Regional variability in therapeutic hypothermia eligibility criteria for neonatal hypoxic-ischemic encephalopathy.

Early induced therapeutic hypothermia represents the cornerstone treatment in neonates with probable hypoxic-ischemic encephalopathy. The selection of patients for treatment usually involves meeting criteria indicating evidence of perinatal hypoxia-ischemia and the presence of moderate or severe encephalopathy. In this review, we highlight the variability that exists between some of the different regional and national eligibility guidelines. Determining the potential presence of perinatal hypoxia-ischemia may require either one, two or three signs amongst history of acute perinatal event, prolonged resuscitation at delivery, abnormal blood gases and low Apgar score, with a range of cutoff values. Clinical neurological exams often define the severity of encephalopathy differently, with varying number of domains required for determining eligibility and blurred interpretation of findings assigned to different severity grades in different systems. The role of early electrophysiological assessment is weighted differently. A clinical implication is that infants may receive different care depending on the location in which they are born. This could also impact epidemiological data, as inference of rates of moderate-severe encephalopathy based on therapeutic hypothermia rates are misleading and influenced by different eligibility methods used. We would advocate that a universally endorsed single severity staging of encephalopathy is vital for standardizing management and neonatal outcome. IMPACT: Variability exists between regional and national therapeutic hypothermia eligibility guidelines for neonates with probable hypoxic-ischemic encephalopathy. Differences are common in both criteria indicating perinatal hypoxia-ischemia and criteria defining moderate or severe encephalopathy. The role of early electrophysiological assessment is also weighted unequally. This reflects in different individual care and impacts research data. A universally endorsed single severity staging of encephalopathy would be crucial for standardizing management.

Machine learning for the early prediction of infants with electrographic seizures in neonatal hypoxic-ischemic encephalopathy.

OBJECTIVE: To assess if early clinical and electroencephalography (EEG) features predict later seizure development in infants with hypoxic-ischemic encephalopathy (HIE). METHODS: Clinical and EEG parameters <12 h of birth from infants with HIE across eight European Neonatal Units were used to develop seizure-prediction models. Clinical parameters included intrapartum complications, fetal distress, gestational age, delivery mode, gender, birth weight, Apgar scores, assisted ventilation, cord pH, and blood gases. The earliest EEG hour provided a qualitative analysis (discontinuity, amplitude, asymmetry/asynchrony, sleep-wake cycle [SWC]) and a quantitative analysis (power, discontinuity, spectral distribution, inter-hemispheric connectivity) from full montage and two-channel amplitude-integrated EEG (aEEG). Subgroup analysis, only including infants without anti-seizure medication (ASM) prior to EEG was also performed. Machine-learning (ML) models (random forest and gradient boosting algorithms) were developed to predict infants who would later develop seizures and assessed using Matthews correlation coefficient (MCC) and area under the receiver-operating characteristic curve (AUC). RESULTS: The study included 162 infants with HIE (53 had seizures). Low Apgar, need for ventilation, high lactate, low base excess, absent SWC, low EEG power, and increased EEG discontinuity were associated with seizures. The following predictive models were developed: clinical (MCC 0.368, AUC 0.681), qualitative EEG (MCC 0.467, AUC 0.729), quantitative EEG (MCC 0.473, AUC 0.730), clinical and qualitative EEG (MCC 0.470, AUC 0.721), and clinical and quantitative EEG (MCC 0.513, AUC 0.746). The clinical and qualitative-EEG model significantly outperformed the clinical model alone (MCC 0.470 vs 0.368, p-value .037). The clinical and quantitative-EEG model significantly outperformed the clinical model (MCC 0.513 vs 0.368, p-value .012). The clinical and quantitative-EEG model for infants without ASM (n = 131) had MCC 0.588, AUC 0.832. Performance for quantitative aEEG (n = 159) was MCC 0.381, AUC 0.696 and clinical and quantitative aEEG was MCC 0.384, AUC 0.720. SIGNIFICANCE: Early EEG background analysis combined with readily available clinical data helped predict infants who were at highest risk of seizures, hours before they occur. Automated quantitative-EEG analysis was as good as expert analysis for predicting seizures, supporting the use of automated assessment tools for early evaluation of HIE.

Sleep state organisation of moderate to late preterm infants in the neonatal unit.

BACKGROUND: Sleep supports neurodevelopment and sleep architecture reflects brain maturation. This prospective observational study describes the nocturnal sleep architecture of healthy moderate to late preterm (MLP) infants in the neonatal unit at 36 weeks post menstrual age (PMA). METHODS: MLP infants, in the neonatal unit of a tertiary hospital in Ireland from 2017 to 2018, had overnight continuous electroencephalography (cEEG) with video for a minimum 12 h at 36 weeks PMA. The total sleep time (TST) including periods of active sleep (AS), quiet sleep (QS), indeterminate sleep (IS), wakefulness and feeding were identified, annotated and quantified. RESULTS: A total of 98 infants had cEEG with video monitoring suitable for analysis. The median (IQR) of TST in the 12 h period was 7.09 h (IQR 6.61-7.76 h), 4.58 h (3.69-5.09 h) in AS, 2.02 h (1.76-2.36 h) in QS and 0.65 h (0.48-0.89 h) in IS. The total duration of AS was significantly lower in infants born at lower GA (p = 0.007) whilst the duration of individual QS periods was significantly higher (p = 0.001). CONCLUSION: Overnight cEEG with video at 36 weeks PMA showed that sleep state architecture is dependent on birth GA. Infants with a lower birth GA have less AS and more QS that may have implications for later neurodevelopment. IMPACT: EEG provides objective information about the sleep organisation of the moderate to late preterm (MLP) infant. Quantitative changes in sleep states occur with each week of advancing gestational age (GA). Active sleep (AS) is the dominant sleep state that was significantly lower in infants born at lower GA. MLP infants who were exclusively fed orally had a shorter total sleep time and less AS compared to infants who were fed via nasogastric tube.

Parent-led massage and sleep EEG for term-born infants: A randomized controlled parallel-group study.

AIM: To examine the impact of parent-led massage on the sleep electroencephalogram (EEG) features of typically developing term-born infants at 4 months. METHOD: Infants recruited at birth were randomized to intervention (routine parent-led massage) and control groups. Infants had a daytime sleep EEG at 4 months and were assessed using the Griffiths Scales of Child Development, Third Edition at 4 and 18 months. Comparative analysis between groups and subgroup analysis between regularly massaged and never-massaged infants were performed. Groups were compared for sleep stage, sleep spindles, quantitative EEG (primary analysis), and Griffiths using the Mann-Whitney U test. RESULTS: In total, 179 out of 182 infants (intervention: 83 out of 84; control: 96 out of 98) had a normal sleep EEG. Median (interquartile range) sleep duration was 49.8 minutes (39.1-71.4) (n = 156). A complete first sleep cycle was seen in 67 out of 83 (81%) and 72 out of 96 (75%) in the intervention and control groups respectively. Groups did not differ in sleep stage durations, latencies to sleep and to rapid eye movement sleep. Sleep spindle spectral power was greater in the intervention group in main and subgroup analyses. The intervention group showed greater EEG magnitudes, and lower interhemispherical coherence on subgroup analyses. Griffiths assessments at 4 months (n = 179) and 18 months (n = 173) showed no group differences in the main and subgroup analyses. INTERPRETATION: Routine massage is associated with distinct functional brain changes at 4 months. WHAT THIS PAPER ADDS: Routine massage of infants is associated with differences in sleep electroencephalogram biomarkers at 4 months. Massaged infants had higher sleep spindle spectral power, greater sleep EEG magnitudes, and lower interhemispherical coherence. No differences between groups were observed in total nap duration or first cycle macrostructure.

The Architecture of Early Childhood Sleep Over the First Two Years.

INTRODUCTION: The architecture and function of sleep during infancy and early childhood has not been fully described in the scientific literature. The impact of early sleep disruption on cognitive and physical development is also under-studied. The aim of this review was to investigate early childhood sleep development over the first two years and its association with neurodevelopment. METHODS: This review was conducted according to the 2009 PRISMA guidelines. Four databases (OVID Medline, Pubmed, CINAHL, and Web of Science) were searched according to predefined search terms. RESULTS: Ninety-three studies with approximately 90,000 subjects from demographically diverse backgrounds were included in this review. Sleep is the predominant state at birth. There is an increase in NREM and a decrease in REM sleep during the first two years. Changes in sleep architecture occur in tandem with development. There are more studies exploring sleep and early infancy compared to mid and late infancy and early childhood. DISCUSSION: Sleep is critical for memory, learning, and socio-emotional development. Future longitudinal studies in infants and young children should focus on sleep architecture at each month of life to establish the emergence of key characteristics, especially from 7-24 months of age, during periods of rapid neurodevelopmental progress.

Neonatal Seizure Management: Is the Timing of Treatment Critical?

OBJECTIVE: To assess the impact of the time to treatment of the first electrographic seizure on subsequent seizure burden and describe overall seizure management in a large neonatal cohort. STUDY DESIGN: Newborns (36-44 weeks of gestation) requiring electroencephalographic (EEG) monitoring recruited to 2 multicenter European studies were included. Infants who received antiseizure medication exclusively after electrographic seizure onset were grouped based on the time to treatment of the first seizure: antiseizure medication within 1 hour, between 1 and 2 hours, and after 2 hours. Outcomes measured were seizure burden, maximum seizure burden, status epilepticus, number of seizures, and antiseizure medication dose over the first 24 hours after seizure onset. RESULTS: Out of 472 newborns recruited, 154 (32.6%) had confirmed electrographic seizures. Sixty-nine infants received antiseizure medication exclusively after the onset of electrographic seizure, including 21 infants within 1 hour of seizure onset, 15 between 1 and 2 hours after seizure onset, and 33 at >2 hours after seizure onset. Significantly lower seizure burden and fewer seizures were noted in the infants treated with antiseizure medication within 1 hour of seizure onset (P = .029 and .035, respectively). Overall, 258 of 472 infants (54.7%) received antiseizure medication during the study period, of whom 40 without electrographic seizures received treatment exclusively during EEG monitoring and 11 with electrographic seizures received no treatment. CONCLUSIONS: Treatment of neonatal seizures may be time-critical, but more research is needed to confirm this. Improvements in neonatal seizure diagnosis and treatment are also needed.

The impact of perinatal inflammation on the electroencephalogram in preterm infants: a systematic review.

BACKGROUND: To summarise the association between perinatal inflammation (PI) exposure and electroencephalography (EEG) features in preterm infants. METHODS: This systematic review included clinical studies of preterm infants born <37 weeks of gestational age (GA), who had both a PI exposure and an EEG assessment performed during the neonatal period. Studies were identified from Medline and Embase databases on the 15th of September 2021. PI was defined by histological chorioamnionitis, clinical chorioamnionitis, or early-onset neonatal infection (EONI). The risk of bias in included studies was assessed using the Joanna Briggs Institute (JBI) appraisal tool. A narrative approach was used to synthesise results. This review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statement. RESULTS: Two cross-sectional studies enrolling 130 preterm children born <32 weeks of GA assessed with one-channel amplitude-integrated EEG (aEEG) during the first four days of life were included. A PI exposure was described in 39 (30%) infants and was associated with a decrease in amplitude and a reduced incidence of sleep-wake cycling patterns. CONCLUSION: These results should be interpreted with caution because of the small number of included studies and their heterogeneity. Further clinical studies evaluating the association of PI with EEG findings are needed. IMPACT: A method to assess developmental trajectories following perinatal inflammation is required. Insufficient data exist to determine EEG features associated with perinatal inflammation. Further clinical studies evaluating this association are needed.

Evolution of early cerebral NIRS in hypoxic ischaemic encephalopathy.

AIM: To describe early cerebral oxygenation (cSO2 ) and fractional tissue oxygen extraction (FTOE) values and their evolution over the first days of life in infants with all grades of hypoxic-ischaemic encephalopathy (HIE) and to determine whether cSO2 and FTOE measured early (6 and 12 h) can predict short-term outcome. METHODS: Prospective, observational study of cerebral near-infrared spectroscopy (NIRS) in infants >36 weeks' gestation with HIE. Ten one-hour epochs of cSO2 and FTOE were extracted for each infant over the first 84 h. Infants with moderate and severe HIE received therapeutic hypothermia (TH). Abnormal outcome was defined as abnormal magnetic resonance imaging (MRI) and/or death. RESULTS: Fifty-eight infants were included (28 mild, 24 moderate, 6 severe). Median gestational age was 39.9 weeks (IQR 38.1-40.7) and birthweight was 3.35 kgs (IQR 2.97-3.71). cSO2 increased and FTOE decreased over the first 24 h in all grades of HIE. Compared to the moderate group, infants with mild HIE had significantly higher cSO2 at 6 h (p = 0.003), 9 h (p = 0.009) and 12 h (p = 0.032) and lower FTOE at 6 h (p = 0.016) and 9 h (0.029). cSO2 and FTOE at 6 and 12 h did not predict abnormal outcome. CONCLUSION: Infants with mild HIE have higher cSO2 and lower FTOE than those with moderate or severe HIE in the first 12 h of life. cSO2 increased in all grades of HIE over the first 24 h regardless of TH status.

Up-Regulation of Nfat5 mRNA and Fzd4 mRNA as a Marker of Poor Outcome in Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To evaluate umbilical cord messenger RNA (mRNA) expression as biomarkers for the grade of hypoxic-ischemic encephalopathy (HIE) and long-term neurodevelopment outcome. STUDY DESIGN: Infants were recruited from the BiHiVE1 study, Ireland (2009-2011), and the BiHiVE2 study, Ireland, and Sweden (2013-2015). Infants with HIE were assigned modified Sarnat scores at 24 hours and followed at 18-36 months. mRNA expression from cord blood was measured using quantitative real-time polymerase chain reaction. RESULTS: We studied 124 infants (controls, n = 37; perinatal asphyxia, n = 43; and HIE, n = 44). Fzd4 mRNA increased in severe HIE (median relative quantification, 2.98; IQR, 2.23-3.68) vs mild HIE (0.88; IQR, 0.46-1.37; P = .004), and in severe HIE vs moderate HIE (1.06; IQR, 0.81-1.20; P = .003). Fzd4 mRNA also increased in infants eligible for therapeutic hypothermia (1.20; IQR, 0.92-2.37) vs those who were ineligible for therapeutic hypothermia group (0.81; IQR, 0.46-1.53; P = .017). Neurodevelopmental outcome was analyzed for 56 infants. Nfat5 mRNA increased in infants with severely abnormal (1.26; IQR, 1.17-1.39) vs normal outcomes (0.97; IQR, 0.83-1.24; P = .036), and also in infants with severely abnormal vs mildly abnormal outcomes (0.96; IQR, 0.80-1.06; P = .013). Fzd4 mRNA increased in infants with severely abnormal (2.51; IQR, 1.60-3.56) vs normal outcomes (0.74; IQR, 0.48-1.49; P = .004) and in infants with severely abnormal vs mildly abnormal outcomes (0.97; IQR, 0.75-1.34; P = .026). CONCLUSIONS: Increased Fzd4 mRNA expression was observed in cord blood of infants with severe HIE; Nfat5 mRNA and Fzd4 mRNA expression were increased in infants with severely abnormal long-term outcomes. These mRNA may augment current measures as early objective markers of HIE severity at delivery.

Improvement in the Prediction of Neonatal Hypoxic-Ischemic Encephalopathy with the Integration of Umbilical Cord Metabolites and Current Clinical Makers.

OBJECTIVE: To validate our previously identified candidate metabolites, and to assess the ability of these metabolites to predict hypoxic-ischemic encephalopathy (HIE) both individually and combined with clinical data. STUDY DESIGN: Term neonates with signs of perinatal asphyxia, with and without HIE, and matched controls were recruited prospectively at birth from 2 large maternity units. Umbilical cord blood was collected for later batch metabolomic analysis by mass spectroscopy along with clinical details. The optimum selection of clinical and metabolites features with the ability to predict the development of HIE was determined using logistic regression modelling and machine learning techniques. Outcome of HIE was determined by clinical Sarnat grading and confirmed by electroencephalogram grade at 24 hours. RESULTS: Fifteen of 27 candidate metabolites showed significant alteration in infants with perinatal asphyxia or HIE when compared with matched controls. Metabolomic data predicted the development of HIE with an area under the curve of 0.67 (95% CI, 0.62-0.71). Lactic acid and alanine were the primary metabolite predictors for the development of HIE, and when combined with clinical data, gave an area under the curve of 0.96 (95% CI, 0.92-0.95). CONCLUSIONS: By combining clinical and metabolic data, accurate identification of infants who will develop HIE is possible shortly after birth, allowing early initiation of therapeutic hypothermia.

Multichannel EEG abnormalities during the first 6 hours in infants with mild hypoxic-ischaemic encephalopathy.

BACKGROUND: Infants with mild HIE are at risk of significant disability at follow-up. In the pre-therapeutic hypothermia (TH) era, electroencephalography (EEG) within 6 hours of birth was most predictive of outcome. This study aims to identify and describe features of early EEG and heart rate variability (HRV) (<6 hours of age) in infants with mild HIE compared to healthy term infants. METHODS: Infants >36 weeks with mild HIE, not undergoing TH, with EEG before 6 hours of age were identified from 4 prospective cohort studies conducted in the Cork University Maternity Services, Ireland (2003-2019). Control infants were taken from a contemporaneous study examining brain activity in healthy term infants. EEGs were qualitatively analysed by two neonatal neurophysiologists and quantitatively assessed using multiple features of amplitude, spectral shape and inter-hemispheric connectivity. Quantitative features of HRV were assessed in both the groups. RESULTS: Fifty-eight infants with mild HIE and sixteen healthy term infants were included. Seventy-two percent of infants with mild HIE had at least one abnormal EEG feature on qualitative analysis and quantitative EEG analysis revealed significant differences in spectral features between the two groups. HRV analysis did not differentiate between the groups. CONCLUSIONS: Qualitative and quantitative analysis of the EEG before 6 hours of age identified abnormal EEG features in mild HIE, which could aid in the objective identification of cases for future TH trials in mild HIE. IMPACT: Infants with mild HIE currently do not meet selection criteria for TH yet may be at risk of significant disability at follow-up. In the pre-TH era, EEG within 6 hours of birth was most predictive of outcome; however, TH has delayed this predictive value. 72% of infants with mild HIE had at least one abnormal EEG feature in the first 6 hours on qualitative assessment. Quantitative EEG analysis revealed significant differences in spectral features between infants with mild HIE and healthy term infants. Quantitative EEG features may aid in the objective identification of cases for future TH trials in mild HIE.

Activin A and Acvr2b mRNA from Umbilical Cord Blood Are Not Reliable Markers of Mild or Moderate Neonatal Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Activin A protein and its receptor ACVR2B have been considered viable biomarkers for the diagnosis of hypoxic-ischemic encephalopathy (HIE). This study aimed to assess umbilical cord blood (UCB) levels of Activin A and Acvr2b messenger RNA (mRNA) as early biomarkers of mild and moderate HIE and long-term neurodevelopmental outcome. METHODS: One-hundred and twenty-six infants were included in the analyses from the BiHiVE2 cohort, a multi-center study, recruited in Ireland and Sweden (2013 to 2015). UCB serum Activin A and whole blood Acvr2b mRNA were measured using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. RESULTS: Activin A analysis included 101 infants (controls, n = 50, perinatal asphyxia, n = 28, HIE, n = 23). No differences were detected across groups (p = 0.69). No differences were detected across HIE grades (p = 0.12). Acvr2b mRNA analysis included 67 infants (controls, n = 22, perinatal asphyxia, n = 23, and HIE, n = 22), and no differences were observed across groups (p = 0.75). No differences were detected across HIE grades (p = 0.58). No differences were detected in neurodevelopmental outcome in infants followed up to 18 to 36 months in serum Activin A or in whole blood Acvr2b mRNA (p = 0.55 and p = 0.90, respectively). CONCLUSION: UCB Activin A and Acvr2b mRNA are not valid biomarkers of infants with mild or moderate HIE; they are unable to distinguish infants with HIE or infants with poor neurodevelopmental outcomes.

Impact of therapeutic hypothermia on infantile spasms: an observational cohort study.

AIM: To establish the incidence of infantile spasms in children in the southern region of the Republic of Ireland and to compare the incidence of infantile spasms before and after the introduction of therapeutic hypothermia in infants with hypoxic-ischemic encephalopathy (HIE). METHOD: Children born between 2003 and 2015 and diagnosed with infantile spasms (epileptic spasms with or without hypsarrhythmia) in the first 2 years of life were identified through audits of electroencephalography reports and paediatric neurology patient lists. Data on live births were obtained from the regional hospital statistics databases. Medical charts of infantile spasm cases were reviewed for demographic information, diagnostic workup results, treatment response, disease course, and developmental outcome. RESULTS: Forty-two infants with infantile spasms were identified. The cumulative incidence of infantile spasms up to the age of 2 years was 4.01 per 10 000 live births. Difference due to sex was minimal (22 males, 20 females) and most infants were delivered at or near term with gestational ages ranging between 30.0 and 41.8 weeks (median [interquartile range] 39.6wks [38.1-40.0wks]). The aetiology for infantile spasms was identified in almost two-thirds of cases, with HIE being the single most common cause (n=7). Other causes included chromosomal and monogenetic abnormalities (n=8). Infantile spasms occurred in moderate and severe grades of HIE, with a significantly higher incidence in those with severe HIE (p=0.029). Infants with severe HIE who did not receive therapeutic hypothermia were six times more likely to develop infantile spasms compared to those who did, but the difference was not statistically significant (4 out of 16 vs 1 out of 24, p=0.138). INTERPRETATION: This study provides detailed information about infantile spasms before and after the introduction of therapeutic hypothermia. HIE severity is a risk factor for the development of infantile spasms. The introduction of therapeutic hypothermia may have had an impact, but the effect was hard to ascertain in this cohort due to the small number of infants. WHAT THIS PAPER ADDS: The incidence of infantile spasms and patient characteristics in the southern region of the Republic of Ireland is similar to internationally published data. None of the infants with a history of mild hypoxic-ischemic encephalopathy (HIE) developed infantile spasms. The risk of infantile spasms was higher in infants with severe HIE. Infantile spasms were more frequent in infants with severe HIE not treated with therapeutic hypothermia.

IMPACTO DE LA HIPOTERMIA COMO TRATAMIENTO EN LOS ESPASMOS INFANTILES: UN ESTUDIO DE COHORTE OBSERVACIONAL: OBJETIVO: Establecer la incidencia de los espasmos infantiles en niños de la República de Irlanda y comparar la incidencia de los espasmos infantiles antes y después de la introducción de la hipotermia terapéutica en niños con encefalopatía hipóxico-isquémica (EHI). MÉTODO: Niños nacidos entre 2003 y 2015 y diagnosticados con espasmos infantiles (espasmos epilépticos con o sin hipsarritmia) en los primeros 2 años de vida fueron identificados por medio de auditorías de reportes de electroencefalográficos y listas de pacientes de neurólogos infantiles. Datos sobre los nacidos vivos se obtuvieron de la base de datos estadística del hospital regional. Las historias clínicas de los casos de espasmos infantiles fueron revisadas para obtener datos demográficos, resultados diagnósticos, respuesta a tratamiento, curso de la enfermedad y resultados del desarrollo. RESULTADOS: Fueron identificados 42 niños con espasmos infantiles. La incidencia acumulada de los espasmos infantiles por encima de los 2 años fue de 4,01 por 10.000 nacidos vivos. La diferencia debida al sexo fue mínima (22 masculinos, 20 femeninos) y la mayoría nacieron en o cercano a término, con edad gestacional entre 30,0 y 41,8 semanas (media (rango Intercuartil) 39,6 semanas (38,1-40,0 semanas). La etiología de espasmos infantiles fue identificada en dos tercios de los casos, siendo EHI la causa más común (7 de 42). Otras causas incluyeron anormalidades cromosómicas y monogénicas (8 de 42). Los espasmos infantiles ocurrieron en los grados moderados y severos de EHI con incidencia significativamente mayor en aquellos casos severos de EHI (p=0,029). Los niños con EHI severo que no recibieron hipotermia terapéutica tuvieron una probabilidad seis veces mayor de desarrollar espasmos infantiles comparados con aquellos quienes la recibieron, pero la diferencia no era estadísticamente significativa (4 de 16 vs 1 de 14, p=0,138). INTERPRETACIÓN: Este estudio proporciona información detallada acerca de los espasmos infantiles antes y después de la introducción de la hipotermia terapéutica. La severidad de la EHI es un factor de riesgo para el desarrollo de los espasmos infantiles. La introducción de la hipotermia terapéutica puede haber tenido un impacto, pero el efecto fue difícil de determinar en esta cohorte debido al pequeño número de recién nacidos.

IMPACTO DA HIPOTERMIA TERAPÊUTICA NOS ESPASMOS INFANTIS: UM ESTUDO DE COORTE OBSERVACIONAL: OBJETIVO: Estabelecer a incidência de espasmos infantis em crianças da República da Irlanda e comparar a incidência de espasmos infantis antes e após a introdução da hipotermia terapêutica em lactentes com encefalopatia hipóxica-isquêmica (EHI). MÉTODO: Crianças nascidas entre 2003 e 2015 e diagnosticadas com espasmos infantis (espasmos epilépticos com ou sem hipsarritmia) nos primeiros 2 anos de vida foram identificadas por meio de checagem dos relatórios de eletroencefalografia e listas de pacientes de neurologia pediátrica. Dados sobre nascidos vivos foram obtidos nas bases de dados estatísticas dos hospitais regionais. Prontuários médicos sobre casos de espasmos infantis foram revisados quanto a dados demográficos, resultados diagnósticos, resposta ao tratamento, curso da doença, e resultado desenvolvimental. RESULTADOS: Quarenta e dois lactentes com espasmos infantis foram identificados. A incidência cumulativa de espasmos infantis até os dois anos de idade foi 4,01 por 10.000 nascidos vidos. Diferenças devida ao sexo foram mínimas (22 meninos, 20 meninas) e a maior parte dos lactentes nasceu próximo ao termo, com idades gestacionais variando de 30,0 41,8 semanas (mediana [intervalo interquartil] 39,6 sem [38,1-40,0sem]). A etiologia dos espasmos infantis foi identificada em dois terços dos casos, com a EHI sendo a causa mais comum (7 em cada 42). Outras causas incluíram anormalidades cromossômicas e monogenéticas (8 em 42). Os espasmos infantis aconteceram em graus moderados a severos de EHI, com incidência significantemente maior naqueles com EHI severa (p=0,029). Lactentes com EHI severa que não receberam hipotermia terapêutica tinham seis vezes mais probabilidade de desenvolver espasmos infantis comparados com os que receberam, mas a diferença não foi estatisticamente significativa. (4 em16 vs 1 em 24, p=0,138). INTERPRETAÇÃO: Este esudo fornece informação detalhada sobre espasmos infantis antes e após a introdução de hipotermia terapêutica. A severidade da EHI é um fator de risco para o desenvolvimento de espasmos infantis. A introdução de hiportermia terapêutica por ter tido um impacto, mas o efeito foi difícil de assegurar nesta coorte devido ao pequeno número de lactentes.

No effect of a musical intervention on stress response to venepuncture in a neonatal population.

AIM: To investigate the effect of a musical intervention on neonatal stress response to venepuncture as measured by salivary cortisol levels and pain profile scores. METHODS: In a randomised control crossover trial, participants were randomised to both a control arm (sucrose) and intervention arm (sucrose and music) for routine venepuncture procedures. Salivary swabs were collected at baseline, 20 minutes post-venepuncture and 4 hours post-venepuncture. Pain levels were assessed using the Premature Infant Pain Profile (PIPP). A total of 16 preterm neonates participated in both arms to complete the study. RESULTS: Cortisol values were elevated at all timepoints in the intervention arm (baseline, 20 minutes, and 4 hours post-procedure) but not significantly so (P = .056, P = .3, and P = .575, respectively). Median change in cortisol values from baseline was +128.48 pg/mL (-47.66 to 517.02) at 20 minutes and +393.52 pg/mL (47.88-1221.34) at 4 hours post-procedure in the control arm compared to -69.564 pg/mL (-860.96 to 397.289) and +100.48 pg/mL (-560.46 to 842.99) at 20 minutes and 4 hours post-procedure in the intervention arm. There was no statistically significant difference observed between groups (P = .311 at 20 minutes, and P = .203 at 4 hours post-procedure). PIPP scores were not significantly different between study arms. CONCLUSION: Our findings did not support the additional benefit of music intervention on neonatal stress response to venepuncture in preterm infants.

The impact of short-term predominate breastfeeding on cognitive outcome at 5 years.

AIM: Breastfeeding is associated with IQ, school attendance and income. Despite the known benefits of breastfeeding, the rate of exclusive breastfeeding up to 6 months is low globally. We examined the effect of short-term breastfeeding on long-term IQ. METHODS: In this secondary analysis of the prospective Cork BASELINE Birth Cohort Study, children were categorised as predominantly breastfed (n = 288) versus exclusively formula-fed (n = 254) at 2-months of age. Infants (n = 404) receiving mixed feeding were excluded. Outcome was assessed using the KBIT-II at 5 years. Multivariable linear regression was used to adjust for confounding variables. RESULTS: Following adjustment for confounding variables, children, predominately breastfed at 2 months of age, demonstrated increased overall IQ (2.00 points (95% CI: 0.35 to 3.65); P = .018) and non-verbal IQ at 5 years of age (1.88 points (95% CI: 0.22 to 3.54); P = .027) compared with those never breastfed. No significant relationship was found with verbal IQ (P = .154). CONCLUSION: A significant increase in composite and non-verbal IQ at 5 years of age was associated with short-term breastfeeding. This study adds to a growing body of evidence that short-term breastfeeding promotes healthy cognitive development.

Core temperature after birth in babies with neonatal encephalopathy in a sub-Saharan African hospital setting.

KEY POINTS: Therapeutic hypothermia (HT) to 33.0-34.0°C for 72 h provides optimal therapy for infants with neonatal encephalopathy (NE) in high-resource settings. HT is not universally implemented in low- and middle-income countries as a result of both limited resources and evidence. Facilitated passive cooling, comprising infants being allowed to passively lower their body temperature in the days after birth, is an emerging practice in some West African neonatal units. In this observational study, we demonstrate that infants undergoing facilitated passive cooling in a neonatal unit in Accra, Ghana, achieve temperatures within the HT target range ∼20% of the 72 h. Depth of HT fluctuates and can be excessive, as well as not maintained, especially after 24 h. Sustained and deeper passive cooling was evident for severe NE and for those that died. It is important to prevent excessive cooling, to understand that severe NE babies cool more and to be aware of facilitated passive cooling with respect to the design of clinical trials in low- and mid-resource settings. ABSTRACT: Neonatal encephalopathy (NE) is a significant worldwide problem with the greatest burden in sub-Saharan Africa. Therapeutic hypothermia (HT), comprising the standard of care for infants with moderate-to-severe NE in settings with sophisticated intensive care, is not available to infants in many sub-Saharan African countries, including Ghana. We prospectively assessed the temperature response in relation to outcome in the 80 h after birth in a cohort of babies with NE undergoing 'facilitated passive cooling' at Korle Bu Teaching Hospital, Accra, Ghana. We hypothesized that NE infants demonstrate passive cooling. Thirteen infants (69% male) ≥36 weeks with moderate-to-severe NE were enrolled. Ambient mean ± SD temperature was 28.3 ± 0.7°C. Infant core temperature was 34.2 ± 1.2°C over the first 24 h and 35.0 ± 1.0°C over 80 h. Nadir mean temperature occurred at 15 h. Temperatures were within target range for HT with respect to 18 ± 14% of measurements within the first 72 h. Axillary temperature was 0.5 ± 0.2°C below core. Three infants died before discharge. Core temperature over 80 h for surviving infants was 35.3 ± 0.9°C and 33.96 ± 0.7°C for those that died (P = 0.043). Temperature profile negatively correlated with Thompson NE score on day 4 (r2  = 0.66): infants with a Thompson score of 0-6 had higher temperatures than those with a score of 7-15 (P = 0.021) and a score of 16+/deceased (P = 0.007). More severe NE was associated with lower core temperatures. Passive cooling is a physiological response after hypoxia-ischaemia; however, the potential neuroprotective effect of facilitated passive cooling is unknown. An awareness of facilitated passive cooling in babies with NE is important for the design of clinical trials of neuroprotection in low and mid resource settings.

Clamping the Umbilical Cord in Premature Deliveries (CUPiD): Neuromonitoring in the Immediate Newborn Period in a Randomized, Controlled Trial of Preterm Infants Born at <32 Weeks of Gestation.

OBJECTIVE: To compare cerebral activity and oxygenation in preterm infants (<32 weeks of gestation) randomized to different cord clamping strategies. STUDY DESIGN: Preterm infants born at <32 weeks of gestation were randomized to immediate cord clamping, umbilical cord milking (cord stripped 3 times), or delayed cord clamping for 60 seconds with bedside resuscitation. All infants underwent electroencephalogram (EEG) and cerebral near infrared spectroscopy for the first 72 hours after birth. Neonatal primary outcome measures were quantitative measures of the EEG (17 features) and near infrared spectroscopy over 1-hour time frames at 6 and 12 hours of life. RESULTS: Forty-five infants were recruited during the study period. Twelve infants (27%) were randomized to immediate cord clamping, 19 (42%) to umbilical cord milking, and 14 (31%) to delayed cord clamping with bedside resuscitation. There were no significant differences between groups for measures of EEG activity or cerebral near infrared spectroscopy. Three of the 45 infants (6.7%) were diagnosed with severe IVH (2 in the immediate cord clamping group, 1 in the umbilical cord milking group; P = .35). CONCLUSIONS: There were no differences in cerebral EEG activity and cerebral oxygenation values between cord management strategies at 6 and 12 hours. TRIAL REGISTRATION: ISRCTN92719670.

Neonatal Seizures-Are We there Yet?

Neonatal seizures are the most prevalent and distinctive sign of neurologic dysfunction in early life and pose an immense challenge for clinicians. Improvements in neonatal care have increased the survival rate of extremely premature infants, considerably changing the spectrum of underlying etiologies, and instigating a gradual shift from mortality to morbidity. Recognizing neonatal seizures can be challenging due to variability in presentation but clinical features can often provide valuable clues about etiology. Yet, the majority of neonatal seizures are subclinical. Even though conventional electroencephalography (EEG) with simultaneous video detection of seizures still represents the diagnostic gold standard, continuous monitoring using a one- to two-channel amplitude-integrated EEG with concurrent unprocessed EEG can be crucial for early recognition and intervention. Furthermore, tremendous progress has been made in neuroimaging, and all infants with seizures should have a magnetic resonance imaging (MRI) to help identify the underlying etiology. While the majority of neonatal seizures are caused by hypoxic-ischemic events, stroke, hemorrhage, or infection, approximately 15% of patients will require more sophisticated algorithms for diagnostic workup, including metabolic and genetic screening. These recent developments have led to renew interest in the classification of neonatal seizures, which aim to help identify etiology and guide appropriate therapeutic and prognostic decisions. In this review, we outline recent progress made in the etiology, diagnosis, and treatment of neonatal seizures and highlight areas that deserve further research.

Validation of Raised Cord Blood Interleukin-16 in Perinatal Asphyxia and Neonatal Hypoxic-Ischaemic Encephalopathy in the BiHiVE2 Cohort.

The role of inflammation is an important factor in the progression of hypoxic-ischaemic encephalopathy (HIE). We have previously shown that interleukin-16 (IL-16) is increased in infants with moderate and severe HIE and relates to poor neurodevelopmental outcomes. We aimed to validate IL-16 as a cord blood-based biomarker for HIE and to examine its relationship to long-term outcomes. The study sample consisted of 105 full-term infants who experienced perinatal asphyxia (PA) (with and without an encephalopathy) along with healthy, gestational age-matched newborn controls. Umbilical cord blood serum was processed and biobanked at delivery. Infants were assigned a modified Sarnat score at 24 h. Analysis of IL-16 cytokine cord blood levels was performed using the sandwich-based enzyme-linked immunosorbent assay (ELISA) technique. Cord blood-based IL-16 was increased in infants with PA and HIE relative to controls (p = 0.025). IL-16 was also increased in the HIE group relative to controls (p = 0.042). There was no significant difference in IL-16 across grades of HIE or in those with abnormal outcomes at 2 years of age. This study validates findings that cord blood-based IL-16 levels are increased in infants with PA, including those who go on to develop HIE.