Dissertations / Theses on the topic 'Prematurity'

Apnoea remains an important problem in the prematurely born infant. Apnoeas can be divided into central, obstructed and mixed apnoea. Apnoeas frequently occur in association with periodic breathing, as well as isolated events. It remains unclear whether there is a common mechanism for all these types of disturbance in normal respiratory activity or whether there are additional factors which determine the type of apnoea. HYPOTHESES The hypotheses explored in this thesis were that isolated central apnoea was due to reduced chemoreceptor sensitivity, in mixed apnoea there was additional activation of the costophrenic inhibitory reflex and apnoea associated with periodic respiration was due to instability of respiratory control, with periods of over ventilation leading to apnoea. METHODS Polygraphic techniques were used to identify the frequency, type and length of apnoeic periods in infants born at/or less than 33 weeks gestation who were otherwise healthy sequential studies were undertaken to determine the pattern of apnoea and how it changed with time. Chemoreceptor sensitivity was assessed by measuring the ventilatory response to an added respiratory dead space of twice the anatomical dead space. The rate of response to the added dead space was assessed to determine if it related to the apnoea types and in particular was reduced in periodic respiration. The respiratory response to an imposed airway obstruction was used to determine the strength of the Hering Breuer and costophrenic inhibitory reflex, as respiratory efforts against an obstruction would induce chest wall distortion. RESULTS Twenty-eight infants with a mean gestation of 29+4 weeks and birth weight was of 1.39kg, were studied on 71 occasions. The prevalence of apnoea in this preterm population was nearly 100%, with the more immature infants at greater risk. Ninety percent of apnoeas (>5secs) were central, 9% mixed and 1 % obstructive; however, 50% of apnoeas over 14s had an obstructive component. Thirty-three percent of apnoeas were associated with a desaturation, the longer the apnoea the greater degree of desaturation. Apnoea associated with periodic respiration accounted for 72.3% of all apnoeas and periodic respiration increased with postmentrual age. In ninety-three percent of the studies there was at least one episode of periodic breathing. This relationship was not related to postmentrual age. A significant relationship was found between the rate of periodic central apnoeas and chemoreceptor sensitivity, as examined by the response to added dead space, related to a increased reliance on chemoreceptors in this group of infants The rate of response to the added dead space however shortened with increasing post menstrual age and that there was a significant inverse relationship between this and the rate of central periodic apnoeas. No significant relationship was found between the response to external obstruction and the rate of apnoea. Although an active Hering Breuer reflex was found in all infants, this was related to both to the gestational and postmenstrual age of the infants. CONCLUSIONS Apnoeas associated with periodic respiration are the commonest form of apnoea. As demonstrated in this thesis these occur most frequently in infants with the most rapidly responding chemoreceptors, these data support the hypothesis that this pattern of respiration is due to an underdamping of the chemoreceptor response. No evidence was found to support the hypothesis that mixed apnoea was associated with activation of the costophrenic inhibitory reflex.

Preterm infants are at increased risk of cardiometabolic and neurodevelopmental disorders in later life. The typical postnatal growth pattern of failure to achieve the equivalent of a normal fetal growth rate, followed up by catch-up growth, altered adiposity and altered hypothalamic-pituitary-adrenal axis (HPA) activity may be predisposing factors. Potential mechanisms that may mediate such programmed effects include altered DNA methylation and faster telomere attrition. A prospective cohort of 46 very preterm (25+2 to 31+5 weeks’ gestation, mean 28.6) and 40 full term (38+3 to 42+2 weeks’ gestation, mean 40.2) infants was established to investigate potential mechanisms. Infants were studied at birth, term equivalent age, 3 months and 1 year corrected for prematurity. At all time points, linear growth and body composition (by densitometry) were measured and buccal (epithelial) cells was collected for measurement of DNA methylation (5mC) and relative telomere length. Compared with full term infants, preterm infants were lighter (p < 0.001) and had a smaller head circumference (p < 0.05) at all time-points and were shorter at term equivalent (p < 0.001) and 3 months corrected age (p = 0.002). Preterm infants also had greater percentage body fat at term equivalent age (mean difference = 5.5%, p < 0.001), which normalised by 3 months corrected (mean difference = 0.9%, p = 0.4). Preterm infants had a blunted salivary cortisol response (mean difference 0.4 μg/dL, p = 0.02) to a stressor (physical examination) at 3 months compared to term infants at this age, suggesting altered activity of the HPA axis. 5mC is fundamental in the control of expression of imprinted genes involved in fetal growth. Notably, a number of studies in humans exposed to an adverse environment in early life have demonstrated altered 5mC at the differentially methylated regions (DMRs) controlling the expression of the key fetal growth factor insulin like growth factor 2 (IGF2) and at the linked H19 imprinting control region (H19 ICR). At birth, preterm infants had a significant decrease in 5mC at DMR2 compared with term infants at birth (β = –11.5, p < 0.001) and compared with preterm infants at term equivalent age (mean difference = -7.4, p = 0.01). By term equivalent age, preterm infants had decreased 5mC at both DMR2 (β = –2.8, p = 0.01) and the H19 ICR (β = –2.3, p = 0.048) compared with term infants at birth, although this difference disappeared at 1 year corrected. Although research has suggested that catch up growth may confer an unfavourable metabolic phenotype, poor initial weight gain can associate with worse cognitive outcome. A pathway was established for obtaining advanced magnetic resonance images of the preterm brain. 5mC at H19 ICR and DMR2 in buccal DNA showed no association with measures of white matter microstructure or whole brain volumes. Term infants demonstrated telomere lengthening over the first year of life (mean difference = -0.3, p = 0.02). There was no significant change in telomere length over the first year of life in preterm infants (mean difference = 0.2, p = 0.34). However, as preterm infants at term equivalent age had longer telomeres compared to term infants at birth (β = 0.6, p < 0.001), ultimately there were no differences between the term and the preterm groups at 1 year corrected age (β = 0.3, p = 0.07). The DNA modification 5-hydroxymethylcytosine (5hmC) is a stable modification in its own right and is also thought to be an intermediate step in DNA demethylation. 5hmC is abundant in the placenta but has not been studied in the context of fetal programming. Additionally, previous research using methods such as bisulphite conversion would not have discriminated between 5mC and 5hmC and therefore the role of 5mC may not have been accurately measured. To study the relationship between 5mC, 5hmC and fetal growth, gene expression of candidate imprinted and non-imprinted genes in full term placental samples from the Edinburgh Reproductive Tissue BioBank was analysed. 5mC and 5hmC within the IGF2/H19 and KvDMR (controlling CDKN1C) loci was estimated using chemical capture and immunoprecipitation techniques that discriminate between modifications. Relationships between the expression of IGF2 (r = 0.3, p = 0.02) and CDKN1C (r = -0.3, p = 0.01) and birth weight across the normal range were found and in keeping with the known action of these genes. 5mC at IGF2 DMR0 (β = 0.3, p = 0.02) and KvDMR (β = 0.3, p = 0.02) and 5hmC at H19 gene body (β = 0.2, p = 0.04) associated with birth weight. Thus, DNA modifications at imprinted DMRs may modulate environmental influences on fetal growth across the normal range. DNA methylation at IGF2/H19 can be influenced by early life events. It remains to be seen whether any changes are present later in childhood and whether they associate with risk factors for the metabolic syndrome.

INTRODUCTION Preterm birth, defined as the birth of a baby of less than 37 weeks gestational age, has a number of consequences at social, ethical, economic and health care level. These consequences affect both hospital health care programs, local programs and prevention plans. The rapid and remarkable innovation of assistance methods and of equipment in the Neonatal Intensive Care Unit has allowed a gradual increase of survival rates of extremely low weight and low gestational age premature infants. Several studies have demonstrated that premature and extremely premature infants show severe short, medium and long-term clinical outcomes, in particular neurological and neurosensorial outcomes. However, long-term follow-ups of infants cohorts selected by area-based surveillance are not available. AIM The aim of this study is to analyse the clinical outcomes of preterm infants in the Veneto Region by means of a follow-up assessment of short, medium and long-term health outcomes according to gestational age, in particular for extremely low weight and extremely low gestational age premature infants. MATERIALS AND METHODS The study has been divided into different phases. In the first preliminary phase a stratification sampling of population has been carried out on the basis of the gestational age of all infants born in the Veneto Region from 2003 to 2009. For this phase the current flow of the Certificate of Delivery Care (CEDAP) has been used. This flow has been mandatory since 2001 and records all newborns of the Region, it contains information on the infant (gender, weight, length, head circumference, gestational age, major resuscitation care in case of assisted intubation and ventilation and medical cardiac resuscitation, minor resuscitation care in case of aspiration and cardiac massage, infant’s admission in neonatal intensive care unit, possible malformations and possible cause of infant mortality), on the delivery (single or multiple, natural or cesarean, possible type of pain relief and type of anesthetic, maternal complications), on pregnancy (number of tests and ultrasound scans, prenatal diagnosis, course of pregnancy: physiological or pathological, threatened abortion, threatened preterm labour, infectious diseases, infections of the genitourinary tract, diabetes and gestosis) and on the mother and the father (age, education, job, marital status, exposure to risk factors such as smoke). Stratification sampling has been carried out according to the gestational week (GW) from 20 GW to 42 GW. In particular, all newborns ≤ 28 gestational weeks in the above mentioned period have been considered. Patients cohorts have thus been arranged and the cohorts of infants born in 2005 and from 2007 to 2009 have been studied. In the next phase, starting from current statistics, patients’ natural history has been reconstructed, when possible, by means of death certificates (ISTAT) in order to assess survival, hospital discharge records for recoveries, intercurrent acute pathologies and chronic pathologies, information flow on the rehabilitation activity ex art. 26 L 833/1978 of the Veneto Region in order to assess the admission to rehabilitative services and the flow Rare Diseases Registry. In particular, the “chronic” patients have been identified, defined as subjects with at least 2 hospitalizations within 12 months, both characterized by the same pathology code of hospital discharge records. Eventually the results have been analysed: mortality, survival rate, patients affected by chronic pathologies, patients affected by rare diseases and patients who have undergone rehabilitation cycles. The patients not included in the categories described above will be sampled and assessed in follow-up after this study according to the following protocol: qualitative assessment of spontaneous motor function, qualitative assessment by means of classification systems (ABC, Gross Motor Function Measure, and, for the most severe cases, Besta scale and QUEST scale), cognitive assessment (Griffiths, WIPPSI, WISC-IV), neurosensorial assessment by means of the analysis of the Multimodal Evoked Potentials (PEV, BAEPs, SEP), assessment of neuroimaging (standard protocol and 3D brain NMRI with DTI and resting state for tractographic assessment). RESULTS During the analysed period from 2003 to 2009 in the Veneto Region 322.598 neonates have been recorded, approximately 46.000 neonates/year. 91,71% of these were born at term (>37 GW), 7,63% were born premature (<37 GW). If we consider preterm neonates, 2,13% were born before 32 GW and 0,55% are ≤ 28 GW. The recorded premature neonates ≤ 28 GW, who are 0,55% of the total amount, are approximately 1785, on average 255/year. Birth mortality total rate in neonates between 2003 and 2009 is 2,9 x 1000 in single deliveries and 8,7 x 1000 in multiple deliveries; the rate grows along with the decrease of gestational age, in particular rates of 8,3 at 36 GW for single deliveries vs 1,1 for multiple deliveries are recorded, 17,8 for single deliveries (35 GW) vs 6,0 for multiple deliveries and 117,6 for single deliveries vs 57,7 for multiple deliveries in neonates born before 28 GW. Premature babies <28 GW increased from 201 in 2003 (0,48% of neonates in 2003) to 301 in 2009 (0,63% of neonates in 2009). Multiple deliveries of neonates < 28 GW are 24% (20% twins, 3% multiple twins) in comparison to 1,2 % of babies born at term (2,7% twins and 0,1% multiple twins) and 3% in comparison to the total amount of deliveries. The percentage of extremely low weight and gestational age neonates and their survival are thus growing rapidly in the Veneto Region. This is due to the growing innovation of care methods and of equipment in the Neonatal Intensive Care Units: even babies born at 20 GW are resuscitated and survive (1 baby born in 2007 recorded, 1 at 19 GW and 1 at 20 GW; in 2008 7 babies born at 21 GW, only two neonatal deaths). Our analysis shows that apparently some factors are implied in preterm birth: one factor is the mother’s age, in particular the percentage of neonates <28 GW decreases from 1,2% for mothers <24 years old to 0,8% between 25 and 29 years and 1,5% if >40 years old (relative risk RR is of 2,3). Another factor is the mother’s ethnic group: among African women and Eastern European women the percentage of preterm neonates is twice as high as among Italian women. If we analyse the women who have delivered preterm babies, 55% are primiparas (RR 1.2), 30% report a spontaneous abortion in their anamnesis before the delivery (RR 1.8), 4% report a stillbirth before the delivery (RR 3.1) and 12% report a voluntary interruption of pregnancy (RR 2.1). 7% are smokers (RR 1.1) and 2,6% undergo medically assisted procreation or MAP (RR 2.03). With regard to MAP, 1.8% babies are born every year; 11% of the neonates ≤28 GW were born by means of MAP vs 1% of babies born at term by means of MAP. If we now analyse the results of neonates born < 28 GW in 2005 and 2007-2009 cohorts, in 2005 the babies who died during the first year of life are 65 (29%); the survivors are 160 (71%). 11 survivors out of the total amount are chronic patients (6.8%); 9 have been rehabilitated (5.6%); 1 affected with a rare disease has been registered (0.6%). Although they were not mentioned in the considered sources, 105 show diagnosis of complications at birth and/or during the first year of life (66%). The percentage of premature babies with severe outcomes is thus 79%. 37 are not mentioned in any source and have had no complications (23%). From 2007 to 2009 dead babies during the first year of life are 250 (31%); survivors are 545 (69%). 61 patients out of the total amount are chronic patients (11%), 1 of them is affected by a rare disease and registered in the Rare Disease Registry, 13 have been rehabilitated (2.3%) and 3 (0.5%) report rare diseases diagnosis on the hospital discharge record; 63 are rehabilitated (12%), 15 out of these are chronic; 11 are affected by rare diseases (2.7%), only two of which are registered in the Rare Disease Registry. Although they were not mentioned in the considered sources, 360 report diagnosis of complications at birth and/or during the first year of life (66%). The percentage of premature babies with severe outcomes is approximately 91%. 72 are not mentioned in any source and have had no complications (13%). CONCLUSIONS The percentage of neonates with severe prematurity is rising remarkably in the Veneto Region due to the growth of the survival rate of babies born between 22 and 28 GW. By means of preliminary analyses, several factors related to the mother’s history, to the reproductive history and to the pregnancy course, as well as to the neonate, can apparently determine a preterm birth. In light of these preliminary data, considering the above mentioned survival and disability rates, it is particularly important to know the babies’ natural history and to verify the short and long-term clinical outcomes in terms of impact on the health care and rehabilitation planning.
INTRODUZIONE La nascita pretermine, definita come nascita che avviene prima di 37 settimane complete di gravidanza, comporta una serie di implicazioni sociali, etiche, economiche e sanitarie che impattano sui programmi assistenziali ospedalieri e territoriali e sui programmi preventivi di salute. La rapida e cospicua innovazione dell’assistenza e delle strumentazioni nelle Unità di Terapia Intensiva Neonatale ha prodotto negli ultimi anni un progressivo aumento della sopravvivenza dei gravi prematuri di basso peso e di bassa età gestazionale. Numerosi studi hanno dimostrato che i bambini nati prematuri ed estremamente prematuri presentano severi esiti clinici a breve e medio termine, in particolare neurologici e neurosensoriali. Non sono tuttavia disponibili follow-up a lungo termine di coorti di bambini selezionate da sorveglianze area-based. SCOPO Lo scopo di questo studio è analizzare gli esiti clinici dei nati prematuri in Regione Veneto, valutando in follow-up gli esiti di salute a breve, medio e lungo termine per età gestazionale, in particolare per i gravi prematuri di basso peso e di bassa età gestazionale. MATERIALI E METODI Lo studio è stato suddiviso in diverse fasi. In una prima fase preliminare è stata condotta una stratificazione per età gestazionale della popolazione di tutti i nati in Regione Veneto nel periodo 2003-2009. Per questa fase è stato utilizzato il flusso corrente del Certificato di Assistenza al Parto (CEDAP). Tale flusso è mandatorio dal 2001 e registra tutti i nati della Regione, contiene informazioni relative al nato (sesso, peso, lunghezza, circonferenza cranica, età gestazionale, necessità di rianimazione maggiori se intubazione e ventilazione assistita e rianimazione cardiologica con farmaci, necessità di rianimazione minore se aspirazione e massaggio, necessità di ricovero del nato in reparto di cure intensive neonatali, eventuale presenza di malformazione ed eventuale causa di nati-mortalità), al parto (genere del parto: semplice o plurimo, modalità parto se spontaneo o cesareo, eventuale tipo di controllo del dolore e tipo di anestesia, complicanze materne legate al parto), alla gravidanza (numero di accertamenti eseguiti in gravidanza, numero di ecografie, indagini prenatali, decorso gravidanza se fisiologico o patologico, se patologico il tipo di condizione morbosa insorta durante la gravidanza: minacce di aborto, minaccia di parto prematuro, malattie infettive, infezioni tratto genito-urinario, diabete e gestosi) e informazioni riguardanti il padre e la madre (tra cui età, scolarità, professione, parità, stato civile, esposizione a fattori di rischio quali il fumo). La stratificazione è stata fatta per settimana gestazionale dalla 20 sg alla 42 sg. In particolare sono stati considerati tutti i nati < 28 settimane gestazionali nel periodo sovra descritto. Sono state pertanto create delle coorti di pazienti e sono state analizzate le coorti dei nati nel 2005 e nel triennio 2007-2009. Nella fase successiva, a partire dalle statistiche correnti, sono state ricostruite le storie naturali di ciascun paziente, quando possibile, utilizzando le schede di morte (ISTAT) per valutare la sopravvivenza, le schede di dimissione ospedaliera (SDO) per le ospedalizzazioni, le patologie acute intercorrenti e patologie croniche, flusso informativo sull’attività di riabilitazione dei centri ex art.26 L 833/1978 per valutare l’accesso a servizi riabilitativi e il flusso Registro Malattie Rare. In particolare sono stati identificati i soggetti “cronici” definiti come i soggetti con almeno 2 ospedalizzazioni nell’arco di 12 mesi caratterizzate entrambe dallo stesso codice di patologia SDO. ,Alla fine sono stati analizzati gli esiti: mortalità, sopravvivenza, soggetti affetti da patologie croniche, soggetti affetti da malattie rare e soggetti che hanno necessitato di cicli di riabilitazione. I soggetti non inclusi nella categorie sovradescritte verranno in un tempo successivo a questo studio campionati e valutati in follow up secondo il protocollo seguente: valutazione qualitativa della motricità spontanea, valutazione quantitativa mediante l’utilizzo di scale di valutazione (ABC, Gross Motor Function Measure, e, per i casi con esiti più gravi, Scala Besta e scala QUEST), valutazione cognitiva (Griffiths, WIPPSI, WISC-IV), valutazione neurosensoriale mediante studio del Potenziali Evocati Multimodali (PEV, BAEPs, SEP), valutazione di neuroimaging (RMN cerebrale con protocollo standard e 3D con DTI e resting state per la valutazione trattografica) trattografica). RISULTATI Nel periodo considerato 2003-2009 in Regione Veneto sono stati registrati 322.598 nati, in media circa 46.000 nati/anno. Di questi 91,71% sono nati a termine (>37 sg), 7,63% nascono prematuri (<37 sg). Se consideriamo i nati pretermine, 2,13% sono nati prima delle 32 sg e 0,55% sono <28 sg. I nati prematuri <28 sg registrati, che rappresentano lo 0,55%, sono 1785 circa, in media 255/anno. Il quoziente di natimortalità totale dei nati dal 2003 al 2009 è 2,9 x 1000 per i parti singoli e 8,7 x 1000 per i parti plurimi; tale quoziente aumenta con il decrescere dell’età gestazionale in particolare si registrano quozienti di 8,3 alla 36 sg per i parti singoli vs 1,1 per i parti plurimi , 17,8 per i parti singoli (35 sg) vs 6,0 per i parti plurimi e 117,6 per i parti singoli vs 57,7 per i parti plurimi nei nati prima delle 28 sg. I nati prematuri <28 sg sono passati da 201 nel 2003 (0,48% dei nati nel 2003) a 301 nel 2009 (0,63% dei nati nel 2009). I parti plurimi dei neonati < 28 sg sono il 24% (20% gemellari e 3% plurigemellari) rispetto al 1,2 % dei nati a termine (2,7% gemellari e 0,1% trigemellari) e il 3% rispetto al totale del parti. La percentuale di nati con prematurità grave e la loro sopravvivenza sono dunque in grande aumento nella Regione Veneto. Questo fenomeno è dovuto alla crescente innovazione dell’assistenza e delle strumentazioni nelle Unità di Terapia Intensiva Neonatale: vengono rianimati e sopravvivono anche nati dalle 20 sg (registrati 1 nati nel 2007 uno alla 19 sg e 1 alla 20 sg; nel 2008 7 nati alla 21 sg di cui solo due decessi alla nascita). Dalle nostre analisi alcuni fattori sembrano implicati nella nascita pretermine: l’età della madre è uno di questi in particolare la percentuale dei nati <28 sg passa da 1,2% per madri <24 aa allo 0,8% tra i 25 e i 29 anni e 1,5% se >40 aa (rischio relativo RR di 2,3). Un altro fattore è la cittadinanza materna: le donne africane e le donne dell’Europa dell’Est hanno una percentuale di nati pretermine doppia rispetto alle donne italiane. Se analizziamo le donne che hanno partorito dei neonati prematuri, il 55% sono primipare (RR 1,2), il 30% segnala in anamnesi un aborto spontaneo precedente al parto (RR pari a 1,8), il 4% un nato morto precedente al parto (RR 3,1) e il 12% una interruzione volontaria di gravidanza precedente (RR 2,1). Il 7% fuma (RR 1,1) e il 2,6% ricorre a una Procreazione Medicalmente Assistita o PMA (RR 2.03). Per quanto riguarda la PMA i nati sono 1,8% all’anno; 11% dei nati <28 sg sono nati da PMA vs 1% dei nati a termine da PMA. Se analizziamo ora gli esiti dei nati < 28 sg nelle coorti 2005 e 2007-2009, nel 2005 i morti entro il primo anno di vita sono 65 (29%); i sopravissuti sono 160 (71%). Dei sopravissuti 11 sono pazienti cronici (6,8%); 9 sono stati riabilitati (5,6%); 1 affetto da malattia rara certificato (0,6%). 105 pur non essendo presenti nelle fonti considerate presentano diagnosi di complicazione alla nascita e/o dentro l’anno (66%). La percentuale di nati prematuri con esiti maggiori è pertanto di 79%. 37 non sono presenti in alcuna fonte né hanno avuto delle complicazioni (23%). Nel triennio 2007-2009 i morti entro il primo anno di vita sono 250 (31%); i sopravissuti sono 545 (69%). Dei sopravissuti 61 sono pazienti cronici (11%) di cui 1 con malattia rare e certificato verificato nel flusso malattie rare, 13 riabilitati (2,3%) e 3 (0,5%) presentano diagnosi di malattie rare alla SDO; 63 sono riabilitati (12%) di questi 13 sono cronici ; 15 affetti da malattia rara (2,7%) di cui solo due con certificato di patologia rara. 360 pur non essendo presenti nelle fonti considerate presentano diagnosi di complicazione alla nascita e/o dentro l’anno (66%). La percentuale di nati prematuri con esiti maggiori è circa 91%. 72 non sono presenti in alcuna fonte né hanno avuto delle complicazioni (13%). CONCLUSIONI La percentuale di nati con prematurità grave è in grande aumento nella Regione Veneto per l’incremento della sopravvivenza dei nati tra le 22 e le 28 sg da analisi preliminari sembra che numerosi fattori relativi alla storia materna, alla storia riproduttiva e al decorso della gravidanza nonché fattori relativi al neonato possano determinare una nascita pretermine. Alla luce di questi dati preliminari, risulta particolarmente rilevante, soprattutto per le ricadute programmatorie dei servizi di assistenza e di riabilitazione, conoscere la storia naturale di questi bambini e verificarne gli esiti in termini di disabilità complesse che ne possono derivare viste le percentuali di sopravvivenza e di disabilità sovra riportate.

Children born prematurely are at higher risk for medical, learning and developmental concerns than children born full term. This study analysed the files of 73 pre-term children who completed an Assessment and Monitoring programme in New Zealand between 1998 and 2007. The participants were 39 boys and 34 girls with gestational ages ranging from 23 weeks to 32 weeks at birth and who attended the programme until they were 4 years chronological age. Analysis of the reports sent to paediatricians following the children’s monitoring visits at 8 months, 12 months, 18 months, 24 months and 36 months (corrected age) and at 48 months, chronological age indicated delays in achieving the expected developmental milestones in expressive language, cognition and gross motor skills for up to half of the cohort. Moreover, the findings further suggest that a ‘sleeper effect’ or ‘invisible prematurity’ emerged for up to half of the cohort at age 36 months. This ‘invisible prematurity’ and the developmental delay in cognition, expressive language and gross motor skills have implications for early childhood teachers as teachers need to develop an awareness of, and skills to identify and work effectively with these young children and their families. Practical teaching and learning strategies are presented for teachers.

The ocular problems associated with premature birth have been with us ever since it was discovered that the application of high levels of inspired oxygen provided a reduction in mortality. The consequence of this reduction in mortality has been a rise in morbidity; these mortality and morbidity rates have oscillated during the attempt to find a reasonable balance. The use of contemporary technology during the attempt both to understand the premature baby's delicate physiology and to maintain life to younger and lighter babies has not yet produced stability. The incidence of typical retinal maldevelopment, retinopathy of prematurity (RCP), was analysed by serial weekly ophthalmoscopy examinations in a regional special care baby unit, 579 examinations being made on 138 babies. The best instrument for this examination was found to be a compact indirect ophthalmoscope incorporating an inverting eyepiece - the Reichert Jung monocular indirect ophthalmoscope. The optimum time for ocular examination to discover potential ocular morbidity was at 33 weeks post-conceptual age (PCA) with continued examinations to the age of 37 weeks PCA. The babies that were found to be at risk of a significant grade of RCP were found to be of a birth weight of less than 1251 grams or had an estimated gestational age at birth of 30 weeks or less. A refractive state of myopia was found to be the norm. The myopia reduced as life progressed to attain emmetropia around the age of 50 weeks PCA or 22 weeks survival. The reduction of the myopic state was found to be dependent on birth weight and gestational age at birth, the youngest and therefore the lightest being more predictable in attaining emmetropia. Refractive variations were found to be coincident with the timings of certain medical treatment regimes and a hypothesis is postulated as to the mechanism of this association.

In recent years, concern about a new epidemic of retinopathy of prematurity (ROP) has focused attention on the increasing incidence of the disease and the factors responsible for its most severe consequences. Two studies designed to address these issues were done using data from three sources: the B.C. Health Surveillance Registry (Registry), Physicians's Notices of Livebirth (PNOB), and the Vancouver General Hospital (VGH). In the first study, Registry and PNOB records were used to determine crude annual birth weight-specific incidence rates for ROP in infants liveborn in the Province of British Columbia (B.C.) in the period 1952-1983. These rates showed that, in B.C., the original epidemic of the disease ended in 1954. Linear regression lines fitted for each of four birth weight categories showed that, in the 29 year period after 1954, there was a significant increase in the incidence of ROP-induced blindness in infants weighing less than 1000 grams at birth. To refine this observation, the data were sub-divided: the 29 year period, to two smaller periods, 1955-1964 and 1965-1983; the less than 1000 gram birth weight category to two sub-categories, 500-749 and 750-999 grams. Since the inter-period incidence should have been similar if the birth weight-specific incidence had not changed since the end of the original epidemic, the crude weight-specific rates for ROP-induced blindness in the early period were used to calculate the expected number of cases in the later period. When weight-standardized incidence ratios (SIR's) and 95% confidence limits were calculated, the results showed that, in the 750-999 gram sub-category, the SIR was significantly increased. Infants born in the period 1965-1983 were 3.07 times more likely to be ROP: blind than their equal weight counterparts in the earlier period. In infants weighing 500-749 and 1000 grams or more, there was no evidence to suggest an increase in incidence after 1954. The second study was done to determine the cofactors that differentiate infants who are blinded by ROP from those who are not. Infants were included if (i) they were born in B.C. between 1955 and 1983, (ii) they were known to the Registry as being ROP: blind (cases) or not blind (controls), and (iii) they were born in or admitted to the VGH within 28 days of birth. When the data from all three data sources were dichotomized and analyzed using univariate techniques, two variables, respiratory distress syndrome (RDS) and neonatal weight loss, showed a significantly protective effect. The effect of RDS disappeared when the data were stratified by birth interval indicating that the observed association was confounded by time. When the variables were reanalyzed in continuous form, none were significantly associated with visual outcome. However, since the power of the cofactor study was extremely low, none of the variables that were included can be eliminated as potential cofactors for the induction of blindness in infants with ROP.
Medicine, Faculty of
Population and Public Health (SPPH), School of
Graduate

This thesis is an investigation into the effects of premature birth on the developing behaviour of both infant and caregiver. A neonatal assessment procedure sensitive to both the neurological and the interpersonal aspects of development and to obstetric complications was developed. This assessment was validated on a total sample of 62 premature and fullterm infants. In a further study utilising 30 infants from the first part of the thesis, the effects of a maternally-administered manual-based intervention for premature infant-mother dyads were evaluated as compared to fullterm and premature diary controls. This focussed on a variety of early interactional activities designed to enhance mutual parent-infant responsiveness in preterm dyads. The results of the study are discussed in terms of the possible clinical utility of such an approach in reducing the likelihood of dysfunctional parenting of the 'High-Risk' newborn. The thesis is set in the context of a review of the pertinent literature on the development of special care facilities for the premature infant, neonatal assessment procedures, mother-infant interaction and intervention research.

Background: The survival rate of premature infants has increased in Sweden over the pastdecade. Preterm infants run the risk of developing a potentially blinding disease known asretinopathy of prematurity (ROP). A recent Swedish national study showed that the frequencyof ROP has increased over the past years and there are regional differences across the country. Aim: Our aim was to evaluate the frequency of ROP in Örebro region (Örebro) and comparewith the rest of Sweden over a 10-year period. Methods: A retrospective cohort study was conducted on all premature infants born beforegestational week 31, screened for ROP in Örebro, from 2008 to 2017. Data such as number ofinfants, birth weight (BW), gestational age (GA) and ROP-outcome was retrieved from anational quality register; SWEDROP. Comparisons were made with national data during thesame time-period. Results:The study included 200 infants with a median GA of 28.4 weeks and BW 1144 grams.Of the screened infants 99 (49.5%) developed ROP and 20 (10%) were treated during the studyperiod. During the study period, mild ROP decreased (p=0.024), severe ROP increased(p=0.032), however there was no change in ROP-treated infants (p=0.159). The percentage ofROP-treated infants was higher in Örebro than the rest of Sweden (p=0.024). Conclusion: Our study showed that the frequency of mild ROP decreased in Örebro whilstsevere ROP increased during the 10-year period. The frequency of infants treated for ROP wassignificantly higher in Örebro compared to the rest of Sweden.

One in every 10 infants is born premature, with premature being defined as being born before 37 weeks gestation. The immediate concerns of premature birth are fairly well understood, but the long-term consequences are much less known. Previous studies have shown pulmonary insufficiencies in adulthood, but less have looked at hemodynamic variables. None have investigated exercise and hypoxia intolerance in adults who survived prematurity. The goals of this study were to determine exercise capacity and hemodynamic response during exercise and hypoxia in prematurely born adults, as well as deriving pulse wave velocity in normoxia and hypoxia. Preterm (N=10) and term-born, age-matched subjects (N=12) performed incremental exercise in normoxia (21% O2) or hypoxia (12% O2) until volitional maximum was reached. Subjects had arterial and venous catheters collecting blood gas concentration and blood pressure, and breath-by-breath metabolics gathering ventilation data. Preterm and term-born subjects were well matched for anthropometrics, pulmonary, and exercise capacity values. The preterm adults had elevated heart rates, systolic blood pressure, pulse pressure throughout the exercise protocol in normoxia and hypoxia. The preterm group experienced an increased diastolic blood pressure and mean arterial pressure during normoxic exercise, but had a transient decrease in diastolic blood pressure and mean arterial pressure in hypoxia. Additionally, adults born prematurely had an increase aortic pulse wave velocity (aPWV). With these findings, we aimed to determine if aortic stiffness was increased in premature infants at birth with the neonatal intensive care unit (NICU), or if there was a phenotype of premature aging in this population. Prior to beginning the study with the NICU, the effects of simulation on clinicians and researchers was investigated. Simulation is often used for noninvasive teaching or practicing procedures. No one has looked into the effect simulation has on research being done in an intensive care unit setting. Bay 1 and 2 nurses (n=23) in the NICU were surveyed to rate their thoughts of clinical research, comfort with new research, comfort with simulation, and comfort with researchers not from the NICU. Nurses did not know what aspects of the NICU were overwhelming to researchers nor did they agree that researchers could identify infants stress cue. Nurses also reported discomfort communicating with parents about novel research technology. But overall, nurses support research in the NICU and are comfortable with new research knowing the research team participated in a NICU-specific simulation. A questionnaire was also filled out by researchers (n=3), neonatal intensive care unit physicians (n=3) and nurses (n=3) prior to and after completing a research study simulation. Prior to simulation, scientists showed more unfamiliarity with the infants, the NICU setting, and simulation than did the physicians or nurses. Physicians and nurses, however, were not familiar with the technology the researchers used. The simulation alleviated the differences found among the groups. Simulation improves nurses’ opinions of new technology and researchers coming into the NICU and working with patients. Simulation helps researchers familiarize themselves with the NICU and infants, while also improving the clinicians’ comfort with the technology and methods being used.

Reactive oxygen species and other radicals (e.g. peroxynitrite) are thought to play a role in the development of chronic lung disease of prematurity (CLD). I hypothesised that serial BAL may washout surfactant and cause persistent radiological changes. I also hypothesised that cellular antioxidants were depleted, and nitric oxide production was increased, in bronchoalveolar lavage fluid (BALF) from infants who developed CLD. Furthermore, my aim was to develop a technique to quantitate nitrite and nitrate in small (<50 microlitres) samples of BALF. 1 studied three groups of infants (those who developed CLD, those who recovered from respiratory distress syndrome (RDS), and control infants ventilated for surgical reasons) and (a) determined the safety of the BAL procedure, (b) developed methods to estimate nitric oxide (NO) products, (c) estimated nitrate and nitrite in BALF and (d) measured glutathione, urate and ascorbate in BALF and plasma. My data showed that serial BAL did not adversely affect radiological appearances. I studied several techniques for reducing nitrite to nitrate, and the Griess reaction and fluorometry to quantitate nitrite. I applied a modified enzymatic method, with fluorometric detection to measure NO products. BALF nitrate concentration was similar in all groups during the first week of life. Thereafter, nitrate concentration was significantly higher (p<0.05) in infants who developed CLD compared to those who did not. Nitrite concentration did not show any trends. There was a delayed increase in BALF ascorbate in the CLD group when compared to the RDS and Control groups. The BALF: plasma ratio of ascorbate was higher in the RDS group at 4 days of age than in the CLD group, suggesting that more mature infants have a better ability to concentrate ascorbate in their lungs. In summary, I noted differences in nitrate and ascorbate concentrations between infants who developed CLD, and those who didn't.

The findings of this thesis suggest that children with CLD continue to have airway abnormalities including reversible airway obstruction, air trapping and impaired gas transfer compare to term and preterm controls at 8-12 years of age. Although they had similar exercise capacity to preterm and term control groups, this was at the expense of using greater proportion of their ventilatory reserve. At school age, they do not have evidence of myocardial dysfunction or subclinical pulmonary arterial hypertension.

Using the Autism Spectrum Disorder (ASD) database of the Department of Paediatric and Adolescent Medicine of The University of Hong Kong, a retrospective cohort study was carried out exploring the relationship between prematurity and symptom severity by using Childhood Autism Rating Scale (CARS). The premature group was found to have no significant difference in total CARS score as compared to the full term group, and no significant correlation was found between CARS score and gestational age [GA] (for children diagnosed or with suspected ASDs). Significantly higher numbers of the premature group (GA 37 weeks, N = 130) had multiple births, family history of ASDs or related disorders, pre/perinatal complications, as well as a significantly lower mean birth weight as compared to the full term group (GA > 37 weeks, N = 683). Mean total CARS score of very premature cases (M = 32.20, SD = 6.29) was found to be 2 points lower than mean total CARS score of those that were full term (GA > 37 weeks [M = 34.08, SD = 6.53]). However, the result was not statistically significant by unpaired t-test analysis. Therefore, results in this cohort show no relationship between prematurity and CARS score of children with ASDs, however further studies should be carried out in order to better validate existing findings.
published_or_final_version
Paediatrics and Adolescent Medicine
Master
Master of Medical Sciences

Background: Screening for Retinopathy of Prematurity (ROP) is recommended to prevent possible blindness. Prior to 2016, resource limitations precluded routine ROP screening at Groote Schuur Hospital (GSH). Previous pilot studies at GSH did not detect ROP requiring treatment. However, improved survival of very low birth weight infants may affect the prevalence of ROP. Objectives: The study objectives were to: i) Determine the prevalence and severity of ROP in a prospective cohort of premature infants; ii) Describe the association with pre-specified potential risk factors; iii) Assess the feasibility of screening for ROP in our resource-limited setting. Methods Infants with a birth weight of < 1251 g or gestational age < 31 weeks admitted to the GSH neonatal unit from November 2012 to May 2013 were screened. A paediatric ophthalmologist examined the infants at 4 weeks chronological age or 32 weeks corrected gestational age, with follow-up examinations as indicated. Results: Screening was performed in 135 of 191 eligible infants. A total of 313 ROP examinations were performed; 38.5% of infants required a single examination and 16.3% required more than four. The mean gestational age and weight at birth were 30.1 ± 1.9 weeks and 1056 ± 172 g respectively. Seventy-four infants were female (54.8%). Only black (57.0%) and coloured (42.9%) infants were represented. ROP was diagnosed in 40 (29.6%) infants: Eight (5.9%) infants had clinically significant ROP. No infants had stage 4 or 5 ROP. No infants weighing more than 1250 g required treatment. Two infants received laser treatment. Infants with ROP had a lower mean gestational age and lower mean birth weight than those without ROP: 29.2 ± 1.6 vs. 30.5 ± 1.9 weeks (P < 0.002) and 988 ± 181 g vs. 1085 ± 160 g (P = 0.001) respectively. Infants with ROP were more likely to have received a blood transfusion (P < 0.002); to have late onset sepsis (P = 0.024); and to have receive d exclusive breast milk feeds (P = 0.005). There were no significant differences in the level of respiratory support, the need for oxygen therapy, the occurrence of apnoea, early sepsis or severe intraventricular haemorrhage in infants with ROP compared to no ROP. On multivariate analysis, only gestational age was independently associated with ROP was gestational age (RR 0.85; 95% CI 95% 0.740 - 0.988; p=0.03). When gestational age was excluded in post-hoc analysis, birth weight (RR 0.99; 95% CI 0.997 - 0.999; P=0.03) and blood transfusions (RR 1.71; 95% CI 1.0 27 - 2.859; P=0.03) were independently associated with ROP. Infants <1000 g had a 2.5 times higher risk of having ROP than their larger counterparts (95% CI 1.05 - 5.90, P=0.03). ROP screening was completed in 91.1% (123/135) of infants. Conclusion Clinically significant ROP was found in this study. In contrast to previous studies conducted in this setting, two patients received laser treatment. Extensive resources were required for successful screening. The strong association with birth weight and gestational age suggests that infants with lower birth weights and gestational ages should be prioritized for screening in our resource-limited setting.

Preterm birth may lead to complications during the neonatal period that can cause visual dysfunctions. Retinopathy of prematurity (ROP) and neurological complications are well known reasons for visual dysfunctions, but preterm children with no or only mild ROP and no evident neurological problems may also be affected visually when they grow up. Retinal development starts early after gestation and continues long after birth. Major processes are underway during the second half of pregnancy when preterm children are born, and a preterm birth could possibly have a negative effect on normal retinal development. The aims of the studies were to evaluate retinal morphology and function in former preterm children and compare the results with children born at term. Former preterm children aged 5 to 17 years and born in a gestational age (GA) of 32 weeks or less were included in the different study groups. Children of similar ages who were born at term and with normal visual acuity (VA) acted as controls. Best corrected VA and refraction in cycloplegia were assessed in all children. Macular thickness and retinal nerve fiber layer (RNFL) thickness were measured with optical coherent tomography (OCT). Total retinal function was assessed with fullfield electroretinography (ffERG) and central macular function was assessed with multifocal electroretinography (mfERG). Preterm children had thicker central maculae than controls. There was a positive correlation between central macular thickness and GA at birth. RNFL thickness was reduced in the preterm children with severe ROP and treated ROP, but children with mild or no ROP did not differ from the fullterm children. The photoreceptor function measured with ffERG and the macular function measured with mfERG were reduced in the preterm group compared to controls. Preterm birth affects the retina both morphologically and functionally, and ROP has been suggested to be a reason for retinal changes. However, the results of this thesis indicate that children with no ROP also have retinal changes, suggesting an effect of prematurity itself. There were no correlations between any retinal changes and VA, but it is possible that larger studies using improved techniques may elucidate this further.

IL-6 trans-signalling was investigated in transformed airway epithelial cells (A549 and BEAS2B cells) and primary small airway epithelial cells (SAEC) in vitro. The cells expressed gp130 but not IL-6R. MCP-1 in response to IL-6 trans-signalling was variable and generally weak. Furthermore, IL-8 release was not downregulated by IL-6 trans-signalling. Instead, an increase in MCP-1 and IL-8 release was observed in response to a combined stimulation of IL-6 trans-signalling and IL-1[Special characters omitted]. This suggests that the pro-resolution paradigm of IL-6 trans-signalling may not be the case in airway epithelial cells.

Maintaining adequate and stable blood oxygen level is important for preterm babies to avoid the risk of brain, lung and retinal injury such as retinopathy of prematurity (ROP). However, wide disparities in policies and practices of oxygenation in preterm babies exist among neonatal care providers as it is still unclear which best method of monitoring and what features of oxygen measurements are important to clinician’s interpretations for assessing preterm babies at risk of developing severe ROP or unstable health condition. This thesis consists of two projects: NZ-ROP that examines multiple factors of severe ROP including summary statistics (mean, standard deviation (SD), coefficient of variation (CV) and desaturation) for oxygen saturation (OS) features in very extreme preterm babies, and NZ-LP that investigates the efficacy of some of these statistics for health monitoring of late preterm babies. The OS data in NZ-ROP were recorded using modified oximeters that have offsets and inherent software artefact, both of which mask the actual saturation for certain OS ranges and may complicate the choice of methods in the analyses. Therefore, novel algorithms involving linear and quadratic interpolations are developed, implemented on the New Zealand data, and validated using the data of a UK preterm baby, as recorded from offsets and non-offsets oximeters. For all data sets, the algorithms produced saturation distributions that were very close to those obtained from the non-offset oximeter. The algorithms perform within the recommended standards of commercial oximeters currently used in the clinical practice. ROP is a multifactorial disease, with oxygenation fluctuations as one of the key contributors. The all-subsets logistic regression, robust and generalised additive statistical modelling, along with a model averaging approach, are applied in NZ-ROP to determine the relationship of variability and level of OS with severe ROP, and the extent of contribution of various clinical predictors to the severity of this eye disease. Desaturation, as a measure of OS variability, has the strongest association with severe ROP among all OS statistics, in particular, the risk of severe ROP is almost three times higher in babies that exhibit greater occurrences of desaturation episodes. Additionally, this study identifies longer periods of ventilation support, frequent desaturation events, extreme prematurity and low birth weight as the most important factors that substantially exacerbate the severity of ROP, and therefore signify babies’ underlying condition of being severely ill. Persistent cardiorespiratory instabilities prior to hospital discharge may expose preterm babies to a greater risk of neuro-developmental impairments. In NZ-LP, the statistical summaries of mean, SD and CV are computed from the OS measurements of healthy stable and unstable babies, and the performance of these statistics in detecting the unstable babies is evaluated using an extremeness index for outlying data and a hierarchical clustering technique. With SD and CV, the clinically unstable babies were very well separated from the group of stable babies, wherein, the separation was even more apparent with the use of CV. These suggest that measures of variability could be better than saturation level for highlighting babies’ underlying instability due to immature physiological systems, but the combination of variability and level through the CV are believed to be even better. Identification and summarisation of useful OS features quantitatively hold great promise for improved monitoring of oxygenation instability and diagnosis of severe ROP for preterm babies.

The blind have generally been considered to be a homogeneous population whose deficits arise from an interaction of loss of vision, age of onset and socialization. Sequelae are posited to exist merely due to the limiting effects of blindness on experience. This is believed to affect all blind persons equally regardless of cause of blindness provided that independent secondary disabilities do not exist. This study investigated the possibility that different causes of blindness are related to specific neuropsychological deficits which cannot be explained by the mere presence of blindness. It was found that neuropsychological differences existed among specific sub-populations of blind persons. These results suggested that the cause of blindness may be a marker for specific Central Nervous System involvement.

This research was conducted to obtain information to clarify the nature of the relationship between degree of prematurity and associated perinatal complications and academic achievement. Previous investigations have suggested that children born prematurely do experience academic deficits, however, significant relationships between prematurity and achievement have not consistently been reported. Advances in neonatal medical care in the past 20 years has ensured the survival of extremely fragile premature infants that previously would have perished. There has been great interest in the developmental progress of these premature survivors. In spite of this interest, questions still remain about academic progress. The present sample included 188 first grade students who were born prematurely. All students were enrolled in a prospective longitudinal follow-up program upon graduation from the neonatal intensive care nursery. Structural equation model testing (LISREL) was used to examine the structure of the relationships between the independent variables and academic achievement. Independent variables included the following; degree of prematurity, perinatal illness, socioeconomic status, ethnicity, and preschool experience. Structural equation model testing revealed that none of the eleven models tested provided a good fit for the data. Hierarchical model testing indicated that one model was preferred over the others. The model that provided the most parsimonious representation of the data specified that there was no direct relationship between degree of prematurity and achievement nor was there a direct relationship between perinatal illness and achievement. This model also included direct relationships between ethnicity, socioeconomic status, and preschool experience and achievement. This analysis revealed that within this sample of premature survivors of neonatal intensive care, neither degree of prematurity nor perinatal illness were significantly related to academic achievement. The significance of socioeconomic status has been well documented in the literature and is supported by this investigation. While preschool experience was significantly related to achievement, the relationship was not in the anticipated direction. That is, children with preschool experience had lower achievement scores than children with no preschool experience. These unexpected results were discussed in terms of the lack of sensitivity of the preschool measure.

This thesis uses data from three cohort studies in order to investigate the effects of foetal and infant growth on respiratory disease in preterm-born children, and the onward effects of this disease on measures of physical activity. Firstly, I investigated change in foetal growth using biometry obtained from antenatal ultrasounds scans, and related this to rates of respiratory symptoms obtained from the Respiratory and Neurological Outcomes of Children Born Preterm Study. I followed-up this work by reporting the effect of accelerated weight gain during infancy on the respiratory health of preterm-born children. The second half of my thesis then used measures of lung function, as well as data on respiratory symptoms, to investigate whether the decrements associated with preterm birth manifested as reduced participation in objectively measured physical activity. Data from the Avon Longitudinal Study of Parents and Children, and from the Millennium Cohort Study, were used in these analyses. My results noted that change in foetal growth trajectory (acceleration or deceleration) between the trimesters of pregnancy was associated with increased respiratory symptoms in preterm-born children. Accelerated infant weight gain was also associated with increased odds of wheeze; this was in a dose-dependent manner across the spectrum of gestation, with the effect being the greatest at ≤32 weeks’ gestation. Moreover, maternal smoking, as well as gestation, were noted to be a mediator of the relationship between infant weight gain and childhood respiratory health. A reduction in moderate-to-vigorous physical activity at 7 years of age was noted in boys who were born at ≤32 weeks’ gestation. This reduction remained after inclusion of other explanatory variables. No differences were noted at the ages of 11 and 15 years. The reduction in physical activity over the course of childhood may explain this observation.

La césarienne est un mode d’accouchement alternatif recommandé lorsque la vie de la mère ou du fœtus pourrait être mise en danger par l’accouchement naturel. Ces dernières années, de nombreuses études ont rapporté que la césarienne augmentait le risque de développer des troubles tels que l’autisme. Pourtant, ces études sont controversées à cause des nombreux facteurs impliqués dans la naissance par césarienne à prendre en compte. Pour résoudre ce problème, nous avons utilisé des souris nées par césarienne et évalué des paramètres liés à l’autisme. En évaluant leur sociabilité, communication verbale et comportements répétitifs, nous avons trouvé que la césarienne n’induit qu’une modification précoce et transitoire de la communication. La césarienne n’affecte pas non plus l’activité cérébrale même si de petites altérations morphologiques éphémères sont observées à la naissance. Par conséquent, la césarienne conduit à des modifications à court terme non suffisantes pour induire l’autisme
Cesarean section (C-section) is an alternative mode of delivery which is recommended when the mother or the fetus’ life might be endangered by natural childbirth. In recent years, epidemiological studies have reported that C-section delivery might increase the probability to develop disorders such as autism. However, these reports remain controversial due to the numerous factors involved in birth by C-section. To tackle this issue, we used mice delivered by C-section and looked at parameters associated with autism. We evaluated sociability, communication and repetitive behaviors in our mice and found that C-section only induces transient and early modifications in their communication. Also, we did not find changes in brain activity, even if small temporal morphological alterations were present after C-section. Therefore, C-section delivery leads to short-term modifications that are not sufficient to induce autism

The improvement of peri-neonatal care has allowed a progressive drastic increase in the survival of high-risk preterm infants, i.e., very preterm or very low birth weight (VLBW) and extremely preterm or extremely low birth weight (ELBW) infants. However, the increased survival correlates with an almost stable incidence of disability as a result of the same prematurity, in particular for the lower gestational age (GA) groups. Furthermore, even infants born moderate and late preterm (32-36 weeks GA), although at a lower risk, are not exempt from clinical problems which also result in significant economic and social costs, considering the large number of these patients. In order to improve the short and long-term outcomes of these infants at risk, increasing attention in neonatology is focused on understanding the pathophysiological mechanisms underlying the prematurity-related diseases, and -at the same time- on the study of the individual diversification of these mechanisms. The concepts of fetal programming and developmental reprogramming represent the biological substrates that explain the importance of the mother-placenta-fetus/newborn triad in the realization of the long-term global health status and justify the interest in the development of a “precision neonatology”, that is, of personalized care solutions according to a tailored approach. The identification of the newborn at risk and its potential problems therefore represents a fundamental step for the implementation of follow-up programs for these newborns, and vice versa an adequate follow-up path allows, over time, the critical analysis of the pathophysiological mechanisms and the perinatal data feedback: both of them represent essential steps in the benchmarking process, which in turn contributes to the definition of individualized strategies for improving clinical and care performance. Throughout the diagnostic-care process that includes the identification of the newborn at risk, the individual risk stratification, the early diagnosis of pathology and the effects of any therapeutic intervention, biomarkers represent essential tools, such as those of oxidative stress (OS, that is critical for fetal programming and common denominator of many prematurity-related pathologies, called in fact “free radical related diseases of prematurity”) and the potential biomarkers identifiable through the modern approaches of metabolomics, “the new clinical chemistry” [Antonucci R. 2010]. With these objectives, the Ph.D. research project has therefore been articulated on various preliminary work fronts, which can open the way to research aimed at developing a precision neonatology in a continuous evolution. The present thesis aims to summarize and unify the evidence-based scientific knowledge extrapolated from the literature and that obtained through the personal studies carried out, especially in the more recent field of metabolomics. The following topics are therefore addressed and illustrated: a brief introduction on the evolution in neonatology and the role and importance of biomarkers between research and clinical practice (Chapter 1); the conditions that define neonatal risk, even those less known and in which the long-term risk is less striking but significantly impacts on social and health costs (Chapter 2); the critical review of the literature regarding biomarkers of oxidative stress, potential clinical biomarkers of diagnostic-prognostic utility in the preterm infant (Chapter 3); the possible preventive and antioxidant defense strategies in the newborn and the potential role of melatonin in preterm infants (Chapter 4); the application of metabolomics in neonatology between physiology and pathophysiology in the long-term follow-up of both full-term and preterm newborns (Chapter 5); finally, the conclusions and future perspectives of the research theme are briefly discussed, for a possible extension of the preliminary works presented through the project of the Ph.D. (Chapter 6).

Retinopathy of prematurity (ROP) is a posterior eye disorder found in prematurely born infants, that can result in blindness. In this thesis a delivery system, for the prophylactic management of the disease was designed and tested based on the hypothesis that delivery of a hypoxia inducible plasmid to the posterior eye might prevent the pathogenesis of the ROP. Major challenges identified for the project included: characterisation of the hypoxia inducible plasmid, efficient transfection of the target cells and delivering the DNA to the posterior eye with a minimally invasive route. To meet these requirements it was proposed to encapsulate a hypoxia responsive plasmid condensed with a cationic peptide (RALA) within PLA-PEG nanoparticles that can deliver the DNA to the posterior eye via transscleral route for efficient transfection of the retinal endothelial cells. In order to pursue this hypothesis the DNA condensation with RALA was optimized to give nanoparticies (RNPs) with a z-average diameter of 58.7±10.3 nm and PDI of 0.252±0.050. These nanoparticies efficiently transfected a variety of cell lines. A series of PLA-PEG block copolymers were synthesized with various PEG chain length and LA/EG ratio, and formulated into composite nanoparticles (diameters <200 nm and PDI <0.200) containing the RNPs. TEM was used for the first time to confirm the presence of a nanoparticle-in-nanoparticle system by TEM. Furthermore, an in vitro DNA release study demonstrated that the composite nanoparticles were able to release DNA, with faster DNA release in the first 24 hrs comprising 10% of the DNA content, followed by a slow continuous release for a prolonged duration. Among the studied formulations PLA25-PEG5 exhibited the fastest release where >30% of DNA content was released over 6 weeks. Finally these nanoparticles were evaluated for their ability to cross the sclera and the results demonstrated that > 1 0% of PLA20-PEG2 and 8% of PLA25-PEG5 . nanoparticles crossed the sclera in a 4 hrs, whereas PLGA nanoparticles exhibited permeation of just 3.2% in this time. While the selected hypoxia responsive plasmid, pE9/GFP, failed to show its specificity to express only in hypoxia conditions the work presented herein demonstrates that the proposed delivery system is viable. Thus, this thesis demonstrates the preparation of a composite nanoparticle system where inner RNPs demonstrated their efficiency to condense the DNA and enable them express inside cells and outer PLA-PEG nanoparticles demonstrated their efficiency to cross the sclera. This system is a promising candidate for the prophylactic management of ROP and may be suited to other gene therapies.

Background: Prematurity is a major risk factor for intraventricular haemorrhage (IVH). Premature infants often require respiratory support. There is little information on neonates with IVH who require respiratory support in low and middle income countries. Objective: To describe the characteristics and short-term outcomes of very low birth weight (VLBW) infants with IVH who required respiratory support in a tertiary neonatal unit with resource limitations. Methods: This was a matched retrospective observational study. The population included VLBW infants with IVH, who received positive pressure respiratory support between January 2014 and December 2016. Outcomes of infants with severe IVH was compared to those with mild IVH. Outcomes were further analysed according to mode of ventilation. Results: 150 infants were included in the study, 56 (37%) received continuous positive airway pressure (CPAP) only and 94 (63%) mechanical ventilation. Severe IVH was associated with surfactant therapy across both ventilation groups (p=0.03). Oxygen requirement at 28 days was more frequent in infants with severe IVH compared to mild IVH (79% vs 38%, p=0.01) (OR 6.11 (95% CI 1.19-31.34), p=0.03). Severe IVH and the presence of coagulopathy were the strongest predictors of death in both ventilation groups (p <0.0001). Pulmonary haemorrhage was the commonest cause of death in those with severe IVH and blood culture confirmed sepsis in those with mild IVH. Periventricular leukomalacia (PVL) was associated with severe IVH in those receiving invasive ventilation (OR 6.67 (95% CI 1.11-40.17)). Conclusion: Mechanical ventilation, coagulopathy and pulmonary haemorrhage were strongly associated with death in VLBW infants with severe IVH in a resource-limited setting. These prognostic factors may have a role in end of life decisions.

The purpose of this study was to explore differences in movement initiation and execution, and their associations with amount of physical activity (PA) and cognitive abilities, in 6 to 8 year old children born PT compared to peers born at term. The sample consisted of in total 78 children divided in subgroups, 16 born very preterm (VPT), 24 born moderate preterm (MPT) and 38 age matched controls born at term (FT) with no diagnosed cognitive or motor impairments. Three-dimensional (3D) kinematic recordings of wrist movements during two bimanual tapping tasks (horizontal and vertical) were finalized and kinematic outcome measures were investigated in relation to PA and performance on WISC-IV. Children born VPT showed significantly longer Latency times and longer Duration of movement execution compared to children born MPT and FT. No significant within group correlations between PA and movement performance were found. Duration of movement execution and Total duration of movement execution were negatively associated with Full-scale intelligence quotient (FSIQ) and processing speed index (SI) in the PT group. Early school aged children born VPT need longer planning time to initiate and execute goal directed bimanual movements, compared to peers born MPT and FT. Kinematic performance did not evidently associate with amount of PA, although kinematics, by means of longer Latency time and Duration of movement execution, negatively associated with SI.
Syftet med denna studie var att undersöka skillnader i initiering och utförande av en rörelse samt deras associationer med fysisk aktivitet och kognitiv förmåga hos förtidigt födda barn i åldrarna 6 till 8 år samt åldersmatchade fullgångna jämnåriga barn. Urvalet bestod av total 78 barn uppdelade i subgrupper, 16 väldigt förtidigt födda, 24 moderat förtidigt födda och 38 åldersmatchade fullgångna kontroller utan några kända kognitiva eller motoriska nedsättningar. Tredimensionella (3D) kinematiska registreringar av handledsrörelser under två bimanuella knapptrycksuppgifter (horisontell och vertikal) genomfördes. Utfallet av rörelsemätningarna studerades i association till fysisk aktivitet och resultat på WISC-IV. Väldigt förtidigt födda barn visade längre latenstid och längre duration av rörelse jämfört med moderat förtidigt födda och fullgångna barn. Inga signifikanta inom grupps korrelationer mellan fysisk aktivitet och rörelseutförande hittades. Utförandets duration samt hela utförandets duration associerade negativt med IQ kvot och processhastighet (SI) hos för tidigt födda barn. Väldigt förtidigt födda barn i tidig skolålder behöver mer tid till rörelseplanering, initiering och utförande av viljestyrda målinriktade rörelser jämfört med jämnåriga barn födda senare i graviditeten. Kinematiskt utfall associerade inte signifikant med fysisk aktivitet, däremot associerade kinematiskt utfall, i form av längre latenstid och duration av utförande, negativt med kognitiv processhastighet.

Although very low birth weight preterm (VLBW) infants with grade 3,4 retinopathy of prematurity (ROP) are at high risk for unfavorable visual outcomes, the middle school vision motor integration (VMI) skills and cognitive outcome scores of these children remain largely unknown. Data for 323 very VLBW survivors of the Multicenter Randomized Indomethacin IVH Prevention Trial (BW 600 1250 g) were analyzed to test the hypothesis that grades 3, 4 ROP would be an important predictor of cognitive and VMI skills. 3 subgroups were evaluated: ROP negative (N = 163), ROP grades 1,2 (N = 137) and ROP grades 3,4 (N = 23) were evaluated prospectively at 12 years of age with a neurocognitive battery. High-resolution volumetric MRI scans were quantified for 40 of the study subjects, and occipital brain volumes were correlated with Beery VMI scores. Children with ROP 3-4 had [arrow up - increased] vision impairment and lower test scores. Whole brain volumes were significantly less for children with any grade of ROP (p = 0.02), occipital white matter volumes tended to be less for the same study subjects (p = 0.08) and both total occipital brain volumes and occipital white matter volumes were significantly correlated with Beery VMI scores (r=0.610, p = 0.009 and r = 0.652, p =0.005, respectively). Prematurely-born children with a history of grade 3-4 ROP continue to have [arrow up - increased] vision impairment, special needs and lower performance on cognitive, language and visual motor integration scores at age 12 years. Both whole occipital brain volumes and occipital white matter volumes were predictive of VMI scores for children with ROP. (supp by NS 27116)

Retinopathy of prematurity (ROP) is a sight threatening proliferative retinal vascular disease affecting premature infants. Vision loss in ROP is preventable through the early identification and treatment of severe disease. Timely screening and accurate diagnosis is therefore crucial for the diagnosis of ROP, however, multiple challenges exist in current screening processes including limited access to expert ophthalmologists required for ROP screening, subjectivity of diagnosis and cost and time burdens involved in transporting infants to tertiary hospitals. Artificial intelligence (AI) has the potential to overcome current challenges in ROP diagnosis and may transform the way ROP is screened for and managed. Through innovative deep learning technology, a well-designed, well-validated detection algorithm may provide accessible, objective analysis of retinal images to assist expert ophthalmologists in detecting referrable ROP. This thesis will introduce readers to the pathophysiology and grading of ROP, evidence for current treatment guidelines and AI applications in ophthalmology. The systematic review will provide the background evidence into requirements for an accurate, reliable AI algorithm in ROP diagnosis and the validation of our AI algorithm, ROP.AI, will provide insight into the revolutionary diagnostic potential of this deep learning program. Finally, we will discuss future plans for ROP.AI including a methodology proposal to implement the algorithm into a prospective clinical trial for the diagnosis of ROP.
Thesis (Masters)
Master of Medical Research (MMedRes)
School of Pharmacy & Med Sci
Griffith Health
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Introdução: O aleitamento materno, além das propriedades nutritivas e imunológicas, propicia momentos essenciais de interação mãe-bebê. Quando o recém-nascido, especialmente o prematuro, é separado da mãe devido à sua internação em uma Unidade Neonatal, diversos fatores podem prejudicar o início do aleitamento materno e sua duração. Pesquisas com crianças nascidas a termo mostram que dentre vários fatores, a percepção de autoeficácia materna está associada com maior tempo de amamentação exclusiva e desmame mais tardio; entretanto, pouco se sabe sobre o papel da autoeficácia em mães de prematuros. Objetivos: Avaliar a percepção de autoeficácia em mães de prematuros durante a internação e após a alta e sua associação com a manutenção do aleitamento materno e desmame. Método: Trata-se de um estudo longitudinal, com 47 mães de prematuros cujos dados sociodemográficos e clínicos foram obtidos a partir de entrevista realizada até o terceiro dia após o nascimento e dos prontuários médicos do bebê. Entre três e sete dias após início da amamentação foram aplicados dois questionários para avaliação de autoeficácia: a) com relação aos cuidados (Perceived Maternal Parenting Self-Efficacy – PMP); b) com relação à amamentação (Brastfeeding Self-Efficacy Scale – Short-Form – BSE - SF). No primeiro retorno após a alta hospitalar do bebê, o BSES – SF foi reaplicado, e 60 dias após o nascimento foi verificado no prontuário, ou por contato telefônico se os bebês continuavam sendo amamentados. Resultados: A mediana da idade gestacional foi de 32 semanas e o tempo médio de internação foi de 20 dias. Na alta 85% dos prematuros estavam em aleitamento materno exclusivo, e até 60 dias após o nascimento 31,7% continuaram em aleitamento materno exclusivo. Nenhuma mãe pontuou para baixa autoeficácia, e altos índices de autoeficácia foram predominantes em mães com maior idade, multíparas e cujo recém-nascido teve melhor vitalidade ao nascer. A autoeficácia não se associou com tempo de amamentação, mas nascer pequeno para a idade gestacional foi fator de proteção e maior idade materna foi fator de risco para o desmame. Conclusão: A alta autoeficácia na amamentação não se associou com risco de desmame. As taxas de aleitamento materno foram elevadas na alta hospitalar mas caíram drasticamente 60 dias após o nascimento, o que sinaliza para a necessidade de retornos mais frequentes aos serviços de saúde após a alta para continuar encorajando o aleitamento materno, dando orientações técnicas ajustadas às necessidades individuais de cada mãe, visando aumentar seu empoderamento, sua percepção de autoeficácia e confiança em sua capacidade de amamentar.
Introduction: Breastfeeding propitiates not only nutritional and immunological advantages, but also essential moments of mother-baby interaction. According to the literature, when a newborn, especially if premature, is separated from the mother to be admitted into a Neonatal Unit, several factors can impair breastfeeding and its duration. Research with infants born at full-term shows that among several factors maternal perception of self-efficacy is associated with exclusively breastfeeding for a longer period and weaning at a later date. However, little is known about the role of self-efficacy in mothers of premature babies. Objectives: Evaluating the perception of self-efficacy in mothers of premature babies during hospitalization and after discharge and its association to breastfeeding and weaning. Methodology: A longitudinal study with 47 mothers of premature babies whose sociodemographic and clinical data were obtained through an on-site interview conducted up to three days after birth and from the baby’s medical charts. From three to seven days after they first started breastfeeding, two questionnaires were used to evaluate self-efficacy: a) the - Perceived Maternal Parenting Self-Efficacy (PMP-E); and b) the Breastfeeding Self-Efficacy Scale – Short-Form (BSES-SF). On the first consultation after discharge the BSES-SF questionnaire was applied once more and and 60 days after birth medical charts were consulted or by phone contact to check whether the mother was still breastfeeding. Results: Average gestational age was 32 weeks at birth and the children were admitted for an average of 20 days. 85.1% of the children were discharged on exclusive breastfeeding and up to 60 days after birth 31.7% continued on exclusive breastfeeding. No mother had a low score on self-efficacy and high levels of self-efficacy were predominant in older mothers who had given birth before and whose children had higher Apgar scores. No mother scored for low self-efficacy, and high self-efficacy rates were predominant in older mothers, multiparous, and whose newborn had better vitality at birth.Self-efficacy was not associated with breastfeeding time but being small for gestational age appeared as a protective factor and having an older mother a risk factor for weaning. Conclusion: The high self-efficacy in breastfeeding was not associated with risk of weaning. Breastfeeding rates were high at hospital discharge but dropped dramatically 60 days after birth, signaling the need for more frequent returns to post-discharge health services to continue encouraging breastfeeding, providing technical guidance tailored to individual needs of each mother, in order to increase their empowerment, their perception of self-efficacy and confidence in their ability to breastfeed.

Inflammation and oxidative stress are increasingly recognised as important independent mediators of preterm brain injury and have been implicated in the pathogenesis of cerebral palsy and cognitive impairment. Such exposures are common for the premature infant in whom infection and inflammatory morbidities occur in around 60%. Furthermore, many preterm infants require oxygen therapy and respiratory support due to lung immaturity. Epidemiological and experimental studies indicate that in addition to the independent effects of inflammation and extreme hyperoxia on the developing brain, inflammation preconditions the developing brain resulting in variable injury when exposed to subsequent hypoxia-ischaemia. However experimental studies employing exposure to more modest oxygen fluctuations are lacking. This thesis characterises a clinically relevant model of prematurity where the developing brain is exposed to low grade inflammation and oxygen fluctuation around a hyperoxic mean. We hypothesise that antenatal inflammation and postnatal oxygen fluctuation, both alone and in combination, have detrimental effects on developing white matter. Pregnant dams received intraperitoneal lipopolysaccharide (LPS) or saline on G18 and G19. Dams and their pups were then reared in room air or fluctuating hyperoxia (circa 10kPa) for seven days. We measured longitudinal brain and body growth in different experimental groups to 12 weeks. Whole brains were examined for mRNA expression of inflammatory cytokines (TNFα, IL-1β, IL-6 and IL-10) and markers of oxidative injury (iNOS, SOD2). To determine the effect of perinatal insults on developing white matter, we analysed the expression of myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) in the internal and external capsule. We also examined white matter tracts for differences in microglia (CD68), oligodendrocyte progenitor cells (NG2), oligodendroglial cells (Olig2) and cell death (cleaved caspase3). Behavioural studies (Morris Watermaze Test, Elevated Plus Test and Open Field Test) were undertaken at 12 weeks of age to detect any long-term functional difference between the groups. Antenatal inflammation reduces both brain and body growth at P7. This normalises by P14 unless this inflammatory insult has been followed by postnatal oxygen fluctuation, where brain and body growth restriction persists until P14. We defined our inflammatory response at P1 following antenatal inflammation and did not observe elevation of mRNA at P1. We demonstrated increased SOD2 at this time point, indicating a reparative process. At P7 we observed a significant reduction in the oxidative response following combined exposure to antenatal inflammation and postnatal oxygen fluctuation, indicating a potential limit to, or suppression of, the reparative process. In terms of white matter injury, antenatal inflammation reduces myelination at P7. There is no synergistic effect of inflammation and oxygen fluctuation on MBP immunohistochemistry at P7. However, MBP mRNA expression is increased in pups exposed to both insults compared to those exposed to inflammation alone suggesting that the oxygen fluctuation may stimulate MBP production in response to oxidative injury. MBP mRNA levels and protein expression have all normalised by P14. We observed a reduction in total cell number in the external capsule and corpus callosum in the dual insult group, without an increase in caspase. In keeping with other studies we detected no effect of our perinatal insults on NG2+ve oligodendrocytes. Olig2+ve cell numbers were also consistent between experimental groups. In further characterisation of the cellular response, antenatal inflammation followed by postnatal oxygen fluctuation resulted in a decrease in GFAP mRNA at P7, an effect which was reversed and significantly increased by P14 suggesting delayed activation of the innate immune system. No difference was observed in microglial numbers between experimental groups. There was however, increased microglial cell death (CD68 + caspase) in the group exposed to antenatal inflammation. When this insult was combined with postnatal oxygen fluctuation there was a comparative decrease in microglial cell death, which may reflect an earlier peak of microglial cell death, due to an increased and sustained inflammatory stimulus. Morris Watermaze testing demonstrated that pups exposed to both insults took longer than controls to locate the hidden platform on day 1, which is a measure of spatial learning. The Elevated Plus Test and Open Field Test demonstrated that pups exposed to both insults were less anxious and took more risks than pups exposed to single insults. In conclusion, within a clinically relevant preterm model, antenatal inflammation transiently disrupts both brain and body growth and myelination of the motor tracts of the developing brain. Moreover, when combined with postnatal oxygen fluctuation, detrimental effects on growth are amplified and sustained. Decreased cell numbers are also observed within white matter tracts. In terms of long term functionality, these pups display disinhibition of behaviour as young adults. Collectively, this thesis demonstrates that synergistic actions of common low-grade perinatal insults may alter normal neurodevelopment, and that this may carry a risk of neurodevelopmental sequelae for preterm infants.

Die Frühgeborenenretinopathie (Retinopathia praematurorum (RPM)) ist eine Erkrankung der Netzhaut, die vor allem sehr unreife Frühgeborene betrifft und in ihrem Endstadium zur Erblindung führen kann. Ein gesicherter Risikofaktor für die Entwicklung einer RPM ist die Gabe von hohen Konzentrationen an Sauerstoff nach der Geburt. Gegenstand dieser Arbeit war die Frage, ob nach der Einführung eines Sauerstoffprotokolls 2007 das Auftreten höherer Stadien der RPM reduziert werden konnte. Das Sauerstoffprotokoll hatte zum Ziel die Gabe von inspiratorischem Sauerstoff nach Möglichkeit zu senken und übermäßige Fluktuationen zu vermeiden. Hierfür wurden 268 Frühgeborene mit einem Gestationsalter < 32Wochen bei Geburt, welche in den Jahren von 2005 bis 2006 (pre-Gruppe) und 2008 bis 2009 (post-Gruppe) in der Universitätsklinik Leipzig geboren und einem RPM-Screening unterzogen wurden, verglichen. Es konnte gezeigt werden, dass die Inzidenz der RPM nach 2007 signifikant niedriger war. So erkrankten in der pre-Gruppe 12 von 102 Kinder an einer höhergradigen RPM (>Stadium 3), wohingegen diese Stadien in der post-Gruppe nicht mehr beobachtet wurden. Demzufolge reduzierte sich auch die Notwendigkeit einer Therapie von 7,4 % auf 0 % (jeweils p = 0.0005). In Hinblick auf die Kerndaten wie Gestationsalter, Geburtsgewicht, Körpergröße, sowie dem Auftreten schwerer Begleiterkrankungen wie u.a. der nekrotisierenden Enterokolitis oder der bronchopulmonalen Dysplasie fanden sich keine Unterschiede zwischen den Gruppen. Allerdings wies die post-Gruppe eine höheren Anteil an männlichen Frühgeborenen auf. Die Mortalität zeigte keine signifikante Veränderung nach der Intervention und lag bei 7.8 % in der pre- bzw. 6.6 % in der post-Gruppe (p = 0.81). Die Auswertung der pulsoximetrisch gemessenen Sauerstoffsättigung (SpO2) und der inspiratorischen Sauerstofffraktion (FiO2) zeigte, dass der SpO2 leicht und der FiO2 deutlich reduziert werden konnte. Ein signifikanter Unterschied ergab sich hier jedoch lediglich für den FiO2, insbesondere in den ersten 14 Lebenstagen. Die logistische Regressionsanalyse legt nahe, dass hohe SpO2- und FiO2-Werte sowie das Auftreten von intrakraniellen Blutungen mit schwerwiegenden ROP-Stadien korrelieren. Ein bedachter Umgang in der Sauerstofftherapie Frühgeborenen könnte in der Lage sein das Auftreten der Frühgeborenenretinopathie zu reduzieren ohne eine Erhöhung der Mortalitätsrate zu riskieren.