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Purpose: To analyze the elevation of HbA1c before full-term delivery in single pregnancy with normal 75 g- Oral glucose tolerance test (OGTT) screening and its association with adverse perinatal outcomes., Methods: From January to December 2022, an observational prospective study was conducted in a Single centre in China. 365 single pregnant women with normal OGTT were included in the study. HbA1c was measured during OGTT and before full-term delivery, and perinatal outcomes were collected. Participants' pre-delivery HBA1c values were analyzed and perinatal outcomes were compared. Logistic regression analysis was used for independent risk factors associated with elevated pre-delivery HbA1c ≥ 6.0%. The predictive value and truncation value were analyzed by ROC curve., Results: 15.89% (58/365) of the Participants had a pre-delivery HBA1C value ≥ 6.0%. The incidence of neonatal asphyxia (13.79%, vs. 3.45%, vs. 2.26%, P = 0.007) and amniotic fluid fecal staining (29.31%, vs. 12.64%, vs. 12.03%, P = 0.004) were significantly increased in this group. The independent risk factor associated with pre-delivery HBA1c ≥ 6.0% was the fasting blood glucose(FBG) value of OGTT (OR = 51.308, 95% CI 12.93-203.67, P < 0.01) and the HBA1c value measured during OGTT (OR = 3.608, 95% CI 1.432-9.151, P = 0.007). When FBG was < 4.18 mmol/L and HBA1c was < 5.51%, The accuracy of predicting the pre-delivery HBA1c < 6.0% was 98.2%., Conclusions: 15.89% of the single pregnancy with normal OGTT had HbA1c ≥ 6.0% before full-term delivery, and they had an increased incidence of neonatal asphyxia and amniotic fluid fecal staining. When the FBG ≥ 4.18 mmol/l or the HBA1c ≥ 5.51% during the OGTT screening, repeated OGTT were recommended in late pregnancy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Oliguria is a sign of impaired kidney function and has been shown to be an early predictor of adverse prognoses in patients with acute kidney injury. The relationship between urine output (UOP) and early lactate levels in neonates with perinatal asphyxia (PA) has not been extensively explored. This study aimed to investigate the link between oliguria during the first 24 h of life and early lactate levels in neonates with PA., Methods: The medical records of 293 term neonates with asphyxia from 9216 hospitalized newborns were retrospectively analyzed, including 127 cases designated as the oliguria group and 166 cases as controls. Peripheral arterial blood gas after PA and UOP within 24 h after birth were analyzed. Logistic regression analyses and receiver operating characteristic curve analysis were conducted., Results: Oliguria occurred in 43.34% of neonates with PA. The median UOP of the oliguria and control groups were 0.65 and 1.46 mL/kg/h, respectively. Elevated lactate levels after PA are an independent risk factor for oliguria in the following 24 h (p = 0.01; OR: 1.19; 95%CI: 1.04-1.35) and show a moderate discriminatory power for oliguria (AUC = 0.62). Using a cut off value of 8.15 mmol/L, the positive and negative predictive values and the specificity were 59.34%, 63.86%, and 78.30%, respectively., Conclusion: Neonates with elevated lactate levels after PA face a risk of oliguria in the following 24 h. Based on early elevated lactate levels after resuscitation, especially ≥ 8.15 mmol/L, meticulously monitoring UOP will allow this vulnerable population to receive early, tailored fluid management and medical intervention., (© 2024. The Author(s).)

Background: The burden of perinatal asphyxia remains high in our environment and when asphyxia is severe, vital organs are affected, with resultant multiorgan hypoxic-iscahemic injury to the heart, the brain, adrenals and other organs., Study Aim: To evaluate for myocardial injury in asphyxiated term neonates with hypoxic ischaemic encephalopathy using serum cardiac troponin-I (cTnI)., Methods: The study was a hospital-based descriptive cross-sectional study involving sixty term asphyxiated neonates and sixty gestational age-and sex-matched controls. The subjects were term neonates with five-minute Apgar score ≤ 6 and HIE while the controls were healthy term neonates with five-minute Apgar score > 6. Five-minute Apgar score was utilized to classify asphyxia into mild, moderate and severe asphyxia. The degree of encephalopathy was determined by modified Sarnat and Sarnat criteria. The serum cTnI was measured in subjects and controls at 12-24 hours of life using Enzyme-linked immunosorbent assay technique. The serum bilirubin levels were also measured in participants to exclude hyperbilirubinemia., Results: The median serum cTnI levels was significantly higher in the subjects (0.56ng/mL; 0.25-0.94ng/mL) than in the controls (0.50ng/mL; 0.00-0.67ng/mL), respectively; p=0.001. Similarly, the median serum cTnI level in HIE stage II (0.56ng/mL; 0.38-0.72ng/mL) or III (0.56ng/ml; 0.50-0.94ng/mL) was also significantly higher than the median value in HIE stage I (0.38ng/mL;0.25-0.72ng/mL) or in controls (0.50ng/mL; 0.00-0.67ng/mL); p<0.001. There was significant positive correlation between serum cTnI levels and severity of HIE in asphyxiated neonates (rs = 0.505, p < 0.001)., Conclusion: serum cTnI levels were elevated in severely asphyxiated neonates with HIE. The concentration of serum cTnI demonstrated significant positive correlation with HIE severity. Hence, the presence of HIE in asphyxiated neonates should prompt an evaluation for myocardial injury using serum cTnI. Any derangement noted should warrant instituting cardiovascular support in order to improve outcome and reduce asphyxia-related mortality., (Copyright © 2024 Copyright: © 2024 Nigerian Journal of Clinical Practice.)

As a rare obstetric disease, fetomaternal hemorrhage (FMH) often causes severe fetal anemia, edema and even death, easily to be confused with severe neonatal asphyxia. Currently, there are several ways to detect or predict FMH, however, most of them are flawed and time-consuming, as well as unsuitable for rapid diagnosis and timely intervention of FMH. To explore the values of umbilical artery blood gas analysis in the rapid diagnosis of FMH, providing basis for rapid guidance of newborn rescue. Five cases of neonates with FMH from the First Affiliated Hospital of Army Military Medical University (Chongqing Southwest Hospital) from January 2013 to January 2016 were selected as the study group. Another 9 cases of severe asphyxia neonates were chosen into the control group. The difference in Apgar score and umbilical artery blood gas analysis between the 2 groups at birth was compared, and the treatments and clinical outcomes of the 2 groups were analyzed. The PH value of umbilical artery blood gas analysis in the study group was higher than that of the control group, but the difference was not statistically significant (P > .05). In the study group, cases with pH value < 7.0 accounted for 0%, whereas the cases with pH < 7.0 accounted for 66.67% in the control group, and the difference between the 2 groups was statistically significant (P < .05). Compared with the control group, the arterial oxygen partial pressure (PO2), the absolute value of (PCO2), lactic acid (lac) and alkali were not significantly different from those of the control group (P > .05), while the total hemoglobin (tHb) and hematocrit (Hct) were significantly lower than the control group (P < .0001). In the study group, tHb in the umbilical cord blood of 2 newborns with FMH death was significantly lower than 40 g/L. FMH should be highly suspected when there is an expression of severe asphyxia in neonates, indicated by significantly lower tHb levels in umbilical cord blood. It is helpful to improve the neonatal outcome by FMH neonatal resuscitation as soon as possible., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Perinatal asphyxia is the main risk factor for mortality and morbidity in neonates and neurological disorders in survived infants. We compared the neonatal and maternal 25 (OH) vitamin D levels in neonates with/without asphyxia., Materials and Methods: This cross-sectional research was done on 229 neonates (including 158 neonates [69%] without asphyxia [control group] and 71 neonates [31%] with asphyxia [case group]) from 2020 to 2023 using the available sampling method. 25 (OH) Vit D levels in mothers and neonates were assessed and compared in the 2 groups. The data collection instrument was a researcher-made checklist, containing the maternal and neonatal characteristics and laboratory evaluations. Data were analyzed by SPSS 23 using the t-test., Results: The mean maternal 25 (OH) Vit D levels in the case and control groups were 16.34±11.87 and 22.80±12.67 ng/mL, respectively. The mean neonatal 25 (OH) Vit D levels in the case and control groups were respectively 12.13±8.62 and 19.55±11.62 ng/mL (P = 0.002). The case group showed severer maternal and neonatal 25 (OH) Vit D deficiency (P = 0.000) compared to the control group., Conclusions: Neonatal and maternal 25 (OH) Vit D deficiency can increase the risk of perinatal asphyxia. Therefore, administration of 25 (OH) Vit D supplements to pregnant mothers may reduce the incidence of asphyxia.

Objective: To assess the incidence and severity of acute kidney injury (AKI) and evaluate risk factors that predict AKI in asphyxiated infants receiving therapeutic hypothermia., Study Design: Infants ≥36 weeks' gestation diagnosed with moderate-to-severe perinatal asphyxia and received therapeutic hypothermia were reviewed retrospectively ( n  = 166). Modified Acute Kidney Injury Network criteria were used to diagnose AKI. The results of infants with AKI were compared with the infants who did not develop AKI., Results: AKI developed in 49 (29.5%) infants, of whom 22 had stage I, 13 had stage II, and 14 had stage III AKI. The overall mortality rate was 15.7% and was significantly higher in infants with AKI when compared with infants without AKI (41 vs. 5%; p  < 0.001). Asystole at birth ( p  = 0.044), placental abruption ( p  = 0.041), outborn status ( p  = 0.041), need for vasopressor support ( p  = 0.031), increased bleeding tendency ( p  = 0.031), initial lactate level ( p  = 0.015), and 12-hour lactate level ( p  = 0.029) were independent risk factors for the development of AKI. Receiver operating characteristic curve analysis demonstrated a good predictive value for initial lactate level (>15 mmol/L), with 69% sensitivity (95% CI: 55-82) and 82% specificity (95% CI: 74-89), and for 12-hour lactate level (>6 mmol/L), with 83.7% sensitivity (95% CI: 70-93) and 73.5% specificity (95% CI: 64.5-81), to predict AKI., Conclusion: AKI is still a common complication of perinatal asphyxia despite treatment with therapeutic hypothermia. Identification of risk factors associated with the development of AKI in asphyxiated infants would be potentially beneficial to reduce morbidity and mortality. Besides perinatal risk factors, initial and 12-hour lactate concentrations can be used for the early prediction of AKI., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: Hypoglycemia is a significant risk factor for perinatal brain injury and adverse outcomes, particularly in infants requiring resuscitation following hypoxic ischemic (HI) insult. We aimed to study blood glucose (BG) levels in physiologically stressed infants in the presence or absence of epinephrine (Epi) administration at resuscitation in the first 24 hours after birth., Study Design: A retrospective chart review of all infants with heart rate (HR) < 100/min at 1 minute requiring positive pressure ventilation (PPV) at birth was performed. Infants were classified into two groups as follows: (1) PPV group : infants' HR improved with PPV only at resuscitation, and Epi group : infants received Epi at resuscitation for persistent bradycardia. Serial measurements of BG levels collected and glucose infusion rate (GIR) calculated at 24 hours., Results: By design, infants in the Epi group had lower cord pH and higher base deficit. BG was significantly lower overtime in premature infants ≤32 weeks of gestation in the Epi group. The BG was markedly higher in near-term and term infants in the Epi group compared with the PPV group. Hypoglycemia was more common despite administration of higher GIR in premature infants ≤32 weeks of gestation., Conclusion: In the presence of physiological stress, premature infants are more at risk for hypoglycemia than term infants., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To evaluate umbilical cord messenger RNA (mRNA) expression as biomarkers for the grade of hypoxic-ischemic encephalopathy (HIE) and long-term neurodevelopment outcome., Study Design: Infants were recruited from the BiHiVE1 study, Ireland (2009-2011), and the BiHiVE2 study, Ireland, and Sweden (2013-2015). Infants with HIE were assigned modified Sarnat scores at 24 hours and followed at 18-36 months. mRNA expression from cord blood was measured using quantitative real-time polymerase chain reaction., Results: We studied 124 infants (controls, n = 37; perinatal asphyxia, n = 43; and HIE, n = 44). Fzd4 mRNA increased in severe HIE (median relative quantification, 2.98; IQR, 2.23-3.68) vs mild HIE (0.88; IQR, 0.46-1.37; P = .004), and in severe HIE vs moderate HIE (1.06; IQR, 0.81-1.20; P = .003). Fzd4 mRNA also increased in infants eligible for therapeutic hypothermia (1.20; IQR, 0.92-2.37) vs those who were ineligible for therapeutic hypothermia group (0.81; IQR, 0.46-1.53; P = .017). Neurodevelopmental outcome was analyzed for 56 infants. Nfat5 mRNA increased in infants with severely abnormal (1.26; IQR, 1.17-1.39) vs normal outcomes (0.97; IQR, 0.83-1.24; P = .036), and also in infants with severely abnormal vs mildly abnormal outcomes (0.96; IQR, 0.80-1.06; P = .013). Fzd4 mRNA increased in infants with severely abnormal (2.51; IQR, 1.60-3.56) vs normal outcomes (0.74; IQR, 0.48-1.49; P = .004) and in infants with severely abnormal vs mildly abnormal outcomes (0.97; IQR, 0.75-1.34; P = .026)., Conclusions: Increased Fzd4 mRNA expression was observed in cord blood of infants with severe HIE; Nfat5 mRNA and Fzd4 mRNA expression were increased in infants with severely abnormal long-term outcomes. These mRNA may augment current measures as early objective markers of HIE severity at delivery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Antenatal glucocorticoids improve outcomes among premature infants but are associated with hyperglycemia, which can exacerbate hypoxic-ischemic injury. It is still unclear how antenatal glucocorticoids or hyperglycemia modulate fetal cardiovascular adaptations to severe asphyxia. In this study, preterm fetal sheep received either saline or 12 mg im maternal dexamethasone, followed 4 h later by complete umbilical cord occlusion (UCO) for 25 min. An additional cohort of fetuses received titrated glucose infusions followed 4 h later by UCO to control for the possibility that hyperglycemia contributed to the cardiovascular effects of dexamethasone. Fetuses were studied for 7 days after UCO. Maternal dexamethasone was associated with fetal hyperglycemia ( P < 0.001), increased arterial pressure ( P < 0.001), and reduced femoral ( P < 0.005) and carotid ( P < 0.05) vascular conductance before UCO. UCO was associated with bradycardia, femoral vasoconstriction, and transient hypertension. For the first 5 min of UCO, fetal blood pressure in the dexamethasone-asphyxia group was greater than saline-asphyxia ( P < 0.001). However, the relative increase in arterial pressure was not different from saline-asphyxia. Fetal heart rate and femoral vascular conductance fell to similar nadirs in both saline and dexamethasone-asphyxia groups. Dexamethasone did not affect the progressive decline in femoral vascular tone or arterial pressure during continuing UCO. By contrast, there were no effects of glucose infusions on the response to UCO. In summary, maternal dexamethasone but not fetal hyperglycemia increased fetal arterial pressure before and for the first 5 min of prolonged UCO but did not augment the cardiovascular adaptations to acute asphyxia.

Brain interstitial pH (pHbrain) alterations play an important role in the mechanisms of neuronal injury in neonatal hypoxic-ischemic encephalopathy (HIE) induced by perinatal asphyxia. The newborn pig is an established large animal model to study HIE, however, only limited information on pHbrain alterations is available in this species and it is restricted to experimental perinatal asphyxia (PA) and the immediate reventilation. Therefore, we sought to determine pHbrain over the first 24h of HIE development in piglets. Anaesthetized, ventilated newborn pigs (n = 16) were instrumented to control major physiological parameters. pHbrain was determined in the parietal cortex using a pH-selective microelectrode. PA was induced by ventilation with a gas mixture containing 6%O2-20%CO2 for 20 min, followed by reventilation with air for 24h, then the brains were processed for histopathology assessment. The core temperature was maintained unchanged during PA (38.4±0.1 vs 38.3±0.1°C, at baseline versus the end of PA, respectively; mean±SEM). In the arterial blood, PA resulted in severe hypoxia (PaO2: 65±4 vs 23±1*mmHg, *p<0.05) as well as acidosis (pHa: 7.53±0.03 vs 6.79±0.02*) that is consistent with the observed hypercapnia (PaCO2: 37±3 vs 160±6*mmHg) and lactacidemia (1.6±0.3 vs 10.3±0.7*mmol/L). Meanwhile, pHbrain decreased progressively from 7.21±0.03 to 5.94±0.11*. Reventilation restored pHa, blood gases and metabolites within 4 hours except for PaCO2 that remained slightly elevated. pHbrain returned to 7.0 in 29.4±5.5 min and then recovered to its baseline level without showing secondary alterations during the 24 h observation period. Neuropathological assessment also confirmed neuronal injury. In conclusion, in spite of the severe acidosis and alterations in blood gases during experimental PA, pHbrain recovered rapidly and notably, there was no post-asphyxia hypocapnia that is commonly observed in many HIE babies. Thus, the neuronal injury in our piglet model is not associated with abnormal pHbrain or low PaCO2 over the first 24 h after PA., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Optimal glucose metabolism is important in neonatal survival especially in the first days of life. Insulin play a significant role in maintaining blood glucose homeostasis. This study set out to determine the serum insulin levels of ill neonates as related to their point-of-admission blood glucose estimation at the Wesley Guild Hospital, Ilesa, Nigeria., Methods: Three hundred babies took part in the study. Blood glucose and serum insulin levels were assayed at admission using Accu-Chek Active glucometer (R) and Accu-Ɔ-Bind ELISA Microwells (R) respectively. Hyperglycaemia was defined as blood glucose ≥7mmol/L and hypoglycaemia as blood glucose <2.2mmol/L., Results: The median (IQR) age of the babies was 10.0 (0.5 - 70.0) hours with male to female ratio of 1.5:1. Seventy-four (24.7%) were preterms and 35 (11.7%) were small-for-gestational age. The mean (SD) blood glucose level of the babies was 4.1(2.1) mmol/L with a range of 0.6-13.4mmol/L. Hyperglycaemia and hypoglycaemia were observed in 18(6.0%) and 40(13.3%) babies respectively. The median (IQR) serum insulin level was 9.8(3.0-35.3) μIU/ml. There was weak positive correlation between serum insulin and blood glucose levels of the babies (r = 0.197, p = 0.001). Birth asphyxia was associated with lower serum insulin, while probable sepsis with relatively higher levels., Conclusion: Serum insulin level increases with increasing blood glucose in ill Nigerian babies at presentation to the hospital. Babies with asphyxia and sepsis particularly tend to have abnormal serum insulin at admission. Hyperinsulinaemia in ill babies may connote a compensatory mechanism to normalise abnormal blood glucose rather than playing significant role in its aetio-pathogenesis., Competing Interests: The authors declare no competing interests., (© Emmanuel Oluwatosin Adeniji et al.)

Low- and middle-income countries and resource-limited regions are major contributors to perinatal and infant mortality. Oxygen is widely used for resuscitation in high- and middle-income settings. However, oxygen supplementation is not available in resource-limited regions. Oxygen supplementation for resuscitation at birth has adverse effects in human/animal model studies. There has been a change with resultant recommendations for restrictive oxygen use in neonatal resuscitation. Neonatal resuscitation without supplemental oxygen decreases mortality and morbidities. Oxygen in resource-limited settings for neonatal resuscitation is ideal as a backup for selected resuscitations but should not be a limiting factor for implementing basic life-saving efforts., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: We hypothesized that compromised cardiac output in asphyxiated infants may influence on the rate of disappearance of lactate due to insufficient perfusion., Methods: The study was a prospective, observational study, where infants with perinatal asphyxia who met the criteria for therapeutic hypothermia were included. Cardiac output, stroke volume and heart rate were measured by electrical velocimetry in 15 newborn infants with perinatal asphyxia during the first six hours of active therapeutic hypothermia. Results from routine blood samples were collected retrospectively. Cardiac parameters were also measured in 10 healthy, term infants after caesarian section. Cardiac parameters were compared between the asphyxiated group and the control group prior to and during hypothermia. Rate of disappearance of lactate was correlated to cardiac output in the asphyxiated infants., Results: Cardiac output was stable in the healthy infants from 0.5 to 6 hours postnatally. The infants with perinatal asphyxia had lower cardiac output prior to and during therapeutic hypothermia compared to the control group. Rate of disappearance of lactate was not related to cardiac output., Conclusion: An association between disappearance of lactate acidosis and low cardiac output was not confirmed. A low rate of disappearance of lactate may rather be an indicator of organ injury due to asphyxia., Competing Interests: The authors have declared no competing interests exist.

Importance: Neonatal hypoxic-ischemic encephalopathy (HIE) remains a significant cause of neurologic disability. Identifying infants suitable for therapeutic hypothermia (TH) within a narrow therapeutic time is difficult. No single robust biochemical marker is available to clinicians., Objective: To assess the ability of a panel of candidate microRNA (miRNA) to evaluate the development and severity of encephalopathy following perinatal asphyxia (PA)., Design, Setting, and Participants: This validation study included 2 cohorts. For the discovery cohort, full-term infants with PA were enrolled at birth to the Biomarkers in Hypoxic-Ischemic Encephalopathy (BiHiVE1) study (2009-2011) in Cork, Ireland. Encephalopathy grade was defined using early electroencephalogram and Sarnat score (n = 68). The BiHiVE1 cohort also enrolled healthy control infants (n = 22). For the validation cohort, the BiHiVE2 multicenter study (2013-2015), based in Cork, Ireland (7500 live births per annum), and Karolinska Huddinge, Sweden (4400 live births per annum), recruited infants with PA along with healthy control infants to validate findings from BiHiVE1 using identical recruitment criteria (n = 80). The experimental design was formulated prior to recruitment, and analysis was conducted from June 2016 to March 2017., Main Outcomes and Measures: Alterations in umbilical cord whole-blood miRNA expression., Results: From 170 neonates, 160 were included in the final analysis. The BiHiVE1 cohort included 87 infants (21 control infants, 39 infants with PA, and 27 infants with HIE), and BiHiVE2 included 73 infants (control [n = 22], PA [n = 26], and HIE [n = 25]). The BiHiVE1 and BiHiVE2 had a median age of 40 weeks (interquartile range [IQR], 39-41 weeks) and 40 weeks (IQR, 39-41 weeks), respectively, and included 56 boys and 31 girls and 45 boys and 28 girls, respectively. In BiHiVE1, 12 candidate miRNAs were identified, and 7 of these miRNAs were chosen for validation in BiHiVE2. The BiHiVE2 cohort showed consistent alteration of 3 miRNAs; miR-374a-5p was decreased in infants diagnosed as having HIE compared with healthy control infants (median relative quantification, 0.38; IQR, 0.17-0.77 vs 0.95; IQR, 0.68-1.19; P = .009), miR-376c-3p was decreased in infants with PA compared with healthy control infants (median, 0.42; IQR, 0.21-0.61 vs 0.90; IQR, 0.70-1.30; P = .004), and mir-181b-5p was decreased in infants eligible for TH (median, 0.27; IQR, 0.14-1.41) vs 1.18; IQR, 0.70-2.05; P = .02)., Conclusions and Relevance: Altered miRNA expression was detected in umbilical cord blood of neonates with PA and HIE. These miRNA could assist diagnostic markers for early detection of HIE and PA at birth.

Objective: Morphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population., Study Design: Term and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008-2010 (SHIVER) and 2010-2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants., Results: 244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5°C) by 6.89%/°C (95% CI 5.37%/°C- 8.41%/°C, p<0.001) and metabolite clearance by 4.91%/°C (95% CI 3.53%/°C- 6.22%/°C, p<0.001) compared to normothermia (36.5°C). Simulations showed that a loading dose of 50 μg/kg followed by continuous infusion of 5 μg/kg/h resulted in morphine plasma concentrations in the desired range (between 10 and 40 μg/L) during hypothermia., Conclusions: Clearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect., Trial Registration: www.trialregister.nl NTR2529., Competing Interests: The authors have declared that no competing interests exist.

Background: Birth asphyxia is a leading case of neonatal morbidity and mortality especially in developing countries. Hypoxic-ischemic encephalopathy (HIE) attributed to asphyxia can be ameliorated with several remedies, although full recovery is currently not feasible. The aim of this trial on infants with HIE who are receiving melatonin therapy, is to assess the added effect of magnesium sulfate (MgSO4) on the expression of S100-B, a marker of brain injury., Methods: This study is a randomized controlled trial on neonates with moderate HIE (Sarnat grade II). Infants were randomized into 2 groups; group1 who received MgSO4 and melatonin; and group 2 who received melatonin only. Serum concentrations of S100-B were measured at baseline, and at days 2 and 6 of therapy., Results: The study included 60 neonates of them 30 infants in group 1 and 30 infants in group 2. S100-B did not differ between groups 1 and 2 at enrollment (median = 13.5 vs 13.2, p = 0.381). However, group 1 had lower concentrations of S100-B at 2 days (median = 8 vs 12, p = 0.001) and at 6 days (median = 3 vs 10.5, p < 0.001), respectively. Compared to baseline, S100-B decreased in in group 2 at day 6 (13.2 vs 10.5, p = 0.011) but did not decrease at day 2 (13.2 vs 12, p = 0.478)., Conclusions: MgSO4 may have an added effect for the reduction in brain injury in infants with HIE who are receiving melatonin.

Objectives: The objective of this study is to document and compare plasma electrolytes of asphyxiated newborns of different degree within 48 hours of life., Study Disign: A comparative cross-sectional study was conducted in the newborn special care unit at the University of Nigeria Teaching Hospital (UNTH), Enugu, South-East Nigeria. Sodium, potassium, bicarbonate and ionized calcium levels were estimated in the plasma samples of neonates with perinatal asphyxia of different degree and healthy newborns (control group) within 48 hours of birth., Main Outcome Measures: The plasma sodium, potassium, bicarbonate and ionized calcium levels were estimated in both, the study subjects and controls., Results: Mean plasma sodium level was significantly lower (134.93±5.24 mmol/l vs 141.90±3.36 mmol/l; P < 0.05), mean plasma bicarbonate level was significantly lower (16.98±3.99 mmol/l vs 18.54±2.36 mmol/l; P < 0.05), and mean plasma ionized calcium level was significantly lower (1.10±0.14 mmol/l vs 1.25 0.11 mmol/l; P < 0.05) in subjects compared to controls while mean plasma potassium was significantly higher (5.07±0.93 mmol/l vs 4.65±0.51 mmol/l P < 0.05) in subjects compare to controls., Conclusion: The tendency to have hyponatremia, hyperkalemia, acidosis and hypocalcemia is very high among the study subjects which underscores the need for great vigilance in electrolyte monitoring when managing an asphyxiated baby.

Background: Neonatal hypoxic ischemic encephalopathy (HIE) is a potentially devastating disorder associated with significant mortality and long-term morbidity., Objective: The aim of this study was to study the role of vitamin D as an adjuvant therapy for management of neonatal HIE., Patients and Methods: This study was carried out on 60 neonates with HIE grade II who were diagnosed according to modified Sarnat staging and were divided in to 2 groups: Group I: Included 30 neonates with Sarnat grade II HIE who received single daily oral dose of vitamin D3 (1000 IU) for 2 weeks in addition to daily subcutaneous (SC) human recombinant erythropoietin (2500 IU/kg) for 5 days and IM or IV magnesium sulphate 250 mg/kg within half an hour of birth, and subsequently 125 mg/kg at 24 and 48 hours of life. Group II: Included 30 neonates with HIE grade II who received erythropoietin and magnesium sulphate as group I but without vitamin D. Two blood samples were taken from all neonates included in both groups; the 1st at diagnosis and the 2nd after 2 weeks of therapy. This study included also 30 healthy neonates as a control group. All neonates included in this study were subjected to: complete clinical examination with assessment of Apgar score at 5 and 10 minutes, measurement of arterial blood gases and serum 25 (OH) vitamin D, calcium, phosphorus, S100-B and IL-17 levels., Results: Before therapy, there were no significant differences between group I and II in PH, PO2 and PCO2 (p= 0.294, 0.462, 0.758 respectively), but after 2 weeks of therapy, there were significantly higher PH levels in group I compared with group II (p <0.001) while there were no significant differences between group I and II regarding PO2 and PCO2. Before therapy, there were no significant differences in serum 25(OH) vitamin D levels between group I and II while there were significantly lower serum 25(OH) vitamin D levels in group I and II compared with controls (P1; comparison between group I and II = 0.742, P2; comparison between group I and controls = 0.001 and P3; comparison between group II and controls = 0. 001). There were no significant differences between group I and II and between group I and II and control as regard serum calcium (P1= 0.943, P2= 0.875 and P3= 0.764) and phosphorus (P1= 0.862, P2= 0.921, P3= 0.786). There were no significant differences between group I and II regarding serum IL-17 levels while there were significantly lower serum IL-17 levels in group I and II compared with controls (P1 = 0.457, P2 = 0.043 and P3 = 0.023). Before therapy, there were no significant differences in serum S100-B levels between group I and II while there were significantly higher serum S100-B levels in group I and II compared with control (P1 = 0.381, P2 = 0.001 and P3= 0.001) but after therapy, there were significantly higher S100-B levels in group II compared with group I and significantly higher S100-B levels in group I and II compared with control (P1= 0.001, P2= 0.043, P3 = 0.001). There were significant negative correlations in group I between serum S100-B and PH and between S100-B and serum vitamin D before and after therapy., Conclusion: Vitamin D was found to improve the cases of group I as demonstrated by the reduction of serum S100-B levels after vitamin D therapy., Recommendations: Extensive multicenter studies are required on a large number of patients with Sarnat grade II HIE with longer duration of follow up to give valid recommendations about the use of vitamin D as an adjuvant therapy in Sarnat grade II HIE., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Perinatal asphyxia is a severe medical condition resulting from oxygen deficiency (hypoxia) at the time of birth, causing worldwide approximately 680,000 newborn deaths every year. Better prediction of severity of damages including early biomarkers is highly demanded. Elevated levels of circulating cell-free DNA (cfDNA) in blood have been reported for a range of different diseases and conditions, including cancer and prematurity. The objective of this study was to validate methods for assessing cfDNA in blood and cerebrospinal fluid (CSF) and to explore temporal variations in a piglet model of neonatal hypoxia-reoxygenation. Different cfDNA extraction methods in combination with cfDNA detection systems were tested, including a fluorescent assay using SYBR Gold and a qRT-PCR-based technique. Newborn piglets (n = 55) were exposed to hypoxia-reoxygenation, hypoxia-reoxygenation and hypothermia, or were part of the sham-operated control group. Blood was sampled at baseline and at post-intervention, further at 30, 270, and 570 minutes after the end of hypoxia. Applying the fluorescent method, cfDNA concentration in piglets exposed to hypoxia (n = 32) increased from 36.8±27.6 ng/ml prior to hypoxia to a peak level of 61.5±54.9 ng/ml after the intervention and deceased to 32.3±19.1 ng/ml at 570 minutes of reoxygenation, whereas the group of sham-operated control animals (n = 11) revealed a balanced cfDNA profile. Animals exposed to hypoxia and additionally treated with hypothermia (n = 12) expressed a cfDNA concentration of 54.4±16.9 ng/ml at baseline, 39.2±26.9 ng/ml at the end of hypoxia, and of 41.1±34.2 ng/ml at 570 minutes post-intervention. Concentrations of cfDNA in the CSF of piglets exposed to hypoxia revealed at post-intervention higher levels in comparison to the controls. However, these observations were only tendencies and not significant. In a first methodological proof-of-principle study exploring cfDNA using a piglet model of hypoxia-reoxygenation variations in the temporal patterns suggest that cfDNA might be an early indicator for damages caused by perinatal asphyxia., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate the correlation between the corrected QT dispersion (QTcd) and serum potassium/sodium levels in order to evaluate their significance for early diagnosis of neonatal asphyxia., Patients and Methods: This study included 124 neonatal asphyxia patients. These patients were divided into mild and severe asphyxia groups based on their clinical features and diagnostic indexing. Sixty healthy infants were selected as controls. QTcd, and serum cardiac troponin T (cTNT), potassium and sodium levels in the three groups were compared, and the correlation between QTcd and serum potassium/sodium was analyzed by Spearman correlation tests., Results: Both mild and severe groups developed significantly higher cTnT and QTcd (p < 0.05), but lower serum potassium and sodium compared with control group (p < 0.05). The severe group had significantly higher cTnT and QTcd (p < 0.05), but lower serum potassium and sodium when compared with mild group (p < 0.05). The serum potassium and sodium were both negatively correlated with QTcd (p < 0.05)., Conclusions: Serum potassium and sodium can be used as indicators for neonatal asphyxia, which may markedly improve early diagnosis, prognosis and treatment efficacy.to the progression of atherosclerosis, which could be a potential target for treating atherosclerosis.

Objectives: To describe the diagnostic test properties of Cardiac Troponin-T (cTnT) in predicting myocardial dysfunction in asphyxiated term neonates by taking echocardiography as the gold standard and to establish the optimum cut-off values of cTnT for myocardial dysfunction, shock, severe hypoxic ischemic encephalopathy (HIE) and mortality by receiver operator characteristic (ROC) curve analysis., Methods: This was a prospective study based on diagnostic test evaluation. The study included 120 term asphyxiated neonates in a tertiary care neonatal intensive care unit (NICU) in Southern India from June 2011 through June 2015. All the neonates were clinically evaluated. Venous blood was taken at 4 h of life for cTnT estimation. Echocardiography was done within 24 h of birth., Results: The mean cTnT level of asphyxiated term neonates was 0.207±0.289 ng/ml (mean ± SD). Asphyxiated neonates with myocardial dysfunction had higher cTnT levels (0.277±0.231) as compared to those without myocardial dysfunction (0.061±0.036, p = 0.0001). Using ROC curve, the cut-off cTnT values for myocardial dysfunction was 0.1145 ng/ml with sensitivity 92.4% and specificity 94.1%. Cardiac Troponin-T levels were significantly higher among asphyxiated neonates with shock (0.378±0.348, p = 0.0001) and the levels also correlated positively with increasing grades of HIE. The cut-off cTnT value for mortality was 0.2505 ng/ml with sensitivity 83.9% and specificity 96.6%., Conclusions: In asphyxiated term neonates, early cTnT elevation is a marker for predicting myocardial dysfunction and elevated cTnT levels had high sensitivity and specificity. There was significant relation with increasing cTnT values and increasing grades of HIE.

Complication of perinatal asphyxia is a major cause of neonatal mortality & morbidity in developing countries. This comparative cross sectional study was conducted in Mymensingh Medical College Hospital, Mymensingh, Bangladesh from May 2012 to September 2012 to determine electrolytes & renal function status in perinatal asphyxia & their impact on outcome. Thirty term normal birth weight babies with perinatal asphyxia in neonatal ward were included as a case group and thirty term normal birth weight neonates of same gestational age, without perinatal asphyxia in the department of Gynae & Obs were enrolled as a control group. Necessary information was collected by clinical examination; investigation and close follow up according to predetermined plan. There was no significant different in sex distribution, number of Antenatal care (ANC), number of gravidum of mother and mode of delivery between two groups. Among perinatal Asphyxia group most common risk factor was prolonged labor. Electrolyte abnormalities were documented (16) 53.3% cases. Among 16 electrolyte abnormalities isolated hyponatremia was found in 6(37.5%) cases, hyponatremia with hyperkalaemia 1(6.25%) case, hyponatremia with hypokalaemia in 1(6.25%) case, isolated hypokalaemia in 3(18.75%) cases and isolated hyperkalaemia in 5(31.25%) cases. None case had hypernatremia. On the other hand in control group Hypokalaemia was 3(10%) cases Hyperkalaemia 1(33.33%) case and none had Hyponatraemia. Among total cases 6 (20%) had renal impairment. Serum creatinine level was higher in case group. Twenty percent (20%) case initial value >1.5mg/dl, 20% 1.2-1.5mg/dl and17% had 0.3-0.8mg/dl. On the other hand in control group 83 % had 0.3-0.8 mg/dl & none hade above 1.1 mg/dl. Among case group 8 were died (27%). There was no death in control group. Among 8 neonatal death cases 3(37.5%) had normal electrolytes, isolated hyponatraemia were in 2(25%) cases, hyponatraemia with Hyperkalaemia in 1(6.25%) case and Isolated Hyperkalaemia in 2(25%) cases. Among those death 3(37.5%) had renal impairment. Case fatality was significantly associated with renal failure 50%, isolated Hyponatraemia 33.33%, Isolated hyperkalaemia 40%, Hyperkalaemia with Hyponatremia 100%. Hospital stay was also prolonged among alive case with abnormal electrolytes. So, we can conclude that electrolyte & renal impairments are significantly associated with morbidity & mortality of perinatal Asphyxia.

Aim: Compare the levels of the brain injury biomarkers Tau and neurofilament light protein (NFL) in cases of asphyxia with those in controls., Materials and Methods: We analyzed the neuronal proteins Tau and NFL in umbilical blood of 10 cases of severe-moderate intrapartum asphyxia and in 18 control cases., Results: The levels of both Tau and neurofilament were significantly higher after asphyxia and it appeared to be a correlation between the levels of the biomarkers and the severity of the insult., Discussion: Future studies are warranted to support or refute the value of Tau/NFLin clinical practice., Conclusion: Fetal asphyxia remains a clinical problem resulting in life-long neurological disabilities. We urgently need more accurate early predictive markers to direct the clinician when to provide neuroprotective therapy.

Introduction: Multi-organ injury causes leakage of several intracellular enzymes into the circulation. We evaluated the correlation between the serum-leaked intracellular enzyme levels at the beginning of treatment and the outcome in perinatally stressed neonates., Materials and Methods: We retrospectively studied neonates whose 1 minute Apgar score was < 7. We collected initial venous blood sample data, including aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), and creatine kinase (CK) levels, and correlated these with patient short-term outcomes., Results: Of 60 neonates, nine patients were treated with therapeutic hypothermia, and 32 needed mechanical ventilation. The therapeutic hypothermia group showed significantly larger base deficit, and higher lactate, AST, ALT, LDH, and CK (all p < 0.01). The duration of mechanical ventilation significantly correlated with AST, ALT, LDH, and CK levels (all p < 0.01)., Conclusion: Initial enzyme levels are useful for predicting the duration of mechanical ventilation in stressed neonates.

Objective: To estimate cord blood amino acid and acylcarnitine levels in term newborns exposed to perinatal asphyxia., Materials and Methods: We studied 45 asphyxiated term newborns (cases) and 20 gestational age-matched healthy newborns (control). 16 cases developed HIE according to clinical scoring and amplitude-integrated electroencephalography. Asphyxiated cases were accordingly subdivided into: HIE group (n = 16) and Asphyxia group (n = 29). Amino acid and acylcarnitine levels were measured in cord blood dried spot samples from all newborns using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Data were analyzed using one-way ANOVA with post hoc test and MetaboAnalyst-2., Results: Distinct metabolite alterations were detected in cases versus control, in HIE versus Asphyxia, and in Survivors within HIE group (n = 6) versus nonsurvivors (n = 10). Principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) showed increased levels of methionine and certain acylcarnitines, but reduced levels of ornithine, histidine, and arginine. Metabolite set enrichment analysis (MSEA); compared to KEGG library metabolite sets, identified some disorders with similar metabolomic derangements., Conclusions: We report UPLC-MS detectable alterations of amino acids and acylcarnitines in asphyxiated newborns at birth, that can serve as early diagnostic bedside biomarkers for HIE and predictors for its short-term outcome, and in the near future, as therapeutic targets.

Background: Thyroid function in asphyxiated newborns who received hypothermia therapy and its relation to neurological outcome are not well described., Methods: We performed a prospective study to measure thyroid function in 12 asphyxiated newborns who received hypothermia therapy. We measured serum thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) on admission, at 24, 72, and 96 h after birth, and at discharge (range, 17-54 days). The 12 newborns were divided into two groups based on the presence of brain injury on head magnetic resonance imaging (six in the abnormal imaging group and six in the normal imaging group), and thyroid function was compared between the two groups., Results: Serum TSH was within the normal range in the 12 newborns. Serum FT3 and FT4 remained low at 24, 72, and 96 h after birth, and returned to normal range at discharge in the 12 newborns. There was no significant difference in serum TSH between the two groups, but serum FT3 at 96 h after birth, and serum FT4 at 72 and 96 h after birth, were significantly lower in the abnormal imaging group than in the normal imaging group (P = 0.02; P = 0.03; and P = 0.01, respectively)., Conclusions: Asphyxiated newborns have transient low thyroid hormone levels at 24-96 h after birth. Serum FT3 and FT4 between 72 and 96 h after birth may predict brain injury in asphyxiated newborns., (© 2018 Japan Pediatric Society.)

Objective: To determine the usefulness of measures, available shortly after birth, as predictors of hypoxic-ischemic encephalopathy (HIE) following perinatal asphyxia., Patients: All inborn patients at Southmead Hospital between January 2012 and March 2014 at ≥36 weeks gestation with a pH <7 or BE >16 on cord or baby's blood within one hour of birth or 10-minute Apgar score ≤5 or requiring intermittent positive pressure ventilation at 10 minutes were eligible for inclusion., Methods: ROC curves were derived for the perinatal clinical and biochemical measures to establish their predictive values for the development of HIE and the area under the curve (AUC) used as the measure of prediction., Results: We identified 79 eligible babies. Infants qualifying for therapeutic hypothermia (TH) based on aEEG abnormalities were considered to have HIE (n = 13; 16.5%), whereas babies with normal aEEG were classified as "non-HIE" (n = 66; 83.5%). The highest AUC measure was associated with the five-minute Apgar score (0.89 (0.79-0.99)). Troponin T (0.81 (0.64-0.98)) and ALT (0.78 (0.60-96)) also showed high values., Conclusions: In this work, the Apgar score, troponin T and ALT were found to be strong and useful predictors of HIE.

Background: Therapeutic hypothermia is neuroprotective in asphyxiated neonates by counteracting mechanisms contributing to brain injury. Although an initial increased permeability is part of an inflammatory reaction and thereby a natural healing process, an excessive endothelial permeability with edema formation may result in impaired hemodynamics. Reduced permeability may, however, benefit healing. Although plasma and interstitial colloid osmotic pressure are accessible and essential parameters for understanding fluid imbalance, the mechanisms of fluid exchange remain poorly understood. The potential influence of therapeutic hypothermia on plasma and interstitial colloid osmotic pressure, and the relationship between inflammatory markers and colloid osmotic pressure in asphyxiated neonates, was investigated., Methods: Seventeen neonates with moderate to severe hypoxic ischemic encephalopathy, born after 35 weeks gestation, received servo-controlled whole body cooling before 6 h of age, followed by gradual rewarming after 72 h. All infants were treated according to a national hypothermia protocol. Interstitial fluid in the skin was collected at 7, 13, 25, 49, and 73 h after birth by subcutaneous implantation of multifilamentous nylon wicks with 60 min of implantation time. Biomarkers of inflammation and colloid osmotic pressure were measured in serum and interstitial fluid., Results: A modest decrease in serum and interstitial colloid osmotic pressure was measured, leaving an unaltered difference in colloid osmotic pressure gradient. A decline in mean arterial pressure was observed between 7 and 13 h of life, with a concomitant decrease in positive fluid balance within the same time frame. White blood cell count and leukocyte subclasses dropped significantly throughout treatment, with elevated interstitial interleukin (IL)-1α and decreased serum IL-1RA, IL-6, and IL-10 during treatment time points., Conclusions: Colloid osmotic pressures measured in serum and interstitial fluid during asphyxia is lower than previously reported, with small alteration of pressure differences across capillaries, reducing vascular filtration. An inherent local and systemic regulation of inflammation together with changes in colloid osmotic pressure may indicate a possible preventive mechanism of edema generation during neonatal asphyxia and therapeutic hypothermia., Trial Registration: ClinicalTrials.gov Identifier: NCT01044940 . Date of registration: January 8, 2010.

The role of inflammation is an important factor in the progression of hypoxic-ischaemic encephalopathy (HIE). We have previously shown that interleukin-16 (IL-16) is increased in infants with moderate and severe HIE and relates to poor neurodevelopmental outcomes. We aimed to validate IL-16 as a cord blood-based biomarker for HIE and to examine its relationship to long-term outcomes. The study sample consisted of 105 full-term infants who experienced perinatal asphyxia (PA) (with and without an encephalopathy) along with healthy, gestational age-matched newborn controls. Umbilical cord blood serum was processed and biobanked at delivery. Infants were assigned a modified Sarnat score at 24 h. Analysis of IL-16 cytokine cord blood levels was performed using the sandwich-based enzyme-linked immunosorbent assay (ELISA) technique. Cord blood-based IL-16 was increased in infants with PA and HIE relative to controls (p = 0.025). IL-16 was also increased in the HIE group relative to controls (p = 0.042). There was no significant difference in IL-16 across grades of HIE or in those with abnormal outcomes at 2 years of age. This study validates findings that cord blood-based IL-16 levels are increased in infants with PA, including those who go on to develop HIE., (© 2018 S. Karger AG, Basel.)

Background: Neuroinflammation and a systemic inflammatory reaction are important features of perinatal asphyxia. Neuroinflammation may have dual aspects being a hindrance, but also a significant help in the recovery of the CNS. We aimed to assess intracellular cytokine levels of T-lymphocytes and plasma cytokine levels in moderate and severe asphyxia in order to identify players of the inflammatory response that may influence patient outcome., Methods: We analyzed the data of 28 term neonates requiring moderate systemic hypothermia in a single-center observational study. Blood samples were collected between 3 and 6 h of life, at 24 h, 72 h, 1 week, and 1 month of life. Neonates were divided into a moderate (n = 17) and a severe (n = 11) group based on neuroradiological and amplitude-integrated EEG characteristics. Peripheral blood mononuclear cells were assessed with flow cytometry. Cytokine plasma levels were measured using Bioplex immunoassays. Components of the kynurenine pathway were assessed by high-performance liquid chromatography., Results: The prevalence and extravasation of IL-1b + CD4 cells were higher in severe than in moderate asphyxia at 6 h. Based on Receiver operator curve analysis, the assessment of the prevalence of CD4+ IL-1β+ and CD4+ IL-1β+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia. Intracellular levels of TNF-α in CD4 cells were increased at all time points compared to 6 h in both groups. At 1 month, intracellular levels of TNF-α were higher in the severe group. Plasma IL-6 levels were higher at 1 week in the severe group and decreased by 1 month in the moderate group. Intracellular levels of IL-6 peaked at 24 h in both groups. Intracellular TGF-β levels were increased from 24 h onwards in the moderate group., Conclusions: IL-1β and IL-6 appear to play a key role in the early events of the inflammatory response, while TNF-α seems to be responsible for prolonged neuroinflammation, potentially contributing to a worse outcome. The assessment of the prevalence of CD4+ IL-1β+ and CD4+ IL-1β+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia.

Objective: Nucleated-red-blood-cells (NRBC) count in umbilical cord of newborns is been suggested as a sign of birth asphyxia. The present study was conducted to explore the value of NRBC count in prognosis of asphyxiated neonates., Methods: Sixty-three neonates with asphyxia were followed up for two years. Maternal and neonatal information was recorded follow by clinical and laboratory evaluation. NRBC-level was determined per 100 white-blood-cells (WBC). After discharge, follow-up of asphyxiated infants was performed using Denver II test at 6, 12, 18 and 24 months. Neonates were divided into two groups, with favorable and unfavorable outcome based on developmental delay or death., Results: We observed that NRBC count with more than 11 per 100 WBC, had sensitivity of 85% and specificity of 90% in predicting complications of asphyxia, while in absolute NRBC count with more than 1554, the sensitivity and specificity were 85% and of 87%, respectively. Combination of NRBC + HIE (hypoxic ischemic encephalopathy) grade had a high-predictive power for determining the prognosis of asphyxia in neonates., Conclusion: We demonstrate that NRBC/100 WBC and absolute NRCB count can be used as prognostic marker for neonatal asphyxia, which in combination with the severity of asphyxia could indicate high infant mortality, and complications of asphyxia. Further studies in a larger and multi center setting trail are warranted to investigate the value of NRBC and HIE in asphyxiate term infants.

The objective of this study was to evaluate the early changes in serial serum levels of copeptin and neuron-specific enolase (NSE) in neonates diagnosed with birth asphyxia, and to determine whether these biomarkers measured in the first 168 hours after birth are predictive of long-term neurodevelopmental outcome. Copeptin and NSE levels were measured from serum samples collected 6, 12, 24, 48, 72, and 168 hours after birth from 75 term neonates diagnosed with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia for 72 hours. In addition, serum copeptin levels after birth were measured from 10 HIE diagnosed neonates, who were randomized to the normothermic arm of the TOBY cohort. All neonates underwent neurodevelopmental assessment using the Bayley Scales of Infant and Toddler Development-II at two years of age. Copeptin levels were highest at 6 hours after birth and steadily decreased, whereas the highest NSE levels were measured at 24 hours after birth. The biomarker levels correlated with blood-gas parameters (base excess, pH and lactate) at 6 and 12 hours after birth. Copeptin and NSE levels in the early postnatal period were significantly higher in neonates with poor outcome compared to those with favorable outcome at two years of age. Furthermore, in the TOBY cohort, copeptin levels were significantly lower in hypothermic compared to normothermic neonates. To conclude, copeptin and NSE measured in the early postnatal period are potential prognostic biomarkers of long-term neurodevelopmental outcome in term neonates diagnosed with HIE and treated with therapeutic hypothermia.

Background: Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating condition resulting from a sustained lack of oxygen during birth. The interest in identifying a relevant biomarker of HIE has thrown into limelight the role of protein S100B as a clinical diagnostic marker of hypoxic brain damage in neonates., Aims: To evaluate the diagnostic value of protein S100B, measured in umbilical cord blood immediately after birth, as a useful biomarker in the diagnosis of HIE Sarnat stages II-III as well as a marker for long-term mortality and morbidity., Study Design: Protein S100B was analyzed in cord blood sampled at birth from 13 newborns later diagnosed with stage II-III HIE and compared with 21 healthy controls. S100B concentrations were related to cord artery pH, amplitude-integrated electroencephalography (aEEG), stage of HIE, and death/sequelae up to an age of 6years. Both parametric and non-parametric statistics were used with a two-sided P<0.05 considered significant., Results: The difference in S100B concentration was marginally statistically significant between HIE cases and controls (P=0.056). Cord blood acidosis (P=0.046), aEEG pattern severity (P=0.030), HIE severity (P=0.027), and condition at 6-year follow-up (healthy/permanent sequelae/death; P=0.027) were all related to an increase in S100B concentration., Conclusions: Protein S100B in neonates suffering from HIE stages II-III appeared elevated in umbilical cord blood at birth. The S100B concentrations were positively associated to the severity of disease and the risk of suffering from neurodevelopmental sequelae and even death., (Copyright © 2017. Published by Elsevier B.V.)

Background: To explore the values of cystatin C (Cys-C) in asphyxial preterm babies as an effective endogenous marker of renal function., Methods: After birth, preterm infants with 5-minute Apgar score <8 were included into the asphyxia group. Finally, 276 preterm infants born in two neonatal intensive care units were studied (including 78 babies in the asphyxia group and 198 babies in the control group). Blood samples were obtained from peripheral veins on day 1, day 7, and day 28 when routine blood screening tests were performed., Results: In first day samples, the mean levels of Cys-C were 2.21 (1.49-2.98) mg/L with gestational age (GA) >32, 1.94 (1.37-2.76) mg/L with GA 28-32, and 1.87 (1.49-2.13) mg/L with GA <28 in the asphyxia group. In seventh day samples, the mean levels of Cys-C were 2.35 (1.57-3.26) mg/L with GA>32, 2.07 (1.42-2.90) mg/L with GA 28-32, and 1.69 (1.13-2.04) mg/L with GA <28. In twenty-eighth day samples, the mean levels of Cys-C were 1.92 (1.61-2.13) mg/L with GA>32, 1.79 (1.29-1.84) mg/L with GA 28-32, and 1.66 (1.21-2.10) mg/L GA <28. There were significant differences not only between the asphyxia and control groups, but also between the mild, moderate, and severe asphyxia groups., Conclusion: Cys-C has a good distinguishability in asphyxial neonates in spite of gestational age or birth weight in the Chinese population. Further studies with large numbers of cases are required to assess whether Cys-C could replace creatinine (Cr) and blood urea nitrogen (BUN) as an endogenous marker of renal function., (© 2016 Wiley Periodicals, Inc.)

Perinatal hypoxia-ischemia is a specific and important pathological event in neonatal care practice. The data on relationship between the concentrations of cytokines in blood and cerebrospinal fluid (CSF) and perinatal brain injury are scarce. The aim of this study is to evaluate changes in interleukin (IL-1β, IL-6, and IL-18) and tumor necrosis factor alpha (TNF-α) levels in newborns with perinatal hypoxia (PNH). CSF and serum samples of 35 term and near-term (35-40 weeks) newborns with PNH, at the age of 3-96 hours, were analyzed using enzyme-linked immunosorbent assay. Control group consisted of 25 non-asphyxic/non-hypoxic infants of the same age sampled for clinically suspected perinatal meningitis, but proven negative and healthy otherwise. The cytokine values in CSF and serum samples were determined in relation to initial hypoxic-ischemic encephalopathy (HIE) staged according the Sarnat/Sarnat method, and compared with neurological outcome at 12 months of age estimated using Amiel-Tison procedure. The concentrations of IL-6 and TNF-α in serum of PNH patients were significantly higher compared to control group (p = 0.0407 and p = 0.023, respectively). No significant difference between average values of cytokines in relation to the stage of HIE was observed. Significantly higher levels of IL-6 and IL-18 corresponded to a mildly abnormal neurological outcome, while higher levels of IL-6 and TNF-α corresponded to a severely abnormal neurological outcome, at 12 months of age. Elevated serum levels of IL-6 and TNF-α better corresponded with hypoxia/ischemia compared to CSF values, within 96 hours of birth. Also, higher serum levels of IL-6, TNF-α, and IL-18 corresponded better with abnormal neurological outcome at 12 months of age, compared to CSF values.

Hypoxic-ischemic encephalopathy (HIE) secondary to perinatal asphyxia is a leading cause of mortality and acquired long-term neurologic co-morbidities in the neonate. The most successful intervention for the treatment of moderate to severe HIE is moderate whole body hypothermia initiated within 6h from birth. The objective and prompt identification of infants who are at risk of developing moderate to severe HIE in the critical first hours still remains a challenge. This work proposes a metabolite score calculated based on the relative intensities of three metabolites (choline, 6,8-dihydroxypurine and hypoxanthine) that showed maximum correlation with hypoxia time in a consolidated piglet model for neonatal hypoxia-ischemia. The metabolite score's performance as a biomarker for perinatal hypoxia and its usefulness for clinical grading and decision making have been assessed and compared to the performance of lactate which is currently considered the gold standard. For plasma samples withdrawn before and directly after a hypoxic insult, the metabolite score performed similar to lactate. However, it provided an enhanced predictive capacity at 2h after resuscitation. The present study evidences the usefulness of the metabolite score for improving the early assessment of the severity of the hypoxic insult based on serial determinations in a minimally invasive biofluid. The applicability of the metabolite score for clinical diagnosis and patient stratification for hypothermia treatment has to be confirmed in multicenter trials involving newborns suffering from HIE., (Copyright © 2017. Published by Elsevier B.V.)

Objective: Asphyxia is a major cause of disabilities in term-born infants. Here we have explored the value in HIE (hypoxic-ischemic-encephalopathy) of using a combination of serum pro-oxidant/antioxidant balance (PAB) assay for predicting the prognosis of asphyxia., Method: Ninety term neonates with asphyxia were enrolled and followed up for two years. Serum PAB, demographic/biochemical characteristics of mothers, and their neonates were determined. The Denver II test was used to assess outcomes., Results: Of the 90 asphyxiated neonates, 47 (52.2%) had a normal outcome and 43 babies (47.8%) had abnormal outcome. Serum PAB levels in neonates with normal and abnormal outcomes were 17.1 ± 9.23 and 48.27 ± 41.30 HK, respectively. A combination of HIE intensity and PAB, compared to other indicators, had a higher predictive-value (95.2%) for outcomes in asphyxiated babies., Conclusion: We demonstrate that PAB in combination with HIE grade may have a better predictive value for the prognosis of asphyxiated babies and predicting future neurologic problems in asphyxiated term infants.

Objectives: Acute kidney injury (AKI) is defined as a decrease in glomerular filtration rate with an increase in serum creatinine (sCr). Perinatal asphyxia (PNA) may be etiological factor for AKI with oxidative stress also implicated. Paraoxonase 1 (PON1) activity has been reported to be decreased in renal disease. The aim of our study was to evaluate paraoxonase 1 (PON1) activity and oxidative stress during the first hours and first days of life and to determine if these parameters could discriminate neonates having AKI from those who do not., Methods: Serum samples at different time points after birth were obtained from 64 preterm newborns with PNA (45 defined as having AKI, 19 as non-AKI). Clinical markers, sCr, total oxidant status (TOS), total antioxidant status (TAS) and PON1 activity were measured., Results: The AKI group had more newborns with hypoxic ischemic encephalopathy, significantly higher serum creatinine (sCr) at 3 and 7d, total antioxidant status (TAS) at 7d; decreased PON1 at 4h, 6h and 7d than the non-AKI group. Within the AKI group, significant positive correlations were found between PON1 activity at 2h and TAS at 2h, PON1 activity at 4h and base deficit (BD); whereas negative correlations between PON1 activity at 2h and ΔsCr (at 24h and at 3d), PON1 activity at 7d and ΔsCr (at 24h and 3d). Oxidative stress status parameters indicated excellent discriminative potential at 4h, 6h and 7d., Conclusions: AKI neonates were characterised by a marked decrease in PON1 activity. PON1 activity may be an important factor for discrimination of newborns having AKI from those that do not., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This study tested the hypothesis that varying degrees of hemodynamic fluctuations seen after birth following immediate cord clamping were related to development of asphyxia with longer cord clamp-to-ventilation intervals, resulting in higher perinatal circulating levels of the catecholamines norepinephrine (NE) and epinephrine (Epi), and thus increased heart rate, blood pressures, and cardiac contractility after birth. Anesthetized preterm fetal lambs were instrumented with 1 ) aortic (AoT) and pulmonary trunk (PT) micromanometers to obtain pressures and the maximal rate of pressure rise (dP/d t max ) as a surrogate measure of ventricular contractility, and 2 ) an AoT catheter to obtain samples for blood gas and catecholamine analyses. After delivery, immediate cord clamping was followed by ventilation ∼40 s ( n = 7), ∼60 s ( n = 8), ∼90 s ( n = 9), or ∼120 s later ( n = 8), with frequent blood sampling performed before and after ventilation. AoT O 2 content fell rapidly after immediate cord clamping ( P < 0.001), with an asphyxial state evident at ≥60 s. Plasma NE and Epi levels increased progressively with longer cord clamp-to-ventilation intervals, with an exponential relation between falling AoT O 2 content and rising catecholamines ( R 2  = 0.64-0.67). Elevated circulating catecholamines persisted for some minutes after ventilation onset, with postbirth surges in heart rate, AoT and PT pressures, and AoT and PT dP/d t max linearly related to log e of catecholamine levels ( R 2  = 0.41-0.54, all P < 0.001). These findings suggest that 1 ) a greater degree of asphyxia-induced sympathoadrenal activation (reflected in elevated circulating catecholamine levels) occurs with longer intervals between immediate cord clamping and subsequent ventilation, and 2 ) this activation is a major determinant of hemodynamic fluctuations evident with birth., (Copyright © 2017 the American Physiological Society.)

Aim: Although birth asphyxia is a major risk factor for neonatal and childhood morbidity and mortality, it has not been investigated much in relation to attention deficit hyperactivity disorder (ADHD). We examined whether birth asphyxia measured by the pH of the blood in the umbilical artery cord was associated with childhood ADHD., Method: A population-based cohort of 295 687 children born in Finland between 1991 and 2002 was followed until December 31, 2007. ADHD was identified by the International Classification of Diseases, 10th edition, as a diagnosis of hyperkinetic disorder. We examined the risk of ADHD with varying pH values using Cox regression, taking time trends into consideration., Results: When compared to the reference group, a pH value below 7.10 was significantly associated with an increased risk of ADHD. The strongest risks were observed among children with a pH value <7.15 and a gestational age of <32 weeks. The pH value did not contribute much to the risk among children with an Apgar score of 0-3., Conclusion: Birth asphyxia, defined by low pH value, may predict an increased risk of ADHD in childhood. The association between the pH value and ADHD was homogenous when stratified by gestational age and the Apgar score., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Perinatal asphyxia and its complication, hypoxic-ischemic encephalopathy, are still among the major causes of perinatal mortality and morbidity. Despite accurate standard postnatal monitoring procedures, the post-insult period is crucial because at a time when radiologic pictures are still silent, brain damage may already be at a subclinical stage. Against this background, the measurement of quantitative parameters, such as constituents of nervous tissue, that are able to detect subclinical lesions at a stage when routine brain monitoring procedures are still silent, could be particularly useful. Therefore, in the present review we report the potentials and limitations of biomarkers in predicting outcome in neonates complicated by perinatal asphyxia., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Estimation of the neurological prognosis of infants suffering from perinatal asphyxia and signs of hypoxic-ischemic encephalopathy is of great clinical importance; however, it remains difficult to satisfactorily assess these signs with current standard medical practices. Prognoses are typically based on data obtained from clinical examinations and neurological tests, such as electroencephalography (EEG) and neuroimaging, but their sensitivities and specificities are far from optimal, and they do not always reliably predict future neurological sequelae. In an attempt to improve prognostic estimates, neurological research envisaged various biochemical markers detectable in the umbilical cord blood of newborns (NB). Few studies examining these biochemical factors in the whole blood of newborns exist. Thus, the aim of this study was to determine the expression and concentrations of proinflammatory cytokines (TNF-α, IL-1β and IL-6) and specific CNS enzymes (S-100 and enolase) in infants with perinatal asphyxia. These data were compared between the affected infants and controls and were related to the degree of HIE to determine their utilities as biochemical markers for early diagnosis and prognosis., Methods: The levels of the proinflammatory cytokines and enzymes were measured by enzyme-linked immunosorbent assay (ELISA) and Reverse Transcription polymerase chain reaction (RT-PCR)., Results: The expression and serum levels of the proinflammatory cytokines, enolase and S-100 were significantly increased in the children with asphyxia compared with the controls., Conclusion: The role of cytokines after hypoxic-ischemic insult has been determined in studies of transgenic mice that support the use of these molecules as candidate biomarkers. Similarly, S-100 and enolase are considered promising candidates because these markers have been correlated with tissue damage in different experimental models., (Copyright © 2016. Published by Elsevier B.V.)

The prompt and reliable identification of infants at risk of hypoxic-ischemic encephalopathy secondary to perinatal asphyxia in the first critical hours is important for clinical decision-making and yet still remains a challenge. This work strives for the evaluation of a panel of metabolic biomarkers that have been associated with the hypoxic-ischemic insult in the perinatal period. Plasma and urine samples from a consolidated newborn piglet model of hypoxia and withdrawn before and at different time points after a hypoxic insult were analyzed and compared to a control group. Time-dependent metabolic biomarker profiles were studied and observed patterns were similar to those of lactate levels, which are currently considered the gold standard for assessing hypoxia. Class prediction performance could be improved by the use of a combination of the whole panel of determined metabolites in plasma as compared to lactate values. Using a multivariate model including lactate together with the studied metabolic biomarkers allowed to improve the prediction performance of duration of hypoxia time, which correlates with the degree of brain damage. The present study evidences the usefulness of choline and related metabolites for improving the early assessment of the severity of the hypoxic insult.

Aim: The creatine phosphokinase (CPK) level is believed to increase in neonatal peripheral blood after tissue damage, including damage from perinatal hypoxia. However, it is not clear whether it is truly a reliable marker for fetal hypoxia. We investigated the chronological changes in neonatal CPK and the reliability of CPK as a marker for fetal hypoxia., Methods: Sixty term neonates admitted to the neonatal intensive care unit at Tokyo Women's Medical University Medical Center East from April 2009 to April 2010 were enrolled in this study. We evaluated whether asphyxia and fetal heart rate (FHR) abnormality could predict the neonatal CPK level by using receiver-operator curve analysis. We also compared umbilical cord blood pH levels with neonatal CPK levels. In addition, we investigated factors that influence neonatal CPK in non-asphyxia cases., Results: The median value of CPK peaked on day 1. There were no significant differences in CPK levels regardless of the presence of asphyxia or FHR abnormality. Non-asphyxiated neonates with older gestational ages and amniotic fluid abnormalities had significantly higher levels of CPK., Conclusion: Our results indicate that the neonatal CPK level is not an appropriate marker for retrospectively predicting either asphyxia or FHR abnormality. There are influencing factors other than asphyxia that increase neonatal CPK. Therefore, one should be careful when making a diagnosis of perinatal hypoxia based solely on increased levels of neonatal CPK after birth., (© 2016 Japan Society of Obstetrics and Gynecology.)

Aim: This study compared obstetric units practicing routine or selective umbilical cord blood gas analysis, with respect to the risk of missing samples in high-risk deliveries and in infants with birth asphyxia., Methods: This was a Swedish population-based cohort study that used register data for 155 235 deliveries of live singleton infants between 2008 and 2014. Risk ratios and 95% confidence intervals were calculated to estimate the association between routine and selective umbilical cord blood gas sampling strategies and the risk of missing samples., Results: Selective sampling increased the risk ratios when routine sampling was used as the reference, with a value of 1.0, and these were significant in high-risk deliveries and birth asphyxia. The risk ratios for selective sampling were large-for-gestational age (9.07), preterm delivery at up to 36 weeks of gestation (8.24), small-for-gestational age (7.94), two or more foetal scalp blood samples (5.96), an Apgar score of less than seven at one minute (2.36), emergency Caesarean section (1.67) and instrumental vaginal delivery (1.24)., Conclusion: Compared with routine sampling, selective umbilical cord blood gas sampling significantly increased the risks of missing samples in high-risk deliveries and in infants with birth asphyxia., (©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Activation of the inflammatory pathway is increasingly recognized as an important mechanism of injury following neonatal asphyxia and encephalopathy. This process may contribute to the poor prognosis seen in some cases, despite therapeutic hypothermia. Our group has previously identified raised interleukin (IL)-6 and IL-16, measured in umbilical cord blood at birth, to be predictive of grade of hypoxic-ischaemic encephalopathy (HIE). Our aim in this study was to examine the ability of these cytokines to predict the 3-year neurodevelopmental outcome in the same cohort. As part of a prospective, longitudinal cohort study set in a single tertiary maternity unit, term infants with biochemical and clinical evidence of perinatal asphyxia were recruited at birth. Umbilical cord blood was collected and analyzed for IL-6 and IL-16 using a Luminex assay. The neurodevelopmental outcome of these infants was assessed at 3 years using the Bayley Scales of Infant and Toddler Development (Edition 3). Early cord blood measurement of IL-6 and IL-16 and long-term outcome were available in 33/69 infants. Median (IQR) IL-16 differentiated infants with a severely abnormal outcome (n = 6) compared to all others (n = 27), (646 [466-1,085] vs. 383.5 [284-494] pg/mL; p = 0.012). IL-16 levels were able to predict a severe outcome with an area under the receiver-operating characteristic (ROC) curve of 0.827 (95% CI 0.628-1.000; p = 0.014). Levels ≥514 pg/mL predicted a severe outcome with a sensitivity of 83% and a specificity of 81%. IL-16 also outperformed other routine biochemical markers available at birth for the prediction of severe outcome. APGAR scores at 1 and 10 min were also predictive of a severe outcome (p = 0.022 and p = 0.036, respectively). A combination of IL-16 with these clinical markers did not improve predictive value, but IL-16 combined with electroencephalogram grading increased the area under the ROC curve. IL-6 did not show any association with 3-year outcome. This is the first report studying the association of IL-16 measured at birth with long-term outcome in a cohort of neonates with perinatal asphyxia. IL-16 may be an early biomarker of severe injury and aid in the long-term prognostication in infants with HIE., (© 2017 S. Karger AG, Basel.)

Background: Troponin-T is a commonly used cardiac biomarker, which could be useful in perinatal asphyxia. We aimed to analyze troponin-T concentrations in asphyxiated neonates and to correlate the concentrations with clinical outcomes., Methods: Data were collected from electronic medical records of neonates diagnosed with perinatal asphyxia over a period of four years., Results: There were 63 neonates with moderate to severe encephalopathy, in whom serial troponin-T concentrations had been done on days 1, 3, and 7. 53 (84%) asphyxiated infants had troponin-T concentration >100 pg/ml at 2-4 h of life.The difference in troponin-T concentrations between moderate and severe encephalopathy was not statistically significant (173 vs. 263 pg/ml, p value 0.40). The difference in the concentrations at 72 hours between cooled and non-cooled neonates was not significant (48.5 vs. 62.5 pg/ml, p value 0.22). Troponin-T concentration was significantly higher in babies with hypotensive shock and hepatic injury, but not acute kidney injury. There was no significant correlation between troponin-T and the extent of resuscitation needed.Troponin-T concentration on day 1 of life was significantly higher in babies who died than who survived (407 vs. 168 pg/ml, p value 0.03). ROC curve for troponin-T to predict mortality had an area under the curve (AUC) of 0.803; the best cut-off value (190 pg/ml) had 82% sensitivity and 80% specificity., Conclusion: There was no significant difference in troponin-T concentrations between cooled and non-cooled neonates. Troponin-T concentration had a good predictive accuracy for mortality before discharge.

Background: Birth asphyxia, estimated to account for a million neonatal deaths annually, can cause a wide variety of neurodevelopmental impairments. There is a need to develop new, swift methods to identify those neonates who would benefit from neuroprotective treatments such as hypothermia., Objectives: To examine the utility of cord serum copeptin, a stable byproduct of arginine vasopressin release, as a biomarker of birth asphyxia based on a comparison with 2 biomarkers of hypoxia and brain trauma: erythropoietin and S100B., Methods: The study population consisted of 140 singleton, term neonates: 113 controls and 27 with birth asphyxia (2/3 criteria met: umbilical artery pH <7.10, base excess ≤12 mmol/L, and 5-min Apgar score <7). All deliveries were planned vaginal, but 51 neonates were born by emergency cesarean section. Copeptin, S100B, and erythropoietin levels in umbilical artery samples were measured by immunoassays., Results: Copeptin correlated in the entire study population more strongly with umbilical artery base excess than S100B and erythropoietin, and only copeptin correlated with arterial pH. Furthermore, only copeptin levels were significantly higher in cases of birth asphyxia, and in vaginally born neonates they were found to increase as a function of labor duration. Copeptin was elevated in neonates born via vacuum extraction, whereas erythropoietin levels showed a slight increase after emergency cesarean section., Conclusions: In this study population, S100B and erythropoietin were not valid biomarkers of birth asphyxia. In contrast, our work suggests that copeptin has high potential to become a routinely used biomarker for acute birth asphyxia and neonatal distress., (© 2017 S. Karger AG, Basel.)