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.).

Development of neonatal connectome dynamics and its prediction for cognitive and language outcomes at age 2.

The functional brain connectome is highly dynamic over time. However, how brain connectome dynamics evolves during the third trimester of pregnancy and is associated with later cognitive growth remains unknown. Here, we use resting-state functional Magnetic Resonance Imaging (MRI) data from 39 newborns aged 32 to 42 postmenstrual weeks to investigate the maturation process of connectome dynamics and its role in predicting neurocognitive outcomes at 2 years of age. Neonatal brain dynamics is assessed using a multilayer network model. Network dynamics decreases globally but increases in both modularity and diversity with development. Regionally, module switching decreases with development primarily in the lateral precentral gyrus, medial temporal lobe, and subcortical areas, with a higher growth rate in primary regions than in association regions. Support vector regression reveals that neonatal connectome dynamics is predictive of individual cognitive and language abilities at 2  years of age. Our findings highlight network-level neural substrates underlying early cognitive development.

Neurodevelopmental outcomes in extremely preterm infants with placental pathologic evidence of fetal inflammatroy response.

OBJECTIVES: Neonates born with fetal inflammatory response (FIR) are at increased risk for adverse neonatal outcomes. Our objective was to determine whether FIR and its severity is associated with neurodevelopmental impairment (NDI) at 2 years of age or death among preterm infants. METHODS: A retrospective cohort study of prospectively collected data of all infants born <29 weeks gestational age (GA). FIR and its severity were diagnosed according to the Amsterdam Placental Workshop Group Consensus Statement. Neurodevelopmental outcomes among all participants were quantified according to Bayley III. RESULTS: Mothers of infants with FIR were significantly younger (P = 0.04) and had a greater prevalence of antenatal steroid use (P < 0.01), infection during pregnancy (P = 0.01), PPROM (P < 0.01), and clinical chorioamnionitis (P < 0.01). Infants with FIR had longer duration of hospitalization (P < 0.01), days on oxygen (P < 0.01), congenital pneumonia (P = 0.03), moderate/severe bronchopulmonary dysplasia (BPD; P < 0.01). Notably, infants with FIR were not at increased risk of NDI or death (primary outcome). Those with moderate to severe FIR (≥ stage 2 FIR) were at increased risk of developing motor & language impairment or death (P < 0.01). CONCLUSION: This is the first report demonstrating an association between the severity of FIR and subsequent NDI in preterm infants born. IMPACT STATEMENT: Fetal Inflammatory Response (FIR) is not associated Neurodevelopmental Impairement (NDI) or Death in preterm infants However, there is significant relationship between moderate to severe FIR and NDI at 2 years of age in preterm infants. This is the first study demonstrating the impact of progression and severity of FIR on NDI or Death in preterm infants. These observations provide additional insight into understanding the impact of intrauterine exposure to inflammation on the NDI or death in preterm infants.

Prognostic value of quantitative EEG in early hours of life for neonatal encephalopathy and neurodevelopmental outcomes.

BACKGROUND: The ability to determine severity of encephalopathy is crucial for early neuroprotective therapies and for predicting neurodevelopmental outcome. The objective of this study was to assess a novel brain state of newborn (BSN) trend to distinguish newborns with presence of hypoxic ischemic encephalopathy (HIE) within hours after birth and predict neurodevelopmental outcomes at 2 years of age. METHOD: This is a prospective cohort study of newborns at 36 weeks' gestation or later with and without HIE at birth. The Total Sanart Score (TSS) was calculated based on a modified Sarnat exam within 6 h of life. BSN was calculated from electroencephalogram (EEG) measurements initiated after birth. The primary outcome at 2 year of age was a diagnosis of death or disability using the Bayley Scales of Infant Development III. RESULTS: BSN differentiated between normal and abnormal neurodevelopmental outcomes throughout the entire recording period from 6 h of life. Additionally, infants with lower BSN values had higher odds of neurodevelopmental impairment and HIE. BSN distinguished between normal (n = 86) and HIE (n = 46) and showed a significant correlation with the concomitant TSS. CONCLUSION: BSN is a sensitive real-time marker for monitoring dynamic progression of encephalopathy and predicting neurodevelopmental impairment. IMPACT: This is a prospective cohort study to investigate the ability of brain state of newborn (BSN) trend to predict neurodevelopmental outcome within the first day of life and identify severity of encephalopathy. BSN predicts neurodevelopmental outcomes at 2 years of age and the severity of encephalopathy severity. It also correlates with the Total Sarnat Score from the modified Sarnat exam. BSN could serve as a promising bedside trend aiding in accurate assessment and identification of newborns who may benefit from additional neuroprotection therapies.

Consensus definition and diagnostic criteria for neonatal encephalopathy-study protocol for a real-time modified delphi study.

BACKGROUND: '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. METHODS: 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. DISCUSSION: 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. IMPACT: The terms Neonatal Encephalopathy and Hypoxic Ischaemic Encephalopathy tend to be used interchangeably in the literature to describe a term newborn with signs of encephalopathy at birth. This creates difficulty in communication with families and carers, and between medical professionals and researchers, as well as creating difficulty with performance of research. The DEFINE project will use a Real-time Delphi approach to create a consensus definition for the term 'Neonatal Encephalopathy'. A definition formed by this consensus approach will be accepted and utilised by the neonatal community to improve research, outcomes, and parental experience.

A comparison of criteria for defining metabolic acidemia in live-born neonates and its effect on predicting serious adverse neonatal outcomes.

BACKGROUND: Metabolic acidemia is a known risk factor for serious adverse neonatal outcomes in both preterm and term infants. OBJECTIVE: This study aimed to evaluate the clinical significance of delivery umbilical cord gas measurements with regard to serious adverse neonatal outcomes, and to determine if distinct thresholds for defining metabolic acidemia differ in their ability to predict such adverse neonatal complications. STUDY DESIGN: This is a retrospective cohort study of singleton live-born deliveries between January 2011 and December 2019. Stratification according to gestational age at birth (≥35 and <35 weeks of gestation) was performed, and comparisons of maternal characteristics, obstetrical complications, intrapartum events, and adverse neonatal outcomes were made between neonates with metabolic acidemia and those without. Metabolic acidemia (based on delivery umbilical cord gas analyses) was defined using both American College of Obstetricians and Gynecologists and Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria. The primary outcome of interest was hypoxic-ischemic encephalopathy requiring whole-body hypothermia. RESULTS: A total of 91,694 neonates born at ≥35 weeks of gestation met the inclusion criteria. By American College of Obstetricians and Gynecologists criteria, 2659 (2.9%) infants had metabolic acidemia. Neonates with metabolic acidemia were at markedly increased risk for neonatal intensive care unit admission, seizures, need for respiratory support, sepsis, and neonatal death. Metabolic acidemia by American College of Obstetricians and Gynecologists criteria was associated with an almost 100-fold increased risk of hypoxic-ischemic encephalopathy requiring whole-body hypothermia (relative risk, 92.69; 95% confidence interval, 64.42-133.35) in neonates born at ≥35 weeks of gestation. Diabetes mellitus, hypertensive disorders of pregnancy, postterm deliveries, prolonged second stages, chorioamnionitis, operative vaginal deliveries, placental abruption and cesarean deliveries were associated with metabolic acidemia in neonates born ≥ 35 weeks of gestation. The highest relative risk was in those diagnosed with placental abruption (relative risk, 9.07; 95% confidence interval, 7.25-11.36). The neonatal cohort born <35 weeks of gestation had similar findings. When comparing those infants born ≥ 35 weeks of gestation with metabolic acidemia by American College of Obstetricians and Gynecologists criteria vs Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria, the Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria identified more neonates at risk for serious adverse neonatal outcomes. In particular, 4.9% more neonates were diagnosed with metabolic acidemia, and 16 more term neonates were identified as requiring whole-body hypothermia. Mean 1-minute and 5-minute Apgar scores were similar and reassuring among neonates born at ≥35 weeks of gestation with and without metabolic acidemia as defined by both American College of Obstetricians and Gynecologists and Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria (8 vs 8 and 9 vs 9, respectively; P<.001). Sensitivity and specificity were 86.7% and 92.2%, respectively, with the Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria, and 74.2% and 97.2% with the American College of Obstetricians and Gynecologists criteria. CONCLUSION: Infants with metabolic acidemia identified on cord gas collection at delivery are at considerably greater risk of serious adverse neonatal outcomes, including an almost 100-fold increased risk of hypoxic-ischemic encephalopathy requiring whole-body hypothermia. Use of the more sensitive Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria for defining metabolic acidemia identifies more neonates born at ≥35 weeks of gestation at risk for adverse neonatal outcomes, including hypoxic-ischemic encephalopathy requiring whole-body hypothermia.

Vein of Galen aneurysmal malformation: rationalizing medical management of neonatal heart failure.

Neonates who present in high output heart failure secondary to vein of Galen aneurysmal malformation can be difficult to manage medically due to the complex physiology that results from the large shunt through the malformation. Though the cardiac function is often normal, right ventricular dilation, severe pulmonary hypertension, and systemic steal can result in inadequate organ perfusion and shock. This report recommends medical management for stabilization of neonates prior to definitive management with endovascular embolization. IMPACT: Vein of Galen aneurysmal malformation (VGAM) is a rare intracranial arteriovenous malformation, which can present in the neonatal period with high output heart failure. Heart failure secondary to VGAM is often difficult to manage and is associated with high mortality and morbidity. Despite optimal medical management, many patients require urgent endovascular embolization for stabilization of their heart failure. This report offers discrete recommendations that can be used by clinicians as guidelines for the medical management of heart failure in newborns with VGAM.

Placental clearance not synthesis tempers exaggerated pro-inflammatory cytokine response in neonates exposed to chorioamnionitis.

BACKGROUND: The source and clearance of cytokines in the fetal circulation in term pregnancies complicated by chorioamnionitis remains unclear as are the contributions of placental transport, synthesis, and clearance. The objectives of the study were to determine (1) fetal and/or placental contributions to synthesis and/or clearance of inflammatory and anti-inflammatory cytokines in term pregnancies complicated by chorioamnionitis and (2) whether this differs in pregnancies further complicated by fetal hypoxia. METHODS: Prospective cohort study of pregnancies >37 weeks gestational age that included: Group 1, uncomplicated cesarean delivery without labor (n = 20); Group 2, uncomplicated vaginal delivery (n = 30); Group 3, pregnancies complicated by chorioamnionitis (n = 10); Group 4, complicated by chorioamnionitis + fetal hypoxia (n = 10). Umbilical arterial (UmA) and venous (UmV) blood were assayed for IL-1ß, IL-2, IL-6, IL-8, TNFα, and IL-10. RESULTS: IL-6 and IL-8 were below assay detection in UmA and UmV blood in Group 1 and increased in Group 2 (P < 0.01), UmA¼UmV (P < 0.01). Their concentrations increased further in Groups 3 and 4 (P = 0.003), UmA¼UmV. Placental clearance was concentration dependent that approaches saturation in the presence of chorioamnionitis. CONCLUSIONS: Marked increases in fetal synthesis of IL-6 and IL-8 occur in chorioamnionitis. Synthesis increase further when complicated by fetal hypoxia. Cytokine removal occurs via placental concentration-dependent mechanisms, potentially contributing to adverse fetal effects. IMPACT: The source and role of the placenta in synthesis and/or clearance of inflammatory mediators in term pregnancies complicated by clinical chorioamnionitis are unclear; however, conventional wisdom suggests the placenta is their source. This is the first study demonstrating that circulating concentrations of fetal IL-6 and IL-8 in clinical chorioamnionitis ± birth asphyxia in term pregnancies are of fetal origin. Circulating fetal inflammatory cytokines are cleared by concentration-dependent placental mechanisms that are nearly saturated in chorioamnionitis ± fetal hypoxia. These observations provide additional insight into understanding the fetal immune response in term pregnancies complicated by clinical chorioamnionitis.

Evaluation of heterogeneity in effect of therapeutic hypothermia by sex among infants with neonatal encephalopathy.

BACKGROUND: Our objective was to examine heterogeneity in the effect of therapeutic hypothermia by sex in infants with moderate or severe neonatal encephalopathy. METHODS: We conducted a post hoc analysis of the Induced Hypothermia trial, which included infants born at gestational ages ≥36 weeks, admitted at ≤6 postnatal hours with evidence of severe acidosis or perinatal complications and moderate or severe neonatal encephalopathy. Multivariate modified Poisson regression models were used to compare the treatment effect of whole-body hypothermia versus control, with an evaluation of interaction by sex, on the primary outcome of death or moderate or severe disability at 18-22 months of corrected age. RESULTS: A total of 101 infants (51 male, 50 female) were randomly assigned to hypothermia treatment and 104 infants (64 male, 40 female) to control. The primary outcome occurred in 45% of the hypothermia group and 63% of the control group (RR 0.73; 95% CI 0.56, 0.94). There was no significant difference (interaction P = 0.50) in the treatment effect of hypothermia on the primary outcome between females (RR 0.79; 95% CI 0.54, 1.17) compared to males (RR 0.63; 95% CI 0.44, 0.91). CONCLUSION: We found no evidence that sex influences the treatment effect of hypothermia in infants with moderate or severe neonatal encephalopathy. IMPACT: Preclinical evidence suggests a differential effect in response to cooling treatment of hypoxic-ischemic injury between males and females. We found no evidence of heterogeneity in the treatment effect of whole-body hypothermia by sex in this post hoc subgroup analysis of infants with moderate or severe neonatal encephalopathy from the National Institute of Child Health and Human Development Neonatal Research Network Induced Hypothermia trial.

Placental vascular malperfusion lesions in fetal congenital heart disease.

BACKGROUND: Fetuses with congenital heart disease are at increased risk of perinatal morbidity and mortality, which is highly influenced by their prenatal health. Placental function is vital for the health of the fetus, but increased rates of pathologic lesions of the placenta have been observed in pregnancies complicated by fetal congenital heart disease. OBJECTIVE: This study aimed to determine the prevalence of both gross and histologic placental pathologies in a cohort of pregnancies complicated by fetal congenital heart disease vs healthy controls using the Amsterdam Placental Workshop Group Consensus Statement sampling and definitions of placental lesions. STUDY DESIGN: This single-center retrospective cohort study included placental examinations from pregnancies diagnosed prenatally with fetal congenital heart disease between 2010 and 2019; moreover, control placentas were collected from pregnancies without maternal or fetal complications. Placentas were sampled and evaluated according to the Amsterdam Placental Workshop Group Consensus Statement and gross and histopathologic diagnoses determined. RESULTS: Approximately 80% of fetuses diagnosed with congenital heart disease (n=305) had a placental examination for comparison with controls (n=40). Of note, 239 placentas (78%) in the group with fetal congenital heart disease had at least 1 gross or histopathologic lesion compared with 11 placentas (28%) in the control group (P<.01). One-third of placentas complicated by fetal congenital heart disease met the criteria for small for gestational age, and 48% of placentas had one or more chronic lesions, including maternal vascular malperfusion (23% vs 0%; P<.01), villitis of unknown etiology (22% vs 0%; P<.01), fetal vascular malperfusion (20% vs 0%; P<.01), and other chronic lesions (16% vs 0%; P<.01). Acute inflammation was equally present in both the group with fetal congenital heart disease and the control group (28% vs 28%; P=1.00). Although gestational age and birthweight z score were similar between the 2 groups, birth head circumference was 1.5 cm less in pregnancies complicated by fetal congenital heart disease with a significantly lower z score compared with the control group (-0.52±1.22 vs 0.06±0.69; P<.01). CONCLUSION: Vascular malperfusion lesions and chronic forms of inflammation occur at markedly higher rates in placentas complicated by fetal congenital heart disease, which may contribute to the decreased head circumference at birth. Further work in neuroplacentology is needed to explore connections among cardiac defects, placental vascular malperfusion lesions, and fetal brain development.

A neonatal neuroNICU collaborative approach to neuromonitoring of posthemorrhagic ventricular dilation in preterm infants.

Morbidity and mortality in prematurely born infants have significantly improved due to advancement in perinatal care, development of NeuroNICU collaborative multidisciplinary approaches, and evidence-based management protocols that have resulted from a better understanding of perinatal risk factors and neuroprotective treatments. In premature infants with intraventricular hemorrhage (IVH), the detrimental secondary effect of posthemorrhagic ventricular dilation (PHVD) on the neurodevelopmental outcome can be mitigated by surgical intervention, though management varies considerably across institutions. Any benefit derived from the use of neuromonitoring to optimize surgical timing and technique stands to improve neurodevelopmental outcome. In this review, we summarize (1) the approaches to surgical management of PHVD in preterm infants and outcome data; (2) neuromonitoring modalities and the effect of neurosurgical intervention on this data; (3) our resultant protocol for the monitoring and management of PHVD. In particular, our protocol incorporates cerebral near-infrared spectroscopy (NIRS) and transcranial doppler ultrasound (TCD) to better understand cerebral physiology and to enable the hypothesis-driven study of the management of PHVD. IMPACT: Review of the published literature concerning the use of near-infrared spectroscopy (NIRS) and a cerebral Doppler ultrasound to study the effect of cerebrospinal fluid drainage on infants with posthemorrhagic ventricular dilation. Presentation of our institution's evidence-based protocol for the use of NIRS and cerebral Doppler ultrasound to study the optimal neurosurgical treatment of posthemorrhagic ventricular dilation, an as yet inadequately studied area.

Neuroplacentology in congenital heart disease: placental connections to neurodevelopmental outcomes.

Children with congenital heart disease (CHD) are living longer due to effective medical and surgical management. However, the majority have neurodevelopmental delays or disorders. The role of the placenta in fetal brain development is unclear and is the focus of an emerging field known as neuroplacentology. In this review, we summarize neurodevelopmental outcomes in CHD and their brain imaging correlates both in utero and postnatally. We review differences in the structure and function of the placenta in pregnancies complicated by fetal CHD and introduce the concept of a placental inefficiency phenotype that occurs in severe forms of fetal CHD, characterized by a myriad of pathologies. We propose that in CHD placental dysfunction contributes to decreased fetal cerebral oxygen delivery resulting in poor brain growth, brain abnormalities, and impaired neurodevelopment. We conclude the review with key areas for future research in neuroplacentology in the fetal CHD population, including (1) differences in structure and function of the CHD placenta, (2) modifiable and nonmodifiable factors that impact the hemodynamic balance between placental and cerebral circulations, (3) interventions to improve placental function and protect brain development in utero, and (4) the role of genetic and epigenetic influences on the placenta-heart-brain connection. IMPACT: Neuroplacentology seeks to understand placental connections to fetal brain development. In fetuses with CHD, brain growth abnormalities begin in utero. Placental microstructure as well as perfusion and function are abnormal in fetal CHD.

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

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

Early brain and abdominal oxygenation in extremely low birth weight infants.

BACKGROUND: Extremely low birth weight (ELBW) infants are at risk for end-organ hypoxia and ischemia. Regional tissue oxygenation of the brain and gut as monitored with near-infrared spectroscopy (NIRS) may change with postnatal age, but normal ranges are not well defined. METHODS: A prospective study of ELBW preterm infants utilized NIRS monitoring to assess changes in cerebral and mesenteric saturation (Csat and Msat) over the first week after birth. This secondary study of a multicenter trial comparing hemoglobin transfusion thresholds assessed cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE) and relationships with perinatal variables. RESULTS: In 124 infants, both Csat and Msat declined over the first week, with a corresponding increase in oxygen extraction. With lower gestational age, lower birth weight, and 5-min Apgar score ≤5, there was a greater increase in oxygen extraction in the brain compared to the gut. Infants managed with a lower hemoglobin transfusion threshold receiving ≥2 transfusions in the first week had the lowest Csat and highest cFTOE (p < 0.001). CONCLUSION: Brain oxygen extraction preferentially increased in more immature and anemic preterm infants. NIRS monitoring may enhance understanding of cerebral and mesenteric oxygenation patterns and inform future protective strategies in the preterm ELBW population. IMPACT: Simultaneous monitoring of cerebral and mesenteric tissue saturation demonstrates the balance of oxygenation between preterm brain and gut and may inform protective strategies. Over the first week, oxygen saturation of the brain and gut declines as oxygen extraction increases. A low hemoglobin transfusion threshold is associated with lower cerebral saturation and higher cerebral oxygen extraction compared to a high hemoglobin transfusion threshold, although this did not translate into clinically relevant differences in the TOP trial primary outcome. Greater oxygen extraction by the brain compared to the gut occurs with lower gestational age, lower birth weight, and 5-min Apgar score ≤5.

Differential cortical microstructural maturation in the preterm human brain with diffusion kurtosis and tensor imaging.

During the third trimester, the human brain undergoes rapid cellular and molecular processes that reshape the structural architecture of the cerebral cortex. Knowledge of cortical differentiation obtained predominantly from histological studies is limited in localized and small cortical regions. How cortical microstructure is differentiated across cortical regions in this critical period is unknown. In this study, the cortical microstructural architecture across the entire cortex was delineated with non-Gaussian diffusion kurtosis imaging as well as conventional diffusion tensor imaging of 89 preterm neonates aged 31-42 postmenstrual weeks. The temporal changes of cortical mean kurtosis (MK) or fractional anisotropy (FA) were heterogeneous across the cortical regions. Cortical MK decreases were observed throughout the studied age period, while cortical FA decrease reached its plateau around 37 weeks. More rapid decreases in MK were found in the primary visual region, while faster FA declines were observed in the prefrontal cortex. We found that distinctive cortical microstructural changes were coupled with microstructural maturation of associated white matter tracts. Both cortical MK and FA measurements predicted the postmenstrual age of preterm infants accurately. This study revealed a differential 4D spatiotemporal cytoarchitectural signature inferred by non-Gaussian diffusion barriers inside the cortical plate during the third trimester. The cytoarchitectural processes, including dendritic arborization and neuronal density decreases, were inferred by regional cortical FA and MK measurements. The presented findings suggest that cortical MK and FA measurements could be used as effective imaging markers for cortical microstructural changes in typical and potentially atypical brain development.

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

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

Nitric oxide and the brain. Part 1: Mechanisms of regulation, transport and effects on the developing brain.

Apart from its known actions as a pulmonary vasodilator, nitric oxide (NO) is a key signal mediator in the neonatal brain. Despite the extensive use of NO for pulmonary artery hypertension (PAH), its actions in the setting of brain hypoxia and ischemia, which co-exists with PAH in 20-30% of affected infants, are not well established. This review focuses on the mechanisms of actions of NO covering the basic, translational, and clinical evidence of its neuroprotective and neurotoxic properties. In this first part, we present the physiology of transport and delivery of NO to the brain and the regulation of cerebrovascular and systemic circulation by NO, as well the role of NO in the development of the immature brain. IMPACT: NO can be transferred from the site of production to the site of action rapidly and affects the central nervous system. Inhaled NO (iNO), a commonly used medication, can have significant effects on the neonatal brain. NO regulates the cerebrovascular and systemic circulation and plays a role in the development of the immature brain. This review describes the properties of NO under physiologic conditions and under stress. The impact of this review is that it describes the effects of NO, especially regarding the vulnerable neonatal brain, and helps understand the conditions that could contribute to neurotoxicity or neuroprotection.

Nitric oxide and the brain. Part 2: Effects following neonatal brain injury-friend or foe?

Nitric oxide (NO) has critical roles in a wide variety of key biologic functions and has intricate transport mechanisms for delivery to key distal tissues under normal conditions. However, NO also plays important roles during disease processes, such as hypoxia-ischemia, asphyxia, neuro-inflammation, and retinopathy of prematurity. The effects of exogenous NO on the developing neonatal brain remain controversial. Inhaled NO (iNO) can be neuroprotective or toxic depending on a variety of factors, including cellular redox state, underlying disease processes, duration of treatment, and dose. This review identifies key gaps in knowledge that should prompt further investigation into the possible role of iNO as a therapeutic agent after injury to the brain. IMPACT: NO is a key signal mediator in the neonatal brain with neuroprotective and neurotoxic properties. iNO, a commonly used medication, has significant effects on the neonatal brain. Dosing, duration, and timing of administration of iNO can affect the developing brain. This review article summarizes the roles of NO in association with various disease processes that impact neonates, such as brain hypoxia-ischemia, asphyxia, retinopathy of prematurity, and neuroinflammation. The impact of this review is that it clearly describes gaps in knowledge, and makes the case for further, targeted studies in each of the identified areas.

Placental origins of neonatal diseases: toward a precision medicine approach.

The placenta is the single most reliable source for precise information on intrauterine environment, as well as maternal and fetal health. It mediates the physiology of two distinct yet highly interconnected individuals. The pathology that develops in the placenta, and the adaptations the placenta undergoes to mitigate this pathology, may influence the later life health of the mother and baby. Pathological placental examination provides a unique opportunity to explore and understand the intrauterine environment, as well as providing a record of events that may be associated with adverse pregnancy outcomes. A number of placental lesions have been described in association with various neonatal morbidities. The purpose of this review is to summarize the evidence for the association of placental pathologic lesions with neurodevelopmental outcomes infants with specific neonatal morbidities, including (1) neonatal encephalopathy, (2) bronchopulmonary dysplasia, (3) congenital heart diseases, and (4) autism spectrum disorders. For each of these disease processes, we will also propose specific research priorities in future studies. We conclude with a hospital-specific protocol for triaging which placentas should receive histological evaluation as a fundamental first step for the field of neuroplacentology to guide precision-based therapeutic approaches in the affected newborns. IMPACT: The purpose of this review is to summarize the evidence for placental origins of neonatal diseases. We propose specific research priorities in the field of neuroplacentology in future studies. We also present a targeted hospital-based approach for triaging which placentas should receive histological evaluation.

Regional heterogeneity of cerebral hemodynamics in mild neonatal encephalopathy measured with multichannel near-infrared spectroscopy.

BACKGROUND: Neuromonitoring at the bedside is the key to understand the pathophysiological mechanisms of brain injury associated with neonatal encephalopathy. The current practice is to monitor the forehead using a noninvasive cerebral oximetry-it remains unknown to what extent cerebral hemodynamics in other brain regions is different to the frontal region. METHOD: A multichannel near-infrared spectroscopy (NIRS) system was used to monitor neonates (n = 14) with fetal acidosis and mild neonatal encephalopathy at four brain regions (the frontal, posterior, left temporal, and right temporal lobes). The data were compared to delineate the regional difference in (1) cerebral hemodynamics and (2) pressure autoregulation. For both analyses, wavelet transform coherence was applied. RESULTS: We observed frontal-posterior heterogeneity as indicated by significantly lower coherence between these two regions (p = 0.02). Furthermore, areas with regional magnetic resonance imaging (MRI)-detected lesions showed greater hemodynamic variations compared to non-affected areas (p = 0.03), while cerebral autoregulation was not affected and showed no difference. CONCLUSION: Cerebral hemodynamics in mild neonatal encephalopathy is heterogeneous across different brain regions, while cerebral autoregulation remains intact. These findings indicate the robustness of the wavelet measure of cerebral autoregulation in this population, but need to be further investigated in the presence of severe injury. IMPACT: This proof-of-concept study is the first to investigate the regional difference of cerebral hemodynamics and autoregulation in mild neonatal encephalopathy. Study findings confirm that brain functions are complex in the developing neonatal brain and that cerebral hemodynamics are region specific in newborns with frontal-posterior heterogeneity among brain regions probed by multichannel NIRS. Regional MRI lesions were associated with differences across NIRS regional channels among the affected side. Cerebral autoregulation with multichannel NIRS is not affected by regional MRI abnormalities.