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.

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.

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.

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.

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.

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.

Autism spectrum disorders in extremely preterm infants and placental pathology findings: a matched case-control study.

BACKGROUND: The prevalence of autism spectrum disorders (ASD) is 5-fold higher in preterm (PT) infants born ≤28 weeks gestational age (GA) as compared to the general population. The relationship between placental pathologic lesions and ASD in PT infants has not been studied. OBJECTIVES: The objective of this study was to determine the association of placental pathology with the occurrence of ASD in PT infants born ≤28 weeks GA. STUDY DESIGN: A matched case-control study to identify confirmed ASD cases (n = 16) and matched controls (n = 48) born at Parkland Hospital between January 2012 and December 2015. Patients were matched using known variables associated with increased risk of ASD in PT infants. Placental histology from all births was reviewed. RESULTS: Children with ASD had 2-fold greater incidence of multiple placental pathologic lesions vs. matched controls [11/16 (69%) vs.16/48 (33%), respectively; P = 0.01]. In contrast, single placental pathologic lesions were not associated with ASD [5/16 (31%) vs. 21/48 (43%), respectively; P = 0.1]. CONCLUSIONS: In this study, we have demonstrated an association between the increasing complexity of histologic placental lesions and the later risk for ASD in infants born ≤28 weeks GA. Thus, placental pathology findings may be valuable in further understanding the prenatal pathologic processes underlying ASD in PT infants. IMPACT: PT infants with ASD have a 2-fold greater incidence of multiple placental pathologies. This is the first study to report an association between the complexity of histologic placental lesions and later risk of ASD in infant born extremely PT (i.e., ≤28 weeks GA). This study reiterates the importance of examining placental pathologic lesions, since placental evidence of antenatal insults correlates with postnatal morbidities and mortality in PT infants.

Cerebral Oxygenation and Autoregulation in Preterm Infants (Early NIRS Study).

OBJECTIVE: To determine if decreased cerebral oxygenation or altered cerebral autoregulation as measured by near-infrared spectroscopy (NIRS) in the first 96 postnatal hours is associated with an increased risk of death or severe neuroradiographic abnormalities in very preterm infants. STUDY DESIGN: The Early NIRS prospective, multicenter study enrolled very preterm infants with a birth weight of <1250 g from 6 tertiary neonatal intensive care units. Mean arterial blood pressure and cerebral oxygen saturation (Csat) were continuously monitored using a neonatal sensor until 96 hours of age. Moving window correlations between Csat and mean arterial blood pressure determined time periods with altered cerebral autoregulation, and percentiles of correlation were compared between infants with and without the adverse outcome of mortality or severe neuroradiographic abnormalities by early cranial ultrasound. RESULTS: Of 103 subjects with mean gestational age of 26 weeks, 21 (20%) died or had severe neuroradiographic abnormalities. Infants with adverse outcomes had a lower mean Csat (67 ± 9%) compared with those without adverse outcomes (72 ± 7%; P = .02). A Csat of <50% was identified as a cut-point for identifying infants with adverse outcome (area under the curve, 0.76). Infants with adverse outcomes were more likely to have significant positive or negative correlations between Csat and mean arterial blood pressure, indicating impaired cerebral autoregulation (P = .006). CONCLUSIONS: Early NIRS monitoring may detect periods of lower cerebral oxygenation and altered cerebral autoregulation, identifying preterm infants at risk for mortality or neuroradiographic injury. An improved understanding of the relationship between altered hemodynamics and cerebral oxygenation may inform future strategies to prevent brain injury.

Inter-rater reliability of the modified Sarnat examination in preterm infants at 32-36 weeks' gestation.

OBJECTIVE: To test the inter-rater reliability of the modified Sarnat neurologic examination in preterm neonates and to correlate abnormalities with the presence of perinatal acidosis. METHODS: Prospective study of 32-36 weeks' gestational age infants admitted to the neonatal intensive care unit. Each infant had two Sarnat examinations performed at <6 h, one by a gold standard (GS) study investigator, and the second either by (a) another GS examiner or (b) an attending physician (28 examiners), all blinded to clinical variables. Agreement was calculated using kappa (k) statistics. RESULTS: One hundred and two (9, fetal acidosis) infants underwent a modified Sarnat examination. Among GS examiners, agreement was excellent (k > 0.8) except for Moro, while among all examiners agreement was very good (k > 0.7) except for both Moro and tone. Subgroup analysis at 32-34 weeks' showed fair/poor Moro compared to excellent agreement at ≥35 weeks. Increasing abnormalities correlated with acidosis (r = -0.6, P < 0.01). CONCLUSIONS: Strong inter-rater reliability for the modified Sarnat was observed except for tone and Moro in preterm infants. Experience of the examiners resulted in improved reliability in tone, while for the Moro agreement improved only beyond 35 weeks. Findings suggest the need of adjustment of the examination form specific for preterm infants.

Impact of multiple placental pathologies on neonatal death, bronchopulmonary dysplasia, and neurodevelopmental impairment in preterm infants.

BACKGROUND: To determine the association of placental pathology, including multiple placental lesions, with the occurrence and severity of bronchopulmonary dysplasia (BPD), death, and neurodevelopmental impairment (NDI) in preterm infants. METHOD: A retrospective cohort study of neonates <29 weeks gestational age (GA) born at Parkland Hospital from 08/2009 to 08/2012. Infants were stratified as follows: Group 1: no significant placental pathology; Group 2: single significant placental lesion; and Group 3: ≥2 placental lesions (multiple lesions). Primary outcome was death and/or BPD. Two-year neurodevelopmental follow-up was compared. RESULTS: In all, 42% (100/241) of infants had one placental lesion, and 34% (82/241) ≥2 lesions. As the number of the pathologic lesions increased (no lesions vs. 1 vs. ≥2), the occurrence of death or BPD increased (25%, 37%, and 52%, respectively; P = 0.004). Moreover, infants with multiple pathologic lesions were more likely to have NDI (29%, 29%, and 46%, respectively; P = 0.03). After logistic regression, infants with multiple pathologic lesions were more likely to develop moderate-to-severe BPD [P < 0.01; OR 3.9 (1.5-10.1)] but not NDI. CONCLUSION(S): Neonates <29 weeks GA with multiple placental pathologic lesions have an increased risk for developing BPD, suggesting an interaction between placental inflammation and vascular pathology and the pathogenesis of BPD; however, the risk of NDI is not increased.

A Total Sarnat Score in Mild Hypoxic-ischemic Encephalopathy Can Detect Infants at Higher Risk of Disability.

To define mild hypoxic-ischemic encephalopathy and distinguish infants at risk of disability in the first 6 hours, this study stratified risk of disability by using early neurologic examination findings of infants enrolled in the Prospective Research for Infants with Mild Encephalopathy cohort. A total Sarnat score of ≥5 when performed at <6 hours of age detected future disability. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01747863.

Placental clearance/synthesis of neurobiomarkers GFAP and UCH-L1 in healthy term neonates and those with moderate-severe neonatal encephalopathy.

BACKGROUND: Fetal concentrations of GFAP and UCH-L1 are elevated in umbilical arterial (UmA) blood of neonates with birth asphyxia plus neonatal encephalopathy (NE), but their source and role of placental clearance/synthesis is unknown. METHODS: Prospective cohort study of term neonates to (a) determine UmA and venous (UmV) blood concentrations of GFAP and UCH-L1 in term uncomplicated pregnancies and their placental synthesis and/or clearance and (b) compare UmA concentrations in uncomplicated pregnancies with those complicated by fetal hypoxia-asphyxia+NE. Three term groups were studied: uncomplicated cesarean delivery without labor (Group 1, n = 15), uncomplicated vaginal delivery with labor (Group 2, n = 15), and perinatal hypoxia-asphyxia+NE (Group 3, n = 8). RESULTS: UmA GFAP concentrations were lower in Group 1 vs. 2 (P = 0.02) and both demonstrated 100% placental clearance. In contrast, UmA and UmV UCH-L1 concentrations were not unaffected by labor. Group 3 UmA GFAP concentrations were 30- and 8-fold higher than Groups 1 and 2, respectively, P = 0.02, whereas UmA UCH-L1 concentrations were similar in all groups. CONCLUSIONS: UmA GFAP is derived from the fetus, and circulating levels, which are modulated by placental clearance, increase during uncomplicated labor and more so in the presence of fetal hypoxia-asphyxia+NE, providing a better biomarker than UCH-L1 for hypoxia-asphyxia+NE.

Should therapeutic hypothermia be offered to babies with mild neonatal encephalopathy in the first 6 h after birth?

Infants with moderate to severe neonatal encephalopathy (NE) benefit significantly from therapeutic hypothermia, with reduced risk of death or disability. However, the need for therapeutic hypothermia for infants with milder NE remains unclear. It has been suggested that these infants should not be offered therapeutic hypothermia as they may not be at risk for adverse neurodevelopmental outcome and that the balance of risk against potential benefit is unknown. Several key questions need to be answered including first, whether one can define NE in the first 6 h after birth so as to accurately distinguish infants with brain injury who may be at risk for adverse neurodevelopmental consequences. Second, will treatment of infants with mild NE with therapeutic hypothermia improve or even worsen neurological outcomes? Although alternate treatment protocols for mild NE may be feasible, the use of the current approach combined with rigorous avoidance of hyperthermia and initiation of hypothermia as early as possible after birth may promote optimal outcomes. Animal experimental data support the potential for greater benefit for mild HIE compared with moderate to severe HIE. This review will summarize current knowledge of mild NE and the challenges to a trial in this population.

Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months.

BACKGROUND: Studies of early childhood outcomes of mild hypoxic-ischemic encephalopathy (HIE) identified in the first 6 h of life are lacking. OBJECTIVE: To evaluate neurodevelopmental outcomes at 18-22 months of PRIME study. STUDY DESIGN: Multicenter, prospective study of mild HIE defined as ≥1 abnormality using the modified Sarnat within 6 h of birth and not meeting cooling criteria. Primary outcome was disability with mild: Bayley III cognitive 70-84 or ≥85 and either Gross Motor Function Classification System (GMFCS) 1 or 2, seizures, or hearing deficit; moderate: cognitive 70-84 and either GMFCS 2, seizures, or hearing deficit; severe: cognitive <70, GMFCS 3-5. RESULTS: Of the 63 infants enrolled, 51 (81%) were evaluated at 19 ± 2 months and 43 (68%) completed Bayley III. Of the 43 infants, 7 (16%) were diagnosed with disability, including 1 cerebral palsy and 2 autism. Bayley scores < 85 in either cognition, motor, or language were detected in 17 (40%): 14 (32%) language, 7 (16%) cognitive, and 6 (14%) motor domain. Infants with disability had more abnormalities on discharge examination and brain MRI, with longer hospital stay (p < 0.001). CONCLUSIONS: In this contemporary untreated cohort of mild HIE, disability occurred in 16% of infants at 18-22 months.

New Wavelet Neurovascular Bundle for Bedside Evaluation of Cerebral Autoregulation and Neurovascular Coupling in Newborns with Hypoxic-Ischemic Encephalopathy.

Neonatal encephalopathy (NE) resulting from birth asphyxia constitutes a major global public health burden for millions of infants every year, and despite therapeutic hypothermia, half of these neonates have poor neurological outcomes. As new neuroprotective interventions are being studied in clinical trials, there is a critical need to establish physiological surrogate markers of therapeutic efficacy, to guide patient selection and/or to modify the therapeutic intervention. The challenge in the field of neonatal brain injury has been the difficulty of clinically discerning NE severity within the short therapeutic window after birth or of analyzing the dynamic aspects of the cerebral circulation in sick NE newborns. To address this roadblock, we have recently developed a new "wavelet neurovascular bundle" analytical system that can measure cerebral autoregulation (CA) and neurovascular coupling (NVC) at multiple time scales under dynamic, nonstationary clinical conditions. This wavelet analysis may allow noninvasive quantification at the bedside of (1) CA (combining metrics of blood pressure and cerebral near-infrared spectroscopy, NIRS) and (2) NVC (combining metrics obtained from NIRS and EEG) in newborns with encephalopathy without mathematical assumptions of linear and stationary systems. In this concept paper, we present case examples of NE using the proposed physiological wavelet metrics of CA and NVC. The new approach, once validated in large NE studies, has the potential to optimize the selection of candidates for therapeutic decision-making, and the prediction of neurocognitive outcomes.

Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

Importance: Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. Objective: To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants: A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. Interventions: Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). Main Outcomes and Measures: The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. Results: Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, -1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively. Conclusions and Relevance: Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness. Trial Registration: clinicaltrials.gov Identifier: NCT00614744.

Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

IMPORTANCE: Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high. OBJECTIVE: To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS: Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks' gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. INTERVENTIONS: A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83). MAIN OUTCOMES AND MEASURES: The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. RESULTS: The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, -1.0% [95% CI, -10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, -3.1% [95% CI, -12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours. CONCLUSIONS AND RELEVANCE: Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01192776.

T1 and T2 values of human neonatal blood at 3 Tesla: Dependence on hematocrit, oxygenation, and temperature.

PURPOSE: Knowledge of blood T1 and T2 is of major importance in many applications of MRI in neonates. However, to date, there has not been a systematic study to examine neonatal blood T1/T2 relaxometry. This present study aims to investigate this topic. METHODS: Using freshly collected blood samples from human umbilical cord, we performed in vitro experiments under controlled physiological conditions to measure blood T1 and T2 at 3 Tesla (T) and their dependence on several factors, including hematocrit (Hct), oxygenation (Y) and temperature. RESULTS: The arterial T1 in neonates was 1825 ± 184 ms (Hct = 0.42 ± 0.08), longer than that of adult blood. Neonatal blood T1 was strongly dependent on Hct (P < 0.001) and Y (P = 0.005), and the dependence of T1 on Y was more prominent at higher Hct. The arterial T2 of neonatal blood was 191 ms at an Hct of 0.42, which was also longer than adult blood. Neonatal blood T2 was positively associated with blood oxygenation and negatively associated with hematocrit level, and can be characterized by an exchange model. Neonatal blood T1 was also positively associated with temperature (P < 0.001). CONCLUSION: The values provided in this report may provide important reference and calibration information for sequence optimization and quantification of in vivo neonatal MRI studies.