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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., Competing Interests: Declaration of Competing Interest This study was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) R01NS104322, U01NS092764, and U01NS092553. A.N. received grant support during the study period from NINDSK23NS105918. C.W. received grant support during the study period from NINDSK02NS102598. The authors reported no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To determine the association of Spanish as a primary language for a family with the health outcomes of Hispanic infants with very low birth weight (VLBW, <1500g)., Study Design: Data from the California Perinatal Quality Care Collaborative (CPQCC) linked to hospital discharge records were analyzed. Hispanic infants with VLBW born between 2009 and 2018 with a primary language of English or Spanish were included. Outcomes selected were hypothesized to be sensitive to language barriers. Multivariable logistic regression models and mixed models estimated associations between language and outcomes., Results: Of 18 364 infants meeting inclusion criteria, 27% (n = 4976) were born to families with Spanish as a primary language. In unadjusted analyses, compared with infants of primarily English-speaking families, these infants had higher odds of hospital readmission within 1 year (OR 1.11 [95% CI 1.02-1.21]), higher odds to receive human milk at discharge (OR 1.32 [95% CI 1.23-1.42]), and lower odds of discharge home with oxygen (OR 0.83 [95% CI 0.73-0.94]). In multivariable analyses, odds of readmission and home oxygen remained significant when adjusting for infant but not maternal and hospital characteristics. Higher odds for receipt of any human milk at discharge were significant in all models. Remaining outcomes did not differ between groups., Conclusions: Significant differences exist between Hispanic infants with VLBW of primarily Spanish-vs English-speaking families. Exploration of strategies to prevent readmissions of infants of families with Spanish as a primary language is warranted., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: We sought to characterize intracranial hemorrhage (ICH) as a seizure etiology in infants born term and preterm. For infants born term, we sought to compare seizure severity and treatment response for multisite vs single-site ICH and hypoxic-ischemic encephalopathy (HIE) with vs without ICH., Study Design: We studied 112 newborn infants with seizures attributed to ICH and 201 infants born at term with seizures attributed to HIE, using a cohort of consecutive infants with clinically diagnosed and/or electrographic seizures prospectively enrolled in the multicenter Neonatal Seizure Registry. We compared seizure severity and treatment response among infants with complicated ICH, defined as multisite vs single-site ICH and HIE with vs without ICH., Results: ICH was a more common seizure etiology in infants born preterm vs term (27% vs 10%, P < .001). Most infants had subclinical seizures (74%) and an incomplete response to initial antiseizure medication (ASM) (68%). In infants born term, multisite ICH was associated with more subclinical seizures than single-site ICH (93% vs 66%, P = .05) and an incomplete response to the initial ASM (100% vs 66%, P = .02). Status epilepticus was more common in HIE with ICH vs HIE alone (38% vs 17%, P = .05)., Conclusions: Seizure severity was greater and treatment response was lower among infants born term with complicated ICH. These data support the use of continuous video electroencephalogram monitoring to accurately detect seizures and a multistep treatment plan that considers early use of multiple ASMs, particularly with parenchymal and high-grade intraventricular hemorrhage and complicated ICH., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To compare key seizure and outcome characteristics between neonates with and without cardiopulmonary disease., Study Design: The Neonatal Seizure Registry is a multicenter, prospectively acquired cohort of neonates with clinical or electroencephalographic (EEG)-confirmed seizures. Cardiopulmonary disease was defined as congenital heart disease, congenital diaphragmatic hernia, and exposure to extracorporeal membrane oxygenation. We assessed continuous EEG monitoring strategy, seizure characteristics, seizure management, and outcomes for neonates with and without cardiopulmonary disease., Results: We evaluated 83 neonates with cardiopulmonary disease and 271 neonates without cardiopulmonary disease. Neonates with cardiopulmonary disease were more likely to have EEG-only seizures (40% vs 21%, P < .001) and experience their first seizure later than those without cardiopulmonary disease (174 vs 21 hours of age, P < .001), but they had similar seizure exposure (many-recurrent electrographic seizures 39% vs 43%, P = .27). Phenobarbital was the primary initial antiseizure medication for both groups (90%), and both groups had similarly high rates of incomplete response to initial antiseizure medication administration (66% vs 68%, P = .75). Neonates with cardiopulmonary disease were discharged from the hospital later (hazard ratio 0.34, 95% CI 0.25-0.45, P < .001), although rates of in-hospital mortality were similar between the groups (hazard ratio 1.13, 95% CI 0.66-1.94, P = .64)., Conclusion: Neonates with and without cardiopulmonary disease had a similarly high seizure exposure, but neonates with cardiopulmonary disease were more likely to experience EEG-only seizures and had seizure onset later in the clinical course. Phenobarbital was the most common seizure treatment, but seizures were often refractory to initial antiseizure medication. These data support guidelines recommending continuous EEG in neonates with cardiopulmonary disease and indicate a need for optimized therapeutic strategies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To evaluate the association of therapeutic hypothermia with magnetic resonance imaging (MRI) findings and 30-month neurodevelopment in term neonatal encephalopathy., Study Design: Cross-sectional analysis of 30-month neurodevelopment (IQR 19.0-31.4) in a prospective cohort of mild-to-severe neonatal encephalopathy imaged on day 4 (1993-2017 with institutional implementation of therapeutic hypothermia in 2007). MRI injury was classified as normal, watershed, or basal ganglia/thalamus. Abnormal motor outcome was defined as Bayley-II psychomotor developmental index <70, Bayley-III motor score <85 or functional motor deficit. Abnormal cognitive outcome was defined as Bayley-II mental developmental index <70 or Bayley-III cognitive score <85. Abnormal composite outcome was defined as abnormal motor and/or cognitive outcome, or death. The association of therapeutic hypothermia with MRI and outcomes was evaluated with multivariable logistic regression adjusted for propensity to receive therapeutic hypothermia., Results: Follow-up was available in 317 (78%) surviving children, of whom 155 (49%) received therapeutic hypothermia. Adjusting for propensity, therapeutic hypothermia was independently associated with decreased odds of abnormal motor (OR 0.15, 95% CI 0.06-0.40, P < .001) and cognitive (OR 0.11, 95% CI 0.04-0.33, P < .001) outcomes. This association remained statistically significant after adjustment for injury pattern. The predictive accuracy of MRI pattern for abnormal composite outcome was unchanged between therapeutic hypothermia-treated (area under the receiver operating curve 0.76; 95% CI 0.61-0.91) and untreated (area under the receiver operating curve 0.74; 95% CI 0.67-0.81) infants. The negative predictive value of normal MRI was high in therapeutic hypothermia-treated and untreated infants (motor 96% vs 90%; cognitive 99% vs 95%)., Conclusions: Therapeutic hypothermia is associated with lower rates of brain injury and adverse 30-month outcomes after neonatal encephalopathy. The predictive accuracy of MRI in the first week of life is unchanged by therapeutic hypothermia. Normal MRI remains reassuring for normal 30-month outcome after therapeutic hypothermia., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the characteristics of term infants with persistent pulmonary hypertension of the newborn (PPHN) associated with moderate or severe hypoxic ischemic encephalopathy (HIE)., Methods: We compared infants with and without PPHN enrolled in 2 randomized trials of therapeutic hypothermia: the induced hypothermia trial of cooling to 33.5°C for 72 hours vs normothermia, and the "usual-care" arm (33.5°C for 72 hours) of the optimizing cooling trial., Results: Among 303 infants with HIE from these 2 studies, 67 (22%) had PPHN and 236 (78%) did not. We compared infants with PPHN with those without PPHN. The proportion of patients treated with therapeutic hypothermia was similar in PPHN and no-PPHN groups (66% vs 65%). Medication use during resuscitation (58% vs 44%), acidosis after birth (pH: 7.0 ± 0.2 vs 7.1 ± 0.2), severe HIE (43% vs 28%), meconium aspiration syndrome (39% vs 7%), pulmonary hemorrhage (12% vs 3%), culture-positive sepsis (12% vs 3%), systemic hypotension (65% vs 28%), inhaled nitric oxide therapy (64% vs 3%), and extracorporeal membrane oxygenation (12% vs 0%) were more common in the PPHN group. Length of stay (26 ± 21 vs 16 ± 14 days) and mortality (27% vs 16%) were higher in the PPHN group., Conclusions: PPHN is common among infants with moderate/severe HIE and is associated with severe encephalopathy, lung disease, sepsis, systemic hypotension, and increased mortality. The prevalence of PPHN was not different between those infants receiving therapeutic hypothermia at 33.5°C in these 2 trials (44/197 = 22%) compared with infants receiving normothermia in the induced hypothermia trial (23/106 = 22%)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We aimed to define determinants of duration of treatment for acute symptomatic neonatal seizures in a contemporary multicenter observational cohort study. After adjustment for potential confounders, only study site and seizure etiology remained significantly associated with the chance of continuing antiseizure medication after discharge to home., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To determine the contemporary etiology, burden, and short-term outcomes of seizures in neonates monitored with continuous video-electroencephalogram (cEEG)., Study Design: We prospectively collected data from 426 consecutive neonates (56% male, 88% term) ≤44 weeks' postmenstrual age with clinically suspected seizures and/or electrographic seizures. Subjects were assessed between January 2013 and April 2015 at 7 US tertiary care pediatric centers following the guidelines of the American Clinical Neurophysiology Society for cEEG for at-risk neonates. Seizure etiology, burden, management, and outcome were determined by chart review by the use of a case report form designed at study onset., Results: The most common seizure etiologies were hypoxic-ischemic encephalopathy (38%), ischemic stroke (18%), and intracranial hemorrhage (11%). Seizure burden was high, with 59% having ≥7 electrographic seizures and 16% having status epilepticus; 52% received ≥2 antiseizure medications. During the neonatal admission, 17% died; 49% of survivors had abnormal neurologic examination at hospital discharge. In an adjusted analysis, high seizure burden was a significant risk factor for mortality, length of hospital stay, and abnormal neurological examination at discharge., Conclusions: In this large contemporary profile of consecutively enrolled newborns with seizures treated at centers that use cEEG per the guidelines of the American Clinical Neurophysiology Society, about one-half had high seizure burden, received ≥2 antiseizure medications, and/or died or had abnormal examination at discharge. Greater seizure burden was associated with increased morbidity and mortality. These findings underscore the importance of accurate determination of neonatal seizure frequency and etiology and a potential for improved outcome if seizure burden is reduced., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To determine the rate of magnetic resonance imaging (MRI)-detected noncystic white matter injury (WMI) in a prospective cohort of premature newborns, and to evaluate its associations with changes in clinical predictors of WMI over the study period., Study Design: A prospective cohort of premature newborns (<33 weeks gestational age) was studied with MRI within 4 weeks of birth and near term-equivalent age. A pediatric neuroradiologist scored the severity of WMI on T1-weighted MRI according to published criteria. WMI was classified as none/mild or moderate/severe. Subjects with severe cystic WMI, periventricular hemorrhagic infarction, or motion artifact on MRI were excluded. Changes in clinical characteristics and predictors of WMI over the study period (1998-2011) were evaluated. Predictors of moderate/severe WMI, including birth year, were evaluated using multivariate logistic regression., Results: Among 267 newborns, 45 (17%) had moderate/severe WMI. The rate of moderate/severe WMI decreased over the study period (P = .002, χ(2) test for trends). On multivariate logistic regression, the odds of moderate/severe WMI decreased by 11% for each birth year of the cohort (OR, 0.89; 95% CI, 0.81-0.98; P = .02). Prolonged exposure to indomethacin also was independently associated with reduced odds of moderate/severe WMI., Conclusion: The decreasing burden of MRI-detected moderate/severe noncystic WMI in our cohort of premature newborns is independent over time of changes in the known clinical predictors of WMI. Prolonged exposure to indomethacin is associated with reduced WMI., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To investigate the contribution of hypoglycemia in the first 24 hours after birth to brain injury in term newborns at risk for neonatal encephalopathy., Study Design: A prospective cohort of 94 term neonates born between 1994 and 2010 with early postnatal brain magnetic resonance imaging studies were analyzed for regions of brain injury. Neurodevelopmental outcome was assessed at 1 year of age., Results: Hypoglycemia (glucose <46 mg/dL) in the first 24 hours after birth was detected in 16% of the cohort. Adjusting for potential confounders of early perinatal distress and need for resuscitation, neonatal hypoglycemia was associated with a 3.72-fold increased odds of corticospinal tract injury (P=.047). Hypoglycemia was also associated with 4.82-fold increased odds of 1-point worsened neuromotor score (P=.038) and a 15-point lower cognitive and language score on the Bayley Scales of Infant Development (P=.015)., Conclusion: Neonatal hypoglycemia is associated with additional risks in the setting of neonatal encephalopathy with increased corticospinal tract injury and adverse motor and cognitive outcomes., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objective: To describe the association between electrographically detected seizures and brain injury evaluated by magnetic resonance imaging in newborns treated with hypothermia., Study Design: A total of 56 newborns treated with hypothermia were monitored using video electroencephalography through cooling and rewarming, and then imaged at a median of 5 days. The electroencephalograms were reviewed for indications of seizure and status epilepticus. Moderate-severe injury detected on magnetic resonance imaging was measured using a classification scheme similar to one predicting abnormal outcome in an analogous population., Results: Seizures were recorded in 17 newborns (30%), 5 with status epilepticus. Moderate-severe injury was more common in newborns with seizures (relative risk, 2.9; 95% CI, 1.2-4.5; P=.02), and was present in all 5 newborns with status epilepticus. Newborns with moderate-severe injury had seizures that were multifocal and of later onset, and they were more likely to experience recurrent seizures after treatment with 20 mg/kg phenobarbital. Newborns with only subclinical seizures were as likely to have injury as those with seizures with a clinical correlate (57% vs 60%)., Conclusion: Seizures represent a risk factor for brain injury in the setting of therapeutic hypothermia, especially in neonates with status epilepticus, multifocal-onset seizures, and a need for multiple medications. However, 40% of our neonates were spared from brain injury, suggesting that the outcome after seizures is not uniformly poor in children treated with therapeutic hypothermia., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objective: To compare the association between perinatal events and the pattern and extent of brain injury on early magnetic resonance imaging in newborn infants with and without therapeutic hypothermia for hypoxic-ischemic encephalopathy., Study Design: We performed a cohort study of 35 treated and 25 nontreated neonates who underwent magnetic resonance imaging. The injury patterns were defined a priori as: normal, watershed, or basal ganglia/thalamus-predominant, as well as a dichotomous outcome of moderate-to-severe versus mild-no injury., Results: Neonates with hypothermia had less extensive watershed and basal ganglia/thalamus injuries and a greater proportion had normal imaging. Therapeutic hypothermia was associated with a decreased risk of both basal ganglia/thalamus injury (relative risk, 0.29; 95% CI, 0.10 to 0.81, P = .01) and moderate-severe injury. Neonates with sentinel events showed a decrease in basal ganglia/thalamus-predominant injury and an increase in normal imaging. All neonates with decreased fetal movements had injury, predominantly watershed, regardless of therapeutic hypothermia., Conclusions: These results validate reports of reduced brain injury after therapeutic hypothermia and suggest that perinatal factors are important indicators of response to treatment., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objective: To assess whether birth at <26 weeks gestation is an important predictor of brain microstructure maturation as determined by using diffusion tensor imaging., Study Design: We performed serial magnetic resonance imaging and diffusion tensor imaging in 176 infants born at <33 weeks gestation. Diffusion parameters were calculated for white and gray matter regions. Linear regression for repeated measures was used to assess the effect of extremely premature birth on brain maturation., Results: In white matter, fractional anisotropy increased by 0.008 per week (95% CI, 0.007-0.009; P < .0001) and mean diffusivity decreased by 0.021 mm(2)/sec per week, (95% CI, -0.24-0.018; P < .0001). Birth at <26 weeks was associated with lower white matter fractional anisotropy (-0.01; 95% CI, -0.018-0.003; P = .008), but this effect was eliminated when co-morbid conditions were added to the model. Moderate-severe brain injury was associated with decreased mean white matter fractional anisotropy (-0.012; 95% CI, -0.02-0.004; P = .002)., Conclusion: Brain microstructure maturation as measured serially in premature infants is independent of extremely premature birth. Brain injury and co-morbid conditions may be the important determinants of microstructure maturation., (Copyright © 2010 Mosby, Inc. All rights reserved.)