Importance The neonatal brain injury score on magnetic resonance imaging following moderate or severe hypoxic-ischemic encephalopathy developed by the National Institute of Child Health and Human Development Neonatal Research Network has been revised to separate watershed and basal ganglia or thalamic injury and their associated outcomes. Objective To evaluate the association of the injury score with outcomes of death or moderate or severe disability among all infants, and with neurodevelopment among survivors in a trial of deeper and longer cooling. Design, Setting, and Participants In this secondary analysis of a multicenter randomized clinical trial, brain imaging was obtained from infants between October 2010 and November 2013. Infants were followed up to 18 months of age, with follow-up completed in January 2016. Data analysis was performed from August 2021 to September 2024. Interventions Infants were assigned to 4 hypothermia groups based on depth and duration of cooling, stratified by center and level of encephalopathy in a 2 x 2 factorial design to cooling at 33.5 degrees C or 32.0 degrees C and to 72 or 120 hours. A 10-level brain injury score was examined. Main Outcomes and Measures The primary outcome was death or moderate or severe disability measured by the Bayley Scales of Infant and Toddler Development III, the Gross Motor Function Classification System level, vision, and hearing. Results This study included 298 infants who had magnetic resonance imaging (MRI) and primary outcome data among 364 infants of the initial cohort (mean [SD] age at MRI, 9.18 [4.49] days). Death or moderate or severe disability occurred in 72 of 298 infants (24%), and disability occurred in 52 of 278 surviving infants (19%). Death or disability occurred in 12 of 28 infants (43%) with any or predominant watershed injury and in 17 of 46 (37%) of those with any or predominant basal ganglia or thalamic injury. Among the 32 infants with hemispheric devastation, 30 (94%) had death or disability, and 17 (89%) survived with moderate or severe disability. Injury scores of increasing severity were associated with death or disability among all infants (odds ratio, 13.66 [95% CI, 7.47-24.95]; area under the curve, 0.84 [95% CI, 0.78-0.90]) and with disability among surviving infants (odds ratio, 10.52 [95% CI, 5.46-20.28]; area under the curve, 0.80 [95% CI, 0.73-0.88]). There were no differences in the injury score between infants undergoing usual care cooling and those cooled to a greater depth or longer duration. Conclusions Among infants with hypoxic-ischemic encephalopathy, outcomes were similar between infants with watershed and basal ganglia injury. Higher imaging scores were associated with risk of death or disability among all infants and with neurodevelopmental disability among surviving infants. Trial RegistrationClinicalTrials.gov Identifier: NCT01192776

Importance The neonatal brain injury score on magnetic resonance imaging following moderate or severe hypoxic-ischemic encephalopathy developed by the National Institute of Child Health and Human Development Neonatal Research Network has been revised to separate watershed and basal ganglia or thalamic injury and their associated outcomes. Objective To evaluate the association of the injury score with outcomes of death or moderate or severe disability among all infants, and with neurodevelopment among survivors in a trial of deeper and longer cooling. Design, Setting, and Participants In this secondary analysis of a multicenter randomized clinical trial, brain imaging was obtained from infants between October 2010 and November 2013. Infants were followed up to 18 months of age, with follow-up completed in January 2016. Data analysis was performed from August 2021 to September 2024. Interventions Infants were assigned to 4 hypothermia groups based on depth and duration of cooling, stratified by center and level of encephalopathy in a 2 × 2 factorial design to cooling at 33.5 °C or 32.0 °C and to 72 or 120 hours. A 10-level brain injury score was examined. Main Outcomes and Measures The primary outcome was death or moderate or severe disability measured by the Bayley Scales of Infant and Toddler Development III, the Gross Motor Function Classification System level, vision, and hearing. Results This study included 298 infants who had magnetic resonance imaging (MRI) and primary outcome data among 364 infants of the initial cohort (mean [SD] age at MRI, 9.18 [4.49] days). Death or moderate or severe disability occurred in 72 of 298 infants (24%), and disability occurred in 52 of 278 surviving infants (19%). Death or disability occurred in 12 of 28 infants (43%) with any or predominant watershed injury and in 17 of 46 (37%) of those with any or predominant basal ganglia or thalamic injury. Among the 32 infants with hemispheric devastation, 30 (94%) had death or disability, and 17 (89%) survived with moderate or severe disability. Injury scores of increasing severity were associated with death or disability among all infants (odds ratio, 13.66 [95% CI, 7.47-24.95]; area under the curve, 0.84 [95% CI, 0.78-0.90]) and with disability among surviving infants (odds ratio, 10.52 [95% CI, 5.46-20.28]; area under the curve, 0.80 [95% CI, 0.73-0.88]). There were no differences in the injury score between infants undergoing usual care cooling and those cooled to a greater depth or longer duration. Conclusions Among infants with hypoxic-ischemic encephalopathy, outcomes were similar between infants with watershed and basal ganglia injury. Higher imaging scores were associated with risk of death or disability among all infants and with neurodevelopmental disability among surviving infants. Trial Registration ClinicalTrials.gov Identifier: NCT01192776

Respiratory Cycle-Related EEG Changes (RCREC) measured during the sleep of children and adults may represent subtle cortical microarousals exacerbated by labored breathing in obstructive sleep apnea. However, the existence of RCREC has not been investigated previously in newborns. Nine North American Fetal Therapy Network centers collaborated in a prospective polysomnographic study (at ≥32 weeks postmenstrual age) of sleep among 171 neonates (gestational age at birth 30-41 weeks) with myelomeningocele in neonatal intensive care units. The RCREC for NREM and REM sleep were computed (AJRCCM 2005;171:652-8) for the entire night in 5 frequency ranges -- delta 2-4 Hz, theta 4-8 Hz, alpha 8-12 Hz, sigma 12-15 Hz, and beta 15-18 Hz) -- using C3-M2 EEG and the nasal-oral thermocouple signal. The RCREC were compared to gestational age at birth, and the apnea-hypopnea index (AHI). Statistically-significant RCREC (ANOVA, p< 0.01) appeared in at least some frequency ranges in most neonates during NREM sleep (delta n=170, theta 164, alpha 159, sigma 160, beta 164), and during REM sleep (delta 170, theta 163, alpha 147, sigma 161, beta 163). In NREM sleep, the RCREC varied inversely with gestational age (delta: Spearman rho=-0.16, p=0.03; theta: rho=-0.34, p=< 0.0001; alpha: rho=-0.45, p=< 0.0001; sigma: rho=-0.23, p=0.003; beta: rho=-0.21, p=0.007). Theta and alpha RCREC increased with AHI (rho=0.18, p=0.02, and rho=0.25, p=0.001, respectively). In REM sleep, RCREC also varied inversely with gestational age (delta: rho=-0.24, p=0.001; theta: rho=-0.20, p=0.009; alpha: rho=-0.28, p=0.0002; sigma: rho=-0.22, p=0.004; beta: rho=-0.18, p=0.02). Only alpha RCREC varied with AHI during active sleep (rho=0.18, p=0.02). These data demonstrate RCREC in neonates for the first time. As in older individuals, only limited associations appear with AHI. Moreover, the synchronization between EEG power and the respiratory cycle increases, on average, with lower gestational age at birth. Although these data are specific to infants with myelomeningocele, we have also found RCREC in preterm newborns without MMC (unpublished observations). Previous findings in children and adults that RCREC may predict daytime sleepiness, as well or better than standard polysomnographic measures (Sleep 2006;29:495-503), suggest that infant RCREC merits additional study. This work was supported by NIH grant R01HL147261

The etiology of perinatal brain injury is multifactorial, but exposure to perinatal hypoxiaischemia (HI) is a major underlying factor. This review discusses the role of exposure to infection/inflammation in the evolution of HI brain injury, changes in immune responsiveness to subsequent inflammatory challenges after HI and modulation of neural outcomes with interaction between perinatal HI and inflammatory insults. The authors critically assess the clinical and preclinical evidence for the neuroprotective efficacy of therapeutic hypothermia and other anti-inflammatory treatments for inflammation-sensitized HI injury.

There is a need to develop therapies for neonatal encephalopathy (NE) in low- and middle-income countries (LMICs) where the burden of disease is greatest and therapeutic hypothermia (HT) is not effective. We aimed to assess the efficacy of melatonin following inflammation-amplified hypoxia-ischaemia (IA-HI) in the newborn piglet. The IA-HI model accounts for the contribution of infection/inflammation in this setting and HT is not cytoprotective. We hypothesised that intravenous melatonin (5% ethanol, at 20 mg/kg over 2 h at 1 h after HI + 10 mg/kg/12 h between 24 and 60 h) is safe and associated with: (i) reduction in magnetic resonance spectroscopy lactate/N-acetylaspartate (MRS Lac/sNAA); (ii) preservation of phosphorus MRS phosphocreatine/phosphate exchange pool (PCr/Epp); (iii) improved aEEG/EEG recovery and (iv) cytoprotection on immunohistochemistry. Male and female piglets underwent IA-HI by carotid artery occlusion and reduction in FiO(2) to 6% at 4 h into Escherichia coli lipopolysaccharide sensitisation (2 mu g/kg bolus + 1 mu g/kg/h over 12 h). At 1 h after IA-HI, piglets were randomised to HI-saline (n = 12) or melatonin (n = 11). There were no differences in insult severity between groups. Target melatonin levels (15-30 mg/L) were achieved within 3 h and blood ethanol levels were <0.25 g/L. At 60 h, compared to HI-saline, melatonin was associated with a reduction of 0.197 log(10) units (95% CrI [-0.366, -0.028], Pr-(sup) 98.8%) in basal-ganglia and thalamic Lac/NAA, and 0.257 (95% CrI [-0.676, 0.164], Pr-(sup) 89.3%) in white matter Lac/NAA. PCr/Epp was higher in melatonin versus HI-saline (Pr-(sup) 97.6%). Melatonin was associated with earlier aEEG/EEG recovery from 19 to 24 h (Pr-(sup) 95.4%). Compared to HI-saline, melatonin was associated with increased NeuN+ cell density (Pr-(sup) 99.3%) across five of eight regions and reduction in TUNEL-positive cell death (Pr-(sup) 89.7%). This study supports the translation of melatonin to early-phase clinical trials. Melatonin is protective following IA-HI where HT is not effective. These data guide the design of future dose-escalation studies in the next phase of the translational pipeline.

Abstract Introduction A prospective, longitudinal, multicenter study was designed to test the hypothesis that sleep-disordered breathing (SDB) is ubiquitous among newborns with myelomeningocele (MMC). We evaluated variability in polysomnography (PSG) scoring and interpretation. Methods Nine US pediatric centers participated. Neonates with MMC born at >30 weeks gestation underwent bedside PSG at ≥35 weeks postmenstrual age, before hospital discharge. PSGs were scored by registered technologists (RPSGTs) at each site using AASM Scoring Manual infant criteria and interpreted by a board-certified sleep medicine physician (BCSMP). A single, central RPSGT blinded to clinical outcomes then re-scored all PSGs. One of two pediatric BCSMPs reviewed each study; the two BCSMPs jointly determined diagnoses for consensus central reports. Differences in scoring and overall PSG interpretation were evaluated with kappa and intraclass correlation coefficients (ICC). Results For 110 neonates with MMC, the median apnea-hypopnea index (AHI) was 26.5 [11.3-43.3] as reported by sites, and 23.0 [IQR 13.0-44.8] as reported centrally (к 0.81). The central apnea index (CAI) was also scored similarly by sites (3.3 [0.9-7.0]) and centrally (2.6 [0.6-7.3]; к 0.88), as were hypopneas (15.2 [7.5;26.9]) and 14.1 [6.4;27.9]; к 0.82). However, the obstructive apnea index (OAI) was reported to be much higher by sites (10.0 [1.9-29.1]) than centrally (1.5 [0.5 – 4.1]; к 0.29). Moreover, overall PSG interpretation differed between sites and central reviewers. Obstructive sleep apnea (OSA) was reported as a diagnosis by sites for 57.6% of neonates, vs. 10.9% by central review (ICC 0.06); central sleep apnea was reported by sites for 26.6% of neonates, vs. 14.5% by central review (ICC 0.50). When hypopneas were the most prevalent respiratory events, central review favored a less specific diagnosis of sleep-disordered breathing. Conclusion Considerable variability in scoring of obstructive apneas, and in polysomnography-based diagnoses, may exist for neonates. Sites may have designated hypopneas as obstructive, driving the diagnosis of OSA, while central review noted equivocal features of neonatal hypopneas, leading to a less specific diagnosis of sleep-disordered breathing. Further work to develop infant respiratory scoring rules, and diagnostic criteria, and to evaluate their clinical use may be warranted. Support (if any) This study is supported by NIH (R01 HL147261).

AIM:To examine the extent to which estimates of a latent trait or underlying construct of motor ability differ in infants born at term and preterm, based on caregiver ratings of the motor domain of PediaTrac v3.0. METHOD:The sample consisted of 571 caregiver-infant dyads (331 born at term, 240 born preterm), 48% female, with 51.7% of caregivers identifying as an ethnic minority. Latent trait of motor ability was estimated based on item response theory modeling. Gestational group differences (term and preterm birth) were examined at the newborn/term-equivalent, 2-, 4-, 6-, 9-, and 12-month time points. RESULTS:Caregiver ratings of latent trait of motor ability were reliably modeled across the range of abilities at each time point. While the group born preterm exhibited significantly more advanced motor abilities at the term-equivalent time point, by 6 months the group born at term was more advanced. Biological sex difference main and interaction effects were not significant. INTERPRETATION:Caregivers provided reliable, longitudinal estimates of motor ability in infancy, reflecting important differences in the motor development of infants born at term and preterm. The findings suggest that significant motor development occurs in infants born preterm from birth to the term-equivalent time point and provide a foundation to examine motor growth trajectories as potential predictors in the early identification of neurodevelopmental conditions and needs. WHAT THIS PAPER ADDS:Longitudinal caregiver ratings of motor function in early infancy yielded reliable estimates of the latent trait of motor ability. Motor ability at the term-equivalent time point was higher in infants born preterm than infants born at term.

Abstract Objective Among neonates with acute symptomatic seizures, we evaluated whether the inability to take full feeds at the time of hospital discharge from neonatal seizure admission is associated with worse neurodevelopmental outcomes, after adjusting for relevant clinical variables. Methods This prospective, nine‐center study of the Neonatal Seizure Registry (NSR) assessed characteristics of infants with seizures, including evidence of brainstem injury on magnetic resonance imaging (MRI), mode of feeding upon discharge, and developmental outcomes at 12, 18, and 24 months. The inability to take oral feeds was identified through a review of medical records. Brainstem injury was identified through a central review of neonatal MRIs. Developmental outcomes were assessed with the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA‐FS) at 12, 18, and 24 months corrected age. Results Among 276 infants, inability to achieve full oral feeds was associated with lower total WIDEA‐FS scores (160.2 ± 25.5 for full oral feeds vs. 121.8 ± 42.9 for some/no oral feeds at 24 months, p < 0.001). At 12 months, a gastrostomy tube was required for 23 of the 49 (47%) infants who did not achieve full oral feeds, compared with 2 of the 221 (1%) who took full feeds at discharge (p < 0.001). Conclusions The inability to take full oral feeds upon hospital discharge is an objective clinical sign that can identify infants with acute symptomatic neonatal seizures who are at high risk for impaired development at 24 months.

Mild therapeutic hypothermia has been extensively studied and validated as an effective and safe treatment for term and near-term infants with moderate and severe hypoxic encephalopathy meeting narrow inclusion criteria. Unanswered questions remain about whether cooling treatment can be optimized to improve outcomes even further, and whether it is reasonable to offer treatment to infants excluded from the foundational studies. Consideration of "off-protocol" cooling practices requires methodical review of available evidence and analysis using both a clinical and a research ethical framework.

The utility of inpatient rapid exome and genome sequencing has been well documented, but implementation continues to be hampered by inadequate insurance reimbursement, clinical genetics support availability, and high costs. Since late 2019, CS Mott Children's Hospital at the University of Michigan has implemented a process through which critically ill pediatric patients can be evaluated with rapid comprehensive sequencing. After consideration of pre-determined criteria, each case is proposed by a consulting Pediatric Geneticist and then promptly evaluated by a multi-disciplinary committee (including Pediatric Geneticists, Cardiologist, Pediatric and Neonatal intensivists, and Neurologist).

Mild therapeutic hypothermia has been extensively studied and validated as an effective and safe treatment for term and near-term infants with moderate and severe hypoxic encephalopathy meeting narrow inclusion criteria. Unanswered questions remain about whether cooling treatment can be optimized to improve outcomes even further, and whether it is reasonable to offer treatment to infants excluded from the foundational studies. Consideration of "off-protocol" cooling practices requires methodical review of available evidence and analysis using both a clinical and a research ethical framework.

Enriched language exposure may benefit infants in the neonatal intensive care unit. We hypothesized that changes in neonatal electroencephalogram (EEG) coherence during sleep, in response to maternal voice exposure, predict language development. Convalescent neonates underwent 12-h polysomnography. A recording of the mother’s voice was randomized to continuous playback in the first or second 6 h. We calculated the imaginary coherence (ICOH—a measure of functional connectivity) between EEG leads. Spearman correlations were computed between ICOH and 18-month Bayley-III language scores. Thirty-five neonates were included (N = 18 33-to-<35 weeks gestation; N = 17 ≥ 35 weeks). Predictive value of ICOH during neonatal non-rapid eye movement (NREM) sleep was left lateralized, and varied with gestational age and voice playback. ICOH in the left-hemispheric (C3-Cz; T3-Cz) channels across multiple EEG frequency bands was associated with 18-month language scores (rho = −0.34 to −0.48). The association was driven by neonates born at 33–34 weeks gestation, and a trend suggested a possible effect of maternal voice at some EEG frequencies. Right hemisphere ICOH (C4-Cz; T4-Cz) was not associated with language outcome. Left-hemispheric EEG functional connectivity during neonatal NREM sleep shows early signs of physiologic asymmetry that may predict language development. We speculate that sleep analyses could have unique prognostic value.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Perinatal development is a critical window for altered, lifelong health trajectory, and evidence supports the role of perinatal programming in chronic metabolic diseases. To examine the impact of diet and bisphenol A (BPA) on the developmental trajectory of NAFLD in offspring, we exposed dams from pre-gestation through lactation to a human-relevant dose of oral BPA coupled with intake of high fat Western or Mediterranean-style diets. We assessed hepatic steatosis by quantifying hepatic triglycerides (TGs) and metabolic health by measuring body weight, relative organ weights, and serum hormone levels in dams and offspring at postnatal day 10 (PND10) and 10-months of age. In dams, consumption of the Western or Mediterranean diet increased hepatic TGs 1.7-2.4-fold, independent of BPA intake. Among offspring, both perinatal diet and BPA exposure had a greater impact on metabolic outcomes than on hepatic steatosis. At PND10, serum leptin levels were elevated 2.6-4.8-fold in pups exposed to the Mediterranean diet, with a trend for sex-specific effects on body and organ weights. At 10-months, sex-specific increases in organ weight and hormone levels were observed in mice perinatally exposed to Western + BPA or Mediterranean + BPA. These findings suggest lifestage-specific interaction of perinatal exposures to experimental diets and BPA on offspring metabolic health without effects on NAFLD later in life. Importantly, alterations in dam phenotype by diet and BPA exposure appear to impact offspring health trajectory, emphasizing the need to define dam diet in assessing effects of environmental exposures on offspring health.

Background Systemic inflammation amplifies neonatal hypoxic–ischemic (HI) brain injury. Azithromycin (AZ), an antibiotic with anti-inflammatory properties, improves sensorimotor function and reduces tissue damage after neonatal rat HI brain injury. The objective of this study was to determine if AZ is neuroprotective in two neonatal rat models of inflammation-amplified HI brain injury. Design/Methods Seven-day-old (P7) rats received injections of toll-like receptor agonists lipopolysaccharide (LPS) or Pam 3 Cys-Ser-(Lys) 4 (PAM) prior to right carotid ligation followed by 50 min (LPS + HI) or 60 min (PAM + HI) in 8% oxygen. Outcomes included contralateral forelimb function (forepaw placing; grip strength), survival, %Intact right hemisphere (brain damage), and a composite score incorporating these measures. We compared postnatal day 35 outcomes in controls and groups treated with three or five AZ doses. Then, we compared P21 outcomes when the first (of five) AZ doses were administered 1, 2, or 4 h after HI. Results In both LPS + HI and PAM + HI models, AZ improved sensorimotor function, survival, brain tissue preservation, and composite scores. Benefits increased with five- vs. three-dose AZ and declined with longer initiation delay. Conclusions Perinatal systemic infection is a common comorbidity of neonatal asphyxia brain injury and contributes to adverse outcomes. These data support further evaluation of AZ as a candidate treatment for neonatal neuroprotection. Impact AZ treatment decreases sensorimotor impairment and severity of brain injury, and improves survival, after inflammation-amplified HI brain injury, and this can be achieved even with a 2 h delay in initiation. This neuroprotective benefit is seen in models of inflammation priming by both Gram-negative and Gram-positive infections. This extends our previous findings that AZ treatment is neuroprotective after HI brain injury in neonatal rats.

Background: Infants with NAS may have disturbed sleep, and increased movement reflecting central nervous system irritability. However, sleep pattern in such infants following control of withdrawal symptoms with methadone hasn’t been quantitatively analyzed. We hypothesized that successful treatment of withdrawal symptoms with methadone would also improve the sleep patterns in infants with NAS. Persistent disordered sleep in the neonatal period if persists even after pharmacological control of withdrawal symptoms may potentially lead to adverse childhood neurodevelopmental outcome. Objective: To characterize sleep-wake states using Actigraphy (activity-based sleep-wake …

Objective To compare the prognostic accuracy of six neonatal illness severity scores (CRIB, CRIB II, SNAP, SNAP II, SNAP-PE, and SNAP-PE II), birthweight (BW), and gestational age (GA) for predicting pre-discharge mortality among very low birth weight (VLBW) infants (<1500 g) and very preterm infants (<32 weeks’ gestational age). Study design PubMed, EMBASE, and Scopus were the data sources searched for studies published before January 2019. Data were extracted, pooled, and analyzed using random-effects models and reported as AUC with 95% confidence intervals (CI). Results Of 1659 screened studies, 24 met inclusion criteria. CRIB was the most discriminate for predicting pre-discharge mortality [AUC 0.88 (0.86–0.90)]. GA was the least discriminate [AUC 0.76 (0.72–0.80)]. Conclusions Although the original CRIB score was the most accurate predictor of pre-discharge mortality, significant heterogeneity between studies lowers confidence in this pooled estimate. A more precise illness severity score to predict pre-discharge mortality is still needed.

BACKGROUND:Approximately 10% of US newborns require a NICU. We evaluated whether the NICU acoustic environment affects neonatal sleep and whether exposure to the mother's voice can modulate that impact.METHODS:In a level IV NICU with single-infant rooms, 47 neonates underwent 12-hour polysomnography. Their mothers were recorded reading children's books. Continuous maternal voice playback was randomized to either the first or second 6 hours of the polysomnogram. Regression models were used to examine sleep-wake stages, entropy, EEG power, and the probability of awakening in response to ambient noise during and without voice playback.RESULTS:After epochs with elevated noise, the probability was higher with (versus without) maternal voice exposure of neonates staying asleep (P = .009). However, the 20 neonates born at ≥35 weeks' gestation, in contrast to those born at 33 to 34 weeks, showed an age-related increase in percent time awake (R 2 = 0.52; P < .001), a decrease in overall sleep (R 2 = 0.52; P < .001), a reduction in rapid eye movement sleep bouts per hour (R 2 = 0.35; P = .003), and an increase in sleep-wake entropy (R 2 = 0.52; P < .001) all confined solely to the 6 hours of maternal voice exposure. These associations remained significant (P = .02 to P < .001) after adjustment for neurologic examination scores and ambient noise.CONCLUSIONS:Hospitalized newborns born at ≥35 weeks' gestation but not at 33 to 34 weeks' gestation show increasing wakefulness in response to their mother's voice. However, exposure to the mother's voice during sleep may also help protect newborns from awakening after bursts of loud hospital noise.

Among older infants and children, sleep‐disordered breathing (SDB) has negative neurocognitive consequences. We evaluated the frequency and potential impact of SDB among newborns who require intensive care.