±350g, following the birth or DOL 21 percentile, respectively. CONCLUSIONS: Individualized growth trajectories for preterm infants converged with the WHOGS when Fenton daily median growth velocities were applied and optimized with a single factor. The simplicity of the model and its ability to predict target weights that correspond to an appropriate fat mass suggests a biological principle. These results provide a superior understanding of preterm infant’s growth including the physiological postnatal adaptation and new trajectories to achieve WHOGS target trajectories. Results can be used to develop a bedside tool to aid clinicians in monitoring growth, guiding nutrition and preventing chronic adult diseases as a consequence of unguided, inappropriate growth. / Thesis / Master of Science (MSc) / It has been well established that growth of preterm infants has a long-term impact on health in adulthood. Since the survivability of preterm infants has drastically improved in the last decades, there has been a shift in focus to improving quality of life, including improved growth. Infants that grow too quickly or too slowly may develop inappropriate body compositions, with either too much or too little fat. A sub-optimal body composition can put infants at an increased risk for developing cardiovascular, metabolic or neurodevelopmental diseases later in life. In order to prevent these diseases and optimize growth, it is necessary to have a better understanding of how preterm infants should grow. This thesis aims to improve the characterization of growth for preterm infants by providing individual reference growth trajectories for preterm infants that take into consideration postnatal adaptation and aim to minimize later disease risk.

Background: Breast milk is an ideal source of nutrition for newborns as it provides nutrients required for growth in addition to numerous bioactive factors which help to develop an infant’s immune system. However, the macronutrient content of breast milk alone is not able to support preterm infant’s rapid growth needs and requires supplementation with fortifiers. There is strong evidence that the current practice of standard fortification (SF) may lead to nutritional deficits and consequently increases an infant’s risk of inadequate postnatal growth. Furthermore, the natural variation of breast milk composition makes it increasingly difficult to provide recommended macronutrient intakes with the SF. Individualized approaches, like adjustable fortification or target fortification (TFO), have been proposed to improve growth during hospitalization. A recent pilot trial demonstrated that TFO, which individually adjusts deficient macronutrient content after SF by analyzing the breast milk for native protein, carbohydrate and fat, is feasible in clinical practice and significantly reduces variation of macronutrient intakes. Objectives: To compare the response of preterm infants to feedings of breast milk with either SF or SF+TFO with respect to: 1) weight at 36 weeks’ post-menstrual age and growth velocity during hospitalization; 2) head circumference, length and body composition; and 3) the relationship between preterm infant’s weight or growth velocity and their macronutrient intake factors including protein intake and protein:energy (P:E) ratio. Methods: This was a single-center, double-blind randomized controlled trial completed at McMaster Children’s Hospital’s Level III NICU with a study period of at least 21 days. Preterm infants (n=103) born at <30 weeks of gestation and tolerating full enteral intakes of breast milk were enrolled and randomized to the Control (SF only) or Intervention (SF+TFO) groups. Native breast milk samples were collected for all infants on each study day and were analyzed for protein, carbohydrate and fat content. In the Control group, SF was provided using Enfamil (Mead Johnson, IL) human milk fortifier at the recommended dosage. In the Intervention group, after the addition of SF, modular macronutrient fortifiers were added based on analysis of the mother’s milk to reach target values based on ESPGHAN recommendations. Adjustment of the modular fortifiers was done three times per week. The primary outcomes were weight at 36 weeks’ PMA and growth velocity during the study period. Head circumference, length and body composition were also assessed at term-equivalent age. Subgroup analysis, stratified around the median protein levels after SF, also compared the growth outcomes between Control and Intervention groups. Multiple regression analysis models examined the effect of macronutrient intake factors and infant characteristics on weight, average growth velocity and daily weight gain. Results: Infants fed with SF+TFO had significantly higher protein (p<0.001), carbohydrate (p<0.001) and fat intakes (p<0.01) in addition to higher protein:energy and carbohydrate:non-protein energy (CHO:NPE) ratios (p<0.001) compared to those fed with SF alone. The average weight at 36 weeks’ PMA and growth velocity during the 21-day study period were higher for infants in the Intervention group (p<0.001). The Intervention group had significantly higher fat-mass (p<0.05) as well as more fat-free mass than the Control group at term-equivalent age (TEA), but were still within normal limits when compared to normative data from our NICU. At TEA, infants fed with TFO also showed significantly higher change in z-scores from birth for length when compared to infants fed SF with low-protein intakes (p<0.05). Change in head circumference z-scores were not statistically significant between groups. Higher average protein intakes and P:E ratios were each positively associated with higher weight at 36 weeks’ PMA (p<0.05). Moreover, higher daily weight gain was positively associated with higher daily protein intake from the previous study day (p<0.05). The absolute difference in day-to-day macronutrient intakes, however, were not significant predictors of daily weight gain. Conclusions: This study shows that target fortification of breast milk is promising as an individualized approach to improve the quality of nutrition for preterm infants. By addressing the variation and deficits of macronutrients that occur after standard fortification, infants were able to achieve higher body weight and faster weight gain. In the short term, target fortification may reduce the preterm infant’s risk for sub-optimal postnatal growth. These improved growth outcomes also have positive clinical implications on infant’s long-term health and development. Protein intake and the P:E ratio were identified as important factors for growth and should be considered in nutritional management and future fortification strategies for breast milk fed preterm infants. / Thesis / Master of Science (MSc)

The major objective of the research is to assess the risk of preterm birth associated with maternal proximity to hazardous waste and pollution from the Sydney Tar Pond sites in Nova Scotia, Canada. The design is spatial modelling of risks of preterm birth in population living in the Cape Breton regional municipality in 1996. The subjects are: 1604 observed cases of preterm birth out of total population of 17559 at risk in 1996. The analysis was done using both the frequentist and the Bayesian approaches. In the frequentist approach, the Poisson model for aggregated data was fitted using the quasi-likelihood approach to accommodate over-dispersion. Weighted regression was also used. In order to accommodate both the random effect and the anticipated spatial effects, Bayesian hierarchical modelling was also used to fit the Poisson model. The result of the Bayesian modelling shows that there is no significant spatial association of risk in the area studied. All the models also show that there is no decrease in risk of preterm birth as we move from the Tar Pond site to other region. None of the other covariates in the model show any significant association with increase risk of preterm birth either. There was no obvious clustering of risk in any region or part. / Thesis / Master of Science (MS)

Purpose: To characterize the environment in both ground and aerial ambulances in an effort to identify and quantify the risk factors associated with intraventricular hemorrhage (IVH) in preterm infants, with the goal of developing a device to mitigate this problem. Methods: A small, stand-alone battery operated device was developed to characterize the environment inside neonatal transports. This device included an array of sensors to measure acceleration forces, sound levels, temperature, pressure, and light intensities. Two of the data acquisition devices were used to collect data inside and outside the transport incubator simultaneously for a period of thirty minutes during a test flight in a transport helicopter. Real-time digital signal processing was performed for the sound signals to reduce data. Furthermore batch digital signal processing was performed on an external computer to calculate the vibration spectrograms, occurrence of impulsive forces, and variations in ambient temperature, pressure and luminance. The results were compared between the two devices to determine whether the current transport incubator design is reducing or increasing the suspected risk factors. Results: The vibration levels registered in the transport incubator during flight were five times greater than in the crew cabin in the vertical direction. High vibration levels were registered in the horizontal direction in the transport incubator, which were not registered in the crew cabin. In contrast, vibration in lateral direction was nearly half of that registered in the crew cabin. Sound levels were on average 70 dBA in the transport incubator. Luminance levels reached values up to 6920 Lux. No major changes in temperature and pressure were registered. Conclusions: IVH is a serious consequence of transporting preterm infants from one health care facility to another and occurs in roughly one out of three infants. To address this problem, a transport monitoring device can help characterize the environment in these transports in an effort to design a new state of the art transport incubator to mitigate this problem. / Master of Science

Made available in DSpace on 2017-07-10T14:17:18Z (GMT). No. of bitstreams: 1 Bruna_ Bugs.pdf: 6843021 bytes, checksum: 23c1d329c1dcde73af6cadec81ba6323 (MD5) Previous issue date: 2016-03-09 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / Life expectancy premature newborns hospitalized have been positively influenced by scientific and technological advances. However, a premature birth breaks the expectations built by the family about a perfect and healthy baby. Thus, having a premature baby is a stress factor to the parents during the hospitalization and at home, because they have the responsibility for the care of a child with many specifics. This research aims to evaluate the influences of educative activities in stress levels of preterm mothers after the hospital discharge. A quantitative study was developed, as a randomized clinical trial, registered under RBR-9yz2pb on Registro Brasileiro de Ensaios Clínicos (Rebec) in which mothers of preterm babies hospitalized in Neonatal Intensive Care Unit (NICU) or Intermediate Care Unit (ICU) were divided into two groups: intervention and control. The Intervention Group (IG) was composed by 15 mothers that participated in educative activities in order to prepare to the hospital discharge. The Control Group (CG) was composed by 27 mothers who received the standard discharge of the unit. Stress levels were assessed in both groups using stress measurement scales validated in Brazil and applied in two moments: between the first and second hospitalization week using Parental Stress Scale: Neonatal Intensive Care Unit and between the third and sixth month after discharge, during the return in the premature follow-up ambulatory , applying the Parenting Stress Index (PSI). The IG answered the PSS-NICU before participating in educative activities. Maternal knowledge was assessed by instrument that obtained reliability by Cronbach's alpha 0.9257. This evaluation happened with a pre-test, applied to the IG and CG during hospitalization and a post-test, applied to the IG after participation in the educative activity and to the CG up to three days after hospital discharge. IG and CG overall stress score assessed by PPS-NICU showed a statistically significant difference (p = 0.022), giving the similarity of the groups in this aspect. The percentile overall score of stress assessed by IEP was not significantly different in the groups (p = 0.115). The reduction of stress after discharge was 2,68 times greater in IG than CG. In the assessment of knowledge, the mothers of the IG hit 13% more questions in the post-test, whereas CG mothers hit 3 % more. Gestational age and birth weight baby influenced the acquisition of knowledge. In the evaluation of the intervention, all mothers said the activity helped them to answer doubts and to increase confidence in taking care of children at home. The educative activity allowed IG mothers did not have increased levels of stress after discharge, considering the greater severity of the babies, providing a balance between the IG and CG. / A expectativa de vida de Recém-Nascidos Pré-Termo (RNPT) hospitalizados têm sido positivamente influenciada pelos avanços científicos e tecnológicos. Contudo, o nascimento prematuro rompe as expectativas construídas pela família sobre a chegada de um bebê perfeito e saudável. Desse modo, ter um filho prematuro é fator estressante para os pais na hospitalização e em casa, pois assumem as responsabilidades pelo cuidado de uma criança com muitas especificidades. Esta pesquisa tem como objetivo avaliar a influência de uma atividade educativa nos níveis de estresse de mães de RNPT após a alta hospitalar. Desenvolveu-se estudo de abordagem quantitativa, do tipo Ensaio Clínico Randomizado (ECR), registrado sob número RBR-9yz2pb no Registro Brasileiro de Ensaios Clínicos (Rebec), em que as mães de RNPT hospitalizados Unidade de Terapia Intensiva Neonatal (UTIN) ou Unidade de Cuidado Intermediário (UCI) foram divididas em dois grupos: o de intervenção e o controle. O Grupo de Intervenção (GI) foi composto de 15 mães que participaram de atividade educativa com fim de preparo para alta hospitalar. O Grupo Controle (GC) foi constituído por 27 mães que receberam o preparo de alta padrão da unidade. O nível de estresse foi avaliado nos dois grupos, por meio de escalas de mensuração do estresse parental validadas no Brasil, aplicadas em dois momentos: entre a primeira e segunda semana de hospitalização, em que era utilizada a Escala de Estresse Parental UTIN (EEP-UTIN) e, após a alta hospitalar, entre o terceiro e sexto mês após alta, durante o retorno no ambulatório de seguimento do prematuro, aplicando-se a escala Índice de Estresse Parental (IEP). O GI ao participar da atividade educativa já havia respondido a EEP-UTIN. A avaliação do conhecimento materno foi mensurada por instrumento que obteve confiabilidade pelo Alfa de Cronbach de 0,9257. Essa avaliação ocorreu por meio de pré-teste, aplicado ao GI e GC durante a hospitalização e pelo pós-teste, aplicado para o GI após a participação na atividade educativa e para o GC até três dias após a alta hospitalar. O escore geral de estresse pela EEP-UTIN do GI e GC apresentou diferença estatística (p=0,022). O percentil de escore geral de estresse pela IEP não apresentou diferença significativa nos grupos (p=0,115). A redução do estresse após a alta foi 2,68 vezes maior no GI que no GC. Na avaliação do conhecimento, as mães do GI acertaram 13% a mais de questões no pós-teste, enquanto que as mães do GC acertaram 3% a mais. A idade gestacional e o peso ao nascer do bebê influenciaram a apreensão do conhecimento das mães. Na avaliação da intervenção, todas as mães disseram que a atividade contribuiu para esclarecer dúvidas e aumentar a confiança para cuidar dos filhos no domicílio. A atividade educativa permitiu que as mães do GI não tivessem seus níveis de estresse elevados após a alta, considerando a maior gravidade dos bebês, possibilitando uma equivalência nos grupos GI e GC.

<b>Background:</b> The survival rate of preterm children has risen steadily due to advances in obstetric and neonatal intensive care. Children born extremely preterm (&le;28 weeks of gestation) are at high risk of long term developmental problems, including cerebral palsy, motor and cognitive impairment, visual and auditory deficits and behavioural problems. This can have serious implications for their quality of life and that of their family and carers. These children take up a disproportionate amount of neonatal intensive care unit resources and overall costs, and as they grow up are more likely to require additional health and social care services beyond routine care to compensate for their functional limitations. The early identification and management of factors that mediate long term outcome is necessary to assist healthcare professionals in selecting appropriate treatment pathways, and to develop, target and evaluate interventions. Many risk factor analyses for neurodevelopmental impairment have been published in preterm populations, but this vast literature has not been formally summarised. Furthermore, there is a dearth of studies reporting longitudinal analysis of neurodevelopmental trajectories from early childhood to adulthood. <b>Objectives:</b> The first aim of this thesis was to perform a comprehensive systematic review of the world literature over the last two decades, to consolidate the evidence about the prognosis of neurodevelopmental outcome in children born very preterm or with very low birth weight. The second aim was to conduct a longitudinal analysis of a cohort of extremely preterm participants followed up into early adulthood to investigate the trajectories of long term sequelae over time, and to examine the association of neurodevelopmental course in relation to the predictive factors identified in the systematic review. <b>Methods:</b> A systematic review was conducted using MEDLINE, EMBASE and PyscINFO databases to identify studies published between January 1 1990 and June 1 2014 reporting multivariable prediction models for the neurodevelopment of children born &le;32 weeks of gestation or with a birth weight &le;1250 grams (protocol registration number CRD42014006943). Seventy-eight studies reporting 222 risk factor models for neurodevelopmental outcome were identified. Two independent reviewers extracted key information about study design, outcome definition, risk factor selection, model development, reporting, and conducted a risk of bias assessment. To address the second objective of the study, a longitudinal analysis of cognitive and behavioural trajectories was conducted using a prospective, population-based cohort study in the United Kingdom and the Republic of Ireland. Three hundred and fifteen surviving infants born less than 26 completed weeks of gestation recruited at birth in 1995 and 160 term-born classroom peers recruited at age six were followed-up to 19 years. Participants were invited for up to four standardized, blinded cognitive assessments and the parent-completed Strengths and Difficulties Questionnaire was used to assess behavioural problems. <b>Results:</b> The systematic review of risk factors for motor impairment in children born very preterm or with very low birth weight provided strong evidence that neonatal brain injury is a robust prognostic factor for cerebral palsy, and some evidence that the use of postnatal steroids increases the risk and the use of antenatal steroids reduces the risk of cerebral palsy. There was moderate evidence that male sex was prognostic for motor impairment at school age in children free of major disability. The systematic review of risk factors for cognitive impairment identified male sex, non-white ethnicity, lower levels of parental education and lower birth weight as significant predictors of global cognitive dysfunction in early infancy, with parental education having a sustained impact after five years of age. There was also evidence that male sex was predictive of delayed language development in early infancy. Gestational age was found to be of limited use as prognostic factor for cerebral palsy, motor and cognitive impairment in cohorts restricted to &le;32 weeks of gestation. There was a dearth of good quality studies investigating risk factors for behavioural problems and psychiatric disorders and the findings of this review were inconclusive. The only factors that appeared to be consistent predictors of general behavioural problems were markers of socio-economic deprivation, neurodevelopmental or cognitive delay, and an abnormal behavioural screen in early infancy. In the longitudinal analysis of the prospective, population-based cohort of extremely preterm children, cognitive trajectories were stable in both the extremely preterm and term-born groups over time with persistent deficit in the extremely preterm group of 25.2 IQ points (95&percnt; CI: -27.8 to -22.6, p&LT;0.001) and only minimal catch-up over time. Participants with neonatal brain injury and of male sex had the largest deficits, but a lower level of maternal education and earlier gestational age at birth were also associated with reduced IQ scores. Behavioural problems were also more prevalent among the extremely preterm participants who had a mean Total Difficulties Score of 4.81 points above their term-born peers (95&percnt; CI: 3.76 to 5.87, p&LT;0.001) and which persisted over the time period. Behavioural difficulties were mainly due to hyperactivity, inattention and peer problems and were strongly associated with a positive behavioural screen in early infancy. <b>Conclusions:</b> The most robust predictors of poor neurodevelopmental outcome identified by the systematic review were neonatal brain injury, male sex, and markers of social disadvantage. The unclear findings for many risk factors may reflect differences in study design, study population, methodological quality and lack of standardization of measures. Or it may simply reflect the fact that prognostic modelling in such a heterogeneous population is challenging and complex, with multiple risk factors acting sequentially over time, and often with the existence of multiple impairments within the same individual. The main conclusions from the longitudinal analysis of children born extremely preterm is that being born too soon appears to place limits on brain plasticity and function which is not recovered over time; with the most vulnerable being males and those with evidence of brain injury early in life. These structural abnormalities may disturb neurodevelopmental processes and impede the brain from maintaining a normal developmental trajectory. If extremely preterm children fail to achieve optimum levels of cognitive function and are still experiencing behavioural problems once they have reached maturity, then this has implications for health and well-being in later adulthood and old age. Cognitive test scores in infancy and early childhood reflect early adult outcomes and a positive behavioural screen in infancy is strongly associated with early adult behavioural outcomes. <b>Recommendations:</b> The systematic review revealed some shortcomings in methodology and reporting that could be improved in future studies, and confirmed that that there is a dearth of properly designed and well-conducted prognostic modelling studies in this field. The findings and recommendations of this critical review should be used as a basis for the design, analysis and reporting of future studies seeking to develop multivariate risk factor or prognostic models in this population. There is an urgent need for larger population cohorts followed up routinely beyond two years as subtle outcomes such as impairment of executive function and fine motor skills cannot be reliably assessed at this age, and the natural course of some disorders may have their onset later in childhood. / Studies with larger sample sizes and greater power are needed for studying less common conditions in preterm populations and there should be more standardisation of outcome and risk factor measurements, particularly with the use of standard diagnostic evaluations to assess psychiatric disorders. Future studies should include a term-born comparison group and adopt appropriate statistical analysis techniques to analyse longitudinal outcome data and the impact of risk factors on these trajectories. Additional research is required to improve the prediction of individual differences, and to identify the neuropathological differences underlying different developmental trajectories and their interaction with environmental influences over time.

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