Reverse Therapy: Impact of Hyperthermia and Rewarming on Newborn Outcomes.

Therapeutic hypothermia is now well established to improve neurodevelopmental outcomes after hypoxic-ischemic encephalopathy (HIE). Although the overall principles of treatment are now well established, many smaller questions are unclear. The potential impact of reversal of hypothermia therapy and the effect of high temperatures on recovery of the neurovascular unit after therapeutic hypothermia for HIE has received relatively little attention. This article will address the effects of hypoxia-ischemia and rewarming and increased temperatures on the neurovascular unit in preclinical and clinical models.

A New Horizon for Understanding the Comparative Effectiveness for Cooling Prospectively Infants with Mild Encephalopathy.

The authors summarize the methodology for a new pragmatic comparative effectiveness research investigation, Cooling Prospectively Infants with Mild Encephalopathy (COOLPRIME), which uses sites' existing mild hypoxic-ischemic encephalopathy (HIE) treatment preference (hypothermia or normothermia) to assess hypothermia effectiveness and safety. COOLPRIME's primary aim is to determine the safety and effectiveness of hypothermia compared to normothermia in mild HIE. Engagement of Families and Community Affected by Hypoxic-Ischemic Encephalopathy strongly favored Effectiveness over Efficacy Trials leading to COOL PRIME design.

Key Inflammatory Biomarkers in Perinatal Asphyxia: A Comprehensive Review.

This article summarizes the current evidence regarding inflammatory biomarkers (placental and postnatal) and provides a comprehensive understanding of their roles: (1) diagnostic accuracy to predict the severity of hypoxic-ischemia encephalopathy (HIE), (2) value in assessing treatment responses, and (3) prediction of both short- and long-term neurodevelopmental outcomes. In the early critical stages of perinatal asphyxia, inflammatory biomarkers may guide clinical decision-making. Additional research is required to increase our understanding of the optimal utility of biomarkers to predict the severity, evolution, and developmental outcomes after exposure to HIE.

Neurodevelopmental outcomes in extremely preterm infants with placental pathologic evidence of fetal inflammatroy response.

OBJECTIVES: Neonates born with fetal inflammatory response (FIR) are at increased risk for adverse neonatal outcomes. Our objective was to determine whether FIR and its severity is associated with neurodevelopmental impairment (NDI) at 2 years of age or death among preterm infants. METHODS: A retrospective cohort study of prospectively collected data of all infants born <29 weeks gestational age (GA). FIR and its severity were diagnosed according to the Amsterdam Placental Workshop Group Consensus Statement. Neurodevelopmental outcomes among all participants were quantified according to Bayley III. RESULTS: Mothers of infants with FIR were significantly younger (P = 0.04) and had a greater prevalence of antenatal steroid use (P < 0.01), infection during pregnancy (P = 0.01), PPROM (P < 0.01), and clinical chorioamnionitis (P < 0.01). Infants with FIR had longer duration of hospitalization (P < 0.01), days on oxygen (P < 0.01), congenital pneumonia (P = 0.03), moderate/severe bronchopulmonary dysplasia (BPD; P < 0.01). Notably, infants with FIR were not at increased risk of NDI or death (primary outcome). Those with moderate to severe FIR (≥ stage 2 FIR) were at increased risk of developing motor & language impairment or death (P < 0.01). CONCLUSION: This is the first report demonstrating an association between the severity of FIR and subsequent NDI in preterm infants born. IMPACT STATEMENT: Fetal Inflammatory Response (FIR) is not associated Neurodevelopmental Impairement (NDI) or Death in preterm infants However, there is significant relationship between moderate to severe FIR and NDI at 2 years of age in preterm infants. This is the first study demonstrating the impact of progression and severity of FIR on NDI or Death in preterm infants. These observations provide additional insight into understanding the impact of intrauterine exposure to inflammation on the NDI or death in preterm infants.

Prognostic value of quantitative EEG in early hours of life for neonatal encephalopathy and neurodevelopmental outcomes.

BACKGROUND: The ability to determine severity of encephalopathy is crucial for early neuroprotective therapies and for predicting neurodevelopmental outcome. The objective of this study was to assess a novel brain state of newborn (BSN) trend to distinguish newborns with presence of hypoxic ischemic encephalopathy (HIE) within hours after birth and predict neurodevelopmental outcomes at 2 years of age. METHOD: This is a prospective cohort study of newborns at 36 weeks' gestation or later with and without HIE at birth. The Total Sanart Score (TSS) was calculated based on a modified Sarnat exam within 6 h of life. BSN was calculated from electroencephalogram (EEG) measurements initiated after birth. The primary outcome at 2 year of age was a diagnosis of death or disability using the Bayley Scales of Infant Development III. RESULTS: BSN differentiated between normal and abnormal neurodevelopmental outcomes throughout the entire recording period from 6 h of life. Additionally, infants with lower BSN values had higher odds of neurodevelopmental impairment and HIE. BSN distinguished between normal (n = 86) and HIE (n = 46) and showed a significant correlation with the concomitant TSS. CONCLUSION: BSN is a sensitive real-time marker for monitoring dynamic progression of encephalopathy and predicting neurodevelopmental impairment. IMPACT: This is a prospective cohort study to investigate the ability of brain state of newborn (BSN) trend to predict neurodevelopmental outcome within the first day of life and identify severity of encephalopathy. BSN predicts neurodevelopmental outcomes at 2 years of age and the severity of encephalopathy severity. It also correlates with the Total Sarnat Score from the modified Sarnat exam. BSN could serve as a promising bedside trend aiding in accurate assessment and identification of newborns who may benefit from additional neuroprotection therapies.

Consensus definition and diagnostic criteria for neonatal encephalopathy-study protocol for a real-time modified delphi study.

BACKGROUND: 'Neonatal encephalopathy' (NE) describes a group of conditions in term infants presenting in the earliest days after birth with disturbed neurological function of cerebral origin. NE is aetiologically heterogenous; one cause is peripartum hypoxic ischaemia. Lack of uniformity in the terminology used to describe NE and its diagnostic criteria creates difficulty in the design and interpretation of research and complicates communication with families. The DEFINE study aims to use a modified Delphi approach to form a consensus definition for NE, and diagnostic criteria. METHODS: Directed by an international steering group, we will conduct a systematic review of the literature to assess the terminology used in trials of NE, and with their guidance perform an online Real-time Delphi survey to develop a consensus diagnosis and criteria for NE. A consensus meeting will be held to agree on the final terminology and criteria, and the outcome disseminated widely. DISCUSSION: A clear and consistent consensus-based definition of NE and criteria for its diagnosis, achieved by use of a modified Delphi technique, will enable more comparability of research results and improved communication among professionals and with families. IMPACT: The terms Neonatal Encephalopathy and Hypoxic Ischaemic Encephalopathy tend to be used interchangeably in the literature to describe a term newborn with signs of encephalopathy at birth. This creates difficulty in communication with families and carers, and between medical professionals and researchers, as well as creating difficulty with performance of research. The DEFINE project will use a Real-time Delphi approach to create a consensus definition for the term 'Neonatal Encephalopathy'. A definition formed by this consensus approach will be accepted and utilised by the neonatal community to improve research, outcomes, and parental experience.

Association between decreased cord blood inter-alpha inhibitor levels and neonatal encephalopathy at birth.

BACKGROUND: Inter-alpha inhibitor proteins (IAIPs) are structurally related proteins found in the systemic circulation with immunomodulatory anti-inflammatory properties. Reduced levels are found in inflammatory related conditions including sepsis and necrotizing enterocolitis, and in neonatal rodents after exposure to hypoxia ischemia. In the current study, cord blood IAIP levels were measured in neonates with and without exposure to hypoxic-ischemic encephalopathy (HIE). METHODS: This is a prospective cohort study including infants born ≥36 weeks over a one-year period. Term pregnancies were divided into two groups: a "reference control" (uncomplicated term deliveries), and "moderate to severe HIE" (qualifying for therapeutic hypothermia). IAIPs were quantified using a sensitive ELISA on the cord blood samples. RESULTS: The study included 57 newborns: Reference control group (n = 13) and moderate/severe HIE group (n = 44). Measurement of IAIP cord blood concentrations in moderate to severe HIE group [278.2 (138.0, 366.0) µg/ml] revealed significantly lower IAIP concentrations compared with the control group [418.6 (384.5, 445.0) µg/ml] (p = 0.002). CONCLUSIONS: These findings suggest a potential role for IAIPs as indicators of neonates at risk for HIE. IAIP levels could have diagnostic implications in the management of HIE. Future research is required to explore the relationship between HIE and IAIPs as biomarkers for disease severity. CATEGORY OF STUDY: Translational.

Development of neonatal connectome dynamics and its prediction for cognitive and language outcomes at age 2.

The functional brain connectome is highly dynamic over time. However, how brain connectome dynamics evolves during the third trimester of pregnancy and is associated with later cognitive growth remains unknown. Here, we use resting-state functional Magnetic Resonance Imaging (MRI) data from 39 newborns aged 32 to 42 postmenstrual weeks to investigate the maturation process of connectome dynamics and its role in predicting neurocognitive outcomes at 2 years of age. Neonatal brain dynamics is assessed using a multilayer network model. Network dynamics decreases globally but increases in both modularity and diversity with development. Regionally, module switching decreases with development primarily in the lateral precentral gyrus, medial temporal lobe, and subcortical areas, with a higher growth rate in primary regions than in association regions. Support vector regression reveals that neonatal connectome dynamics is predictive of individual cognitive and language abilities at 2  years of age. Our findings highlight network-level neural substrates underlying early cognitive development.

Postnatal Cerebral Hemodynamics and Placental Vascular Malperfusion Lesions in Neonates With Congenital Heart Disease.

BACKGROUND: Neonates with congenital heart disease (CHD) have smaller brain volume at birth. High rates of placental vascular malperfusion lesions may play a role in disrupted brain development. METHODS: This is a single-center retrospective cohort study of infants born between 2010 and 2019 who were diagnosed with a major cardiac defect requiring surgery in the first year of life. Doppler ultrasound RI of the middle cerebral artery (MCA) and anterior cerebral artery were calculated within the first 72 hours of life. Placentas were evaluated using a standardized approach. RESULTS: Over the study period, there were 52 patients with hypoplastic left heart syndrome (HLHS), 22 with single-ventricle right ventricular outflow tract obstruction (SV-RVOTO), 75 with a two-ventricle cardiac defect (2V), and 25 with transposition of the great arteries (TGA). MCA Doppler RI were significantly higher for all subgroups of CHD compared with control subjects (0.68 ± 0.11 in control subjects compared with 0.78 ± 0.13 in HLHS, P = 0.03; 0.77 ± 0.10 in SV-RVOTO, P = 0.002; 0.78 ± 0.13 in 2V, P = 0.03; and 0.80 ± 0.14 in TGA; P = 0.001) with the highest average MCA RI in the TGA group. In subgroup analyses, placental fetal vascular malperfusion in the 2V group was associated with higher MCA RI, but this relationship was not present in other subgroups, nor in regards to maternal vascular malperfusion. CONCLUSIONS: Major forms of CHD are associated with significantly higher cerebral artery RI postnatally, but placental vascular malperfusion lesions may not contribute to this hemodynamic adaptation.

Genetic and Congenital Anomalies in Infants With Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Infants with hypoxic ischemic encephalopathy (HIE) may have underlying conditions predisposing them to hypoxic-ischemic injury during labor and delivery. It is unclear how genetic and congenital anomalies impact outcomes of HIE. METHODS: Infants with HIE enrolled in a phase III trial underwent genetic testing when clinically indicated. Infants with known genetic or congenital anomalies were excluded. The primary outcome, i.e., death or neurodevelopmental impairment (NDI), was determined at age two years by a standardized neurological examination, Bayley Scales of Infant Development, Third Edition (BSID-III), and the Gross Motor Function Classification Scales. Secondary outcomes included cerebral palsy and BSID-III motor, cognitive, and language scores at age two years. RESULTS: Of 500 infants with HIE, 24 (5%, 95% confidence interval 3% to 7%) were diagnosed with a genetic (n = 15) or congenital (n = 14) anomaly. Infants with and without genetic or congenital anomalies had similar rates of severe encephalopathy and findings on brain magnetic resonance imaging. However, infants with genetic or congenital anomalies were more likely to have death or NDI (75% vs 50%, P = 0.02). Among survivors, those with a genetic or congenital anomaly were more likely to be diagnosed with cerebral palsy (32% vs 13%, P = 0.02), and had lower BSID-III scores in all three domains than HIE survivors without such anomalies. CONCLUSIONS: Among infants with HIE, 5% were diagnosed with a genetic or congenital anomaly. Despite similar clinical markers of HIE severity, infants with HIE and a genetic or congenital anomaly had worse neurodevelopmental outcomes than infants with HIE alone.

Development of sensorimotor-visual connectome gradient at birth predicts neurocognitive outcomes at 2 years of age.

Functional connectome gradients represent fundamental organizing principles of the brain. Here, we report the development of the connectome gradients in preterm and term babies aged 31-42 postmenstrual weeks using task-free functional MRI and its association with postnatal cognitive growth. We show that the principal sensorimotor-to-visual gradient is present during the late preterm period and continuously evolves toward a term-like pattern. The global measurements of this gradient, characterized by explanation ratio, gradient range, and gradient variation, increased with age (p < 0.05, corrected). Focal gradient development mainly occurs in the sensorimotor, lateral, and medial parietal regions, and visual regions (p < 0.05, corrected). The connectome gradient at birth predicts cognitive and language outcomes at 2-year follow-up (p < 0.005). These results are replicated using an independent dataset from the Developing Human Connectome Project. Our findings highlight early emergent rules of the brain connectome gradient and their implications for later cognitive growth.

Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants: A Secondary Near-Infrared Spectroscopy Study of the Transfusion of Prematures Randomized Clinical Trial (TOP NIRS).

Importance: Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes. Objective: To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age. Design, Setting, and Participants: This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022. Interventions: Near-infrared spectroscopy monitoring of Csat and Msat. Main Outcomes and Measures: Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment. Results: A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower-hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher-hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs -0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03). Conclusions and Relevance: In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia. Trial Registration: ClinicalTrials.gov Identifier: NCT01702805.

Sex Vulnerabilities to Hypoxia-Ischemia at Birth.

This cross-sectional study examines the incidence of hypoxic ischemic encephalopathy in male vs female neonates.