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Neonatal hypoxic-ischemic encephalopathy (HIE) causes permanent motor deficit "cerebral palsy (CP)," and may result in significant disability and death. Therapeutic hypothermia (TH) had been established as the first effective therapy for neonates with HIE; however, TH must be initiated within the first 6 hours after birth, and the number needed to treat is from 9 to 11 to prevent brain damage from HIE. Therefore, additional therapies for HIE are highly needed. In this review, we provide an introduction on the mechanisms of HIE cascade and how TH and cell therapies such as umbilical cord blood cells and mesenchymal stromal cells (MSCs), especially umbilical cord-derived MSCs (UC-MSCs), may protect the brain in newborns, and discuss recent progress in regenerative therapies using UC-MSCs for neurological disorders.The brain damage process "HIE cascade" was divided into six stages: (1) energy depletion, (2) impairment of microglia, (3) inflammation, (4) excitotoxity, (5) oxidative stress, and (6) apoptosis in capillary, glia, synapse and/or neuron. The authors showed recent 13 clinical trials using UC-MSCs for neurological disorders.The authors suggest that the next step will include reaching a consensus on cell therapies for HIE and establishment of effective protocols for cell therapy for HIE. KEY POINTS: · This study includes new insights about cell therapy for neonatal HIE and CP in schema.. · This study shows precise mechanism of neonatal HIE cascade.. · The mechanism of cell therapy by comparing umbilical cord blood stem cell with MSC is shown.. · The review of recent clinical trials of UC-MSC is shown..

Objective Infants with a history of neonatal hypoxic-ischemic encephalopathy (HIE) are at risk for oral motor dysfunction. Previous studies have associated the need for gastrostomy tube at neonatal intensive care unit discharge with brainstem injury on magnetic resonance imaging (MRI). However, the factors associated with time to full oral feeds in this population have not been previously described. This study aimed to study factors associated with time to full oral feeds in this population. Study design This is a single-center, retrospective study that examined these factors using Cox regression. Results A total of 150 infants who received therapeutic hypothermia from 2011 to 2017 were included in this study. The single clinical factor significantly associated with time to full oral feeds was the severity of background abnormality on electroencephalogram in the first 24 hours of age (severe vs. mild 95% confidence interval [CI]: 0.34-0.74; moderate vs. mild 95% CI: 0.19-0.45). Brainstem injury on MRI was the factor most highly associated with need for gastrostomy tube placement (p = 0.028), though the overall incidence of need for gastrostomy tube feeds in this population was low (5%). Conclusion These findings may help clinicians counsel families on what to expect in neonates with HIE and make decisions on the need for and timing to pursue gastrostomy tube in this population. Key points · The overall incidence of the need for assisted feeding at NICU discharge is low in this population.. · MRI brainstem injury was most highly associated with need for gastrostomy tube placement.. · Worsening severity of background abnormality on EEG was associated with longer time to oral feeds..

Background When the newborn brain is exposed to hypoxia, as in hypoxic ischemic encephalopathy (HIE), it causes an inflammatory response. A wide variety of inflammatory markers are therefore used in the diagnosis of HIE. Objective We aimed to determine the diagnostic role of systemic inflammatory indices in infants with moderate-to-severe HIE. We have also investigated the effect of hypothermia treatment over those indices. Study Design A retrospective cohort study of infants suffering from moderate-to-severe HIE was conducted in a tertiary-level neonatal intensive care unit between September 2019 and March 2021. Systemic inflammatory indices including systemic immune-inflammation index (SII), pan-immune-inflammation value (PIV), systemic inflammation response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) were calculated for infants with HIE and controls at baseline, and after therapeutic hypothermia in those with HIE. Results A total of 103 infants (53 in the HIE group and 50 in the control group) were included in the study. Median gestational ages (GA) were 39 (37–40) and 38 (37–39) weeks, and median birth weights (BW) were 3,165 (2,890–3,440) and 3,045 (2,850–3,460) g in the HIE and control groups, respectively. GA, BW, mode of delivery, and gender of infants were similar between the groups. Infants in the HIE group had significantly higher NLR (p = 0.001), SII (p = 0.001), PIV (p = 0.001), and SIRI (p = 0.004) values when compared with the control group. Those indices decreased significantly after hypothermia treatment in the HIE group. Areas under curve for NLR, PLR, MLR, SII, SIRI, and PIV to predict HIE were found to be 0.808, 0.597, 0.653, 0.763, 0.686, and 0.663, respectively. Cutoff values having a good ability to predict HIE for SII and NLR were 410 and 1.12. Elevated NLR level above 1.12 was found to be an independent predictor for HIE, as revealed by multivariate analyses. No associations were found between systemic inflammatory indices and amplitude-integrated electroencephalography (aEEG) patterns, presence of seizures, and death. Conclusion Systemic inflammatory indices may represent reliable and readily available predictors of HIE risk. NLR seems to be an independent factor in diagnosing moderate-to-severe HIE. Key Points

Objective Describe the association between cardiac dysfunction and death or moderate-to-severe abnormalities on brain magnetic resonance imaging (MRI) in neonates undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE). Study design Retrospective study in neonates with moderate or severe HIE undergoing therapeutic hypothermia between 2008 and 2017. Primary outcome was death or moderate-to-severe brain injury using the Barkovich score. Conventional and speckle-tracking echocardiography measures were extracted from available echocardiograms to quantify right (RV) and left (LV) ventricular functions. Results A total of 166 newborns underwent therapeutic hypothermia of which 53 (36.5%) had echocardiography performed. Ten (19%) died prior to hospital discharge, and 11 (26%) had moderate-to-severe brain injury. There was no difference in chronologic age at echocardiography between the normal and adverse outcome groups (22 [±19] vs. 28 [±21] hours, p = 0.35). Cardiac findings in newborns with abnormal outcome included lower systolic and diastolic blood pressure (BP) at echocardiography (p = 0.004) and decreased tricuspid annular plane systolic excursion (a marker of RV systolic function; p = 0.01), while the ratio of systolic pulmonary artery (PA) pressure to systolic BP indicated isosystemic pressures (>2/3 systemic) in both groups. A multilogistic regression analysis, adjusting for weight and seizure status, indicated an association between abnormal outcome and LV function by longitudinal strain, as well as by ejection fraction. Conclusion Newborns who died or had moderate-to-severe brain injury had a higher incidence of cardiac dysfunction but similar PA pressures when compared with those who survived with mild or no MRI abnormalities. Key points · Newborns with HIE with functional LV/RV dysfunction are at risk for death or brain injury.. · All neonates with HIE had elevated pulmonary pressure, but neonates with poor outcome had RV dysfunction.. · When evaluating newborns with HIE by echocardiography, beyond estimation of pulmonary pressure, it is important to assess biventricular function..

Objective Elevation of serum troponin I has been reported in newborns with hypoxic ischemic encephalopathy (HIE), but it is diagnostic and prognostic utility for newborn under 6 hours is not clear. Study the predictive value of early serum troponin I levels in newborns with HIE undergoing therapeutic hypothermia (TH) for persistent residual encephalopathy (RE) at discharge. Study Design Retrospective chart review of newborns admitted with diagnosis of HIE to neonatal intensive care unit (NICU) for TH over a period of 3 years. Troponin levels were drawn with the initial set of admission laboratories while initiating TH. Newborns were followed up during hospital course and stratified into three groups based on predischarge examination and their electrical encephalography and cranial MRI findings: Group 1: no RE, Group 2: mild-to-moderate RE, and Group 3: severe RE or needing assisted medical technology or death. Demographic and clinical characteristics including troponin I levels were compared in each group. Results Out of 104 newborns who underwent TH, 65 infants were in Group 1, 26 infants in Group 2, and 13 newborns in Group 3. All groups were comparable in demographic characteristics. There was a significant elevation of serum troponin in group 2 (mild-to-moderate RE) and group 3 (severe RE) as compared with group 1 (no RE). Receiver operator curve analysis for any RE (groups 2 and 3) compared with group 1 (no RE as control) had 0.88 (0.81–0.95) area under curve, p Conclusion In newborns undergoing TH for HIE, the elevation of troponin within 6 hours of age predicts high risk of having RE at discharge. Key Points

Hypoxic-ischemic encephalopathy (HIE) is the main cause of long-term neurodevelopmental morbidity in term born infants worldwide. Melatonin is a hormone with antioxidant and anti-inflammatory effects that make it a promising molecule for the treatment of perinatal asphyxia. Probably, the synergistic use of hypothermia associated with melatonin treatment may improve the neurological outcome in infants with HIE. In the past 20 years, the efficacy of melatonin in reducing oxidative stress has been demonstrated in animals; however, clinical trials with sufficient sample size of newborns are lacking to date. Since in 2000 we were among the first to study the neuroprotective properties of melatonin on infants, in this review, we want to summarize the advantages and limitations of the investigations conducted to date. KEY POINTS: · HIE is the main cause of morbidity in term born infants worldwide.. · Melatonin is a promising molecule for the treatment of perinatal asphyxia.. · This review summarizes advantages and limitations of the investigations conducted on melatonin..

Objective Therapeutic hypothermia (TH) is currently the only effective therapy available to improve outcomes in neonates with hypoxic-ischemic encephalopathy (HIE) and has maximal effect when initiated within 6 hours of birth. Neonates affected by HIE are commonly born outside of cooling centers and transport is a barrier to timely initiation. In this study, we sought to determine if the initiation of servo-controlled TH in transport allowed neonates to reach target temperature earlier, without a significant delay in the transfer process, for both local and long-distance transport. Study Design In this single-center cohort study of neonates referred to a level IV neonatal intensive care unit for TH, we determined the chronologic age at which target temperature was reached for those cooled in transport. Short-term outcome measures were assessed, including survival, incidence of electrographic seizures, discharge feeding method, and length of hospitalization. Results In a study population of 85 neonates, those receiving TH during transport (n = 23), achieved target temperature (33–34°C) 77 minutes sooner (230 ± 71 vs. 307 ± 79 minutes of life (MOL); p Conclusion For those starting TH in transport, time to target temperature was decreased. In our cohort, cooling in transport was associated with improved short-term outcomes, although additional studies are needed to correlate these findings with long-term outcomes. Key Points

Objective This study aimed to assess risk for fetal acidemia, low Apgar scores, and hypoxic ischemic encephalopathy based on decision-to-incision time interval in the setting of emergency cesarean delivery. Study Design This unplanned secondary analysis of the Maternal–Fetal Medicine Units prospective observational cesarean registry dataset evaluated risk for hypoxic ischemic encephalopathy, umbilical cord pH ≤7.0, and Apgar score ≤4 at 5 minutes based on decision-to-incision time for emergency cesarean deliveries. Cesarean occurring for nonreassuring fetal heart rate monitoring, bleeding previa, nonreassuring antepartum testing, placental abruption, or cord prolapse was classified as emergent. Decision-to-incision time was categorized as Results Of 5,784 women included in the primary analysis, 12.4% had a decision-to-incision interval ≤10 minutes, 20.2% 11 to 20 minutes, 14.9% 21 to 30 minutes, 18.2% 31 to 50 minutes, and 16.5% >50 minutes. Risk for umbilical cord pH ≤7.0 was highest at ≤10 and 11 to 20 minutes (10.2 and 7.9%, respectively), and lowest at 21 to 30 minutes (3.9%), 31 to 50 minutes (3.9%), and >50 minutes (3.5%) (p 50 minutes (2.0%) (p Conclusion Shorter decision-to-incision times were associated with increased risk for adverse outcomes in the setting of emergency cesarean. Key Points

Objective This study evaluates the effect of admission characteristics of uncomplicated moderate to late preterm infants on timing of discharge. One of the first questions that families of infants admitted to the Neonatal Intensive Care Unit (NICU) ask is, “When is my baby going home?” Moderate to late preterm infants are the largest cohort of NICU patients but little data exist about their length of stay (LOS).Study Design A retrospective electronic chart review was completed on 12,498 infants admitted to our NICU between January 1, 2009 and December 31, 2015. All inborn infants with a gestational age between 320/7 and 366/7 weeks were studied.Results A total of 3,240 infants met our inclusion criteria. The mean postmenstrual age at discharge was 363/7 weeks. Infants who were small for gestational age were significantly more likely to have an increased LOS. Infants born between 34 and 366/7 weeks had a significantly increased LOS if they had respiratory distress syndrome. Admission diagnoses of neonatal abstinence syndrome, meconium aspiration syndrome, hydrops, hypoxic ischemic encephalopathy, biliary emesis, ABO incompatibly, and a genetic diagnosis all had increased LOS for all late preterm infants.Conclusion For uncomplicated moderate to late preterm infants, clinicians can counsel families that their infants will likely be discharged at 36 weeks of postmenstrual age. Small for gestational age infants and those with specific diagnoses may stay longer.

Objective This study aimed to determine the degree to which whole-body hypothermia (WBH) impacts hemodynamic and respiratory status during hypothermia and the subsequent rewarming period in neonates with hypoxic–ischemic encephalopathy (HIE). Study Design This is a retrospective study reviewing the medical records of infants treated with WBH. Data including oxygenation index (OI), ventilator efficiency index (VEI), fraction of inspired oxygen (FiO2), blood lactate level, heart rate (HR), and mean blood pressure (MBP) were collected from defined time points from the beginning, middle, and end of WBH and then every 2 hours from the beginning of rewarming for 14 hours thereafter. The analysis included 65 infants. Data were analyzed using a piecewise linear regression with a mixed-effect model. Results HR decreased during WBH and significantly increased during rewarming. Lactate level, OI, VEI, FiO2, and MBP all decreased during WBH but showed no significant change during and after rewarming. Conclusion There was a decrease in metabolic demand as measured by oxygen requirement, OI, HR, and MBP during WBH, but only HR increased during rewarming, with no significant change in the other parameters. Some of this effect may be explained by improvement in the respiratory condition over time.

Objective This study aimed to compare the utility of electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) to detect brain dysfunction and injury across a cohort of newborn infants treated with selective head cooling (SHC) or whole body cooling (WBC). Study Design Therapeutic hypothermia (TH) is a standard neuroprotection tool for hypoxic-ischemic encephalopathy (HIE) in neonates. Sixty-six newborns, SHC (n = 22) and WBC (n = 44), were studied utilizing standardized scoring systems for interpretation of EEG and MRI based on the severity of the findings. Results SHC- and WBC-treated groups did not differ significantly amongst most of the baseline parameters. EEGs obtained postcooling were abnormal in 58 of 61 (95%) infants. The severity of the EEG background changes (depressed and undifferentiated background) was more prevalent in the SHC (8/21 [38%]) than in the WBC group (5/40 [13%]). Brain MRIs showed HIE changes in 26 of 62 (42%) newborns treated with TH. MRI abnormalities of basal ganglia, thalamic, and parenchymal lesions were more common in the SHC (5/19) versus the WBC group (3/43); p = 0.04. Conclusion EEG abnormalities and MRI findings of HIE were more prevalent in the SHC than in the WBC group. WBC may offer better or at least similar neuroprotection to infants with HIE.

Objective This study aimed to describe normal C-reactive protein (CRP) levels of newborns diagnosed with hypoxic-ischemic encephalopathy (HIE) and assess the influence of therapeutic hypothermia (TH) and the severity of HIE. Study Design We prospectively recruited infants ≥35 weeks of gestational age diagnosed with HIE from 2000 to 2013 and compared CRP levels in the first 120 hours of life according to the severity of HIE and the use of TH, which was introduced in 2009. Results Moderate HIE was diagnosed in 115 newborns, severe HIE in 90 (hypothermia was performed in 151 cases), and mild HIE in 20. Cooled newborns showed lower levels of CRP in the first 34 hours, but reached higher median maximum CRP levels (15.4 vs. 8.5 mg/L), and at a significantly older age (53 vs. 17 hours). Levels of CRP in mild HIE were lower than those of moderate–severe forms. Moderate and severe HIE had similar CRP levels, but time to maximum CRP was significantly less in moderate cases. Conclusion CRP levels of mild HIE are similar to healthy newborns, while CRP elevations can be expected in newborns with moderate–severe HIE. TH produced a slower rise, with a higher and late maximum CRP peak level.

Objective To determine the short-term outcomes (abnormal brain magnetic resonance imaging [MRI]/death) in infants born with a 10-minute Apgar score of 0 who received therapeutic hypothermia and compare them with infants with higher scores. Study Design This is a retrospective review of 293 neonates (gestational age ≥ 35 weeks) born between November 2006 and October 2015 admitted with hypoxic-ischemic encephalopathy who received therapeutic hypothermia. Results of brain MRIs were assessed by the basal ganglia/watershed scoring system. Short-term outcomes were compared between infants with Apgar scores of 0, 1 to 4, and ≥5 at 10 minutes. Results Eight of 17 infants (47%) with an Apgar of 0 at 10 minutes survived, having 4 (24%) without abnormalities on the brain MRI and 7 (41%) without severe abnormalities. There was no significant difference in the combined outcomes of “death/abnormal MRI” and “death/severe abnormalities on the MRI” between infants with Apgar scores of 0 and 1 to 4. Follow-up data were available for six of eight surviving infants, and none had moderate or severe neurodevelopmental impairment. Conclusion In the cooling era, 47% of infants with no audible heart rate at 10 minutes and who were admitted to the neonatal intensive care unit survived; 24% without abnormalities on the brain MRI and 41% without severe abnormalities.

Objective Hypoxic-ischemic encephalopathy (HIE) may be associated with intrapartum sentinel events or may be unexplained. We sought to identify risk factors for unexplained HIE cases and compare their morbidity and mortality to cases associated with sentinel events. Study Design Retrospective cohort study of all neonates admitted with suspected HIE treated with whole-body hypothermia from January 2007 through July 2017. Cases of unexplained HIE were compared with those with a sentinel event. Results A total of 223 neonates met the inclusion criteria, of which 86 (38.6%) experienced a sentinel event and 137 (61.4%) did not. Placental histopathology was performed for 28/31 (90.3%) and 48/53 (90.6%) inborn neonates with and without sentinel events, respectively. Placentas from unexplained HIE cases more often exhibited histologic chorioamnionitis (43.8% vs. 17.9%, p = 0.02) and funisitis (25% vs. 3.6%, p = 0.02). Neonatal morbidity and mortality were similar. On multivariable regression, nulliparity (odds ratio [OR], 4.11, 95% confidence interval [CI]: 1.24–13.62) and histologic funisitis (OR, 20.33, 95% CI: 1.11–373.4) remained significant. Conclusion Other than nulliparity and infection which could be identified on umbilical cord examination following delivery but not on clinical assessment prior to delivery, there are no other identifiable risk factors for HIE in the absence of a sentinel event, and morbidity and mortality are similar between groups.

Introduction The risk factors of intracranial hemorrhages (ICH) in the context of neonatal hypoxic ischemic encephalopathy (HIE) and related interventions are unclear. Objective This article examines the prevalence and risk factors associated with ICH in neonates with HIE. Study Design This is a retrospective cohort study of neonates with HIE in Southern Alberta. ICH (subdural [SDH], subarachnoid [SAH], intraventricular [IVH], intraparenchymal [IPH]) were diagnosed by magnetic resonance imaging (MRI). Perinatal and neonatal characteristics were examined. Relation of hemorrhages with hypoxic changes on MRI and HIE stages were assessed. Results Number of HIE patients, n = 157; brain MRI was done in 138 infants; median gestation, 40 weeks; and cooled = 103 (66%). Prevalence of SDH, IPH, IVH, and SAH were 47, 22, 11, and 10 (34.1%, 15.9%, 7.8%, 7.2%), respectively. There was no significant increase in hemorrhage with mode of delivery, seizures, hypo/hypercarbia, severe thrombocytopenia, or deranged coagulation. All hemorrhages increased with higher HIE stage, regardless of the HIE severity in MRI. Adjusting for HIE staging, cooling, and gestation, IPH was observed more in infants who received inotropes (odds ratio [OR], 3.32; 95% confidence interval [CI], 1.20, 9.20). Conclusion SDH followed by IPH were the most common ICH. Thrombocytopenia and deranged coagulation did not increase risk of hemorrhages in HIE. Our study was not powered to determine the impact of inotrope use on the risk of IPH.

Objective The aim of this article is to assess whether near-infrared spectroscopy (NIRS) identifies, during hypothermia treatment, the asphyxiated newborns who later develop brain injury. Study Design In this study, asphyxiated newborns, for whom later brain injury was defined by brain imaging and/or autopsy results, were monitored by NIRS during therapeutic hypothermia. We compared regional cerebral oxygenation saturation (rSO2) measured by NIRS at key time points for newborns who developed or did not develop later brain injury. Results A total of 18 asphyxiated newborns treated with hypothermia were enrolled. rSO2 was higher in the asphyxiated newborns who developed later brain injury. Sensitivity within the first 10 hours of hypothermia treatment for an adverse outcome was 100% (95% confidence interval [CI], 70–100%) and specificity was 83% (95% CI, 36–99%). Conclusions NIRS appears to identify asphyxiated newborns at risk of developing brain injury as early as the first 10 hours of hypothermia treatment. Thus, NIRS may have an important role as an early outcome predictor in this population.

Objective The objective of this study was to compare complications and mortality in neonates with hypoxic ischemic encephalopathy (HIE) on extracorporeal membrane oxygenation (ECMO) who did and did not receive therapeutic hypothermia (TH). Study Design The Extracorporeal Life Support Organization registry was queried from 2005 to 2013 to identified infants with HIE. Infants ≤30 days of age with HIE on respiratory ECMO were included. Fisher's exact test and the Wilcoxon's rank-sum test were used to compare neonates with and without TH. Logistic regression was used to examine the association of TH with complications and mortality. Results There were no difference between neonates with HIE who did (n = 78) and did not (n = 109) receive TH in demographics, severity of illness, complications, and mortality (p = 0.21). Conclusion No differences in complications or mortality in neonates with HIE and respiratory ECMO were observed between those who did and did not receive TH. We suggest that for neonates requiring respiratory ECMO who also have HIE, TH is not contraindicated.

Objective Asphyxia can lead to autonomic nervous system dysfunction, including depressed heart rate variability (HRV). We tested the hypothesis that low HRV is associated with adverse short-term outcomes of abnormalities on electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) and death in neonates with hypoxic ischemic encephalopathy (HIE). Study Design Neonates undergoing hypothermia therapy for HIE underwent monitoring of HRV. HRV in the first day after birth and after hypothermia and rewarming (days 4–7) were analyzed in relation to death and severity of abnormal findings on EEG and MRI. Results A total of 37 neonates had data available in the first 24 hour after birth and 67 had data days 2 to 7. Depressed HRV was significantly associated with adverse outcomes of death or moderate-to-severe abnormalities on EEG or MRI. In the first 24 hours, the odds ratio (OR) of one or more adverse outcomes for every 10-millisecond decrease in HRV was 3.19 (95% CI, 1.3–7.8; p = 0.01). HRV improved over time but low HRV remained significantly associated with adverse outcomes days 4 to 7 (OR, 2.72; CI, 1.32–5.61; p Conclusions Monitoring HRV, which is reflected in the heart rate characteristic index, may provide useful adjunct information on the severity of brain injury in infants with HIE.

Objective The recent availability of servo-controlled cooling equipment on transport makes it possible to commence active cooling at the referral unit for infants with hypoxic-ischemic encephalopathy. This study aimed to compare the temperature and transfer variables in passively and actively cooled babies. Study Design This is a retrospective cohort study comparing two groups—passively cooled (July 2011 to August 2012) versus actively cooled group (September 2012 to June 2013), following introduction of active hypothermia using servo-controlled cooling mattress by the London Neonatal Transfer Service (NTS). Results Seventy-six infants were passively cooled and 69 were actively cooled. There was a significant difference between the temperatures of the two groups at each point in the transfer episode: on arrival of NTS, during stabilization, during transfer, and at the receiving hospital. Median time to achieve target temperature was 30 (95% confidence interval [CI]: 23–37) minutes in actively cooled, significantly shorter in comparison to 130 (95% CI: 83–177) minutes in passively cooled babies. Of the 69 newborns, 62 (90%) had temperature within target range at receiving center in actively cooled group as compared with 30/76 (40%) in passively cooled group. Conclusion The use of active cooling during neonatal transfer achieves target temperature in a shorter period and maintains better temperature stability.

Objective This study aims to evaluate the correlation of changes in serum insulin-like growth factor-1 (IGF-1) levels with the clinical staging of hypoxic–ischemic encephalopathy (HIE) in term newborns. Study Design A prospective study of 29 newborns with HIE (stage I = 15, stage II + III = 14) and 28 healthy term newborns as the control group was performed in the neonatal intensive care unit. IGF-1 levels were obtained within 6 hours after birth from HIE and control groups and again on day 3 from HIE group. HIE was classified using the Sarnat staging I to III. Results IGF-1 levels were significantly lower in the HIE group than in the control group ( p = 0.024). It was lower in the HIE stage II to III group compared with HIE stage I group at birth ( p p = 0.009). The mean IGF-1 levels were significantly higher on day 3 than on day 1 among stage II to III HIE ( p = 0.006) and it was inversely correlated with staging ( R = − 0.475, p = 0.009). There was a significant correlation between IGF-1 levels and Apgar score at 5 ( R = 0.39, p = 0.042) and 10 minutes ( R = 0.38, p = 0.035). Conclusions IGF-1 was lower in HIE and inversely correlated with clinical staging. It was increased with clinical improvement in the subsequent days.

We sought to analyze associations between aberrant hematologic counts and adverse outcome in neonates with hypoxic ischemic encephalopathy (HIE) due to various intrapartum asphyxial insult types and to describe the postnatal changes in counts. Hematologic counts between 0 and 120 hours of age of 316 consecutively admitted neonates with HIE were collected retrospectively. Asphyxial insult types were categorized as acute near-total, prolonged partial, or "mixed." Associations between hematologic counts and adverse outcome by 2 years of age were analyzed. No associations were found between patterns of hematologic counts in the first 12 hours and adverse outcome. Lymphocyte counts peaked in the first 2 hours of age in all insult types (46% had values > 10.0 x 10 (9)/L) and by 4 to 6 hours reached normal levels. Nucleated red blood cell counts peaked between 6 and 8 hours of age and fell to normal levels by 36 to 72 hours of age (56% had values > 1860 x 10 (6)/L). Relatively few subjects had low platelet counts by age 12 hours; the nadir occurred on days 2 to 3. No associations were found between hematologic counts and adverse outcome. The characteristic hematologic changes found are attributable to the asphyxial insults, not to brain injury. Because of inconsistent changes, hematologic counts cannot be used on their own to time asphyxial insults.

We assessed the effects of hypoxic-ischemic encephalopathy (HIE) and whole-body hypothermia therapy on auditory brain stem evoked responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). We performed serial assessments of ABRs and DPOAEs in newborns with moderate or severe HIE, randomized to hypothermia ( N = 4) or usual care ( N = 5). Participants were five boys and four girls with mean gestational age (standard deviation) of 38.9 (1.8) weeks. During the first week of life, peripheral auditory function, as measured by the DPOAEs, was disrupted in all nine subjects. ABRs were delayed but central transmission was intact, suggesting a peripheral rather than a central neural insult. By 3 weeks of age, peripheral auditory function normalized. Hypothermia temporarily prolonged the ABR, more so for waves generated higher in the brain stem but the effects reversed quickly on rewarming. Neonatal audiometric testing is feasible, noninvasive, and capable of enhancing our understanding of the effects of HIE and hypothermia on auditory function.

Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality. Electroencephalography (EEG) and brain magnetic resonance imaging (MRI) are frequently performed in these infants, but the prognostic value of the combined use of EEG and MRI needs additional exploration. The purpose of this study was to investigate, in neonates with HIE, the role of early EEG and conventional MRI in the prediction of infants at risk for persistent encephalopathy at 18 months of age. Thirty-four term infants with HIE were enrolled in this prospective study. EEG was recorded within the first 72 hours after birth and a brain MRI scan was done between 1 and 4 weeks of age. Denver Developmental Screening Test II was performed at 6, 12, and 18 months of age. Three infants (9%) had mild HIE, 21 infants (62%) had moderate HIE, and 10 infants (29%) had severe HIE. The EEG background was normal, moderately, severely, and extremely discontinuous in eight (24%), three (9%), sixteen (47%), and seven (20%) neonates, respectively. EEG background activities correlated significantly with HIE severity ( P = 0.0001). MRI findings significantly correlated with EEG background ( P = 0.001). Normal MRI scans and minimal basal ganglia lesions were always associated with normal EEG background. Patients with severe basal ganglia and thalamic lesions in MRI (n = 2) had extreme discontinuous EEG background. For the prediction of poor outcomes, abnormal EEG background activity had a sensitivity (Sn) = 100%, a specificity (Sp) = 100%, positive predictive value (PPV) = 100%, and negative predictive value (NPV) = 100%, whereas values of abnormal MRI scans were Sn of 100%, Sp = 43%, PPV = 82%, and NPV=100%. EEG background activity is the best element to predict abnormal outcomes. Severe basal ganglia and thalamic injuries on MRI scans are associated with poor outcomes. Otherwise, MRI does not contribute to the prediction of outcomes at 18 months of age.

Objective The objective of this study was to estimate the association between time from uterine incision to delivery and hypoxic neonatal outcomes in nonanomalous term infants. Methods All women undergoing in-labor term cesarean deliveries (CDs) in the first 2 years of an ongoing prospective cohort study were included. The primary exposure was time in seconds from uterine incision to delivery. The primary outcome was a composite of hypoxia-associated neonatal outcomes, defined as at least one of: seizures, hypoxic ischemic encephalopathy, need for hypothermia treatment, and death within 7 days. Results Of 812 patients who underwent in-labor CD, the composite hypoxia outcome occurred in 18 (2.2%) neonates. There was no significant difference in the rate of hypoxic morbidity with increasing increments of 60 seconds from uterine incision to delivery (p = 0.35). There was a significantly increased risk of hypoxic morbidity in those delivered in the highest quintile (>240 seconds) compared with those in the lowest quintile (≤60 seconds) in cesareans performed for an indication other than nonreassuring fetal status (relative risk, 5.58; 95% confidence interval, 1.30–23.91). Conclusion Overall, duration from uterine incision to delivery for in-labor cesareans of nonanomalous term infants was not associated with an increase in risk of hypoxia-associated morbidities.

We report a case of a neonate who presented with hypoxic ischemic encephalopathy, persistent hypoglycemia and hypotension, intractable metabolic acidosis, renal failure and a coagulopathy but who, at autopsy, was found to have massive infiltration of nonhematopoietic tissues with blasts. The diagnosis of congenital erythroleukemia was confirmed by the detection of glycophorin A, a major erythrocyte membrane protein, on the surface of the blasts. The clinical presentation and course of the case described here have not previously been reported for this extremely rare condition.

We investigated pCO(2) patterns and the relationship between pCO(2) levels and neurodevelopmental outcome in term infants with hypoxic-ischemic encephalopathy. Blood gases during the first 72 hours of life were collected from 52 infants with hypoxic-ischemic encephalopathy. Moderate hypocapnia (pCO(2)3.3 kPa), severe hypocapnia (pCO(2)2.6 kPa), and hypercapnia (pCO(2)6.6 kPa) were correlated to neurodevelopmental outcome at 24 months. Normocapnia was documented in 416/551 (75.5%) of samples and was present during the entire 72 hours in only 6 out of 52 infants. Mean (standard deviation) pCO(2) values did not differ between infants with normal and abnormal outcomes: 5.43 (2.4) and 5.41 (2.03), respectively. There was no significant association between moderate hypocapnia, severe hypocapnia, or hypercapnia and adverse outcome (odds ratio [OR] = 1.84, 95% confidence interval [CI] = 0.49 to 6.89; OR = 3.16, CI = 0.14 to 28.45; and OR = 1.07, CI = 0.24 to 5.45, respectively). In conclusion, only one in nine newborns had normocapnia throughout the first 72 hours. Severe hypocapnia was rare and occurred only in ventilated babies. Hypercapnia and hypocapnia in infants with hypoxic-ischemic encephalopathy during the first 72 hours of life were not associated with adverse outcome.

Despite widespread use of fetal heart rate monitoring, the timing of injury in hypoxic-ischemic encephalopathy (HIE) remains unclear. Our aim was to examine fetal heart rate patterns during labor in infants with clinical and electroencephalographic (EEG) evidence of HIE and to relate these findings to neurodevelopmental outcome. Timing of onset of pathological cardiotocographs (CTGs) was determined in each case by two blinded reviewers and related to EEG grade at birth and neurological outcome at 24 months. CTGs were available in 35 infants with HIE (17 mild, 12 moderate, 6 severe on EEG). Admission CTGs were normal in 24/35 (69%), suspicious in 8/35 (23%), and pathological in 3/35 (8%). All CTGs developed nonreassuring features prior to delivery. Three patterns of fetal heart rate abnormalities were seen: group 1, abnormal CTGs on admission in 11/35 (31%); group 2, normal CTGs on admission with gradual deterioration to pathological in 20/35 cases (57%); and group 3, normal CTGs on admission with acute sentinel events in 4/35 (11.5%). The median (interquartile range) duration between the development of pathological CTGs and delivery was 145 (81, 221) minutes in group 2 and 22 (12, 28) minutes in group 3. There was no correlation between duration of pathological CTG trace and grade of encephalopathy (R = 0.09, P = 0.63) or neurological outcome (P = 0.75). However, the grade of encephalopathy was significantly worse in group 3 (P = 0.001), with a trend to worse outcomes. The majority of infants with HIE have normal CTG traces on admission but develop pathological CTG patterns within hours of delivery. More severe encephalopathy was associated with normal admission CTG and acute sentinel events shortly before delivery.

Evidence suggests that hypothermia for hypoxic ischemic encephalopathy in the term neonate may decrease the risk of death or neurodevelopmental impairment. The objective of this study was to determine how hypothermia has been incorporated into practice. An anonymous survey was sent to medical directors of United States neonatal intensive care units (NICUs) in October 2005. We received completed surveys from 441 (54.5%) of 809 of NICUs. Only 6.4% of respondents used hypothermia. The most common method was total body cooling (64.3%) compared with head cooling (25%) or both (10.7%). At centers that did not offer hypothermia, 29% transferred infants to an institution that did. Centers that offered hypothermia were more likely at academic institutions (76.9%) compared with private practices (11.5%; p < 0.001). Hypothermia was more likely offered at institutions that offered extracorporeal membrane oxygenation (ECMO; 57%) than centers where ECMO was not offered (43%; p < 0.001). There has not been widespread use of hypothermia. There are a variety of protocols used. As results of further outcome studies become available, educational efforts and national practice guidelines will be essential.

Using noninvasive measurement of cranial blood flow, we previously demonstrated that full-term asphyxiated neonates have decreased cerebral perfusion that can persist up to 5 days of age. In an attempt to test their postischemic cerebrovascular CO2 reactivity, we measured cranial blood flow in ten asphyxiated term (39 +/- 0.8 weeks and 3078 K 400 gm) infants with and without inhaled carbon dioxide (3 percent). The end tidal CO2 (PaCO2) increased significantly, from 28.8 +/- 1.0 mm Hg to 32.3 +/- 2.0 mm Hg after CO2 inhalation (p less than 0.01), whereas the cranial blood flow showed no significant change (38.5 +/- 5.0 ml/min/100 gm brain weight to 37.6 +/- 6.0 ml/min/100 gm brain weight). We conclude that term infants with hypoxic-ischemic encephalopathy have low cranial blood flow at 3 days of age. Their cerebrovascular response to inhaled CO2 is variable and suggests some impairment.