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Abstract

Learning difficulties are frequently diagnosed in children born with intrauterine growth restriction (IUGR). Models of various animal species with IUGR were studied and demonstrated specific susceptibility and alterations of the hippocampal formation and its related neural structures. The main purpose was to study memory functions of children born with asymmetric IUGR in a large-scale cohort using a long-term prospective paradigm. One hundred and ten infants diagnosed with IUGR were followed-up from birth to 9 years of age. Their performance was compared with a group of 63 children with comparable gestational age and multiple socioeconomic factors. Memory functions (short-term, super- and long-term spans) for different stimuli types (verbal and visual) were evaluated using Visual Auditory Digit Span tasks (VADS), Rey Auditory Verbal Learning Test (Rey-AVLT), and Rey Osterrieth Complex Figure Test (ROCF). Children with IUGR had short-term memory difficulties that hindered both serial verbal processing system and simultaneous processing of high-load visuo-spatial stimuli. The difficulties were not related to prematurity, neonatal complications or growth catch-up, but were augmented by lower maternal education. Recognition skills and benefits from reiteration, typically affected by hippocampal dysfunction, were preserved in both groups. Memory profile of children born with IUGR is characterized primarily by a short-term memory deficit that does not necessarily comply with a typical hippocampal deficit, but rather may reflect an executive short-term memory deficit characteristic of anterior hippocampal-prefrontal network. Implications for cognitive intervention are discussed.

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... It is known that fetuses with FGR are more likely to exhibit long-term cognitive impairment and memory deficit, as has been demonstrated within this study. 17 The statistically significant results from our study were found in assessments of cognitive function focusing on recall of objects verbal and spatial; the area of the brain controlling this function being the hippocampal region which controls declarative memory, with children with elevated UAD PI in utero having poorer scores in these assessments. There were no cases of abnormal development within the study cohort as such cases were excluded at the selection process. ...
... What can be extrapolated clinically from this study is that the cohort of patients with an elevated UAD PI were more likely to have lower but not abnormal scores in assessments of short-term and declarative memory function than their normal UAD PI peers, which may express itself as a child having executive-attention deficit and/or mild learning difficulties, somewhat similar to that of children who had FGR in utero. 17 It is important to note, however, that despite these changes they did not affect the overall academic ability, mental processing and reasoning or overall behavioural function. The latter supports the theory that reduced placental blood flow, notably during the second half of pregnancy, correlates with a reduction in the number of neurons within this area of the fetal brain; as correlated with the histological brains of primates and humans at this stage in addition to vulnerability of hippocampus to injury in the prenatal period. ...
... Additionally, due to the demonstrated apparent deficit in short-term memory at childhood follow-up, a focus should be made on those children who had FGR to facilitate orientation, and direct attention and reiteration of material to optimise learning performance. 17 CONCLUSION An elevated UAD PI at 28 weeks' gestation in the absence of FGR or prematurity is associated with some adverse cognitive findings in children aged 12 years. A potential explanation for this phenomenon is an element of placental insufficiency in the presence of the appropriately grown fetus which affects the development of the fetal hippocampus, and this information processing and memory long-term further studies should be performed before firm conclusions or guidance can be drawn from the findings of this study. ...
Conference Paper
Objective To evaluate if an elevated fetal umbilical artery Doppler (UAD) pulsatility index (PI) is associated with adverse 1. neurocognitive, 2. respiratory and 3. cardiovascular function in children aged twelve. Methods This prospective case–control study compared children with an elevated and normal UAD PI at 28 weeks. All were delivered at full‐term and were not growth restricted. Outcome measures included: 1. Neurocognition – assessed using British Ability Score‐II and Achenbach Child Behavioural Checklist Parent Rated scales. 2. Respiratory; (i) asthma/atopy; (ii) spirometry measurements; and (iii) CRP and leptin. 3. Cardiovascular – (i) blood‐pressure; (ii) pulse wave velocity; (iii) cardio‐respiratory fitness; and (v) homocysteine and cholesterol. Results 195 subjects were included, with variable proportions between groups depending on system. 1. Neurocognition – elevated UAD PI was associated with lower scores in cognitive assessments of information processing and memory including; (i) recall of objects immediate verbal (P = 0.002); (ii) delayed verbal (P = 0.008); and (iii) recall of objects immediate spatial (P = 0.002) 2. Respiratory – No association was found UAD PI and asthma (P = 0.47) or atopy (P = 0.75), spirometry measures, elevated CRP (P = 0.69) or leptin (P = 0.20). 3. Cardiovascular – no association was found with raised resting pulse (P = 0.3), pulse wave velocity (P = 0.90) or arterial compliance (P = 0.27). Conclusion An elevated UAD PI in the absence of prematurity or fetal growth restriction is associated with lower scores of declarative memory in children but is not associated with altered respiratory or cardiovascular risk function in children aged twelve.
... The slower maturation of cognitive function eventually manifests as reduced IQ scores and academic performance in childhood, with 15% of children born IUGR having IQs below 85 (Leitner et al., 2007). Children born IUGR and either with (Esteban et al., 2010;Fischi-Gomez et al., 2015;Geva et al., 2006a;Geva et al., 2006b;Kok et al., 1998;Smedler et al., 1992) or without (Geva et al., 2006a;Geva et al., 2006b;Leitner et al., 2007;Low et al., 1992) prematurity are also more likely to have low neurodevelopmental scores, reduced levels of achievement at school, short-term memory difficulties, language difficulties, inflexibility, behavioural problems, attentional deficits, hyperactivity, impairments in social functioning, mood and motor control (Esteban et al., 2010;Fischi-Gomez et al., 2015;Geva et al., 2006a;Geva et al., 2006b;Kok et al., 1998;Leitner et al., 2007;Low et al., 1992;Smedler et al., 1992), deficits that are significantly predicted by the perinatal head circumference to body weight ratio at birth (Leitner et al., 2007). ...
... The slower maturation of cognitive function eventually manifests as reduced IQ scores and academic performance in childhood, with 15% of children born IUGR having IQs below 85 (Leitner et al., 2007). Children born IUGR and either with (Esteban et al., 2010;Fischi-Gomez et al., 2015;Geva et al., 2006a;Geva et al., 2006b;Kok et al., 1998;Smedler et al., 1992) or without (Geva et al., 2006a;Geva et al., 2006b;Leitner et al., 2007;Low et al., 1992) prematurity are also more likely to have low neurodevelopmental scores, reduced levels of achievement at school, short-term memory difficulties, language difficulties, inflexibility, behavioural problems, attentional deficits, hyperactivity, impairments in social functioning, mood and motor control (Esteban et al., 2010;Fischi-Gomez et al., 2015;Geva et al., 2006a;Geva et al., 2006b;Kok et al., 1998;Leitner et al., 2007;Low et al., 1992;Smedler et al., 1992), deficits that are significantly predicted by the perinatal head circumference to body weight ratio at birth (Leitner et al., 2007). ...
... The slower maturation of cognitive function eventually manifests as reduced IQ scores and academic performance in childhood, with 15% of children born IUGR having IQs below 85 (Leitner et al., 2007). Children born IUGR and either with (Esteban et al., 2010;Fischi-Gomez et al., 2015;Geva et al., 2006a;Geva et al., 2006b;Kok et al., 1998;Smedler et al., 1992) or without (Geva et al., 2006a;Geva et al., 2006b;Leitner et al., 2007;Low et al., 1992) prematurity are also more likely to have low neurodevelopmental scores, reduced levels of achievement at school, short-term memory difficulties, language difficulties, inflexibility, behavioural problems, attentional deficits, hyperactivity, impairments in social functioning, mood and motor control (Esteban et al., 2010;Fischi-Gomez et al., 2015;Geva et al., 2006a;Geva et al., 2006b;Kok et al., 1998;Leitner et al., 2007;Low et al., 1992;Smedler et al., 1992), deficits that are significantly predicted by the perinatal head circumference to body weight ratio at birth (Leitner et al., 2007). ...
Article
Poor white matter development in intrauterine growth restricted (IUGR) babies remains a major, untreated problem in neonatology. New therapies, guided by an understanding of the mechanisms that underlie normal and abnormal oligodendrocyte development and myelin formation, are required. Much of our knowledge of the mechanisms that underlie impaired myelination come from studies in adult demyelinating disease, preterm brain injury, or experimental models of hypoxia-ischemia. However relatively less is known for IUGR which is surprising because IUGR is a leading cause of perinatal mortality and morbidity, second only to premature birth. IUGR is also a significant risk factor for the later development of cerebral palsy, and is a greater risk compared to some of the more traditionally researched antecedents - asphyxia and inflammation. Recent evidence suggests that the white matter injury and reduced myelination in the brains of some preterm babies is due to impaired maturation of oligodendrocytes thereby resulting in the reduced capacity to synthesize myelin. Therefore, it is not surprising that the hypomyelination observable in the central nervous system of IUGR infants has similarly lead to investigations identifying a delay or blockade in the progress of maturation of oligodendrocytes in these infants. This review will discuss current ideas thought to account for the poor myelination often present in the neonate's brain following IUGR, and discuss novel interventions that are promising as treatments that promote oligodendrocyte maturation, and thereby repair the myelination deficits that otherwise persist into infancy and childhood and lead to neurodevelopmental abnormalities.
... It is known that fetuses with FGR are more likely to exhibit long-term cognitive impairment and memory deficit, as has been demonstrated within this study. 17 The statistically significant results from our study were found in assessments of cognitive function focusing on recall of objects verbal and spatial; the area of the brain controlling this function being the hippocampal region which controls declarative memory, with children with elevated UAD PI in utero having poorer scores in these assessments. There were no cases of abnormal development within the study cohort as such cases were excluded at the selection process. ...
... What can be extrapolated clinically from this study is that the cohort of patients with an elevated UAD PI were more likely to have lower but not abnormal scores in assessments of short-term and declarative memory function than their normal UAD PI peers, which may express itself as a child having executive-attention deficit and/or mild learning difficulties, somewhat similar to that of children who had FGR in utero. 17 It is important to note, however, that despite these changes they did not affect the overall academic ability, mental processing and reasoning or overall behavioural function. The latter supports the theory that reduced placental blood flow, notably during the second half of pregnancy, correlates with a reduction in the number of neurons within this area of the fetal brain; as correlated with the histological brains of primates and humans at this stage in addition to vulnerability of hippocampus to injury in the prenatal period. ...
... Additionally, due to the demonstrated apparent deficit in short-term memory at childhood follow-up, a focus should be made on those children who had FGR to facilitate orientation, and direct attention and reiteration of material to optimise learning performance. 17 CONCLUSION An elevated UAD PI at 28 weeks' gestation in the absence of FGR or prematurity is associated with some adverse cognitive findings in children aged 12 years. A potential explanation for this phenomenon is an element of placental insufficiency in the presence of the appropriately grown fetus which affects the development of the fetal hippocampus, and this information processing and memory long-term further studies should be performed before firm conclusions or guidance can be drawn from the findings of this study. ...
Article
Full-text available
Objective To determine if an elevated fetal umbilical artery Doppler (UAD) pulsatility index (PI) at 28-weeks gestation, in the absence of fetal growth restriction (FGR) and prematurity, is associated with adverse neurocognitive outcome in children aged twelve. Methods Prospective cohort study, comparing children with a normal fetal UAD PI (<90th centile) (n=110) and those with an elevated PI (≥90th centile) (n=40). UAD was performed at 28-, 32- and 34-weeks gestation. At 12 years of age all children were assessed under standardized conditions in Queen’s University, Belfast, UK to determine cognitive and behavioural outcomes using the British Ability Score-II and Achenbach Child Behavioural Checklist Parent Rated Version under standardized conditions. Regression analysis was performed, controlling for confounders of gender, socioeconomic status, and age at assessment. Results The mean age of follow up was 12.4 years (+/- 0.5 SD) with 44% of children male (n=63). When UAD was assessed at 28-weeks’ the elevated fetal UAD group had lower scores in cognitive assessments of information processing and memory. Parameters included (i) Recall of objects immediate verbal (p=0.002), (ii) delayed verbal (p=0.008) and (iii) recall of objects immediate spatial (p=0.0016). There were no significant differences between the Doppler groups at 32 or 34 weeks’ gestation. Conclusion An elevated UAD PI at 28 weeks’ gestation in the absence of FGR or prematurity is associated with poorer scores of declarative memory in children aged twelve years. A potential explanation for this is an element of placental insufficiency in the presence of the appropriately grown fetus, which impacts on development of the fetal hippocampus and information processing and memory long-term. These findings, however, had no impact upon overall academic ability, mental processing and reasoning or overall behavioural function.
... At 5-6 years of age deficits are noted in the ability to solve multi-step problems, as required for solving tasks, such as the Tower of London; scanning efficiently for a pre-selected set of visual stimuli without being distracted by similar patterns, exhibiting inhibitory control skills in stop-signal paradigms, and maintaining set in auditory tasks. These deficits impede upon the children's fluency and creative abilities at this age (Geva et al., 2006b). ...
... Overall, executive functions and attention and problem solving (Geva et al., 2006b), graphomotor ability (Leitner et al., 2000), visuospatial functioning (Sommerfelt et al., 2002), as well as language (Frisk et al., 2002) have been frequently reported to be affected by IUGR. These deficits have been interpreted as contributing particularly to cognitive performance and academic achievements. ...
... First, data suggest that the major memory deficit encountered by children born with IUGR is particularly evident in short-term memory tasks, which may be accounted for by a lack of sufficient attention allocation to novel stimuli, rather than a deficit in information processing. Manipulating the level of directed attention by facilitating orientation should benefit learning performance (Geva et al., 2006b. ...
Chapter
Full-text available
Intrauterine growth restriction (IUGR) is a pathological prenatally occurring process that is characterized by a decrease in fetal growth velocity. It is associated with a higher incidence of fetal and parental stress, perinatal complications, and lifelong neurodevelopmental and neuropsychological consequences evident both at short term and at long term in a third to one-half of children. This chapter’s focus is on characterizing IUGR-related neuropsychological susceptibilities and the factors that mediate its severity, with a particular interest in time-locked growth catch-up processes. The neuropsychological profile presents a particular susceptibility to attention, auditory processing, and higher order tasks, such as planning and organization tasks and specific language tasks. Behavior is sometimes characterized by increased susceptibility to attention and specific learning deficits, inhibitory control difficulties, and/or internalized issues such as maladjustment and depression. Specific deficits seem to recover with somatic growth catch-up, particularly as a function of weight and head circumference catch-up within the first years of life. Interdisciplinary intervention guidelines are outlined.
... Further studies showed that the adverse perinatal factors causing FGR also lead to long-term negative consequences. Apart from the augmented risk for metabolic, cardiovascular and renal diseases [6,7], FGR is associated with long-term neurocognitive impairment [8][9][10]. Children with FGR have a higher risk for deficiencies in learning, memory and attention as adolescents and adults compared to matching control groups [11][12][13][14][15][16][17]. ...
... Fetal growth restriction (FGR), which is most commonly caused by undernutrition and placental insufficiency, remains a highly relevant global health problem [2]. Neurocognitive short-and long-term consequences subsequent to impaired neuronal development including the hippocampus have been described after FGR [8,9]. The present study was designed to test the hypothesis that dysregulation of mTOR signaling during the period of maximal brain growth between birth and PND 12 and altered cellular composition are common hippocampal signatures after FGR of different origins in male rats. ...
Article
Full-text available
Fetal growth restriction (FGR) has been linked to long-term neurocognitive impairment, especially in males. To determine possible underlying mechanisms, we examined hippocampal cellular composition and mTOR signaling of male rat FGR offspring during main brain growth and development (postnatal days (PND) 1 and 12). FGR was either induced by a low-protein diet throughout pregnancy, experimental placental insufficiency by bilateral uterine vessel ligation or intrauterine stress by “sham” operation. Offspring after unimpaired gestation served as common controls. Low-protein diet led to a reduced cell density in the molecular dentate gyrus subregion, while intrauterine surgical stress was associated with increased cell density in the cellular CA2 subregion. Experimental placental insufficiency caused increased mTOR activation on PND 1, whereas intrauterine stress led to mTOR activation on PND 1 and 12. To determine long-term effects, we additionally examined mTOR signaling and Tau phosphorylation, which is altered in neurodegenerative diseases, on PND 180, but did not find any changes among the experimental groups. Our findings suggest that hippocampal cellular proliferation and mTOR signaling are dysregulated in different ways depending on the cause of FGR. While a low-protein diet induced a decreased cell density, prenatal surgical stress caused hyperproliferation, possibly via increased mTOR signaling.
... Indeed, existing studies are dissimilar in different aspect such as inclusion and exclusion criteria, definition of FGr and outcome measures, thus, making the interpretation and comparison of outcomes difficult. 28 it must be emphasized that the concept of early and late FGr is relatively new 12 and, therefore, most of the available literature is based on mixed population of growth restricted fetuses (early and late). in early FGr the risk of damage to the central nervous system is high, while it is less in late FGr and leads to subtle cognitive impairments and poor school performance 17,29 including memory problems, 30 learning abilities, 31 attention 32 and social skills. 33 The effect of cerebral blood flow redistribution on the brain ...
... decreased adc values could be explained as an abnormal maturation and could probably explain development of cognitive, behavioral, and emotional disorders, especially in the frontal area, which seems particularly vulnerable to hypoxia and chronic vascular insult. 76 the fronto-parietal area is involved in the regulation of different functions, reported to be abnormal in FGr fetuses, including memory problems, 30 learning abilities, 31 attention 32 and social skills. 33 Finally, batalle et al. 56 found, in one-year children born FGR (defined as birthweight below the 10 th percentile) a different brain organization. ...
Article
Introduction: Late fetal growth restriction has increasingly gain interest. Differently from early fetal growth restriction, the severity of this condition and the impact on perinatal mortality and morbidity is less severe. Nevertheless, there is some evidence to suggest that fetuses exposed to growth restriction late in pregnancy are at increased risk of neurological dysfunction and behavioural impairment. Evidence acquisition: The aim of our review is to discuss the available evidence on the neurodevelopmental outcome in fetuses exposed to growth restriction late in pregnancy. Cerebral blood flow redistribution, a Doppler hallmark of late fetal growth restriction, has been associated with this increased risk, although there are still some controversies. Currently, most of the available studies are heterogeneous and do not distinguish between early and late fetal growth restriction when evaluating the long-term outcome, thus, making the correlation between late fetal growth restriction and neurological dysfunction difficult to interpret. Evidence synthesis and conclusions: The available evidence suggests that fetuses exposed to late growth restriction are at increased risk of neurological dysfunction and behavioural impairment. The presence of the cerebral blood flow redistribution seems to be associated with adverse neurodevelopmental outcome, however, from the present literature the causality cannot be ascertained.
... Intrauterine growth-restricted (IUGR) newborns face high rates of neonatal mortality and morbidity [1] including neurological deficits ranging from behavioral and motor disabilities to cerebral palsy [2][3][4]. White matter injury is common in these infants and is characterized by a lack of mature oligodendrocytes and myelin. Oligodendrocyte progenitors (OPCs) are unable to differentiate and are arrested in an immature state, resulting in a lack of myelin and the susceptibility to further damage [5,6]. ...
... Growth-restricted newborns are at high risk for neonatal mortality as well as motor deficits, behavioral deficits, and cerebral palsy due, at least in part, to lack of proper myelination [2][3][4]. In this study, we used a well-tested model of uteroplacental insufficiency in which we have previously demonstrated a significant developmental delay in oligodendrocyte maturation and myelination as well as behavioral defects in the adult [5]. ...
Article
Full-text available
Background: Intrauterine growth restriction (IUGR) is a common complication of pregnancy and is associated with significant neurological deficits in infants, including white matter damage. Previous work using an animal model of IUGR has demonstrated that IUGR rats exhibit neurobehavioral deficits and developmental delays in oligodendrocyte maturation and myelination, but the mechanisms which cause this delay are unknown. Inflammation may be an important etiological factor in IUGR and has been recognized as playing a fundamental role in the pathogenesis of myelin disorders, including cerebral palsy. Methods: To create the model, the uterine arteries of pregnant rats were ligated at embryonic day 15. Rats delivered spontaneously. Cytokine and chemokine expression was evaluated at one prenatal and three postnatal time points, and myelin protein expression and oligodendrocyte cell numbers were evaluated by several methods at postnatal day 14. IL-4 was identified as a potential inhibitor of myelination, and rat pups were injected with IL-4 function blocking antibody from postnatal days 1-5 and myelination was assessed. Results: Here, we show a novel mechanism of white matter injury. IUGR induces an exaggerated Th2 response in the developing rat brain, including upregulation of several Th2 cytokines. Of these, IL-4 is significantly increased during the period corresponding to robust developmental myelination. We show that neutralizing IL-4 antibody therapy given in the newborn period ameliorates inflammation and restores myelin protein expression and oligodendrocyte cell number in the IUGR brain to control levels, demonstrating a novel role for Th2 responses and IL-4 in IUGR and white matter injury. In addition, IL-4 directly affects oligodendrocytes in vitro decreasing differentiation. Conclusions: In this study, we have identified inflammation as a factor in the decrease in myelin seen in an animal model of IUGR. IL-4, an inflammatory protein often thought to be protective in the adult, is specifically increased, and treatment of these animals to prevent this increase ameliorates white matter damage. Our results suggest that the immune system plays a role in IUGR that is different in the perinatal period than in the adult and preventing this exaggerated Th2 response may be a potential therapeutic target.
... Foetuses with IUGR are at an increased risk for both perinatal and long-term neurological morbidities, including decreased academic performance and standardized testing levels, which are tied to hippocampal functions. Previous studies have demonstrated that IUGR also reduces infant hippocampal volumes, a change that is associated with behavioural differences and learning disorders during childhood [2][3][4] . ...
... The programmed death (apoptosis) of neural precursor cells during earlier stages of neural development affects the proliferation of neural precursor cells and young postmitotic neuroblasts, and a low-protein diet can decrease neuronal apoptosis according to the neurotrophic theory 27,28 . Previous studies have shown that brain volume was reduced following a reduction in the number of nerve cells 3,29 . Previous studies have also demonstrated that Casp3 deficiency decreased the number of progenitor cells lost to programmed cell death, resulting in marked dysplasia and nervous system malformations 30 . ...
Article
Full-text available
In humans, malnutrition during pregnancy results in intrauterine growth restriction (IUGR) and an increased risk of neurological morbidities; altered miRNA characteristics have been suggested to contribute to IUGR neurological pathogenesis. A miRNA microarray was used to identify differentially expressed miRNA molecules in the hippocampi of rats with IUGR. Five of the molecules in question were selectively validated using real-time PCR in rats with IUGR. We then investigated the role of miR-199a-5p in hippocampal pathology. Bioinformatics analysis results suggested that TNF-α, caspase-3 and SIRT1 were potential targets of miR-199a-5p. Changes in PI3K, SIRT1 and caspase-3 protein expressions levels in the hippocampus were confirmed by Western blot analysis (all P < 0.05). Studies using the pheochromocytoma cell line PC12 cells and primary neurons demonstrated that miR-199a-5p modulated PI3K, caspase-3 and SIRT1 expression. Additionally, there was an inverse correlation between miR-199a-5p and caspase-3 expression, though dual-luciferase reporter assays showed that caspase-3 is not a target of miR-199a-5p. We conclude that IUGR affects hippocampal miRNAs characteristics. Our results also indicated that aberrantly high expression levels of miR-199a-5p may play an important role in the pathogenesis of IUGR by regulating SIRT1 and PI3K.
... Children born with IUGR are predisposed to long-term cognitive and neurodevelopmental impairment that is associated with learning difficulties and decreased academic performance (Arcangeli, Thilaganathan, Hooper, Khan, & Bhide, 2012;de Bie, Oostrom, & Delemarre-van de Waal, 2010). Longitudinal studies on IUGR babies have recently identified the cephalization index (CI = head circumference/BW) as one of the best perinatal parameters for the prediction of neurodevelopmental outcome (Geva, Eshel, Leitner, Fattal-Valevski, & Harel, 2006). A high CI in IUGR babies seems to be indicative of intrauterine blood flow redistribution, also known as the brain sparing effect, and is strongly correlated with a reduction in IQ, difficulties in creative problem solving, deficits in attention and executive functions, and alterations in visuomotor organization (Flood et al., 2014;Van den Broek, Kok, Houtzager, & Scherjon, 2010). ...
... These authors reported that IUGR babies present alterations in spatial orientation and spatial memory (Leitner, Heldman, Harel, & Pick, 2005). In addition, typical hippocampal deficits, such as executive short-term memory deficits characteristic of anterior hippocampal-prefrontal network alteration have also been reported in IUGR babies (Geva et al., 2006). The similar poor spatial memory performance shown by ischemic and IUGR rats might be related to their parallel anthropometric evolution, as described in a cohort of IUGR patients, in whom the presence of catch up growth was related to better neurological prognosis and an increased CI with learning and memory disabilities (Fattal-Valevski et al., 2009;Leitner et al., 2007). ...
Article
Full-text available
Introduction: 1Intrauterine growth restriction (IUGR) is the failure of the fetus to achieve its inherent growth potential, and it has frequently been associated with neurodevelopmental problems in childhood. Neurological disorders are mostly associated with IUGR babies with an abnormally high cephalization index (CI) and a brain sparing effect. However, a similar correlation has never been demonstrated in an animal model. The aim of this study was to determine the correlations between CI, functional deficits in learning and memory and alterations in synaptic proteins in a rat model of IUGR. Methods: 2Utero-placental insufficiency was induced by meso-ovarian vessel cauterization (CMO) in pregnant rats at embryonic day 17 (E17). Learning performance in an aquatic learning test was evaluated 25 days after birth and during 10 days. Some synaptic proteins were analyzed (PSD95, Synaptophysin) by Western blot and immunohistochemistry. Results: 3Placental insufficiency in CMO pups was associated with spatial memory deficits, which are correlated with a CI above the normal range. CMO pups presented altered levels of synaptic proteins PSD95 and synaptophysin in the hippocampus. Conclusions: 4The results of this study suggest that learning disabilities may be associated with altered development of excitatory neurotransmission and synaptic plasticity. Although interspecific differences in fetal response to placental insufficiency should be taken into account, the translation of these data to humans suggest that both IUGR babies and babies with a normal birth weight but with intrauterine Doppler alterations and abnormal CI should be closely followed to detect neurodevelopmental alterations during the postnatal period.
... Fetal growth restriction (FGR) has been related to neu- robehavioral problems during the childhood period [1,2] that also persist in the long term [3,4] . Interestingly, long- term follow-up studies have described cognitive impair- ments and learning difficulties at school age [5] involving short-term memory, and attention and anxiety problems [3,4] . ...
... Fetal growth restriction (FGR) has been related to neu- robehavioral problems during the childhood period [1,2] that also persist in the long term [3,4] . Interestingly, long- term follow-up studies have described cognitive impair- ments and learning difficulties at school age [5] involving short-term memory, and attention and anxiety problems [3,4] . ...
Article
Introduction: Chronic reduction of oxygen and nutrient delivery to the fetus has been related to neurodevelopmental problems. Placental underperfusion induces a significant reduction in oxygen and nutrient delivery, whereas maternal undernutrition causes mainly nutrient deficiency. A comparison of the neurodevelopmental effects of both situations in pregnant rabbits was performed. Materials and methods: The placental underperfusion model was induced after uteroplacental vessel ligation at 25 days of pregnancy. The undernutrition model was induced after a reduction of 70% of the basal maternal intake at 22 days of pregnancy. Neurobehavioral tests were applied in the derived offspring at the neonatal period and over the long term. Structural brain differences were evaluated by brain networks obtained from diffusion magnetic resonance imaging. Results: Birth weight was significantly lower in both cases. However, stillbirth was only increased in the placental underperfusion model. Cases from both models presented poorer neurobehavioral performance and network infrastructure, being more pronounced in the placental underperfusion model. Discussion: Prenatal insults during the last third of gestation resulted in functional and structural disturbances. The degree of neurodevelopmental impairment and its association with structural brain reorganization seemed to be related to the type of the prenatal insult, showing stronger effects in the placental underperfusion model.
... Along with this, perinatal conditions, such as IUGR and prematurity have been shown to influence the normal brain development, affecting network connectivity in the short-and long-term (Batalle et al., 2012;Ball et al., 2013;Fischi-Gómez et al., 2015). This altered brain connectivity has been related to the impairment in cognitive and social functions that have been described in childhood and adolescence as a consequence of IUGR (Geva et al., 2006;Wiles et al., 2006;Leitner et al., 2007;Heinonen et al., 2010;Baschat, 2011;Guellec et al., 2011;Levine et al., 2015). In this study, we used connectomics to evaluate brain networks from early infancy to school age in preterm born children with or without IUGR, and to compare the developmental network trajectories in both populations, as well as their relationship to social and cognitive performance. ...
... Although structural changes at some given neurodevelopmental period have been previously described, the changes in brain networks from infancy to early adolescence have not been reported. Actually, longitudinal analyses of IUGR have mainly focused on the neuropsychological outcomes (Leitner et al., 2000(Leitner et al., , 2007Geva et al., 2006), but correlation between these outcomes and changes in brain structure was not described in these studies. One of the strengths of our study is the fact of having very well characterized cohorts with both image acquisitions and neuropsychological evaluation available so both cognitive and structural differences, and the relationship between them, could be assessed. ...
Article
Full-text available
Adverse conditions during fetal life have been associated to both structural and functional changes in neurodevelopment from the neonatal period to adolescence. In this study, connectomics was used to assess the evolution of brain networks from infancy to early adolescence. Brain network reorganization over time in subjects who had suffered adverse perinatal conditions is characterized and related to neurodevelopment and cognition. Three cohorts of prematurely born infants and children (between 28 and 35 weeks of gestational age), including individuals with a birth weight appropriated for gestational age and with intrauterine growth restriction (IUGR), were evaluated at 1, 6, and 10 years of age, respectively. A common developmental trajectory of brain networks was identified in both control and IUGR groups: network efficiencies of the fractional anisotropy (FA)-weighted and normalized connectomes increase with age, which can be related to maturation and myelination of fiber connections while the number of connections decreases, which can be associated to an axonal pruning process and reorganization. Comparing subjects with or without IUGR, a similar pattern of network differences between groups was observed in the three developmental stages, mainly characterized by IUGR group having reduced brain network efficiencies in binary and FA-weighted connectomes and increased efficiencies in the connectome normalized by its total connection strength (FA). Associations between brain networks and neurobehavioral impairments were also evaluated showing a relationship between different network metrics and specific social cognition-related scores, as well as a higher risk of inattention/hyperactivity and/or executive functional disorders in IUGR children.
... Our results show that suboptimal cognitive functioning in IUGR-A infants is strongly apparent in working memory. More broadly, we also observe an impact in domains addressing higher-order cortical association areas, including verbal skills, visuomotor organization, abstract thinking, attention, learning, and short-term memory, which depend mainly on frontal brain activity (Friederici, 2012;Geva, Eshel, Leitner, Fattal-Valevski, & Harel, 2006;Nyhus & Badre, 2015). IUGR is associated with a reduction in frontal volume, identifiable through magnetic resonance imaging (Tolsa et al., 2004) and sonographic biometric estimation (Makhoul et al., 2004). ...
... This is an interesting finding, as no such predictor of learning difficulties in IUGR children has been reported previously, although it has been observed that these difficulties are more prevalent when anthropometric catch-up is incomplete (Geva et al., 2006). Our results are consistent with those of the latter authors, as the IUGR-A group, at 6 years of age, had not yet achieved head circumference catch-up. ...
Article
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Objective To determine whether cerebroplacental ratio, an indicator of fetal cerebral redistribution (FCR), predicts adverse results for neurodevelopment in intrauterine growth restriction (IUGR) infants. Methods In a cohort of 5,702 infants, 64 were IUGR born at term with FCR. Five were excluded. Of the remainder, 32 presented an abnormal cerebroplacental ratio (IUGR-A) and 27 a normal one (IUGR-B). The controls were 61 appropriate-for-gestational-age children. Cognitive and academic outcomes and the odds ratio of lower academic scores were assessed by multivariate analysis of covariance and logistic regression. Results IUGR-A children presented deficits in cognitive functioning and academic achievement in all domains. IUGR-B children presented slight deficits. Suboptimal cognitive functioning in IUGR-A was more marked in working memory. Abnormal cerebroplacental ratio predicted low academic scores in IUGR-A. Conclusions FCR is a risk factor for IUGR infants, and cerebroplacental ratio identifies those most severely affected. Intervention programs may produce benefits in early-middle childhood.
... As such, it is not possible to understand the potential distinction between the impact of early-onset and late-onset FGR in studies on hippocampal development and subsequent function. Whilst not investigating hippocampal structure specifically, two studies by Geva et al., 115,116 assessed children diagnosed at birth with FGR and found lower IQ, memory impairments, and more frequent neuropsychological difficulties including executive functioning, inflexibility-creativity, and language. Future research should aim to improve our understanding of these observed functional impairments with accompanying analysis of hippocampal structure, to uncover the depth of this association, particularly in late-onset FGR. ...
Article
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The hippocampus is a neuron-rich specialised brain structure that plays a central role in the regulation of emotions, learning and memory, cognition, spatial navigation, and motivational processes. In human fetal development, hippocampal neurogenesis is principally complete by mid-gestation, with subsequent maturation comprising dendritogenesis and synaptogenesis in the third trimester of pregnancy and infancy. Dendritogenesis and synaptogenesis underpin connectivity. Hippocampal development is exquisitely sensitive to perturbations during pregnancy and at birth. Clinical investigations demonstrate that preterm birth, fetal growth restriction (FGR), and acute hypoxic-ischaemic encephalopathy (HIE) are common perinatal complications that alter hippocampal development. In turn, deficits in hippocampal development and structure mediate a range of neurodevelopmental disorders, including cognitive and learning problems, autism, and Attention-Deficit/Hyperactivity Disorder (ADHD). In this review, we summarise the developmental profile of the hippocampus during fetal and neonatal life and examine the hippocampal deficits observed following common human pregnancy complications. Impact The review provides a comprehensive summary of the developmental profile of the hippocampus in normal fetal and neonatal life. We address a significant knowledge gap in paediatric research by providing a comprehensive summary of the relationship between pregnancy complications and subsequent hippocampal damage, shedding new light on this critical aspect of early neurodevelopment.
... Despite these heterogeneities and contradictions, outcomes such as poor results in intelligence coefficients, poor academic results, cognitive and emotional alterations, and attention and hyperactivity disorders, as well as behavioral disabilities have been described with early-onset FGR. The most severe cases have been linked with motor disorders and cerebral palsy [6,[14][15][16][17][18][19][20]. These results do not shed much light on late-onset FGR when reaching the gestational term [21][22][23][24][25][26][27]. ...
Article
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(1) Background: Fetal growth restriction (FGR) increases the risk of adverse neurodevelopmental outcomes, especially in preterm newborns. This study aims to describe the behavioral results of FGR at 6 years of age and to demonstrate the relationship of certain predictive factors with this development. (2) Methods: This retrospective cohort study included 70 children born in 2015 at the University Hospital Carlos Haya, Málaga, Spain who had been exposed to FGR during pregnancy; neonatal and infant data were recorded retrospectively. Children were assessed prospectively at 6 years of age by means of a strengths and difficulties questionnaire (SDQ) to study behavioral outcomes. (3) Results: We demonstrated that there are higher behavioral disability rates in children exposed to FGR during pregnancy and, in particular, high rates of hyperactivity or conduct problems. We also proved a negative relationship between the birth weight percentile and the total behavioral scale score, along with a positive correlation between hyperactivity and the emotional and behavioral scales. Learning difficulties were more frequent in early-onset FGR than in late-onset FGR. (4) Conclusions: Our study of behavioral development has demonstrated higher behavioral disability rates in children with FGR at 6 years of age; specifically, high rates of hyperactivity or conduct problems. At the same time, we have proved a negative relationship between the birth weight percentile and the total behavioral scale score.
... Precisamente, estos factores pueden desembocar en deficiencias motoras y cognitivas, ya que un porcentaje de estos niños prematuros o extremadamente prematuros desarrollarán secuelas neurológicas a largo plazo (Cooke y Foulder-Huges, 2003, citado en Jiménez, et al., 2008Figueras, 1998citado en Narbehaus y Segarra, 2004Geva et al., 2006;Jiménez, Figueras y Botet, 1995;Leitmer et al., 2007;Oros et al., 2014;Platt et al., 2007). ...
Thesis
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El Informe de Acción Global sobre Nacimientos Prematuros: Nacidos demasiado pronto (OMS, 2012) indica que 15 millones de bebés (11,1%), nacen demasiado pronto cada año, de los cuales más de un millón mueren poco después del nacimiento y otros muchos conviven con alguna discapacidad física, neurológica y/o educativa. Las estadísticas indican que los índices de prematuridad han aumentado considerablemente en los últimos años, debido, principalmente a los avances en las técnicas de neonatología, obstetricia y farmacología. Esta situación ha provocado un aumento de la esperanza de vida de los niños prematuros y, en consecuencia, un aumento de la morbilidad inmediata y a medio plazo de este grupo de niños. El objetivo principal de esta Tesis Doctoral, reside en valorar los efectos que las intervenciones en Atención Temprana desde el ámbito hospitalario, ejercen en el desarrollo mental de los niños prematuros en el primer trimestre y a los 18 meses de vida de edad corregida. Por tanto, se pretende valorar la eficacia de las intervenciones tempranas en el ámbito hospitalario en la población de niños de riesgo biológico, como puede ser la prematuridad. Se trata de un estudio longitudinal, de corte cuasi-experimental, con un tamaño muestral de 52 sujetos, que consta de un grupo experimental (N=31) que recibió tratamiento, tanto durante su ingreso en la Unidad de Neonatología del Hospital General Universitario de Elche, como después en el Centro de Desarrollo Infantil y Atención Temprana (CDIAT) de la Fundación Salud Infantil de la misma ciudad; y un grupo control (N=21) que sólo recibió tratamiento de Atención Temprana en el CDIAT tras el alta del hospital. La asignación a un grupo u otro dependía de los criterios del hospital de referencia, de la elección de los padres y de los criterios de inclusión del estudio. Estos niños fueron evaluados durante el primer trimestre de vida y a los 3, 6, 9, 12 y 18 meses de edad corregida, mediante las escalas de evaluación infantil Bayley 2 ed. para comprobar el nivel de desarrollo mental. Los resultados, en general, indican que existen diferencias en cuanto a las condiciones neonatales iniciales de ambos grupos, siendo inferiores las del grupo experimental frente a las del control. Concretamente, las condiciones de partida del grupo de niños prematuros intervenidos en el hospital se caracterizaba por tener menos semanas de gestación, menor peso, talla y perímetro cefálico al nacimiento, menor puntuación en el Test de APGAR, tras el nacimiento y mayor nivel de riesgo perinatal. Sin embargo, y a pesar de esas peores condiciones iniciales, una vez que se evaluaron las intervenciones tempranas, en diferentes momentos temporales, durante los primeros 18 meses de vida, se pudo comprobar que los niños que habían sido intervenidos en el hospital presentaban no sólo una evolución mental favorable en todo el período temporal evaluado, sino que el nivel de progreso mental en el primer trimestre de vida era superior al de los niños que no fueron intervenidos. También se constató una evolución mental positiva en el grupo de niños intervenidos sólo en el CDIAT. Finalmente, se observa, en los resultados obtenidos en este trabajo, que los niños pertenecientes a ambos grupos experimentan una mejora entre su estado inicial y final de desarrollo mental. Podemos concluir a partir de nuestros resultados que las intervenciones tempranas realizadas sobre el niño y la familia, tanto en el ámbito hospitalario como en el CDIAT, producen efectos positivos en su desarrollo inmediato y a medio plazo. Palabras clave: prematuridad, riesgo perinatal, atención temprana, desarrollo mental.
... Em um estudo 37 que objetivou quantificar as taxas de padrões imaturos no eletroencefalograma (EEG) neonatal e associá-las ao neurodesenvolvimento, crianças PIG foram diagnosticadas A RCIU assimétrica afeta as redes neurais do córtex frontal, com implicações diretas na aprendizagem e funções de memória 46,47 e, conforme sugerido por alguns autores, 48 ela compromete também o processamento auditivo, interferindo na percepção da fala. ...
Article
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Resumo Objetivo: Realizar uma revisão sistemática para verificar a associação entre o nascimento a termo de crianças pequenas para a idade gestacional (PIG) e os desfechos no desenvolvimento da linguagem oral. Fontes de dados: Artigos dos bancos de dados MEDLINE/PubMed, Web of Science, Embase, LILACS, SciELO e Cochrane Library foram identificados, selecionados e avaliados criticamente por dois revisores independentes e um juiz, às cegas, sem restrições de idioma e período de publicação. A ferramenta PRISMA foi utilizada e foram incluídos estudos originais envolvendo crianças nascidas a termo e PIG, desfechos relacionados a aspectos do desenvolvimento da linguagem oral, bem como o uso de testes, escalas e/ou questionários específicos para a investigação, cuja metodologia estava descrita na íntegra, com crianças como população-alvo. Síntese dos dados: Nove artigos foram incluídos a partir dos critérios de elegibilidade. Os estudos demonstraram que nascer PIG pode interferir em aspectos relacionados à linguagem e relataram que as chances de crianças PIG apresentarem um desempenho inferior são maiores quando comparadas as com tamanho adequado para a idade gestacional. Observou-se que os diferentes estudos não tinham um delineamento uniforme e seus objetivos eram bastante diversificados. Além disso, poucos focavam em questões relacionadas à avaliação da linguagem e foi possível notar uma variabilidade de instrumentos utilizados para investigar esse domínio. Conclusões: Os efeitos do baixo peso ao nascer em nascidos a termo persistem além do período neonatal e podem ter impacto no desempenho infantil, principalmente no que se refere ao desenvolvimento da linguagem oral.
... Asymmetric IUGR affects the frontal cortex neural networks, with direct implications for learning and memory functions, 46,47 and, as suggested by authors, 48 impairments also in auditory processing that directly interferes with speech perception. ...
Article
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Objective: To perform a systematic review in order to verify the association between full-term birth of small for gestational age (SGA) children and the outcomes in the development of oral language.Data source:Articles from MEDLINE/PubMed, Web of Science, Embase, Lilacs, SciELO and Cochrane Library databases were identified, selected and critically evaluated by two independent reviewers and a judge, blindly, without language restriction and publication period. The PRISMA tool was used, and original studies with a theme involving children born full-term and SGA were included, outcome related to aspects of oral language development, as well as the use of tests, scales and/or specific questionnaires for the investigation, whose methodology was described in full, with children as the target population.Data synthesis:The researchers included nine articles based on the eligibility criteria. Studies have shown that being born SGA can interfere in aspects related to language and reported greater chances of under performance in SGA children when compared to children with appropriate size for gestational age. It was observed that the different studies did not have a uniform design, and the objectives were quite diverse. Furthermore, few of them had as focus issues related to the assessment of language, as well as the variability of instruments used to investigate this domain. Conclusions: The effects of low weight for gestation age in full-term infants continue beyond the neonatal period and may impact on children's performance, mainly with regard to oral language development.
... Deficits in fine and gross motor function, memory, and increased hyperactivity are also noted in children born with FGR. [46][47][48][49] Due to these early and persistent alterations in brain structure, along with associated neurodevelopmental deficits, there is a critical need for clinical intervention to treat the FGR newborn. ...
Article
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Fetal growth restriction (FGR) occurs when a fetus is unable to grow normally due to inadequate nutrient and oxygen supply from the placenta. Children born with FGR are at high risk of lifelong adverse neurodevelopmental outcomes, such as cerebral palsy, behavioral issues, and learning and attention difficulties. Unfortunately, there is no treatment to protect the FGR newborn from these adverse neurological outcomes. Chronic inflammation and vascular disruption are prevalent in the brains of FGR neonates and therefore targeted treatments may be key to neuroprotection. Tissue repair and regeneration via stem cell therapies have emerged as a potential clinical intervention for FGR babies at risk for neurological impairment and long-term disability. This review discusses the advancement of research into stem cell therapy for treating neurological diseases and how this may be extended for use in the FGR newborn. Leading preclinical studies using stem cell therapies in FGR animal models will be highlighted and the near-term steps that need to be taken for the development of future clinical trials.
... Behavioral testing of our 3-to 6-month-old IUGR mice revealed marked memory deficits represented by a lack of object recognition, contextual memory, and cued memory during short-term recall. This echoes what is known in children born with IUGR who have been described to have poor memory in childhood and adulthood in multiple studies (Hadders-Algra and Touwen, 1990;Geva et al., 2006;Leitner et al., 2007;Guellec et al., 2011). We find it intriguing that IUGR females from this hypertensive disease of pregnancy model appeared to perform poorer than IUGR males. ...
Article
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Human infants who suffer from intrauterine growth restriction (IUGR), which is a failure to attain their genetically predetermined weight, are at increased risk for postnatal learning and memory deficits. Hippocampal dentate gyrus (DG) granule neurons play an important role in memory formation; however, it is unknown whether IUGR affects embryonic DG neurogenesis, which could provide a potential mechanism underlying abnormal postnatal learning and memory function. Using a mouse model of the most common cause of IUGR, induced by hypertensive disease of pregnancy, we first assessed adult learning and memory function. We quantified the percentages of embryonic hippocampal DG neural stem cells (NSCs) and progenitor cells and developing glutamatergic granule neurons, as well as hippocampal volumes and neuron cell count and morphology 18 and 40 d after delivery. We characterized the differential embryonic hippocampal transcriptomic pathways between appropriately grown and IUGR mouse offspring. We found that IUGR offspring of both sexes had short-term adult learning and memory deficits. Prenatally, we found that IUGR caused accelerated embryonic DG neurogenesis and Sox2+ neural stem cell depletion. IUGR mice were marked by decreased hippocampal volumes and decreased doublecortin+ neuronal progenitors with increased mean dendritic lengths at postnatal day 18. Consistent with its known molecular role in embryonic DG neurogenesis, we also found evidence for decreased Wnt pathway activity during IUGR. In conclusion, we have discovered that postnatal memory deficits are associated with accelerated NSC differentiation and maturation into glutamatergic granule neurons following IUGR, a phenotype that could be explained by decreased embryonic Wnt signaling.
... Children with early-onset FGR tend to have a high incidence of prematurity, a risk factor for adverse neurological outcomes. Premature infants with FGR have a higher incidence of neurodevelopmental disorders compared with premature infants with adequate growth [3][4][5][6][7]. Late-onset FGR could also be related to alterations in cognitive development, academic results, and learning. ...
Article
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Background: Fetal growth restriction (FGR) is a pregnancy complication. Multiple studies have connected FGR to poor cognitive development, behavior disorders, and academic difficulties during childhood. Brain sparing has traditionally been defined as an adaptive phenomenon in which the brain obtains the blood flow that it needs. However, this adaptive phenomenon might not have a complete protective effect. This publication aims to systematically review the consequences of brain redistribution on neurodevelopment in children who presented with placental intrauterine growth restriction. Methods: We performed a systematic review according to PRISMA guidelines. It included studies on intrauterine growth restriction or small-for-gestational-age (SGA) fetuses, which middle cerebral artery was measured, and neurodevelopment assessed during childhood. PUBMED and EMBASE databases were searched for relevant published studies. Results: Of the 526 studies reviewed, only 12 were included. Brain sparing was associated with poor cognitive function and lower scores in IQ. Cerebral redistribution was related to better executive function and better behavior at 4 years old but not at 12 years old. Conclusions: We can assume that fetal brain sparing could not be a fully protective phenomenon. We could not find clinical differences in behavioral and executive functions because the results were heterogeneous. Some cognitive abilities could be affected in FGR brain sparing fetuses.
... Placental insufficiency affects up to 7% of all gestations 4,5 and in approximately 50% of these cases it derives in clinically evident middle and long-term neurological consequences defined as subtle cognitive and behavioral disabilities. [6][7][8][9] Different animal models and advanced imaging techniques have been used to better understand the mechanisms underlying neuronal impairments and perinatal brain maturation alterations induced by IUGR. 10 However, there is still a large knowledge gap on the mechanisms underlying these alterations 2 and a lack of research models to better characterize the IUGR-associated brain injury (reviewed by Fleiss et al. 2019 11 ). ...
Article
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The aim of this study was to develop a rabbit neurosphere culture to characterize differences in basic processes of neurogenesis induced by intrauterine growth restriction (IUGR). A novel in vitro neurosphere culture has been established using fresh or frozen neural progenitor cells from newborn (PND0) rabbit brains. After surgical IUGR induction in pregnant rabbits and cesarean section 5 days later, neural progenitor cells from both control and IUGR groups were isolated and directly cultured or frozen at -80°C. These neural progenitor cells spontaneously formed neurospheres after 7 days in culture. The ability of control and IUGR neurospheres to migrate, proliferate, differentiate to neurons, astrocytes, or oligodendrocytes was compared and the possibility to modulate their responses was tested by exposure to several positive and negative controls. Neurospheres obtained from IUGR brains have a significant impairment in oligodendrocyte differentiation, whereas no significant differences are observed in other basic processes of neurogenesis. This impairment can be reverted by in vitro exposure of IUGR neurospheres to thyroid hormone, which is known to play an essential role in white matter maturation in vivo. Our new rabbit neurosphere model and the results of this study open the possibility to test several substances in vitro as neuroprotective candidates against IUGR induced neurodevelopmental damage while decreasing the number of animals and resources and allowing a more mechanistic approach at a cellular functional level.
... Some infants with FGR exhibit abnormalities upon neurological examination, including a lower degree of organization and degraded neurobehavioral profiles, particularly in the orientation and motor domains (Feldman and Eidelman, 2006). Moreover, it is well known that children born with FGR exhibit long-term global cognitive impairment and short-term memory difficulties (Geva et al., 2006). Despite such a diverse range of serious diseases that last for a lifetime, there are few established treatments for neonates with FGR. ...
Article
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Fetal growth restriction (FGR) is a major complication of prenatal ischemic/hypoxic exposure and affects 5%–10% of pregnancies. It causes various disorders, including neurodevelopmental disabilities due to chronic hypoxia, circulatory failure, and malnutrition via the placenta, and there is no established treatment. Therefore, the development of treatments is an urgent task. We aimed to develop a new FGR rat model with a gradual restrictive load of uterus/placental blood flow and to evaluate the treatment effect of the administration of umbilical cord-derived mesenchymal stromal cells (UC-MSCs). To create the FGR rat model, we used ameroid constrictors that had titanium on the outer wall and were composed of C-shaped casein with a notch and center hole inside that gradually narrowed upon absorbing water. The ameroid constrictors were attached to bilateral ovarian/uterine arteries on the 17th day of pregnancy to induce chronic mild ischemia, which led to FGR with over 20% bodyweight reduction. After the intravenous administration of 1 × 105 UC-MSCs, we confirmed a significant improvement in the UC-MSC group in a negative geotaxis test at 1 week after birth and a rotarod treadmill test at 5 months old. In the immunobiological evaluation, the total number of neurons counted via the stereological counting method was significantly higher in the UC-MSC group than in the vehicle-treated group. These results indicate that the UC-MSCs exerted a treatment effect for neurological impairment in the FGR rats.
... Behavioral testing of young adult IUGR mice revealed a marked deficit in short-term implicit memory that was represented by a lack of object recognition, contextual memory, and cued memory during short-term recall. Our finding of implicit memory deficit echoes what is known in IUGR children who have been described to have poorer memory performance in multiple studies (3,(21)(22)(23). Because learning and memory deficits can be affected by other domains of behavior (24), we performed several other complementary tests that may impact hippocampal-based tasks. ...
Preprint
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Background Children born with intrauterine growth restriction (IUGR) are at increased risk for cognitive impairment including learning and memory deficits. Dentate gyrus (DG) granule neurons relay cortical information into the hippocampus proper for memory formation, and their production is highly dependent on environmental signals. However, it is unknown whether IUGR affects DG neurogenesis, and thus provides a potential mechanism underlying abnormal learning and memory function. Methods Using a hypertensive disease of pregnancy mouse model of IUGR, we assessed multiple behaviors, quantified neural stem and progenitor cells (NSPCs) and developing neurons in the DG, and characterized transcriptional effects on molecular pathways in the hippocampus. Results We found that the predominant behavioral phenotype in IUGR offspring, short-term implicit learning and memory deficits, was associated with accelerated DG neurogenesis and NSPC depletion. Consistent with known molecular regulators of DG neurogenesis, we also found strong evidence for decreased Wnt pathway activity following IUGR. Conclusion We have discovered that postnatal memory deficits are associated with accelerated NSPC differentiation following IUGR, a phenotype that could be explained by decreased Wnt signaling.
... Notably, the infant in question may have a developmental disorder and a careful follow-up procedure is planned. Multiple follow-up studies of the development of FGR infants into school-age childhood have revealed deficits in gross and fine motor skills, cognition, memory and academic ability, as well as neuropsychological dysfunctions encompassing poor attention, hyperactivity, and altered mood [21][22][23][24][25]. Hence, additional case studies and a developmental evaluation up to the school age are warranted. ...
Article
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To assess the long-term effects of tadalafil, a therapeutic agent for fetal growth restriction (FGR), we evaluated the developmental progress of 1.5-year-old infants whose mothers had taken tadalafil during pregnancy. Twenty-four infants were assessed. We evaluated infant body weight, height, and head circumference, and performed the Kyoto Scale of Psychological Development (KSPD) test, a standardized developmental assessment covering Postural–Motor (P–M), Cognitive–Adaptive (C–A), and Language-Social (L–S) functions. The sum score was converted to a developmental quotient (DQ). The mean gestational week of the included cases was 36.1 (29–39) weeks, and the mean birth weight was 1841 (874–2646) g. Twenty-one and 20 out of the 24 cases, respectively, attained body weight and height similar to those of age-matched normal infants (within the 3rd percentile); all cases caught up in head circumference. KSPD was performed for 18 cases at 1.5 years of corrected age. The mean DQ scores were 87 (in total): 82 in P–M, 90 in C–A, and 88 in L–S. The total DQ score in one case (5.6%) was less than 70, and ranged from 70 to 85 in five cases (27.7%), and was more than 85 in 11 cases (61.1%). The growth and development of infants born of tadalafil-treated mothers seem to show good progress at a corrected age of 1.5 years.
... 38 The growth-restricted fetus responses to the chronic hypoxia with slowing its growth rate, and redistributing cardiac output to favour essential organs such as brain (brain sparing). 38,39 Post-natal catch-up growth, defined as growth velocity greater than the median for a given age and sex following a period of growth inhibition, is the consequence of an infant being born with weight in a lower centile than the infant's genetic potential. 40,41 Catch-up growth in the first 2 years has certain advantages; it causes superior neuro- development, enhanced immune function, and a taller final adult height. ...
Article
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Background and objectives: Resting metabolic rate and cognitive function may be associated with several factors, such as birth weight, growth, and fat-free mass in adulthood. The Tanjungsari Cohort Study (TCS) of 1988, to do with a maternal-child Risk Approach Strategy (RAS), provided the opportunity to determine the associations between birth weight, growth at 2 years, and body composition with adult resting metabolic rate and cognitive function. Methods and study design: In 2009 some 197 and, in 2017,144 of these representative participants from the TCS were assessed for energy intake, anthropometry, body composition, indirect calorimetry, and cognitive function in relation to low (ALBW, n=66) or normal (ANBW, n=78) birth weight. Associations were adjusted for basic demographic data. Results: Resting metabolic rate was positively associated with birth weight, body weight at 2 years of age, body mass index and fat free mass in adult life. Time to finish the Trail Making Test-A (TMT-A), a test of attention span, was significantly longer in the ALBW than the ANBW group (41.4±12.8 vs 37.8±15.6, p=0.005). In the ALBW group, weight catch-up improved TMT-A and logical memory test scores (29.5 vs 34.9.41, p=0.004; and 39.3 vs 29.4, p=0.04, respectively). Conclusions: Low birth weight was associated with poorer attention span in adult life; body weight gain at 2 years of age with better attention and memory function in adult life; a greater body mass index in adult life with better memory in adult life.
... Further, a longitudinal study observing FGR offspring with evidence of brain sparing from birth to middle school age (9-10 years old) found a complex set of neurodevelopmental deficits, such as a significant reduction in IQ, compared to age-matched appropriately-grown children (168). Multiple follow-up studies of FGR infants into school age describe diminished gross and fine motor skills, cognition, memory, and academic ability, as well as neuropsychological dysfunctions encompassing poor attention, hyperactivity and altered mood (143,(169)(170)(171). FGR infants born preterm and those with fetal circulatory redistribution are at the greatest risk for the worst outcomes (172). ...
Article
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Being born small lays the foundation for short-term and long-term implications for life. Intrauterine or fetal growth restriction describes the pregnancy complication of pathological reduced fetal growth, leading to significant perinatal mortality and morbidity, and subsequent long-term deficits. Placental insufficiency is the principal cause of FGR, which in turn underlies a chronic undersupply of oxygen and nutrients to the fetus. The neonatal morbidities associated with FGR depend on the timing of onset of placental dysfunction and growth restriction, its severity, and the gestation at birth of the infant. In this review, we explore the pathophysiological mechanisms involved in the development of major neonatal morbidities in FGR, and their impact on the health of the infant. Fetal cardiovascular adaptation and altered organ development during gestation are principal contributors to postnatal consequences of FGR. Clinical presentation, diagnostic tools and management strategies of neonatal morbidities are presented. We also present information on the current status of targeted therapies. A better understanding of neonatal morbidities associated with FGR will enable early neonatal detection, monitoring and management of potential adverse outcomes in the newborn period and beyond.
... Moreover, growth-restricted infants show poor use of environmental stimuli, reduced social responsiveness, more insulated cry states, and poor motor performance as compared with normal birth weight infants (Padilla et al., 2011). Persisting and long-term outcomes are also observed, with cognitive impairments (e.g., executive functioning; Geva et al., 2006) and behavioral problems described in childhood (Sung et al., 1993); motor problems, learning difficulties and lower academic achievements during school age period (Leitner et al., 2007;Esteban et al., 2010), as well as increased risk for neurodevelopmental disorders, such as ADHD (Heinonen et al., 2013). Apart from evidence of neurodevelopmental and cognitive outcomes, socio-emotional development still appears as unexplored in the developmental context of growth restriction, although few signs of early atypical social interactions are described (Watt, 1990;Feldman and Eidelman, 2009), as well as later poor socio-cognitive performances at school age and mood disorders (Fischi-Gómez et al., 2015). ...
Article
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Intrauterine growth restriction (IUGR) is defined as a fetal growth retardation, resulting in an estimated fetal weight less than the 10th centile for gestational age. IUGR developing brain is affected by the atypical fetal growth, presenting altered structure and connectivity and increased risk for neurodevelopmental impairments. Behaviorally, IUGR infants show reduced responsiveness and engagement with human faces during mother-child exchanges. The neural mechanisms of these patterns of interactions remain unexplored, as well as their potential role in shaping socio-cognitive trajectories of development. Aim of this research project will be to longitudinally investigate mother-infant interactions and infant’s event-related potential (ERP) components of face processing (infant N170, P400, Negative central) in 4 and 9 months IUGR as potential early markers of expected atypical cognitive and behavioral outcomes observed at 12 months. Thirty IUGR participants will be recruited after receiving the in utero diagnosis (>28th gestational week). Thirty healthy infants will be enrolled as the control group. Maternal environment will be assessed via Emotional Availability Scales (EASs), with child responsiveness and maternal sensitivity as variables of interest. Infants’ scalp-recorded cortical activity in response to social and non-social stimuli will be investigated using a high-density EEG system (EGI Geodesic system). Neurodevelopment will be measured at 12 months of child’s life, using Bayley Scales for Infant Development (BSID), while the possible presence of emotional-behavioral problems will be rated via Child Behavior Checklist (CBCL). We expect that being IUGR significantly affects cognitive and behavioral outcomes, through mediation effects of both infants’ neural and behavioral capacity to respond to social stimuli. Indeed, we expect an altered response to social stimuli in IUGR infants, resulting in smaller ERP components amplitude in response to human faces compared to healthy matched peers. A significant association between neural response to social stimuli and infants’ responsiveness to maternal stimulation during interactions is expected, with impoverished performances on the interactive domain in IUGR, compared to healthy peers. This study will enhance understanding on neural mechanisms underpinning the interactive patterns sustaining socio-cognitive development in IUGR and healthy infants. The study will help in clarifying the role of postnatal environment in buffering the vulnerability experienced by children delayed in their fetal growth.
... The less information is sampled before making a decision, the more impulsive is the individual. Reflection impulsivity may mediate the known effects of IUGR on such behaviors 4,[16][17][18] . ...
Article
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Individuals born after intrauterine growth restriction (IUGR) are more impulsive towards palatable foods, but it is not clear 1) if IUGR-related impulsivity is specific for foods and solely based on response inhibition and 2) if the development of impulsivity is due to being born IUGR per se or to growing up fast in the first few years of life (catch up growth). Children were classified in the IUGR group if the birth weight ratio was below 0.85. Delta z score for BMI was used as a measure of catch up growth. In MAVAN (N = 274), impulsivity was measured by the Information Sampling Task from the Cambridge Neuropsychological Test Automated Battery (IST - CANTAB), and in GUSTO using the Sticker Delay Task (N = 327). There is a significant effect of interaction between being born IUGR and the magnitude of catch up growth on the reflection impulsivity from IST-CANTAB at 60 months, in which greater catch up growth associates with greater impulsivity in the IST fixed condition in IUGR children. The finding was reproduced in children from the GUSTO cohort using the Sticker Delay Task. We confirmed that catch up growth interacts with IUGR, having a major role in the development of impulsivity in the first years of life and influencing inhibitory control and decision making processes.
... Due to its constant increase in both industrialized and developing countries, where 2.8 million children out of 135 million born in 2010 were born preterm and growth restricted (4), IUGR represents an important public health problem. Indeed, growth-restricted infants showed a higher risk of perinatal morbidity and of neurodevelopmental alteration with long-term cognitive and neurobehavioral handicaps (5,6). Interestingly, studies based on magnetic resonance imaging have clearly evidenced that the cognitive and psychiatric deficits observed (7)(8)(9) are correlated to alterations of brain white and gray matter (7,10,11), including altered neural circuitry (12,13). ...
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... Intrauterine growth restriction (IUGR) is the failure of the fetus to reach its growth potential, due to placental, maternal or fetal factors [1]. IUGR affects 3-7% of all newborns [2] and is associated with the development of metabolic diseases [3,4] and neurocognitive problems [5,6,7] during adulthood. There is a growing body of evidence that nutritional or vascular alterations during critical windows of development may lead to IUGR, with lasting effects on cellular structure and function, increasing the risk of developing chronic diseases [8]. ...
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Background Intrauterine growth restriction (IUGR) and rapid postnatal weight gain or catch up growth (CUG) increase the susceptibility to metabolic syndrome during adult life. Longitudinal studies have also revealed a high incidence of learning difficulties in children with IUGR. The aim of the present study was to investigate the effect of nutrition and CUG on learning memory in an IUGR animal model. We hypothesized that synaptic protein expression and transcription, an essential mechanism for memory consolidation, might be affected by intrauterine undernutrition. Methods IUGR was induced by 50% maternal caloric undernutrition throughout late gestation. During the suckling period, dams were either fed ad libitum or food restricted. The pups were divided into: Normal prenatal diet-Normal postnatal diet (NN), Restricted prenatal diet- Normal postnatal diet + catch up growth (RN+), Normal prenatal diet-Restricted postnatal diet (NR) and Restricted prenatal diet-Restricted postnatal diet (RR). At 4 weeks of age, memory was assessed via a water maze test. To evaluate synaptic function, 2 specific synaptic proteins (postsynaptic density-95 [PSD95], synaptophysin) as well as insulin receptors (IR) were tested by Western Blot and quantitative polymerase chain reaction (qPCR). Brain-derived neurotrophic factor and serum insulin levels were also studied. Results and conclusions The RN+ group presented a learning curve similar to the NN animals. The RR animals without CUG showed learning disabilities. PSD95 was lower in the RR group than in the NN and RN+ mice. In contrast, synaptophysin was similar in all groups. IR showed an inverse expression pattern to that of the PSD95. In conclusion, perinatal nutrition plays an important role in learning. CUG after a period of prenatal malnutrition seems to improve learning skills. The functional alterations observed might be related to lower PSD95 activity and a possible dysfunction in the hormone regulation of synaptic plasticity.
... Neurodevelopmental abnormalities seen in FGR have been described for specific brain areas including the anterior hippocampal-prefrontal network, parahippocampal complex, striatum and thalamus [31,32]. Magnetic resonance imaging (MRI) studies consistently demonstrate structural brain changes in FGR infants during both the fetal and neonatal period. ...
Chapter
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Cerebral palsy (CP) is the most common cause of physical disability in children. CP currently has no cure and there are only few interventions to prevent the development of disability. There are four principal complications of pregnancy or birth that can damage the developing brain and lead to CP: preterm birth, fetal growth restriction, infection during pregnancy and severe hypoxia-ischemia at birth. Umbilical cord blood (UCB) cells are a very promising therapy for the treatment of CP. While UCB therapy for juveniles with CP is currently being assessed in clinical trials, very little is known about their mechanisms of action or which cells found in umbilical cord blood protect against and/or repair brain injury. In this chapter, we first explore the complications that can lead to perinatal brain injury. We then discuss the different cell types found in UCB and the specific properties that make each of them individually attractive therapeutic candidates for treatment of perinatal brain injury. While UCB holds much promise as a therapy for CP, it is imperative that more research is conducted to understand how the different cell types found in UCB can protect against brain injury in order to design more effective and targeted therapies.
... Previous studies of infants born with IUGR have also demonstrated a decreased volume of gray matter in the thalami 25 . Structural changes in these brain areas comprising commissural, projection and associative tracts could explain developmental disabilities encountered in IUGR infants later in life, such as cognitive, emotional or behavioral disorders 5,[27][28][29] . ...
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Objective: Diffusion-weighted magnetic resonance imaging (DWI) is a sensitive method for assessing brain maturation and detecting brain lesions, providing apparent diffusion coefficient (ADC) values as a measure of water diffusion. Abnormal ADC values are seen in ischemic brain lesions, such as those associated with acute or chronic hypoxia. The aim of this study was to assess whether ADC values in the fetal brain were different in fetuses with severe intrauterine growth restriction (IUGR) compared with normal controls. Methods: Brain magnetic resonance imaging (MRI) with single-shot axial DWI (b = 0 and b = 700 s/mm2 ) was performed in 30 fetuses with severe IUGR (estimated fetal weight < 3rd centile with absent or reversed umbilical artery Doppler flow) and in 24 normal controls of similar gestational age. Brain morphology and biometry were analyzed. ADC values were measured in frontal and occipital white matter, centrum semiovale, thalami, cerebellar hemisphere and pons. Frontal-occipital and frontal-cerebellar ADC ratios were calculated, and values were compared between IUGR fetuses and controls. Results: There was no difference in gestational age at MRI between IUGR and control fetuses (IUGR, 30.2 ± 1.6 weeks vs controls, 30.7 ± 1.4 weeks). Fetal brain morphology and signals were normal in all fetuses. Brain dimensions (supratentorial ± infratentorial) were decreased (Z-score, < -2) in 20 (66.7%) IUGR fetuses. Compared with controls, IUGR fetuses had significantly lower ADC values in frontal white matter (1.97 ± 0.23 vs 2.17 ± 0.22 × 10-3 mm2 /s; P < 0.0001), thalami (1.04 ± 0.15 vs 1.13 ± 0.10 ×10-3 mm2 /s; P = 0.0002), centrum semiovale (1.86 ± 0.22 vs 1.97 ± 0.23 ×10-3 mm2 /s; P = 0.01) and pons (0.85 ± 0.19 vs 0.94 ± 0.12 ×10-3 mm2 /s; P = 0.043). IUGR fetuses had a lower frontal-occipital ADC ratio than did normal fetuses (1.00 ± 0.11 vs 1.08 ± 0.05; P = 0.003). Conclusions: ADC values in IUGR fetuses were significantly lower than in normal controls in the frontal white matter, thalami, centrum semiovale and pons, suggesting abnormal maturation in these regions. However, the prognostic value of these ADC changes is still unknown. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.
... The impaired functional outcomes in IUGR 58 and SGA infants, children and adults are highly correlated with these morphological outcomes [24, 59 25, 27-30]. Compared to infants born at a size appropriate for their gestational age (AGA), IUGR 60 and SGA infants have more immature neurobehavioural scores [17, 24-26, 31, 32] and, as children, 61 have lower IQ and poorer language, working and short-term memory, executive function and 62 visuomotor skills [33][34][35][36][37][38][39][40][41][42]. There are also higher incidences of cerebral palsy, attention deficit 63 hyperactivity symptoms and behavioural problems in offspring of IUGR pregnancies compared to 64 AGA [27,31,33,38,43,44]. ...
Article
IUGR in humans is associated with impaired pre- and postnatal neurodevelopment, and subsequent postnatal cognition, resulting in lower IQ, poorer memory, visuomotor and executive function skills, as well as behavioural and attentional problems. Experimental models of IUGR are needed to allow direct testing of causality and interventions, and have benefits in reducing both confounding by comorbidities such as prematurity, and variation due to environment and genetics. This review describes and discusses experimental models of IUGR in which neurodevelopmental and cognitive outcomes of IUGR have been reported. We consider the timing of neurodevelopment relative to birth and to the period of restriction, as well as the effects of each experimental perturbation on the fetal environment and development, before discussing neurodevelopmental and cognitive outcomes for progeny as fetuses, neonates and into adolescent and adult life. Experimental IUGR induces broadly similar outcomes to human IUGR, with altered brain morphology, in particular grey matter loss and discordant trajectory of white matter development, and poorer cognition and memory reported in various studies. Nevertheless, there remain gaps in knowledge of neurodevelopment in experimental models. We end the review with recommendations for the design of future studies to further investigate the mechanisms underlying adverse neurodevelopmental consequences of IUGR, and to evaluate interventions that may subsequently improve outcomes of IUGR in humans.
... Where brain-sparing (elevated umbilical/cerebral ratio) was apparent, IQ at 5 years of age was 9 points lower (87 versus 96) compared to children with a normal umbilical/cerebral ratio (Scherjon et al., 2000). Multiple follow-up studies of FGR infants into school-age childhood find deficits in gross and fine motor skills, cognition, memory, and academic ability, as well as neuropsychological dysfunctions encompassing poor attention, hyperactivity and altered mood (Low et al., 1992, Geva et al., 2006a, Geva et al., 2006b, Fischi-Gomez et al., 2014. ...
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Fetal growth restriction (FGR) is a significant complication of pregnancy describing a fetus that does not grow to full potential due to pathological compromise. FGR affects 3 - 9 % of pregnancies in high-income countries, and is a leading cause of perinatal mortality and morbidity. Placental insufficiency is the principal cause of FGR, resulting in chronic fetal hypoxia. This hypoxia induces a fetal adaptive response of cardiac output redistribution to favour vital organs, including the brain and is subsequently called brain-sparing. Despite this, it is now apparent that brain-sparing does not ensure normal brain development in growth restricted fetuses. In this review we have brought together available evidence from human and experimental animal studies to describe the complex changes in brain structure and function that occur as a consequence of FGR. In both humans and animals, neurodevelopmental outcomes are influenced by the timing of the onset of FGR, the severity of FGR, and gestational age at delivery. FGR is broadly associated with reduced total brain volume and altered cortical volume and structure, decreased total number of cells and myelination deficits. Brain connectivity is also impaired, evidenced by neuronal migration deficits, reduced dendritic processes, and less efficient networks with decreased long-range connections. Subsequent to these structural alterations, short- and long-term functional consequences have been described in school children who were FGR, most commonly including problems in motor skills, cognition, memory and neuropsychological dysfunctions. This article is protected by copyright. All rights reserved.
... Múltiples arrugas en acordeón de la gestación, permaneciendo constante su valor al llegar a término y correspondiendo el IP 2,3 g/cm 3 al p10 y el IP 2,2 g/cm 3 al p3. Se consideraron los valores < 2,2 g/cm 3 como índice de malnutrición 1,4,13 , a partir del resultado de este índice se clasificaron los PEG también en PEG tipo i (simétrico) los que presentaron un IP > 2,2 g/cm 3 y en PEG tipo ii (asimétrico) los que presentaron un IP < 2,2 g/cm 3 . La valoración mediante CANS score se realizó en las primeras 24 h de vida a todos los recién nacidos incluidos, evaluando los 9 signos clínicos descritos por Metcoff (tabla 1). ...
Article
Introduction: Foetal malnutrition (FM) is the result of a loss or failure of intrauterine acquisition of the correct amount of fat and muscle mass, with short and long term implications. As the diagnosis of FM is essentially clinical, the aim of this study is to detect the incidence of FM using the Clinical Assessment of Nutritional Status (CANS) score, and compare the results with the classic anthropometric parameters. Patients and methods: Retrospective population of term infants was studied between 2003 and 2014 (n=14,477). They were classified into adequate weight (AGA), small weight (SGA) and large weight (LGA) for gestational age newborns. The CANS score was performed on all infants enrolled in the study, and the ponderal index (PI) was calculated, considering an FM cut off value of a CANS score <25 and PI <2.2g/cm(3). Results: Using the CANS score, 7.6% (n 1,101) of the population showed FM, 50.3% (n=538) of SGA, 76.2% (n=193) subgroup <p3, and 4.67% (n=559) of AGA. The CANS score was <25 in 7.26% (n=1,043) of newborns with PI ≥2.2g/cm(3) (n=14.356), and the CANS score was >24 in 49% with PI <2.2g/cm(3) (n=109) CONCLUSIONS: It is worthwhile identifying all newborns with FM due to the risks they may have in the short and long term. CANS score assessment allows a better identification of nutritional status of infants than only using the curves of weight for gestational age.
Article
Background: Fetal growth restriction (FGR) is a risk factor for neurodevelopmental problems, yet remains poorly understood. We sought to examine the relationship between intrauterine development and neonatal neurobehavior in pregnancies diagnosed with antenatal FGR. Methods: We recruited women with singleton pregnancies diagnosed with FGR and measured placental and fetal brain volumes using MRI. NICU Network Neurobehavioral Scale (NNNS) assessments were performed at term equivalent age. Associations between intrauterine volumes and neurobehavioral outcomes were assessed using generalized estimating equation models. Results: We enrolled 44 women diagnosed with FGR who underwent fetal MRI and 28 infants underwent NNNS assessments. Placental volumes were associated with increased self-regulation and decreased excitability; total brain, brainstem, cortical and subcortical gray matter (SCGM) volumes were positively associated with higher self-regulation; SCGM also was positively associated with higher quality of movement; increasing cerebellar volumes were positively associated with attention, decreased lethargy, non-optimal reflexes and need for special handling; brainstem volumes also were associated with decreased lethargy and non-optimal reflexes; cerebral and cortical white matter volumes were positively associated with hypotonicity. Conclusion: Disrupted intrauterine growth in pregnancies complicated by antenatally diagnosed FGR is associated with altered neonatal neurobehavior. Further work to determine long-term neurodevelopmental impacts is warranted. Impact: Fetal growth restriction is a risk factor for adverse neurodevelopment, but remains difficult to accurately identify. Intrauterine brain volumes are associated with infant neurobehavior. The antenatal diagnosis of fetal growth restriction is a risk factor for abnormal infant neurobehavior.
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Objective: This study aimed to describe neurodevelopment in fetal growth restriction children at the age of six. Secondly, we tried to demonstrate influencing factors that can improve or exacerbate this development, as well as predictive factors that might select a population at risk to assist with early childhood support. Method: It was a study of 70 children affected with FGR. FGR was based on these definitions: birth weight below the 3rd percentile or birth weight below the 10th percentile with an abnormal hemodynamic Doppler study. Neurodevelopment was assessed at 6 years old by means of Batelle Development Inventory. A global development quotient under a 100 score was considered a neurodevelopment delay. All variables regarding pregnancy care, delivery episode, postpartum, neonatal care, sociodemographic issues, and the need for support in the first years were studied. Results: The mean gestational age at diagnosis was 33.14 weeks (standard deviation (SD = 4.31), with 32.9% of early-onset diagnoses. The mean gestational age at delivery was 35.61 (SD = 3.21), and the cesarean rate was 64.3%. The average age of the children at the moment of the evaluation was 76.20-month-old (SD = 3.70). The mean global development quotient was 97.28 (SD = 13.97). We were able to record a 57.1% of global development delay. In the cases of cognition, only 17.1% of the children registered a delay. Motor and communication skills were the most frequently affected. We discovered that socioeconomic status was positively related to the global development quotient, as well as both gestational age at delivery and middle cerebral artery pulsatility index was positively related to the global development quotient. Conclusions: We found a higher neurodevelopment delay rate (57.1%). We could relate a higher gestational age at delivery and a higher MCA percentile with better global neurodevelopment quotients.
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Aberrant maternal inflammation and oxidative stress are the two main mechanisms of pathological pregnancy. The silence information regulator (sirtuin) family is a highly conserved family of nicotinamide adenine dinucleotide (NAD)-dependent deacylases. By regulating the post-translational modification of proteins, sirtuin is involved in various biological processes including oxidative stress and inflammation. Nowadays, emerging evidence indicates that sirtuin may be closely related to the occurrence and development of pathological pregnancy. The down-regulation of sirtuin can cause spontaneous preterm delivery by promoting uterine contraction and rupture of fetal membranes, cause gestational diabetes mellitus through promoting oxidative stress and affecting the activity of key enzymes in glucose metabolism, cause preeclampsia by reducing the proliferation and invasion ability of trophoblasts, cause intrahepatic cholestasis of pregnancy by promoting the production of bile acids and T helper 1 cell (Th1) cytokines, and cause intrauterine growth restriction through inducing mitochondrial dysfunction. Moreover, the expression and activation of sirtuin can be modulated through dietary interventions, thus sirtuin is expected to become a new target for the prevention and treatment of pregnancy complications. This article reviews the role of the sirtuin family in the occurrence and development of pathological pregnancy and its influence on the development of the offspring.
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Introduction: Uteroplacental Insufficiency (UPI) produces critical neurodevelopmental problems affecting the Intrauterine Growth Restricted (IUGR) in offspring. This study aimed to investigate the possible neuroprotective roles of Hesperidin (Hes) on the fetal cerebral cortex of the UPI rat model. Methods: In this experimental study, 40 pregnant Wistar rats (age: ~40 days, Mean±SD weight: 180±10 g) were randomly divided into 5 groups (n= 8/group). The study groups included control (normal saline, orally), UPI+NS (uterine vessel ligation+normal saline, orally), UPI+HES25, UPI+HES50, and UPI+HES100 (uterine vessel ligation+25, 50 and 100 mg/kg Hes, orally). After being anesthetized by ketamine and xylazine, UPI was induced by permanent bilateral closure of the uterine vessels on Gestation Day (GD) 18. From GD15, the Hes/NS-treated groups received Hes/normal saline until GD21. On GD21, the uterus, placenta, and fetus were dissected out and weighed. The oxidative stress parameters, including Catalase (CAT) activity, Malondialdehyde (MDA), and Total Antioxidant Capacity (TAC) were measured in the fetal cerebral cortex. The expression of Brain-Derived Neurotrophic Factor (BDNF) and Tropomyosin Receptor Kinase B (TrkB) was assessed by RT qPCR methods. The obtained data were analyzed by Analysis of Variance (ANOVA) and Tukey’s post hoc test. Results: The present study findings identified a significant difference in the uterine and fetus weight in Hes-treated mothers (P< 0.05). In the fetus, Hes reduced MDA, and increased CAT activity and TAC (P˂0.001 in the UPI+Hes100 group, compared to the UPI+NS group). UPI reduced BDNF and TrkB mRNA expression, compared to the control group (P
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Objective This study employed magnetic resonance imaging (MRI) to compare brain volumes of discordant twins and examined their neurodevelopment after birth by using a validated exam.Study designA prospective historical cohort study of discordant dichorionic diamniotic (DCDA) or monochorionic diamniotic (MCDA) twin fetuses, who undergone an MRI scan to evaluate growth restriction in the discordant twin (weight < 10th centile) during 6 years period, at a single tertiary center. Twenty-seven twin pairs were included in the volumetric study and 17 pairs were included in the neurodevelopmental outcome examination. The volumes of the supratentorial brain region, both hemispheres, eyes, and the cerebellum were measured by 3D MRI semi-automated volume measurements. Volumes were plotted on normal growth curves and discordance was compared between weight at birth and brain structure volumes. Neurodevelopmental outcome was evaluated using the VABS-II questionnaire at a mean age of 4.9 years.ResultsThe volume of major brain structures was significantly larger in the appropriate-for-gestational-age twins (AGA) compared to the small-for-gestational-age (SGA) co-twins (p < 0.001). The birth weight discordance was 32.3% (24.9–48.6) and was significantly greater (p < 0.001) than the discordance of the prenatal supratentorial brain (13.6% [5.6–18]), cerebellum volume (21.7% [9.5–30.8]). Further neurodevelopmental outcome evaluation found no significant difference between the AGA twin and the SGA twin.Conclusion In discordant twins, the smaller twin showed a “brain-preserving effect,” which in our study was not associated with a worse neurodevelopmental outcome. The use of MRI in such cases may aid in decision-making and parental consultation.Key Points • Weight discordance at birth was significantly greater compared to intrauterine brain volume discordance measured by 3D MRI. • Small-for-gestational-age (SGA) fetuses preserve brain development. • In highly discordant twins, there was no long-term difference in neurodevelopmental outcome at a mean age of 4.9 years.
Article
Intrauterine growth restriction (IUGR) is associated with hippocampal alterations that can increase the risk of short‐term memory impairments later in life. Despite the role of hippocampal neurogenesis in learning and memory, research into the long‐lasting impact of IUGR on these processes is limited. We aimed to determine the effects of IUGR on neuronal proliferation, differentiation and morphology, and on memory function at adolescent equivalent age. At embryonic day (E) 18 (term ∼E22), placental insufficiency was induced in pregnant Wistar rats via bilateral uterine vessel ligation to generate IUGR offspring (n = 10); control offspring (n = 11) were generated via sham surgery. From postnatal day (P) 36–44, spontaneous location recognition (SLR), novel object location and recognition (NOL, NOR), and open field tests were performed. Brains were collected at P45 to assess neurogenesis (immunohistochemistry), dendritic morphology (Golgi staining), and brain‐derived neurotrophic factor expression (BDNF; Western blot analysis). In IUGR versus control rats there was no difference in object preference in the NOL or NOR, the similar and dissimilar condition of the SLR task, or in locomotion and anxiety‐like behavior in the open field. There was a significant increase in the linear density of immature neurons (DCX+) in the subgranular zone (SGZ) of the dentate gyrus (DG), but no difference in the linear density of proliferating cells (Ki67+) in the SGZ, nor in areal density of mature neurons (NeuN+) or microglia (Iba‐1+) in the DG in IUGR rats compared to controls. Dendritic morphology of dentate granule cells did not differ between groups. Protein expression of the BDNF precursor (pro‐BDNF), but not mature BDNF, was increased in the hippocampus of IUGR compared with control rats. These findings highlight that while the long‐lasting prenatal hypoxic environment may impact brain development, it may not impact hippocampal‐dependent learning and memory in adolescence.
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Children who were growth restricted in utero (FGR) and are born small for gestational age (SGA) may experience poorer long term neurological and cognitive outcomes. Those also born preterm may have particular difficulties. The objective of this paper was to review the literature on school age neurocognitive outcome for term and preterm children that was published in the last fifteen years. Considering term born children first, there is evidence that these children are at higher risk for Cerebral Palsy (CP) than those born appropriate for gestational age (AGA); information on neuromotor function in the absence of CP is somewhat contradictory. With regards to cognitive outcome, the most common finding was that being born SGA and/or FGR at term does not impact negatively on general intellectual functioning, commonly assessed by IQ scores. There was some indication that they may experience particular problems with attention. With regards to children born preterm, the risk of CP appears not to be increased compared to those preterms born AGA. For preterm children who do not develop CP, motor outcome is more affected by post-natal and post-neonatal brain growth than intrauterine growth. In contrast to term born children, preterm SGA and/or FGR children are at increased risk of cognitive and behavioural difficulties, and in common with term born children, are at higher risk than their AGA counterparts of difficulties with attentional control. In conclusion, preterm born SGA and/or FGR children are at higher risk of neurodevelopmental problems in the school years. It is important to continue to follow up children into the school age years because these difficulties may take time to emerge, and may be more visible in the more demanding school environment.
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Intrauterine growth restriction (IUGR) is often the result of compromised placental function and suboptimal uteroplacental blood flow. Children born with IUGR have impaired cognitive functioning and specific memory deficits, indicating long-lasting impairments in hippocampal functioning; indeed, hippocampal volume is reduced in infants with IUGR. Animal studies have provided valuable insight into the nature of deficits in hippocampal-dependent functions observed in children born with IUGR; outcomes of experimental IUGR reveal reduced neuron numbers and morphological alterations in the cornu ammonis fields 1 and 3 and dentate gyrus subregions of the hippocampus. However, whether such early and ongoing structural changes in the hippocampus could account for deficits in spatial memory reported in adolescent rats with IUGR is yet to be established. Understanding the association between hippocampal structural and functional alterations in IUGR will aid in the development of interventions to minimise the effect of IUGR on the hippocampus and long-term cognitive outcomes.
Chapter
Based on considerable epidemiologic and laboratory based experimental evidence, it is clear that the optimal conditions for fetal growth and development require an environment of maternal homeostasis and well-being, and with the mother’s ability to respond appropriately to a particular stress. In view of its association with increased morbidity and mortality, fetal growth restriction (FGR) is to be avoided at all costs. Chapter 14 presents the clinical aspects of one not uncommon stress, that of high altitude or other [causes of] long-term hypoxia (LTH). Because fetal growth critically depends upon adequate maternal oxygenation, in addition to residence at high altitude (>2500 m), FGR may be associated with conditions such as that of mothers who are moderate to heavy smokers or with cyanotic heart disease, lung disease, severe anemia, and other conditions that cause prolonged hypoxia (Giussani et al. 2001; Hutter et al. 2010; Longo 1984, 1987; Longo and Goyal 2014; Neerhof and Thaete 2008). The importance of oxygen for fetal physiology was a foundation for my research interests and the development of surgical approaches to directly investigate the fetus during pregnancy (methodology described in Yellon and Apostolakis 1994). The chapter reviews the development of ideas in terms of the many physiologic, biochemical, cellular, and molecular aspects of LTH for the fetus and newborn.
Chapter
In his essay “On being the right size,” the British geneticist, biometrician, and popularizer of science John Burdon Sanderson (JBS) Haldane (1892–1964) theorized on and presented some mathematical analysis for the optimal size of various organisms. In addition to consideration of body mass, he included surface area, weight-bearing bone structure, respiratory and circulating mechanisms, and other features of comparative anatomy and physiology (Haldane 1927). His analysis extended from insects to birds to a number of mammals which varied in size from mice to the rhinoceros. Haldane concluded “… that for every type of animal there is an optimal size” (Haldane 1927). A number of studies have disclosed that even for the fetus development follows clearly defined mathematical principles (Roberts 1906; see below). Prior to full maturity, timely growth, both physical and mental, is one of the best indicators of a fully functional physiological system and health. As is appreciated, optimal growth of the embryo-fetus and its various organs is a complex process that is a function of genetic makeup, state of maternal health, the availability of nutrients and oxygen, as well as a multitude of growth factors and hormones of maternal, placental, and fetal origin. In addition, a host of environmental factors that influence epigenetic programming play vital roles in this process. These factors are associated with physiologic, biochemical, and molecular changes, most of which are only poorly understood (Cheek 1975; Timiras 1972; Winick 1972). From mid-century onward, considerable emphasis has been placed on the mechanisms of cell division and multiplication (hyperplasia) and cell enlargement with cytoplasmic growth (hypertrophy) that result in the deposition of new tissue and change in anatomical form (Cheek 1975; Cockburn 1988; Fowden 1989; Winick 1972; Winick and Noble 1965).
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Fetal growth restriction (FGR) affects 7–10% pregnancies. Conventional and tissue Doppler imaging has noted cardiac compromise during fetal and early neonatal periods in this cohort. In this article, we discuss the use of salient ultrasound parameters across age groups. During fetal life, certain feto-placental sonographic parameters have been linked to adverse perinatal outcomes and are predictive of later life hypertension. During the early postnatal period altered morphometry (hypertrophied and globular hearts) with sub-clinical impairment of cardiac function has been noted in both term and preterm infants with FGR. Vascular imaging has noted thickened and stiffer arteries in association with significantly elevated blood pressure. Similar findings in the pediatric age groups indicate persistence of these alterations, and have formed the basis of intervention studies. Assessment methodology and clinical relevance of these parameters, especially in designing and monitoring of intervention strategies is discussed. Frontline care givers (obstetricians and neonatologists) are increasingly using point of care ultrasound to discern these manifestations of FGR during the sub-clinical phase.
Chapter
Small for gestational age (SGA) is most commonly defined as birthweight for age below the 10th percentile of the reference, and it is used as a marker of growth failure and represents a major global health problem. This chapter starts with a description of the different methods to assess SGA and the challenges and limitations associated with them, especially in low- and middle-income countries. This is followed by the epidemiology of SGA and its determinants. Finally, the short- and long-term consequences of SGA in terms of mortality, morbidity, and development are explored.
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In a recent paper and forthcoming volume, the former President of the American Psychological Association, Robert Sternberg, calls for an effort to reintegrate psychological science (Sternberg, in press; Sternberg & Grigorenko, 2001). In this paper we argue that D. O. Hebb, beginning with his technical volume in 1949 and continuing through a series of introductory textbooks, has convincingly presented the basis for such integration. The basis for this integration lies in understanding how genes and experience shape neural networks underlying human thoughts, feelings, and actions. Why has not Hebb's accomplishment been generally recognized as providing the needed integration for psychology? We suggest that the methods available to Hebb, mostly animal research and behavioural human experiments, were not sufficient to provide empirical methods for linking his conceptual nervous system to real events in the human brain. This methodology has now been provided by neuroimaging. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
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The developmental status of some potential components of hippocampal circuitry was studied at the time of the emergence of the hippocampal cytoarchitectonic subfields. The laminar distribution of synapses as seen with electron microscopy was correlated with Golgi architectonics in 15- and 16.5-week-old human fetuses. A systematic electron microscopic analysis of the distribution of synapses demonstrated that they were restricted to the two zones bordering the cortical plate, viz. the marginal and subplate zones, which contain dendritic branches of pyramidal and large polymorphous non-pyramidal neurons. The density of synapses (number per unit area) was higher in the marginal zone than in the subplate zone. Most synapses were of the asymmetric axodendritic type, although some were symmetric axodendritic synapses. The possible origins of the axons forming these synapses are discussed. This study demonstrates that the human hippocampus shows an early onset of synapse formation, with a characteristic distribution of synapses in restricted laminae. The finding of early synapse formation is consistent with observations made in other cortical areas during development. The prevalence of synaptogenesis at a superficial level of the cortex seems, however, to be specific to the "archicortex".
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To investigate the effects of small for gestational age (SGA) in very low birthweight (VLBW) infants on growth and development until the fifth year of life. VLBW (< 1500 g) infants, selected from a prospective study, were classified as SGA (n = 115) on the basis of birth weight below the 10th percentile for gestational age and were compared with two groups of appropriate for gestational age (AGA) infants matched according to birth weight (AGA-BW; n = 115) or gestation at birth (AGA-GA; n = 115). Prenatal, perinatal, and postnatal risk factors were recorded, and duration and intensity of treatment were computed from daily assessments. Body weight, length, and head circumference were measured at birth, five and 20 months (corrected for prematurity), and at 56 months. General development was assessed at five and 20 months with the Griffiths scale of babies abilities, and cognitive development at 56 months with the Columbia mental maturity scales, a vocabulary (AWST) and language comprehension test (LSVTA). Significant group differences were found in complications (pregnancy, birth, and neonatal), parity, and multiple birth rate. The AGA-GA group showed most satisfactory growth up to 56 months, with both the AGA-BW and SGA groups lagging behind. The AGA-GA group also scored significantly more highly on all developmental and cognitive tests than the other groups. Developmental test results were similar for the SGA and AGA-BW groups at five and 20 months, but AGA-BW infants (lowest gestation) had lower scores on performance intelligence quotient and language comprehension at 56 months than the SGA group. When prenatal and neonatal complications, parity, and multiple birth were accounted for, group differences in growth remained, but differences in cognitive outcome disappeared after five months. Being underweight and with a short gestation (SGA and VLBW) leads to poor weight gain and head growth in infancy but does not result in poorer growth than in infants of the same birth weight but shorter gestation (AGA-BW) in the long term. SGA is related to early developmental delay and later language problems; however, neonatal complications may have a larger detrimental effect on long term cognitive development of VLBW infants than whether they are born SGA or AGA.
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The fact that medial temporal lobe structures, including the hippocampus, are critical for declarative memory is firmly established by now. The understanding of the role that these structures play in declarative memory, however, despite great efforts spent in the quest, has eluded investigators so far. Given the existing scenario, novel ideas that hold the promise of clarifying matters should be eagerly sought. One such idea was recently proposed by Vargha-Khadem and her colleagues on the basis of their study of three young people suffering from anterograde amnesia caused by early-onset hippocampal pathology. The idea is that the hippocampus is necessary for remembering ongoing life's experiences (episodic memory), but not necessary for the acquisition of factual knowledge (semantic memory). We discuss the reasons why this novel proposal makes good sense and why it and its ramifications should be vigorously pursued. We review and compare declarative and episodic theories of amnesia, and argue that the findings reported by Vargha-Khadem and her colleagues fit well into an episodic theory that retains components already publicized, and adds new ones suggested by the Vargha-Khadem et al. study. Existing components of this theory include the idea that acquisition of factual knowledge can occur independently of episodic memory, and the idea that in anterograde amnesia it is quite possible for episodic memory to be more severely impaired than semantic memory. We suggest a realignment of organization of memory such that declarative memory is defined in terms of features and properties that are common to both episodic and semantic memory. The organization of memory thus modified gives greater precision to the Vargha-Khadem et al. neuroanatomical model in which declarative memory depends on perihippocampal cortical regions but not on the hippocampus, whereas episodic memory, which is separate from declarative memory, depends on the hippocampus.
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Recent neuroimaging studies have obtained evidence of activation in the medial temporal lobe (MTL) during episodic encoding and retrieval. On the basis of a meta-analysis of MTL activations in studies that used positron emission tomography (PET), Lepage et al. (Hippocampus 1998;8:313–322) suggested that episodic encoding tends to involve the anterior MTL, whereas episodic retrieval tends to involve the posterior MTL. In a meta-analysis of studies that used PET and functional magnetic resonance imaging, Schacter and Wagner (Hippocampus 1999;9:7–24) reported weaker evidence for such a rostrocaudal distribution of encoding and retrieval activations. However, these meta-analyses were based largely on studies that examined encoding or retrieval separately. Here, we report a direct, within-subjects comparison of MTL activation during episodic encoding and retrieval by using PET. Results indicated that both encoding and retrieval were associated with blood flow increases in similar MTL regions with little indication that encoding and retrieval are preferentially associated with activity in the anterior versus the posterior MTL. Direct comparisons revealed greater blood flow increases in posterior MTL during encoding than retrieval. Hippocampus 1999;9:575–581. © 1999 Wiley-Liss, Inc.
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Despite many methodological difficulties, studies evaluating the relationship between being small for gestational age (SGA) at birth and various measures of adverse neurologic outcome generally show significant associations. Nevertheless, cerebral palsy is rarely found in SGA infants. Minimal neurologic dysfunction is more commonly seen in males and lower socioeconomic SGA children, and is often associated with attention deficits, hyperactivity, clumsiness, and poor school performance. Vision and hearing are generally not disturbed in SGA infants.
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Short-term memory was assessed in two groups of amnesic patients. Six patients had confirmed or suspected damage to the hippocampal formation, and six patients had diencephalic damage as a result of alcoholic Korsakoff's syndrome. Verbal short-term memory was evaluated with seven separate administrations of the standard digit span test in order to obtain a precise measure of short-term memory. Nonverbal short-term memory was evaluated with four tests that assessed apprehension, retention, and the ability to manipulate nonverbal material--all within the span of immediate memory. One of these four tests assessed short-term memory for spatial location. Patients with damage to the hippocampal formation had a digit span equivalent to that of control subjects and also performed normally on the four tests of nonverbal short-term memory. The patients with Korsakoff's syndrome had a marginally low digit span and performed poorly on three of the four nonverbal tasks, a finding consistent with the deficits in attention and visuospatial processing previously described for this patient group. These deficits are likely due to the frontal lobe atrophy typically associated with Korsakoff's syndrome, rather than to diencephalic damage. The results support the view that short-term (immediate) memory, including short-term spatial memory, is independent of the hippocampus.
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We examined the association of fetal and newborn complications, socioeconomic status, and home environment with learning deficits as assessed between 9 and 11 years of age. A total of 218 high-risk newborns have been assessed at 1, 4, and 9 to 11 years of age. Fetal and newborn complications included 77 newborns with growth retardation. Socioeconomic variables included parental occupation and education. Outcome measures at 9 to 11 years included the Woodcock Reading Mastery Test and the Wide Range Achievement Test. Motor and cognitive development was assessed by a neurologic examination, the Bruininks-Oseretsky Test of Motor Proficiency, and the Wechsler Intelligence Scale for Children. Behavior was assessed with the Achenbach Child Behavior Check List and Connor's Teacher Rating Scale. Learning deficits were identified in 77 of the 218 children (35%). Children with learning deficits had lower full-scale IQ scores and behavioral problems of inattention and anxiety. Both fetal growth retardation and the father's occupation score were independently associated with these learning deficits. Fetal growth retardation, socioeconomic status, and behavioral characteristics of inattention and anxiety are associated with less favourable academic achievement at 9 to 11 years of age.
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The relationship between extremely low birthweight (ELBW) and psychiatric disorder was investigated in a cohort of children of 500 to 1000g birthweight, born between 1980 and 1982. At five years of age data were collected for 82 of 90 survivors on psychiatric symptoms, parent-reported developmental delay and various aspects of psychosocial disadvantage. Compared with controls, ELBW children did not come from more disadvantaged environments, but were much more likely to experience developmental delay and problems with motor co-ordination. 16 per cent had an attention deficit disorder with hyperactivity (ADDH), compared with 6.9 per cent of controls. Rates of conduct disorder and emotional disorder were not raised, indicating that ELBW is a specific risk factor for ADDH. Controlling for the effect of neurodevelopmental problems rendered the association between ELBW and ADDH non-significant.
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The effect of an 8% casein and a control 25% casein diet on the granule cells in the dorsal blade of the dentate gyrus of the rat hippocampal formation was studied at 30, 90 and 220 days of age. Female rats were fed either an 8% or 25% casein diet 5 weeks prior to conception and the litters were maintained on these respective diets until killed. In rapid-Golgi-impregnated cells, we measured major and minor axes of the soma of the dentate granule neurons, the number of spines on 50-microns segments of proximal, middle and terminal regions of the largest dendrite per granule cell and the number of dendrites intersecting 8 concentric rings 38 microns apart. At all 3 ages studied undernourished rats showed, when compared to controls, significant reductions of the major and minor axes of the somata and significant reductions in the number of spines on dendrites in the middle and terminal dendritic segments. Dendritic branching was significantly reduced in undernourished rats compared to controls in all but the 4th concentric rings, with the greatest effect being seen on the outer 3 concentric rings at 90 and 220 days of age. The location of the deficit in dendritic synaptic spines and the greatest deficit in dendritic branching correspond to the sites of termination of the lateral and medial perforant pathway projection to the dentate gyrus on the terminal and middle dendritic segments of the granule cells. The deficits noted in the granule cells of the dentate gyrus in this study were more severe than those found in our previous studies on the effect of the low protein diet in these same rats on visual cortical pyramidal cells and on the 3 cell types in the nucleus raphe dorsalis and nucleus locus coeruleus.
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Predictive estimates of future neurological maldevelopment as a result of vascular induced intrauterine injury are based on the assumption that the body is more affected than the brain resulting in asymmetrical intrauterine growth retarded (IUGR) newborns. The higher the brain:body ratio, the more severe the IUGR process and the greater the risk for the brain to be affected. This prompted us to study in human newborns, a cephalization index based on the ratio of head circumference to body weight to express the degree of brain maturity and possible vulnerability in relation to gestational age. The newborn cephalization index was correlated with neurodevelopment. A trend could be delineated; in the later gestational age, the higher the cephalization index reflecting a greater degree of brain vulnerability, the more severe the clinical pathology; especially the likelihood of cerebral palsy and severe psychomotor retardation. The cephalization index may serve as an additional screening device for high risk intrauterine growth retarded newborns.
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Vascular induced intrauterine growth retardation (IUGR) was achieved by total ligation of approximately 30% of the placental vessels to half the fetuses in the last third of gestation in pregnant rabbits. A correlation between brain weight, body weight and head circumference was established in fetuses and rabbit pups in the perinatal period. The brain:body ratio in restricted IUGR animals was significantly higher than their homologous normal controls. A cephalization index based on the brain:body ratio is proposed to assess adverse effects on brain maturity in the presence of IUGR induced by placental insufficiency.
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Sensory-evoked potentials were recorded from the dentate gyrus of the rat hippocampus during performance of a differential auditory discrimination task. The short latency (20 ms) component (N1) of the sensory-evoked potential showed systematic amplitude fluctuations dependent upon the sequence of positive and negative trials preceding the presentation of a given trial and did not depend on the associated reward values of the individual tone stimuli which evoked the potential. The amplitude fluctuations could be accurately depicted by a model which retained the sequence for the five preceding trials in a "buffer" with exponentially decaying influence as a function of time of trial occurrence within the sequence. The results provide evidence that the hippocampus encodes accurate short-lasting representations of sensory events which can provide the basis for storage of information pertaining to past experiences.
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Seventy-nine patients with unilateral frontal- or temporal-lobe excisions and 18 normal control subjects were tested on four self-ordered tasks requiring the organization of a sequence of pointing responses. There were two verbal and two nonverbal tasks. Patients wih excisions from the left frontal lobe exhibited significant impairments on all four tasks, whilst patients with excisions from the right frontal lobe showed deficits only on the two nonverbal tasks. Patients with temporal-love lesions not extending posteriorly, on the medial side, beyond the pes of the hippocampus were unimpaired on all tasks, whereas those with more radical hippocampal excisions exhibited material-specific deficits that varied with the side of the lesion.
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The Visual Aural Digit Span Test (VADS Test), developed and standardized as a diagnostic test for learning disabilities in kindergarten to sixth-grade pupils, was adapted for use with seventh graders. Eight-digit sequences were added to the VADS Test, and normative data for children aged 12 to 14 are presented. An investigation of the relationship between the VADS Test scores and reading achievement showed the validity of the test for middle school pupils.
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Although the entorhinal cortex is a key structure connecting the hippocampal formation with the rest of the cerebral cortex, little is known about its early chemoanatomical development in primates. In the present study, a cytoarchitectonic analysis and immunocytochemical detection of somatostatin, neurotensin, parvalbumin, calbindin-D 28K, DARPP-32, as well as tyrosine hydroxylase, dopamine-beta-hydroxylase, and serotonin, were carried out on serial sections of the entorhinal cortex of six rhesus monkey fetuses aged E47 to E90 (gestation period 165 days). At E56 the cortical plate of the entorhinal cortex already exhibited a sublamination; at E64 the lamina dissecans was partly formed, allowing the emergence of the lamina principalis externa and interna, and at E83 most of the regional and laminar subdivisions characteristic of the adult cortex could