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Children
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Neonatal Brain Injury and Neurodevelopmental Outcomes: Prediction, Assessment, and Interventions
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Neonatal Brain Injury and Neurodevelopmental Outcomes: Prediction, Assessment, and Interventions

A special issue of Children (ISSN 2227-9067). This special issue belongs to the section "Pediatric Neonatology".

Deadline for manuscript submissions: 10 September 2026 | Viewed by 2073

Editors

Dr. Thitinart Sithisarn
*
E-Mail Website
Guest Editor
College of Medicine, University of Kentucky, Lexington, KY 40536, USA
Interests: neonatal brain injury; neurodevelopmental follow-up; perinatal addiction; translational study and animal models
* Associate Professor
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Henrietta S. Bada

E-Mail Website
Guest Editor
College of Medicine, University of Kentucky, Lexington, KY 40536, USA
Interests: newborn brain disorders; perinatal addiction; neurodevelopmental follow-up; neo-natal physiologic measures

Special Issue Information

Dear Colleagues,

Neonatal brain injury has long been recognized as a leading cause of neonatal mortality and lifelong neurodevelopmental disability. Historically, conditions such as hypoxic–ischemic encephalopathy, prematurity-related brain injuries, infections, and substance exposures have been associated with adverse cognitive, motor, and behavioral outcomes. Advances in neonatal intensive care, neuroimaging, and neurophysiology have improved survival, yet many infants remain at risk for subtle or evolving impairments that challenge early detection and intervention.

The aim of this Special Issue, “Neonatal Brain Injury and Neurodevelopmental Outcomes: Prediction, Assessment, and Interventions”, is to provide a comprehensive and multidisciplinary platform to examine mechanisms of injury, refine risk prediction, and evaluate tools for early assessment and outcome monitoring. We seek to highlight cutting-edge research, including advanced neuroimaging, neurophysiologic monitoring, biomarkers, machine learning approaches, and translational models that inform neuroprotection, brain repair and outcomes.

We invite submissions of original research, systematic and narrative reviews, and clinically focused translational studies addressing neonatal brain injury across gestational ages. Contributions exploring early prediction and interventions, neuroprotective strategies, longitudinal outcomes, and population-level differences in neurodevelopmental outcomes or implementation challenges are particularly encouraged.

Dr. Thitinart Sithisarn
Prof. Dr. Henrietta S. Bada
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Children is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neonatal brain injury
  • neurodevelopmental outcomes
  • hypoxic–ischemic encephalopathy
  • prematurity-related brain injury
  • prenatal substance exposure
  • neuroimaging
  • biomarkers
  • machine learning
  • neuroprotection
  • translational research

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Published Papers (4 papers)

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Research

23 pages, 2532 KB  
Article
Three-Domain Serial Cranial Ultrasound Phenotypes and Outcomes in Very Preterm Infants with Severe Brain Injury: A Single-Center Cohort Study
by Noemí Núñez-Enamorado, Ana Camacho-Salas, María López-Maestro, María Carmen Gallego-Herrero, Ana Martínez de Aragón, Sara Vila-Bedmar, Sara Vázquez-Román, Berta Zamora-Crespo, Carmen Rosa Pallás-Alonso and María Teresa Moral-Pumarega
Children 2026, 13(7), 844; https://doi.org/10.3390/children13070844 - 23 Jun 2026
Viewed by 295
Abstract
Background/Objectives: Severe brain injury (SBI) in very preterm infants includes heterogeneous lesions with distinct timing, burden and outcomes. We used cranial ultrasound (CUS) to describe SBI entity, documented timing, three-domain burden, deaths following documented withdrawal, withholding or non-escalation of life-sustaining treatment for poor [...] Read more.
Background/Objectives: Severe brain injury (SBI) in very preterm infants includes heterogeneous lesions with distinct timing, burden and outcomes. We used cranial ultrasound (CUS) to describe SBI entity, documented timing, three-domain burden, deaths following documented withdrawal, withholding or non-escalation of life-sustaining treatment for poor neurological prognosis (neuro-WWLST), and survivor outcomes. Methods: Retrospective single-center cohort (1991–2020) of 2841 very preterm infants (<32 weeks’ gestation and/or birth weight ≤ 1500 g) with complete CUS within 48 h after birth. CUS was summarized by four windows, three domains—parenchymal lesion, intraventricular hemorrhage (IVH) and ventriculomegaly—and three mutually exclusive entities: periventricular hemorrhagic infarction (PVHI), cystic periventricular leukomalacia (cPVL and grade 3 IVH without PVHI/cPVL (IVH3 entity). Cross-outcome analyses used common maximal-burden CUS. Results: SBI occurred in 286/2841 infants (10.1%) and neuro-WWLST death in 45/2841 infants (1.6%); 43/45 occurred within SBI, and 43/89 SBI deaths (48.3%) followed documented neuro-WWLST. Using common maximal-burden CUS, severe three-domain involvement was more frequent among neuro-WWLST deaths than survivors (37.2% vs. 8.6%). Among SBI survivors with follow-up, cerebral palsy (CP) occurred in 87/176 (49.4%) and clinically classified school-age cognitive sequelae in 50/155 (32.3%). Outcomes varied by entity, with mainly ambulatory unilateral CP after PVHI, more frequent non-ambulatory bilateral CP after cPVL, and a heterogeneous IVH3 profile. Severe three-domain involvement identified a small subgroup with higher outcome burden, but outcomes were not deterministic. Conclusions: A structured, descriptive CUS approach separating lesion entity, documented timing and multidomain burden may support transparent cohort-level description of SBI trajectories, documented neuro-WWLST deaths and survivor outcomes. Full article
(This article belongs to the Special Issue Neonatal Brain Injury and Neurodevelopmental Outcomes: Prediction, Assessment, and Interventions)
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17 pages, 676 KB  
Article
Neurodevelopmental Outcome in Very Low Birth Weight Preterm Infants: An Exploratory Multivariable Analysis Including Sonographic Brain Volume Trajectories—Data from the NeoNEVS Project
by Simon Loth, Julia Hauer, Marcus Krüger, Renée Lampe, Irina Sidorenko, Alexander Bieber and Christian Brickmann
Children 2026, 13(6), 815; https://doi.org/10.3390/children13060815 - 13 Jun 2026
Viewed by 523
Abstract
Background: Extremely and very preterm infants are at high risk for adverse neurodevelopmental outcomes. Early prediction remains challenging when relying on static clinical markers or single time-point neuroimaging. Serial cranial ultrasound (CUS) enables repeated bedside assessment of cerebral growth and may provide [...] Read more.
Background: Extremely and very preterm infants are at high risk for adverse neurodevelopmental outcomes. Early prediction remains challenging when relying on static clinical markers or single time-point neuroimaging. Serial cranial ultrasound (CUS) enables repeated bedside assessment of cerebral growth and may provide longitudinal trajectory biomarkers integrable with routine clinical data. Methods: In this retrospective two-center cohort study, 89 preterm infants (<32 weeks’ gestation and/or <1500 g birth weight) were assessed using the Bayley-III at 24 months corrected age. Brain volume trajectory features were derived from serial CUS using a standardized ellipsoid model. A three-level analytical framework was applied as follows: univariate regression (62 models, Bonferroni and Benjamini–Hochberg correction), multivariate SVM classification with five-fold GroupKFold cross-validation, ensuring patient-level data separation and feature importance analysis with interaction characterization using stratified Spearman correlation and two-dimensional partial dependence plots. Results: Multivariate classification yielded modest but above-chance performance (balanced accuracy 0.277–0.463, Cohen’s κ 0.042–0.152). Respiratory morbidity duration—mechanical ventilation and BPD severity—were the most robustly associated univariate predictors, surviving Bonferroni correction. Brain volume trajectory features showed no significant univariate associations but contributed conditionally within the multivariate framework as follows: the interaction between brain volume slope and trajectory linearity was the strongest for cognitive outcome (Δr = 0.47), and postnatal growth restriction showed amplified adverse effects at lower birth weight for motor outcome (Δr = 0.47). Conclusions: This study demonstrates the value of ML methods as structured analytical tools for characterizing predictor–outcome relationships in preterm neurodevelopment; respiratory morbidity and brain volume trajectory features emerged as the most informative predictor classes. Prospective multicenter validation is required before clinical translation. Full article
(This article belongs to the Special Issue Neonatal Brain Injury and Neurodevelopmental Outcomes: Prediction, Assessment, and Interventions)
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13 pages, 1160 KB  
Article
Anxiety Symptoms in Preschool Children Born Very Preterm: Associations with Cognition and Neonatal Striatal Volumes
by Carmen Rodríguez-Barrios, Natalia Jiménez-Luque, Yolanda Marín Almagro, Irene Gutierrez-Rosa, Manuel Lubián-Gutiérrez, Bahram Jafrasteh, Isabel Benavente-Fernández and Simón Pedro Lubián-López
Children 2026, 13(5), 695; https://doi.org/10.3390/children13050695 - 19 May 2026
Viewed by 380
Abstract
Background/Objectives: Children born very preterm (VP) are at increased risk of later emotional and cognitive difficulties, including anxiety symptoms during childhood. Altered early brain development, particularly within subcortical circuits involved in emotional regulation, may contribute to this vulnerability. This study aimed to assess [...] Read more.
Background/Objectives: Children born very preterm (VP) are at increased risk of later emotional and cognitive difficulties, including anxiety symptoms during childhood. Altered early brain development, particularly within subcortical circuits involved in emotional regulation, may contribute to this vulnerability. This study aimed to assess anxiety symptoms in preschool-aged children born VP, examine their relationship with cognitive performance, and determine whether neonatal brain volumes at term-equivalent age (TEA) were associated with later anxiety symptoms. We also explored whether cognition mediated the association between neonatal striatal volumes and anxiety. Methods: We conducted a longitudinal cohort study of infants born at ≤32 weeks of gestation and/or with a birth weight ≤1500 g admitted to a tertiary neonatal intensive care unit between 2018 and 2021. At 4–6 years of age, anxiety symptoms were assessed using the Child Behavior Checklist (CBCL) Anxiety Problems subscale, and cognitive performance was evaluated with the Wechsler Preschool and Primary Scale of Intelligence-IV (WPPSI-IV). Neonatal magnetic resonance imaging performed at TEA was used to obtain regional brain volumetric measures. Associations were analyzed using adjusted linear regression, interaction-based volumetric modeling, path analysis, and receiver operating characteristic analysis. Results: Ninety-five children were included, and 24 (25.3%) showed clinically relevant anxiety symptoms according to the CBCL Anxiety Problems subscale. Higher WPPSI-IV scores were associated with lower anxiety scores (β = −0.183; p = 0.042). The best-fitting MRI model included caudate volume, putamen volume, and their interaction, with a significant association between the putamen–caudate interaction and anxiety symptoms (β = −17.807; p < 0.001). In the path model, both cognition and the putamen–caudate interaction were directly associated with anxiety, whereas the indirect effect through cognition was not significant. The final MRI model showed acceptable discrimination for clinically relevant anxiety (AUC = 0.796). Conclusions: Anxiety symptoms were frequent in preschool-aged children born VP and were associated with lower cognitive performance. Neonatal striatal volumetric organization, particularly the interaction between the putamen and caudate volumes, was independently associated with later anxiety symptoms, suggesting that cognitive and early neural factors may contribute to anxiety risk through parallel rather than mediated pathways. Full article
(This article belongs to the Special Issue Neonatal Brain Injury and Neurodevelopmental Outcomes: Prediction, Assessment, and Interventions)
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13 pages, 1437 KB  
Article
Multimodal Assessment of Cerebral Perfusion and EEG Maturation in Preterm Infants at Term-Equivalent Age
by Yahui Zhang, Yanxia You, Jianqiu Huang, Yunfeng Liu and Tongyan Han
Children 2026, 13(5), 647; https://doi.org/10.3390/children13050647 - 5 May 2026
Viewed by 434
Abstract
Background/Objective: Preterm birth poses notable neurodevelopmental risks, with cerebral microcirculatory disturbances potentially contributing to long-term impairment. Existing monitoring modalities lack bedside capacity to evaluate these microvascular changes during critical brain development. We characterized cerebral microperfusion and functional maturation patterns in preterm versus full-term [...] Read more.
Background/Objective: Preterm birth poses notable neurodevelopmental risks, with cerebral microcirculatory disturbances potentially contributing to long-term impairment. Existing monitoring modalities lack bedside capacity to evaluate these microvascular changes during critical brain development. We characterized cerebral microperfusion and functional maturation patterns in preterm versus full-term neonates using combined ultra-micro angiography (UMA) and an amplitude-integrated electroencephalogram (aEEG). Methods: In this prospective study, 76 neonates (23 extremely/very preterm [EP/VPT], 27 moderate-late preterm, and 26 term controls) were assessed at term-equivalent age. UMA helped quantify regional microperfusion (color pixel percentage, abbreviated as CPP in this context to differentiate from cerebral perfusion pressure), whereas aEEG (Burdjalov scores) helped evaluate functional maturation at 37–38 and 40 weeks’ postmenstrual age. Results: EP/VPT infants demonstrated significant cerebral hyperperfusion with distinct cortex–white matter perfusion gradients. Although preterm infants showed advanced aEEG maturation at 37–38 weeks, this difference normalized by 40 weeks. Conclusion: Gestation-dependent cerebral hyperperfusion and transient EEG maturation differences in EP/VPT infants at term-equivalent age support the value of UMA–aEEG integration for neurovascular assessment. The observed perfusion–EEG patterns suggest prematurity-specific neuroadaptation, warranting further investigation of long-term functional correlates. Full article
(This article belongs to the Special Issue Neonatal Brain Injury and Neurodevelopmental Outcomes: Prediction, Assessment, and Interventions)
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