Altered structural connectome and motor problems of very preterm born children at school-age.

Infants born very preterm (<32 weeks of gestation) show distinct cognitive and motor problems throughout childhood. This study aims 1) to investigate differences in the structural connectome between very preterm born children and term born controls at school-age, and 2) to examine the relationship of the structural connectome with cognitive and motor problems. This study included 29 very preterm (12 males, mean age 8.6 years) and 52 term born peers (25 males, mean age 8.7 years). Wechsler Intelligence Scale for Children and Movement Assessment Battery for Children were used. Brain network measures of smallworldness, clustering coefficient and shortest path length based on fiber density of white matter tracts were determined from Diffusion Tensor Imaging data using probabilistic tractography. Smallworldness (F(1,79) = -2.09, p = .04, d = 0.52) and clustering coefficient (F(1,79) = -2.63, p = .01, d = 0.64) were significantly higher for very preterm children as compared to term peers. For Total Motor Impairment score and Manual Dexterity, there was a significant interaction between group and smallworldness (Beta = -10.81, p = .03 and Beta = -2.99, p = .004, respectively). Greater Total Motor Impairment and poorer Manual Dexterity were only significantly related to higher smallworldness in term controls (r = 0.35, p = .01 and r = 0.27, p = .04, respectively). Poorer Ball Skills were significantly related to higher smallworldness in both groups (Beta = -0.30, p = .03). This study clearly shows a more segregated network organization in very preterm children as compared to term peers. Importantly, motor problems go together with altered organization of the structural connectome in term born children, whereas this potential compensational process is only found for Ball Skills for very preterm children.

Neurocognitive processes underlying academic difficulties in very preterm born adolescents.

Very preterm birth is associated with academic difficulties, but the underlying neurocognitive mechanisms of these difficulties remain largely unclear. The present study aimed to assess the role of working memory (WM), attentional processes, and processing speed in academic difficulties of very preterm born adolescents at 13 years. Participants included 55 very preterm and 61 full-term adolescents. Academic performance, visuospatial WM, alerting, orienting, executive attention, sustained attention, and processing speed (simple and choice reaction time [RT]) were compared between groups. Mediation analyses with multiple, parallel mediators were performed to examine whether these functions mediate the relation between very preterm birth and academic performance. Very preterm born adolescents showed poorer reading comprehension, arithmetic, visuospatial WM, alerting, sustained attention, and choice RT than full-term controls. The relationship between very preterm birth and arithmetic was mediated by visuospatial WM, sustained attention, and choice RT. The relationship between very preterm birth and reading comprehension was mediated by visuospatial WM and choice RT. The findings indicate that very preterm birth affects arithmetic and reading comprehension through its negative effect on visuospatial WM, sustained attention, and processing speed. These neurocognitive processes may identify very preterm born children at risk for academic difficulties and could serve as targets for interventions.

Voluntary and Involuntary Control of Attention in Adolescents Born Very Preterm: A Study of Eye Movements.

Very preterm birth is associated with attention deficits that interfere with academic performance. A better understanding of attention processes is necessary to support very preterm born children. This study examined voluntary and involuntary attentional control in very preterm born adolescents by measuring saccadic eye movements. Additionally, these control processes were related to symptoms of inattention, intelligence, and academic performance. Participants included 47 very preterm and 61 full-term born 13-years-old adolescents. Oculomotor control was assessed using the antisaccade and oculomotor capture paradigm. Very preterm born adolescents showed deficits in antisaccade but not in oculomotor capture performance, indicating impairments in voluntary but not involuntary attentional control. These impairments mediated the relation between very preterm birth and inattention, intelligence, and academic performance.

Social Adjustment in Adolescents Born Very Preterm: Evidence for a Cognitive Basis of Social Problems.

OBJECTIVE: To increase the understanding of social adjustment and autism spectrum disorder symptoms in adolescents born very preterm by studying the role of emotion recognition and cognitive control processes in the relation between very preterm birth and social adjustment. STUDY DESIGN: A Dutch cohort of 61 very preterm and 61 full-term adolescents aged 13 years participated. Social adjustment was rated by parents, teachers, and adolescents and autism spectrum disorder symptoms by parents. Emotion recognition was assessed with a computerized task including pictures of child faces expressing anger, fear, sadness, and happiness with varying intensity. Cognitive control was assessed using a visuospatial span, antisaccade, and sustained attention to response task. Performance measures derived from these tasks served as indicators of a latent cognitive control construct, which was tested using confirmatory factor analysis. Mediation analyses were conducted with emotion recognition and cognitive control as mediators of the relation between very preterm birth and social problems. RESULTS: Very preterm adolescents showed more parent- and teacher-rated social problems and increased autism spectrum disorder symptomatology than controls. No difference in self-reported social problems was observed. Moreover, very preterm adolescents showed deficits in emotion recognition and cognitive control compared with full-term adolescents. The relation between very preterm birth and parent-rated social problems was significantly mediated by cognitive control but not by emotion recognition. Very preterm birth was associated with a 0.67-SD increase in parent-rated social problems through its negative effect on cognitive control. CONCLUSIONS: The present findings provide strong evidence for a central role of impaired cognitive control in the social problems of adolescents born very preterm.

Implicit Learning Abilities in Adolescents Born Very Preterm.

Very preterm birth is associated with neurodevelopmental impairments and outcomes have not improved over the last decades. Insight in learning processes is important for the development of effective interventions. Implicit learning is of particular interest because of its independence from working memory processes that are affected by preterm birth. This study examined implicit learning abilities in 49 very preterm and 61 full-term 13-year-old adolescents. The degree of implicit learning was not different between groups. This indicates intact implicit learning abilities in adolescents born very preterm. Implicit learning strategies may be beneficial for skill learning in very preterm born children.

EEG profiles and associated neurodevelopmental outcomes after very preterm birth.

OBJECTIVES: To assess brain oscillations in very preterm and full-term born adolescents and explore subgroups based on integrative patterns of brain oscillations with different frequencies. Additionally, subgroups were related to functional outcomes and very preterm birth. METHODS: A Dutch cohort of 53 very preterm and 61 full-term born adolescents aged 13 years participated. Resting-state electroencephalography was recorded. Absolute and relative delta, theta, alpha, and beta power were compared between groups. Latent class analysis (LCA) was used to identify subgroups with distinct activity patterns and to relate these patterns to intelligence, academic performance, motor skills, and very preterm birth. RESULTS: Very preterm adolescents exhibited decreased relative beta activity. LCA with four classes showed the best model fit. The class with the highest level of delta and lowest levels of theta, alpha, and beta power was associated with lowest intelligence, academic, and motor estimates. Very preterm born adolescents were more likely than controls to be members of this class. CONCLUSION: Very preterm born adolescents showed altered oscillatory activity, indicating long-lasting effects of very preterm birth on brain functioning. Distinct activity patterns were associated with both functional outcomes and very preterm birth. SIGNIFICANCE: Specific patterns of brain oscillations may serve as biomarkers for poor functional outcome after very preterm birth.

Academic trajectories of very preterm born children at school age.

OBJECTIVES: To characterise the developmental trajectories of arithmetic, reading comprehension and spelling abilities of very preterm and full-term born children during primary school. DESIGN: A longitudinal analysis of academic performance data of very preterm and full-term born children was performed. Academic performance was assessed in grade 1-6 of primary school using a pupil monitoring system, with 11 measurements of arithmetic and spelling performance and 7 measurements of reading comprehension. Data were analysed using mixed-effects models. PATIENTS: A Dutch cohort of 52 very preterm children born between 2001-2003 and 58 full-term controls participated. RESULTS: No group-by-time interactions were found for any of the academic domains, indicating no differences in progress between groups. Through the course of primary school, very preterm born children scored on average 0.53 SD lower on arithmetic (95% CI -0.71 to -0.35, p<0.001), 0.31 SD on reading comprehension (95% CI -0.48 to -0.14, p<0.001) and 0.21 SD on spelling (95% CI -0.37 to -0.05, p=0.01) compared with full-term peers. CONCLUSIONS: This is the first longitudinal study to show that the academic difficulties of very preterm born children persisted during primary school. Their progression was similar to full-term born peers, suggesting intact learning abilities. This provides opportunities for interventions to improve the academic outcomes of very preterm born children.

Cognitive Outcomes of Children Born Extremely or Very Preterm Since the 1990s and Associated Risk Factors: A Meta-analysis and Meta-regression.

Importance: Despite apparent progress in perinatal care, children born extremely or very preterm (EP/VP) remain at high risk for cognitive deficits. Insight into factors contributing to cognitive outcome is key to improve outcomes after EP/VP birth. Objective: To examine the cognitive abilities of children of EP/VP birth (EP/VP children) and the role of perinatal and demographic risk factors. Data Sources: PubMed, Web of Science, and PsycINFO were searched without language restriction (last search March 2, 2017). Key search terms included preterm, low birth weight, and intelligence. Study Selection: Peer-reviewed studies reporting intelligence scores of EP/VP children (<32 weeks of gestation) and full-term controls at age 5 years or older, born in the antenatal corticosteroids and surfactant era, were included. A total of 268 studies met selection criteria, of which 71 covered unique cohorts. Data Extraction and Synthesis: MOOSE guidelines were followed. Data were independently extracted by 2 researchers. Standardized mean differences in intelligence per study were pooled using random-effects meta-analysis. Heterogeneity in effect size across studies was studied using multivariate, random-effects meta-regression analysis. Main Outcomes and Measures: Primary outcome was intelligence. Covariates included gestational age, birth weight, birth year, age at assessment, sex, race/ethnicity, socioeconomic status, small for gestational age, intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis, sepsis, and postnatal corticosteroid use. Results: The 71 included studies comprised 7752 EP/VP children and 5155 controls. Median gestational age was 28.5 weeks (interquartile range [IQR], 2.4 weeks) and the mean age at assessment ranged from 5.0 to 20.1 years. The median proportion of males was 50.0% (IQR, 8.7%). Preterm children had a 0.86-SD lower IQ compared with controls (95% CI, -0.94 to -0.78, P < .001). Results were heterogeneous across studies (I2 = 74.13; P < .001). This heterogeneity could not be explained by birth year of the cohort. Multivariate meta-regression analysis with backward elimination revealed that BPD explained 65% of the variance in intelligence across studies, with each percent increase in BPD rate across studies associated with a 0.01-SD decrease in IQ (0.15 IQ points) (P < .001). Conclusions and Relevance: Extremely or very preterm children born in the antenatal corticosteroids and surfactant era show large deficits in intelligence. No improvement in cognitive outcome was observed between 1990 and 2008. These findings emphasize that improving outcomes after EP/VP birth remains a major challenge. Bronchopulmonary dysplasia was found to be a crucial factor for cognitive outcome. Lowering the high incidence of BPD may be key to improving long-term outcomes after EP/VP birth.

A randomised trial of enteral glutamine supplementation for very preterm children showed no beneficial or adverse long-term neurodevelopmental outcomes.

AIM: This study evaluated the long-term effects of enteral glutamine supplementation on neurodevelopmental outcomes of a Dutch cohort of very preterm children at 13 years of age. METHODS: The cohort was enrolled in a randomised placebo-controlled trial between 2001 and 2003 in which infants received glutamine- or alanine-supplemented enteral nutrition during the first month of life. Participants were invited for follow-up at a mean age of 13.30 years. Motor, neurocognitive, academic and behavioural outcomes were assessed in 61 children. RESULTS: No differences were found between the groups regarding motor, intellectual, academic and behavioural functioning. Forward span visuospatial working memory performance was better in the controls (crude/adjusted model: d = 0.67/0.64, p = 0.02/0.02), but no difference was found for backward span. After the data were adjusted for confounders, the groups differed regarding parent-rated attention (crude/adjusted model: d = 0.47/0.73, p = 0.07/0.003), but both groups scored within the normal range. CONCLUSION: This was the first study on the long-term effects of enteral glutamine supplementation on the neurodevelopmental outcomes of very preterm children. Our study provided no evidence that enteral glutamine supplementation had any beneficial or adverse effects on the children's motor, neurocognitive, academic and behavioural outcomes at 13 years of age.

Academic performance of children born preterm: a meta-analysis and meta-regression.

BACKGROUND: Advances in neonatal healthcare have resulted in decreased mortality after preterm birth but have not led to parallel decreases in morbidity. Academic performance provides insight in the outcomes and specific difficulties and needs of preterm children. OBJECTIVE: To study academic performance in preterm children born in the antenatal steroids and surfactant era and possible moderating effects of perinatal and demographic factors. DESIGN: PubMed, Web of Science and PsycINFO were searched for peer-reviewed articles. Cohort studies with a full-term control group reporting standardised academic performance scores of preterm children (<37 weeks of gestation) at age 5 years or older and born in the antenatal steroids and surfactant era were included. Academic test scores and special educational needs of preterm and full-term children were analysed using random effects meta-analysis. Random effects meta-regressions were performed to explore the predictive role of perinatal and demographic factors for between-study variance in effect sizes. RESULTS: The 17 eligible studies included 2390 preterm children and 1549 controls. Preterm children scored 0.71 SD below full-term peers on arithmetic (p<0.001), 0.44 and 0.52 SD lower on reading and spelling (p<0.001) and were 2.85 times more likely to receive special educational assistance (95% CI 2.12 to 3.84, p<0.001). Bronchopulmonarydysplasia explained 44% of the variance in academic performance (p=0.006). CONCLUSION: Preterm children born in the antenatal steroids and surfactant era show considerable academic difficulties. Preterm children with bronchopulmonarydysplasia are at particular risk for poor academic outcome.

A crucial role for white matter alterations in interference control problems of very preterm children.

BACKGROUND: Attention problems are among the most prominent behavioral deficits reported in very preterm children (below 32 wk of gestation) at school age. In this study, we aimed to elucidate the brain abnormalities underlying attention problems in very preterm children by investigating the role of abnormalities in white and gray brain matter during interference control, using functional magnetic resonance imaging (fMRI)-guided probabilistic diffusion tensor tractography. METHODS: Twenty-nine very preterm children (mean (SD) age: 8.6 (0.3) y), and 47 term controls (mean (SD) age: 8.7 (0.5) y), performed a fMRI version of the Eriksen Flanker task measuring interference control. RESULTS: Very preterm children showed slower reaction times than term controls when interfering stimuli were presented, indicating poorer interference control. Very preterm children and term controls did not differ in mean activation of the cortical regions involved in interference control. However, impaired fractional anisotropy (FA) was found in very preterm children in specifically those fiber tracts that innervate the cortical regions involved in interference control. Lower FA was related to poorer interference control in very preterm children. CONCLUSION: White matter alterations have a crucial role in the interference control problems of very preterm children at school age.

A crucial role of altered fractional anisotropy in motor problems of very preterm children.

BACKGROUND: Very preterm children (<32 weeks of gestation) are characterized by impaired white matter development as measured by fractional anisotropy (FA). This study investigates whether altered FA values underpin the widespread motor impairments and higher incidence of developmental coordination disorder (DCD) in very preterm children at school-age. METHODS: Thirty very preterm born children (mean (SD) age of 8.6 (0.3) years) and 47 term born controls (mean [SD] age 8.7 [0.5] years) participated. Motor development was measured using the Movement Assessment Battery for Children. A score below the 15th percentile was used as a research diagnosis of DCD. FA values, as measure of white matter abnormalities, were determined for 18 major white matter tracts, obtained using probabilistic diffusion tensor tractography. RESULTS: Large-sized reductions in FA of the cingulum hippocampal tract right (d = 0.75, p = .003) and left (d = 0.76, p = .001), corticospinal tract right (d = 0.56, p = .02) and left (d = 0.65, p = .009), forceps major (d = 1.04, p < .001) and minor (d = 0.54, p = .02) were present in very preterms, in particular with a research diagnosis of DCD. Reduced FA values moderately to strongly related to motor impairments. A ROC curve for average FA, as calculated from tracts that significantly discriminated between very preterm children with and without a research diagnosis of DCD, showed an area under curve of 0.87 (95% CI 0.74-1.00, p = .001). CONCLUSIONS: This study provides clear evidence that reduced FA values are strongly underpinning motor impairment and DCD in very preterm children at school-age. In addition, outcomes demonstrate that altered white matter FA values can potentially be used to discriminate between very preterm children at risk for motor impairments, although future studies are warranted.

Glutamine effects on brain growth in very preterm children in the first year of life.

BACKGROUND & AIMS: Glutamine supplementation in the neonatal period has been associated with increased brain structure volumes at school-age in very preterm children. The aim of this study was to clarify the emergence and specificity of differences in brain structure volumes, using growth trajectories of head circumference, weight, and length. METHODS: Sixty-five very preterm (<32 weeks gestation) children, who originally took part in a randomized controlled trial on glutamine supplementation, participated. Head circumference, weight, and length, were measured at the neonatal intensive care unit, and at routine follow-up assessments at the outpatient clinic and well baby clinics. Magnetic Resonance Imaging was used to determine brain structure volumes at school-age. Growth trajectories were investigated using multilevel modeling analyses. RESULTS: Head circumference in the first year of life was positively associated with white matter volume and grey matter volume (range r = 0.55-0.81, all p < 0.002) at school-age. Furthermore, neonatal glutamine supplementation was associated with increased head circumference growth (p = 0.008) in the first year of life, but not with increased growth in weight (p = 0.44) and length (p = 0.73). CONCLUSIONS: This study indicates a specific increase in head circumference growth in very preterm children that received neonatal glutamine supplementation, and suggests that group differences in brain structure volumes at school-age may have emerged during the first year of life.

Visual search and attention in five-year-old very preterm/very low birth weight children.

INTRODUCTION: This study aimed to establish visual search performance and attention functioning in very preterm/very low birth weight (VP/VLBW) children using novel and well established measures, and to study their contribution to intellectual functioning. METHODS: Visual search and attention network efficiency were assessed in 108 VP/VLBW children and 72 age matched term controls at 5.5 years corrected age. Visual search performance was investigated with a newly developed paradigm manipulating stimulus density and stimulus organization. Attention functioning was studied using the Attention Network Test (ANT). Intellectual functioning was measured by a short form of the Wechsler Preschool and Primary Scale of Intelligence. Data were analyzed using ANOVAs and multiple regression analyses. RESULTS: Visual search was less efficient in VP/VLBW children as compared to term controls, as indicated by increased search time (0.31 SD, p = .04) and increased error rate (0.36 SD, p = .02). In addition, VP/VLBW children demonstrated poorer executive attention as indicated by lower accuracy for the executive attention measure of the ANT (0.61 SD, p < .001). No differences were found for the alerting (0.06 SD, p = .68) and orienting attention measures (0.13 SD, p = .42). Visual search time and error rate, and executive attention, collectively, accounted for 14% explained variance in full scale IQ (R(2) = .14, p < .001). DISCUSSION: VP/VLBW children were characterized by less efficient visual search ability and reduced executive attention. Visual attention dysfunctions contributed to intelligence, suggesting the opportunity to improve intellectual functioning by using interventions programs that may enhance attention capacities.

Perinatal infections and neurodevelopmental outcome in very preterm and very low-birth-weight infants: a meta-analysis.

IMPORTANCE: Perinatal infections are commonly present in preterm and very low-birth-weight (VLWB) infants and might contribute to adverse neurodevelopmental outcome. OBJECTIVE: To summarize studies evaluating the effect of perinatal infections on neurodevelopmental outcome in very preterm/VLBW infants. EVIDENCE REVIEW: On December 12, 2011, we searched Medline, PsycINFO, Embase, and Web of Knowledge for studies on infections and neurodevelopmental outcome. All titles and abstracts were assessed for eligibility by 2 independent reviewers. We also screened the reference lists of identified articles to search for additional eligible studies. Preselected criteria justified inclusion in this meta-analysis: (1) the study included infants born very preterm (≤32 weeks) and/or with VLBW (≤1500 g); (2) the study compared infants with and without perinatal infection; (3) there was follow-up using the Bayley Scales of Infant Development 2nd edition; and (4) results were published in an English-language peer-reviewed journal. The quality of each included study was assessed using the Newcastle-Ottawa Scale. FINDINGS: This meta-analysis includes 18 studies encompassing data on 13.755 very preterm/VLBW infants. Very preterm/VLBW infants with perinatal infections had poorer mental (d = -0.25; P < .001) and motor (d = -0.37; P < .001) development compared with very preterm/VLBW infants without infections. Mental development was most impaired by necrotizing enterocolitis (d = -0.40; P < .001) and meningitis (d = -0.37; P < .001). Motor development was most impaired by necrotizing enterocolitis (d = -0.66; P < .001). Chorioamnionitis did not affect mental (d = -0.05; P = .37) or motor (d = 0.19; P = .08) development. CONCLUSIONS AND RELEVANCE: Postnatal infections have detrimental effects on mental and motor development in very preterm/VLBW infants.

Predictive value of the Bayley scales of infant development on development of very preterm/very low birth weight children: a meta-analysis.

BACKGROUND AND AIMS: The Bayley scales of infant development (BSID) is the most widely used measure to assess neurodevelopment of very preterm (gestational age ≤32 weeks) and very low birth weight (VLBW, ≤1500 g) infants in the first three years of life. This meta-analysis determines the predictive value of the mental developmental index (MDI) and the psychomotor developmental index (PDI)/motor composite, collectively referred to as Bayley motor scale, of the BSID-I, -II and Bayley-III for later cognitive and motor functioning in very preterm/VLBW children. METHODS: Cochrane Library, PubMed, PsychINFO and CINAHL were searched for English-language peer-reviewed studies published before March 2013. Studies were included if they reported odds ratios or correlations between the MDI or Bayley motor scale scores obtained in the first three years of life, and standardized cognitive or motor assessment obtained later in life in very preterm/VLBW children. Meta-analytic methods were applied to aggregate available data. RESULTS: A total of 16 studies met inclusion criteria. Across 14 studies (n=1330 children), MDI scores were strongly predictive for later cognitive functioning, r=0.61 (95% CI: 0.57-0.64), explained variance 37%, p<.001. The relationship between MDI scores and later cognitive function was not mediated by birth weight (p=.56), gestational age (p=.70), and time interval between assessments (p=.55). Across five studies (n=555 children), Bayley motor scale scores were moderately predictive for later motor function, r=0.34 (95% CI: 0.26-0.42), explained variance 12%, p<.001. CONCLUSIONS: In very preterm/VLBW children, MDI scores explain 37% of the variance in later cognitive functioning, whereas Bayley motor scale scores explain 12% of later motor function. Thus a large proportion of the variance remains unexplained, underlining the importance of enhancing prediction of developmental delay in very preterm children.

The crucial role of the predictability of motor response in visuomotor deficits in very preterm children at school age.

AIM: We aimed to clarify the underpinnings of widespread visuomotor deficits in very preterm children. METHOD: Fifty-eight very preterm children (26 males, 32 females; mean [SD] age 7 y 6 mo [5 mo], gestational age 29.2 wks [1.6]; birthweight 1237 g [336]), recruited from a tertiary level neonatal intensive care unit, and 64 age-matched, comparison children born at term (28 males, 36 females; mean age [SD] 7 y 8 mo [7 mo]) participated. IQ was measured using a short form of the Wechsler Intelligence Scale for Children (3rd edition). A research diagnosis of developmental coordination disorder (DCD) was defined as a score below the 15th centile on the Movement Assessment Battery for Children. Visuomotor performance was assessed using a computerized task, in which children followed a predictable (structured condition) or an unpredictable (non-structured condition) trail on a touch screen using their index finger. RESULTS: Forty-six per cent of the very preterm children had a research diagnosis of DCD, compared with 16% of children born at term (p<0.001, odds ratio 4.69 [95% CI 2.01-10.99]). No group difference in visuomotor performance was present for the structured condition. In the non-structured condition, children born very preterm with and without a research diagnosis of DCD had poorer visuomotor performance than those born at term. INTERPRETATION: The predictability of the required motor response plays a crucial role in visuomotor deficits in very preterm children, regardless of DCD status.

Effects of glutamine on brain development in very preterm children at school age.

OBJECTIVES: The amino acid glutamine has been shown to reduce the number of serious neonatal infections in very preterm children, which may benefit long-term brain development. The aims of the current follow-up study were to (1) determine the long-term effects of glutamine-enriched feeding in the first month after birth in very preterm children on measures of brain development at school age, and (2) elucidate a potential mediating role of serious neonatal infections. METHODS: Fifty-two very preterm children who originally took part in a randomized controlled trial on enteral glutamine supplementation between day 3 and 30 after birth participated at a mean (SD) age of 8.6 (0.3) years. Measures of brain development included volumetric outcomes of major brain structures, as well as fractional anisotropy (FA) values of major white matter tracts. RESULTS: Glutamine supplementation in the first month was associated with medium-sized increases in white matter (d = 0.54, P = .03), hippocampus (d = 0.47, P = .02), and brain stem (d = 0.54, P = .04) volumes at school age. Exploratory analyses using an uncorrected P value indicated higher FA values of the bilateral cingulum hippocampal tract in the glutamine group. All differences were either strongly associated (hippocampus volume, brain stem volume, and FA values of cingulum hippocampal tract) or completely mediated (white matter volume) by the lower number of serious neonatal infections in the glutamine group. CONCLUSIONS: Short-term glutamine supplementation after birth increases white matter, hippocampus, and brain stem volumes in very preterm children at school age, mediated by a decrease in serious neonatal infections.

Post-traumatic amnesia predicts intelligence impairment following traumatic brain injury: a meta-analysis.

CONTEXT: Worldwide, millions of patients with traumatic brain injury (TBI) suffer from persistent and disabling intelligence impairment. Post-traumatic amnesia (PTA) duration is a promising predictor of intelligence following TBI. OBJECTIVES: To determine (1) the impact of TBI on intelligence throughout the lifespan and (2) the predictive value of PTA duration for intelligence impairment, using meta-analytic methods. METHODS: Electronic databases were searched for peer reviewed articles, published until February 2012. Studies reporting intelligence following TBI and injury severity by PTA duration were included. Meta-analytic methods generated effect sizes for full scale IQ (FSIQ), performance IQ (PIQ) and verbal IQ (VIQ), following mild TBI (PTA duration 1-24 h) and severe TBI (PTA duration >7 days), during the subacute phase of recovery (≤6 months post-injury) and the chronic phase (>6 months post-injury). Meta-regression elucidated the predictive value of PTA duration for intelligence impairment. RESULTS: Patients with severe TBI exhibited large depressions in FSIQ in the subacute phase of recovery (d = -1.07, 95% CI to 1.52 to -0.62; p<0.001), persisting into the chronic phase (d = -0.78, 95% CI -1.06 to -0.51; p<0.001). PIQ was more severely affected than VIQ in the subacute phase (Q1 =3.85; p<0.05) but not in the chronic phase (Q1 =0.03, p=0.87). Most importantly, longer PTA duration strongly predicted greater depressions of FSIQ and PIQ in the subacute phase (-0.76 ≤ ßs ≤ -0.73, Ps<0.01) and FSIQ, PIQ and VIQ in the chronic phase (-0.80 ≤ ßs ≤ -0.61, Ps<0.05). CONCLUSIONS: PTA duration is a valuable predictor of intelligence impairment following TBI. Results support the routine assessment of PTA duration in clinical settings.