Language performance and brain volumes, asymmetry, and cortical thickness in children born extremely preterm.

BACKGROUND: Children born preterm are more prone to have language difficulties. Few studies focus on children born extremely preterm (EPT) and the structural differences in language-related regions between these children and children born at term. METHODS: Our study used T1-weighted magnetic resonance imaging (MRI) scans to calculate the brain volumetry, brain asymmetry, and cortical thickness of language-related regions in 50 children born EPT and 37 term-born controls at 10 years of age. The language abilities of 41 of the children born EPT and 29 term-born controls were then assessed at 12 years of age, using the Wechsler Intelligence Scale for Children, Fifth Edition and the Clinical Evaluations of Language Fundamentals, Fourth Edition. The differences between MRI parameters and their associations with language outcomes were compared in the two groups. RESULTS: Brain volume and cortical thickness of language-related regions were reduced in children born EPT, but volumetric asymmetry was not different between children born EPT and at term. In children born EPT the brain volume was related to language outcomes, prior to adjustments for full-scale IQ. CONCLUSIONS: These findings expand our understanding of the structural correlates underlying impaired language performance in children born with EPT. IMPACT: The article expands understanding of the structure-function relationship between magnetic resonance imaging measurements of language-related regions and language outcomes for children born extremely preterm beyond infancy. Most literature to date has focused on very preterm children, but the focus in this paper is on extreme prematurity and language outcomes. While the brain volume and cortical thickness of language-related regions were reduced in children born EPT only the volume, prior to adjustment for full-scale IQ, was associated with language outcomes. We found no differences in volumetric asymmetry between children born EPT and at term.

Predictive value of Bayley-III Motor Index for later motor difficulties in children born extremely preterm.

AIM: To investigate the predictive ability of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) Motor Index, in children born extremely preterm (<27 gestational weeks) without cerebral palsy. METHODS: Children from the EXPRESS study (all extremely preterm births in Sweden, 2004-2007) without neurosensory impairments assessed with Bayley-III at 2.5 years corrected age and Movement Assessment Battery for Children, Second Edition (MABC-2), at 6.5 years comprised the eligible study population (n = 282). Motor difficulty was defined as MABC-2 ≤5th percentile. RESULTS: Motor difficulties were found in 57 of 282 children (20.2%) at 6.5 years. The Bayley-III explained 18.0% of the variance in the MABC-2 (p < 0.001). The area under the receiver operating curve was 0.71 (95% confidence interval 0.64-0.79, p < 0.001). At a Bayley-III cut-off value of 85, sensitivity, specificity and positive and negative predictive values for motor difficulties were 26.3% (15.5-39.7), 92.9% (88.1-95.9), 48.4% (33.0-64.0) and 83.3% (80.9-85.4). Likelihood ratios were inconclusive. CONCLUSION: The Bayley-III at 2.5 years corrected age was a modest predictor of motor outcome in children born extremely preterm at 6.5 years, and underestimated the rate of motor difficulties. Children require follow-up beyond preschool age.

Discrete white matter abnormalities at age 8-11 years in children born extremely preterm are not associated with adverse cognitive or motor outcomes.

AIM: Little is known about the prevalence of discrete white matter abnormalities (WMA) beyond the first years in children born extremely preterm (EPT) and the relation to neurodevelopmental outcomes. Our aim was to investigate the prevalence of discrete WMA in children born EPT and the relationship to neonatal white matter injuries (WMI), white matter (WM) volume, WM diffusivity and neurodevelopment. METHODS: The study was a part of a longitudinal follow-up study of EPT neonates. All children were scanned at Karolinska University hospital 2004-2007 (neonates) and 2014-2015 (children at 8-11 years). WMA was qualitatively assessed by visual inspection. Developmental assessment was conducted at 12 years. RESULTS: In total, 112 children (median age 10.3 years, 56 girls) underwent MRI of the brain (68 EPT, 45 controls). In the EPT group, a subset had MRI around term equivalent age (n = 61). In the EPT group, the prevalence of discrete WMA at 8-11 years was 52%. There was a positive association between WMI at TEA and 8-11 years. There was no association between WMI and WM volumes or diffusivity at 8-11 years. Discrete WMA was not related to neurodevelopmental outcomes. CONCLUSION: Discrete WMA was prevalent in children born EPT at 8-11 years but were not related to neurodevelopmental outcomes.

The type and timing of patent ductus arteriosus treatment was associated with neurodevelopment when extremely preterm infants reached 6.5 years.

AIM: This study investigated patent ductus arteriosus (PDA) treatment and neurodevelopmental outcomes when extremely preterm born children reached 6.5 years. METHOD: Our cohort was 435 children with neonatal PDA treatment data and neurodevelopmental follow-up data, born in 2004-2007, who participated in the Extremely Preterm Infants in Sweden Study. Pharmacological or surgical PDA treatment and the age at PDA treatment, were investigated in relation to the risks of moderate to severe neurodevelopmental impairment (NDI) and full-scale intelligence quotient (FSIQ) at 6.5 years. RESULTS: The children who received PDA drug treatment, including those who also had surgery, had the same risk of moderate to severe NDI or lower FSIQ as untreated children. However, children who had primary PDA surgery faced increased risks of NDI, with an adjusted incidence rate ratio of 1.62 (95% confidence interval [CI] 1.28-2.06) and a lower adjusted mean difference FSIQ of -7.1 (95% CI -11 to -3.2). Surgery at less than 10 days of life was associated with a significantly increased risk of moderate to severe NDI and lower FSIQ than surgery after 20 days. CONCLUSION: Drug treatment followed by deferred surgery appeared to be a safer option for extremely preterm infants severely affected by PDA.

Minor neurological dysfunction and associations with motor function, general cognitive abilities, and behaviour in children born extremely preterm.

AIM: To study the prevalence of minor neurological dysfunction (MND) at 6 years of age in a cohort of children born extremely preterm without cerebral palsy (CP) and to investigate associations with motor function, cognitive abilities, and behaviour. METHOD: This study assessed 80 children born at less than 27 weeks of gestation and 90 children born at term age between 2004 and 2007 at a mean age of 6 years 6 months. The assessments included a simplified version of the Touwen Infant Neurological Examination, the Movement Assessment Battery for Children, Second Edition (MABC-2), Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV), the Strengths and Difficulties Questionnaire (SDQ), and the parent version of the Five to Fifteen questionnaire. RESULTS: Fifty-one of the children born preterm had normal neurology, 23 had simple MND, and six had complex MND compared with 88 who had normal neurology and two simple MND in the term-born group (p<0.001). There were significant differences between the children with normal neurology and MND in the preterm group in MABC-2-assessed motor function (p<0.001), general cognitive abilities with WISC-IV (p=0.005), and SDQ overall behavioural problems and peer problems reported by the parents (p=0.021 and p=0.003 respectively). SDQ teacher-reported overall behavioural and hyperactivity problems were significantly different between children with normal and simple MND (p=0.036 and p=0.019). INTERPRETATION: Children born extremely preterm, in the absence of CP, are at risk of MND and this is associated with motor function, cognitive ability, and behaviour. WHAT THIS PAPER ADDS: Extremely preterm birth carries a risk of minor neurological dysfunction (MND). MND in children born extremely preterm is associated with impaired motor function and cognitive abilities, and behavioural problems. Male sex is associated with MND in children born extremely preterm.

Changes in prevalence of non-optimal neurological condition between 6.5 and 12 years in children born extremely preterm.

AIM: To assess prevalence of non-optimal neurological condition and associations with motor function in children born extremely preterm (EPT) up to early adolescence, and to examine potential changes in neurological condition between 6.5 and 12 years. METHOD: A prospective cohort of one hundred six children (EPT n = 62, term n = 44) was assessed at 6.5 and 12 years. Four domains derived from the Touwen Neurological Examination (coordination and balance, posture and muscle tone, reflexes, and nerve function of the eyes and face) were used to assess the presence of a non-optimal neurological condition (defined as the presence of any abnormal domain). The Movement Assessment Battery for Children 2nd ed. was used to evaluate motor function. RESULTS: Twenty-seven children born EPT (44%) were assessed as having a non-optimal neurological condition compared with 4 (9%) in the control group (p=<0.001) at 12 years. Between age 6.5 and 12 years the number of children born EPT with a non-optimal neurological condition decreased from 37 to 27 (p = 0.007). At 12 years these children also had significantly lower MABC-2 total test scores, compared to those with normal neurology: median (range) 57 (32-79) versus 75 (43-99), respectively (p=<0.001). The same was shown for subscale scores; manual dexterity (p=<0.001), aiming/catching (p = 0.004), and balance (p = 0.004). CONCLUSION: The prevalence of a non-optimal neurological condition reduced with increasing age. However, still, at 12 years, these neurological impairments remained significantly more common in the EPT group than in their term-born peers and was shown to be related to a reduced motor function.

Extreme prematurity and perinatal risk factors related to extremely preterm birth are associated with complex patterns of regional brain volume alterations at 10 years of age: a voxel-based morphometry study.

Objective: Structural brain volumetric differences have been investigated previously in very preterm children. However, children born extremely preterm, at the border of viability, have been studied to a lesser degree. Our group previously analyzed children born extremely preterm at term using voxel-based morphometry. In this study, we aimed to examine regional gray and white matter differences for children born extremely preterm derived from the same cohort during childhood. We also aimed to explore the effect of perinatal risk factors on brain volumes in the same group. Methods: At 10 years of age, 51 children born extremely preterm (before 27 weeks and 0 days) and 38 term-born controls with high-quality 3.0 Tesla magnetic resonance images were included. Statistical analyses using voxel-based morphometry were conducted on images that were normalized using age-specific templates, modulated, and smoothed. Analyses were also performed in stratified groups of children born extremely preterm in the absence or presence of perinatal risk factors that have previously been shown to be associated with volumetric differences at term. Results: We found volumetric decreases in gray and white matter in the temporal lobes, gray matter decreases in the precuneus gyri, and white matter decreases in the anterior cingulum for children born extremely preterm (all p < 0.001, and pfwe < 0.05). Gray and white matter increases were predominantly observed in the right posterior cingulum and occipital lobe (all p < 0.001, and pfwe < 0.05). Of the examined perinatal risk factors, intraventricular hemorrhage grades I-II compared with no intraventricular hemorrhage and patent ductus arteriosus ligation compared with no treated patent ductus arteriosus or patent ductus arteriosus treated with ibuprofen led to volumetric differences at 10 years of age (all p < 0.001, and pfwe < 0.05). Conclusions: Children born extremely preterm exhibit volumetric alterations in a pattern overlapping that previously found at term, where many regions with differences are the main hubs of higher order networks. Some, but not all, risk factors known to be associated with structural alterations at term were associated with alterations at 10 years of age.

Exploring the distribution of grey and white matter brain volumes in extremely preterm children, using magnetic resonance imaging at term age and at 10 years of age.

OBJECTIVES: To investigate differences in brain volumes between children born extremely preterm and term born controls at term age and at 10 years of age. STUDY DESIGN: Children born extremely preterm (EPT), up to 26 weeks and 6 days gestational age, in Stockholm between January 1 2004 to March 31 2007 were included in this population-based cohort study. A total of 45 EPT infants were included at term age and 51 EPT children were included at 10 years of age. There were 27 EPT children included at both time points. Two different control groups were recruited; 15 control infants were included at term age and 38 control children at 10 years of age. The primary outcomes were the grey and white matter volumes. Linear regression, adjusted for intracranial volume and sex, was used. RESULTS: At term age, the extremely preterm infants had significantly smaller grey matter volume compared to the control infants with an adjusted mean difference of 5.0 cm3 and a 95% confidence interval of -8.4 to -1.5 (p = 0.004). At 10 years of age the extremely preterm children had significantly smaller white matter volume compared to the control children with an adjusted mean difference of 6.0 cm3 and a 95% confidence interval of -10.9 to -1.0 (p = 0.010). CONCLUSION: Extremely preterm birth was associated with reduced grey matter volume at term age and reduced white matter volume at 10 years of age compared to term born controls.

Visual-motor integration and fine motor skills at 6½ years of age and associations with neonatal brain volumes in children born extremely preterm in Sweden: a population-based cohort study.

OBJECTIVES: This exploratory study aimed to investigate associations between neonatal brain volumes and visual-motor integration (VMI) and fine motor skills in children born extremely preterm (EPT) when they reached 6½ years of age. SETTING: Prospective population-based cohort study in Stockholm, Sweden, during 3 years. PARTICIPANTS: All children born before gestational age, 27 weeks, during 2004-2007 in Stockholm, without major morbidities and impairments, and who underwent MRI at term-equivalent age. MAIN OUTCOME MEASURES: Brain volumes were calculated using morphometric analyses in regions known to be involved in VMI and fine motor functions. VMI was assessed with The Beery-Buktenica Developmental Test of Visual-Motor Integration-sixth edition and fine motor skills were assessed with the manual dexterity subtest from the Movement Assessment Battery for Children-second edition, at 6½ years. Associations between the brain volumes and VMI and fine motor skills were evaluated using partial correlation, adjusted for total cerebral parenchyma and sex. RESULTS: Out of 107 children born at gestational age <27 weeks, 83 were assessed at 6½ years and 66/83 were without major brain lesions or cerebral palsy and included in the analyses. A representative subsample underwent morphometric analyses: automatic segmentation (n=34) and atlas-based segmentation (n=26). The precentral gyrus was associated with both VMI (r=0.54, P=0.007) and fine motor skills (r=0.54, P=0.01). Associations were also seen between fine motor skills and the volume of the cerebellum (r=0.42, P=0.02), brainstem (r=0.47, P=0.008) and grey matter (r=-0.38, P=0.04). CONCLUSIONS: Neonatal brain volumes in areas known to be involved in VMI and fine motor skills were associated with scores for these two functions when children born EPT without major brain lesions or cerebral palsy were evaluated at 6½ years of age. Establishing clear associations between early brain volume alterations and later VMI and/or fine motor skills could make early interventions possible.

Clinical Implications of Diffuse Excessive High Signal Intensity (DEHSI) on Neonatal MRI in School Age Children Born Extremely Preterm.

OBJECTIVE: Magnetic resonance imaging (MRI) of the brain carried out during the neonatal period shows that 55-80% of extremely preterm infants display white matter diffuse excessive high signal intensity (DEHSI). Our aim was to study differences in developmental outcome at the age of 6.5 years in children born extremely preterm with and without DEHSI. STUDY DESIGN: This was a prospective cohort study of 83 children who were born in Stockholm, Sweden, between 2004 and 2007, born at gestational age of < 27 weeks + 0 days and who underwent an MRI scan of their brain at term equivalent age. The outcome measures at 6.5 years included testing 66 children with the modified Touwen neurology examination, the Movement Assessment Battery for Children 2, the Wechsler Intelligence Scale for Children-Fourth Edition, Beery Visual-motor Integration test-Sixth Edition, and the Strengths and Difficulties Questionnaire. Group-wise comparisons were done between children with and without DEHSI using Student t-test, Mann Whitney U test, Chi square test and regression analysis. RESULTS: DEHSI was detected in 39 (59%) of the 66 children who were assessed at 6.5 years. The presence of DEHSI was not associated with mild neurological dysfunction, scores on M-ABC assessment, cognition, visual-motor integration, or behavior at 6.5 years. CONCLUSION: The presence of qualitatively defined DEHSI on neonatal MRI did not prove to be a useful predictor of long-term impairment in children born extremely preterm.