Regional variability in therapeutic hypothermia eligibility criteria for neonatal hypoxic-ischemic encephalopathy.

Early induced therapeutic hypothermia represents the cornerstone treatment in neonates with probable hypoxic-ischemic encephalopathy. The selection of patients for treatment usually involves meeting criteria indicating evidence of perinatal hypoxia-ischemia and the presence of moderate or severe encephalopathy. In this review, we highlight the variability that exists between some of the different regional and national eligibility guidelines. Determining the potential presence of perinatal hypoxia-ischemia may require either one, two or three signs amongst history of acute perinatal event, prolonged resuscitation at delivery, abnormal blood gases and low Apgar score, with a range of cutoff values. Clinical neurological exams often define the severity of encephalopathy differently, with varying number of domains required for determining eligibility and blurred interpretation of findings assigned to different severity grades in different systems. The role of early electrophysiological assessment is weighted differently. A clinical implication is that infants may receive different care depending on the location in which they are born. This could also impact epidemiological data, as inference of rates of moderate-severe encephalopathy based on therapeutic hypothermia rates are misleading and influenced by different eligibility methods used. We would advocate that a universally endorsed single severity staging of encephalopathy is vital for standardizing management and neonatal outcome. IMPACT: Variability exists between regional and national therapeutic hypothermia eligibility guidelines for neonates with probable hypoxic-ischemic encephalopathy. Differences are common in both criteria indicating perinatal hypoxia-ischemia and criteria defining moderate or severe encephalopathy. The role of early electrophysiological assessment is also weighted unequally. This reflects in different individual care and impacts research data. A universally endorsed single severity staging of encephalopathy would be crucial for standardizing management.

Long-term developmental condition following neonatal arterial ischemic stroke: A systematic review.

BACKGROUND: Neonatal arterial ischemic stroke (NAIS) is the most frequent subtype of perinatal stroke. Its elusive pathophysiology, its abrupt and unexpected occurrence, and the uncertainty of the post-NAIS developmental condition may lead to parental emotional distress and psychological difficulties. The aim of this study was to summarize the current data on long-term developmental conditions following NAIS to support parental information given within the neonatal unit. METHODS: This systematic review included clinical studies of term infants with NAIS, who had a developmental assessment at ≥5 years of age. Studies were identified from the Medline and Embase databases on June 1, 2022. The Joanna Briggs Institute (JBI) appraisal tool was used to assess the risk of bias. Results were synthesized using a narrative approach. The 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was followed to report this work. RESULTS: Three cohort studies enrolling 205 children assessed from 5 to 7 years after NAIS were included. Most of the children presented long-term developmental conditions allowing them to be integrated into a regular school program, to participate in physical activities, and to have a good quality of life. Global intellectual deficiency and moderate-to-severe cerebral palsy occurred in less than 10% of the children. CONCLUSION: Physicians should not overestimate the incidence of moderate-to-severe developmental outcome following NAIS when discussing the prognosis with parents. A parental information sheet about NAIS and its long-term developmental conditions is provided.

From early motor ability to global cognitive development seven years after neonatal arterial ischemic stroke.

The developmental condition of children after neonatal arterial ischemic stroke (NAIS) is characterized by cognitive and motor impairments. We hypothesized that independent walking age would be a predictor of later global cognitive functioning in this population. Sixty-one children with an available independent walking age and full-scale IQ score seven years after NAIS were included in this study. Full-scale IQ was assessed using the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV). Independent walking age was negatively correlated with full-scale IQ score at seven years of age (Pearson correlation coefficient of -0.27; 95% confidence interval from 0.48 to -0.01; p <0.05). Early motor function is correlated with later global cognitive functioning in children after NAIS. Assessing and promoting early motor ability is essential in this population.

Magnetic resonance venography to evaluate cerebral sinovenous thrombosis in infants receiving therapeutic hypothermia.

BACKGROUND: The incidence of cerebral sinovenous thrombosis (CSVT) in infants receiving therapeutic hypothermia for neonatal encephalopathy remains controversial. The aim of this study was to identify if the routine use of magnetic resonance venography (MRV) in term-born infants receiving hypothermia is associated with diagnostic identification of CSVT. METHODS: We performed a retrospective review of 291 infants who received therapeutic hypothermia from January 2014 to March 2020. Demographic and clinical data, as well as the incidence of CSVT, were compared between infants born before and after adding routine MRV to post-rewarming magnetic resonance imaging (MRI). RESULTS: Before routine inclusion of MRV, 209 babies were cooled, and 25 (12%) underwent MRV. Only one baby (0.5%) was diagnosed with CSVT in that period, and it was detected by structural MRI, then confirmed with MRV. After the inclusion of routine MRV, 82 infants were cooled. Of these, 74 (90%) had MRV and none were diagnosed with CSVT. CONCLUSION: CSVT is uncommon in our cohort of infants receiving therapeutic hypothermia for neonatal encephalopathy. Inclusion of routine MRV in the post-rewarming imaging protocol was not associated with increased detection of CSVT in this population. IMPACT: Cerebral sinovenous thrombosis (CSVT) in infants with NE receiving TH may not be as common as previously indicated. The addition of MRV to routine post-rewarming imaging protocol did not lead to increased detection of CSVT in infants with NE. Asymmetry on MRV of the transverse sinus is a common anatomic variant. MRI alone may be sufficient in indicating the presence of CSVT.

Pathogenesis and prevention of intraventricular hemorrhage.

Despite improvements in the mortality rates of preterm infants, rates of germinal matrix intraventricular hemorrhage (IVH) have remained static with an overall incidence of 25% in infants less than 32 weeks. The importance of the lesion relates primarily to the underlying injury to the developing brain and the associated long-term neurodevelopmental consequences. This clinical-orientated review focuses on the pathogenesis of IVH and discusses the evidence behind proposed prevention strategies.

The impact of perinatal inflammation on the electroencephalogram in preterm infants: a systematic review.

BACKGROUND: To summarise the association between perinatal inflammation (PI) exposure and electroencephalography (EEG) features in preterm infants. METHODS: This systematic review included clinical studies of preterm infants born <37 weeks of gestational age (GA), who had both a PI exposure and an EEG assessment performed during the neonatal period. Studies were identified from Medline and Embase databases on the 15th of September 2021. PI was defined by histological chorioamnionitis, clinical chorioamnionitis, or early-onset neonatal infection (EONI). The risk of bias in included studies was assessed using the Joanna Briggs Institute (JBI) appraisal tool. A narrative approach was used to synthesise results. This review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statement. RESULTS: Two cross-sectional studies enrolling 130 preterm children born <32 weeks of GA assessed with one-channel amplitude-integrated EEG (aEEG) during the first four days of life were included. A PI exposure was described in 39 (30%) infants and was associated with a decrease in amplitude and a reduced incidence of sleep-wake cycling patterns. CONCLUSION: These results should be interpreted with caution because of the small number of included studies and their heterogeneity. Further clinical studies evaluating the association of PI with EEG findings are needed. IMPACT: A method to assess developmental trajectories following perinatal inflammation is required. Insufficient data exist to determine EEG features associated with perinatal inflammation. Further clinical studies evaluating this association are needed.

Comparison of numerical and standard sarnat grading using the NICHD and SIBEN methods.

OBJECTIVE: The NICHD and SIBEN assessments are adapted from the Sarnat grade, and used to determine severity of neonatal encephalopathy (NE). We compare NICHD and SIBEN methods, and their ability to define a minimum threshold associated with significant cerebral injury. STUDY DESIGN: Between 2016 and 2019, 145 infants with NE (77-mild; 65-moderate; 3-severe) were included. NICHD and SIBEN grade and numerical scores were assigned. Kappa scores described agreement between methods, and ROC curves their ability to predict MR injury. RESULTS: Good agreement existed between grading systems (K = 0.86). SIBEN defined more infants as moderate, and less as mild, than NICHD (p < 0.001). Both numerical scores were superior to standard grades in predicting MR injury. CONCLUSION: Despite good agreement between methods, SIBEN defines more infants as moderate NE. Both numerical scores were superior to standard grade, and comparable to each other, in defining a minimum threshold for cerebral injury. Further assessment contrasting their predictive ability for long-term outcome is required.

Differences in standardized neonatal encephalopathy exam criteria may impact therapeutic hypothermia eligibility.

BACKGROUND: Therapeutic hypothermia (TH) is routinely provided to those with moderate or severe neonatal encephalopathy (NE). Subtle differences exist in the standardized exams used to define NE severity. We aimed to assess if an infant's TH eligibility status differed if they were evaluated using either the NICHD/Neonatal Research Network's (NICHD-NRN) or TOBY/British Association of Perinatal Medicine's (TOBY-BAPM) neurological exam. METHODS: Encephalopathic infants ≥36 weeks with evidence of perinatal asphyxia and complete documentation of the neurological exam <6 h of age were included. TH eligibility using the NICHD-NRN and TOBY-BAPM criteria was determined based upon the documented exams. RESULTS: Ninety-one encephalopathic infants were included. Despite good agreement between the two exams (κ = 0.715, p < 0.001), TH eligibility differed between them (p < 0.001). A total of 47 infants were deemed eligible by at least one method-46 using NICHD-NRN and 35 using TOBY-BAPM. Of the 12 infants eligible per NICHD-NRN, but ineligible per TOBY-BAPM, two developed electrographic seizures and seven demonstrated hypoxic-ischemic cerebral injury. CONCLUSIONS: Both the NICHD-NRN and TOBY-BAPM exams are evidence-based. Despite this, there is a significant difference in the number of infants eligible for TH depending on which exam is used. The NICHD-NRN exam identifies a greater proportion as eligible. IMPACT: There are subtle differences in the NICHD-NRN and TOBY-BAPM's encephalopathy exams used to determine eligibility for TH. This results in a significant difference in the proportion of infants determined to be eligible for TH depending on which encephalopathy exam is used. The NICHD-NRN encephalopathy exam identifies more infants as being eligible for TH than the TOBY-BAPM encephalopathy exam. This may result in different rates of cooling depending on which evidence-based neurological exam for evaluation of encephalopathy a center uses.

Case Report: Electroencephalography in a neonate with isolated sulfite oxidase deficiency - a case report and literature review.

Isolated sulfite oxidase deficiency (ISOD) is a rare autosomal recessive neuro-metabolic disorder caused by a mutation in the sulfite oxidase (SUOX) gene situated on chromosome 12. Due to the deficiency of this mitochondrial enzyme (sulfite oxidase), the oxidative degradation of toxic sulfites is disrupted. The most common form of this disease has an early onset (classical ISOD) in the neonatal period, with hypotonia, poor feeding and intractable seizures, mimicking hypoxic-ischaemic encephalopathy. The evolution is rapidly progressive to severe developmental delay, microcephaly and early death. Unfortunately, there is no effective treatment and the prognosis is very poor. In this article, we described the evolution of early continuous electroencephalography (EEG) in a case of ISOD with neonatal onset, as severely encephalopathic background, with refractory seizures and distinct delta-beta complexes. The presence of the delta-beta complexes might be a diagnostic marker in ISOD. We also performed a literature review of published cases of neonatal ISOD that included EEG monitoring.

Predictive modelling of hypoxic ischaemic encephalopathy risk following perinatal asphyxia.

Hypoxic Ischemic Encephalopathy (HIE) remains a major cause of neurological disability. Early intervention with therapeutic hypothermia improves outcome, but prediction of HIE is difficult and no single clinical marker is reliable. Machine learning algorithms may allow identification of patterns in clinical data to improve prognostic power. Here we examine the use of a Random Forest machine learning algorithm and five-fold cross-validation to predict the occurrence of HIE in a prospective cohort of infants with perinatal asphyxia. Infants with perinatal asphyxia were recruited at birth and neonatal course was followed for the development of HIE. Clinical variables were recorded for each infant including maternal demographics, delivery details and infant's condition at birth. We found that the strongest predictors of HIE were the infant's condition at birth (as expressed by Apgar score), need for resuscitation, and the first postnatal measures of pH, lactate, and base deficit. Random Forest models combining features including Apgar score, most intensive resuscitation, maternal age and infant birth weight both with and without biochemical markers of pH, lactate, and base deficit resulted in a sensitivity of 56-100% and a specificity of 78-99%. This study presents a dynamic method of rapid classification that has the potential to be easily adapted and implemented in a clinical setting, with and without the availability of blood gas analysis. Our results demonstrate that applying machine learning algorithms to readily available clinical data may support clinicians in the early and accurate identification of infants who will develop HIE. We anticipate our models to be a starting point for the development of a more sophisticated clinical decision support system to help identify which infants will benefit from early therapeutic hypothermia.

Multichannel EEG abnormalities during the first 6 hours in infants with mild hypoxic-ischaemic encephalopathy.

BACKGROUND: Infants with mild HIE are at risk of significant disability at follow-up. In the pre-therapeutic hypothermia (TH) era, electroencephalography (EEG) within 6 hours of birth was most predictive of outcome. This study aims to identify and describe features of early EEG and heart rate variability (HRV) (<6 hours of age) in infants with mild HIE compared to healthy term infants. METHODS: Infants >36 weeks with mild HIE, not undergoing TH, with EEG before 6 hours of age were identified from 4 prospective cohort studies conducted in the Cork University Maternity Services, Ireland (2003-2019). Control infants were taken from a contemporaneous study examining brain activity in healthy term infants. EEGs were qualitatively analysed by two neonatal neurophysiologists and quantitatively assessed using multiple features of amplitude, spectral shape and inter-hemispheric connectivity. Quantitative features of HRV were assessed in both the groups. RESULTS: Fifty-eight infants with mild HIE and sixteen healthy term infants were included. Seventy-two percent of infants with mild HIE had at least one abnormal EEG feature on qualitative analysis and quantitative EEG analysis revealed significant differences in spectral features between the two groups. HRV analysis did not differentiate between the groups. CONCLUSIONS: Qualitative and quantitative analysis of the EEG before 6 hours of age identified abnormal EEG features in mild HIE, which could aid in the objective identification of cases for future TH trials in mild HIE. IMPACT: Infants with mild HIE currently do not meet selection criteria for TH yet may be at risk of significant disability at follow-up. In the pre-TH era, EEG within 6 hours of birth was most predictive of outcome; however, TH has delayed this predictive value. 72% of infants with mild HIE had at least one abnormal EEG feature in the first 6 hours on qualitative assessment. Quantitative EEG analysis revealed significant differences in spectral features between infants with mild HIE and healthy term infants. Quantitative EEG features may aid in the objective identification of cases for future TH trials in mild HIE.

Surgery requiring general anesthesia in preterm infants is associated with altered brain volumes at term equivalent age and neurodevelopmental impairment.

BACKGROUND: The aim of the study was to describe and contrast the brain development and outcome among very preterm infants that were and were not exposed to surgery requiring general anesthesia prior to term equivalent age (TEA). METHODS: Preterm infants born ≤30 weeks' gestation who did (n = 25) and did not (n = 59) have surgery requiring general anesthesia during the preterm period were studied. At TEA, infants had MRI scans performed with measures of brain tissue volumes, cortical surface area, Gyrification Index, and white matter microstructure. Neurodevelopmental follow-up with the Bayley Scales of Infant and Toddler Development, Third Edition was undertaken at 2 years of corrected age. Multivariate models, adjusted for clinical and social risk factors, were used to compare the groups. RESULTS: After controlling for clinical and social variables, preterm infants exposed to surgical anesthesia demonstrated decreased relative white matter volumes at TEA and lower cognitive and motor composite scores at 2-year follow-up. Those with longer surgical exposure demonstrated the greatest decrease in white matter volumes and lower cognitive and motor outcomes at age 2 years. CONCLUSIONS: Very preterm infants who required surgery during the preterm period had lower white mater volumes at TEA and worse neurodevelopmental outcome at age 2 years. IMPACT: In very preterm infants, there is an association between surgery requiring general anesthesia during the preterm period and reduced white mater volume on MRI at TEA and lower cognitive and motor composite scores at age 2 years. It is known that the very preterm infant's brain undergoes rapid growth during the period corresponding to the third trimester. The current study suggests an association between surgery requiring general anesthesia during this period and worse outcomes.

Hypothermia and Cardiovascular Instability.

Severely asphyxiated neonates have acute heart failure as part of their multiorgan dysfunction syndrome during the first days of life. Supporting the cardiovascular system during this phase is part of contemporary treatment and regarded as vital for limiting the neurodevelopmental injury. The decision to treat cardiovascular instability should be based on evaluation of end-organ function. Neonatologist-performed echocardiography in combination with other diagnostic modalities enables comprehensive real-time assessment. This review discusses associations between hemodynamics and adverse outcome, modalities for evaluating the hemodynamic state of the infant, and therapeutic approaches during intensive care.

Untargeted metabolomic analysis and pathway discovery in perinatal asphyxia and hypoxic-ischaemic encephalopathy.

Elucidating metabolic effects of hypoxic-ischaemic encephalopathy (HIE) may reveal early biomarkers of injury and new treatment targets. This study uses untargeted metabolomics to examine early metabolic alterations in a carefully defined neonatal population. Infants with perinatal asphyxia who were resuscitated at birth and recovered (PA group), those who developed HIE (HIE group) and healthy controls were all recruited at birth. Metabolomic analysis of cord blood was performed using direct infusion FT-ICR mass spectrometry. For each reproducibly detected metabolic feature, mean fold differences were calculated HIE vs. controls (ΔHIE) and PA vs. controls (ΔPA). Putative metabolite annotations were assigned and pathway analysis was performed. Twenty-nine putatively annotated metabolic features were significantly different in ΔPA after false discovery correction ( q < 0.05), with eight of these also significantly altered in ΔHIE. Altered putative metabolites included; melatonin, leucine, kynurenine and 3-hydroxydodecanoic acid which differentiated between infant groups (ΔPA and ΔHIE); and D-erythrose-phosphate, acetone, 3-oxotetradecanoic acid and methylglutarylcarnitine which differentiated across severity grades of HIE. Pathway analysis revealed ΔHIE was associated with a 50% and 75% perturbation of tryptophan and pyrimidine metabolism, respectively. We have identified perturbed metabolic pathways and potential biomarkers specific to PA and HIE, which measured at birth, may help direct treatment.

MRI as a biomarker for mild neonatal encephalopathy.

Historically, there has been limited neuro-imaging data acquired on infants with mild neonatal encephalopathy (NE). This likely reflects the traditional assumption that these infants had a universally good prognosis. As new evidence has emerged challenging this assumption, there has been a renewed interest in the neuro-imaging findings of these infants. To date, magnetic resonance imaging (MRI) studies in infants with mild NE have demonstrated abnormalities in 20-40% of cases suggestive that the injury occurs during the peripartum period with a predominant watershed pattern of injury. The severity of the injury on MRI in infants with mild NE varies, but includes patterns of injury that have been associated with long-term neuro-developmental impairment.

Brain growth in the NICU: critical periods of tissue-specific expansion.

ObjectiveTo examine, using serial magnetic resonance imaging (MRI), total and tissue-specific brain growth in very-preterm (VPT) infants during the period that coincides with the early and late stages of the third trimester.MethodsStructural MRI scans were collected from two prospective cohorts of VPT infants (≤30 weeks of gestation). A total of 51 MRI scans from 18 VPT subjects were available for volumetric analysis. Brain tissue was classified into cerebrospinal fluid, cortical gray matter, myelinated and unmyelinated white matter, deep nuclear gray matter, and cerebellum. Nine infants had sufficient serial scans to allow comparison of tissue growth during the periods corresponding to the early and late stages of the third trimester.ResultsTissue-specific differences in ex utero brain growth trajectories were observed in the period corresponding to the third trimester. Most notably, there was a marked increase in cortical gray matter expansion from 34 to 40 weeks of postmenstrual age, emphasizing this critical period of brain development.ConclusionUtilizing serial MRI to document early brain development in VPT infants, this study documents regional differences in brain growth trajectories ex utero during the period corresponding to the first and second half of the third trimester, providing novel insight into the maturational vulnerability of the rapidly expanding cortical gray matter in the NICU.

Cord Blood IL-16 Is Associated with 3-Year Neurodevelopmental Outcomes in Perinatal Asphyxia and Hypoxic-Ischaemic Encephalopathy.

Activation of the inflammatory pathway is increasingly recognized as an important mechanism of injury following neonatal asphyxia and encephalopathy. This process may contribute to the poor prognosis seen in some cases, despite therapeutic hypothermia. Our group has previously identified raised interleukin (IL)-6 and IL-16, measured in umbilical cord blood at birth, to be predictive of grade of hypoxic-ischaemic encephalopathy (HIE). Our aim in this study was to examine the ability of these cytokines to predict the 3-year neurodevelopmental outcome in the same cohort. As part of a prospective, longitudinal cohort study set in a single tertiary maternity unit, term infants with biochemical and clinical evidence of perinatal asphyxia were recruited at birth. Umbilical cord blood was collected and analyzed for IL-6 and IL-16 using a Luminex assay. The neurodevelopmental outcome of these infants was assessed at 3 years using the Bayley Scales of Infant and Toddler Development (Edition 3). Early cord blood measurement of IL-6 and IL-16 and long-term outcome were available in 33/69 infants. Median (IQR) IL-16 differentiated infants with a severely abnormal outcome (n = 6) compared to all others (n = 27), (646 [466-1,085] vs. 383.5 [284-494] pg/mL; p = 0.012). IL-16 levels were able to predict a severe outcome with an area under the receiver-operating characteristic (ROC) curve of 0.827 (95% CI 0.628-1.000; p = 0.014). Levels ≥514 pg/mL predicted a severe outcome with a sensitivity of 83% and a specificity of 81%. IL-16 also outperformed other routine biochemical markers available at birth for the prediction of severe outcome. APGAR scores at 1 and 10 min were also predictive of a severe outcome (p = 0.022 and p = 0.036, respectively). A combination of IL-16 with these clinical markers did not improve predictive value, but IL-16 combined with electroencephalogram grading increased the area under the ROC curve. IL-6 did not show any association with 3-year outcome. This is the first report studying the association of IL-16 measured at birth with long-term outcome in a cohort of neonates with perinatal asphyxia. IL-16 may be an early biomarker of severe injury and aid in the long-term prognostication in infants with HIE.

The Frequency and Severity of Magnetic Resonance Imaging Abnormalities in Infants with Mild Neonatal Encephalopathy.

OBJECTIVE: To assess and contrast the incidence and severity of abnormalities on cerebral magnetic resonance imaging (MRI) between infants with mild, moderate, and severe neonatal encephalopathy who received therapeutic hypothermia. STUDY DESIGN: This retrospective cohort studied infants with mild, moderate, and severe neonatal encephalopathy who received therapeutic hypothermia at a single tertiary neonatal intensive care unit between 2013 and 2015. Two neuroradiologists masked to the clinical condition evaluated brain MRIs for cerebral injury after therapeutic hypothermia using the Barkovich classification system. Additional abnormalities not included in this classification system were also noted. The rate, pattern, and severity of abnormalities/injury were compared across the grades of neonatal encephalopathy. RESULTS: Eighty-nine infants received therapeutic hypothermia and met study criteria, 48 with mild neonatal encephalopathy, 35 with moderate neonatal encephalopathy, and 6 with severe neonatal encephalopathy. Forty-eight infants (54%) had an abnormality on MRI. There was no difference in the rate of overall MRI abnormalities by grade of neonatal encephalopathy (mild neonatal encephalopathy 54%, moderate neonatal encephalopathy 54%, and severe neonatal encephalopathy 50%; P= .89). Basal ganglia/thalamic injury was more common in those with severe neonatal encephalopathy (mild neonatal encephalopathy 4%, moderate neonatal encephalopathy 9%, severe neonatal encephalopathy 34%; P = .03). In contrast, watershed injury did not differ between neonatal encephalopathy grades (mild neonatal encephalopathy 36%, moderate neonatal encephalopathy 32%, severe neonatal encephalopathy 50%; P = .3). CONCLUSION: Mild neonatal encephalopathy is commonly associated with MRI abnormalities after therapeutic hypothermia. The grade of neonatal encephalopathy during the first hours of life may not discriminate adequately between infants with and without cerebral injury noted on MRI after therapeutic hypothermia.