Early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy: a multicentre double-blind pilot randomised controlled trial.

OBJECTIVE: To examine the feasibility of early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy (HIE). DESIGN: Double-blind pilot randomised controlled trial. SETTING: Eight neonatal units in South Asia. PATIENTS: Neonates (≥36 weeks) with moderate or severe HIE admitted between 31 December 2022 and 3 May 2023. INTERVENTIONS: Erythropoietin (500 U/kg daily) or to the placebo (sham injections using a screen) within 6 hours of birth and continued for 9 days. MRI at 2 weeks of age. MAIN OUTCOMES AND MEASURES: Feasibility of randomisation, drug administration and assessment of brain injury using MRI. RESULTS: Of the 154 neonates screened, 56 were eligible; 6 declined consent and 50 were recruited; 43 (86%) were inborn. Mean (SD) age at first dose was 4.4 (1.2) hours in erythropoietin and 4.1 (1.0) hours in placebo. Overall mortality at hospital discharge occurred in 5 (19%) vs 11 (46%) (p=0.06), and 3 (13%) vs 9 (40.9%) (p=0.04) among those with moderate encephalopathy in the erythropoietin and placebo groups. Moderate or severe injury to basal ganglia, white matter and cortex occurred in 5 (25%) vs 5 (38.5%); 14 (70%) vs 11 (85%); and 6 (30%) vs 2 (15.4%) in the erythropoietin and placebo group, respectively. Sinus venous thrombosis was seen in two (10%) neonates in the erythropoietin group and none in the control group. CONCLUSIONS: Brain injury and mortality after moderate or severe HIE are high in South Asia. Evaluation of erythropoietin monotherapy using MRI to examine treatment effects is feasible in these settings. TRIAL REGISTRATION NUMBER: NCT05395195.

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.

Time to regain birthweight and association with neurodevelopmental outcomes among extremely preterm newborns.

OBJECTIVE: Determine association between time to regain birthweight and 2-year neurodevelopment among extremely preterm (EP) newborns. STUDY DESIGN: Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial evaluating time to regain birthweight, time from birth to weight nadir, time from nadir to regain birthweight, and cumulative weight loss with 2-year corrected Bayley Scales of Infant and Toddler Development 3rd edition. RESULTS: Among n = 654 EP neonates, those with shorter nadir-to-regain had lower cognitive scores (≤1 day versus ≥8 days: -5.0 points, [CI -9.5, -0.6]) and lower motor scores (≤1 day versus ≥8 days: -4.6 points [CI -9.2, -0.03]) in adjusted stepwise forward regression modeling. Increasingly cumulative weight loss was associated with lower cognitive scores (≤-50 percent-days: -5.6, [CI -9.4, -1.8]), motor scores (≤-50 percent-days: -4.2, [CI -8.2, -0.2]); and language scores (≤-50 percent-days: -6.0, [CI -10.1, -1.9]). CONCLUSION: Faster nadir-to-regain and excessive cumulative weight loss are associated with adverse 2-year neurodevelopmental outcomes. TRIAL REGISTRATION: PENUT Trial Registration: NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 . CLINICAL TRIAL REGISTRATION: This study is a post-hoc secondary analysis of pre-existing data from the PENUT Trial (NCT #01378273).

Platelet Transfusion and Death or Neurodevelopmental Impairment in Children Born Extremely Preterm.

Importance: Infants born extremely preterm receive transfusions at higher platelet count thresholds than older children and adults due to concerns for intracranial hemorrhage. A recent randomized trial comparing 2 platelet transfusion thresholds showed the higher threshold was associated with increased risk of long-term adverse neurodevelopmental outcomes. Objective: To evaluate the association of platelet transfusion exposure with death and severe neurodevelopmental impairment (NDI) at 2 years' corrected age in a cohort of infants born extremely preterm. Design, Setting, and Participants: An observational cohort study and secondary analysis of the Preterm Erythropoietin Neuroprotection Trial, a randomized, placebo-controlled clinical trial of erythropoietin neuroprotection in neonates born extremely preterm, was conducted in 30 neonatal intensive care units in the US from December 1, 2013, to September 31, 2016. This analysis included 819 infants born extremely preterm at 24 to 27 completed weeks of gestation who had a documented outcome (death or neurodevelopmental assessment). Analysis was performed in April 2023. Exposures: Any platelet transfusion during neonatal intensive care unit hospitalization. Main Outcomes and Measures: The primary composite outcome was death or severe NDI evaluated at 2 years' corrected age using the Bayley Scales of Infant Development-Third Edition (BSID-III) and the Gross Motor Function Classification System and was defined as the presence of severe cerebral palsy or a BSID-III composite motor or cognitive score 2 SDs below the mean. Confounding by indication for platelet transfusion was addressed with covariate adjustment and propensity score methods. Results: Of the 819 infants included in the analysis (429 [52.4%] male; mean [SD] gestational age, 25.5 [1.1] weeks), 245 (30.0%) received at least 1 platelet transfusion during their initial hospitalization. The primary outcome occurred in 46.5% (114 of 245) of infants exposed to a platelet transfusion and 13.9% (80 of 574) of nonexposed infants with a corresponding odds ratio of 2.43 (95% CI, 1.24-4.76), adjusted for propensity score, gestational age at birth, and trial treatment group. The individual components of death and severe NDI were directionally consistent with the overall composite outcome. Conclusions and Relevance: The findings of this study suggest that platelet transfusion in infants born extremely preterm may be associated with an increased risk of death or severe NDI at 2 years' corrected age, although the possibility of residual confounding by indication cannot be excluded.

Contemporary definitions of infant growth failure and neurodevelopmental and behavioral outcomes in extremely premature infants at two years of age.

BACKGROUND: Associations of 2-year neurodevelopmental and behavioral outcomes with growth trajectories of preterm infants are unknown. METHODS: This secondary analysis of a preterm cohort examined in-hospital and discharge to 2-year changes in anthropometric z-scores. Two-year follow-up included Bayley Scales of Infant Development (BSID-III) and Child Behavior Checklist. RESULTS: Among 590 infants, adjusted in-hospital growth was not associated with any BSID-III subscale. Occipitofrontal circumference (OFC) growth failure (GF) in-hospital was associated with increased adjusted odds of attention problems (aOR 1.65 [1.03, 2.65]), aggressive behavior (aOR 2.34 [1.12, 4.89]), and attention-deficit-hyperactivity symptoms (aOR 1.86 [1.05, 3.30]). Infants with OFC GF at 2 years had lower adjusted BSID-III language scores (-4.0 [-8.0, -0.1]), increased odds of attention problems (aOR 2.29 [1.11, 4.74]), aggressive behavior (aOR 3.09 [1.00, 9.56]), and externalizing problems (aOR 3.01 [1.07, 8.45]) compared to normal OFC growth cohort. CONCLUSION: Infants with OFC GF are at risk for neurodevelopmental and behavioral impairment. CLINICAL TRIAL REGISTRATION: This study is a secondary analysis of pre-existing data from the PENUT Trial Registration: NCT01378273.

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.

Darbepoetin alfa to reduce transfusion episodes in infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions in the Netherlands: an open-label, single-centre, phase 2, randomised, controlled trial.

BACKGROUND: Up to 88% of infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions require erythrocyte transfusions after birth. We aimed to investigate the effect of darbepoetin alfa on the prevention of postnatal anaemia in infants with haemolytic disease of the fetus and newborn. METHODS: We conducted an open-label, single-centre, phase 2 randomised controlled trial to evaluate the effect of darbepoetin alfa on the number of erythrocyte transfusions in infants with haemolytic disease of the fetus and newborn. All infants who were treated with intrauterine transfusion and born at 35 weeks of gestation or later at the Leiden University Medical Center, Leiden, Netherlands, were eligible for inclusion. Included infants were randomised by computer at birth to treatment with 10 µg/kg darbepoetin alfa subcutaneously once a week for 8 weeks or standard care (1:1 allocation, in varying blocks of four and six, with no stratification). Treating physicians and parents were not masked to treatment allocation, but the research team, data manager, and statistician were masked to treatment allocation during the process of data collection. The primary outcome was the number of erythrocyte transfusion episodes per infant from birth up to 3 months of life in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03104426) and has been completed. FINDINGS: Between Oct 31, 2017, and April 31, 2022, we recruited 76 infants, of whom 44 (58%) were randomly assigned to a treatment group (20 [45%] were allocated to receive darbepoetin alfa and 24 [55%] were allocated to receive standard care). Follow-up lasted 3 months and one infant dropped out of the trial before commencement of treatment. A significant reduction in erythrocyte transfusion episodes was identified with darbepoetin alfa treatment compared with standard care (median 1·0 [IQR 1·0-2·0] transfusion episodes vs 2·0 [1·3-3·0] transfusion episodes; p=0·0082). No adverse events were reported and no infants died during the study. INTERPRETATION: Darbepoetin alfa reduced the transfusion episodes after intrauterine transfusion treatment for haemolytic disease of the fetus and newborn. Treatment with darbepoetin alfa or other types of erythropoietin should be considered as part of the postnatal treatment of severe haemolytic disease of the fetus and newborn. FUNDING: Sanquin Blood Supply. TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.

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.

Brain Injury Outcomes after Adjuvant Erythropoietin Neuroprotection for Moderate or Severe Neonatal Hypoxic-Ischemic Encephalopathy: A Report from the HEAL Trial.

INTRODUCTION: Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset of perinatal brain injuries. METHODS: This study was a secondary analysis of neuroimaging data from the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which was conducted from 2016 - 2021 at 17 sites involving 23 US academic medical centers. Participants were neonates >36 weeks' gestation undergoing therapeutic hypothermia for moderate or severe HIE who received 5 doses of study drug (Epoetin alpha 1000 U/kg/dose) or placebo in the first week of life. Treatment assignment was stratified by trial site and severity of encephalopathy. The primary outcome was the locus, pattern and acuity of brain injury as determined by three independent readers using a validated HIE Magnetic Resonance Imaging (MRI) scoring system. RESULTS: Of the 500 infants enrolled in HEAL, 470 (94%) had high quality MRI data obtained at a median of 4.9 days of age (IQR 4.5 - 5.8). The incidence of injury to the deep grey nuclei, cortex, white matter, brainstem and cerebellum was similar between Epo and placebo groups. Likewise, the distribution of injury patterns was similar between groups. Among infants imaged at less than 8 days (n=414), 94 (23%) evidenced only acute, 93 (22%) only subacute and 89 (21%) both acute and subacute injuries, with similar distribution across treatment groups. CONCLUSION: Adjuvant erythropoietin did not reduce the incidence of regional brain injury. Subacute brain injury was more common than previously reported, which has key implications for the development of adjuvant neuroprotective therapies for this population.

Placental Histologic Abnormalities and 2-Year Outcomes in Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: We aimed to examine the association between placental abnormalities and neurodevelopmental outcomes in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) that underwent therapeutic hypothermia. We hypothesized that subjects with acute placental abnormalities would have reduced risk of death or neurodevelopmental impairment (NDI) at 2 years of age after undergoing therapeutic hypothermia compared to subjects without acute placental changes. STUDY DESIGN: Among 500 subjects born at ≥36 weeks gestation with moderate or severe HIE enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, a placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute only, chronic only, or both acute and chronic histologic abnormalities. We calculated adjusted relative risks (aRRs) for associations between placental pathologic abnormalities and death or NDI at age 2 years, adjusting for HIE severity, treatment assignment, and site. RESULT: 321/500 subjects (64%) had available placental pathology reports. Placental abnormalities were characterized as acute only (20%), chronic only (21%), both acute and chronic (43%), and none (15%). The risk of death or NDI was not statistically different between subjects with and without an acute placental abnormality (46 vs. 53%, aRR 1.1, 95% confidence interval (CI): 0.9, 1.4). Subjects with two or more chronic lesions were more likely to have an adverse outcome than subjects with no chronic abnormalities, though this did not reach statistical significance (55 vs. 45%, aRR 1.24, 95% CI: 0.99, 1.56). CONCLUSION: Placental pathologic findings were not independently associated with risk of death or NDI in subjects with HIE. The relationship between multiple chronic placental lesions and HIE outcomes deserves further study.

New frontiers in neonatal red blood cell transfusion research.

Red blood cell (RBC) transfusions are common in neonates requiring intensive care. Recent studies have compared restricted versus liberal transfusion guidelines, but limitations exist on evaluations of outcomes in populations that never required a transfusion compared to those receiving any transfusion. Although there are well-established risks associated with RBC transfusions, new data has emerged that suggests additional clinically relevant associations, including adverse neurodevelopmental outcomes, donor sex differences, and inflammation or immunosuppression. Further research is needed to delineate the magnitude of these risks and to further improve the safety of transfusions. The goal of this review is to highlight underappreciated, yet clinically important risks associated with neonatal RBC transfusions and to introduce several areas in which neonates may uniquely benefit from alterations in practice.

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.

Reducing Severe Intraventricular Hemorrhage in Preterm Infants With Improved Care Bundle Adherence.

BACKGROUND AND OBJECTIVES: Intraventricular hemorrhage prevention bundles (IVHPBs) can decrease the incidence of intraventricular hemorrhage (IVH) in premature infants. Our center had a high rate of severe (grade III/IV) IVH (9.8%), and poor adherence (24%) to an IVHPB in neonates born ≤1250 g or ≤30 gestational weeks. Improvement initiatives were planned to decrease the incidence of severe IVH by 30% over 2 years. METHODS: A multidisciplinary team undertook interventions including in-service training, prompt initiation of IVHPB, revision of guidelines, and process standardization. Baseline data were collected from May 2016 to June 2018, with interventions occurring from July 2018 to May 2020. Adherence to the IVHPB was the primary process measure, and incidence of severe IVH the primary outcome measure. Control charts were used to analyze the effect of interventions on outcome. Balancing measures included use of breast milk at discharge, use of mechanical ventilation after initial resuscitation, and bronchopulmonary dysplasia. RESULTS: A total of 240 infants were assessed preintervention, and 185 during interventions. Adherence to the IVHPB improved from 24% to 88%. During this period, the incidence of severe IVH decreased from 9.8% to 2.4%, a 76% reduction from baseline. A higher adherence score was associated with reduced odds of IVH (odds ratio 0.30; 95% confidence interval 0.10-0.90, P = .03). CONCLUSIONS: Interventions focused on enhancing adherence to an IVHPB were associated with a reduced rate of severe IVH in high-risk neonates, highlighting the importance of assessing adherence to clinical guidelines.

Association of High-Dose Erythropoietin With Circulating Biomarkers and Neurodevelopmental Outcomes Among Neonates With Hypoxic Ischemic Encephalopathy: A Secondary Analysis of the HEAL Randomized Clinical Trial.

Importance: The ability to predict neurodevelopmental impairment (NDI) for infants diagnosed with hypoxic ischemic encephalopathy (HIE) is important for parental guidance and clinical treatment as well as for stratification of patients for future neurotherapeutic studies. Objectives: To examine the effect of erythropoietin on plasma inflammatory mediators in infants with moderate or severe HIE and to develop a panel of circulating biomarkers that improves the projection of 2-year NDI over and above the clinical data available at the time of birth. Design, Setting, and Participants: This study is a preplanned secondary analysis of prospectively collected data from infants enrolled in the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which tested the efficacy of erythropoietin as an adjunctive neuroprotective therapy to therapeutic hypothermia. The study was conducted at 17 academic sites comprising 23 neonatal intensive care units in the United States between January 25, 2017, and October 9, 2019, with follow-up through October 2022. Overall, 500 infants born at 36 weeks' gestation or later with moderate or severe HIE were included. Intervention: Erythropoietin treatment 1000 U/kg/dose on days 1, 2, 3, 4 and 7. Main Outcomes and Measures: Plasma erythropoietin was measured in 444 infants (89%) within 24 hours after birth. A subset of 180 infants who had plasma samples available at baseline (day 0/1), day 2, and day 4 after birth and either died or had 2-year Bayley Scales of Infant Development III assessments completed were included in the biomarker analysis. Results: The 180 infants included in this substudy had a mean (SD) gestational age of 39.1 (1.5) weeks, and 83 (46%) were female. Infants who received erythropoietin had increased concentrations of erythropoietin at day 2 and day 4 compared with baseline. Erythropoietin treatment did not alter concentrations of other measured biomarkers (eg, difference in interleukin [IL] 6 between groups on day 4: -1.3 pg/mL; 95% CI, -4.8 to 2.0 pg/mL). After adjusting for multiple comparisons, we identified 6 plasma biomarkers (C5a, interleukin [IL] 6, and neuron-specific enolase at baseline; IL-8, tau, and ubiquitin carboxy-terminal hydrolase-L1 at day 4) that significantly improved estimations of death or NDI at 2 years compared with clinical data alone. However, the improvement was only modest, increasing the AUC from 0.73 (95% CI, 0.70-0.75) to 0.79 (95% CI, 0.77-0.81; P = .01), corresponding to a 16% (95% CI, 5%-44%) increase in correct classification of participant risk of death or NDI at 2 years. Conclusions and Relevance: In this study, erythropoietin treatment did not reduce biomarkers of neuroinflammation or brain injury in infants with HIE. Circulating biomarkers modestly improved estimation of 2-year outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02811263.