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.).

Intrauterine drug exposure as a risk factor for cerebral palsy.

AIM: To determine whether infants with intrauterine drug exposure (IUDE) are similarly at risk for cerebral palsy (CP) as other high-risk populations, whether CP classification differs based on IUDE status, and describe the association of CP with specific substances among exposed infants. METHOD: This was a retrospective analysis of infants in a high-risk follow-up program (n=5578) between January 2014 and February 2018 with a history of IUDE or who received a CP diagnosis. CP rates were compared using two-sample z-tests. CP classification was assessed using Fisher's exact, Cochran-Armitage, and Wilcoxon rank-sum tests. Models for CP risk were assessed using multivariable logistic regression. RESULTS: Among all infants with IUDE (n=1086), 53.8% were male with a mean (SD) birth gestational age of 36.8 (3.6) weeks. Among unexposed infants with CP (n=259), 54.4% were male with a mean (SD) birth gestational age of 29.9 (5.7) weeks. Opioids were the most common exposure (93.7%) of all infants with IUDE. The CP rate in the IUDE (5.2%) and unexposed (5.7%) high-risk populations were not significantly different (p=0.168), nor were there differences in CP typology, topography, or severity between exposed (n=57) and unexposed (n=259) infants (all p>0.05). In patients with IUDE and after controlling for established CP risk factors, the observed odds of CP varied among substances. INTERPRETATION: We suggest that IUDE should be considered a 'newborn-detectable risk' in the guidelines for the early detection of CP.

Perspectives from the Society for Pediatric Research. Neonatal encephalopathy clinical trials: developing the future.

The next phase of clinical trials in neonatal encephalopathy (NE) focuses on hypothermia adjuvant therapies targeting alternative recovery mechanisms during the process of hypoxic brain injury. Identifying infants eligible for neuroprotective therapies begins with the clinical detection of brain injury and classification of severity. Combining a variety of biomarkers (serum, clinical exam, EEG, movement patterns) with innovative clinical trial design and analyses will help target infants with the most appropriate and timely treatments. The timing of magnetic resonance imaging (MRI) and MR spectroscopy after NE both assists in identifying the acute perinatal nature of the injury (days 3-7) and evaluates the full extent and evolution of the injury (days 10-21). Early, intermediate outcome of neuroprotective interventions may be best defined by the 21-day neuroimaging, with recognition that the full neurodevelopmental trajectory is not yet defined. An initial evaluation of each new therapy at this time point may allow higher-throughput selection of promising therapies for more extensive investigation. Functional recovery can be assessed using a trajectory of neurodevelopmental evaluations targeted to a prespecified and mechanistically derived hypothesis of drug action. As precision medicine revolutionizes healthcare, it should also include the redesign of NE clinical trials to allow safe, efficient, and targeted therapeutics. IMPACT: As precision medicine revolutionizes healthcare, it should also include the redesign of NE clinical trials to allow faster development of safe, effective, and targeted therapeutics. This article provides a multidisciplinary perspective on the future of clinical trials in NE; novel trial design; study management and oversight; biostatistical methods; and a combination of serum, imaging, and neurodevelopmental biomarkers can advance the field and improve outcomes for infants affected by NE. Innovative clinical trial designs, new intermediate trial end points, and a trajectory of neurodevelopmental evaluations targeted to a prespecified and mechanistically derived hypothesis of drug action can help address common challenges in NE clinical trials and allow for faster selection and validation of promising therapies for more extensive investigation.

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.

Neonatal Opioid Withdrawal Syndrome: An Update on Developmental Outcomes.

Infants and children with prenatal opioid exposure generally have development within the normal range; however, they seem to be at risk for behavioral problems and for lower scores on cognitive, language, and motor assessments than children without prenatal opioid exposure. It is as of yet unclear whether prenatal opioid exposure itself causes issues with development and behavior, or whether it is simply correlated, due to other confounding factors.

Developing a multimodal maternal infant perinatal outpatient delivery system: the MOMI PODS program.

Progress in maternal child health has been hampered by poor rates of outpatient follow up for postpartum individuals. Primary care after delivery can effectively detect and treat several pregnancy-related complications and comorbidities, but postpartum linkage to primary care remains low. In this manuscript, we share the experience of implementing a novel mother-infant dyad program, the Multimodal Maternal Infant Perinatal Outpatient Delivery System (MOMI PODS), to improve primary care linkage and community resource access postpartum via integration into pediatric care structures. With a focus on providing care for people who are publicly insured, we designed a program to mitigate maternal morbidity risk factors in postpartum individuals with chronic disease or pregnancy complications. We discuss the systematic process of designing, executing, and evaluating a collaborative clinical program with involvement of internal medicine/pediatric, family medicine, and obstetric clinicians via establishing stakeholders, identifying best practices, drawing from the evidence base, designing training and promotional materials, training partners and providers, and evaluating clinic enrollment. We share the challenges encountered such as in achieving sufficient provider capacity, consistent provision of care, scheduling, and data tracking, as well as mitigation strategies to overcome these barriers. Overall, MOMI PODS is an innovative approach that integrates outpatient postpartum care into traditional pediatric structures to increase access, showing significant promise to improve healthcare utilization and promote postpartum health.

One-Year Neurodevelopmental Outcomes After Neonatal Opioid Withdrawal Syndrome: A Prospective Cohort Study.

Purpose: The aims of this study were, in a cohort of children with neonatal opioid withdrawal syndrome (NOWS), (a) to report 1-year neurodevelopmental outcomes and specifically characterize speech, language, and hearing outcomes and (b) to report the prevalence of cleft lip and/or cleft palate. Method: This prospective observational cohort study includes newborns with confirmed in utero opioid exposure who received pharmacological treatment for NOWS. During 1-year-old developmental visits, we administered standardized assessments (Bayley Scales of Infant and Toddler Development-Third Edition [Bayley-III] or Developmental Assessment of Young Children-Second Edition [DAYC-2]-due to COVID-19 restrictions). We compared Bayley-III scores to standardized population means using one-sample z tests. We report estimates, 95% confidence intervals, and two-sided p values. Results: We enrolled 202 infants (October 2018 to March 2020). Follow-up at 1-year was 80%. Infants with NOWS had lower Bayley-III scores at 1 year compared to published norms for cognitive, language, and motor domains. One infant with NOWS was diagnosed with isolated cleft palate and Pierre Robin sequence. All infants passed the newborn hearing screen, and 7.5% had a formal hearing evaluation after neonatal intensive care unit discharge, with 40% having abnormal or inconclusive results; middle ear effusion was the leading cause of abnormal hearing (66.7%). Ten percent of children received a speech-language pathology referral prior to 2 years of age. Infants born to mothers with mental health conditions were more likely to have Bayley-III or DAYC-2 scores below 95 in language or motor domains. Conclusions: Infants with pharmacologically treated NOWS have significantly lower cognitive, language, and motor scores on standardized developmental testing compared to population means at 1 year of age. Early speech-language pathology referral is frequently necessary to promote optimal development in this population. Supplemental Material: https://doi.org/10.23641/asha.20044403.

Cerebral perfusion and neurological examination characterise neonatal opioid withdrawal syndrome: a prospective cohort study.

OBJECTIVE: To test the hypothesis that cerebral blood flow (CBF) assessed with arterial spin labelling (ASL) MRI is increased and standardised neurological examination is altered in infants with neonatal opioid withdrawal syndrome (NOWS) compared with those without. DESIGN: Prospective cohort study. SETTING: Level IV neonatal intensive care unit and outpatient primary care centre. PARTICIPANTS: Infants with NOWS receiving pharmacological treatment and unexposed controls matched for gestational age at birth and post-menstrual age at MRI. MAIN OUTCOMES: CBF assessed by ASL on non-sedated 3-Tesla MRI and standardised Hammersmith Neonatal Neurological Examination (HNNE) within 14 days of birth. RESULTS: Thirty infants with NOWS and 31 control infants were enrolled and included in the final analysis. Global CBF across the brain was higher in the NOWS group compared with controls (14.2 mL/100 g/min±5.5 vs 10.7 mL/100 g/min±4.3, mean±SD, Cohen's d=0.72). HNNE total optimality score was lower in the NOWS group compared with controls (25.9±3.6 vs 28.4±2.4, mean±SD, Cohen's d=0.81). A penalised logistic regression model including both CBF and HNNE items discriminated best between the two groups. CONCLUSIONS: Increased cerebral perfusion and neurological examination abnormalities characterise infants with NOWS compared with those without intrauterine drug exposure and suggest prenatal substance exposure affects fetal brain development. Identifying neurological and neuroimaging characteristics of infants with NOWS can contribute to understanding mechanisms underlying later outcomes and to designing potential new treatments.

Deep Medullary Vein White Matter Injury Global Severity Score Predicts Neurodevelopmental Impairment.

AIM: To examine associations between the deep medullary vein white matter injury global severity scoring system and neurodevelopmental impairment. METHODS: This is a prospective observational cohort study of infants born at ≥32 weeks, diagnosed with deep medullary vein thrombosis and infarction on neuroimaging in the first month of life. Developmental testing was performed using validated measures for early, preschool, and school-age follow-up. RESULTS: Nineteen (37%) patients had major neurodevelopmental impairment. Global severity score was higher among patients with neurodevelopmental impairment (21.6 vs 13.4, P = .04). Overall, 78% of patients with epilepsy had neurodevelopmental impairment. A greater degree of asymmetry with right-sided injury predominance was associated with lower Bayley-III cognitive scores and presence of neurodevelopmental impairment (P < .01). CONCLUSIONS: Results suggest a need for targeted clinical surveillance for patients with a high global severity score and/or asymmetric, predominantly right cerebral white matter injury and for those who develop epilepsy.

Standardized Neurodevelopmental Surveillance of High-risk Infants Using Telehealth: Implementation Study during COVID-19.

INTRODUCTION: Neurodevelopmental surveillance is critical for high-risk infants following neonatal intensive care discharge and is traditionally performed in-person. COVID-19 interruption of regular surveillance necessitated a rapid development of telehealth models for effective and standardized care. METHODS: We used implementation science and lean methodologies to develop an effective telehealth neurodevelopmental surveillance program for high-risk infants. Interventions included reorganization of visit flow processes and a telehealth toolkit for standardized neurological and developmental assessments. We tested and improved our intervention through plan-do-study-act cycles, value-added analysis, and parent- and provider-satisfaction questionnaires. Process metrics (standard elements, subspecialty referrals, diagnostic tests, and prescriptions ordered) were compared in group-level analyses between telehealth patients (N = 97) March 16, 2020-July 1, 2020 and a matched in-person cohort at the same period the previous year. Run charts examined shifts in balancing measures (provider efficiency and missed visits) over 8 weeks before and after implementation. RESULTS: Primary outcomes were visit completion (100%), patient parent satisfaction (>90% strongly agreed or agreed telehealth procedures were valuable and easy to use) and ability to accurately diagnose cerebral palsy (no statistical difference with comparison visits). Providers (N = 6) rated telehealth experiences favorably. Process metrics indicated no differences between telehealth and in-person visits (all P > 0.05). Following telehealth implementation, provider efficiency increased to near baseline (median 88.9% versus 91.7%) and median missed visits decreased to 0% from 20% (in-person). CONCLUSIONS: Implementation of telehealth for neurodevelopmental surveillance in a tertiary high-risk infant follow-up clinic successfully provided standardized and timely care during stay-at-home orders; broader telehealth applications may overcome access barriers in this field.

A controlled trial of working memory training for children and adolescents with ADHD.

This study assessed the efficacy of a 5-week, intensive working memory training program for 52 children and adolescents (ages 7-17) who had Attention-Deficit/Hyperactivity Disorder (ADHD) and other comorbid diagnoses. This study provided a treatment replication since the waitlist control group also completed training and was included in the follow-up data analyses. Parents and teachers completed paper-and-pencil measures of working memory, executive functioning, and ADHD symptoms at baseline, posttreatment, and 4-month follow-up. Parent ratings indicated that participants improved on inattention, overall number of ADHD symptoms, initiation, planning/organization, and working memory. Teacher ratings approached significance at posttreatment and at 4-month follow-up on and Initiate scale. Working memory training appears promising as an intervention in improving executive functioning and ADHD symptoms.

Prenatal Exposures Are Associated With Worse Neurodevelopmental Outcomes in Infants With Neonatal Opioid Withdrawal Syndrome.

Aim: To define a developmental trajectory in infants with neonatal opioid withdrawal syndrome (NOWS) and determine whether the impacted developmental domain varies with the type of antenatal exposure. Methods: We performed a retrospective cohort study of infants treated pharmacologically for NOWS and assessed using a standardized schedule for follow-up visits. We compared outcomes of the study population to published norms using one-sample t-tests. Multivariable models examined associations with exposures in addition to opioids. Results: In our cohort of 285 infants with 9-12-months testing, 164 (55.7%) were seen at 3-4 months, and 125 (44%), at 15-18 months. The majority (58%) had intrauterine drug exposures in addition to opioids. Neurodevelopmental scores of infants with NOWS at 3-4 and 9-12 months were not different from published norms. Cognitive and language scores at 15-18 months were worse than published norms. Male sex, older maternal age, and additional barbiturate or alcohol exposure were associated with worse outcomes. Conclusion: Infants with pharmacologically treated NOWS had development similar to unexposed infants during the 1st year but worse cognitive and language scores during the 2nd year. These data support the need for a prospective follow-up of large cohorts of infants with NOWS, with systematic assessments and an evaluation of contributing factors.

Gabapentin Use for Hospitalized Neonates.

BACKGROUND: Despite some clinician advocacy for the use of gabapentin to treat neonatal irritability of presumed neurological origin, the extent of gabapentin administration to hospitalized neonates is unknown. We aimed to identify trends in gabapentin utilization among infants hospitalized in neonatal intensive care units (NICUs) across the United States and to evaluate the associations between clinical diagnoses and gabapentin treatment. METHODS: We analyzed neonates admitted to the NICU using the Pediatric Health Information System (2005 to 2016) to measure treatment timing, duration, and frequency. We used modified Poisson regression with a robust between-cluster variance estimator to calculate a probability (adjusted relative risk) for gabapentin administration. RESULTS: Of 278,403 neonates, 374 were administered gabapentin (0.13%). The median treatment duration was 16 days (25th to 75th percentile: 8; 40). Gabapentin use increased from 0% in 2005 to 0.39% in 2016. Treatment was prescribed to neonates at 31 of 48 studied hospitals; 73% of total treated infants localized to five neonatal intensive care units. Term (0.16%) and ≤28 weeks' gestation preterm infants (0.22%) were most likely to receive gabapentin. Varying by gestational age, a diagnosis of chromosomal abnormalities, severe bronchopulmonary dysplasia, hemorrhagic stroke, and neonatal abstinence syndrome were associated with higher treatment with gabapentin. The majority (88.8%) of treated infants did not have a seizure diagnosis. CONCLUSION: Gabapentin use in NICU in the United States increased in recent years and varies markedly between institutions. Term infants, ≤28 weeks' gestation preterm infants, and neonates with chronic genetic, neurological, and gastrointestinal diagnoses were more likely to receive gabapentin.

Neonatal Vein of Labbé Infarction Size is Associated With Long-Term Language Outcomes.

BACKGROUND: The vein of Labbé is a superficial cortical vein, which drains the lateral surface of the temporal lobe. Thrombosis of the vein of Labbé can occur in the neonatal period. The developmental outcomes of infants who had vein of Labbé thrombosis are unknown as few studies of outcomes exist. METHODS: We completed a retrospective review of infants born ≥34 weeks of gestation, diagnosed with vein of Labbé thrombosis, and/or infarction on neuroimaging during the first 30 days of life. Size of each temporal lobe infarction was estimated based on the number of temporal lobe segments involved. Primary outcomes were the presence of major neurodevelopmental impairments in childhood and Bayley scores at two years. RESULTS: Our cohort of 19 infants had a median gestational age of 38 weeks (interquartile range 36 to 39) and mean birth weight 2892 ± 920 grams. The most common presenting symptoms of vein of Labbé thrombosis and infarction of surrounding tissue were seizures, apnea, lethargy, and either hypertonia or hypotonia. At the latest clinical follow-up appointment documented in the electronic medical record (mean 4.4 ± 3.08 years), 44% had major neurodevelopmental impairment. Patients with large vein of Labbé infarctions had significantly worse average Bayley scores than those with small to moderate lesions, and differences in language composite were statistically significant (72.7 vs 107.8, P = 0.017). CONCLUSIONS: Neonates with large vein of Labbé infarctions are more likely to have poor language outcomes. This finding suggests a need for targeted surveillance to ensure early identification of deficits and referral for intervention.