Abstract Salla disease (SD) is a rare lysosomal storage disorder, belonging to the Finnish disease heritage. The condition leads to intellectual disabilities. Two main categories of the disease have been identified – a conventional subtype and a severe subtype. The gene locus of SD has been assigned to a restricted region on the long arm of chromosome 6. The gene SLC17A5 is responsible for lysosomal-membrane sialic acid transport. The objective of this study was to describe the neurocognitive developmental spectrum of SD in a long follow-up study. In the original study (1997–1999), the sample consisted of 41 Finnish patients with Salla disease. They were examined by a paediatric neurologist, a psychologist and a speech therapist. The follow-up study (2010–2012) concerned of 27 (66%) patients from the original SD patient sample. The study included neurological and neuropsychological investigations. A case study of a mildly affected female patient was also reported. In the first study, the typical neurocognitive profile of SD was outlined and the different phenotypes confirmed. The neurocognitive profile of SD consisted of a strong motor handicap, but also well-developed skills in verbal comprehension and interaction. In the follow-up study, the main finding was that the verbal skills related to comprehension did not diminish over time. However, the skills that demanded productive speech were worsened by both dyspraxia and dysarthria, markers of dysfunction of the cerebellum. The neurocognitive and neurological status of the mildly affected female patient remained stable during the long follow-up time. In addition the MRI findings revealed mild dysfunction. The results indicate that the neurocognitive deficits related to SD are clear in childhood, but the illness does not have a rapid progressive nature after teenage years. The motor handicap is strong but the cognitive skills related to verbal comprehension, and interactive skills, do not deteriorate in adulthood. Four different neurodevelopmental periods can be outlined. / Tiivistelmä Tämän tutkimuksen tavoitteena oli kuvata Sallan tautiin liittyvä neurokognitiivisen kehityksen kulku pitkän seurantatutkimuksen aikana. Sallan tauti, erittäin harvinainen lysosomaalinen kertymäsairaus, kuuluu suomalaiseen tautiperimään. Nämä perinnölliset sairaudet ovat Suomessa yleisempiä kuin muissa maissa. Sallan tauti etenee älylliseen kehitysvammaisuuteen. Kaksi taudin päätyyppiä, tavanomainen ja vakava-asteinen fenotyyppi, on tunnistettu. Sallan taudin aiheuttavan geenin sijainti on paikallistettu kromosomiin 6. SLC17A5-geeni vastaa sialihapon kuljetuksesta solujen lysosomeissa. Ensimmäisen tutkimuksen (1997–1999) aineisto koostui 41 suomalaisesta Sallan tautia sairastavasta potilaasta. Neurologi, psykologi sekä puheterapeutti tutkivat jokaisen potilaan. Seuranta-aineisto (2010–2012) koostui 27 (66 %) potilaasta. Tutkimukseen kuului neurologin sekä neuropsykologin tutkimus. Lieväoireisen naispotilaan kehityskulku julkaistiin erillisenä tapaustutkimuksena. Ensimmäisessä tutkimuksessa selvitettiin Sallan taudille ominainen neurokognitiivinen profiili, lisäksi vahvistettiin kahden eri fenotyypin olemassaolo. Neurokognitiivisiin tyyppioireisiin kuuluivat vahvat motoriset defektit, mutta toisaalta hyvin kehittyneet kielelliset taidot puheen ymmärtämisen osalta. Myös vuorovaikutustaidot olivat vahvat. Seurantatutkimuksen päätulos oli puheen ymmärtämisen taitojen säilyminen taudin edetessä. Puheen tuottamiseen liittyvien vaikeuksien osalta sekä dyspraksia että dysartria heikensivät kielellistä toimintakykyä. Nämä kielelliset defektit liittyvät pikkuaivojen toimintahäiriöihin. Lieväoireisen naispotilaan neurologiset ja neurokognitiiviset löydökset eivät olleet edenneet pitkän seurantatutkimuksen aikana. Myös aivojen kuvantamistutkimuksen tulokset olivat lievät. Sallan tautiin liittyvät neurokognitiiviset muutokset ovat selkeät lapsuusiässä, mutta sairauden luonne aikuisiällä ei ole nopeasti etenevä. Motorisen toimintakyvyn defektit ovat vahvat, mutta kielellisen ymmärtämisen ja vuorovaikutuksen taidot eivät heikkene aikuisilla potilailla. Taudista voidaan erotella neljä erilaista kehityksellistä vaihetta.

Rugby is a popular sport in South Africa, and has been played by young boys from as early as seven years old (South African Rugby Union [SARU], 2011). Despite various physical health benefits, it carries a high risk for injury, especially head injury, and consequently has a high incidence of concussion (Alexander, 2009; Laubscher, 2006; Shuttleworth-Edwards, Smith & Radloff, 2008). It is common for 12 to 13 per cent of adolescent rugby players to report mild traumatic brain injury or concussion per season (Laubscher, 2006; Shuttleworth-Edwards et al., 2008). The true incidence is however considered to be higher, even as high as 70.4% (Shuttleworth-Edwards et al., 2008). Concussion, otherwise known as mild traumatic brain injury (mTBI) is described as a traumatically induced alteration in mental status, or traumatically induced cerebral dysfunction (Kraus, McArthur, Silvermand & Jayaraman, 1996) which may, or may not involve loss of consciousness (Quality Standards Subcommittee, American Academy of Neurology [AAN], 1997). The nature of concussion has traditionally been considered to be transient, and symptoms are usually resolved within a few days or weeks (Kirkwood et al., 2008; Taylor et al., 2010). However, when concussions are not fully resolved prior to players returning to the game, they may be vulnerable to second impact syndrome. This syndrome causes herniation and brain oedema, which may result in death (Patel, 2005), as has been reported in South African press (Alexander, 2009; South African Press Association [SAPA], 2012). Even without second impact syndrome, repeated concussions may render the brain neurocognitively vulnerable, leading to an array of short- and long-term cognitive symptoms (Alexander, 2009; Shuttleworth-Edwards et al., 2008). Short-term problems include difficulties with attention, focus and concentration; following multi-step instruction, engaging in mental problem-solving; verbal expression, receiving and processing verbal and visual information; maintaining effective levels of mental and physical energy; controlling mood; suppressing impulsive behaviours; initiating and maintaining productive interpersonal relationships with peers; engaging in meaningful conversation and participating in group activities (Jantz & Coulter, 2007). Short-term cognitive impairments due to repeated concussion have also been found, and include amongst the former symptoms, also problems with delayed memory, learning, social functioning, and abstract thinking (Anderson, Brown, Newitt & Hoile, 2011; Laubscher, 2006). Long-term sequelae follow when children did not return to their baseline level of functioning after three months (Kirkwood et al., 2008; Taylor et al., 2010). Long-term sequelae include problems with memory, visuo-motor processing, executive functioning, learning and abstract thinking (Anderson, 2002; Anderson et al., 2010; Horton et al., 2010; Lezak et.al., 2004; Shuttleworth-Edwards & Radloff, 2008). As mTBI is traditionally thought to be of transient nature, researchers tend to investigate moderate to severe TBI, rather than mTBI (Alexander, 2009; Anderson et al., 2010; Patel, 2005). This could easily lead to important facts about mTBI being missed or not acknowledged. Nevertheless, recent investigations are uncovering facts about mTBI that could transform the way in which we understand mTBI, providing increasing evidence that mTBI is more serious than widely believed (Blakemore, 2012; Maxwell, 2011; Toleda et al., 2012). However, there remains a lack of research investigating mTBI from a single cause. Considering the above information, the current study provides unique information about mTBI. It specifically investigated the long-term effects of mTBI on adolescents from a homogenous cause, which makes results more comparable. The importance of this study is highlighted in the face of evidence for the long-term effects of multiple concussions, that were sustained during school rugby, on academic achievement (Alexander, 2009; Laubscher, 2006).In the light of grey areas in existing research, the aim of this current study was to investigate whether there is a significant difference in academic achievement within and between two groups of adolescents that had either played rugby and sustained multiple concussions, or had not played rugby nor sustained any concussions, when measured at four points in time over six years. A retrospective data-analysis was performed on matched, controlled, prospective longitudinal data, which was obtained from a study that evaluated the impact of repeated mTBI on the cognitive and academic functioning of early adolescent rugby players over time (Alexander, 2009). This study elaborates on a subset of the previous data, adding the gr. 12 results for academic aggregate scores, to the previously reported academic dataset. Participants were selected from Alexander‟s study (2009), and had either played rugby and obtained two or more concussions (Rugby/Concussed (RC- group); n=17), or did not play rugby nor sustained any concussions (Non-rugby/Non-concussed (NRC-group); n=13). Academic aggregate scores from baseline (gr. 7) through gr. 12 were analysed using quantitative statistical measures. A normal probability plot determined that the data was distributed normally. Descriptive statistics were reported, where after repeated measures ANOVA‟s were conducted to determine the statistical significance of differences in academic scores between and within the groups over time. These results indicated that the NRC-group displayed statistically significant increase in academic achievement over time (p = .000), whereas the RC-group did not display any significant differences, despite displaying a downwards trend in achievement. The difference between the two groups was measured at its highest in gr. 12 (p = .003), indicating that the NRC-group performed statistically significantly better than the RC-group over time. However, a Pearson‟s correlation test revealed that the estimated IQ (Vocabulary subscale of the WISC-III) (Wechsler, 1991) had a positive correlation on academic achievement [r(34) = .54, p < .05)]. To control for the effect that this correlation had on the academic results, an ANCOVA was conducted. This analysis indicated a statistically significant difference in academic achievement between the two groups in gr.12 (p = .004), with a large effect size (d = 1.41), implicating practical significance. Findings consequently confirmed our hypothesis. The significant increase in academic achievement observed within the NRC-group over time, is consistent with what could be expected if the brain is allowed to develop normally without disruption such as mTBI (Blakemore, 2012; Horton et al., 2010). The finding that the RC group did not display statistically significant intra-group differences in academic achievement when measured over time, but that academic achievement followed a downward trend, is difficult to substantiate in the literature. The few research studies on the effect of cumulative concussion on young athletes do not isolate academic achievement as a variable (Iverson et al., 2004; Shuttleworth-Edwards et al., 2008). Further research into intra-group differences in this specific area of enquiry and population group is therefore necessary. Normal cognitive and brain development, maintains that the brain develops in a posterior to anterior direction, and the prefrontal regions which are vulnerable to concussion, develop last (Anderson, 2010; Blakemore, 2012; Lezak, 2004). Whereas the primary motor and sensory areas and areas for receptive and expressive language are fully developed by the age of ten years, the prefrontal brain areas that are responsible for more complex and abstract thought repertoires only start maturing in early adolescence and this development continues up to the age of 24 and even into the early 30s (Toleda et al., 2012). Injury to the developing brain at this critical stage of maturation may adversely affect the development of cognitive skills, preventing the child from acquiring the effective cognitive strategies needed for normal academic functioning and adequate academic achievement after TBI (Horton et al., 2010). However, if there is no insult to the brain, cognitive functions are expected to develop normally as a result of synaptic pruning and increased white-matter volume in the prefrontal cortex (Blakemore, 2012), making it likely that the maturation of these abilities will lead to greater cognitive and academic ability (Blakemore & Choudhury, 2006), such as seen for the NRC-group in this study. Limitations for this study include a small sample size and the testing of only one variable. It is therefore recommended that future studies include more variables, and aim at creating a larger, randomized sample size, possibly providing a more representative pool of participants to study this phenomenon in South African context. It is also advised that future studies consider using neuropsychological measures to test cognitive functioning. As previous studies have indicated specific impairment in executive functioning after TBI, it may be worth researching the effect of concussion on executive functioning more thoroughly (Anderson, 2002; Anderson et al., 2010; Horton et al., 2010). Further it may be valuable to consider using functional MRI studies to broaden existing knowledge about the interaction between pathophysiology and cognitive functioning This study also highly recommends that schools and rugby clubs catering for child and adolescent players reconsider the importance of implementing proper return to play protocols after players obtain concussions. / Thesis (MA (Clinical Psychology))--North-West University, Potchefstroom Campus, 2013

Rugby is a popular sport in South Africa, and has been played by young boys from as early as seven years old (South African Rugby Union [SARU], 2011). Despite various physical health benefits, it carries a high risk for injury, especially head injury, and consequently has a high incidence of concussion (Alexander, 2009; Laubscher, 2006; Shuttleworth-Edwards, Smith & Radloff, 2008). It is common for 12 to 13 per cent of adolescent rugby players to report mild traumatic brain injury or concussion per season (Laubscher, 2006; Shuttleworth-Edwards et al., 2008). The true incidence is however considered to be higher, even as high as 70.4% (Shuttleworth-Edwards et al., 2008). Concussion, otherwise known as mild traumatic brain injury (mTBI) is described as a traumatically induced alteration in mental status, or traumatically induced cerebral dysfunction (Kraus, McArthur, Silvermand & Jayaraman, 1996) which may, or may not involve loss of consciousness (Quality Standards Subcommittee, American Academy of Neurology [AAN], 1997). The nature of concussion has traditionally been considered to be transient, and symptoms are usually resolved within a few days or weeks (Kirkwood et al., 2008; Taylor et al., 2010). However, when concussions are not fully resolved prior to players returning to the game, they may be vulnerable to second impact syndrome. This syndrome causes herniation and brain oedema, which may result in death (Patel, 2005), as has been reported in South African press (Alexander, 2009; South African Press Association [SAPA], 2012). Even without second impact syndrome, repeated concussions may render the brain neurocognitively vulnerable, leading to an array of short- and long-term cognitive symptoms (Alexander, 2009; Shuttleworth-Edwards et al., 2008). Short-term problems include difficulties with attention, focus and concentration; following multi-step instruction, engaging in mental problem-solving; verbal expression, receiving and processing verbal and visual information; maintaining effective levels of mental and physical energy; controlling mood; suppressing impulsive behaviours; initiating and maintaining productive interpersonal relationships with peers; engaging in meaningful conversation and participating in group activities (Jantz & Coulter, 2007). Short-term cognitive impairments due to repeated concussion have also been found, and include amongst the former symptoms, also problems with delayed memory, learning, social functioning, and abstract thinking (Anderson, Brown, Newitt & Hoile, 2011; Laubscher, 2006). Long-term sequelae follow when children did not return to their baseline level of functioning after three months (Kirkwood et al., 2008; Taylor et al., 2010). Long-term sequelae include problems with memory, visuo-motor processing, executive functioning, learning and abstract thinking (Anderson, 2002; Anderson et al., 2010; Horton et al., 2010; Lezak et.al., 2004; Shuttleworth-Edwards & Radloff, 2008). As mTBI is traditionally thought to be of transient nature, researchers tend to investigate moderate to severe TBI, rather than mTBI (Alexander, 2009; Anderson et al., 2010; Patel, 2005). This could easily lead to important facts about mTBI being missed or not acknowledged. Nevertheless, recent investigations are uncovering facts about mTBI that could transform the way in which we understand mTBI, providing increasing evidence that mTBI is more serious than widely believed (Blakemore, 2012; Maxwell, 2011; Toleda et al., 2012). However, there remains a lack of research investigating mTBI from a single cause. Considering the above information, the current study provides unique information about mTBI. It specifically investigated the long-term effects of mTBI on adolescents from a homogenous cause, which makes results more comparable. The importance of this study is highlighted in the face of evidence for the long-term effects of multiple concussions, that were sustained during school rugby, on academic achievement (Alexander, 2009; Laubscher, 2006).In the light of grey areas in existing research, the aim of this current study was to investigate whether there is a significant difference in academic achievement within and between two groups of adolescents that had either played rugby and sustained multiple concussions, or had not played rugby nor sustained any concussions, when measured at four points in time over six years. A retrospective data-analysis was performed on matched, controlled, prospective longitudinal data, which was obtained from a study that evaluated the impact of repeated mTBI on the cognitive and academic functioning of early adolescent rugby players over time (Alexander, 2009). This study elaborates on a subset of the previous data, adding the gr. 12 results for academic aggregate scores, to the previously reported academic dataset. Participants were selected from Alexander‟s study (2009), and had either played rugby and obtained two or more concussions (Rugby/Concussed (RC- group); n=17), or did not play rugby nor sustained any concussions (Non-rugby/Non-concussed (NRC-group); n=13). Academic aggregate scores from baseline (gr. 7) through gr. 12 were analysed using quantitative statistical measures. A normal probability plot determined that the data was distributed normally. Descriptive statistics were reported, where after repeated measures ANOVA‟s were conducted to determine the statistical significance of differences in academic scores between and within the groups over time. These results indicated that the NRC-group displayed statistically significant increase in academic achievement over time (p = .000), whereas the RC-group did not display any significant differences, despite displaying a downwards trend in achievement. The difference between the two groups was measured at its highest in gr. 12 (p = .003), indicating that the NRC-group performed statistically significantly better than the RC-group over time. However, a Pearson‟s correlation test revealed that the estimated IQ (Vocabulary subscale of the WISC-III) (Wechsler, 1991) had a positive correlation on academic achievement [r(34) = .54, p < .05)]. To control for the effect that this correlation had on the academic results, an ANCOVA was conducted. This analysis indicated a statistically significant difference in academic achievement between the two groups in gr.12 (p = .004), with a large effect size (d = 1.41), implicating practical significance. Findings consequently confirmed our hypothesis. The significant increase in academic achievement observed within the NRC-group over time, is consistent with what could be expected if the brain is allowed to develop normally without disruption such as mTBI (Blakemore, 2012; Horton et al., 2010). The finding that the RC group did not display statistically significant intra-group differences in academic achievement when measured over time, but that academic achievement followed a downward trend, is difficult to substantiate in the literature. The few research studies on the effect of cumulative concussion on young athletes do not isolate academic achievement as a variable (Iverson et al., 2004; Shuttleworth-Edwards et al., 2008). Further research into intra-group differences in this specific area of enquiry and population group is therefore necessary. Normal cognitive and brain development, maintains that the brain develops in a posterior to anterior direction, and the prefrontal regions which are vulnerable to concussion, develop last (Anderson, 2010; Blakemore, 2012; Lezak, 2004). Whereas the primary motor and sensory areas and areas for receptive and expressive language are fully developed by the age of ten years, the prefrontal brain areas that are responsible for more complex and abstract thought repertoires only start maturing in early adolescence and this development continues up to the age of 24 and even into the early 30s (Toleda et al., 2012). Injury to the developing brain at this critical stage of maturation may adversely affect the development of cognitive skills, preventing the child from acquiring the effective cognitive strategies needed for normal academic functioning and adequate academic achievement after TBI (Horton et al., 2010). However, if there is no insult to the brain, cognitive functions are expected to develop normally as a result of synaptic pruning and increased white-matter volume in the prefrontal cortex (Blakemore, 2012), making it likely that the maturation of these abilities will lead to greater cognitive and academic ability (Blakemore & Choudhury, 2006), such as seen for the NRC-group in this study. Limitations for this study include a small sample size and the testing of only one variable. It is therefore recommended that future studies include more variables, and aim at creating a larger, randomized sample size, possibly providing a more representative pool of participants to study this phenomenon in South African context. It is also advised that future studies consider using neuropsychological measures to test cognitive functioning. As previous studies have indicated specific impairment in executive functioning after TBI, it may be worth researching the effect of concussion on executive functioning more thoroughly (Anderson, 2002; Anderson et al., 2010; Horton et al., 2010). Further it may be valuable to consider using functional MRI studies to broaden existing knowledge about the interaction between pathophysiology and cognitive functioning This study also highly recommends that schools and rugby clubs catering for child and adolescent players reconsider the importance of implementing proper return to play protocols after players obtain concussions. / Thesis (MA (Clinical Psychology))--North-West University, Potchefstroom Campus, 2013

Abstract Children born preterm are prone to acute brain insults related to subsequent neurodevelopmental impairments. However, the role of specific biomarkers and perinatal clinical factors in the pathogenesis of brain injury and neurodevelopmental sequelae has remained poorly understood. The present study evaluated whether specific immunoproteins at birth predict the risk of intraventricular hemorrhage (IVH) and whether their receptors are localized at the bleeding site. We further investigated whether children who went on to develop cerebral palsy (CP) could be identified on the basis of blood immunoproteins collected during the perinatal period. The association between single nucleotide polymorphisms in the chemokine CCL18 gene and susceptibility to CP was also studied. Finally, we investigated the association of pre- and postnatal factors with cognitive outcomes in very preterm-born schoolchildren without impairments. The present study revealed that a low concentration of CCL18 in cord blood was an independent risk factor of IVH in very preterm infants. The CCL18 receptor, CCR3, was detectable in the periventricular area and in the neurons of the hippocampus in preterm infants already at 23 weeks of gestation. We also identified a cluster of cord blood cytokines that was associated with the risk of CP. In addition, inflammatory cytokine levels were associated with CP risk on days 1 and 7 after birth. The genetic study showed that both IVH and the CCL18 polymorphism independently and additively had an influence on CP susceptibility. Our study further demonstrated that schoolchildren born very preterm without CP or cognitive impairment had poorer performance in visuospatial–sensorimotor skills and in attention–executive functions than term-born children. Fetal growth restriction was an independent risk factor of compromised neurocognitive outcome in very preterm children predicting difficulties in language, memory and learning. In conclusion, specific cytokines and cytokine clusters serve as biomarkers of different pathways involved in damage to the brain structures and in the pathogenesis of CP. In addition, genetic factors can affect these processes. Further, fetal growth restriction and prematurity play important roles in neurocognitive development later in life. / Tiivistelmä Hyvin ennenaikaisina syntyneet lapset ovat alttiita akuuteille aivovaurioille sekä myöhemmin ilmeneville kehityshäiriöille. Eri välittäjäaineiden sekä raskaudenaikaisten ja syntymänjälkeisten kliinisten tekijöiden vaikutusta aivojen vaurioherkkyyteen sekä neurologiseen ja neurokognitiiviseen kehitykseen ei kuitenkaan ole tutkittu riittävästi. Tässä tutkimuksessa tarkasteltiin, ennustaako jokin napaverestä tutkituista sytokiineista aivoverenvuotoa hyvin ennenaikaisesti syntyneillä vastasyntyneillä. Lisäksi selvitettiin, onko sytokiinin spesifinen reseptori osoitettavissa vuotoherkällä alueella aivoissa. Tutkimme myös, ennustaako jokin napaveren immunoproteiini-profiilin komponentti CP-vamman syntyä joko itsenäisesti tai yhdessä muiden perinataalisten riskitekijöiden kanssa sekä lisääkö tietyn sytokiinin (CCL18) geneettinen vaihtelu CP-vamman riskiä hyvin ennenaikaisesti syntyneillä lapsilla. Lisäksi selvitimme, vaikuttavatko raskaudenaikaiset tekijät ja vastasyntyneisyyskauden sairaudet neurokognitiiviseen kehitykseen kouluiässä. Tämän tutkimuksen mukaan napaveren matala CCL18-kemokiinipitoisuus oli itsenäinen aivoverenvuodon riskitekijä. CCR3-reseptori, johon CCL18 sitoutuu, oli osoitettavissa sekä vuotoherkällä alueella että hermosoluissa 23. raskausviikon iästä lähtien. Havaitsimme myös, että tietyt napaveren sytokiiniryppäät ja yksittäisten tulehdusvastevälittäjäaineiden pitoisuudet 1. ja 7. elinpäivänä olivat yhteydessä CP-riskiin. Lisäksi havaitsimme yhteyden CCL18-kemokiinin geneettisen vaihtelun ja aivoverenvuodon sekä CP-vamman kehittymisen välillä. Tutkimuksemme mukaan hyvin ennenaikaisesti syntyneet koululaiset, joilla ei ollut CP- tai kehitysvammaa, suoriutuivat täysiaikaisina syntyneitä verrokkeja heikommin visuaalista hahmotusta ja sensomotoriikkaa sekä tarkkaavuutta ja toiminnanohjausta mittaavissa testeissä. Lisäksi havaitsimme sikiöaikaisen kasvuhäiriön ennustavan itsenäisesti heikkoa suoritusta kieltä, muistia ja oppimista testaavissa tehtävissä ennenaikaisesti syntyneillä lapsilla. Tietyt sytokiinit ja sytokiiniryppäät ovat yhteydessä aivovauriomekanismeihin. Nämä mekanismit saattavat yhdessä perinnöllisen alttiuden kanssa vaikuttaa myös CP-vamman syntyyn. Sikiöaikainen kasvuhäiriö ja ennenaikaisuus vaikuttavat lapsen myöhempään neurokognitiiviseen kehitykseen.

Contexte: Le retard de croissance intra-utérin (RCIU) désigne l’incapacité du fœtus à atteindre son potentiel de croissance déterminé génétiquement en raison de diverses causes. Il est défini le plus souvent par un poids de naissance inférieur au 10ème percentile pour l’âge gestationnel sur les courbes néonatales. Ce travail de thèse a comme objectif de répondre aux questions non-résolues sur la définition et les conséquences du RCIU dans le contexte de la grande prématurité: (1) Quelle est la meilleure définition du RCIU à utiliser pour identifier les enfants à risque ? (2) Quels sont les risques de mortalité et de morbidités néonatales respiratoires et neurologiques associés au RCIU et existe-t-il des interactions avec les pathologies de la grossesse responsables de cette naissance très prématurée ? (3) Quel est l’impact du RCIU sur le devenir neuro-développemental à 2 ans, en particulier chez les enfants nés extrêmement prématurément ? Méthodes: Nous avons utilisé deux sources de données. L’étude MOSAIC (Models for OrganiSing Access to Intensive Care for Very Preterm Babies in Europe) est une étude européenne en population qui porte sur l’ensemble des naissances survenues entre 22 et 31 semaines d’aménorrhée en 2003 dans dix régions européennes. Les enfants ont été suivis jusqu’à la sortie d’hospitalisation (population d’étude : 4525 enfants). La deuxième source est une cohorte d’enfants nés avant 27SA qui ont été hospitalisés dans le service de réanimation néonatale à l'hôpital de Port-Royal de 1999 à 2008 et qui ont eu un examen pédiatrique et une évaluation selon l’échelle de Brunet-Lézine qui inclut quatre domaines du développement global de l’enfant : la motricité globale, la motricité fine, le langage et l’interaction sociale (445 enfants admis, 268 enfants suivis à 2 ans). Résultats: Dans les deux populations, les risques de décès et de dysplasie broncho-pulmonaire étaient plus élevés pour les enfants ayant un poids de naissance <10éme percentile des courbes néonatales, mais également pour des enfants avec un poids plus élevé (entre le 10éme et le 24éme percentile des courbes néonatales ou <10ème percentile des courbes fœtales). Par contre, il n’y avait pas de lien entre les complications neurologiques et le faible poids, ni d’interaction avec les pathologies de la grossesse. Le RCIU était associé à un risque élevé du retard neurocognitif à deux ans d’âge corrigé chez les extrêmes prématurés, surtout dans le domaine de la motricité fine et de l’interaction sociale mais pas dans le domaine du langage et de la motricité globale. Nous n’avons pas trouvé d’association entre le RCIU et le risque d’infirmité motrice cérébrale à deux ans d’âge corrigé. Conclusions: L’utilisation du 10ème percentile des courbes néonatales n’est pas adaptée pour identifier l’impact du RCIU chez les grands prématurés ; l’utilisation de multiples seuils ou de courbes de croissance fœtale est nécessaire. Le RCIU accroit les risques de mortalité et de dysplasie broncho-pulmonaire, mais n’est pas associé aux lésions cérébrales sévères ; ces associations sont observées dans différents contextes périnatals (pathologies vasculaires et infectieuses, et naissances à des âges gestationnels très précoces). Le RCIU représente un facteur pronostic défavorable pour le neuro-développement à moyen terme. Nos résultats soulèvent de nouvelles questions sur le suivi adapté pour les enfants ayant un RCIU après leur sortie de l’hôpital et aussi sur les éventuels mécanismes biologiques pouvant expliquer les liens entre le RCIU avec une morbidité respiratoire et certains domaines du développement neurocognitif à moyen terme. / Background: Intrauterine growth restriction (IUGR) refers to the inability of the fetus to achieve its genetically determined growth potential due to various causes. Most often, it is defined by a birth weight less than the 10th percentile for gestational age using neonatal growth curves. This thesis aims to answer unresolved questions about the definition and consequences of IUGR in the context of very preterm birth: (1) what is the best definition of IUGR for identifying children at risk? (2) What are the risks of mortality and neonatal respiratory and neurological morbidity associated with IUGR and are there interactions with the underlying pregnancy complications responsible for the very preterm birth? (3) What is the impact of IUGR on neurodevelopmental at 2 years, especially for children born extremely preterm ? Methods: We used two data sources. The MOSAIC study (Models for Organising Access to Intensive Care for Very Preterm Babies in Europe) is a European population-based study that included all births occurring between 22 and 31 weeks of gestation in 2003 in ten European regions. The children were followed until hospital discharge (study population = 4525 infants). The second source is a cohort of children born before 27 weeks of GA who were hospitalized in the neonatal intensive care unit at the Port Royal Hospital from 1999 to 2008 and had a pediatric examination and Brunet-Lézine (BL) neurodevelopmental assessment at 2 years of corrected age (445 children in the cohort, 268children followed at 2 years). The BL assessment includes four areas of child development: gross motor, fine motor, language and social interaction skills. Results: In both populations, the risk of death and bronchopulmonary dysplasia were higher for children with a birth weight <10th percentile of neonatal growth curves but also for children with a higher birth weight (between the 10th and the 24th percentile of neonatal growth curves or <10th percentile of fetal growth curves). In contrast, there was no link between neurological complications and low birth weight and no interactions with pregnancy complications. IUGR was associated with neurocognitive delay among extremely preterm children evaluated at two years of corrected age, especially for fine motor and social interaction skills, but not for language and gross motor skills. We did not find any association between IUGR and the risk of cerebral palsy at two years of corrected age. Conclusions: The use of the 10th percentile of neonatal growth curves is not suitable for identifying the impact of IUGR in very preterm infants; using higher thresholds or fetal growth curves is necessary. IUGR increased the risks of mortality and bronchopulmonary dysplasia, but was not associated with severe brain damage; these associations are observed in multiple clinical contexts (vascular and infectious pregnancy complications, and births at very early gestational ages). IUGR is a risk factor for poor medium-term neuro-development. Our results raise new questions about the appropriate surveillance for children with IUGR after discharge from the hospital and also about possible biological mechanisms that could explain the relationship between IUGR and respiratory morbidity and neurocognitive development.