BACKGROUND:Appropriate terminology and definitions of neonatal encephalopathy (NE), hypoxic-ischemic encephalopathy (HIE), and perinatal asphyxia (PA) remain controversial. Participant criteria used in therapeutic hypothermia (TH) trials are frequently used as case definitions for NE/HIE/PA but studies are inconsistent. This review aims to assess variations in terminology and case participant criteria between trials for NE/HIE/PA. METHODS:Search strategy retrieved articles from databases (Embase, MEDLINE, CENTRAL, CDSR and WHO) for randomized controlled trials (RCTs) of interventions for NE/HIE/PA using any definition for NE/HIE/PA. Outcomes were a description of the terminology, definitions, and participant criteria. Two reviewers independently screened results. Qualitative results were synthesized in a narrative summary. RESULTS:The search provided 6768 results. 67 were included in the qualitative synthesis. HIE was the most frequently used term (56/67). NE was the least frequent (16/67). Some of the common inclusion criteria were Apgar scores (63/67), metabolic acidosis (58/67), and reduced level of consciousness (57/67). Most frequently employed exclusion criteria were prematurity (63/67), major congenital abnormalities (62/67), and identification beyond 6 h from birth (62/67). DISCUSSION:This review identified variations in terminology and in-trial participant criteria between studies. These results will inform a consensus process for developing a definition and case definition of NE/HIE/PA. IMPACT:Our article demonstrated significant variations in the terminology used to describe the condition of NE/HIE/PA, which demonstrates a need for more consistent definitions in terminology. A broad but meaningful definition of the condition would provide an inclusive approach while permitting subclassifications within the condition, and permitting comparisons and benchmarking across different settings. Developing consistency across these areas, as far as possible, would allow improved interpretation of interventions on long-term prognosis and greater generalizability of trial results.

A proposed interdisciplinary fetal neonatal neurology collaborative offers life-course brain health training across three time-sensitive teaching opportunities. The educational organization includes a broad representation of inter-related fields. Formal training will re-enforce career-long learning that fosters creative thinking. Acquiring a life-course perspective of brain health can contribute solutions to the global public health crisis involving neurological and mental health disorders across the lifespan. Teaching transdisciplinary interventions begins with parental childhood and reproductive health which will influence the maternal-placental-fetal triad throughout pregnancy into labor and delivery. The second teaching opportunity focuses on the symptomatic minority who receive neonatal neurocritical care and convalescent care. The third educational cluster focuses on improving clinical skills as the unrecognized majority of children present over the preschool years with continued development through the school years. Teaching preventive neurology and mental health introduce proactive interventions that more effectively support rescue and reparative choices into adulthood. The science of uncertainty will be taught to all stakeholders that integrates information to improve critical thinking skills. This tripartite interdisciplinary educational program will help trainees distinguish adverse effects from neurodegeneration on primary fetal neuroplasticity mechanisms from secondary pathways based on systems-science. Supervised clinical experiences during each rotation will supplement didactic teaching with input from each trainee’s mentoring committee. Future providers will learn to anticipate adaptive from maladaptive disease pathways to prepare for career-long experiences. Curriculum topics will focus on brain health strategies that differentiate resilience from vulnerability based on time-dependent gene–environment interactions. Attention to structural, social and environmental drivers of health will incorporate intersectionality perspectives into equitable neuroprotective plans. Training will engage, educate and empower women to improve brain health for themselves and their children. This interdisciplinary collaborative program will apply real-world situations to encourage research development that will narrow the knowledge-practice gap. Continuity of brain care bundles will enable providers, women, and their families to achieve brain health across each and successive generations. A lower global burden of neurologic and mental health disorders will contribute to an improved quality of life with greater economic prosperity.

The role of therapeutic hypothermia (TH) in infants born at 35 weeks’ gestation remains uncertain, with discordant findings between randomized and observational studies and evolving clinical guidance. This commentary examines how this uncertainty has translated into substantial variability in clinical practice and highlights the limitations of relying on any single evidence source in isolation. Current American Academy of Pediatrics (AAP) guidance explicitly recommends parental discussion and shared decision-making (SDM) in this setting. We argue that care at 35 weeks represents a preference-sensitive clinical scenario in which SDM is essential but inconsistently implemented. Drawing on ethical frameworks and emerging neonatal neurocritical care models, we emphasize the importance of transparent communication, parental engagement, and clinician training in supporting decision-making. Finally, we discuss the need for pragmatic, parent-informed research approaches to generate timely and clinically meaningful evidence in this rare and complex population.

INTRODUCTION:Hypoxic ischaemic encephalopathy (HIE) causes significant burdens to families, health care systems, and society. At a multistakeholder meeting organized by the conect4children (c4c) project, families and advocacy groups noted that their voices are under-represented during the planning and execution of research. AIM:To provide the voices of a group of HIE families from Europe and North America METHODS: This is an informal description of the personal experience of 6 families with extensive experience of HIE and advocacy. The experiences of these families were captured during teleconferences and e-mail exchanges. RESULTS:The families agreed that high quality clinical care that is timely, well-organized, and evidence-based supports research. Unfortunately, best clinical practice is not universally followed. The literature provides many good practices for incorporating families into all stages of research that need to be implemented. Recommendations for engaging families in research are presented. CONCLUSIONS:Effective research will be promoted if families and people with lived experience of neonatal care are part of the study team, and study leadership, at all stages of research. Participation in research by families will be promoted by action to overcome the variations in care that affect families and to promote optimal care in all settings. IMPACT:What does this article add to the existing literature? Hypoxic Ischaemic Encephalopathy merits specific attention in the context of other types of neonatal encephalopathy. Family experience is central to research about hypoxic ischaemic encephalopathy. The voices of families with experience of hypoxic ischaemic encephalopathy are not listened to sufficiently. We propose an action plan to improve research for hypoxic ischaemic encephalopathy in the light of family experience.

Neonatal encephalopathy refers to disturbed neurological function in the neonatal period and has multiple potential aetiologies. A systematic review showed that neonatal encephalopathy, hypoxic-ischaemic encephalopathy, and perinatal asphyxia are often used interchangeably in clinical trials and communications. We aimed to establish an international, consensus-based definition as a preliminary step towards standardising terminology. Findings from a systematic review of definitions guided the creation of a real-time Delphi survey. Three consensus meetings were held to finalise the definition, which was approved by the steering committee. Participants were recruited from a broad range of stakeholder groups, including health-care providers; researchers; parents, family members, guardians, or representatives of children with neonatal encephalopathy; or adults who had neonatal encephalopathy as infants. From Feb 1 to May 31, 2024, the survey received 235 complete and 143 partial responses. Respondents were from 52 countries, with 75 (20%) from low-income and middle-income countries. Although most respondents were health-care workers, 23 (6%) represented parents and caregivers. 62 individuals participated in at least one consensus development meeting. The final definition was organised into primary, secondary, and tertiary domains. The primary domain is as follows: neonatal encephalopathy is a heterogeneous clinical condition characterised by abnormal or impaired brain function with multiple potential causes. It presents with an altered level of consciousness and may include seizures, abnormal primitive and deep tendon reflexes, altered muscle tone, posture or movements, or an abnormal brain-related breathing pattern. Neonatal encephalopathy can be associated with a heightened risk of morbidity and mortality. This Delphi process established a novel consensus definition for neonatal encephalopathy, with contributions from a diverse range of international stakeholders, including families. Adopting consensus-based terminology and definitions will enhance communication among health-care professionals and families, facilitate research and data synthesis, improve the interpretation and application of research findings, and ultimately improve care.

The International Neonatal Consortium Seizure Working Group of the Critical Path Institute provides an update to the original recommendations for design of clinical trials to treat neonatal seizures based on recent experiences from several trials and developments in the field. Although there aren’t sufficient new data to inform definitions of optimal efficacy endpoints, the Working Group recommended inclusion of alternate measures of seizure burden reduction as secondary or exploratory endpoints, to elucidate clinically meaningful efficacy endpoints for future trials. It was recommended to include additional key covariates, such as timing of seizure onset/cessation, randomization, and ASM administration. There are new recommendations regarding potential for unmasked or single-masked trials, and reporting of concomitant medications and adverse events, and genetic testing. Importantly, specific recommendations were added regarding improved strategies for recruitment and consent, including the use of novel technologies and the involvement of patient advocacy groups. Recommendations regarding trial infrastructure and operational feasibility were included to facilitate trial initiation and conduct, given the many logistical challenges of conducting neonatal seizure treatment trials. Finally, the recommendations consider accommodations for local or national regulations and resources, to ensure that trials are conducted as appropriate to the setting in which the patients are treated.

OBJECTIVE:Epilepsy is a known potential outcome following acute provoked neonatal seizures, but its onset, treatment patterns, and health care utilization through childhood remain poorly characterized. This study aimed to define the incidence and timing of postneonatal epilepsy, identify perinatal predictors, and describe the clinical burden of epilepsy among survivors of acute provoked neonatal seizures through early childhood. METHODS:This prospective, multicenter cohort study followed neonates with acute provoked seizures from the Neonatal Seizure Registry (NSR-II) in an extended follow-up through early childhood (Developmental Functional Evaluation). Neonatal clinical and neuroimaging data were collected, and epilepsy outcomes (including semiology, treatments, and health care use) were assessed annually through at least 5 years via structured interviews and medical record review. Kaplan-Meier and Cox proportional hazards models evaluated epilepsy risk, with data censored at loss to follow-up. RESULTS:Among 282 neonates evaluated for epilepsy in NSR-II, 183 (65%) continued into the extended follow-up study. Across the entire follow-up period through early childhood, 50 (18%) developed epilepsy, with a cumulative incidence of 21.6% (95% confidence interval [CI] = 16.7%-27.7%). Earlier epilepsy onset was associated with ≥3 days of neonatal seizures (hazard ratio [HR] = 2.8, 95% CI = 1.5-5.2), abnormal discharge neurological exam (HR = 2.4, 95% CI = 1.3-4.4), and deep gray/brainstem injury (HR = 2.4, 95% CI = 1.2-4.7). Prematurity (<37 weeks) was associated with later epilepsy onset (HR = 3.7, 95% CI = 2.0-6.8). Half (50%) of children with epilepsy developed intractable epilepsy, and 40% required intensive care unit admission. Despite this, only one child received vagus nerve stimulation, and none underwent other epilepsy surgeries. SIGNIFICANCE:These findings highlight the early and persistent epilepsy risk after neonatal seizures. Preterm infants face increased risk later in childhood compared to infants born at term. Risk factor stratification may improve early surveillance, guide clinical decisions, and support family counseling. The underutilization of epilepsy surgery in this cohort suggests multifactorial barriers that warrant further investigation.

OBJECTIVE:To develop and pilot an intervention to support communication and decision-making for critically ill infants. STUDY DESIGN:In this single-arm, mixed-methods, prospective, feasibility study, we enrolled infants, parents, and clinicians at a single tertiary care center. The Building Rapport, Improving Dialogue, and Growing Empathy intervention contains a values clarification exercise and question prompt list that parents can opt to share with the health care team. Parent and clinician participants completed surveys and semistructured interviews ≥72 hours postintervention. The primary outcome was intervention feasibility, defined as an enrollment rate ≥50% and a complete data collection rate ≥80%. Secondary outcomes included intervention acceptability and preparation for decision-making (Preparedness for Decision-Making Scale, score: 0-100, higher scores indicating higher preparedness). Statistical analyses were descriptive, and interviews were analyzed using a rapid-cycle qualitative approach. RESULTS:Thirty clinicians and 44 parents of 30 infants were enrolled (enrollment rate: 56%; complete data collection rate: 97%). The majority of parents and clinicians endorsed the tool as helpful, would recommend the tool to other parents, and would use the tool in the future. Preparedness for decision-making was high for both mothers (median score = 82, IQR: 70.0-90.0) and fathers (median score = 60, IQR: 38-74). Qualitative analysis of the intervention's impact identified 4 themes: (1) providing a scaffold; (2) validating and affirming experience; (3) preparing for a conversation; and (4) facilitating connection. CONCLUSIONS:The Building Rapport, Improving Dialogue, and Growing Empathy intervention was feasible and acceptable to parents and clinicians. Future work should assess its impact on values-congruent decision-making, therapeutic alliance, and infant outcomes. TRIAL REGISTRATION:NCT05733975.

OBJECTIVE:To assess variability among data elements collected among existing neonatal hypoxic-ischemic encephalopathy (HIE) data registries worldwide and to determine the need for future harmonization of standard common data elements. STUDY DESIGN:This was a cross-sectional study of data elements collected from current or recently employed HIE registry data forms. Registries were identified by literature search and email inquiries to investigators worldwide. Data elements were categorized by group consensus. RESULTS:A total of 1281 data elements were abstracted from 22 registries based in 14 countries, including 3 middle-income countries. Registries had a median of 106.5 distinct data elements per registry (range 59-458). The most commonly collected data were related to pregnancy, therapeutic hypothermia, and short-term hospital outcomes. The least consistently collected data were laboratory values other than acid/base status values. Only 4 variables were consistently collected in every registry. Five registries included neurodevelopmental follow-up fields and 5 others linked their data to a separate follow-up registry. CONCLUSION:Many HIE registries are collecting patient data around the world, but there is considerable variability in the number, type, and format of data collected. Future attempts to develop standard common data elements to harmonize data collection globally will be crucial to facilitate worldwide collaboration and to optimize management and outcome of neonatal HIE.

Introduction Infants with hypoxic-ischaemic encephalopathy (HIE) are at a high risk for neurodevelopmental impairment, and adjunctive treatments to promote brain repair are needed. The antidiabetic drug metformin has recently been recognised as a neurorestorative agent, but, to date, has not been used in infants. Herein, we describe a clinical trial of the safety, feasibility and pharmacokinetics of metformin in infants with HIE. Methods and analysis In collaboration with patient and family stakeholders, we designed a pragmatic clinical trial. To determine appropriate dosing of metformin, we performed physiologically based pharmacokinetic (PBPK) modelling after scaling a published adult PBPK model of metformin to an infant population of full-term newborns to 3-month-olds. Based on this PBPK modelling and target drug exposure, we determined an optimal target dose of 32 mg/kg/day. Trial participants will complete baseline bloodwork and then receive 3 weeks of metformin at 25% of the target dose, followed by 3 weeks of metformin at 50% of the target dose. At a mid-study (6 week) visit, repeat laboratory testing will be done, followed by an additional 6 weeks of metformin at target dosing. The final study visit will include repeat labs following therapy at target dosing. At-home blood glucose monitoring will be used between study visits. Pharmacokinetics of metformin will be evaluated with bloodwork collected at study visits. The incidence of safety events and feasibility measures will be reported using descriptive statistics. Our infant PBPK model will be validated with study samples and the dose for future trials adjusted based on new knowledge about metformin PK in infants.Ethics and dissemination Approval of the Boston Children’s Hospital Research Ethics Committee will be obtained prior to study initiation. Trial oversight will be under the direction of a Data Safety Monitoring Board.Trial registration number This study has been registered at www.clinicaltrials.gov under NCT06429007.

Background: Parents of neonates with seizures report persistent symptoms of depression, anxiety, and posttraumatic stress. We aimed to characterize the parent experience of caring for children impacted by neonatal seizures, including longitudinal assessment across childhood. Methods: This prospective, observational, multicenter study was conducted at Neonatal Seizure Registry (NSR) sites in partnership with the NSR Parent Advisory Panel. Parents completed surveys at discharge; 12, 18, and 24 months; and 3, 4, 5, 7, and 8 years. Surveys included demographic information and openended questions targeting parent experience. A conventional content analysis approach was used. Results: A total of 320 caregivers completed at least one open-ended question, with the majority of respondents at discharge (n = 142),12 months (n = 169),18 months (n = 208), and 24 months (n = 245). We identified the following three primary themes. (1) Personal Burden of Care: Parents experienced emotional distress, financial strain, physical demands, and fears for their child's unknown outcome; (2) Managing Day-to-Day Life: Parents described difficulties navigating their parenting role, including managing their child's challenging behaviors and understanding their child's needs amid neuro- developmental impairment; (3) My Joys as a Parent: Parents valued bonding with their child, being a caregiver, and watching their child's personality grow. Conclusions: Parents of children impacted by neonatal seizures face persistent challenges, which are interwoven with the joys of being a parent. Our findings suggest that future interventions should pro- mote resiliency, address caregivers' psychosocial needs longitudinally, and provide enhanced support for parents caring for children with medical complexity. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Many of the therapeutics commonly used in neonatal intensive care units (NICU) are not specifically labeled or approved for use in neonates (ie, defined as infants less than 28 days of life, or less than 28 days corrected age for preterm infants).a As such, clinicians lack critical safety and efficacy information on the use of medical products to treat neonatal conditions. Additionally, neonatal-specific medical conditions frequently lack safe and effective treatments, resulting in an unmet need for drug development. Some progress has been made in advancing therapeutics in pediatric populations as a result of legislative actions such as the U.S. Food and Drug Administration (FDA) Modernization Act of 1997 pediatric exclusivity provision,( 1 US Food and Drug Administration Modernization Act. Pub LNo. 105–115, 111 Stat 2296 (1997). Google Scholar ) the Best Pharmaceuticals for Children Act of 2002,( 2 Best Pharmaceuticals for Children Act. Pub L No. 107–109, 115 Stat 1408 (2002). Google Scholar ) the Pediatric Research Equity Act of 2003,( 3 Pediatric Research Equity Act. Pub L No. 108-155, 117 Stat 1936-1943 (2003). Google Scholar ) and the FDA Safety and Innovation Act of 2012.( 4 US Food and Drug Administration Safety and Innovation Act of 2012. Pub L No. 112-114. Google Scholar ) These statutes have created greater incentives for research and medical product development for pediatric populations, resulting in more approved therapies for children.( 5 Laughon M.M. Avant D. Tripathi N. Hornik C.P. Cohen-Wolkowiez M. Clark R.H. et al. Drug labeling and exposure in neonates. JAMA Pediatr. 2014; 168: 130-136 Crossref PubMed Scopus (88) Google Scholar ) Despite this progress, there remains a lack of labeling and product approvals in neonates.

Parents of newborns with hypoxic ischemic encephalopathy (HIE) can face communication challenges in the neonatal intensive care unit. Both specialty palliative care and primary palliative care trained clinicians can assist parents as they navigate traumatic experiences and uncertain prognoses. Using evidence-based frameworks, the authors provide samples of how to communicate with parents and promote parent well-being across the care trajectory. The authors demonstrate how to involve parents in a shared decision-making process and give special consideration to the complexities of hospital discharge and the transition home. Sustained investment to guide the development of effective communication skills is crucial to support families of infants with HIE.

Parents play a pivotal role in neurodevelopmental outcomes of their children in the neonatal intensive care unit (NICU) and beyond. Integration of parents in clinical care and research is synergistic. Engaged parents yield more comprehensive clinical care and more robust and meaningful research products. Subsequently, successful clinical and research efforts improve outcomes for children. We review strategies for parental integration into NICU clinical care and research, including parental involvement in therapeutic interventions and neurodevelopmental care, and effective communication strategies for clinicians and researchers. We discuss challenges in neonatal trials and emphasize the need for building a culture of research, collaborative partnerships with patient advocacy organizations, and ongoing support beyond the NICU. Overall, we call for recognizing and fostering the impactful role of parents as teammates with clinicians and researchers in optimizing neurodevelopmental outcomes in the NICU and beyond.

‘Neonatal encephalopathy’ (NE) describes a group of conditions in term infants presenting in the earliest days after birth with disturbed neurological function of cerebral origin. NE is aetiologically heterogenous; one cause is peripartum hypoxic ischaemia. Lack of uniformity in the terminology used to describe NE and its diagnostic criteria creates difficulty in the design and interpretation of research and complicates communication with families. The DEFINE study aims to use a modified Delphi approach to form a consensus definition for NE, and diagnostic criteria. Directed by an international steering group, we will conduct a systematic review of the literature to assess the terminology used in trials of NE, and with their guidance perform an online Real-time Delphi survey to develop a consensus diagnosis and criteria for NE. A consensus meeting will be held to agree on the final terminology and criteria, and the outcome disseminated widely. A clear and consistent consensus-based definition of NE and criteria for its diagnosis, achieved by use of a modified Delphi technique, will enable more comparability of research results and improved communication among professionals and with families.

Parents of neonates with neurologic conditions face a specific breadth of emotional, logistical, and social challenges, including difficulties coping with prognostic uncertainty, the need to make complex medical decisions, and navigating new hopes and fears. These challenges place parents in a vulnerable position and at risk of developing mental health issues, which can interfere with bonding and caring for their neonate, as well as compromise their neonate’s long-term neurodevelopment. To optimize neurologic and developmental outcomes, emerging neonatal neuro-critical care (NNCC) programs must concurrently attend to the unique needs of the developing newborn brain and of his/her parents. This can only be accomplished by embracing a family-centered care environment—one which prioritizes effective parent-clinician communication, longitudinal parent support, and parents as equitable partners in clinical care. NNCC programs offer a multifaceted approach to critical care for neonates at-risk for neurodevelopmental impairments, integrating expertise in neonatology and neurology. This review highlights evidence-based strategies to guide NNCC programs in developing a family-partnered approach to care, including primary staffing models; staff communication, implicit bias, and cultural competency trainings; comprehensive and tailored caregiver training; single-family rooms; flexible visitation policies; colocalized neonatal and maternal care; uniform mental health screenings; follow-up care referrals; and connections to peer support.

Purpose: Continuous EEG (cEEG) monitoring is increasingly used in the management of neonates with seizures. There remains debate on what clinically relevant information can be gained from cEEG in neonates with suspected seizures, at high risk for seizures, or with definite seizures, as well as the use of cEEG for prognosis in a variety of conditions. In this guideline, we address these questions using American Clinical Neurophysiology Society structured methodology for clinical guideline development. Methods: A working group was formed from American Clinical Neurophysiology Society membership with expertise in neonatal cEEG and a set of priority questions developed. We performed literature searches in PubMed and EMBASE to identify relevant studies. Evidence tables were compiled from extracted data and quality assessments performed. A modification of the GRADE process was used to evaluate the body of evidence and draft recommendations. Results: Our working group identified six priority questions to evaluate the accuracy of cEEG for neonatal seizure diagnosis and the formulation of prognosis. An initial literature search yielded 18,167 results, which were distilled to a set of 217 articles. Overall, the quality of evidence for most priority questions was rated as very low and we provided conditional recommendations based on published literature and expert consensus. For each priority question, we also considered the benefits and harms of cEEG, with relative harms considered to be far less than the potential benefits across recommendations. Conclusions: We present evidence-based clinical guidelines regarding indications for cEEG monitoring in neonates. Considering resource utilization and feasibility, when cEEG monitoring results have a likelihood of altering clinical decision making, the authors felt the resource investment was justifiable.

OBJECTIVE:To evaluate whether abnormal sleep is associated with adverse outcomes for children who survived acute provoked neonatal seizures, and their parents. STUDY DESIGN:This 9-center study prospectively followed newborns with acute provoked seizures. When children reached age 5 years, parents completed the Children's Sleep Habits Questionnaire (CSHQ), the Pediatric Sleep Questionnaire-Sleep Related Breathing Disorders (PSQ-SRBD) subscale, the Vineland Adaptive Behavior Scales-3, and the Hospital Anxiety Depression Scale. Children were also assessed with the Wechsler Preschool and Primary Scale of Intelligence-IV (WPPSI-IV). Spearman correlations and multivariable analyses were used to evaluate risk factors for sleep problems. RESULTS:The mean CSHQ score was 45 ± 7; 77 of 118 children (65%) had an abnormal score (above the healthy sleep threshold of 41). On the PSQ-SRBD, 32 of 119 children (27%) screened positive for sleep-disordered breathing (SDB). SDB symptoms were more common among children with cerebral palsy (42% with vs 22% without; P = .03) and epilepsy (54% with vs 24% without; P = .02). Children with lower scores on the Vineland-3 (rho = -0.25; P = .01) and WPPSI-IV (rho = -0.31; P = .004) at 5 years of age were more likely to have symptoms of SDB. Worse CSHQ and PSQ-SRBD scores were associated with higher parental anxiety (rho = 0.28 [P = .002] and rho = 0.34 [P = .0002], respectively) and depression scores on the Hospital Anxiety Depression Scale (rho = 0.16 [P = .08] and rho = 0.17 [P = .07], respectively). CONCLUSIONS:Two-thirds of early school-aged survivors of acute provoked neonatal seizures had parent-reported sleep abnormalities and one-quarter screened positive for SDB. Early screening and effective treatment for sleep disorders could be an innovative, practice-changing approach to improve outcomes after neonatal seizures.