Attention and regional gray matter development in very preterm children at age 12 years

Objectives: This study examines the selective, sustained, and executive attention abilities of very preterm (VPT) born children in relation to concurrent structural magnetic resonance imaging (MRI) measures of regional gray matter development at age 12 years. Methods: A regional cohort of 110 VPT (≤32 weeks gestation) and 113 full term (FT) born children were assessed at corrected age 12 years on the Test of Everyday Attention-Children. They also had a structural MRI scan that was subsequently analyzed using voxel-based morphometry to quantify regional between-group differences in cerebral gray matter development, which were then related to attention measures using multivariate methods. Results: VPT children obtained similar selective (p=.85), but poorer sustained (p=.02) and executive attention (p=.01) scores than FT children. VPT children were also characterized by reduced gray matter in the bilateral parietal, temporal, prefrontal and posterior cingulate cortices, bilateral thalami, and left hippocampus; and increased gray matter in the occipital and anterior cingulate cortices (family-wise error-corrected

Early brain morphometrics from neonatal MRI predict motor and cognitive outcomes at 2-years corrected age in very preterm infants

Infants born very preterm face a range of neurodevelopmental challenges in cognitive, language, behavioural and/or motor domains. Early accurate identification of those at risk of adverse neurodevelopmental outcomes, through clinical assessment and Magnetic Resonance Imaging (MRI), enables prognostication of outcomes and the initiation of targeted early interventions. This study utilises a prospective cohort of 181 infants born <31 weeks gestation, who had 3T MRIs acquired at 29-35 weeks postmenstrual age and a comprehensive neurodevelopmental evaluation at 2 years corrected age (CA). Cognitive, language and motor outcomes were assessed using the Bayley Scales of Infant and Toddler Development – Third Edition and functional motor outcomes using the Neuro-sensory Motor Developmental Assessment. By leveraging advanced structural MRI pre-processing steps to standardise the data, and the state-of-the-art developing Human Connectome Pipeline, early MRI biomarkers of neurodevelopmental outcomes were identified. Using Least Absolute Shrinkage and Selection Operator (LASSO) regression, significant associations between brain structure on early MRIs with 2-year outcomes were obtained (r = 0.51 and 0.48 for motor and cognitive outcomes respectively) on an independent 25% of the data. Additionally, important brain biomarkers from early MRIs were identified, including cortical grey matter volumes, as well as cortical thickness and sulcal depth across the entire cortex. Adverse outcome on the Bayley-III motor and cognitive composite scores were accurately predicted, with an Area Under the Curve of 0.86 for both scores. These associations between 2-year outcomes and patient prognosis and early neonatal MRI measures demonstrate the utility of imaging prior to term equivalent age for providing earlier commencement of targeted interventions for infants born preterm

Effectiveness-implementation hybrid-2 randomised trial of a collaborative Shared Care Model for Detecting Neurodevelopmental Impairments after Critical Illness in Young Children (DAISY): pilot study protocol

INTRODUCTION In Australia, while paediatric intensive care unit (PICU) mortality has dropped to 2.2%, one in three survivors experience long-term neurodevelopmental impairment, limiting their life-course opportunities. Unlike other high-risk paediatric populations, standardised routine neurodevelopmental follow-up of PICU survivors is rare, and there is limited knowledge regarding the best methods. The present study intends to pilot a combined multidisciplinary, online screening platform and general practitioner (GP) shared care neurodevelopmental follow-up model to determine feasibility of a larger, future study. We will also assess the difference between neurodevelopmental vulnerability and parental stress in two intervention groups and the impact of child, parent, sociodemographic and illness/treatment risk factors on child and parent outcomes. METHODS AND ANALYSIS Single-centre randomised effectiveness-implementation (hybrid-2 design) pilot trial for parents of children aged ≥2 months and <4 years discharged from PICU after critical illness or injury. One intervention group will receive 6 months of collaborative shared care follow-up with GPs (supported by online outcome monitoring), and the other will be offered self-directed screening and education about post-intensive care syndrome and child development. Participants will be followed up at 1, 3 and 6 months post-PICU discharge. The primary outcome is feasibility. Secondary outcomes include neurodevelopmental vulnerability and parental stress. An implementation evaluation will analyse barriers to and facilitators of the intervention. ETHICS AND DISSEMINATION The study is expected to lead to a full trial, which will provide much-needed guidance about the clinical effectiveness and implementation of follow-up models of care for children after critical illness or injury. The Children's Health Queensland Human Research Ethics Committee approved this study. Dissemination of the outcomes of the study is expected via publication in a peer-reviewed journal, presentation at relevant conferences, and via social media, podcast presentations and open-access medical education resources. REGISTRATION DETAILS The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry as 'Pilot testing of a collaborative Shared Care Model for Detecting Neurodevelopmental Impairments after Critical Illness in Young Children' (the DAISY Pilot Study). TRIAL REGISTRATION NUMBER ACTRN12621000799853

Longitudinal cohort study investigating neurodevelopmental and socioemotional outcomes in school-entry aged children after open heart surgery in Australia and New Zealand: the NITRIC follow-up study protocol

Introduction: Despite growing awareness of neurodevelopmental impairments in children with congenital heart disease (CHD), there is a lack of large, longitudinal, population-based cohorts. Little is known about the contemporary neurodevelopmental profile and the emergence of specific impairments in children with CHD entering school. The performance of standardised screening tools to predict neurodevelopmental outcomes at school age in this high-risk population remains poorly understood. The NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial randomised 1371 children <2 years of age, investigating the effect of gaseous nitric oxide applied into the cardiopulmonary bypass oxygenator during heart surgery. The NITRIC follow-up study will follow this cohort annually until 5 years of age to assess outcomes related to cognition and socioemotional behaviour at school entry, identify risk factors for adverse outcomes and evaluate the performance of screening tools. Methods and analysis: Approximately 1150 children from the NITRIC trial across five sites in Australia and New Zealand will be eligible. Follow-up assessments will occur in two stages: (1) annual online screening of global neurodevelopment, socioemotional and executive functioning, health-related quality of life and parenting stress at ages 2–5 years; and (2) face-to-face assessment at age 5 years assessing intellectual ability, attention, memory and processing speed; fine motor skills; language and communication; and socioemotional outcomes. Cognitive and socioemotional outcomes and trajectories of neurodevelopment will be described and demographic, clinical, genetic and environmental predictors of these outcomes will be explored. Ethics and dissemination: Ethical approval has been obtained from the Children’s Health Queensland (HREC/20/QCHQ/70626) and New Zealand Health and Disability (21/NTA/83) Research Ethics Committees. The findings will inform the development of clinical decision tools and improve preventative and intervention strategies in children with CHD. Dissemination of the outcomes of the study is expected via publications in peer-reviewed journals, presentation at conferences, via social media, podcast presentations and medical education resources, and through CHD family partners.Trial registration numberThe trial was prospectively registered with the Australian New Zealand Clinical Trials Registry as ‘Gene Expression to Predict Long-Term Neurodevelopmental Outcome in Infants from the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) Study – A Multicentre Prospective Trial’. Trial registration: ACTRN12621000904875

Behavioural adjustment sequelae in children born very preterm: measurement issues and neonatal neurological correlates.

Background: Children born very preterm are at an elevated risk of behavioural adjustment problems, particularly Attention-Deficit/Hyperactivity Disorder (ADHD) or inattention/hyperactivity difficulties. Importantly, these risks remain even after controlling for the effects of social risk factors correlated with very preterm birth. Behavioural outcomes in follow-up studies of children born very preterm are typically assessed using parent reports only. However, the extent to which behavioural problems are evident across multiple contexts (i.e., parent or teacher report) is not well known. Furthermore, the neonatal neuropathology underlying these behavioural difficulties in this population remains poorly understood. Aims: Three research studies are undertaken primarily to examine: (1) the degree of agreement between parent and teacher reports of child behaviour adjustment, and the extent of situational (parent- or teacher-identified) and pervasive (parent- and teacher-identified) inattention/hyperactivity problems at ages 4, 6, and 9 years among children born very preterm and full-term; (2) to cross-validate the classification of children with situational and pervasive inattention/hyperactivity problems across the ages of 4 to 9, for a clinical diagnosis of ADHD at age 9 years; (3) to document risk of persistent ADHD symptoms between ages 4 and 9 years in children born very preterm, and to examine associations between qualitative measures of neonatal cerebral white matter injury/abnormality and quantitative volumetric measures of cerebral structural development, identified using magnetic resonance imaging (MRI) at term equivalent age, and children’s later risks of persistent symptoms. Persistent ADHD symptoms were defined as behavioural inattention/hyperactivity problems shown at ages 4, 6, and 9, along with meeting the criteria for an ADHD clinical diagnosis at age 9 years. Methods: As part of a prospective longitudinal study, a regional cohort of 110 very preterm (≤ 33 weeks of gestation) and 113 full-term children born between 1998 and 2000 were studied from birth to age 9 years. At term equivalent age, all children born very preterm and 10 children born full-term underwent an MRI scan that was analysed using qualitative measures for cerebral white matter injury/abnormality, and quantitative volumetric techniques with tissue segmentation and regional parcellation for cortical and subcortical grey matter, myelinated and unmyelinated white matter, and cerebrospinal fluid. At ages 4, 6 (corrected for the extent of prematurity), and 9 years (uncorrected), children were screened for behavioural adjustment problems including inattention/hyperactivity symptoms using the parent and teacher rated Strengths and Difficulties Questionnaire (SDQ). At age 9, the Development and Well-Being Assessment (DAWBA) structured psychiatric interview was also completed with primary caregiver and an independent clinical diagnosis of ADHD determined by a child psychiatrist blinded to child’s perinatal history and group status. Results: Agreement between parent and teacher reports regarding child behaviour adjustment was lower for children born very preterm than full-term (mean alternative chance-correlated coefficient, AC₁ = 0.63 vs. 0.80). Across all assessment time-points, very preterm birth was associated with on average a 2-fold increased risk of behavioural inattention/hyperactivity problems. These elevated risks largely reflected high rates of situational symptoms (very preterm = 22.3% − 31.7%; full-term = 10.9% − 16.7%). In contrast, rates of pervasive symptoms were relatively modest (very preterm = 6.8% − 11.5%; full-term = 4.7% − 7.3%). Examination of the predictive validity of inattention/hyperactivity problems identified using parent and teacher reports showed that children exhibiting situational symptoms at ages 4 and 6 were much less likely than those exhibiting pervasive symptoms, for a subsequent clinical diagnosis of ADHD at age 9 years (very preterm = 29% − 47.8% vs. 66.7% − 75%; full-term = 13.3% − 22.2% vs. 33.3% − 40%). Furthermore, receiver operating characteristic curves fitted to the data showed that children born very preterm exhibiting inattention/hyperactivity problems at two or three time-points (area under curve, AUC = .909) have better predictive validity for later ADHD diagnosis, compared to those exhibiting symptoms at age 4 (AUC = .794) or 6 years (AUC = .813) only. Children born very preterm were also at an elevated risk of persistent ADHD symptoms across the ages of 4 to 9 years, with the risk being 5-fold higher than their full-term peers (13.1% vs. 2.8%). Results also revealed possible associations between neonatal neuropathology and later risk of persistent ADHD symptoms. There were no significant linear associations between increasing severity of qualitative neonatal MRI measures of white matter injury/abnormality and very preterm children’s later risk of persistent ADHD symptoms. However, reduction in total cerebral tissue volumes and corresponding increase of cerebrospinal fluid (adjusted for intracranial volume) were significantly associated with increased risk of persistent symptoms in children born very preterm (p = .001). In terms of regional tissue volumes, total cerebral tissues in the dorsal prefrontal region showed the largest volumetric reductions among all the subregions in children born very preterm exhibiting persistent ADHD symptoms, with 3.2 ml (7%) and 8.2 ml (16%) lower tissue volumes than children born very preterm and full-term without persistent symptoms, respectively. Conclusions: Reliance on a single informant to examine child behaviour outcomes at a single time-point may lead to an under- or over-estimation of later ADHD risks. Combining reports from multiple informants and repeated assessments over time may provide better clinical prognostic validity. Children born very preterm are at an increased risk of behavioural inattention/hyperactivity problems during their early school years; although risks of more severe, pervasive problems are relatively modest compared with situational problems. Behavioural adjustment difficulties recognised as early as during preschool age using standardised behaviour screening tools can be a reliable indicator for identifying children born very preterm at risk of subsequent ADHD diagnosis. Finally, study findings suggest that increased risk of ADHD symptoms in children born very preterm can at least in part be accounted for by disturbances to neonatal cerebral growth and maturation

Peer relationship outcomes of school-age children born very preterm

To characterize the friendship networks, peer relationships, and bullying experiences of 12-year-old children born extremely preterm (EPT; 23-27 weeks of gestation), very preterm (VPT; 28-32 weeks of gestation), and full term (FT; 38-41 weeks of gestation), and to identify child characteristics placing children at risk of peer problems.A regional cohort of 44 EPT, 60 VPT, and 109 FT born children were followed prospectively to 12 years of age. The nature of children's close friendships, peer relations, and bullying experiences were assessed using a multimethod approach, including parent, teacher, and child report.Across all measures, children born EPT had more peer social difficulties than children born VPT and FT. They were more likely to report no close friendships (5%-14% EPT vs 0%-3% VPT/FT), dissatisfaction with their peer network (16% vs 1%-2%), and less time interacting face-to-face with friends (16%-23% vs 5%-8%). They were also 3 times more likely to be rated by their parents and teachers as experiencing problems relating to peers (P ≤ .001). In contrast, rates of chronic bullying (≥2 times/week) were similar for EPT and VPT children (12%-14% vs 4% FT). Emotional problems, inattention/hyperactivity, and motor deficits were associated with an increased risk of peer relationship problems, whereas higher body mass index, delayed pubertal development, vision problems, and inattention/hyperactivity problems were associated with frequent bullying.With the exception of bullying, risks of peer social difficulties were greatest among children born EPT. Peer social relationships should be monitored as part of longer term developmental surveillance and support

Social development of children born very preterm: A systematic review

To review systematically studies examining the development of social competence in children born very preterm (VPT) (gestatio