Neurodevelopmental Outcomes in Children After Fetoscopic Endoluminal Tracheal Occlusion for Severe Congenital Diaphragmatic Hernia: Results From a Multidisciplinary Clinic.

BACKGROUND: We compared early neurodevelopmental morbidity in young children with severe CDH who underwent FETO to those without fetal therapy. METHODS: We conducted a prospective study of severe CDH patients undergoing FETO (n = 18) at a single North American center from 2015 to 2021 (NCT02710968). Outpatient survivors (n = 12) were evaluated by a multidisciplinary team and compared to expectantly managed CDH patients. Neurodevelopmental outcomes were assessed using the Capute Scales [Clinical Linguistic and Auditory Milestone Scales (CLAMS) and Cognitive Adaptive Test (CAT)], with a developmental quotient (DQ) < 85 indicative of at-risk for delay. RESULTS: At one year, 58% (n = 7) of FETO patients underwent evaluation, with notable concern for language delay (CLAMS median DQ, 80.1 [interquartile range, 67.6-86.7]). FETO scores improved by 24-months, whereas high severity/non-FETO scores declined [CLAMS median DQ (Difference in DQ), 92.3 (+12.2) vs. 77.1 (-13.4), respectively; p = 0.049]. On the initial CAT, FETO patients had concern for visual motor and problem-solving delays, with a median DQ of 81.3 (62.1-89.4). At 24-months, FETO patients had improving scores [Median CAT DQ, 90.8 (+9.5)], whereas high severity/non-FETO [87.5 (-3.0), p = 0.28] had declining scores. CONCLUSION: These initial data suggest that FETO is associated with favorable neurodevelopmental outcomes at 24-months compared to severe CDH under expectant management. LEVEL OF EVIDENCE: III.

Factors affecting early childhood growth in hypoxic-ischemic encephalopathy treated with hypothermia.

INTRODUCTION: There is an extensive body of research regarding neurological outcomes following neonatal hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH), with limited data on growth outcomes. We examined perinatal characteristics associated with postnatal growth in this population. METHODS: Convenience cohort of 66 infants with HIE who underwent TH and participated in follow-up at 24 months of age were included. Regression modeling including perinatal anthropomorphics, markers of HIE, and systemic injury was used to evaluate growth at 24 months. RESULTS: Birth head circumference was associated with weight (p = 0.036). MRI severity, pH at admission and birth head circumference were associated with height (p = 0.043, p = 0.015 and p = 0.043 respectively). MRI severity and length of intubation were associated with head circumference (p = 0.038 and p < 0.001 respectively). CONCLUSION: There was a significant association between specific early factors and growth at 24 months among infants with HIE treated with TH.

Pilot Translational Precision Biobehavioral Assays for Early Detection of Motor Impairments in a Rat Model of Cerebral Palsy.

BACKGROUND: Cutting-edge neonatal programs diagnose cerebral palsy (CP) or "high risk of CP" using validated neurobehavioral exams in combination with risk history and neuroimaging. In rat models, digital gait analyses are the gold standard adult assessment, but tools in infant rats are limited. Refinement of infant rat neurobehavioral correlates of CP will establish translational behavioral biomarkers to delineate early mechanisms of CP in both humans and rodent models of CP. OBJECTIVE: To facilitate precision medicine approaches of neurodevelopmental health and integrate basic and clinical research approaches for CP, we developed and piloted a new assay of neonatal rat neurobehavior to mimic human neonate exams. METHODS: Our established rat model of CP secondary to chorioamnionitis (CHORIO) that induces bilateral motor impairment reminiscent of spastic CP was used. On postnatal day 10 (P10), 5 min videos were recorded of 26 (6 sham and 20 CHORIO) animals moving freely in a cage were reviewed by an evaluator trained in the human General Movements Assessment (GMA). Non-blinded observation revealed two behaviors that differed between rat pups in each group (time spent rearing; multi-dimensional nose sweeping; and sniffing). Each video was re-coded for these criteria by an evaluator blind to group status. Differences between sham and CP groups were analyzed using a Mann-Whitney U-test or Student's t-test (p < 0.05 level of significance). RESULTS: Neonatal rats with CP exhibited sensorimotor impairment and decreased spatial exploration. CP rats spent significantly less time rearing (17.85 ± 1.60 s vs. 34.8 ± 2.89 s, p = 0.007) and engaged in multi-dimensional nose sweeping and sniffing (2.2 ± 0.58 episodes vs. 5.5 ± 0.96 episodes, p = 0.03) than sham controls. CONCLUSIONS: These pilot findings of harmonized translational and precision biobehavioral assays provide an opportunity for increased expediency of clinical trials at the earliest stages of brain development.

Morbidity in children after fetoscopic endoluminal tracheal occlusion for severe congenital diaphragmatic hernia: Results from a multidisciplinary clinic.

BACKGROUND: Although fetoscopic endoluminal tracheal occlusion (FETO) was recently shown to improve survival in a multicenter, randomized trial of severe congenital diaphragmatic hernia (CDH), morbidity outcomes remain essentially unknown. The purpose of this study was to assess long-term outcomes in children with severe CDH who underwent FETO. METHODS: We conducted a prospective study of severe CDH patients undergoing FETO at an experienced North American center from 2015-2021 (NCT02710968). This group was compared to a cohort of non-FETO CDH patients with severe disease as defined by liver herniation, large defect size, and/or ECMO use. Clinical data were collected through a multidisciplinary CDH clinic. Statistics were performed with t-tests and Chi-squared analyses (p≤0.05). RESULTS: There were 18 FETO and 17 non-FETO patients. ECMO utilization was 56% in the FETO cohort. Despite significantly lower median observed/expected lung-to-head ratio (O/E LHR) in the FETO group, [FETO: 23% (IQR:18-25) vs. non-FETO: 36% (IQR: 28-41), p<0.001], there were comparable survival rates at discharge (FETO: 78% vs. non-FETO: 59%, p = 0.23) and at 5-years (FETO: 67% vs. non-FETO: 59%, p = 0.53) between the two cohorts. At a median follow up of 5.8 years, metrics of pulmonary hypertension, pulmonary morbidity, and gastroesophageal reflux disease improved among patients after FETO. However, most FETO patients remained on bronchodilators/inhaled corticosteroids (58%) and were feeding tube dependent (67%). CONCLUSIONS: These North American data show that prenatal tracheal occlusion, in conjunction with a long-term multidisciplinary CDH clinic, is associated with acceptable long-term survival and morbidity in children after FETO. LEVEL OF EVIDENCE: Level III.

Reduction in school individualized education program (IEP) services during the COVID-19 pandemic.

Purpose: The COVID-19 pandemic created novel challenges for school systems and students, particularly students with disabilities. In the shift to remote/distance learning, this report explores the degree to which children with disabilities did not receive the special education and related services defined in their individualized education program (IEP). Methods: Patients attending an outpatient tertiary care center for neurodevelopmental disabilities in Maryland were surveyed on the impact of the pandemic on educational services provision. Results: Nearly half (46%) of respondents qualified for special education and related services through an IEP before the start of the COVID-19 pandemic. Among those with IEPs, 48% attested to reduced frequency and/or duration of special education and/or related services during the pandemic. The reduction was greatest in occupational therapy services (47%), followed physical therapy services (46%), and special education services (34%). Conclusion: This survey of children with disabilities observes a substantial reduction in IEP services reported in their completed surveys. To address the observed reduction in IEP services, we sought additional education for clinicians on the rights of students with disabilities in anticipation of students' re-entry to the classroom. A special education law attorney provided an instructional session on compensatory education and recovery services to prepare clinicians to properly inform parents about their rights and advocate for patients with unmet IEP services during the pandemic.

Infantile Cocktail of Erythropoietin and Melatonin Restores Gait in Adult Rats with Preterm Brain Injury.

Cerebral palsy (CP) is the most common cause of physical disability for children worldwide. Many infants and toddlers are not diagnosed with CP until they fail to achieve obvious motor milestones. Currently, there are no effective pharmacologic interventions available for infants and toddlers to substantially improve their trajectory of neurodevelopment. Because children with CP from preterm birth also exhibit a sustained immune system hyper-reactivity, we hypothesized that neuro-immunomodulation with a regimen of repurposed endogenous neurorestorative medications, erythropoietin (EPO) and melatonin (MLT), could improve this trajectory. Thus, we administered EPO + MLT to rats with CP during human infant-toddler equivalency to determine whether we could influence gait patterns in mature animals. After a prenatal injury on embryonic day 18 (E18) that mimics chorioamnionitis at ∼25 weeks human gestation, rat pups were born and raised with their dam. Beginning on postnatal day 15 (P15), equivalent to human infant ∼1 year, rats were randomized to receive either a regimen of EPO + MLT or vehicle (sterile saline) through P20. Gait was assessed in young adult rats at P30 using computerized digital gait analyses including videography on a treadmill. Results indicate that gait metrics of young adult rats treated with an infantile cocktail of EPO + MLT were restored compared to vehicle-treated rats (p < 0.05) and similar to sham controls. These results provide reassuring evidence that pharmacological interventions may be beneficial to infants and toddlers who are diagnosed with CP well after the traditional neonatal window of intervention.

Parent preferences for neurodevelopmental screening in the neonatal intensive care unit.

AIM: To determine whether, and how, neonatal intensive care unit (NICU) parents want to receive early neurodevelopmental screening information about their child's future risk of cerebral palsy and other disabilities. METHOD: This was a qualitative interview study. Parents of hospitalized infants born preterm completed semi-structured interviews. Data were analysed using a directed content analysis approach. RESULTS: Thematic saturation was achieved after 19 interviews. Four themes characterized parent perceptions of early neurodevelopmental screening: (1) acceptability: most parents were in favour of neurodevelopmental screening if parents could refuse; (2) disclosure of results: parents want emotional preparation for results, especially false positives; (3) emotional burden of uncertainty: parents of children in the NICU balance taking their infant's illness 'day by day' and preparing for an uncertain future. Parents expressed distress with screening that increased uncertainty about the future; and (4) disability: prior experience with disability informs parent concerns. INTERPRETATION: Parents interpret the risks and benefits of NICU developmental screening through the lens of prior experiences with disability. Most expressed interest in screening and emphasized a desire for autonomy, pretest counselling, and emotional preparation. WHAT THIS PAPER ADDS: Most parents with infants in the neonatal intensive care unit expressed interest in early screening for developmental disability. Prior experience with disability informed concerns about specific deficits. Parents emphasized a desire for autonomy, pretest counselling, and emotional preparation.

Early neurodevelopmental outcome in preterm posthemorrhagic ventricular dilatation and hydrocephalus: Neonatal ICU Network Neurobehavioral Scale and imaging predict 3-6-month motor quotients and Capute Scales.

OBJECTIVE: Brain injury remains a serious complication of prematurity. Almost half of infants with severe intraventricular hemorrhage (IVH) develop posthemorrhagic ventricular dilatation (PHVD) and 20% need surgery for posthemorrhagic hydrocephalus (PHH). This population is associated with an increased risk of later neurodevelopmental disability, but there is uncertainty about which radiological and examination features predict later disability. In this study the authors sought to devise and describe a novel combination of neurobehavioral examination and imaging for prediction of neurodevelopmental disability among preterm infants with PHVD and PHH. METHODS: The study patients were preterm infants (< 36 weeks gestation) with IVH and PHVD, with or without PHH. Ventricular index (VI), anterior horn width (AHW), thalamooccipital distance (TOD), ventricle/brain (V/B) ratio, and resistive indices (RIs) were recorded on the head ultrasound (HUS) just prior to surgery, or the HUS capturing the worst PHVD when surgery was not indicated. The posterior fossa was assessed with MRI. Neonatal ICU Network Neurobehavioral Scale (NNNS) examinations were performed at term age equivalent for each infant. A neurodevelopmental assessment using the Capute Scales (Capute Cognitive Adaptive Test [CAT] scores and Capute Clinical Linguistic Auditory Milestone Scale [CLAMS] scores) and a motor quotient (MQ) assessment were performed between 3 and 6 months of age corrected for degree of prematurity (corrected age). MQs < 50 reflect moderate to severe delays in early motor milestone attainment, CAT scores < 85 reflect delays in early visual and problem-solving abilities, and CLAMS scores < 85 reflect delays in early language. RESULTS: Twenty-one infants underwent assessments that included imaging and NNNS examinations, Capute Scales assessments, and MQs. NNNS nonoptimal reflexes (NOR) and hypertonicity subscores and AHW were associated with MQs < 50: NOR subscore OR 2.46 (95% CI 1.15-37.6, p = 0.034), hypertonicity subscore OR 1.68 (95% CI 1.04-3.78, p = 0.037), and AHW OR 1.13 (95% CI 1.01-1.39, p = 0.041). PVHI, cystic changes, and neurosurgical intervention were associated with CAT scores < 85: PVHI OR 9.2 (95% CI 1.2-73.2, p = 0.037); cystic changes OR 12.0 (95% CI 1.0-141.3, p = 0.048), and neurosurgical intervention OR 11.2 (95% CI 1.0-120.4, p = 0.046). Every 1-SD increase in the NOR subscore was associated with an increase in odds of a CAT score < 85, OR 4.0 (95% CI 1.0-15.0, p = 0.044). Worse NNNS NOR subscores were associated with early language delay: for a 1-SD increase in NOR subscore, there was an increase in the odds of a CLAMS score < 85, OR 19.5 (95% CI 1.3-303, p = 0.034). CONCLUSIONS: In former preterm children with severe IVH and PHVD, neonatal neurological examination findings and imaging features are associated with delays at 3-6 months in motor milestones, visual and problem-solving abilities, and language.

Preschool Language Outcomes following Perinatal Hypoxic-Ischemic Encephalopathy in the Age of Therapeutic Hypothermia.

Early studies following perinatal hypoxic-ischemic encephalopathy (HIE) suggested expressive language deficits and academic difficulties, but there is only limited detailed study of language development in this population since the widespread adoption of therapeutic hypothermia (TH). Expressive and receptive language testing was performed as part of a larger battery with 45 children with a mean age of 26 months following perinatal HIE treated with TH. Overall cohort outcomes as well as the effects of gender, estimated household income, initial pH and base excess, and pattern of injury on neonatal brain MRI were assessed. The cohort overall demonstrated expressive language subscore, visual-reception subscore, and early learning composite scores significantly below test norms, with relative sparing of receptive language subscores. Poorer expressive language manifested as decreased vocabulary size and shorter utterances. Expressive language subscores showed a significant gender effect, and estimated socioeconomic status showed a significant effect on both receptive and expressive language subscores. Initial blood gas markers and modified Sarnat scoring did not show a significant effect on language subscores. Binarized MRI abnormality predicted a significant effect on both receptive and expressive language subscores; the presence of specific cortical/subcortical abnormalities predicted receptive language deficits. Overall, the language development profile of children following HIE in the era of hypothermia shows a relative strength in receptive language. Gender and socioeconomic status predominantly predict expressive language deficits; abnormalities detectable on MRI predominantly predict receptive language deficits.

The Relationship Between Clinical Imaging and Neurobehavioral Assessment in Posthemorrhagic Ventricular Dilation of Prematurity.

Introduction: Neonatal intraventricular hemorrhage (IVH) and subsequent posthemorrhagic ventricular dilation and hydrocephalus of prematurity are associated with brain injury and neurodevelopmental impairment in the preterm population. Neuroimaging assesses cerebral injury and guides neurosurgical intervention; however, the relationship of head ultrasound (HUS) and magnetic resonance imaging (MRI) parameters to neonatal exams in this group has not been well described. The NICU Network Neurobehavioral Scale (NNNS) is a reproducible, highly reliable battery with motor and cognitive domain scores. Objective: To evaluate the relationship between neonatal neurobehavioral findings on the NNNS and measures of ventricular dilation and associated brain injury on HUS and MRI. Materials and Methods: Neonates with IVH and ventricular dilatation with and without posthemorrhagic hydrocephalus were enrolled. NNNS exams were performed at approximately term age equivalent. HUS indices were measured on the last HUS before initial neurosurgical procedure or that with worst ventriculomegaly if no intervention. The posterior fossa was assessed with MRI at term. Descriptive statistics including medians, interquartile ranges, means, and percentages were performed. Correlations were estimated using Pearson's method. Results: 28 patients had NNNS and HUS, and 18 patients also had an MRI. Ventricle size measures for the cohort were significantly above normal. Motor and cognitive subscores on the NNNS exam varied from established baseline scores for postmenstrual age. Children who required neurosurgical intervention had higher ventricle/brain ratios and worse NNNS habituation scores. Ventricle sizes were modestly correlated with motor abnormalities (0.24-0.59); larger anterior horn width correlated with nonoptimal reflexes, hypertonicity and hypotonicity. Ventricle sizes were modestly correlated with cognitive scores (-0.44 to 0.27); larger ventricular index correlated with worse attention. Periventricular hemorrhagic infarction correlated with worse habituation. Conclusion: For this cohort of preterm infants with IVH, surgical intervention for posthemorrhagic hydrocephalus correlated with both larger degrees of ventriculomegaly and worse NNNS exams. Findings on both HUS and MRI correlated with motor and cognitive abnormalities on neonatal neurobehavioral exam, suggesting that larger neonatal ventricle sizes and white matter injury have detectable correlates on exam. The NNNS exam provides important additional information when assessing posthemorrhagic ventricular dilation and hydrocephalus of prematurity.

The Role of Diffusion Tensor Imaging in Detecting Hippocampal Injury Following Neonatal Hypoxic-Ischemic Encephalopathy.

BACKGROUND AND PURPOSE: Neonatal hypoxic-ischemic injury of the brain and resultant encephalopathy (HIE) leads to major developmental impairments by school age. Conventional/anatomical MRI often fails to detect hippocampal injury in mild cases. We hypothesize that diffusion tensor imaging (DTI) has greater sensitivity for identifying subtle hippocampal injury. METHODS: We retrospectively analyzed DTI data collected from a cohort of neonates with HIE and controls. Conventional MRI sequences were classified qualitatively according to severity using a modified Barkovich scale. Using multivariate linear regression, we compared hippocampal DTI scalars of HIE patients and controls. Spearman correlation was used to test the association of DTI scalars in the hippocampal and thalamic regions. A multiple regression analysis tested the association of the DTI scalars with short-term outcomes. RESULTS: Fifty-five neonates with HIE (42% males) and 13 controls (54% males) were included. Hippocampal DTI scalars were similar between HIE and control groups, even when restricting the HIE group to those with moderate-to-severe injury (8 subjects). DTI scalars of the thalamus were significantly lower in the moderate-to-severely affected patients compared to controls (right fractional anisotropy [FA] .148 vs. .182, P = .01; left FA .147 vs. .181, P = .03). Hippocampal and thalamic DTI scalars were correlated (P < .001). Hippocampal DTI scalars were not associated with short-term outcomes. CONCLUSIONS: Quantitative DTI analysis of the hippocampus in neonates following HIE is a feasible technique to examine neuronal injury. Although DTI scalars were useful in identifying thalamic injury in our cohort, hippocampal DTI analysis did not provide additional information regarding hippocampal injury following HIE.

Preterm neuroimaging and neurodevelopmental outcome: a focus on intraventricular hemorrhage, post-hemorrhagic hydrocephalus, and associated brain injury.

Intraventricular hemorrhage in the setting of prematurity remains the most common cause of acquired hydrocephalus. Neonates with progressive post-hemorrhagic hydrocephalus are at risk for adverse neurodevelopmental outcomes. The goal of this review is to describe the distinct and often overlapping types of brain injury in the preterm neonate, with a focus on neonatal hydrocephalus, and to connect injury on imaging to neurodevelopmental outcome risk. Head ultrasound and magnetic resonance imaging findings are described separately. The current state of the literature is imprecise and we end the review with recommendations for future radiologic and neurodevelopmental research.

A pilot cohort study of cerebral autoregulation and 2-year neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy who received therapeutic hypothermia.

BACKGROUND: Neurodevelopmental disabilities persist in survivors of neonatal hypoxic-ischemic encephalopathy (HIE) despite treatment with therapeutic hypothermia. Cerebrovascular autoregulation, the mechanism that maintains cerebral perfusion during changes in blood pressure, may influence outcomes. Our objective was to describe the relationship between acute autoregulatory vasoreactivity during treatment and neurodevelopmental outcomes at 2 years of age. METHODS: In a pilot study of 28 neonates with HIE, we measured cerebral autoregulatory vasoreactivity with the hemoglobin volume index (HVx) during therapeutic hypothermia, rewarming, and the first 6 h of normothermia. The HVx, which is derived from near-infrared spectroscopy, was used to identify the individual optimal mean arterial blood pressure (MAPOPT) at which autoregulatory vasoreactivity is greatest. Cognitive and motor neurodevelopmental evaluations were completed in 19 children at 21-32 months of age. MAPOPT, blood pressure in relation to MAPOPT, blood pressure below gestational age + 5 (ga + 5), and regional cerebral oximetry (rSO2) were compared to the neurodevelopmental outcomes. RESULTS: Nineteen children who had HIE and were treated with therapeutic hypothermia performed in the average range on cognitive and motor evaluations at 21-32 months of age, although the mean performance was lower than that of published normative samples. Children with impairments at the 2-year evaluation had higher MAPOPT values, spent more time with blood pressure below MAPOPT, and had greater blood pressure deviation below MAPOPT during rewarming in the neonatal period than those without impairments. Greater blood pressure deviation above MAPOPT during rewarming was associated with less disability and higher cognitive scores. No association was observed between rSO2 or blood pressure below ga + 5 and neurodevelopmental outcomes. CONCLUSION: In this pilot cohort, motor and cognitive impairments at 21-32 months of age were associated with greater blood pressure deviation below MAPOPT during rewarming following therapeutic hypothermia, but not with rSO2 or blood pressure below ga + 5. This suggests that identifying individual neonates' MAPOPT is superior to using hemodynamic goals based on gestational age or rSO2 in the acute management of neonatal HIE.

Measuring word learning: dynamic versus static assessment of kindergarten vocabulary.

UNLABELLED: This preliminary study investigated the potential of using a dynamic approach to assessing expressive word mapping. Because measuring word mapping with productive language responses is much more difficult than measuring receptive word mapping, incorporating a dynamic measure allowed us to tap partial mapping and provided useful information on word learning. Participants were 24 typically developing African American children, from high-risk backgrounds and low-risk backgrounds, as determined by school and family demographics. Performance was compared on the PPVT-III and on the dynamic assessment of word mapping. The dynamic assessment of word mapping provided information about complete and partial mapping of words. Additionally, there was an interaction between risk and performance on the vocabulary and word learning measures. These data suggest that the use of the dynamic measure in conjunction with traditional vocabulary measures may have the potential to provide an estimate of word-learning ability. LEARNING OUTCOMES: Readers will (1) be able to identify the need for word-learning measures and (2) become familiar with the combined technique of using dynamic assessment and fast mapping.