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Aim: To compare trajectories of social functioning in peer problems and prosocial behavior from 5 to 13 years between individuals born very preterm (VPT) and full-term (FT)., Methods: Participants were from the Victorian Infant Brain Study (VIBeS) longitudinal cohort, consisting of 224 individuals born VPT and 77 born FT recruited at birth. Social functioning was measured using the parent-rated Strengths and Difficulties Questionnaire (SDQ) peer problems and prosocial behavior subscales at 5, 7, and 13 years' corrected age. Multilevel mixed effects models were fitted., Results: Peer problems increased with age (adjusted mean difference per year = 0.04, 95% confidence interval [CI] = 0.01, 0.07, p = 0.02), with higher peer problems in the VPT compared with the FT group (adjusted mean difference between groups = 0.46, 95% CI = 0.06, 0.86, p = 0.02). Prosocial behavior increased from early to middle childhood and decreased approaching adolescence, but was similar between VPT and FT groups (adjusted mean difference between groups = -0.05, 95% CI = -0.50, 0.40, p = 0.82)., Conclusion: Children born VPT are at greater risk for peer problems than FT peers and may benefit from receiving greater early social support., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Associations of neonatal infection with brain growth and later neurodevelopmental outcomes in very preterm (VP) infants are unclear. This study aimed to assess associations of neonatal sepsis in VP infants with (1) brain growth from term-equivalent age to 13 years; and (2) 13-year brain volume and neurodevelopmental outcomes., Methods: 224 infants born VP ( < 30 weeks' gestation/<1250 g birthweight) were recruited. Longitudinal brain volumes for 68 cortical and 14 subcortical regions were derived from MRI at term-equivalent, 7 and/or 13 years of age for 216 children (79 with neonatal sepsis and 137 without). 177 children (79%) had neurodevelopmental assessments at age 13. Of these, 63 with neonatal sepsis were compared with 114 without. Brain volumetric growth trajectories across time points were compared between sepsis and no-sepsis groups using mixed effects models. Linear regressions compared brain volume and neurodevelopmental outcome measures at 13 years between sepsis and no sepsis groups., Results: Growth trajectories were similar and there was little evidence for differences in brain volumes or neurodevelopmental domains at age 13 years between those with or without sepsis., Conclusions: Neonatal sepsis in children born VP does not appear to disrupt subsequent brain development, or to have functional consequences in early adolescence., Impact Statement: Neonatal sepsis has been associated with poorer short-term neurodevelopmental outcomes and reduced brain volumes in very preterm infants. This manuscript provides new insights into the long-term brain development and neurodevelopmental outcomes of very preterm-born children who did or did not have neonatal sepsis. We found that regional brain volumes up to 13 years, and neurodevelopmental outcomes at age 13, were similar between those with and without neonatal sepsis. The links between neonatal sepsis and long-term neurodevelopment remain unclear., (© 2024. The Author(s).)

Background: Limited serial neuroimaging studies use magnetic resonance imaging (MRI) to define the evolution of hypoxic-ischemic insults to the brain of term infants and encompass both the primary injury and its secondary impact on cerebral development. The optimal timing of MRI to fully evaluate the impact of hypoxic-ischemic encephalopathy on brain development and associated neurodevelopmental sequelae remains unknown., Methods: Goals: (a) review literature related to serial neuroimaging in term infants with HIE; (b) describe pilot data in two infants with HIE treated with therapeutic hypothermia who had a brain injury at day 3-5 and underwent four additional MRIs over the next 12 weeks of life and developmental evaluation at 24 months of age., Results: Early MRI defines primary injury on diffusion-weighted imaging, yet the full impact may not be fully apparent until after 1 month of life., Conclusion: The full impact of an ischemic injury on the neonatal brain may not be fully visible until several weeks after the initial insult. This suggests the benefit of obtaining later time points for MRI to fully define the extent of injury and its neurodevelopmental impact., Impact: Few studies inform the nature of the evolution of brain injury with hypothermia in HIE, limiting understanding of potential neuroprotection. MRI is the standard of care for prognosis in infants with HIE, however timing for optimal prognostic prediction remains unclear. Insights from MRI after the first week of life may assist in defining the full extent of brain injury and prognostic significance. A pilot study using five MRI timepoints up to 3 months of age, is presented. More data is required with a systematic evaluation of the impact of early brain injury on brain development in term infants with HIE following TH., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: This study aimed to describe the family psychosocial experience in a level-III neonatal intensive care unit (NICU), and to assess how it evolved after rollout of an educational smartphone application (App) called "My Brigham Baby.", Study Design: We surveyed 25 NICU parents pre-App rollout (before coronavirus disease 2019 [COVID-19] pandemic) and 25 parents post-App rollout (during pandemic). Collected data included parental self-reported discharge readiness, symptoms of stress and anxiety, and parenting skill confidence. Survey scores were assessed as total or mean scores, and by category of severity., Results: Pre-and post-App parents had comparable demographics, and their infants had similar clinical characteristics during their NICU stay. Discharge readiness differed by group status ( p  = 0.02) and was characterized by a greater frequency in being "very ready" for discharge among the post-App rollout parent group compared with the pre-App group (56 vs. 20%, p  = 0.027), and parenting confidence shifted toward more optimal scores post-App rollout. Parental stress and anxiety symptoms did not significantly differ between groups despite possible stress contagion from the COVID-19 pandemic., Conclusion: This pilot study suggests that technology Apps are feasible interventions within NICU settings and may enhance parental experiences related to NICU hospitalization., Key Points: · Parents' experience increased psychological distress during the time their infant is cared for in the NICU, which has downstream consequences for the family unit.. · In our study, surveyed parents reported higher discharge readiness and parenting confidence shifted toward improvement after rollout of a family education and support smartphone application in a level-III NICU.. · This pilot study suggests that technology applications are feasible interventions that might enhance parental experiences during NICU hospitalization.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: This study aimed to describe the evolution of amplitude-integrated electroencephalography (aEEG) in neonatal encephalopathy (NE) during therapeutic hypothermia (TH) and evaluate the association between aEEG parameters and magnetic resonance imaging (MRI) injury., Study Design: aEEG data of infants who underwent TH were reviewed for background, sleep wake cycling (SWC), and seizures. Conventional electroencephalography (cEEG) background was assessed from the reports. Discordance of background on aEEG and cEEG was defined if there was a difference in the severity of the background. MRI injury (total score ≥ 5) was assessed by using the Weeke scoring system., Results: A total of 46 infants were included; 23 (50%) with mild NE and 23 (50%) with moderate to severe NE. Comparing mild NE with moderate to severe NE, the initial aEEG background differed with more mild being continuous (70 vs. 52%), with fewer being discontinuous (0 vs. 22%) and flat tracing (0 vs. 4%), whereas burst suppression (4 vs. 4%) and low voltage (26 vs. 18%) did not differ. There was a notably common discordance between the background assessment on cEEG with aEEG in 82% with continuous and 40% low voltage aEEG background. MRI abnormalities were identified in four infants with mild NE and seven infants with moderate to severe NE. MRI injury was associated with aEEG seizures in infants with moderate to severe NE., Conclusion: aEEG seizures are useful to predict MRI injury in moderate to severe NE infants. There is a large discrepancy between aEEG, cEEG, and MRI in neonates treated by TH., Key Points: · MRI injury was identified in 29% of moderate NE infants and in 50% of severe NE infants.. · aEEG seizures were associated with MRI injury in the moderate to severe NE infants.. · MRI injury was identified in 16% infants with mild NE.. · Mild NE infants with normal aEEG were unlikely to have MRI injury.. · There was a large discrepancy between aEEG, cEEG, and MRI in infants treated by TH.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: The role of music in the NICU continues to evolve, with recent studies documenting the positive impact of music therapy for hospitalized infants and families. With many potential benefits and no substantial adverse effects reported to date in medically stable infants, we aimed to create a clinical guideline to integrate this therapy into the NICU operations., Methods: we launched and implemented a pilot music therapy clinical program within a subunit of a level-III NICU, building upon available evidence., Results: In this report, we describe our experience with initial program development and early outcomes in terms of population served, frequency of music therapy, and therapeutic modalities employed to implement service delivery., Conclusion: we highlight the importance of establishing practices that are aligned with currently available data and recommendations, in order to facilitate delivery of a safe, evidence-based, meaningful therapeutic experience with monitoring of preliminary effects of the therapy on all those involved in the experience.

Early life experiences can exert a significant influence on cortical and cognitive development. Very preterm birth exposes infants to several adverse environmental factors during hospital admission, which affect cortical architecture. However, the subsequent consequence of very preterm birth on cortical growth from infancy to adolescence has never been defined; despite knowledge of critical periods during childhood for establishment of cortical networks. Our aims were to: chart typical longitudinal cortical development and sex differences in cortical development from birth to adolescence in healthy term-born children; estimate differences in cortical development between children born at term and very preterm; and estimate differences in cortical development between children with normal and impaired cognition in adolescence. This longitudinal cohort study included children born at term (≥37 weeks' gestation) and very preterm (<30 weeks' gestation) with MRI scans at ages 0, 7 and 13 years (n = 66 term-born participants comprising 34 with one scan, 18 with two scans and 14 with three scans; n = 201 very preterm participants comprising 56 with one scan, 88 with two scans and 57 with three scans). Cognitive assessments were performed at age 13 years. Cortical surface reconstruction and parcellation were performed with state-of-the-art, equivalent MRI analysis pipelines for all time points, resulting in longitudinal cortical volume, surface area and thickness measurements for 62 cortical regions. Developmental trajectories for each region were modelled in term-born children, contrasted between children born at term and very preterm, and contrasted between all children with normal and impaired cognition. In typically developing term-born children, we documented anticipated patterns of rapidly increasing cortical volume, area and thickness in early childhood, followed by more subtle changes in later childhood, with smaller cortical size in females than males. In contrast, children born very preterm exhibited increasingly reduced cortical volumes, relative to term-born children, particularly during ages 0-7 years in temporal cortical regions. This reduction in cortical volume in children born very preterm was largely driven by increasingly reduced cortical thickness rather than area. This resulted in amplified cortical volume and thickness reductions by age 13 years in individuals born very preterm. Alterations in cortical thickness development were found in children with impaired language and memory. This study shows that the neurobiological impact of very preterm birth on cortical growth is amplified from infancy to adolescence. These data further inform the long-lasting impact on cortical development from very preterm birth, providing broader insights into neurodevelopmental consequences of early life experiences., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Brain injury is highly associated with preterm birth. Complications of prematurity, including spontaneous or necrotizing enterocolitis (NEC)-associated intestinal perforations, are linked to lifelong neurologic impairment, yet the mechanisms are poorly understood. Early diagnosis of preterm brain injuries remains a significant challenge. Here, we identified subventricular zone echogenicity (SVE) on cranial ultrasound in preterm infants following intestinal perforations. The development of SVE was significantly associated with motor impairment at 2 years. SVE was replicated in a neonatal mouse model of intestinal perforation. Examination of the murine echogenic subventricular zone (SVZ) revealed NLRP3-inflammasome assembly in multiciliated FoxJ1 + ependymal cells and a loss of the ependymal border in this postnatal stem cell niche. These data suggest a mechanism of preterm brain injury localized to the SVZ that has not been adequately considered. Ultrasound detection of SVE may serve as an early biomarker for neurodevelopmental impairment after inflammatory disease in preterm infants., Competing Interests: Declaration of interests E.J.B. and S.G.G. are scientific cofounders at Tellus Therapeutics—a startup company developing therapies for neonatal brain injury. There is no intellectual property associated with this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Purpose: White matter injury in infants born preterm is associated with adverse neurodevelopmental outcomes, depending on the extent and location. White matter injury can be visualized with MR imaging in the initial weeks following preterm birth but is more commonly defined at term-equivalent-age MR imaging. Our aim was to see how white matter injury detection in MR imaging compares between the 2 time points., Materials and Methods: This study compared white matter injury on early brain MR imaging (30-34 weeks' postmenstrual age) with white matter injury assessment at term-equivalent (37-42 weeks) MR imaging, using 2 previously published and standardized scoring systems, in a cohort of 30 preterm infants born at <33 weeks' gestational age., Results: There was a strong association between the systematic assessments of white matter injury at the 2 time points ( P  = .007) and the global injury severity ( P  < .001)., Conclusions: Although the optimal timing to undertake neuroimaging in the preterm infant remains to be determined, both early (30-34 weeks) and term-equivalent MR imaging provide valuable information on white matter injury and the risk of associated sequelae., (© 2024 by American Journal of Neuroradiology.)

Background: The preterm infants are at risk of cerebellar injury and the risk factors for necrotizing enterocolitis (NEC) associated cerebellar injury are not fully understood., Aim: Determine the risk factors of cerebellar injury in infants with surgical necrotizing enterocolitis (NEC)., Methods: Retrospective study compared clinical/pathological information between surgical NEC infants with and those without cerebellar injury detected on brain MRI obtained at term equivalent age. Cerebellar Injury patterns that we identified on MRI brain were cerebellar hemorrhage, siderosis and/or cerebellar volume loss., Results: Cerebellar injury (21/65, 32.3%) in preterm infants with NEC was associated with patent ductus arteriosus (PDA) (18/21(85.7%) vs. 25/44(56.8%); p = 0.021), blood culture positive sepsis (13/21 (61.9%) vs. 11/44 (25%); p = 0.004) following NEC, predominantly grew gram positive bacteria (9/21(42.9%) vs. 4/44(9.1%); p = 0.001), greater red cell transfusion, higher rates of cholestasis following NEC and differences in intestinal histopathology (more hemorrhagic and reparative lesions) on univariate analysis. Those with cerebellar injury had higher grade white matter injury (14/21 (66.7%) vs. 4/44(9.1%) p = 0.0005) and higher-grade ROP (70.6% vs. 38.5%; p = 0.027) than those without cerebellar injury.On multilogistic regression, the positive blood culture sepsis (OR 3.9, CI 1.1-13.7, p = 0.03), PDA (OR 4.5, CI 1.0-19.9, p = 0.04) and severe intestinal pathological hemorrhage (grade 3-4) (OR 16.9, CI 2.1-135.5, p = 0.007) were independently associated with higher risk of cerebellar injury., Conclusion: Preterm infants with surgical NEC with positive blood culture sepsis, PDA, and severe intestinal hemorrhagic lesions (grade 3-4) appear at greater risk for cerebellar injury.

As the first extra-uterine setting for hospitalized infants, the neonatal intensive care unit (NICU) environment can make a lasting impact on their long-term neurodevelopment. This impact is likely mediated through both specific characteristics of the physical design of the care environment, as well as the experiences that occur within this environment. Recent studies document many established benefits of single-family rooms (SFRs). However, there is concern that infants who spend a prolonged time in SFRs without their parents being intimately involved in their care have reduced opportunities for meaningful experiences, with possible adverse consequences. The purpose of this report is to share an example of an application of the family-centered developmental care model through a hybrid NICU design, inclusive of both SFRs and semi-private bays. In this paper, we empirically describe the physical and operational considerations of a hybrid model, outline the strengths and challenges of this approach, and discuss implications for patients, families, and professionals., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Children born very preterm (VP) remain at risk for long-term neurodevelopmental impairment. Patterns of brain growth and injury, and how early neuropromotive therapies might mitigate developmental risk in VP infants remain insufficiently understood., Methods: This is a prospective cohort study of VP infants born at/before 32 weeks gestation. The study will enroll n  = 75 consecutively-born VP infants in a level-III NICU. Exposed infants will be categorized into two groups (group 1: low-risk, n  = 25 or group 2: high-risk, n  = 25) based on the degree of neurological injury on early brain magnetic resonance imaging (MRI) at enrollment. Infants in the low-risk group (i.e., without significant injury defined as intraventricular hemorrhage with dilation, moderate or severe white matter injury, or cerebellar hemorrhage) will receive neurodevelopmental support utilizing the Supporting and Enhancing NICU Sensory Experiences (SENSE) program, while infants in the high-risk group (with neurological injury) will receive more intensive neurorehabilitative support (SENSE-plus). Age-specific, tailored sensory experiences will be facilitated contingently, preferentially by the infant's family with coaching from NICU staff. VP infants in exposure groups will undergo a brain MRI approximately every 2 weeks from enrollment until term-equivalent to monitor brain growth and evolution of injury. Exposed infants will be compared with a reference group (group 3: n  = 25), i.e. VP infants whose families decline initial enrollment in SENSE, and subsequently undergo a term-equivalent brain MRI for other purposes. The primary aim of this study is characterization of term-equivalent brain growth and development among VP infants receiving NICU-based neuropromotive interventions compared to VP infants receiving the standard of care. Secondary aims include defining the timing and factors associated with total and regional brain growth on serial brain MRI among VP infants, (Aim 2), and using early imaging to tailor developmental intervention in the NICU while exploring associations with outcomes in VP infants at discharge and at two years corrected age (Aim 3)., Discussion: This study will address gaps in understanding patterns of brain growth and injury drawing on serial MRI of hospitalized VP infants. These data will also explore the impact of intensive, tailored neuropromotive support delivered prior to term-equivalent on child and family outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Erdei, Cherkerzian, Pineda and Inder.)

Background: Preterm birth adversely impacts brain development and contributes to neurodevelopmental impairment; the temporal lobe may be particularly vulnerable to the impact of very preterm (VP) birth. Yet, no prior magnetic resonance imaging (MRI) scoring system incorporated a method to quantify temporal lobe size in VP infants., Methods: We developed and applied three metrics (temporal lobe length, extra-axial space, and temporal horn width) to quantify temporal lobe structure on term-equivalent brain MRIs obtained from 74 VP and 16 term infants. We compared metrics between VP and term infants and explored associations of each metric with perinatal risk factors., Results: All metrics had excellent reliability (intra-class correlation coefficient 0.62-0.98). VP infants had lower mean temporal lobe length (76.8 mm versus 79.2 mm, p = 0.02); however, the difference attenuated after correction for postmenstrual age. VP infants had larger temporal horn widths compared with term infants (2.6 mm versus 1.8 mm, p < 0.001). Temporal lobe length was positively associated with gestational age, birth weight, and male sex, and negatively associated with the duration of parenteral nutrition., Conclusions: The proposed metrics are reliable and sensitive in distinguishing differences in temporal lobe development between VP and full-term infants., Impact: We developed a novel method for quantifying temporal lobe size among very preterm infants at term equivalent using simple metrics performed on brain MRI. Temporal lobe metrics were reliable, correlated with brain volume from volumetric analysis, and were sensitive in identifying differences in temporal lobe development among preterm compared with term infants, specifically larger temporal horn size in preterm infants. This temporal lobe metric system will enable future work to delineate the perinatal and postnatal factors that impact temporal lobe growth, and better understand the relationship between temporal lobe disturbance and neurodevelopment in very preterm infants., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: MRI is the gold standard test to define brain injury in infants with neonatal encephalopathy(NE). As imaging findings evolve considerably over the first week, early imaging may not fully reflect the final nature of the injury. This study aimed to compare day 4 versus second week MRI in infants with NE., Methods: Retrospective cohort study including infants who received therapeutic hypothermia(TH) for NE and had two MRIs: early (≤7days) and late (>7days). MRIs were clinically reported and also reviewed by study investigators., Results: 94infants with NE were included (40mild,49moderate,5severe). Twenty-four infants(26%) had a normal early scan of which 3/24(13%) had injury noted on repeat MRI. Seventy infants(74%) had abnormal findings noted on early MRI, of which 4/70(6%) had further evolution of injury while 11/70(16%) had complete resolution of findings. Applying a grading system resulted in a change of grade in 7 infants., Conclusion: In infants who received TH for NE, 19% had changes noted between their early and late MRIs. While the impact on predicting neurodevelopmental outcome was not studied, relying solely on early MRI may overestimate injury in a proportion of infants and miss injury in others. Combining early and late MRI allows for better characterization of injury., Impact: MRI is the gold standard tool to define brain injury in infants with NE, however, imaging findings evolve considerably over the first week of life. Most centers perform a single MRI on day 4 after rewarming. In our cohort, 19% of infants had a notable change in their MRI findings between early (within the first week) and late (beyond the first week) scans. Relying solely on early MRI may overestimate injury in a proportion of infants and miss injury in others. Combining early and late MRI following hypothermia allows for better characterization of brain injury., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Introduction: Periventricular leukomalacia occurs in up to 25% of very preterm infants resulting in adverse neurodevelopmental outcomes. In its acute phase, periventricular leukomalacia is clinically silent. Although ultrasonography is widely available, its sensitivity in the early detection of periventricular leukomalacia is low. Case Report and Published Literature: We identified a preterm infant with early diffusion-weighted imaging changes that later evolved to periventricular leukomalacia. Thirty-two cases of abnormal diffusion-weighted imaging reliably heralding severe periventricular leukomalacia in the preterm infant have been published in the literature. Notable features include the following: (1) infants were more mature preterm infants (29-36 weeks' gestation); (2) findings were often serendipitous with benign clinical courses; (3) diffusion-weighted imaging changes only were evident in the first weeks of life with later evolution to more classical abnormalities on conventional magnetic resonance imaging (MRI) or ultrasonography. Conclusion: Diffusion-weighted imaging in the first week of life may be a reliable early marker of severe periventricular leukomalacia injury in more mature preterm infants.

Early life experiences, such as very preterm (VP) birth, can affect brain and cognitive development. Several prior studies investigated brain structure in adults born VP; synthesising these studies may help to provide a clearer understanding of long-term effects of VP birth on the brain. We systematically searched Medline and Embase for articles that investigated brain structure using MRI in adulthood in individuals born VP (<32 weeks' gestation) or with very low birth weight (VLBW; <1500 g), and controls born at term or with normal birth weight. In total, 77 studies met the review inclusion criteria, of which 28 studies were eligible for meta-analyses, including data from up to 797 VP/VLBW participants and 518 controls, aged 18-33 years. VP/VLBW adults exhibited volumetric, morphologic and microstructural alterations in subcortical and temporal cortical regions compared with controls, with pooled standardised mean differences up to - 1.0 (95% confidence interval: -1.2, -0.8). This study suggests there is a persisting neurological impact of VP birth, which may provide developmental neurobiological insights for adult cognition in high-risk populations., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Tensor-based investigations suggest that delayed or disrupted white matter development may relate to adverse behavioral outcomes in individuals born very preterm (VP); however, metrics derived from such models lack specificity. Here, we applied a fixel-based analysis framework to examine white matter microstructural and macrostructural correlates of concurrent internalizing and externalizing problems in VP and full-term (FT) children at 7 and 13 years., Methods: Diffusion imaging data were collected in a longitudinal cohort of VP and FT individuals (130 VP and 29 FT at 7 years, 125 VP and 44 FT at 13 years). Fixel-based measures of fiber density, fiber-bundle cross-section, and fiber density and cross-section were extracted from 21 white matter tracts previously implicated in psychopathology. Internalizing and externalizing symptoms were assessed using the Strengths and Difficulties Questionnaire parent report at 7 and 13 years., Results: At age 7 years, widespread reductions in fiber-bundle cross-section and fiber density and cross-section and tract-specific reductions in fiber density were related to more internalizing and externalizing symptoms irrespective of birth group. At age 13 years, fixel-based measures were not related to internalizing symptoms, while tract-specific reductions in fiber density, fiber-bundle cross-section, and fiber density and cross-section measures were related to more externalizing symptoms in the FT group only., Conclusions: Age-specific neurobiological markers of internalizing and externalizing problems identified in this study extend previous tensor-based findings to inform pathophysiological models of behavior problems and provide the foundation for investigations into novel preventative and therapeutic interventions to mitigate risk in VP and other high-risk infant populations., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The incidence of cerebral sinovenous thrombosis (CSVT) in infants receiving therapeutic hypothermia for neonatal encephalopathy remains controversial. The aim of this study was to identify if the routine use of magnetic resonance venography (MRV) in term-born infants receiving hypothermia is associated with diagnostic identification of CSVT., Methods: We performed a retrospective review of 291 infants who received therapeutic hypothermia from January 2014 to March 2020. Demographic and clinical data, as well as the incidence of CSVT, were compared between infants born before and after adding routine MRV to post-rewarming magnetic resonance imaging (MRI)., Results: Before routine inclusion of MRV, 209 babies were cooled, and 25 (12%) underwent MRV. Only one baby (0.5%) was diagnosed with CSVT in that period, and it was detected by structural MRI, then confirmed with MRV. After the inclusion of routine MRV, 82 infants were cooled. Of these, 74 (90%) had MRV and none were diagnosed with CSVT., Conclusion: CSVT is uncommon in our cohort of infants receiving therapeutic hypothermia for neonatal encephalopathy. Inclusion of routine MRV in the post-rewarming imaging protocol was not associated with increased detection of CSVT in this population., Impact: Cerebral sinovenous thrombosis (CSVT) in infants with NE receiving TH may not be as common as previously indicated. The addition of MRV to routine post-rewarming imaging protocol did not lead to increased detection of CSVT in infants with NE. Asymmetry on MRV of the transverse sinus is a common anatomic variant. MRI alone may be sufficient in indicating the presence of CSVT., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: Early meaningful auditory experiences in the neonatal intensive care unit (NICU) enhance language outcomes and promote cognitive and social-emotional development., Methods: This is a descriptive report sharing our level III NICU experience of building a reading-aloud enrichment program with the goals of enhancing infant neurodevelopment and strengthening early parent-infant relationships., Results: We propose a roadmap for program development, outline challenges and possible ways to mitigate them, and highlight opportunities for further research in this area., Key Points: · Early auditory experiences enhance language, cognitive, and social-emotional development.. · High-risk infants experience an atypical neurosensory environment while receiving care in the NICU.. · Reading aloud in the NICU enhances language enrichment and supports early foundational relationships.. · We describe our center's experience with building a reading-aloud enrichment program in the NICU.., Competing Interests: P.K. is the national medical director of Reach Out and Read (with no financial compensation). The other authors have no relevant conflicts of interest to disclose., (Thieme. All rights reserved.)

Background: Children born very preterm (VP) display altered growth in corticolimbic structures compared with full-term peers. Given the association between the cortiocolimbic system and anxiety, this study aimed to compare developmental trajectories of corticolimbic regions in VP children with and without anxiety diagnosis at 13 years., Methods: MRI data from 124 VP children were used to calculate whole brain and corticolimbic region volumes at term-equivalent age (TEA), 7 and 13 years. The presence of an anxiety disorder was assessed at 13 years using a structured clinical interview., Results: VP children who met criteria for an anxiety disorder at 13 years ( n = 16) displayed altered trajectories for intracranial volume (ICV, p < 0.0001), total brain volume (TBV, p = 0.029), the right amygdala ( p = 0.0009) and left hippocampus ( p = 0.029) compared with VP children without anxiety ( n = 108), with trends in the right hippocampus ( p = 0.062) and left medial orbitofrontal cortex ( p = 0.079). Altered trajectories predominantly reflected slower growth in early childhood (0-7 years) for ICV ( β = -0.461, p = 0.020), TBV ( β = -0.503, p = 0.021), left ( β = -0.518, p = 0.020) and right hippocampi ( β = -0.469, p = 0.020) and left medial orbitofrontal cortex ( β = -0.761, p = 0.020) and did not persist after adjusting for TBV and social risk., Conclusions: Region- and time-specific alterations in the development of the corticolimbic system in children born VP may help to explain an increase in anxiety disorders observed in this population.

Defining neonatal encephalopathy clinically to qualify for therapeutic hypothermia is challenging. This study examines magnetic resonance imaging outcomes of 39 infants who were evaluated and not cooled using criteria inclusive of mild encephalopathy. Infants evaluated for therapeutic hypothermia are at risk for brain injury and may benefit from neuroimaging and follow-up., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The potential influence of exposure to analgesic-sedative agents (ASA) before, during, and after surgical NEC and peri-operative clinical status on white matter injury (WMI) in preterm infants has not been fully defined, and a comprehensive evaluation may inform future research and clinical interventions., Methods: A retrospective study comparing ASA exposure before/during /after surgical NEC and peri-operative clinical status in neonates with and without WMI., Results: Infants with any WMI (grade 2-4, n = 36/67, 53.7%) had a higher number of surgical procedures receiving ASA (5 [IQR: 3, 8] vs. 3 [2, 4]; p = 0.002) and had a longer duration of hypotension during their first (48.0 hours [26.0, 48.0] vs. 15.5 [6, 48]; p = 0.009) and second surgery (20 hours [0, 48h] vs. 0 [0, 22]; p = 0.017), received more hydrocortisone (35% vs.13.3%,p = 0.04) than those without any WMI. There were no differences in fentanyl/morphine/midazolam exposure before/during/after the NEC onset in the two groups.Infants with severe WMI (19/67, 28.3%, grade 3/4) had a higher incidence of AKI (P = 0.004), surgical morbidity (p = 0.047), more surgical procedures (6.5 [3, 10] vs. 4 [2, 5]; p = 0.012), and received higher mean fentanyl doses(p = 0.03) from birth until NEC onset than those without severe WMI. The univariate associations between these factors and severe WMI remained insignificant after multivariable logistic regression., Conclusion: Infants with WMI had more surgical procedures receiving ASA and had a longer duration of hypotension during surgeries. A large multicenter prospective study is needed to understand the full impact of ASA.

Background: Therapeutic hypothermia (TH) is routinely provided to those with moderate or severe neonatal encephalopathy (NE). Subtle differences exist in the standardized exams used to define NE severity. We aimed to assess if an infant's TH eligibility status differed if they were evaluated using either the NICHD/Neonatal Research Network's (NICHD-NRN) or TOBY/British Association of Perinatal Medicine's (TOBY-BAPM) neurological exam., Methods: Encephalopathic infants ≥36 weeks with evidence of perinatal asphyxia and complete documentation of the neurological exam &lt;6 h of age were included. TH eligibility using the NICHD-NRN and TOBY-BAPM criteria was determined based upon the documented exams., Results: Ninety-one encephalopathic infants were included. Despite good agreement between the two exams (κ = 0.715, p &lt; 0.001), TH eligibility differed between them (p &lt; 0.001). A total of 47 infants were deemed eligible by at least one method-46 using NICHD-NRN and 35 using TOBY-BAPM. Of the 12 infants eligible per NICHD-NRN, but ineligible per TOBY-BAPM, two developed electrographic seizures and seven demonstrated hypoxic-ischemic cerebral injury., Conclusions: Both the NICHD-NRN and TOBY-BAPM exams are evidence-based. Despite this, there is a significant difference in the number of infants eligible for TH depending on which exam is used. The NICHD-NRN exam identifies a greater proportion as eligible., Impact: There are subtle differences in the NICHD-NRN and TOBY-BAPM's encephalopathy exams used to determine eligibility for TH. This results in a significant difference in the proportion of infants determined to be eligible for TH depending on which encephalopathy exam is used. The NICHD-NRN encephalopathy exam identifies more infants as being eligible for TH than the TOBY-BAPM encephalopathy exam. This may result in different rates of cooling depending on which evidence-based neurological exam for evaluation of encephalopathy a center uses., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: To determine associations between body composition and concurrent measures of brain development including (1) Tissue-specific brain volumes and (2) White matter microstructure, among very preterm infants at term equivalent age., Design: Prospective observational study., Setting: Single-centre academic level III neonatal intensive care unit., Patients: We studied 85 infants born <33 weeks' gestation., Methods: At term equivalent age, infants underwent air displacement plethysmography to determine body composition, and brain MRI from which we quantified tissue-specific brain volumes and fractional anisotropy (FA) of white matter tracts. We estimated associations of fat and lean mass Z-scores with each brain outcome, using linear mixed models adjusted for intrafamilial correlation among twins and potential confounding variables., Results: Median gestational age was 29 weeks (range 23.4-32.9). One unit greater lean mass Z-score was associated with larger total brain volume (10.5 cc, 95% CI 3.8 to 17.2); larger volumes of the cerebellum (1.2 cc, 95% CI 0.5 to 1.9) and white matter (4.5 cc, 95% CI 0.7 to 8.3); and greater FA in the left cingulum (0.3%, 95% CI 0.1% to 0.6%), right uncinate fasciculus (0.2%, 95% CI 0.0% to 0.5%), and right posterior limb of the internal capsule (0.3%, 95% CI 0.03% to 0.6%). Fat Z-scores were not associated with any outcome., Conclusions: Lean mass-but not fat-at term was associated with larger brain volume and white matter microstructure differences that suggest improved maturation. Lean mass accrual may index brain growth and development., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite improvements in the mortality rates of preterm infants, rates of germinal matrix intraventricular hemorrhage (IVH) have remained static with an overall incidence of 25% in infants less than 32 weeks. The importance of the lesion relates primarily to the underlying injury to the developing brain and the associated long-term neurodevelopmental consequences. This clinical-orientated review focuses on the pathogenesis of IVH and discusses the evidence behind proposed prevention strategies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To evaluate the utility of the 1 Tesla (1 T) Embrace (Aspect Imaging) neonatal magnetic resonance imaging (MRI) scanner in a level III NICU., Study Design: Embrace brain MRI findings for 207 infants were reviewed, including 32 scans directly compared within 5 days with imaging on a 3 T Siemens Trio. Clinical MRI scan abnormalities were also compared to cranial ultrasound findings., Result: Of the 207 Embrace brain MRIs, 146 (70.5%) were obtained for clinical indications and 61 (29.5%) were research cases. Abnormal findings were found in 80 scans, most commonly hemorrhage and white matter injury. Notable findings included a stroke, medullary brainstem tumor, and polymicrogyria. In the 1 T versus 3 T comparison cohort, results were discordant in only one infant with punctate foci of susceptibility noted only on the 3 T scan., Conclusion: The Embrace MRI scans detected clinically relevant brain abnormalities and in a subset were clinically comparable to 3 T scans., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

There have been many studies demonstrating children born very preterm exhibit brain white matter microstructural alterations, which have been related to neurodevelopmental difficulties. These prior studies have often been based on diffusion MRI modelling and analysis techniques, which commonly focussed on white matter microstructural properties in children born very preterm. However, there have been relatively fewer studies investigating the free-water content of the white matter, and also the microstructure and free-water content of the cortical grey matter, in children born very preterm. These biophysical properties of the brain change rapidly during fetal and neonatal brain development, and therefore such properties are likely also adversely affected by very preterm birth. In this study, we investigated the relationship of very preterm birth (<30 weeks' gestation) to both white matter and cortical grey matter microstructure and free-water content in childhood using advanced diffusion MRI analyses. A total of 130 very preterm participants and 45 full-term control participants underwent diffusion MRI at age 13 years. Diffusion tissue signal fractions derived by Single-Shell 3-Tissue Constrained Spherical Deconvolution were used to investigate brain tissue microstructural and free-water composition. The tissue microstructural and free-water composition metrics were analysed using a voxel-based analysis and cortical region-of-interest analysis approach. Very preterm 13-year-olds exhibited reduced white matter microstructural density and increased free-water content across widespread regions of the white matter compared with controls. Additionally, very preterm 13-year-olds exhibited reduced microstructural density and increased free-water content in specific temporal, frontal, occipital and cingulate cortical regions. These brain tissue composition alterations were strongly associated with cerebral white matter abnormalities identified in the neonatal period, and concurrent adverse cognitive and motor outcomes in very preterm children. The findings demonstrate brain microstructural and free-water alterations up to thirteen years from neonatal brain abnormalities in very preterm children that relate to adverse neurodevelopmental outcomes., Competing Interests: Conflicts of Interest Nothing to report., (Copyright © 2022. Published by Elsevier Inc.)

Very preterm birth (VP; <32 weeks' gestation) is associated with altered brain gray matter development and lower math ability. In typically developing children, the neural correlates of math ability may change dynamically with age, though evidence in VP children is limited. In a prospective longitudinal cohort of children born VP and full term (FT), we aimed to investigate associations between 1) concurrent regional brain volumes and math ability at 7 (n = 148 VP; n = 34 FT) and 13-years (n = 130 VP; n = 46 FT), and 2) regional volumetric growth across childhood (term-equivalent age (TEA) to 7-years; 7 to 13-years) and math ability from 7 to 13-years, and improvement in ability from 7 to 13 years. For both aims we investigated whether associations differed between birth groups. Cross-sectionally, frontal, temporal and subcortical regional volumes were positively associated with math ability for both birth groups. For FT children, greater growth of specific temporal regions was associated with higher math ability, and greater improvements. For VP children, similar associations were only observed for growth from TEA to 7-years with 13-year ability and improvements in ability. In conclusion, VP birth appears to alter associations of brain development across the first 13 years with childhood math ability., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Point-of-care human milk analysis is now feasible in the neonatal intensive care unit (NICU) and allows accurate measurement of macronutrient delivery. Higher macronutrient intakes over this period may promote brain growth and development. In a prospective, observational study of 55 infants born at <32 weeks’ gestation, we used a mid-infrared spectroscopy-based human milk analyzer to measure the macronutrient content in repeated samples of human milk over the NICU hospitalization. We calculated daily nutrient intakes from unfortified milk and assigned infants to quintiles based on median intakes over the hospitalization. Infants underwent brain magnetic resonance imaging at term equivalent age to quantify total and regional brain volumes and fractional anisotropy of white matter tracts. Infants in the highest quintile of energy intake from milk, as compared with the lower four quintiles, had larger total brain volume (31 cc, 95% confidence interval [CI]: 5, 56), cortical gray matter (15 cc, 95%CI: 1, 30), and white matter volume (23 cc, 95%CI: 12, 33). Higher protein intake was associated with larger total brain (36 cc, 95%CI: 7, 65), cortical gray matter (22 cc, 95%CI: 6, 38) and deep gray matter (1 cc, 95%CI: 0.1, 3) volumes. These findings suggest innovative strategies to close nutrient delivery gaps in the NICU may promote brain growth for preterm infants.

Objective: To examine 5-year outcomes in children enrolled in a pilot randomized controlled trial of a high loading dose of caffeine after preterm birth., Study Design: Seventy-four very low birth weight neonates were randomized within the first 24 h of life to receive a high (80 mg/kg) or standard (20 mg/kg) loading dose of caffeine citrate. At 5 years of age, we conducted standardized neurodevelopmental tests and collected parent reports of child socioemotional problems., Result: Seventy-four percent of survivors returned for follow up. Children obtained similar scores on neurodevelopmental and socioemotional evaluations. There was no difference in the incidence of any neurodevelopmental delay after controlling for confounding factors., Conclusion: Five-year follow up of a pilot trial of high loading dose caffeine citrate documented no profound impacts on childhood neurodevelopment or socioemotional outcome., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: To review and synthesize the literature on human milk and structural brain development and injury in preterm infants, focusing on the application of quantitative brain magnetic resonance imaging (MRI) in this field., Methods: For this narrative review, we searched PubMed for articles published from 1990 to 2021 that reported observational or interventional studies of maternal milk or donor milk in relation to brain development and/or injury in preterm infants assessed with quantitative MRI at term equivalent age. Studies were characterized with respect to key aspects of study design, milk exposure definition, and MRI outcomes., Findings: We identified 7 relevant studies, all of which were observational in design and published between 2013 and 2021. Included preterm infants were born at or below 33 weeks' gestation. Sample sizes ranged from 22 to 377 infants. Exposure to human milk included both maternal and donor milk. No study included a full-term comparison group. Main MRI outcome domains were white matter integrity (assessed with diffusion tensor imaging, resting state functional connectivity, or semiautomated segmentation of white matter abnormality) and total and regional brain volumes. Studies revealed that greater exposure to human milk versus formula was associated with favorable outcomes, including more mature and connected cerebral white matter with less injury and larger regional brain volumes, notably in the deep nuclear gray matter, amygdala-hippocampus, and cerebellum. No consistent signature effect of human milk exposure was found; instead, the beneficial associations were regional and tissue-specific neuroprotective effects on the areas of known vulnerability in the preterm infant., Implications: Evidence to date suggests that human milk may protect the preterm infant from the white matter injury and dysmaturation to which this population is vulnerable. Brain MRI at term equivalent age is emerging as a useful tool to investigate the effects of human milk on the preterm brain. When grounded in neurobiological knowledge about preterm brain injury and development, this approach holds promise for allowing further insight into the mechanisms and pathways underlying beneficial associations of human milk with neurodevelopmental outcomes in this population and in the investigation of specific milk bioactive components with neuroprotective or neurorestorative potential., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Children born very preterm (VP) are at higher risk of emotional and behavioral problems compared with full-term (FT) children. We investigated the neurobiological basis of internalizing and externalizing symptoms in individuals born VP and FT by applying a graph theory approach., Methods: Structural and diffusion magnetic resonance imaging data were combined to generate structural connectomes and calculate measures of network integration and segregation at 7 (VP: 72; FT: 17) and 13 (VP: 125; FT: 44) years. Internalizing and externalizing symptoms were assessed at 7 and 13 years using the Strengths and Difficulties Questionnaire. Linear regression models were used to relate network measures and internalizing and externalizing symptoms concurrently at 7 and 13 years., Results: Lower network integration (characteristic path length and global efficiency) was associated with higher internalizing symptoms in VP and FT children at 7 years, but not at 13 years. The association between network integration (characteristic path length) and externalizing symptoms at 7 years was weaker, but there was some evidence for differential associations between groups, with lower integration in the VP group and higher integration in the FT group associated with higher externalizing symptoms. At 13 years, there was some evidence that associations between network segregation (average clustering coefficient, transitivity, local efficiency) and externalizing symptoms differed between the VP and FT groups, with stronger positive associations in the VP group., Conclusions: This study provides insights into the neurobiological basis of emotional and behavioral problems after preterm birth, highlighting the role of the structural connectome in internalizing and externalizing symptoms in childhood and adolescence., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The objective of this study was to determine the risk factors and outcomes of white matter brain injury (WMBI) on magnetic resonance imaging (MRI) at term-equivalent age in infants with surgical necrotizing enterocolitis (NEC)., Methods: This retrospective study compared clinical/pathological information between infants with and those without WMBI., Results: Out of 69 infants with surgical NEC, 17 (24.6%) had mild WMBI, 13 (18.8%) had moderate WMBI, and six (8.7%) had severe WMBI on the brain MRI. Several clinical factors (gestational age, more red blood cell (RBC) transfusions before NEC onset, pneumoperitoneum, earlier NEC onset age, postoperative ileus, acute kidney injury (AKI) by serum creatinine, postnatal steroids, hospital stay) and histopathological findings (necrosis, hemorrhage) had univariate associations with WMBI. Associations with RBC transfusion (odds ratio (OR) 23.6 [95% confidence interval (CI): 4.73-117.97]; p = 0.0001), age at NEC onset (OR 0.30 [95%CI: 0.11-0.84]; p = 0.021), necrosis (OR 0.10 [95%CI: 0.01-0.90]; p = 0.040), and bowel hemorrhage (OR 7.79 [95%CI: 2.19-27.72]; p = 0.002) persisted in multivariable association with grade 3-4 WMBI. The infants with WMBI had lower mean motor, cognitive, language scores, and higher ophthalmic morbidity at 2 years of age., Conclusions: The WMBI was most likely associated with earlier NEC onset, higher RBC transfusions, and less necrosis and greater hemorrhage lesions on intestinal pathology in preterm infants with surgical NEC., Impact: In preterm infants with surgical NEC, brain MRI showed injury in the white matter in 52%, gray matter in 10%, and cerebellar region in 30%. Preterm infants with severe WMBI (grade 3-4) had less necrosis and greater hemorrhagic lesions on histopathology of the bowel. Preterm infants with WMBI were more likely to have a more severe postoperative course, AKI, and longer length of hospitalization. Neuroprotective strategies to prevent brain injury in preterm infants with surgical NEC are needed with the goal of improving the neurodevelopmental outcomes., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: The NICHD and SIBEN assessments are adapted from the Sarnat grade, and used to determine severity of neonatal encephalopathy (NE). We compare NICHD and SIBEN methods, and their ability to define a minimum threshold associated with significant cerebral injury., Study Design: Between 2016 and 2019, 145 infants with NE (77-mild; 65-moderate; 3-severe) were included. NICHD and SIBEN grade and numerical scores were assigned. Kappa scores described agreement between methods, and ROC curves their ability to predict MR injury., Results: Good agreement existed between grading systems (K = 0.86). SIBEN defined more infants as moderate, and less as mild, than NICHD (p < 0.001). Both numerical scores were superior to standard grades in predicting MR injury., Conclusion: Despite good agreement between methods, SIBEN defines more infants as moderate NE. Both numerical scores were superior to standard grade, and comparable to each other, in defining a minimum threshold for cerebral injury. Further assessment contrasting their predictive ability for long-term outcome is required., (© 2021. The Author(s).)

Background and Objectives: To investigate brain regional white matter development in full-term (FT) and very preterm (VP) children at term equivalent and 7 and 13 years of age based on the ratio of T 1 - and T 2 -weighted MRI ( T 1 -w/ T 2 -w), including (1) whether longitudinal changes differ between birth groups or sexes, (2) associations with perinatal risk factors in VP children, and (3) relationships with neurodevelopmental outcomes at 13 years., Methods: Prospective longitudinal cohort study of VP (born <30 weeks' gestation or <1,250 g) and FT infants born between 2001 and 2004 and followed up at term equivalent and 7 and 13 years of age, including MRI studies and neurodevelopmental assessments. T 1 -w/ T 2 -w images were parcellated into 48 white matter regions of interest., Results: Of 224 VP participants and 76 FT participants, 197 VP and 55 FT participants had useable T 1 -w/ T 2 -w data from at least one timepoint. T 1 -w/ T 2 -w values increased between term equivalent and 13 years of age, with little evidence that longitudinal changes varied between birth groups or sexes. VP birth, neonatal brain abnormalities, being small for gestational age, and postnatal infection were associated with reduced regional T 1 -w/ T 2 -w values in childhood and adolescence. Increased T 1 -w/ T 2 -w values across the white matter at 13 years were associated with better motor and working memory function for all children. Within the FT group only, larger increases in T 1 -w/ T 2 -w values from term equivalent to 7 years were associated with poorer attention and executive function, and higher T 1 -w/ T 2 -w values at 7 years were associated with poorer mathematics performance., Discussion: VP birth and multiple known perinatal risk factors are associated with long-term reductions in the T 1 -w/ T 2 -w ratio in white matter regions in childhood and adolescence, which may relate to alterations in microstructure and myelin content. Increased T 1 -w/ T 2 -w ratio at 13 years appeared to be associated with better motor and working memory function and there appeared to be developmental differences between VP and FT children in the associations for attention, executive functioning, and mathematics performance., (© 2021 American Academy of Neurology.)

Very preterm (VP) birth is associated with an increased risk for later neurodevelopmental and behavioural challenges. Although the neurobiological underpinnings of such challenges continue to be explored, previous studies have reported brain volume and morphology alterations in children and adolescents born VP compared with full-term (FT)-born controls. How these alterations relate to the trajectory of brain maturation, with potential implications for later brain ageing, remains unclear. In this longitudinal study, we investigate the relationship between VP birth and brain development during childhood and adolescence. We construct a normative 'brain age' model to predict age over childhood and adolescence based on measures of brain cortical and subcortical volumes and cortical morphology from structural MRI of a dataset of typically developing children aged 3-21 years (n = 768). Using this model, we examined deviations from normative brain development in a separate dataset of children and adolescents born VP (<30 weeks' gestation) at two timepoints (ages 7 and 13 years) compared with FT-born controls (120 VP and 29 FT children at age 7 years; 140 VP and 47 FT children at age 13 years). Brain age delta (brain-predicted age minus chronological age) was, on average, higher in the VP group at both timepoints compared with controls, however this difference had a small to medium effect size and was not statistically significant. Variance in brain age delta was higher in the VP group compared with controls; this difference was significant at the 13-year timepoint. Within the VP group, there was little evidence of associations between brain age delta and perinatal risk factors or cognitive and motor outcomes. Under the brain age framework, our results may suggest that children and adolescents born VP have similar brain structural developmental trajectories to term-born peers between 7 and 13 years of age., (Copyright © 2021. Published by Elsevier Inc.)

Aim: This paper summarises published evidence on the use of recorded music in high-risk infants to reduce stress and improve neurodevelopment, forming recommendations for proposed clinical applications in neonatal intensive care units., Methods: We searched two comprehensive library catalogues and two databases for articles evaluating the impact of recorded music interventions on hospitalised preterm infants. Original and review papers published in English in the 10 years prior to this search were selected if the study included a component of recorded music interventions., Results: Most original studies (80.95%) and all literature reviews (100%) reported positive effects of recorded music interventions for preterm infants, primarily in the short term. No negative effects were reported. Evidence is emerging regarding the neurobiological mechanisms of recorded music on longer-term effects on preterm infant neurodevelopment. Clinical applications were suggested drawing upon available evidence. Due to generally small sample sizes and variability in study design, unanswered questions remain., Conclusion: Carefully designed recorded music interventions appear to be safe, feasible and effective in reducing stress and improving neurodevelopment of hospitalised infants. Additional rigorous, well-powered trials with relevant outcomes are needed to further refine specific elements for recorded music interventions to better inform practice., (©2021 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objective: To identify attention profiles at 7 and 13 years, and transitions in attention profiles over time in children born very preterm (VP; <30 weeks' gestation) and full term (FT), and examine predictors of attention profiles and transitions., Methods: Participants were 167 VP and 60 FT children, evaluated on profiles across five attention domains (selective, shifting and divided attention, processing speed, and behavioral attention) at 7 and 13 years using latent profile analyses. Transitions in profiles were assessed with contingency tables. For VP children, biological and social risk factors were tested as predictors with a multinomial logistic regression., Results: At 7 and 13 years, three distinct profiles of attentional functioning were identified. VP children were 2-3 times more likely to show poorer attention profiles compared with FT children. Transition patterns between 7 and 13 years were stable average, stable low, improving, and declining attention. VP children were two times less likely to have a stable average attention pattern and three times more likely to have stable low or improving attention patterns compared with FT children. Groups did not differ in declining attention patterns. For VP children, brain abnormalities on neonatal MRI and greater social risk at 7 years predicted stable low or changing attention patterns over time., Conclusions: VP children show greater variability in attention profiles and transition patterns than FT children, with almost half of the VP children showing adverse attention patterns over time. Early brain pathology and social environment are markers for attentional functioning.

Inflammation may adversely affect early human brain development. We aimed to assess the role of maternal nutrition and infections on cord blood inflammation. In a pregnancy cohort in Sylhet, Bangladesh, we enrolled 251 consecutive pregnancies resulting in a term livebirth from July 2016-March 2017. Stillbirths, preterm births, and cases of neonatal encephalopathy were excluded. We prospectively collected data on maternal diet (food frequency questionnaire) and morbidity, and analyzed umbilical cord blood for interleukin (IL)-1α, IL-1β, IL-6, IL-8 and C-reactive protein. We determined associations between nutrition and infection exposures and cord cytokine elevation (≥75% vs. <75%) using logistic regression, adjusting for confounders. One-third of mothers were underweight (BMI < 18.5 kg/m 2 ) at enrollment. Antenatal and intrapartum infections were observed among 4.8% and 15.9% of the sample, respectively. Low pregnancy intakes of B vitamins (B1, B2, B3, B6, B9 (folate)), fat-soluble vitamins (D, E), iron, zinc, and linoleic acid (lowest vs. middle tertile) were associated with higher risk of inflammation, particularly IL-8. There was a non-significant trend of increased risk of IL-8 and IL-6 elevation with history of ante-and intrapartum infections, respectively. In Bangladesh, improving micronutrient intake and preventing pregnancy infections are targets to reduce fetal systemic inflammation and associated adverse neurodevelopmental outcomes.

Neuroimaging is widely used to aid in the diagnosis and clinical management of neonates with neonatal encephalopathy (NE). Yet, despite widespread use clinically, there are few published guidelines on neuroimaging for neonates with NE. This review outlines the primary patterns of brain injury associated with hypoxic-ischemic injury in neonates with NE and their frequency, associated neuropathological features, and risk factors. In addition, it provides an overview of neuroimaging methods, including the most widely used scoring systems used to characterize brain injury in these neonates and their utility as predictive biomarkers. Last, recommendations for neuroimaging in neonates with NE are presented., (Copyright © 2021. Published by Elsevier Ltd.)

Children born very preterm (VPT; <32 weeks' gestation) have alterations in brain white matter and poorer math ability than full-term (FT) peers. Diffusion-weighted magnetic resonance imaging studies suggest a link between white matter microstructure and math in VPT and FT children, although longitudinal studies using advanced modelling are lacking. In a prospective longitudinal cohort of VPT and FT children we used Fixel-Based Analysis to investigate associations between maturation of white matter fibre density (FD), fibre-bundle cross-section (FC), and combined fibre density and cross-section (FDC) and math computation ability at 7 (n = 136 VPT; n = 32 FT) and 13 (n = 130 VPT; n = 44 FT) years, as well as between change in white matter and math computation ability from 7 to 13 years (n = 103 VPT; n = 21 FT). In both VPT and FT children, higher FD, FC and FDC in visual, sensorimotor and cortico-thalamic/thalamo-cortical white matter tracts were associated with better math computation ability at 7 and 13 years. Longitudinally, accelerated maturation of the posterior body of the corpus callosum (FDC) was associated with greater math computation development. White matter-math associations were similar for VPT and FT children. In conclusion, white matter maturation is associated with math computation ability across late childhood, irrespective of birth group., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To correlate arterial umbilical cord gas (aUCG) and infant blood gas with severity of neurological injury., Study Design: Retrospective single-site study of infants evaluated for therapeutic hypothermia. Clinical neurological examination and a validated MRI scoring system were used to assess injury severity., Results: Sixty-eight infants were included. aUCG base deficit (BD) and lactate correlated with infant blood gas counterparts (r = 0.43 and r = 0.56, respectively). aUCG and infant pH did not correlate. Infant blood gas lactate (R ADJ 2  = 0.40), infant BD (R ADJ 2  = 0.26), infant pH (R ADJ 2  = 0.17), aUCG base deficit (R ADJ 2  = 0.08), and aUCG lactate (R ADJ 2  = 0.11) were associated with clinical neurological examination severity. aUCG and infant blood gas measures were not correlated with MRI score., Conclusion: Metabolic measures from initial infant blood gases were most associated with the clinical neurological examination severity and can be used to evaluate hypoxic-ischemic cerebral injury risk., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Examine relationships between parenting and brain structure and growth in children born very preterm (VPT)., Methods: Participants were 118 children born VPT (<30weeks' gestation or <1,250 g birth weight) and their parents. Parenting behavior was observed at 2 years' corrected age. Brain magnetic resonance imaging scans were performed at term equivalent age and 7 years' corrected age with brain volumes and white matter microstructure analyzed., Results: More sensitive parenting at 2 years was associated with larger basal ganglia volumes at 7 years for boys, greater growth in basal ganglia volume from term to 7 years, and greater growth in amygdala volume growth for boys. More intrusive parenting was associated with smaller intracranial and grey matter volumes at 7 years, as well as lower fractional anisotropy and higher radial diffusivity in the cerebellar white matter, cerebral peduncle, corticospinal tract, anterior thalamic radiation, and superior longitudinal fasciculus at 7., Conclusions: Early positive parenting may be more strongly associated with subcortical brain development for boys born VPT, while early intrusive parenting may be associated with smaller cortical brain volumes and altered white matter microstructure in children born VPT.

Background: Endogenous erythropoietin (EPO) concentrations vary widely in preterm infants and may be associated with perinatal risk factors and neurological outcomes. Erythropoietin is elevated in fetal hypoxia but is also a potential neuroprotectant., Methods: In a prospective study of 27 infants ≤ 30 weeks gestation, serum erythropoietin concentrations were measured during the first month of life, on day 1 and weeks 1, 2, and 4, and related to perinatal risk factors and outcomes including retinopathy of prematurity and cerebral injury evaluated near term-equivalent post menstrual age using magnetic resonance imaging with quantitative scoring., Results: Lower birth weight was associated with higher EPO concentrations throughout the first 2 weeks of life (r = -0.6, p < 0.01). Higher day 1 and week 1 EPO concentrations were associated with lower Apgar score at 1 minute (r = - 0.5) and 5 minutes (r = -0.7), respectively (p < 0.01). Higher day 1 EPO concentrations and 2-week area under the curve were associated with increased risk (p = 0.01) and severity (r = 0.5, p < 0.02) of retinopathy of prematurity. Higher EPO concentrations at 2 weeks were associated with increased total brain injury score (r = 0.5, p < 0.05)., Conclusion: Elevated endogenous erythropoietin concentrations in the first two weeks of life are associated with lower birth weight and increased risk of adverse outcomes., Competing Interests: The authors have declared that no competing interests exist.