Correlation analysis between the amniotic fluid contamination and clinical grading of neonatal hypoxic-ischemic encephalopathy and biomarkers of brain damage.

BACKGROUND: Amniotic fluid contamination (AFC) is a risk factor for neonatal hypoxic ischemic encephalopathy (HIE); however, the correlation between AFC level and the incidence and clinical grading of HIE, in addition to relevant biomarkers of brain damage, have not been assessed. METHODS: This single-center observational study included 75 neonates with moderate-to-severe HIE. The neonates with HIE were divided into four subgroups according to the AFC level: normal amniotic fluid with HIE group (NAF-HIE), I°AFC with HIE group (I°AFC-HIE), II°AFC with HIE group (II°AFC-HIE), and III°AFC with HIE group (III°AFC-HIE). The control groups consisted of 35 healthy neonates. The clinical grading of neonatal HIE was performed according to the criteria of Sarnat and Sarnat. Serum tau protein and S100B were detected by enzyme-linked immunosorbent assay kits. Correlations of serum tau protein and S100B were evaluated using the Pearson correlation analysis. RESULTS: (1) The incidence of neonatal HIE in the NAF-HIE group was 20 cases (26. 7%), I°AFC-HIE was 13 cases (17.3%), II°AFC-HIE was 10 cases (13.3%), and III°AFC-HIE was 32 cases (42. 7%). The incidence of moderate-to-severe HIE in the I°-III°AFC-HIE groups was 73.3% (55/75). (2) In 44 cases with severe HIE, 26 cases (59.1%) occurred in the III°AFC-HIE group, which had a significantly higher incidence of severe HIE than moderate HIE (p < 0.05). In NAF-HIE and I°AFC-HIE groups, the incidence of moderate HIE was 45.2% and 29.0%, respectively, which was higher than that of severe HIE (X2 = 9.2425, p < 0.05; X2 = 5.0472, p < 0.05, respectively). (3) Serum tau protein and S100B levels in the HIE groups were significantly higher than in the control group (all p < 0.05), and were significantly higher in the III°AFC-HIE group than in the NAF-HIE and I°AFC-HIE groups (all p < 0.05). (4) Serum tau protein and S100B levels in the severe HIE group were significantly higher in the moderate HIE group (all p < 0.05). (5) Serum tau protein and S100B levels were significantly positively correlated (r = 0.7703, p < 0.0001). CONCLUSION: Among children with severe HIE, the incidence of III°AFC was higher, and the levels of serum tau protein and S100B were increased. AFC level might be associated with HIE grading.

Correlation Study on the Prognostic Value of miR-21 and S-100B Protein Levels in Neonatal Hypoxic-Ischemic Encephalopathy Undergoing Hypothermia Therapy.

OBJECTIVE: To evaluate the variations in serum levels of microRNA-21 (miR-21) and S-100B protein in neonates with hypoxic-ischemic encephalopathy (HIE) after receiving hypothermia therapy and explore the correlation of these biomarkers with the neurodevelopmental prognosis of the infants. METHODS: This retrospective analysis included 90 neonatal HIE patients diagnosed and treated between January 2019 and December 2022. Real-time quantitative PCR and enzyme-linked immunosorbent assay (ELISA) methods were used to measure miR-21 and S-100B protein levels. Neurodevelopmental assessments were conducted at one year, and follow-up was performed using the Bayley Scales of Infant and Toddler Development third edition. Statistical analysis was carried out using SPSS software, with t-tests for continuous variables, chi-square tests for categorical data, Pearson correlation coefficient for correlation analysis, and multivariate regression analysis to adjust for confounding factors. RESULTS: After hypothermia therapy, the observation group showed a significant decrease in miR-21 and S-100B protein levels (P < 0.001), and neurodevelopmental scores were significantly higher than the control group (P < 0.05). Correlation analysis indicated a negative correlation between miR-21 and neurodevelopmental scores (r=-0.62, P < 0.001), as well as a negative correlation between S-100B protein levels (r=-0.76, P < 0.001). Multivariate regression analysis demonstrated that miR-21 levels and S-100B protein levels maintained independent negative correlations with neurodevelopmental scores (P < 0.001). CONCLUSION: Hypothermia therapy significantly reduces serum levels of miR-21 and S-100B protein in neonatal HIE patients and may be associated with better prognosis. miR-21 and S-100B serve as prognostic biomarkers, aiding in predicting and improving the treatment outcomes and long-term prognosis of neonatal HIE.

Characteristics of neonatal hypoxic-ischemic encephalopathy at high altitude and early results of therapeutic hypothermia.

BACKGROUND: Altitude hypoxia and limited socioeconomic conditions may result in distinctive features of neonatal hypoxic-ischemic encephalopathy (HIE). Therapeutic hypothermia (TH) has not been used at altitude. We examined characteristics of HIE and early outcomes of TH in 3 centers at two high altitudes, 2 at 2,261 m and 1 at 3,650 m. METHODS: The incidence of HIE at NICUs was noted. TH was conducted when personnel and devices were available in 2019~2020. Standard inclusion criteria were used, with the addition of admission age >6 hours and mild HIE. Demographic and clinical data included gestational age, gender, weight, Apgar score, ethnics, age on admission, age at TH and clinical degree of HIE. EEG was monitored for 96 hours during hypothermia and rewarming. MRI was performed before discharge. RESULTS: There was significant difference in ethnics, HIE degree, age at TH across 3 centers. The overall NICU incidence of HIE was 4.0%. Among 566 HIE patients, 114 (20.1%) received TH. 63 (55.3%) patients had moderate/severe HIE. Age at TH >6 hours occurred in 34 (29.8%) patients. EEG discharges showed seizures in 7~11% of patients, whereas spikes/sharp waves in 94~100%, delta brushes in 50~100%. After TH, MRI showed moderate to severe brain injury in 77% of patients, and correlated with center, demographic and clinical variables (Ps≤0.0003). Mortality was 5% during hospitalization and 11% after discharge until 1 year. CONCLUSIONS: At altitude, the incidence of HIE was high and brain injury was severe. TH was limited and often late >6 hours. EEG showed distinct patterns attributable to altitude hypoxia. TH was relatively safe. TRIAL REGISTRATION: The study was registered on February 23, 2019 in Chinese Clinical Trial Register (ChiCTR1900021481).

Morroniside protects HT-22 cells against oxygen-glucose deprivation/reperfusion through activating the Nrf2/HO-1 signaling pathway.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a devastating condition that affects neurodevelopment and results in brain injury in infants. Morroniside (MOR), a natural secoiridoid glycoside, has been found to possess neuroprotective effect. However, the effects of MOR on neonatal HIE are unclear. An in vitro HIE model was established in murine hippocampal neurons HT-22 cells using oxygen-glucose deprivation/reoxygenation (OGD/R) stimulation. Our results showed that MOR improved OGD/R-caused cell viability reduction in HT-22 cells. MOR suppressed the production of reactive oxygen species (ROS) and malondialdehyde (MDA) in OGD/R-induced HT-22 cells in a dose-dependent manner. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX) were significantly elevated by MOR. Moreover, MOR treatment caused a significant increase in bcl-2 expression, and obvious decreases in the expression levels of bax, cleaved caspase-3, and cleaved caspase-9 expression. Furthermore, MOR significantly upregulated the expression levels of nuclear Nrf2 and HO-1 in OGD/R-treated HT-22 cells. Additionally, knockdown of Nrf2 or HO-1 abrogated the effects of MOR on OGD/R-induced oxidative stress and apoptosis in HT-22 cells. In conclusion, these findings suggested that MOR protects HT-22 cells against OGD/R via regulating the Nrf2/HO-1 signaling pathway.

CREG mitigates neonatal HIE injury through survival promotion and apoptosis inhibition in hippocampal neurons via activating AKT signaling.

Neonatal hypoxic ischemic encephalopathy (Neonatal HIE) is a common but serious disease caused by perinatal asphyxia injury in newborns. Elevated neuronal apoptosis plays an important role in the injury process post hypoxia ischemia of the brain, which accurate mechanism is still worthy to be studied. Cellular repressor of E1A-stimulated genes (CREG) possesses the protective effect in ischemia-reperfusion in multiple organs, including livers and hearts. The main purpose of this work was to investigate whether CREG was involved in alleviating neonatal HIE and explore the possible mechanisms. We found that CREG expression was downregulated in the hippocampus of neonatal HIE rats as well as oxygen-glucose deprivation/reperfusion (OGD/R)-treated hippocampal neurons. Besides, CREG overexpression promoted survival while inhibited apoptosis in OGD/R-induced hippocampal neurons accompanied by AKT signaling activation, which could be reversed by CREG silence. In addition, the protective effects of CREG overexpression could be antagonized by AKT deactivation, indicating the function of CREG was attributed by regulating AKT pathway. Collectedly, we demonstrated that CREG protected hippocampal neurons from hypoxic ischemia-induced injury through regulating survival and apoptosis via activating AKT signaling pathway.

Serum troponin I: a potential biomarker of hypoxic-ischemic encephalopathy in term newborns.

OBJECTIVE: This study was intended to evaluate the predictive values of serum procalcitonin (PCT), lactate, creatine kinase (CK-MB), and troponin I on the diagnosis and staging of neonatal hypoxic-ischemic encephalopathy (HIE). MATERIALS AND METHODS: We retrospectively retrieved data from electronic medical records at our children's hospital, and we included all term newborns admitted between December 2018 and June 2020 with features of perinatal asphyxia. Receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to measure and evaluate the predictive values of biomarkers. p values < 0.05 were set as statistical significance. RESULTS: A total of 201 neonates were included. They were grouped as control (n = 40), mild HIE (n = 105), moderate HIE (n = 36), and severe HIE (n = 20). Serum lactate, PCT, CK-MB, and troponin I levels in severe hypoxic-ischemic brain injury group were significantly higher than those in mild to moderate hypoxic-ischemic brain injury group and control group (p < 0.05). Based on ROC and AUC analysis, troponin I showed highest predictive ability with AUC of 0.904, and sensitivity and specificity of 95.00% and 87.50% respectively. CONCLUSION: Serum troponin I has a good predictive value for neonatal hypoxic-ischemic encephalopathy after perinatal asphyxia.

Hypothermia Does Not Boost the Neuroprotection Promoted by Umbilical Cord Blood Cells in a Neonatal Hypoxia-Ischemia Rat Model.

Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of death and long-term disability in the perinatal period. Currently, therapeutic hypothermia is the standard of care for this condition with modest efficacy and strict enrollment criteria. Therapy with umbilical cord blood cells (UCBC) has come forward as a strong candidate for the treatment of neonatal HIE, but no preclinical studies have yet compared the action of UCBC combined with hypothermia (HT) with the action of each therapy by itself. Thus, to evaluate the potential of each therapeutic approach, a hypoxic-ischemic brain lesion was induced in postnatal day ten rat pups; two hours later, HT was applied for 4 h; and 24, 48, and 72 h post-injury, UCBC were administered intravenously. The neonatal hypoxic-ischemic injury led to a brain lesion involving about 48% of the left hemisphere that was not improved by HT (36%) or UCBC alone (28%), but only with the combined therapies (25%; p = 0.0294). Moreover, a decrease in glial reactivity and improved functional outcomes were observed in both groups treated with UCBC. Overall, these results support UCBC as a successful therapeutic approach for HIE, even when treatment with therapeutic hypothermia is not possible.

Neonatal hypoxic-ischemic encephalopathy diagnosis and treatment: a National Survey in China.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) affects as many as 100,000 infants each year in China. Therapeutic hypothermia reduces HIE related mortality and long-term neurodevelopmental disabilities. National guidelines for HIE management were published a decade ago. This study aimed to investigate the current status of HIE diagnosis and treatment in China. METHOD: This prospective cross-sectional national survey used a questionnaire evaluating practices related to HIE management. Descriptive statistics and Chi-square or Fisher's exact test were used, and a p-value of < 0.05 was considered significant. RESULTS: The 273 hospitals that completed the survey were located in 31 of the 34 provincial districts in China. Eighty-eight percent of the hospitals were Level III hospitals, and 74% treated 10 or more HIE cases annually. Awareness rates of the national guidelines for HIE diagnosis, HIE treatment, and therapeutic hypothermia protocol were 85, 63, and 78%, respectively. Neurological manifestations and blood gas were used as HIE diagnostic criteria by 96% (263/273) and 68% (186/273) of the hospitals, respectively. Therapeutic hypothermia was used in 54% (147/273) of hospitals. The percentage of general hospitals that implemented therapeutic hypothermia (43%, 71/165) was significantly lower than that in maternity and infant hospitals (67%, 49/73) (χ2 = 11.752, p = 0.001) and children's hospitals (77%, 27/35) (χ2 = 13.446, p < 0.001). Reasons for not providing therapeutic hypothermia included reduction of HIE cases in recent years (39%), high cost of cooling devices and treatment (31%), lack of training (26%), and safety concerns (4%). Among the hospitals that provided therapeutic hypothermia, 27% (39/147) were in full compliance with the recommended protocol. Eighty-one percent (222/273) of the hospitals treated HIE infants with putative neuroprotective agents alone or in combination with cooling. Ninety-one percent of the hospitals had long-term neurodevelopmental follow-up programs for infants with HIE. CONCLUSIONS: There is significant heterogeneity in HIE diagnosis and treatment in China. Therapeutic hypothermia has not become a standard of care for neonatal HIE nationwide. Unproven agents are widely used for HIE treatment. Nationwide standardization of HIE management and dissemination of therapeutic hypothermia represent the opportunities to reduce mortality and improve long-term neurodevelopmental outcomes of children affected by HIE.

Regulatory Mechanism of MicroRNA-30b on Neonatal Hypoxic-Ischemic Encephalopathy (HIE).

OBJECTIVE: This study is to investigate the role of microRNA (miR)-30b in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonates. METHODS: Totally 26 cases of neonatal HIE were included in this study. The protein expression levels of CD26P and PAI-1 were detected with ELISA. Serum levels of miR-30b and PAI-1 mRNA was measured by quantitative real-time PCR. Human brain microvascular endothelial cells (HBMECs) were cultured under hypoxic condition, and the intracellular expression levels of miR-30b and PAI-1 were evaluated. Dual-luciferase reporter assay was performed to confirm the interaction between miR-30b and PAI-1. RESULTS: Compared with the control group, both the mRNA and protein expression levels of PAI-1 in the serum were up-regulated in the neonates with HIE, together with up-regulated serum CD26P levels. However, the serum expression level of miR-30b was down-regulated in neonatal HIE. In hypoxia-induced HBMECs, the mRNA and protein expression levels of PAI-1 were significantly up-regulated, while the miR-30b expression level was significantly down-regulated. Dual-luciferase reporter assay showed that PAI-1 was the direct target of miR-30b. CONCLUSION: Neonatal HIE is accompanied with abnormal platelet activation, significantly up-regulated serum PAI-1 expression levels, and down-regulated miR-30b expression. MiR-30b might regulate the disease pathogenesis and immune responses via modulating PAI-1.

Neuroprotection of N-benzyl Eicosapentaenamide in Neonatal Mice Following Hypoxic-Ischemic Brain Injury.

Maca (Lepidium meyenii) has emerged as a popular functional plant food because of its medicinal properties and nutritional value. Macamides, as the exclusively active ingredients found in maca, are a unique series of non-polar, long-chain fatty acid N-benzylamides with multiple bioactivities such as antifatigue characteristics and improving reproductive health. In this study, a new kind of macamide, N-benzyl eicosapentaenamide (NB-EPA), was identified from maca. We further explore its potential neuroprotective role in hypoxic-ischemic brain injury. Our findings indicated that treatment with biosynthesized NB-EPA significantly alleviates the size of cerebral infarction and improves neurobehavioral disorders after hypoxic-ischemic brain damage in neonatal mice. NB-EPA inhibited the apoptosis of neuronal cells after ischemic challenge. NB-EPA improved neuronal cell survival and proliferation through the activation of phosphorylated AKT signaling. Of note, the protective property of NB-EPA against ischemic neuronal damage was dependent on suppression of the p53-PUMA pathway. Taken together, these findings suggest that NB-EPA may represent a new neuroprotectant for newborns with hypoxic-ischemic encephalopathy.

Long-Term Outcomes of Perinatal Hypoxia and Asphyxia at an Early School Age.

Background and Objectives: Late long-term outcomes of perinatal asphyxia (PA) in school-age are often unclear. To assess long-term outcomes at an early school age in children who had experienced perinatal hypoxia or asphyxia, where therapeutic hypothermia was not applied. Materials and Methods: The case group children were 8-9-year-old children (n = 32) who were born at full term and experienced hypoxia or asphyxia at birth, where therapeutic hypothermia (TH) was not applied. The control group consisted of 8-9-year-old children (n = 16) born without hypoxia. A structured neurological examination was performed at an early school age. The neuromotor function was assessed using the Gross Motor Function Classification System (GMFCS). Health-related quality-of-life was assessed using the Health Utilities Index (HUI) questionnaire. Intellectual abilities were assessed using the Wechsler Intelligence Scale for Children (WISC). Results: The case group, compared with controls, had significantly (p = 0.002) lower mean [SD] full-scale IQ (87(16.86) vs. 107(12.15)), verbal-scale IQ (89(17.45) vs. 105(11.55)), verbal comprehension index (89(17.36) vs. 105(10.74)), working memory index (89(15.68) vs. 104(11.84)), performance IQ (87(16.51) vs. 108(15.48)) and perceptual organization index (85(15.71) vs. 105(15.93)). We did not find any significant differences in the incidence of disorders of neurological examination, movement abilities and health-related quality of life at an early school age between the case and the control group children. Conclusion: In children who experienced perinatal asphyxia but did not have cerebral paralysis (CP), where therapeutic hypothermia was not applied, cognitive assessment scores at an early school age were significantly lower compared to those in the group of healthy children, and were at a low average level.

COX5A over-expression protects cortical neurons from hypoxic ischemic injury in neonatal rats associated with TPI up-regulation.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) represents as a major cause of neonatal morbidity and mortality. However, the underlying molecular mechanisms in brain damage are still not fully elucidated. This study was conducted to determine the specific potential molecular mechanism in the hypoxic-ischemic induced cerebral injury. METHODS: Here, hypoxic-ischemic (HI) animal models were established and primary cortical neurons were subjected to oxygen-glucose deprivation (OGD) to mimic HIE model in vivo and in vitro. The HI-induced neurological injury was evaluated by Zea-longa scores, Triphenyte-trazoliumchloride (TTC) staining the Terminal Deoxynucleotidyl Transferased Utp Nick End Labeling (TUNEL) and immunofluorescent staining. Then the expression of Cytochrome c oxidase subunit 5a (COX5A) was determined by immunohistochemistry, western blotting (WB) and quantitative real time Polymerase Chain Reaction (qRT-PCR) techniques. Moreover, HSV-mediated COX5A over-expression virus was transducted into OGD neurons to explore the role of COX5A in vitro, and the underlying mechanism was predicted by GeneMANIA, then verified by WB and qRT-PCR. RESULTS: HI induced a severe neurological dysfunction, brain infarction, and cell apoptosis as well as obvious neuron loss in neonatal rats, in corresponding to the decrease on the expression of COX5A in both sides of the brain. What's more, COX5A over-expression significantly promoted the neuronal survival, reduced the apoptosis rate, and markedly increased the neurites length after OGD. Moreover, Triosephosephate isomerase (TPI) was predicted as physical interactions with COX5A, and COX5A over-expression largely increased the expressional level of TPI. CONCLUSIONS: The present findings suggest that COX5A plays an important role in promoting neurological recovery after HI, and this process is related to TPI up-regulation.

Early Blood Biomarkers Distinguish Inflammation from Neonatal Hypoxic-Ischemia Encephalopathy.

Neonatal hypoxic-ischemic encephalopathy is the most common cause of neurological disability in infancy. Superimposed inflammation may further worsen neurological outcomes. Reliable biomarkers which are both sensitive to hypoxic-ischemia and inflammation are critically needed. We tested plasma osteopontin (OPN) and glial fibrillary astrocytic protein (GFAP) within the reported therapeutic window (90 min after hypoxic-ischemic (HI) injury) in neonatal rats with different HI severity and inflammation. Two different HI severity groups (mild-HI with 75 min hypoxia and severe-HI with 150 min hypoxia) were established. Inflammation-sensitized HI brain injury induced by lipopolysaccharide (LPS) further increased apoptotic neurons and infarct volumes. In HI alone groups, OPN was significantly decreased (p < 0.001) but GFAP was slightly increased (p < 0.05) at 90 min after HI either in mild-HI or severe-HI compared with naïve group. In LPS-sensitized HI groups, both OPN and GFAP were significantly increased either in LPS-mild-HI or LPS-severe-HI groups compared with the naïve group (all p < 0.05). Induced inflammation by LPS exaggerated neonatal HI brain injury. The plasma OPN and GFAP levels may be useful to differentiate HI alone groups from inflammation-sensitized HI groups or naïve group.

Cerebral blood flow velocity and oxygenation correlate predominantly with right ventricular function in cooled neonates with moderate-severe hypoxic-ischemic encephalopathy.

The relationship between right ventricular (RV) function and cerebral blood flow (CBF) velocity and cerebral oxygenation was assessed in neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH). Echocardiographic, transcranial Doppler, and hemodynamic data from 37 neonates with moderate-severe HIE + TH were reviewed. Twenty healthy newborns served as controls. Cardiac dysfunction in HIE + TH was characterized by a predominant RV dysfunction, with concomitantly reduced CBF velocity. A significant correlation was found between CBF velocity and tricuspid annular plane systolic excursion (TAPSE), RV output (RVO), and stroke volume (SVRV), as well as with left ventricular output and stroke volume. Brain oxygenation (rSO2) correlated significantly with RVO, SVRV, TAPSE, ejection fraction, and fractional shortening, whereas cerebral fractional tissue oxygen extraction (FTOEc) correlated with RVO, SVRV, RV myocardial performance index, and superior vena cava flow. CBF velocity and cerebral NIRS correlations were stronger with parameters of right ventricular performance.Conclusion: CBF velocity and brain oxygenation correlate predominantly with RV function in HIE + TH. This suggests a preferential contribution of RV performance to cerebral hemodynamics in this context. What is Known: • Neonates with hypoxic ischemic encephalopathy frequently exhibit alterations of cardiac function and cerebral blood flow. • These are considered organ-specific consequences of perinatal asphyxia. What is New: • We show that cerebral blood flow velocity and brain oxygenation are correlated predominantly with right ventricular function during therapeutic hypothermia. • This suggests a potential direct contribution of right ventricular performance to cerebral hemodynamics in this context.

Platycodin D protects cortical neurons against oxygen-glucose deprivation/reperfusion in neonatal hypoxic-ischemic encephalopathy.

Neonatal hypoxic-ischemic encephalopathy is one of the leading causes of death in infants. Increasing evidence indicates that oxidative stress and apoptosis are major contributors to hypoxic-ischemic injury and can be used as particularly promising therapeutic targets. Platycodin D (PLD) is a triterpenoid saponin that exhibits antioxidant properties. The aim of this study was to evaluate the effects of PLD on hypoxic-ischemic injury in primary cortical neurons. We found that oxygen-glucose deprivation/reperfusion (OGD/R) induced inhibition of cell viability and cytotoxicity, which were attenuated by PLD treatment. PLD treatment inhibited oxidative stress induced by OGD/R, which was evidenced by the reduced level of reactive oxygen species and increased activities of catalase, superoxide dismutase, and glutathione peroxidase. Histone-DNA enzyme-linked immunosorbent assay revealed that apoptosis was significantly decreased after PLD treatment in OGD/R-treated cortical neurons. The increased bax expression and decreased bcl-2 expression induced by OGD/R were reversed by PLD treatment. Furthermore, PLD treatment caused the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in OGD/R-stimulated cortical neurons. Suppression of this pathway blocked the protective effects of PLD on OGD/R-induced cell injury. These findings suggested that PLD executes its protective effects on OGD/R-induced cell injury via regulating the PI3K/Akt/mTOR pathway in cortical neurons.

Planned home birth and the association with neonatal hypoxic ischemic encephalopathy.

OBJECTIVE: To evaluate the association between planned home birth and neonatal hypoxic ischemic encephalopathy (HIE). METHODS: This is a case-control study in which a database of neonates who underwent head cooling for HIE at our institution from 2007 to 2011 was linked to New York City (NYC) vital records. Four normal controls per case were then randomly selected from the birth certificate data after matching for year of birth, geographic location, and gestational age. Demographic and obstetric information was obtained from the vital records for both the cases and controls. Location of birth was analyzed as hospital or out of hospital birth. Details from the out of hospital deliveries were reviewed to determine if the delivery was a planned home birth. Maternal and pregnancy characteristics were examined as covariates and potential confounders. Logistic regression was used to determine the odds of HIE by intended location of delivery. RESULTS: Sixty-nine neonates who underwent head cooling for HIE had available vital record data on their births. The 69 cases were matched to 276 normal controls. After adjusting for pregnancy characteristics and mode of delivery, neonates with HIE had a 44.0-fold [95% confidence interval (CI) 1.7-256.4] odds of having delivered out of hospital, whether unplanned or planned. Infants with HIE had a 21.0-fold (95% CI 1.7-256.4) increase in adjusted odds of having had a planned home birth compared to infants without HIE. CONCLUSION: Out of hospital birth, whether planned home birth or unplanned out of hospital birth, is associated with an increase in the odds of neonatal HIE.

Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats.

OBJECTIVE: Hypoxic ischemic (HI) encephalopathy remains the leading cause of perinatal brain injury resulting in long term disabilities. Stabilization of blood brain barrier (BBB) after HI is an important target, therefore, in this study we aim to determine the role of sestrin2, a stress inducible protein which is elevated after various insults, on BBB stabilization after moderate and severe HI injuries. METHODS: Rat pups underwent common carotid artery ligation followed by either 150min (severe model) or 100min (moderate model) of hypoxia. 1h post HI, rats were intranasally administered with recombinant human sestrin2 (rh-sestrin2) and sacrificed for infarct area, brain water content, righting reflex and geotaxis reflex. Sestrin2 was silenced using siRNA and an activator/inhibitor of hypoxia inducible factor1α (HIF1α) was used to examine their roles on BBB permeability. RESULTS: Rats subjected to severe HI exhibited larger infarct area and higher sestrin2 expression compared to rats in the moderate HI group. rh-sestrin2 attenuated brain infarct and edema, while silencing sestrin2 reversed these protective effects after severe HI. HIF1α induced sestrin2 activation in severe HI but not in moderate HI groups. A HIF1a agonist was shown to increase permeability of the BBB via vascular endothelial growth factor (VEGF) after moderate HI. However, after severe HI, HIF1α activated both VEGF and sestrin2. But HIF1α dependent sestrin2 activation was the predominant pathway after severe HI which inhibited VEGF and attenuated BBB permeability. CONCLUSIONS: rh-sestrin2 attenuated BBB permeability via upregulation of endogenous sestrin2 which was induced by HIF1α after severe HI. However, HIF1α's effects as a prodeath or prosurvival signal were influenced by the severity of HI injury.

Risk Factors for Neonatal Arterial Ischemic Stroke: The Importance of the Intrapartum Period.

OBJECTIVE: To investigate risk factors for neonatal arterial ischemic stroke (NAIS), and compare them with those present in term controls and infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Antepartum and intrapartum data were collected at presentation from 79 infants with NAIS and compared with 239 controls and 405 infants with HIE. The relationships between risk factors and NAIS were explored using univariable and multivariable regression. RESULTS: Compared with controls, infants with NAIS more frequently had a family history of seizures/neurologic diseases, primiparous mothers, and male sex. Mothers of infants with NAIS experienced more intrapartum complications: prolonged rupture of membranes (21% vs 2%), fever (14% vs 3%), thick meconium (25% vs 7%), prolonged second stage (31% vs 13%), tight nuchal cord (15% vs 6%), and abnorm8al cardiotocography (67% vs 21%). Male sex (OR 2.8), family history of seizures (OR 6.5) or neurologic diseases (OR 4.9), and ≥1 (OR 5.8) and ≥2 (OR 21.8) intrapartum complications were independently associated with NAIS. Infants with NAIS and HIE experienced similar rates though different patterns of intrapartum complications. Maternal fever, prolonged rupture of membranes, prolonged second stage, tight nuchal cord, and failed ventouse delivery were more common in NAIS; thick meconium, sentinel events, and shoulder dystocia were more frequent in HIE. Abnormal cardiotocography occurred in 67% of NAIS and 77.5% of infants with HIE. One infant with NAIS and no infant with HIE was delivered by elective cesarean (10% of controls). CONCLUSIONS: NAIS is multifactorial in origin and shares risk factors in common with HIE. Intrapartum events may play a more significant role in the pathogenesis of NAIS than previously recognized.

Neuroprotective Strategies after Neonatal Hypoxic Ischemic Encephalopathy.

Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating disease that primarily causes neuronal and white matter injury and is among the leading cause of death among infants. Currently there are no well-established treatments; thus, it is important to understand the pathophysiology of the disease and elucidate complications that are creating a gap between basic science and clinical translation. In the development of neuroprotective strategies and translation of experimental results in HIE, there are many limitations and challenges to master based on an appropriate study design, drug delivery properties, dosage, and use in neonates. We will identify understudied targets after HIE, as well as neuroprotective molecules that bring hope to future treatments such as melatonin, topiramate, xenon, interferon-beta, stem cell transplantation. This review will also discuss some of the most recent trials being conducted in the clinical setting and evaluate what directions are needed in the future.

Eucapnic pH coupled with arterial cord pH improves hypoxic-ischemic encephalopathy prediction.

OBJECTIVE: To consider the classical use of "pH < 7.0 and/or a base deficiency ≥12 mmol/L" as markers of the risk of neonatal hypoxic-ischemic encephalopathy (HIE), recalling various criticisms of the use of these markers in favor of that of neonatal eucapnic pH, which appears to be a better marker of this risk. METHODS: Fifty-five cases of acidemia with pH < 7.00 were collected from a cohort from the Nice University Hospital with eight cases of HIE. We compared the receiver operating characteristics curves established from the positive likelihood ratio (+LR) for each case of: umbilical cord artery pH (pHa), neonatal eucapnic pH (pH euc-n) in isolation (not matched to pHa), and matched pHa to its own pH euc-n. RESULTS: The areas under the curve (AUC) are identical for pHa and pH euc-n, but AUC for the matched pair pHa-pH euc-n appears superior but non-significant because of the small number in our cohort. However, using the bootstrap method, the partial AUC for a sensitivity greater than 75% indicates the significant superiority (P < 0.01) of the matched pair pHa-pH euc-n approach. CONCLUSION: The originality of this study lies in the use of two methodologic approaches: (1) standardized partial analysis of the AUCs of the pHa curve and that of pHa matched to its own pH euc-n, and (2) bootstrap statistical technique, that allowed us to conclude (P < 0.01) that the combined use of pH measured at the cord coupled with its eucapnic correction is better for diagnosing metabolic acidosis and best predicting the risk of HIE.