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.

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.

Feeding and developmental outcomes after neonatal seizures-A prospective observational study.

Objective: Among neonates with acute symptomatic seizures, we evaluated whether inability to take full feeds at time of hospital discharge from neonatal seizure admission is associated with worse neurodevelopmental outcomes, after adjusting for relevant clinical variables. Methods: This prospective, 9-center study of the Neonatal Seizure Registry (NSR) assessed characteristics of infants with seizures including: evidence of brainstem injury on MRI, mode of feeding upon discharge, and developmental outcomes at 12, 18, and 24 months. Inability to take oral feeds was identified through review of medical records. Brainstem injury was identified through 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 G-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: 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.

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.

Correlating Quantitative MRI-based Apparent Diffusion Coefficient Metrics with 24-month Neurodevelopmental Outcomes in Neonates from the HEAL Trial.

Background Multiple qualitative scoring systems have been created to capture the imaging severity of hypoxic ischemic brain injury. Purpose To evaluate quantitative volumes of acute brain injury at MRI in neonates with hypoxic ischemic brain injury and correlate these findings with 24-month neurodevelopmental outcomes and qualitative brain injury scoring by radiologists. Materials and Methods In this secondary analysis, brain diffusion-weighted MRI data from neonates in the High-dose Erythropoietin for Asphyxia and Encephalopathy trial, which recruited participants between January 2017 and October 2019, were analyzed. Volume of acute brain injury, defined as brain with apparent diffusion coefficient (ADC) less than 800 × 10-6 mm2/sec, was automatically computed across the whole brain and within the thalami and white matter. Outcomes of death and neurodevelopmental impairment (NDI) were recorded at 24-month follow-up. Associations between the presence and volume (in milliliters) of acute brain injury with 24-month outcomes were evaluated using multiple logistic regression. The correlation between quantitative acute brain injury volume and qualitative MRI scores was assessed using the Kendall tau-b test. Results A total of 416 neonates had available MRI data (mean gestational age, 39.1 weeks ± 1.4 [SD]; 235 male) and 113 (27%) showed evidence of acute brain injury at MRI. Of the 387 participants with 24-month follow-up data, 185 (48%) died or had any NDI. Volume of acute injury greater than 1 mL (odds ratio [OR], 13.9 [95% CI: 5.93, 32.45]; P < .001) and presence of any acute injury in the brain (OR, 4.5 [95% CI: 2.6, 7.8]; P < .001) were associated with increased odds of death or any NDI. Quantitative whole-brain acute injury volume was strongly associated with radiologists' qualitative scoring of diffusion-weighted images (Kendall tau-b = 0.56; P < .001). Conclusion Automated quantitative volume of brain injury is associated with death, moderate to severe NDI, and cerebral palsy in neonates with hypoxic ischemic encephalopathy and correlated well with qualitative MRI scoring of acute brain injury. Clinical trial registration no. NCT02811263 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Huisman in this issue.

Neonatal brain MRI and short-term outcomes after acute provoked seizures.

OBJECTIVE: We investigated how diagnosis and injury location on neonatal brain MRI following onset of acute provoked seizures was associated with short term outcome. STUDY DESIGN: A multicenter cohort of neonates with acute provoked seizures enrolled in the Neonatal Seizure Registry. MRIs were centrally evaluated by a neuroradiologist for location of injury and radiologic diagnosis. Clinical outcomes were determined by chart review. Multivariate logistic regression was used to examine the association between MRI findings and outcomes. RESULTS: Among 236 newborns with MRI at median age 4 days (IQR 3-8), 91% had abnormal MRI. Radiologic diagnoses of intracranial hemorrhage (OR 3.2 [1.6-6.5], p < 0.001) and hypoxic-ischemic encephalopathy (OR 2.7 [1.4-5.4], p < 0.003) were associated with high seizure burden. Radiologic signs of intracranial infection were associated with abnormal neurologic examination at discharge (OR 3.9 [1.3-11.6], p < 0.01). CONCLUSION: Findings on initial MRI can help with expectant counseling on short-term outcomes following acute provoked neonatal seizures.

Using Neonatal Magnetic Resonance Imaging to Predict Gross Motor Disability at Four Years in Term-Born Children With Neonatal Encephalopathy.

BACKGROUND: Children with neonatal encephalopathy (NE) are at risk for basal ganglia/thalamus (BG/T) and watershed patterns of brain injury. Children with BG/T injury are at high risk for motor impairment in infancy, but the predictive validity of a published rating scale for outcome at age four years is not known. We examined a cohort of children with NE and magnetic resonance imaging (MRI) to examine the relationship between BG/T injury and severity of cerebral palsy (CP) in childhood. METHODS: Term-born neonates at risk for brain injury due to NE were enrolled from 1993 to 2014 and received MRI within two weeks of birth. Brain injury was scored by a pediatric neuroradiologist. The Gross Motor Function Classification System (GMFCS) level was determined at four years. The relationship between BG/T injury and dichotomized GMFCS (no CP or GMFCS I to II = none/mild versus III to V = moderate/severe CP) was evaluated with logistic regression, and predictive performance was assessed by cross-validated area under the receiver operating characteristic curve (AUROC). RESULTS: Among 174 children, higher BG/T scores were associated with more severe GMFCS level. Clinical predictors had a low AUROC (0.599), compared with that of MRI (0.895). Risk of moderate to severe CP was low (<20%) in all patterns of brain injury except BG/T = 4, which carried a 67% probability (95% confidence interval 36% to 98%) of moderate to severe CP. CONCLUSIONS: The BG/T injury score can be used to predict the risk and severity of CP at age four years and thereby inform early developmental interventions.

Safety of High Dose Erythropoietin Used with Therapeutic Hypothermia as Treatment for Newborn Hypoxic-Ischemic Encephalopathy: Secondary Analysis of the HEAL Randomized Controlled Trial.

OBJECTIVE: To assess whether high dose erythropoietin (Epo) treatment of cooled infants with neonatal hypoxic ischemic encephalopathy results in a higher risk of prespecified serious adverse events (SAEs). STUDY DESIGN: Five hundred infants born at ≥36 weeks of gestation with moderate or severe hypoxic ischemic encephalopathy undergoing therapeutic hypothermia were randomized to Epo or placebo on days 1, 2, 3, 4, and 7. Pretreatment and posttreatment SAEs were compared with adjusted generalized linear models, with posttreatment models adjusted for the presence of a pretreatment SAE. Clinical risk factors and potential mechanisms for SAEs were also examined. RESULTS: The rate of experiencing at least one posttreatment SAE did not significantly differ between groups (adjusted relative risk [aRR], 95% CI: 1.17, 0.92-1.49); however, posttreatment thrombosis was identified more often in the Epo group (n = 6, 2.3%) than the placebo group (n = 1, 0.4%; aRR, 95% CI: 5.09, 1.32-19.64). The rate of posttreatment intracranial hemorrhage identified at the treatment sites by either ultrasound or magnetic resonance imaging was slightly elevated in the Epo group (n = 61, 24%) but not significantly different from the placebo group (n = 46, 19%; aRR, 95% CI: 1.21, 0.85, 1.72). CONCLUSIONS: A small increased risk of major thrombotic events was identified in the Epo treatment group. TRIAL REGISTRATION: NCT02811263.

How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy?

BACKGROUND: In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. METHODS: Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4-6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. RESULTS: Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5-5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. CONCLUSION: In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. IMPACT: Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

The ALIGN Framework: A Parent-Informed Approach to Prognostic Communication for Infants With Neurologic Conditions.

BACKGROUND AND OBJECTIVES: Clinicians often communicate complex, uncertain, and distressing information about neurologic prognosis to parents of critically ill infants. Although communication tools have been developed in other disciplines and settings, none address the unique needs of the neonatal and pediatric neurology context. We aimed to develop a parent-informed framework to guide clinicians in communicating information about neurologic prognosis. METHODS: Parents of infants with neurologic conditions in the intensive care unit were enrolled in a longitudinal study of shared decision-making from 2018 to 2020. Parents completed semistructured interviews following recorded family meetings with the health care team, at hospital discharge, and 6 months after discharge. All interviews targeted information about parent preferences for prognostic disclosure. We analyzed the data using a conventional content analysis approach. Two study team members independently coded all interview transcripts, and discrepancies were resolved in consensus. We used NVIVO 12 qualitative software to index and organize codes. RESULTS: Fifty-two parents of 37 infants completed 123 interviews. Parents were predominantly mothers (n = 37/52, 71%) with a median age of 31 (range 19-46) years. Half were Black (n = 26/52, 50%), and a minority reported Hispanic ethnicity (n = 2/52, 4%). Inductive analysis resulted in the emergence of 5 phases of prognostic communication (Approach, Learn, Inform, Give support, and Next steps: ALIGN): (1) Approach: parents appreciated receiving consistent information about their child's neurologic outcome from clinicians who knew their child well. (2) Learn: parents valued when clinicians asked them how they preferred receiving information and what they already knew about their child's outcome prior to information delivery. (3) Inform: parents valued honest, thorough, and balanced information that disclosed prognostic uncertainty and acknowledged room for hope. (4) Give support: parents valued empathic communication and appreciated clinicians who offered real-time emotional support. (5) Next steps: parents appreciated clinicians who connected them to resources, including peer support. DISCUSSION: The ALIGN framework offers a novel, parent-informed strategy to effectively communicate neurologic prognosis. Although ALIGN represents key elements of a conversation about prognosis, each clinician can adapt this framework to their own approach. Future work will assess the effectiveness of this framework on communication quality and prognostic understanding.

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.

Seizure Burden, EEG, and Outcome in Neonates With Acute Intracranial Infections: A Prospective Multicenter Cohort Study.

BACKGROUND: Limited data exist regarding seizure burden, electroencephalogram (EEG) background, and associated outcomes in neonates with acute intracranial infections. METHODS: This secondary analysis was from a prospective, multicenter study of neonates enrolled in the Neonatal Seizure Registry with seizures due to intracranial infection. Sites used continuous EEG monitoring per American Clinical Neurophysiology Society guidelines. High seizure burden was defined a priori as seven or more EEG-confirmed seizures. EEG background was categorized using standardized terminology. Primary outcome was neurodevelopment at 24-months corrected age using Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS). Secondary outcomes were postneonatal epilepsy and motor disability. RESULTS: Twenty-seven of 303 neonates (8.9%) had seizures due to intracranial infection, including 16 (59.3%) bacterial, 5 (18.5%) viral, and 6 (22.2%) unknown. Twenty-three neonates (85%) had at least one subclinical seizure. Among 23 children with 24-month follow-up, the WIDEA-FS score was, on average, 23 points lower in children with high compared with low seizure burden (95% confidence interval, [-48.4, 2.1]; P = 0.07). After adjusting for gestational age, infection etiology, and presence of an additional potential acute seizure etiology, the effect size remained unchanged (ß = -23.8, P = 0.09). EEG background was not significantly associated with WIDEA-FS score. All children with postneonatal epilepsy (n = 4) and motor disability (n = 5) had high seizure burden, although associations were not significant. CONCLUSION: High seizure burden may be associated with worse neurodevelopment in neonates with intracranial infection and seizures. EEG monitoring can provide useful management and prognostic information in this population.

Prognostic Discussion for Infants with Neurologic Conditions: Qualitative Analysis of Family Conferences.

OBJECTIVE: We characterize the content and role of prognostic discussion for infants with neurologic conditions. METHODS: In this descriptive qualitative study, we prospectively enrolled infants (age < 1 year) in the intensive care unit with a neurologic condition anticipated to have ≥1 family conference about prognosis or goals of care. We audiorecorded family conferences as they occurred. We used a rapid-cycle qualitative approach to identify and refine themes. RESULTS: Forty infants and 61 parents were enrolled; 68 family conferences occurred for 24 infants. The majority of infant cases (n = 23/24, 96%) and conferences (n = 64/68, 94%) included discussion of neurologic prognosis. Common infant diagnoses included prematurity (n = 12, 52%), genetic conditions (n = 9, 35%), and brain malformations (n = 7, 30%). We identified 2 themes relating to the characterization of the infant's prognosis: (1) predictions of impairment and (2) rationale for prognostic predictions. We identified 3 themes characterizing the role of prognostic discussion: (1) aligning parent and clinician understanding of infant outcome, (2) influencing decision-making, and (3) preparing for life at home. We identified 2 themes characterizing discussion of prognostic uncertainty: (1) multilayered types of uncertainty and (2) holding space for hope alongside uncertainty. INTERPRETATION: In this cohort of infants with neurologic conditions and their parents, we identified salient themes characterizing the content and role of discussion about neurologic outcome. Our findings highlight that prognostic discussion focuses on anticipated impairments, informs decision-making, and helps families prepare for home life. Future work should characterize whether these findings align with parent preferences for prognostic disclosure. ANN NEUROL 2022;92:699-709.

Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Outcome of Neonates Presenting With Severe Cardiac Failure due to Cerebral Arteriovenous Fistula.

BACKGROUND: Congenital cerebral arteriovenous fistulas (AVFs), including vein of Galen malformations, presenting in infancy carry variable mortality and morbidity. This study aimed to describe the outcome of neonates with cerebral AVFs who present with refractory cardiac failure. METHODS: Retrospective chart review of neonates with refractory cardiac failure due to cerebral AVFs presenting before 28 days of age in a single-center neuro-intensive care nursery over a 12-year period (2008-2020) was conducted. RESULTS: Seventeen neonates were included. Twelve had a vein of Galen malformation, four a non-galenic pial AVF, and one a dural AVF. Seven neonates (41%) died without receiving an embolization procedure. The remaining ten were critically ill. Seven (70%) were mechanically ventilated and on nitric oxide, 5 (50%) were on pressors, and 6 (60%) had renal and/or hepatic dysfunction. Seven (70%) had pre-existing brain injury on imaging. The first embolization procedure occurred at a median age of 4 days (range: 0-8 d). Complications included intracranial hemorrhage in 8 of 10 (80%) and seizures in 5 of 8 (62%). Five (50%) neonates who underwent embolization died. Among the 5 neonates who survived, all have motor impairment. Four (80%) developed hydrocephalus requiring a ventriculoperitoneal shunt, and 2 (40%) developed epilepsy and are nonverbal. CONCLUSION: In this cohort of critically ill neonates with cerebral AVF, all seven who did not receive embolization and half of ten who were treated died. The five survivors all have neurodevelopmental impairment. This information may be helpful to parents and providers who make decisions regarding life-sustaining treatments for neonates with cerebral AVFs and refractory cardiac failure.