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.).

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.

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.

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.

Perinatal Azithromycin Provides Limited Neuroprotection in an Ovine Model of Neonatal Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Hypoxic-ischemic brain injury/encephalopathy affects about 1.15 million neonates per year, 96% of whom are born in low- and middle-income countries. Therapeutic hypothermia is not effective in this setting, possibly because injury occurs significantly before birth. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal azithromycin administration in near-term lambs following global ischemic injury to support earlier treatment approaches. METHODS: Ewes and their lambs of both sexes (n=34, 141-143 days) were randomly assigned to receive azithromycin or placebo before delivery as well as postnatally. Lambs were subjected to severe global hypoxia-ischemia utilizing an acute umbilical cord occlusion model. Outcomes were assessed over a 6-day period. RESULTS: While maternal azithromycin exhibited relatively low placental transfer, azithromycin-treated lambs recovered spontaneous circulation faster following the initiation of cardiopulmonary resuscitation and were extubated sooner. Additionally, peri- and postnatal azithromycin administration was well tolerated, demonstrating a 77-hour plasma elimination half-life, as well as significant accumulation in the brain and other tissues. Azithromycin administration resulted in a systemic immunomodulatory effect, demonstrated by reductions in proinflammatory IL-6 (interleukin-6) levels. Treated lambs exhibited a trend toward improved neurodevelopmental outcomes while histological analysis revealed that azithromycin supported white matter preservation and attenuated inflammation in the cingulate and parasagittal cortex. CONCLUSIONS: Perinatal azithromycin administration enhances neonatal resuscitation, attenuates neuroinflammation, and supports limited improvement of select histological outcomes in an ovine model of hypoxic-ischemic brain injury/encephalopathy.

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.

Parental Age and Childhood Risk for Cerebral Palsy in California.

OBJECTIVE: To investigate the associations between maternal or paternal age at the time of delivery and offspring's risk for cerebral palsy (CP) in California. STUDY DESIGN: We conducted a population-based, case-control study that included 8736 singleton CP cases and 90 250 singleton controls, matched by sex and birth year, selected from California birth certificate records from 1994 to 2010. We estimated OR and 95% CIs for CP diagnosis according to maternal and paternal age recorded on the birth certificates. Causal mediation analysis was performed to estimate direct and indirect effects of parental ages on CP with preterm delivery as a potential mediator. RESULTS: Children born to younger mothers (≤19 years) or older mothers (35-39 years; ≥40 years) had a greater risk of CP compared with children of mothers aged 25-29 years (ORs ranging from 1.13 to 1.59). Compared with paternal age 25-29 years, older paternal age (40-44 years; ≥45 years) also was associated with an increased risk for CP independent of maternal age. When analyzing jointly using both parents of ages 20-34 years as the reference, the greatest risk was estimated for older parents (≥35 years). Preterm birth was estimated to mediate 19%-34% of the total effects between maternal or paternal age and offspring CP risk. CONCLUSIONS: Young maternal age and an older age in either or both parents were associated with a greater risk of CP in their children. Although preterm birth was a mediator, additional factors related to parental age need further exploration to explain risk of CP.

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.

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.

Neuroprotective therapies in the NICU in term infants: present and future.

Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has proven beneficial, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a critical need to find additional pharmacological and non-pharmacological interventions that improve the outcomes for these children. There are many potential candidates; however, it is unclear whether these interventions have additional benefits when used with TH. Although primary and delayed (secondary) brain injury starting in the latent phase after HI are major contributors to neurodisability, the very late evolving effects of tertiary brain injury likely require different interventions targeting neurorestoration. Clinical trials of seizure management and neuroprotection bundles are needed, in addition to current trials combining erythropoietin, stem cells, and melatonin with TH. IMPACT: The widespread use of therapeutic hypothermia (TH) in the treatment of neonatal encephalopathy (NE) has reduced the associated morbidity and mortality. However, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. This review details the pathophysiology of NE along with the evidence for the use of TH and other beneficial neuroprotective strategies used in term infants. We also discuss treatment strategies undergoing evaluation at present as potential adjuvant treatments to TH in NE.

Defining Longer-Term Outcomes in an Ovine Model of Moderate Perinatal Hypoxia-Ischemia.

Hypoxic-ischemic encephalopathy (HIE) is the leading cause of neonatal morbidity and mortality worldwide. Approximately 1 million infants born with HIE each year survive with cerebral palsy and/or serious cognitive disabilities. While infants born with mild and severe HIE frequently result in predictable outcomes, infants born with moderate HIE exhibit variable outcomes that are highly unpredictable. Here, we describe an umbilical cord occlusion (UCO) model of moderate HIE with a 6-day follow-up. Near-term lambs (n = 27) were resuscitated after the induction of 5 min of asystole. Following recovery, lambs were assessed to define neurodevelopmental outcomes. At the end of this period, lambs were euthanized, and brains were harvested for histological analysis. Compared with prior models that typically follow lambs for 3 days, the observation of neurobehavioral outcomes for 6 days enabled identification of animals that recover significant neurological function. Approximately 35% of lambs exhibited severe motor deficits throughout the entirety of the 6-day course and, in the most severely affected lambs, developed spastic diparesis similar to that observed in infants who survive severe neonatal HIE (severe, UCOs). Importantly, and similar to outcomes in human neonates, while initially developing significant acidosis and encephalopathy, the remainder of the lambs in this model recovered normal motor activity and exhibited normal neurodevelopmental outcomes by 6 days of life (improved, UCOi). The UCOs group exhibited gliosis and inflammation in both white and gray matters, oligodendrocyte loss, neuronal loss, and cellular death in the hippocampus and cingulate cortex. While the UCOi group exhibited more cellular death and gliosis in the parasagittal cortex, they demonstrated more preserved white matter markers, along with reduced markers of inflammation and lower cellular death and neuronal loss in Ca3 of the hippocampus compared with UCOs lambs. Our large animal model of moderate HIE with prolonged follow-up will help further define pathophysiologic drivers of brain injury while enabling identification of predictive biomarkers that correlate with disease outcomes and ultimately help support development of therapeutic approaches to this challenging clinical scenario.

Mild hypoxic-ischemic encephalopathy (HIE): timing and pattern of MRI brain injury.

BACKGROUND: Mild hypoxic-ischemic encephalopathy (HIE) is increasingly recognized as a risk factor for neonatal brain injury. We examined the timing and pattern of brain injury in mild HIE. METHODS: This retrospective cohort study includes infants with mild HIE treated at 9 hospitals. Neonatal brain MRIs were scored by 2 reviewers using a validated classification system, with discrepancies resolved by consensus. Severity and timing of MRI brain injury (i.e., acute, subacute, chronic) was scored on the subset of MRIs that were performed at or before 8 days of age. RESULTS: Of 142 infants with mild HIE, 87 (61%) had injury on MRI at median age 5 (IQR 4-6) days. Watershed (23%), deep gray (20%) and punctate white matter (18%) injury were most common. Among the 125 (88%) infants who received a brain MRI at ≤8 days, mild (44%) injury was more common than moderate (11%) or severe (4%) injury. Subacute (37%) lesions were more commonly observed than acute (32%) or chronic lesions (1%). CONCLUSION: Subacute brain injury is common in newborn infants with mild HIE. Novel neuroprotective treatments for mild HIE will ideally target both subacute and acute injury mechanisms. IMPACT: Almost two-thirds of infants with mild HIE have evidence of brain injury on MRI obtained in the early neonatal period. Subacute brain injury was seen in 37% of infants with mild HIE. Neuroprotective treatments for mild HIE will ideally target both acute and subacute injury mechanisms.

Parental Enrollment Decision-Making for a Neonatal Clinical Trial.

OBJECTIVE: To describe the parental experience of recruitment and assess differences between parents who participated and those who declined to enroll in a neonatal clinical trial. STUDY DESIGN: This was a survey conducted at 12 US neonatal intensive care units of parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and encephaLopathy (HEAL) trial or who were eligible but declined enrollment. Questions assessed 6 factors of the parental experience of recruitment: (1) interactions with research staff; (2) the consent experience; (3) perceptions of the study; (4) decisional conflict; (5) reasons for/against participation; and (6) timing of making the enrollment decision. RESULTS: In total, 269 of 387 eligible parents, including 183 of 242 (75.6%) of those who enrolled their children in HEAL and 86 of 145 (59.3%) parents who declined to enroll their children in HEAL, were included in analysis. Parents who declined to enroll more preferred to be approached by clinical team members rather than by research team members (72.9% vs 49.2%, P = .005). Enrolled parents more frequently reported positive initial impressions (54.9% vs 10.5%, P < .001). Many parents in both groups made their decision early in the recruitment process. Considerations of reasons for/against participation differed by enrollment status. CONCLUSIONS: Understanding how parents experience recruitment, and how this differs by enrollment status, may help researchers improve recruitment processes for families and increase enrollment. The parental experience of recruitment varied by enrollment status. These findings can guide future work aiming to inform optimal recruitment strategies for neonatal clinical trials.

Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE. STUDY DESIGN: Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system. RESULTS: Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities. CONCLUSIONS: Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02811263.

Placental pathology and neonatal brain MRI in a randomized trial of erythropoietin for hypoxic-ischemic encephalopathy.

BACKGROUND: Newborns with hypoxic-ischemic encephalopathy (HIE) may exhibit abnormalities on placental histology. In this phase II clinical trial ancillary study, we hypothesized that placental abnormalities correlate with MRI brain injury and with response to treatment. METHODS: Fifty newborns with moderate/severe encephalopathy who received hypothermia were enrolled in a double-blind, placebo-controlled trial of erythropoietin for HIE. A study pathologist reviewed all available clinical pathology reports to determine the presence of chronic abnormalities and acute chorioamnionitis. Neonatal brain MRIs were scored using a validated HIE scoring system. RESULTS: Placental abnormalities in 19 of the 35 (54%) patients with available pathology reports included chronic changes (N = 13), acute chorioamnionitis (N = 9), or both (N = 3). MRI subcortical brain injury was less common in infants with a placental abnormality (26 vs. 69%, P = 0.02). Erythropoietin treatment was associated with a lower global brain injury score (median 2.0 vs. 11.5, P = 0.003) and lower rate of subcortical brain injury (33 vs. 90%, P = 0.01) among patients with no chronic placental abnormality but not in patients whose placentas harbored a chronic abnormality. CONCLUSION: Erythropoietin treatment was associated with less brain injury only in patients whose placentas exhibited no chronic histologic changes. Placentas may provide clues to treatment response in HIE.

Dried blood spot compared to plasma measurements of blood-based biomarkers of brain injury in neonatal encephalopathy.

BACKGROUND: Data correlating dried blood spots (DBS) and plasma concentrations for neonatal biomarkers of brain injury are lacking. We hypothesized that candidate biomarker levels determined from DBS can serve as a reliable surrogate for plasma levels. METHODS: In the context of a phase II multi-center trial evaluating erythropoietin for neuroprotection in neonatal encephalopathy (NE), DBS were collected at enrollment ( < 24 h), day 2, 4, and 5. Plasma was collected with the first and last DBS. The relationship between paired DBS-plasma determinations of brain-specific proteins and cytokines was assessed by correlation and Bland-Altman analyses. For analytes with consistent DBS-plasma associations, DBS-derived biomarker levels were related to brain injury by MRI and 1-year outcomes. RESULTS: We enrolled 50 newborns with NE. While S100B protein, tumor necrosis factor α, interleukin (IL)1 ß, IL-6, IL-8 demonstrated significant DBS-plasma correlations, Bland-Altman plots demonstrated that the methods are not interchangeable, with a 2 to 4-fold error between measurements. No significant relationships were found between DBS levels of TNFα, IL-6, and IL-8 and outcomes. CONCLUSION: Further work is needed to optimize elution and assay methods before using DBS specimens as a reliable surrogate for plasma levels of candidate brain injury biomarkers in NE.

Antenatal and Intrapartum Risk Factors for Hypoxic-Ischemic Encephalopathy in a US Birth Cohort.

OBJECTIVE: To identify risk factors for hypoxic-ischemic encephalopathy (HIE) within a recent US birth cohort. STUDY DESIGN: In a retrospective cohort study of 44 572 singleton infants ≥36 weeks of gestation born at Kaiser Permanente Northern California in 2008-2015, we identified all infants with HIE based on the presence of 3 inclusion criteria: clinical signs of neonatal encephalopathy, NICU admission, and either a 10-minute Apgar of ≤5 or a base excess of ≤-15 mmol/L. Neonatal acidemia was defined as a base excess of ≤-12 mmol/L. We ascertained antenatal and intrapartum complications from electronic records. Multivariable analysis was performed using logistic regression. RESULTS: There were 45 infants (1.0 per 1000) with HIE and 197 (4.4 per 1000) with neonatal acidemia. Of the infants with HIE, 64% had an intrapartum complication consisting of a sentinel event (36%), clinical chorioamnionitis (40%), or both (11%). Risk factors for HIE on multivariable analysis were sentinel event (relative risk [RR], 16.1; 95% CI, 8.4-33) and clinical chorioamnionitis (RR, 5.2; 95% CI, 2.7-9.9). After removing the 16 infants with HIE who were exposed to a sentinel event from multivariate analysis, maternal age of ≥35 years (RR, 2.5; 95% CI, 1.1-5.6) and a urinary tract infection during pregnancy (RR, 2.6; 95% CI, 1.0-6.5) emerged as potential antenatal risk factors for HIE. CONCLUSIONS: A significant proportion of HIE is preceded by a sentinel event, emphasizing the importance of developing improved methodologies to predict and prevent this perinatal complication. Strategies focused on reducing other complications such as clinical chorioamnionitis and/or maternal pyrexia may also improve our ability to prevent HIE.

Plasma Biomarkers of Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: To evaluate plasma brain specific proteins and cytokines as biomarkers of brain injury in newborns with hypoxic-ischemic encephalopathy (HIE) and, secondarily, to assess the effect of erythropoietin (Epo) treatment on the relationship between biomarkers and outcomes. STUDY DESIGN: A study of candidate brain injury biomarkers was conducted in the context of a phase II multicenter randomized trial evaluating Epo for neuroprotection in HIE. Plasma was collected at baseline (<24 hours) and on day 5. Brain injury was assessed by magnetic resonance imaging (MRI) and neurodevelopmental assessments at 1 year. The relationships between Epo, brain-specific proteins (S100B, ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1], total Tau, neuron specific enolase), cytokines (interleukin [IL]-1ß, IL-6, IL-8, IL-10, IL-12P70, IL-13, interferon-gamma [IFN-γ], tumor necrosis factor alpha [TNF-α], brain-derived neurotrophic factor [BDNF], monocyte chemoattractant protein-1), and brain injury were assessed. RESULTS: In 50 newborns with encephalopathy, elevated baseline S100B, Tau, UCH-L1, IL-1ß, IL-6, IL-8, IL-10, IL-13, TNF-α, and IFN-γ levels were associated with increasing brain injury severity by MRI. Higher baseline Tau and lower day 5 BDNF were associated with worse 1 year outcomes. No statistically significant evidence of Epo treatment modification on biomarkers was detected in this small cohort. CONCLUSIONS: Elevated plasma brain-specific proteins and cytokine levels in the first 24 hours of life are associated with worse brain injury by MRI in newborns with HIE. Only Tau and BDNF levels were found to be related to neurodevelopmental outcomes. The effect of Epo treatment on the relationships between biomarkers and brain injury in HIE requires further study. TRIAL REGISTRATION: ClinicalTrials.gov: 01913340.