Surgical interventions and short-term outcomes for preterm infants with post-haemorrhagic hydrocephalus: a multicentre cohort study.

OBJECTIVE: To (1) describe differences in types and timing of interventions, (2) report short-term outcomes and (3) describe differences among centres from a large national cohort of preterm infants with post-haemorrhagic hydrocephalus (PHH). DESIGN: Cohort study of the Children's Hospitals Neonatal Database from 2010 to 2022. SETTING: 41 referral neonatal intensive care units (NICUs) in North America. PATIENTS: Infants born before 32 weeks' gestation with PHH defined as acquired hydrocephalus with intraventricular haemorrhage. INTERVENTIONS: (1) No intervention, (2) temporising device (TD) only, (3) initial permanent shunt (PS) and (4) TD followed by PS (TD-PS). MAIN OUTCOME MEASURES: Mortality and meningitis. RESULTS: Of 3883 infants with PHH from 41 centres, 36% had no surgical intervention, 16% had a TD only, 19% had a PS only and 30% had a TD-PS. Of the 46% of infants with TDs, 76% were reservoirs; 66% of infants with TDs required PS placement. The percent of infants with PHH receiving ventricular access device placement differed by centre, ranging from 4% to 79% (p<0.001). Median chronological and postmenstrual age at time of TD placement were similar between infants with only TD and those with TD-PS. Infants with TD-PS were older and larger than those with only PS at time of PS placement. Death before NICU discharge occurred in 12% of infants, usually due to redirection of care. Meningitis occurred in 11% of the cohort. CONCLUSIONS: There was significant intercentre variation in rate of intervention, which may reflect variability in care or referral patterns. Rate of PS placement in infants with TDs was 66%.

The Current State of Neonatal Neurodevelopmental Follow-up Programs in North America: A Children's Hospitals Neonatal Consortium Report.

OBJECTIVE: This study aimed to determine neonatal neurodevelopmental follow-up (NDFU) practices across academic centers. STUDY DESIGN: This study was a cross-sectional survey that addressed center-specific neonatal NDFU practices within the Children's Hospitals Neonatal Consortium (CHNC). RESULTS: Survey response rate was 76%, and 97% of respondents had a formal NDFU program. Programs were commonly staffed by neonatologists (80%), physical therapists (77%), and nurse practitioners (74%). Median gestational age at birth identified for follow-up was ≤32 weeks (range 26-36). Median duration was 3 years (range 2-18). Ninety-seven percent of sites used Bayley Scales of Infant and Toddler Development, but instruments used varied across ages. Scores were recorded in discrete electronic data fields at 43% of sites. Social determinants of health data were collected by 63%. Care coordination and telehealth services were not universally available. CONCLUSION: NDFU clinics are almost universal within CHNC centers. Commonalities and variances in practice highlight opportunities for data sharing and development of best practices. KEY POINTS: · Neonatal NDFU clinics help transition high-risk infants home.. · Interdisciplinary neonatal intensive care unit follow-up brings together previously separated outpatient service lines.. · This study reviews the current state of neonatal NDFU in North America..

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.

Esophageal Versus Rectal Temperature Monitoring During Whole-Body Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy: Association with Short- and Long-Term Outcomes.

OBJECTIVE: To compare the short- and long-term outcomes of infants with hypoxic-ischemic encephalopathy (HIE) treated with whole-body therapeutic hypothermia (TH), monitored by esophageal vs rectal temperature. STUDY DESIGN: We conducted a secondary analysis of the multicenter High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial. All infants had moderate or severe HIE and were treated with whole-body TH. The primary outcome was death or neurodevelopmental impairment (NDI) at 22-36 months of age. Secondary outcomes included seizures, evidence of brain injury on magnetic resonance imaging, and complications of hypothermia. Logistic regression was used with adjustment for disease severity and site as clustering variable because cooling modality differed by site. RESULTS: Of the 500 infants who underwent TH, 294 (59%) and 206 (41%) had esophageal and rectal temperature monitoring, respectively. There were no differences in death or NDI, seizures, or evidence of injury on magnetic resonance imaging between the 2 groups. Infants treated with TH and rectal temperature monitoring had lower odds of overcooling (OR 0.52, 95% CI 0.34-0.80) and lower odds of hypotension (OR 0.57, 95% CI 0.39-0.84) compared with those with esophageal temperature monitoring. CONCLUSIONS: Although infants undergoing TH with esophageal monitoring were more likely to experience overcooling and hypotension, the rate of death or NDI was similar whether esophageal monitoring or rectal temperature monitoring was used. Further studies are needed to investigate whether esophageal temperature monitoring during TH is associated with an increased risk of overcooling and hypotension.

Relationship of Neonatal Seizure Burden Before Treatment and Response to Initial Antiseizure Medication.

OBJECTIVE: To assess among a cohort of neonates with hypoxic-ischemic encephalopathy (HIE) the association of pretreatment maximal hourly seizure burden and total seizure duration with successful response to initial antiseizure medication (ASM). STUDY DESIGN: This was a retrospective review of data collected from infants enrolled in the HEAL Trial (NCT02811263) between January 25, 2017, and October 9, 2019. We evaluated a cohort of neonates born at ≥36 weeks of gestation with moderate-to-severe HIE who underwent continuous electroencephalogram monitoring and had acute symptomatic seizures. Poisson regression analyzed associations between (1) pretreatment maximal hourly seizure burden, (2) pretreatment total seizure duration, (3) time from first seizure to initial ASM, and (4) successful response to initial ASM. RESULTS: Among 39 neonates meeting inclusion criteria, greater pretreatment maximal hourly seizure burden was associated with lower chance of successful response to initial ASM (adjusted relative risk for each 5-minute increase in seizure burden 0.83, 95% CI 0.69-0.99). There was no association between pretreatment total seizure duration and chance of successful response. Shorter time-to-treatment was paradoxically associated with lower chance of successful response to treatment, although this difference was small in magnitude (relative risk 1.007, 95% CI 1.003-1.010). CONCLUSIONS: Maximal seizure burden may be more important than other, more commonly used measures in predicting response to acute seizure treatments.

Cranial Point-of-Care Ultrasound for Neonatal Providers: A Feasibility Study.

OBJECTIVE: Despite strong evidence for its utility in clinical management and diagnosis of intracranial hemorrhage (ICH), the use of neonatal cranial point-of-care ultrasound (POCUS) has not been standardized in neonatal intensive care units (NICUs) in the United States. The primary aim of this study was to evaluate the feasibility of training NICU providers to perform cranial POCUS by tracking the quality of image acquisition following training. METHODS: Observational single-center cohort study of cranial POCUS images obtained by trained neonatal practitioners (attendings, fellows, and advanced practice providers) using a protocol developed by a radiologist and neonatologist. Exams were performed on infants born ≤1250 g and/or ≤30 weeks gestation within the first 3 days after birth. A survey to assess attitudes regarding cranial POCUS was given before each of three training sessions. Demographic and clinical data collection were portrayed with descriptive statistics. Metrics of image quality were assessed by a radiologist and sonographer independently. Analysis of trends in quality of POCUS images over time was performed using a multinomial Cochran-Armitage test. RESULTS: Eighty-two cranial POCUS scans were performed over a 2-year period. Infant median age at exam was 14 hours (IQR 7-22 hours). Metrics of image quality depicted quarterly demonstrated a significant improvement in depth (P = .01), gain (P = .048), and quality of anatomy images captured (P < .001) over time. Providers perceived increased utility and safety of cranial POCUS over time. CONCLUSION: Cranial POCUS image acquisition improved significantly following care team training, which may enable providers to diagnose ICH at the bedside.

Evolution of the Sarnat exam and association with 2-year outcomes in infants with moderate or severe hypoxic-ischaemic encephalopathy: a secondary analysis of the HEAL Trial.

OBJECTIVE: To study the association between the Sarnat exam (SE) performed before and after therapeutic hypothermia (TH) and outcomes at 2 years in infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE). DESIGN: Secondary analysis of the High-dose Erythropoietin for Asphyxia and EncephaLopathy Trial. Adjusted ORs (aORs) for death or neurodevelopmental impairment (NDI) based on SE severity category and change in category were constructed, adjusting for sedation at time of exam. Absolute SE Score and its change were compared for association with risk for death or NDI using locally estimated scatterplot smoothing curves. SETTING: Randomised, double-blinded, placebo-controlled multicentre trial including 17 centres across the USA. PATIENTS: 479/500 enrolled neonates who had both a qualifying SE (qSE) before TH and a SE after rewarming (rSE). INTERVENTIONS: Standardised SE was used across sites before and after TH. All providers underwent standardised SE training. MAIN OUTCOME MEASURES: Primary outcome was defined as the composite outcome of death or any NDI at 22-36 months. RESULTS: Both qSE and rSE were associated with the primary outcome. Notably, an aOR for primary outcome of 6.2 (95% CI 3.1 to 12.6) and 50.3 (95% CI 13.3 to 190) was seen in those with moderate and severe encephalopathy on rSE, respectively. Persistent or worsened severity on rSE was associated with higher odds for primary outcome compared with those who improved, even when qSE was severe. CONCLUSION: Both rSE and change between qSE and rSE were strongly associated with the odds of death/NDI at 22-36 months in infants with moderate or severe HIE.

Rectal temperature after hypoxia-ischemia predicts white matter and cortical pathology in the near-term ferret.

BACKGROUND: Neonatal encephalopathy (NE) remains a common cause of infant morbidity and mortality. Neuropathological corollaries of NE associated with acute hypoxia-ischemia include a central injury pattern involving the basal ganglia and thalamus, which may interfere with thermoregulatory circuits. Spontaneous hypothermia (SH) occurs in both preclinical models and clinical hypoxic-ischemic NE and may provide an early biomarker of injury severity. To determine whether SH predicts the degree of injury in a ferret model of hypoxic-ischemic NE, we investigated whether rectal temperature (RT) 1 h after insult correlated with long-term outcomes. METHODS: Postnatal day (P)17 ferrets were presensitized with Escherichia coli lipopolysaccharide before undergoing hypoxia-ischemia/hyperoxia (HIH): bilateral carotid artery ligation, hypoxia-hyperoxia-hypoxia, and right ligation reversal. One hour later, nesting RTs were measured. RESULTS: Animals exposed to HIH were separated into normothermic (NT; ≥34.4 °C) or spontaneously hypothermic (SH; <34.4 °C) groups. At P42, cortical development, ex vivo MRI, and neuropathology were quantitated. Whole-brain volume and fractional anisotropy in SH brains were significantly decreased compared to control and NT animals. SH brains also had significantly altered gyrification, greater cortical pathology, and increased corpus callosum GFAP staining relative to NT and control brains. CONCLUSION: In near-term-equivalent ferrets, nesting RT 1 h after HIH may predict long-term neuropathological outcomes. IMPACT: High-throughput methods to determine injury severity prior to treatment in animal studies of neonatal brain injury are lacking. In a gyrified animal model of neonatal inflammation-sensitized hypoxic-ischemic brain injury in the ferret, rectal temperature 1 h after hypoxia predicts animals who will have increased cortical pathology and white matter changes on MRI. These changes parallel similar responses in rodents and humans but have not previously been correlated with long-term neuropathological outcomes in gyrified animal models. Endogenous thermoregulatory responses to injury may provide a translational marker of injury severity to help stratify animals to treatment groups or predict outcome in preclinical studies.

Time to Reaching Target Cooling Temperature and 2-year Outcomes in Infants with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To determine if time to reaching target temperature (TT) is associated with death or neurodevelopmental impairment (NDI) at 2 years of age in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Newborn infants ≥36 weeks of gestation diagnosed with moderate or severe HIE and treated with therapeutic hypothermia were stratified based on time at which TT was reached, defined as early (ie, ≤4 hours of age) or late (>4 hours of age). Primary outcomes were death or NDI. Secondary outcomes included neurodevelopmental assessment with Bayley Scales of Infant and Toddler Development, third edition (BSID-III) at age 2. RESULTS: Among 500 infants, the median time to reaching TT was 4.3 hours (IWR, 3.2-5.7 hours). Infants in early TT group (n = 211 [42%]) compared with the late TT group (n = 289 [58%]) were more likely to be inborn (23% vs 13%; P < .001) and have severe HIE (28% vs 19%; P = .03). The early and late TT groups did not differ in the primary outcome of death or any NDI (adjusted RR, 1.05; 95% CI, 0.85-0.30; P = .62). Among survivors, neurodevelopmental outcomes did not differ significantly in the 2 groups (adjusted mean difference in Bayley Scales of Infant Development-III scores: cognitive, -2.8 [95% CI, -6.1 to 0.5], language -3.3 [95% CI, -7.4 to 0.8], and motor -3.5 [95% CI, -7.3 to 0.3]). CONCLUSIONS: In infants with HIE, time to reach TT is not independently associated with risk of death or NDI at age 2 years. Among survivors, developmental outcomes are similar between those who reached TT at <4 and ≥4 hours of age. TRIAL REGISTRATION: High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL); NCT02811263; https://beta. CLINICALTRIALS: gov/study/NCT02811263.

Association of EEG Background and Neurodevelopmental Outcome in Neonates With Hypoxic-Ischemic Encephalopathy Receiving Hypothermia.

BACKGROUND AND OBJECTIVES: Predicting neurodevelopmental outcome for neonates with hypoxic-ischemic encephalopathy (HIE) is important for clinical decision-making, care planning, and parent communication. We examined the relationship between EEG background and neurodevelopmental outcome among children enrolled in a trial of erythropoietin or placebo for neonates with HIE treated with therapeutic hypothermia. METHODS: Participants had EEG recorded throughout hypothermia. EEG background was classified as normal, discontinuous, or severely abnormal (defined as burst suppression, low voltage suppressed, or status epilepticus) at 5 1-hour epochs: onset of recording, 24, 36, 48, and 72 hours after birth. The predominant background pattern during the entire continuous video EEG monitoring recording was calculated using the arithmetic mean of the 5 EEG background ratings (normal = 0; discontinuous = 1; severely abnormal = 2) as follows: "predominantly normal" (mean = 0), "normal/discontinuous" (0 < mean<1), "predominantly discontinuous" (mean = 1), "discontinuous/severely abnormal" (1 < mean<2), or "predominantly severely abnormal" (mean = 2). Primary outcome was death or neurodevelopmental impairment (NDI) defined as cerebral palsy, Gross Motor Function Classification Score ≥1, or cognitive score <90 on Bayley Scales of Infant Toddler Development, third edition at age 2 years. Neurodevelopment was also categorized into a 5-level ordinal measure: no, mild, moderate, severe NDI, or death for secondary analysis. We used generalized linear regression models with robust standard errors to assess the relative risk of death or NDI by EEG background in both unadjusted and adjusted analyses controlling for the effects of treatment group, sex, HIE severity, and study recruitment site. RESULTS: Among 142 neonates, the predominant background EEG pattern was predominantly normal in 35 (25%), normal/discontinuous in 68 (48%), predominantly discontinuous in 11 (7.7%), discontinuous/severely abnormal in 16 (11%), and predominantly severely abnormal in 12 (8.5%). Increasing severity of background across monitoring epochs was associated with increasingly worse clinical outcomes. Children with severe EEG background abnormality at any time point (n = 36, 25%) were significantly more likely to die or have severe NDI at 2 years (adjusted relative risk: 7.95, 95% CI 3.49-18.12). DISCUSSION: EEG background is strongly associated with NDI at age 2 years. These results can be used to assist health care providers to plan follow-up care and counsel families for decision-making related to goals of care.

Early Glycemic State and Outcomes of Neonates With Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: In infants with hypoxic-ischemic encephalopathy (HIE), conflicting information on the association between early glucose homeostasis and outcome exists. We characterized glycemic profiles in the first 12 hours after birth and their association with death and neurodevelopmental impairment (NDI) in neonates with moderate or severe HIE undergoing therapeutic hypothermia. METHODS: This post hoc analysis of the High-dose Erythropoietin for Asphyxia and Encephalopathy trial included n = 491 neonates who had blood glucose (BG) values recorded within 12 hours of birth. Newborns were categorized based on their most extreme BG value. BG >200 mg/dL was defined as hyperglycemia, BG <50 mg/dL as hypoglycemia, and 50 to 200 mg/dL as euglycemia. Primary outcome was defined as death or any NDI at 22 to 36 months. We calculated odds ratios for death or NDI adjusted for factors influencing glycemic state (aOR). RESULTS: Euglycemia was more common in neonates with moderate compared with severe HIE (63.6% vs 36.6%; P < .001). Although hypoglycemia occurred at similar rates in severe and moderate HIE (21.4% vs 19.5%; P = .67), hyperglycemia was more common in severe HIE (42.3% vs 16.9%; P < .001). Compared with euglycemic neonates, both, hypo- and hyperglycemic neonates had an increased aOR (95% confidence interval) for death or NDI (2.62; 1.47-4.67 and 1.77; 1.03-3.03) compared to those with euglycemia. Hypoglycemic neonates had an increased aOR for both death (2.85; 1.09-7.43) and NDI (2.50; 1.09-7.43), whereas hyperglycemic neonates had increased aOR of 2.52 (1.10-5.77) for death, but not NDI. CONCLUSIONS: Glycemic profile differs between neonates with moderate and severe HIE, and initial glycemic state is associated death or NDI at 22 to 36 months.

Characteristics, Genetic Testing, and Diagnoses of Infants with Neonatal Encephalopathy Not Due to Hypoxic Ischemic Encephalopathy: A Cohort Study.

OBJECTIVE: To characterize the presentation and evaluation of infants with neonatal encephalopathy (NE) not due to hypoxic-ischemic encephalopathy (non-HIE NE) and to describe the genetic abnormalities identified. STUDY DESIGN: Retrospective cohort study of 193 non-HIE NE neonates admitted to a level IV NICU from 2015 through 2019. For changes in testing over time, Cochrane-Armitage test for trend was used with a Bonferroni-corrected P-value, and comparison between groups was performed using Fisher exact test. RESULT: The most common symptom of non-HIE NE was abnormal tone in 47% (90/193). Ten percent (19/193) died prior to discharge, and 48% of survivors (83/174) required medical equipment at discharge. Forty percent (77/193) underwent genetic testing as an inpatient. Of 52 chromosomal studies, 54 targeted tests, and 16 exome sequences, 10%, 41%, and 69% were diagnostic, respectively, with no difference in diagnostic rates between infants with and without an associated congenital anomaly and/or dysmorphic feature. Twenty-eight genetic diagnoses were identified. CONCLUSIONS: Neonates with non-HIE NE have high rates of morbidity and mortality and may benefit from early genetic testing, even in the absence of other exam findings. This study broadens our knowledge of genetic conditions underlying non-HIE NE, which may enable families and care teams to anticipate the needs of the individual, allow early initiation of targeted therapies, and facilitate decisions surrounding goals of care.

Cerebral Glucose Concentration in Neonatal Hypoxic-Ischemic Encephalopathy during Therapeutic Hypothermia.

OBJECTIVE: To determine cerebral glucose concentration and its relationship with glucose infusion rate (GIR) and blood glucose concentration in neonatal encephalopathy during therapeutic hypothermia (TH). METHODS: This was an observational study in which cerebral glucose during TH was quantified by magnetic resonance (MR) spectroscopy and compared with mean blood glucose at the time of scan. Clinical data (gestational age, birth weight, GIR, sedative use) that could affect glucose use were collected. The severity and pattern of brain injury on MR imaging were scored by a neuroradiologist. Student t test, Pearson correlation, repeated measures ANOVA, and multiple regression analysis were performed. RESULTS: Three-hundred-sixty blood glucose values and 402 MR spectra from 54 infants (30 female infants; mean gestational age 38.6 ± 1.9 weeks) were analyzed. In total, 41 infants had normal-mild and 13 had moderate-severe injury. Median GIR and blood glucose during TH were 6.0 mg/kg/min (IQR 5-7) and 90 mg/dL (IQR 80-102), respectively. GIR did not correlate with blood or cerebral glucose. Cerebral glucose was significantly greater during than after TH (65.9 ± 22.9 vs 60.0 ± 25.2 mg/dL, P < .01), and there was a significant correlation between blood glucose and cerebral glucose during TH (basal ganglia: r = 0.42, thalamus: r = 0.42, cortical gray matter: r = 0.39, white matter: r = 0.39, all P < .01). There was no significant difference in cerebral glucose concentration in relation to injury severity or pattern. CONCLUSIONS: During TH, cerebral glucose concentration is partly dependent on blood glucose concentration. Further studies to understand brain glucose use and optimal glucose concentrations during hypothermic neuroprotection are needed.

Preterm infants variability in cerebral near-infrared spectroscopy measurements in the first 72-h after birth.

BACKGROUND: Cerebral near-infrared spectroscopy is a non-invasive tool used to measure regional cerebral tissue oxygenation (rScO2) initially validated in adult and pediatric populations. Preterm neonates, vulnerable to neurologic injury, are attractive candidates for NIRS monitoring; however, normative data and the brain regions measured by the current technology have not yet been established for this population. METHODS: This study's aim was to analyze continuous rScO2 readings within the first 6-72 h after birth in 60 neonates without intracerebral hemorrhage born at ≤1250 g and/or ≤30 weeks' gestational age (GA) to better understand the role of head circumference (HC) and brain regions measured. RESULTS: Using a standardized brain MRI atlas, we determined that rScO2 in infants with smaller HCs likely measures the ventricular spaces. GA is linearly correlated, and HC is non-linearly correlated, with rScO2 readings. For HC, we infer that rScO2 is lower in infants with smaller HCs due to measuring the ventricular spaces, with values increasing in the smallest HCs as the deep cerebral structures are reached. CONCLUSION: Clinicians should be aware that in preterm infants with small HCs, rScO2 displayed may reflect readings from the ventricular spaces and deep cerebral tissue. IMPACT: Clinicians should be aware that in preterm infants with small head circumferences, cerebral near-infrared spectroscopy readings of rScO2 displayed may reflect readings from the ventricular spaces and deep cerebral tissue. This highlights the importance of rigorously re-validating technologies before extrapolating them to different populations. Standard rScO2 trajectories should only be established after determining whether the mathematical models used in NIRS equipment are appropriate in premature infants and the brain region(s) NIRS sensors captures in this population, including the influence of both gestational age and head circumference.

Temperature dysregulation during therapeutic hypothermia predicts long-term outcome in neonates with HIE.

Few reliable or easily obtainable biomarkers to predict long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) have been identified. We previously showed that mattress temperature (MT), as proxy for disturbed temperature regulation during therapeutic hypothermia (TH), predicts injury on early MRI and holds promise as physiologic biomarker. To determine whether MT in neonates treated with TH for moderate-severe HIE is associated with long-term outcome at 18-22 months, we performed a secondary analysis of the Optimizing Cooling trial using MT data from 167 infants treated at a core temperature of 33.5°C. Median MTs from four time-epochs (0-6 h, 6-24 h, 24-48 h, and 48-72 h of TH) were used to predict death or moderate-severe neurodevelopmental impairment (NDI), using epoch-specific derived and validated MT cutoffs. Median MT of infants who died or survived with NDI was consistently 1.5-3.0°C higher throughout TH. Infants requiring a median MT above the derived cut-offs had a significantly increased odds of death or NDI, most notably at 0-6 h (aOR 17.0, 95%CI 4.3-67.4). By contrast, infants who remained below cut-offs across all epochs had 100% NDI-free survival. MTs in neonates with moderate-severe HIE during TH are highly predictive of long-term outcome and can be used as physiologic biomarker.

Association of Hospital Resource Utilization With Neurodevelopmental Outcomes in Neonates With Hypoxic-Ischemic Encephalopathy.

Importance: Intercenter variation exists in the management of hypoxic-ischemic encephalopathy (HIE). It is unclear whether increased resource utilization translates into improved neurodevelopmental outcomes. Objective: To determine if higher resource utilization during the first 4 days of age, quantified by hospital costs, is associated with survival without neurodevelopmental impairment (NDI) among infants with HIE. Design, Setting, and Participants: Retrospective cohort analysis of neonates with HIE who underwent therapeutic hypothermia (TH) at US children's hospitals participating in the Children's Hospitals Neonatal Database between 2010 and 2016. Data were analyzed from December 2021 to December 2022. Exposures: Infants who survived to 4 days of age and had neurodevelopmental outcomes assessed at greater than 11 months of age were divided into 2 groups: (1) death or NDI and (2) survived without NDI. Resource utilization was defined as costs of hospitalization including neonatal neurocritical care (NNCC). Data were linked with Pediatric Health Information Systems to quantify standardized costs by terciles. Main Outcomes and Measures: The main outcome was death or NDI. Characteristics, outcomes, hospitalization, and NNCC costs were compared. Results: Among the 381 patients who were included, median (IQR) gestational age was 39 (38-40) weeks; maternal race included 79 (20.7%) Black mothers, 237 (62.2%) White mothers, and 58 (15.2%) mothers with other race; 80 (21%) died, 64 (17%) survived with NDI (combined death or NDI group: 144 patients [38%]), and 237 (62%) survived without NDI. The combined death or NDI group had a higher rate of infants with Apgar score at 10 minutes less than or equal to 5 (65.3% [94 of 144] vs 39.7% [94 of 237]; P < .001) and a lower rate of infants with mild or moderate HIE (36.1% [52 of 144] vs 82.3% [195 of 237]; P < .001) compared with the survived without NDI group. Compared with low-cost centers, there was no association between high- or medium-hospitalization cost centers and death or NDI. High- and medium-EEG cost centers had lower odds of death or NDI compared with low-cost centers (high vs low: OR, 0.30 [95% CI, 0.16-0.57]; medium vs low: OR, 0.29 [95% CI, 0.13-0.62]). High- and medium-laboratory cost centers had higher odds of death or NDI compared with low-cost centers (high vs low: OR, 2.35 [95% CI, 1.19-4.66]; medium vs low: OR, 1.93 [95% CI, 1.07-3.47]). High-antiseizure medication cost centers had higher odds of death or NDI compared with low-cost centers (high vs. low: OR, 3.72 [95% CI, 1.51-9.18]; medium vs low: OR, 1.56 [95% CI, 0.71-3.42]). Conclusions and Relevance: Hospitalization costs during the first 4 days of age in neonates with HIE treated with TH were not associated with neurodevelopmental outcomes. Higher EEG costs were associated with lower odds of death or NDI yet higher laboratory and antiseizure medication costs were not. These findings serve as first steps toward identifying aspects of NNCC that are associated with outcomes.

Predicting 2-year neurodevelopmental outcomes in extremely preterm infants using graphical network and machine learning approaches.

Background: Infants born extremely preterm (<28 weeks' gestation) are at high risk of neurodevelopmental impairment (NDI) with 50% of survivors showing moderate or severe NDI when at 2 years of age. We sought to develop novel models by which to predict neurodevelopmental outcomes, hypothesizing that combining baseline characteristics at birth with medical care and environmental exposures would produce the most accurate model. Methods: Using a prospective database of 692 infants from the Preterm Epo Neuroprotection (PENUT) Trial, which was carried out between December 2013 and September 2016, we developed three predictive algorithms of increasing complexity using a Bayesian Additive Regression Trees (BART) machine learning approach to predict both NDI and continuous Bayley Scales of Infant and Toddler Development 3rd ed subscales at 2 year follow-up using: 1) the 5 variables used in the National Institute of Child Health and Human Development (NICHD) Extremely Preterm Birth Outcomes Tool, 2) 21 variables associated with outcomes in extremely preterm (EP) infants, and 3) a hypothesis-free approach using 133 potential variables available for infants in the PENUT database. Findings: The NICHD 5-variable model predicted 3-4% of the variance in the Bayley subscale scores, and predicted NDI with an area under the receiver operator curve (AUROC, 95% CI) of 0.62 (0.56-0.69). Accuracy increased to 12-20% of variance explained and an AUROC of 0.77 (0.72-0.83) when using the 21 pre-selected clinical variables. Hypothesis-free variable selection using BART resulted in models that explained 20-31% of Bayley subscale scores and AUROC of 0.87 (0.83-0.91) for severe NDI, with good calibration across the range of outcome predictions. However, even with the most accurate models, the average prediction error for the Bayley subscale predictions was around 14-15 points, leading to wide prediction intervals. Higher total transfusion volume was the most important predictor of severe NDI and lower Bayley scores across all subscales. Interpretation: While the machine learning BART approach meaningfully improved predictive accuracy above a widely used prediction tool (NICHD) as well as a model utilizing NDI-associated clinical characteristics, the average error remained approximately 1 standard deviation on either side of the true value. Although dichotomous NDI prediction using BART was more accurate than has been previously reported, and certain clinical variables such as transfusion exposure were meaningfully predictive of outcomes, our results emphasize the fact that the field is still not able to accurately predict the results of complex long-term assessments such as Bayley subscales in infants born EP even when using rich datasets and advanced analytic methods. This highlights the ongoing need for long-term follow-up of all EP infants. Funding: Supported by the National Institute of Neurological Disorders and StrokeU01NS077953 and U01NS077955.

Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo.

BACKGROUND: An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo. METHODS: Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models. RESULTS: Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo). CONCLUSION: In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia. IMPACT: In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

Survey of Quaternary Neonatal Management of Posthemorrhagic Hydrocephalus.

OBJECTIVE: This study aimed to determine clinical care practices for infants at risk for posthemorrhagic hydrocephalus (PHH) across level IV neonatal intensive care units (NICUs). STUDY DESIGN: Cross-sectional survey that addressed center-specific surveillance, neurosurgical intervention, and follow-up practices within the Children's Hospitals Neonatal Consortium. RESULTS: We had a 59% (20/34 sites) response rate, with 10 sites having at least two participants. Respondents included neonatologists (53%) and neurosurgeons (35%). Most participants stated having a standard guideline for PHH (79%). Despite this, 42% of respondents perceive inconsistencies in management. Eight same-center pairs of neonatologists and neurosurgeons were used to determine response agreement. Half of these pairs disagreed on nearly all aspects of care. The greatest agreement pertained to a willingness to adopt a consensus-based protocol. CONCLUSION: Practice variation in the management of infants at risk of PHH in level IV NICUs exists despite the perception that a common practice is available and used. KEY POINTS: · Practice variation exists despite the perception that common practices are available/used for PHH.. · Our survey had same-center pairs of neonatologist and neurosurgeons to determine response agreement.. · The greatest agreement pertained to a willingness to adopt a consensus-based protocol..

Association Between Early EEG Background and Outcomes in Infants With Mild HIE Undergoing Therapeutic Hypothermia.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) occurs in 1-4:1000 live births. Although neonates with moderate-severe HIE have been studied over several decades, newborns with mild HIE remain understudied, including seizure occurrence, electroencephalography (EEG) characteristics, and outcome. METHODS: We conducted a retrospective cohort study of neonates ≥35 weeks of gestation with mild HIE who underwent therapeutic hypothermia to correlate the early EEG background pattern with clinical course and outcomes. RESULTS: Of the included 29 neonates, 10 infants had a moderately to severely abnormal EEG background and 19 had either a normal or a mildly abnormal background. Those with moderately to severely abnormal background also had more multiorgan dysfunction (90% vs 42%, P = 0.02) and a higher incidence of subdural and intraventricular hemorrhages (80% vs 26%, P = 0.02). The overall seizure incidence was 20.7% and was significantly higher in newborns with more severely abnormal background compared to neonates with less abnormal background (50% vs 5%; P = 0.01; relative risk, 9.5; 95% confidence interval, 1.28-70.6). Seizure onset was between 11 and 63 hours of life. Regardless of the EEG background pattern, seizures were brief with an overall low seizure burden. None of the newborns with normal or mildly abnormal background had a new onset of seizures after 24 hours of recording or developed epilepsy during infancy. CONCLUSIONS: In neonates with mild HIE, early moderately to severely abnormal EEG background is common and strongly associated with an increased risk for seizures.