Blood Biomarkers in the Fetally Growth Restricted and Small for Gestational Age Neonate: Associations with Brain Injury.

Fetal growth restriction (FGR) and small for gestational age (SGA) infants have increased risk of mortality and morbidity. Although both FGR and SGA infants have low birthweights for gestational age, a diagnosis of FGR also requires assessments of umbilical artery Doppler, physiological determinants, neonatal features of malnutrition, and in utero growth retardation. Both FGR and SGA are associated with adverse neurodevelopmental outcomes ranging from learning and behavioral difficulties to cerebral palsy. Up to 50% of FGR, newborns are not diagnosed until around the time of birth, yet this diagnosis lacks further indication of the risk of brain injury or adverse neurodevelopmental outcomes. Blood biomarkers may be a promising tool. Defining blood biomarkers indicating an infant's risk of brain injury would provide the opportunity for early detection and therefore earlier support. The aim of this review was to summarize the current literature to assist in guiding the future direction for the early detection of adverse brain outcomes in FGR and SGA neonates. The studies investigated potential diagnostic blood biomarkers from cord and neonatal blood or serum from FGR and SGA human neonates. Results were often conflicting with heterogeneity common in the biomarkers examined, timepoints, gestational age, and definitions of FGR and SGA used. Due to these variations, it was difficult to draw strong conclusions from the results. The search for blood biomarkers of brain injury in FGR and SGA neonates should continue as early detection and intervention is critical to improve outcomes for these neonates.

Effects of fetal growth restriction on the perinatal neurovascular unit and possible treatment targets.

The neurovascular unit (NVU) within the brain is a multicellular unit that synergistically acts to maintain blood-brain barrier function and meet cerebral metabolic demand. Recent studies have indicated disruption to the NVU is associated with neuropathology in the perinatal brain. Infants with fetal growth restriction (FGR) are known to be at increased risk of neurodevelopmental conditions including motor, learning, and behavioural deficits. There are currently no neuroprotective treatments for these conditions. In this review, we analyse large animal studies examining the effects of FGR on the perinatal NVU. These studies show altered vascularity in the FGR brain as well as blood-brain barrier dysfunction due to underlying cellular changes, mediated by neuroinflammation. Neuroinflammation is a key mechanism associated with pathological effects in the FGR brain. Hence, targeting inflammation may be key to preserving the multicellular NVU and providing neuroprotection in FGR. A number of maternal and postnatal therapies with anti-inflammatory components have been investigated in FGR animal models examining targets for amelioration of NVU disruption. Each therapy showed promise by uniquely ameliorating the adverse effects of FGR on multiple aspects of the NVU. The successful implementation of a clinically viable neuroprotective treatment has the potential to improve outcomes for neonates affected by FGR. IMPACT: Disruption to the neurovascular unit is associated with neuropathology in fetal growth restriction. Inflammation is a key mechanism associated with neurovascular unit disruption in the growth-restricted brain. Anti-inflammatory treatments ameliorate adverse effects on the neurovascular unit and may provide neuroprotection.

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.

Umbilical Cord Blood Cell Clearance Post-Infusion in Immune-Competent Children with Cerebral Palsy.

Umbilical cord blood cells have therapeutic potential for neurological disorders, through a paracrine mechanism of action. A greater understanding of the safety and immunological effects of allogeneic donor cord blood cells in the context of a healthy recipient immune system, such as in cerebral palsy, is needed. This study aimed to determine how quickly donor cord blood cells were cleared from the circulation in children with cerebral palsy who received a single intravenous infusion of 12/12 human leucocyte antigen (HLA)-matched sibling cord blood cells. Twelve participants with cerebral palsy aged 2-12 years received cord blood cell infusions as part of a phase I trial of umbilical blood infusion for cerebral palsy. Digital droplet PCR analysis of DNA copy number variants specific to donor and recipient was used to assess donor DNA clearance at five timepoints post-infusion, a surrogate measure of cell clearance. Donor cells were cleared by 3 months post-infusion in 11/12 participants. When detected, donor DNA was at a fraction of 0.01-0.31% of total DNA with no signs of graft-versus-host disease in any participant. The donor DNA clearance times provided by this study have important implications for understanding the safety of allogeneic cord blood cell infusion for cerebral palsy and translational tissue engineering or regenerative medicine research in other disorders.

Neurological examination at 32-weeks postmenstrual age predicts 12-month cognitive outcomes in very preterm-born infants.

BACKGROUND: To determine the diagnostic accuracy of Hammersmith Neonatal Neurological Examination (HNNE) at 30-32 weeks postmenstrual age (PMA, 'Early') and term equivalent age (TEA) in infants born <31 weeks PMA to predict cognitive outcomes at 12 months corrected age (CA). METHODS: Prospective cohort study of 119 infants (73 males; median 28.4 weeks gestational age at birth) who underwent Early and TEA HNNE. At 12 months CA, 104 participants completed Bayley Scales of Infant and Toddler Development, 3rd Edition, (Bayley-III). Optimum cut-off points for each HNNE subscale were determined to establish diagnostic accuracy for predicting adverse cognitive outcomes on the Bayley-III Cognitive Composite Scale (≤85). RESULTS: The best diagnostic accuracy for HNNE total score at 30-32 weeks PMA predicting cognitive impairment occurred at cut-off ≤16.7 (sensitivity (Se) = 71%, specificity (Sp) = 51%). The Abnormal Signs subscale demonstrated the best balance of sensitivity/specificity combination (Se = 71%, Sp = 71%; cut-off ≤1.5). For HNNE at TEA, the total score at cut-off ≤24.5 had Se = 71% and Sp = 47% for predicting cognitive impairment. The Tone Patterns subscale demonstrated the strongest diagnostic accuracy at TEA (Se = 71%, Sp = 63%; cut-off ≤3). CONCLUSIONS: Early and TEA HNNE demonstrated moderate diagnostic accuracy for cognitive outcomes at 12-months CA in infants born <31 weeks gestational age. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry; Trial Registration Number: ACTRN12613000280707; web address of trial: http://www.ANZCTR.org.au/ACTRN12613000280707.aspx . IMPACT: Early Hammersmith Neonatal Neurological Examination (HNNE) assessment at 30-32 weeks postmenstrual age has moderate diagnostic accuracy for cognitive outcomes at 12 months corrected age in infants born <31 weeks gestation. Early HNNE at 30-32 weeks has stronger predictive validity than HNNE at term equivalent age. Early HNNE may provide an early marker for risk-stratification to optimise the planning of post-discharge support and follow-up services for infants born preterm.

Diagnostic accuracy of the Hammersmith Neonatal Neurological Examination in predicting motor outcome at 12 months for infants born very preterm.

AIM: To evaluate the predictive validity of the Hammersmith Neonatal Neurological Examination (HNNE) performed early (at 32 weeks postmenstrual age) and at term-equivalent age (TEA) for 12-month motor outcomes in infants born very preterm. METHOD: This was a diagnostic study using data from a prospective birth cohort. A total of 104 infants born preterm at less than 31 weeks gestational age (males n = 61; mean = 28 weeks 1 day [SD 1 week 6 days], range 23 weeks 1 day-30 weeks 6 days) underwent HNNE early and at TEA, which were scored by comparison with term data. Motor outcomes at 12 months corrected age were determined using the Bayley Scales of Infant and Toddler Development, Third Edition (scores ≤85). Cut-off points were determined using receiver operating characteristic curves. RESULTS: Sixteen (15%) infants born preterm had motor impairment at 12 months corrected age. The HNNE total score cut-off points with the best combination of sensitivity and specificity at early and TEA assessments were 15.2 or lower (sensitivity 77%, 95% confidence interval [CI] = 46%-95%; specificity 74%, 95% CI = 63%-83%) and 23.5 or lower (sensitivity 67%, 95% CI = 38%-88%; specificity 66%, 95% CI = 54%-76%) respectively. The most predictive subscale at the early assessment was reflexes (sensitivity 86%, 95% CI = 57%-98%; specificity 62%, 95% CI = 51%-72%; cut-off point ≤3); at TEA, it was spontaneous movements (sensitivity 73%, 95% CI = 45%-92%; specificity 60%, 95% CI = 48%-70%; cut-off point ≤2). INTERPRETATION: The HNNE provides moderate predictive accuracy for motor outcome at 12 months corrected age in infants born very preterm. Although modest at both time points, early assessment had stronger predictive ability for motor outcomes than TEA when scored using term data, highlighting the value of performing the HNNE earlier in the neonatal period. Performing HNNE earlier may assist risk stratification when planning follow-up services.

Early detection of developmental delay in infants born very preterm or with very low birthweight.

AIM: This study aimed to identify early clinical biomarkers from birth to 16 weeks corrected age to predict typical outcome and developmental delay in infants born very preterm or with very low birthweight. METHOD: A prospective cohort of infants on the Sunshine Coast, Australia, was assessed using the Premie-Neuro Examination, the General Movement Assessment (GMA), the Alberta Infant Motor Scale, and the Infant Sensory Profile 2. At 24 months corrected age, delay was identified using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) and Neurosensory Motor Developmental Assessment (NSMDA). RESULTS: One hundred and four infants were recruited; 79 completed outcome assessments (43 females, 36 males; mean gestational age 30 weeks [SD 1 week 6 days], mean birthweight 1346 g [SD 323]). The incidence of developmental delay (motor or cognitive) was 6.3%. Suboptimal quality of fidgety general movements (temporal organization) at 16 weeks corrected age demonstrated the best predictive accuracy (Bayley-III motor: sensitivity 100% [95% confidence interval {CI} 3-100], specificity 75% [95% CI 63-84], area under the curve [AUC] 0.87); Bayley-III cognitive: sensitivity 100% [95% CI 3-100], specificity 75% [95% CI 64-84], AUC 0.88); NSMDA motor: sensitivity 100% [95% CI 40-100], specificity 81% [95% CI 70-90], AUC 0.91 [95% CI 0.86-0.95]). GMA trajectories that combined abnormal writhing general movements at 4 to 5 weeks corrected age with suboptimal quality of fidgety movement at 16 weeks corrected age were strongly predictive of developmental delay, superior to all other clinical tools, and perinatal and demographic variables investigated (p = 0.01, Akaike information criterion method 18.79 [score corrected for small sample size], accounting for 93% of the cumulative weight). INTERPRETATION: Only the GMA had sufficient predictive validity to act as a biomarker for both conditions: typical outcome and developmental delay (motor or cognitive). GMA trajectories that assessed both writhing general movements at 4 to 5 weeks corrected age and quality of fidgety movement at 16 weeks corrected age predicted adverse neurodevelopmental outcome, accurately differentiating between infants with typical outcomes and those at increased risk for motor or cognitive delay.

Brain Outcomes in Runted Piglets: A Translational Model of Fetal Growth Restriction.

Fetal growth restriction (FGR) is associated with long-term neurodevelopmental disabilities including learning and behavioral disorders, autism, and cerebral palsy. Persistent changes in brain structure and function that are associated with developmental disabilities are demonstrated in FGR neonates. However, the mechanisms underlying these changes remain to be determined. There are currently no therapeutic interventions available to protect the FGR newborn brain. With the wide range of long-term neurodevelopmental disorders associated with FGR, the use of an animal model appropriate to investigating mechanisms of injury in the FGR newborn is crucial for the development of effective and targeted therapies for babies. Piglets are ideal animals to explore how perinatal insults affect brain structure and function. FGR occurs spontaneously in the piglet, unlike other animal models that require surgical or chemical intervention, allowing brain outcomes to be studied without the confounding impacts of experimental interventions. The FGR piglet mimics many of the human pathophysiological outcomes associated with FGR including asymmetrical growth restriction with brain sparing. This review will discuss the similarities observed in brain outcomes between the FGR human and FGR piglet from a magnetic resonance imaging in the living and a histological perspective. FGR piglet studies provide the opportunity to determine and track mechanisms of brain injury in a clinically relevant animal model of FGR. Findings from these FGR piglet studies may provide critical information to rapidly translate neuroprotective interventions to clinic to improve outcomes for newborn babies.

Effect of asthma management with exhaled nitric oxide versus usual care on perinatal outcomes.

INTRODUCTION: Asthma exacerbations in pregnancy are associated with adverse perinatal outcomes. We aimed to determine whether fractional exhaled nitric oxide (F ENO)-based asthma management improves perinatal outcomes compared to usual care. METHODS: The Breathing for Life Trial was a multicentre, parallel-group, randomised controlled trial conducted in six hospital antenatal clinics, which compared asthma management guided by F ENO (adjustment of asthma treatment according to exhaled nitric oxide and symptoms each 6-12 weeks) to usual care (no treatment adjustment as part of the trial). The primary outcome was a composite of adverse perinatal events (preterm birth, small for gestational age (SGA), perinatal mortality or neonatal hospitalisation) assessed using hospital records. Secondary outcomes included maternal asthma exacerbations. Concealed random allocation, stratified by study site and self-reported smoking status was used, with blinded outcome assessment and statistical analysis (intention to treat). RESULTS: Pregnant women with current asthma were recruited; 599 to the control group (608 infants) and 601 to the intervention (615 infants). There were no significant group differences for the primary composite perinatal outcome (152 (25.6%) out of 594 control, 177 (29.4%) out of 603 intervention; OR 1.21, 95% CI 0.94-1.56; p=0.15), preterm birth (OR 1.14, 95% CI 0.78-1.68), SGA (OR 1.06, 95% CI 0.78-1.68), perinatal mortality (OR 3.62, 95% CI 0.80-16.5), neonatal hospitalisation (OR 1.24, 95% CI 0.89-1.72) or maternal asthma exacerbations requiring hospital admission or emergency department presentation (OR 1.19, 95% CI 0.69-2.05). CONCLUSION: F ENO-guided asthma pharmacotherapy delivered by a nurse or midwife in the antenatal clinic setting did not improve perinatal outcomes.

Electroencephalographic studies in growth-restricted and small-for-gestational-age neonates.

Foetal growth restriction (FGR) and being born small for gestational age (SGA) are associated with neurodevelopmental delay. Early diagnosis of neurological damage is difficult in FGR and SGA neonates. Electroencephalography (EEG) has the potential as a tool for the assessment of brain development in FGR/SGA neonates. In this review, we analyse the evidence base on the use of EEG for the assessment of neonates with FGR or SGA. We found consistent findings that FGR/SGA is associated with measurable changes in the EEG that present immediately after birth and persist into childhood. Early manifestations of FGR/SGA in the EEG include changes in spectral power, symmetry/synchrony, sleep-wake cycling, and the continuity of EEG amplitude. Later manifestations of FGR/SGA into infancy and early childhood include changes in spectral power, sleep architecture, and EEG amplitude. FGR/SGA infants had poorer neurodevelopmental outcomes than appropriate for gestational age controls. The EEG has the potential to identify FGR/SGA infants and assess the functional correlates of neurological damage. IMPACT: FGR/SGA neonates have significantly different EEG activity compared to AGA neonates. EEG differences persist into childhood and are associated with adverse neurodevelopmental outcomes. EEG has the potential for early identification of brain impairment in FGR/SGA neonates.

Combined hypothermia and mesenchymal stem cells in animal models of neonatal hypoxic-ischaemic encephalopathy: a systematic review.

BACKGROUND: The objective of this study was to systematically review the literature to determine the effect of combined hypothermia (HTH) and mesenchymal stem cell (MSC) therapy (administered during or immediately before or after HTH) compared with HTH alone on brain injury and neurobehavioural outcomes in animal models of neonatal hypoxic-ischaemic encephalopathy. METHODS: Primary outcomes assessed were neuropathological measures and neurobehavioural measures of brain outcome. Secondary outcomes were brain protein proinflammatory cytokine status. Risk of bias (ROB) was assessed with the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) ROB assessment tool. RESULTS: Of 393 studies identified, 3 studies in postnatal day 7 (P7) male Sprague-Dawley rats met the inclusion criteria. Meta-analyses were undertaken for neuropathological measures (apoptotic cells, astrocytes, microglia), neurobehavioral measures (rotarod test and negative geotaxis), and proinflammatory cytokine levels. Two of the three studies scored low or unclear ROB across all measures. Treatment with HTH-MSCs together significantly improved astrocyte optical density by standardised mean difference (SMD) of 0.71 [95% confidence interval (CI) -1.14, -0.28]. No other measures showed significant differences. CONCLUSIONS: There is insufficient preclinical data to confirm the efficacy of combined HTH-MSC therapy over HTH alone. Future studies should utilise a reporting checklist such as in SYRCLE or Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines to improve reporting standards. IMPACT: Very few articles investigating the use of MSCs for the treatment of hypoxic-ischaemic encephalopathy are clinically relevant. Continuing to publish studies in models of hypoxic-ischaemic encephalopathy without the inclusion of HTH therapy does not progress the field towards improved clinical outcomes. This study shows that HTH and MSC therapy improves measures of astrogliosis. More studies are required to establish the efficacy of HTH and MSCs on measures of neuropathology and neurobehavior. The reporting of preclinical data in this space could be improved by using reporting checklists such as the SYRCLE or ARRIVE tools.

Predictors of Maternal Bonding and Responsiveness for Mothers of Very Preterm Infants.

Identify predictors of maternal bonding and responsiveness for mothers of very preterm infants (< 32 weeks gestational age) at 6 weeks and 12 months corrected-age (CA). Cross-sectional and longitudinal study containing 39 mothers of very preterm infants. At 6 weeks CA maternal self-efficacy made a significant unique contribution to the variance in self-reported maternal bonding and responsiveness (21% and 26%, respectively). At 12 months CA maternal trauma symptoms, depressive symptoms and self-efficacy made a significant unique contribution to the variance in bonding (14%, 9% and 9%, respectively). Maternal self-efficacy made a significant 31% unique contribution to the variance in responsiveness. The combined effects of maternal trauma symptoms, depressive symptoms and self-efficacy at 6 weeks CA predicted maternal responsiveness at 12 months CA (p = .042). Supporting maternal self-efficacy is key to facilitating bonding and responsiveness up to 12 months CA following a very preterm birth.Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12612000194864.

Early clinical and MRI biomarkers of cognitive and motor outcomes in very preterm born infants.

BACKGROUND: This study aimed to identify which MRI and clinical assessments, alone or in combination, from (i) early (32 weeks postmenstrual age, PMA), (ii) term equivalent age (TEA) and (iii) 3 months corrected age (CA) are associated with motor or cognitive outcomes at 2 years CA in infants born <31 weeks gestation. METHODS: Prospective cohort study of 98 infants who underwent early and TEA MRI (n = 59 males; median birth gestational age 28 + 5 weeks). Hammersmith Neonatal Neurological Examination (HNNE), NICU Neonatal Neurobehavioural Scale and General Movements Assessment (GMs) were performed early and at TEA. Premie-Neuro was performed early and GMs, Test of Infant Motor Performance and visual assessment were performed at TEA and 3 months CA. Neurodevelopmental outcomes were determined using Bayley Scales of Infant and Toddler Development 3rd edition. RESULTS: The best combined motor outcome model included 3-month GMs (ß = -11.41; 95% CI = -17.34, -5.49), TEA MRI deep grey matter score (ß = -6.23; 95% CI = -9.47, -2.99) and early HNNE reflexes (ß = 3.51; 95% CI = 0.86, 6.16). Combined cognitive model included 3-month GMs (ß = -10.01; 95% CI = -15.90, -4.12) and TEA HNNE score (ß = 1.33; 95% CI = 0.57, 2.08). CONCLUSION: Early neonatal neurological assessment improves associations with motor outcomes when combined with term MRI and 3-month GMs. Term neurological assessment combined with 3-month GMs improves associations with cognitive outcomes. IMPACT: We present associations between 32- and 40-week MRI, comprehensive clinical assessments and later 2-year motor and cognitive outcomes for children born <31 weeks gestation. MRI and clinical assessment of motor, neurological and neurobehavioural function earlier than term equivalent age in very preterm infants is safe and becoming more available in clinical settings. Most of these children are discharged from hospital before term age and so completing assessments prior to discharge can assist with follow up. MRI and neurological assessment prior to term equivalent age while the child is still in hospital can provide earlier identification of children at highest risk of adverse outcomes and guide follow-up screening and intervention services.

Clinical tools used in young infants born very preterm to predict motor and cognitive delay (not cerebral palsy): a systematic review.

AIM: This systematic review evaluates the accuracy of clinical tools used at a corrected age of 6 months or younger to predict motor and cognitive delay (not cerebral palsy) at 24 months' corrected age, in infants born very preterm. METHOD: Six databases were searched. Quality was evaluated using the Quality Assessment of Diagnostic Accuracy Studies tool. Predictive analysis included calculation of sensitivity and specificity, inspection of summary receiver operating characteristics curves, and bivariate meta-analysis. RESULTS: Six assessments were identified in 10 studies of 992 infants. Overall prevalence of motor delay was 13.8% and cognitive delay was 11.7%. Methodological quality was variable for patient selection, reference standard, flow, and timing. All studies had a low risk of bias for the index test. General Movement Assessment (GMA) predicted motor and cognitive outcomes with good accuracy for mild, moderate, and severe delays (fidgety age: pooled diagnostic odds ratio=12.3 [5.9-29.8]; hierarchical summary receiver operating characteristics curve=0.733). The Hammersmith Infant Neurological Examination (HINE) demonstrated excellent predictive accuracy for severe motor delay (3mo and 6mo; sensitivity 93% [68-100%], specificity 100% [96-100%]) but showed limited ability to predict milder delays. INTERPRETATION: In the population of infants born very preterm, few assessment tools used at 6 months or younger corrected age have proven predictive accuracy for cognitive and motor delay at 24 months' corrected age. Only the GMA and HINE demonstrated useful predictive validity. WHAT THIS PAPER ADDS: General movements have predictive validity for both motor and cognitive dysfunction in infants born very preterm. The Hammersmith Infant Neurological Examination showed the highest predictive accuracy for severe motor delay. The General Movement Assessment was the best tool to predict mild-to-moderate motor and cognitive delays.

Brain microstructure and morphology of very preterm-born infants at term equivalent age: Associations with motor and cognitive outcomes at 1 and 2 years.

Very preterm-born infants are at risk of adverse neurodevelopmental outcomes. Brain magnetic resonance imaging (MRI) at term equivalent age (TEA) can probe tissue microstructure and morphology, and demonstrates potential in the early prediction of outcomes. In this study, we use the recently introduced fixel-based analysis method for diffusion MRI to investigate the association between microstructure and morphology at TEA, and motor and cognitive development at 1 and 2 years corrected age (CA). Eighty infants born <31 weeks' gestation successfully underwent diffusion MRI (3T; 64 directions; b â€‹= â€‹2000s/mm2) at term equivalent age, and had neurodevelopmental follow-up using the Bayley-III motor and cognitive assessments at 1 year (n â€‹= â€‹78) and/or 2 years (n â€‹= â€‹76) CA. Diffusion MRI data were processed using constrained spherical deconvolution (CSD) and aligned to a study-specific fibre orientation distribution template, yielding measures of fibre density (FD), fibre-bundle cross-section (FC), and fibre density and bundle cross-section (FDC). The association between FD, FC, and FDC at TEA, and motor and cognitive composite scores at 1 and 2 years CA, and change in composite scores from 1 to 2 years, was assessed using whole-brain fixel-based analysis. Additionally, the association between diffusion tensor imaging (DTI) metrics (fractional anisotropy FA, mean diffusivity MD, axial diffusivity AD, radial diffusivity RD) and outcomes was investigated. Motor function at 1 and 2 years CA was associated with CSD-based measures of the bilateral corticospinal tracts and corpus callosum. Cognitive function was associated with CSD-based measures of the midbody (1-year outcomes only) and splenium of the corpus callosum, as well as the bilateral corticospinal tracts. The change in motor/cognitive outcomes from 1 to 2 years was associated with CSD-based measures of the splenium of the corpus callosum. Analysis of DTI-based measures showed overall less extensive associations. Post-hoc analysis showed that associations were weaker for 2-year outcomes than they were for 1-year outcomes. Infants with better neurodevelopmental outcomes demonstrated higher FD, FC, and FDC at TEA, indicating better information transfer capacity which may be related to increased number of neurons, increased myelination, thicker bundles, and/or combinations thereof. The fibre bundles identified here may serve as the basis for future studies investigating the predictive ability of these metrics.

Predicting motor outcome in preterm infants from very early brain diffusion MRI using a deep learning convolutional neural network (CNN) model.

BACKGROUND AND AIMS: Preterm birth imposes a high risk for developing neuromotor delay. Earlier prediction of adverse outcome in preterm infants is crucial for referral to earlier intervention. This study aimed to predict abnormal motor outcome at 2 years from early brain diffusion magnetic resonance imaging (MRI) acquired between 29 and 35 weeks postmenstrual age (PMA) using a deep learning convolutional neural network (CNN) model. METHODS: Seventy-seven very preterm infants (born <31 weeks gestational age (GA)) in a prospective longitudinal cohort underwent diffusion MR imaging (3T Siemens Trio; 64 directions, b â€‹= â€‹2000 â€‹s/mm2). Motor outcome at 2 years corrected age (CA) was measured by Neuro-Sensory Motor Developmental Assessment (NSMDA). Scores were dichotomised into normal (functional score: 0, normal; n â€‹= â€‹48) and abnormal scores (functional score: 1-5, mild-profound; n â€‹= â€‹29). MRIs were pre-processed to reduce artefacts, upsampled to 1.25 â€‹mm isotropic resolution and maps of fractional anisotropy (FA) were estimated. Patches extracted from each image were used as inputs to train a CNN, wherein each image patch predicted either normal or abnormal outcome. In a postprocessing step, an image was classified as predicting abnormal outcome if at least 27% (determined by a grid search to maximise the model performance) of its patches predicted abnormal outcome. Otherwise, it was considered as normal. Ten-fold cross-validation was used to estimate performance. Finally, heatmaps of model predictions for patches in abnormal scans were generated to explore the locations associated with abnormal outcome. RESULTS: For the identification of infants with abnormal motor outcome based on the FA data from early MRI, we achieved mean sensitivity 70% (standard deviation SD 19%), mean specificity 74% (SD 39%), mean AUC (area under the receiver operating characteristic curve) 72% (SD 14%), mean F1 score of 68% (SD 13%) and mean accuracy 73% (SD 19%) on an unseen test data set. Patch-based prediction heatmaps showed that the patches around the motor cortex and somatosensory regions were most frequently identified by the model with high precision (74%) as a location associated with abnormal outcome. Part of the cerebellum, and occipital and frontal lobes were also highly associated with abnormal NSMDA/motor outcome. DISCUSSION/CONCLUSION: This study established the potential of an early brain MRI-based deep learning CNN model to identify preterm infants at risk of a later motor impairment and to identify brain regions predictive of adverse outcome. Results suggest that predictions can be made from FA maps of diffusion MRIs well before term equivalent age (TEA) without any prior knowledge of which MRI features to extract and associated feature extraction steps. This method, therefore, is suitable for any case of brain condition/abnormality. Future studies should be conducted on a larger cohort to re-validate the robustness and effectiveness of these models.

Body composition in very preterm infants before discharge is associated with macronutrient intake.

Very preterm infants experience poor postnatal growth relative to intra-uterine growth rates but have increased percentage body fat (%fat). The aim of the present study was to identify nutritional and other clinical predictors of infant %fat, fat mass (FM) (g) and lean mass (LM) (g) in very preterm infants during their hospital stay. Daily intakes of protein, carbohydrate, lipids and energy were recorded from birth to 34 weeks postmenstrual age (PMA) in fifty infants born <32 weeks. Clinical illness variables and anthropometric data were also collected. Body composition was assessed at 34-37 weeks PMA using the PEA POD Infant Body Composition System. Multiple regression analysis was used to identify independent predictors of body composition (%fat, FM or LM). Birth weight, birth weight z-score and PMA were strong positive predictors of infant LM. After adjustment for these factors, the strongest nutrient predictors of LM were protein:carbohydrate ratios (102-318 g LM/0·1 increase in ratio, P = 0·006-0·015). Postnatal age (PNA) and PMA were the strongest predictors of infant FM or %fat. When PNA and PMA were accounted for a higher intake of energy (-1·41 to -1·61 g FM/kJ per kg per d, P = 0·001-0·012), protein (-75·5 to -81·0 g FM/g per kg per d, P = 0·019-0·038) and carbohydrate (-27·2 to -30·0 g FM/g per kg per d, P = 0·012-0·019) were associated with a lower FM at 34-37 weeks PMA. Higher intakes of energy, protein and carbohydrate may reduce fat accumulation in very preterm infants until at least 34-37 weeks PMA.

Neuropathology in intrauterine growth restricted newborn piglets is associated with glial activation and proinflammatory status in the brain.

BACKGROUND: The fetal brain is particularly vulnerable to intrauterine growth restriction (IUGR) conditions evidenced by neuronal and white matter abnormalities and altered neurodevelopment in the IUGR infant. To further our understanding of neurodevelopment in the newborn IUGR brain, clinically relevant models of IUGR are required. This information is critical for the design and implementation of successful therapeutic interventions to reduce aberrant brain development in the IUGR newborn. We utilise the piglet as a model of IUGR as growth restriction occurs spontaneously in the pig as a result of placental insufficiency, making it a highly relevant model of human IUGR. The purpose of this study was to characterise neuropathology and neuroinflammation in the neonatal IUGR piglet brain. METHODS: Newborn IUGR (< 5th centile) and normally grown (NG) piglets were euthanased on postnatal day 1 (P1; < 18 h) or P4. Immunohistochemistry was utilised to examine neuronal, white matter and inflammatory responses, and PCR for cytokine analysis in parietal cortex of IUGR and NG piglets. RESULTS: The IUGR piglet brain displayed less NeuN-positive cells and reduced myelination at both P1 and P4 in the parietal cortex, indicating neuronal and white matter disruption. A concurrent decrease in Ki67-positive proliferative cells and increase in cell death (caspase-3) in the IUGR piglet brain was also apparent on P4. We observed significant increases in the number of both Iba-1-positive microglia and GFAP-positive astrocytes in the white matter in IUGR piglet brain on both P1 and P4 compared with NG piglets. These increases were associated with a change in activation state, as noted by altered glial morphology. This inflammatory state was further evident with increased expression levels of proinflammatory cytokines (interleukin-1ß, tumour necrosis factor-α) and decreased levels of anti-inflammatory cytokines (interleukin-4 and -10) observed in the IUGR piglet brains. CONCLUSIONS: These findings suggest that the piglet model of IUGR displays the characteristic neuropathological outcomes of neuronal and white matter impairment similar to those reported in the IUGR human brain. The activated glial morphology and elevated proinflammatory cytokines is indicative of an inflammatory response that may be associated with neuronal damage and white matter disruption. These findings support the use of the piglet as a pre-clinical model for studying mechanisms of altered neurodevelopment in the IUGR newborn.

A Randomized Trial of Baby Triple P for Preterm Infants: Child Outcomes at 2 Years of Corrected Age.

OBJECTIVE: To determine the efficacy of a hospital-based intervention that transitions into existing community support, in enhancing developmental outcomes at 2 years of corrected age in infants born at less than 32 weeks. STUDY DESIGN: In total, 323 families of 384 infants born <32 weeks were randomized to receive intervention or care-as-usual. The intervention teaches parents coping skills, partner support, and effective parenting strategies over 4 hospital-based and 4 home-phone sessions. At 2 years of corrected age maternally reported child behavior was assessed by the Infant and Toddler Social Emotional Adjustment Scale. Observed child behavior was coded with the Revised Family Observation Schedule. Cognitive, language, and motor skills were assessed with the Bayley Scales of Infant and Toddler Development III. RESULTS: Mean gestational age of infants was 28.5 weeks (SD = 2.1), and mothers' mean age was 30.6 years (SD = 5.8). A total of 162 families (n = 196 infants) were allocated to intervention and 161 families (n = 188 infants) received care-as-usual. There was no significant adjusted difference between treatment groups on dysregulation (0.2; 95% CI -2.5 to 3.0, P = .9) externalizing (0.3; 95% CI -1.6 to 2.2, P = .8), internalizing (-1.5; 95% CI -4.3 to 1.3, P = .3), observed aversive (0.00; -0.04 to 0.04, P = .9), or nonaversive behavior (-0.01; 95% CI -0.05 to 0.03, P = .7). Intervention children scored significantly higher on cognition (3.5; 95% CI 0.2-6.8, P = .04) and motor skill (5.5; 95% CI 2.5-8.4, P < .001), and approached significance on language (3.8; 95% CI -0.3 to 7.9, P = .07). CONCLUSIONS: Baby Triple P for Preterm Infants increases cognitive and motor skills but does not impact behavior. The results are evidence that hospital-based interventions can improve some developmental outcomes for infants <32 weeks. TRIAL REGISTRATION: ACTRN 12612000194864.

Therapeutic potential to reduce brain injury in growth restricted newborns.

Brain injury in intrauterine growth restricted (IUGR) infants is a major contributing factor to morbidity and mortality worldwide. Adverse outcomes range from mild learning difficulties, to attention difficulties, neurobehavioral issues, cerebral palsy, epilepsy, and other cognitive and psychiatric disorders. While the use of medication to ameliorate neurological deficits in IUGR neonates has been identified as warranting urgent research for several years, few trials have been reported. This review summarises clinical trials focusing on brain protection in the IUGR newborn as well as therapeutic interventions trialled in animal models of IUGR. Therapeutically targeting mechanisms of brain injury in the IUGR neonate is fundamental to improving long-term neurodevelopmental outcomes. Inflammation is a key mechanism in neonatal brain injury; and therefore an appealing target. Ibuprofen, an anti-inflammatory drug currently used in the preterm neonate, may be a potential therapeutic candidate to treat brain injury in the IUGR neonate. To better understand the potential of ibuprofen and other therapeutic agents to be neuroprotective in the IUGR neonate, long-term follow-up information of neurodevelopmental outcomes must be studied. Where agents such as ibuprofen are shown to be effective, have a good safety profile and are relatively inexpensive, they can be widely adopted and lead to improved outcomes.