Initial lactate levels linked to oliguria in term neonates with perinatal asphyxia.

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.

Evaluation of Myocardial Injury Using Serum Cardiac Troponin-I in Asphyxiated Neonates at Enugu State University Teaching Hospital, Enugu, South-East Nigeria.

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.

Up-Regulation of Nfat5 mRNA and Fzd4 mRNA as a Marker of Poor Outcome in Neonatal Hypoxic-Ischemic Encephalopathy.

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.

Glucose Levels during the First 24 Hours following Perinatal Hypoxia.

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.

Acute Kidney Injury in Neonates with Perinatal Asphyxia Receiving Therapeutic Hypothermia.

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.

Effects of antenatal dexamethasone and hyperglycemia on cardiovascular adaptation to asphyxia in preterm fetal sheep.

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.

Validation of Raised Cord Blood Interleukin-16 in Perinatal Asphyxia and Neonatal Hypoxic-Ischaemic Encephalopathy in the BiHiVE2 Cohort.

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.

Transcapillary fluid flux and inflammatory response during neonatal therapeutic hypothermia: an open, longitudinal, observational study.

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.

Thyroid function in asphyxiated newborns who received hypothermia therapy.

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.

Correlations of Enzyme Levels at Birth in Stressed Neonates with Short-Term Outcomes.

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.

Cord Blood IL-16 Is Associated with 3-Year Neurodevelopmental Outcomes in Perinatal Asphyxia and Hypoxic-Ischaemic Encephalopathy.

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.

Distinct cytokine patterns may regulate the severity of neonatal asphyxia-an observational study.

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-1ß+ and CD4+ IL-1ß+ 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-ß levels were increased from 24 h onwards in the moderate group. CONCLUSIONS: IL-1ß 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-1ß+ and CD4+ IL-1ß+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia.

Greater sympathoadrenal activation with longer preventilation intervals after immediate cord clamping increases hemodynamic lability at birth in preterm lambs.

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/dtmax) 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 O2 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 O2 content and rising catecholamines (R2 = 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/dtmax linearly related to loge of catecholamine levels (R2 = 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.

Change of cystatin C values in preterm infants with asphyxia-From two centers of China.

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.

Birth asphyxia measured by the pH value of the umbilical cord blood may predict an increased risk of attention deficit hyperactivity disorder.

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.

A policy of routine umbilical cord blood gas analysis decreased missing samples from high-risk births.

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.

Is the neonatal creatine phosphokinase level a reliable marker for fetal hypoxia?

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.

A study of microRNAs from dried blood spots in newborns after perinatal asphyxia: a simple and feasible biosampling method.

BACKGROUND: The potential of microRNAs (miRNAs) as bedside biomarkers in selecting newborns with hypoxic-ischemic encephalopathy (HIE) for neuroprotection has yet to be explored. Commonly, blood-based biomarker tests use plasma or serum which don't allow evaluation of both intracellular and extracellular changes. METHODS: We describe a technique to extract and compare expression of miRNAs from a single small 6-mm-diameter dried blood spot (DBS) stored at room temperature with those from EDTA-blood, plasma, and urine. Three miRNAs (RNU6B, let7b, and miR-21) were quantified via extraction and quantitative RT-PCR performed from a DBS and compared with levels from EDTA-blood, plasma, and urine. Secondarily, candidate miRNAs let7b, miR-21, miR-29b, miR-124, and miR-155 in DBS were evaluated as potential biomarkers for HIE. RESULTS: Candidate miRNAs were extractable in all biosamples from newborns, with the highest expression in DBS. There was a good correlation between miRNAs' levels in DBS and EDTA-blood at -80 °C. No significant difference was observed in the miRNA levels between the favorable and unfavorable outcome groups for babies with HIE. CONCLUSION: DBS may be useful for studying the potential of miRNAs as biomarkers for brain injury.

Potential protective role of endogenous glutamate-oxaloacetate transaminase against glutamate excitotoxicity in fetal hypoxic-ischaemic asphyxia.

AIM: Fetal blood contains higher concentrations of glutamate-oxaloacetate transaminase (GOT; a blood enzyme able to metabolize glutamate) than maternal blood. The aim of this study was to determine the relationship between GOT and glutamate levels in arterial blood samples from umbilical cord in control newborn infants and newborn infants with hypoxic-ischaemic insult and/or symptoms of hypoxia-ischemia after delivery. METHOD: A total of 46 newborn infants (28 females, 18 males) were prospectively included in the study. Twenty-three infants (18 females, five males) were included as control participants and 23 (10 females, 13 males) were included as newborn infants at risk of adverse neurological outcome (defined as umbilical blood with pH <7.1). RESULTS: Analysis of glutamate concentration and GOT activity in umbilical blood samples showed that newborn infants with pH <7.1 had higher levels of glutamate (142.4 µmol/L [SD 61.4] vs 62.8 µmol/L [SD 25.5]; p<0.001) and GOT (83.1 U/L [SD 60.9] vs 34.9 U/L [SD 18.2]; p<0.001) compared to newborn infants without fetal distress. Analysis of Apgar scores and blood pH values (markers of perinatal distress) showed that conditions of severe distress were associated with higher glutamate and GOT levels. INTERPRETATION: During fetal development, the ability of GOT to metabolize glutamate suggests that this enzyme can act as an endogenous protective mechanism in the control of glutamate homeostasis.

Serum Levels of Cardiac Troponin I in Asphyxiated Neonates Predict Mortality.

BACKGROUND: Cardiac troponin I (cTnI) is a well-established marker for detecting myocardial ischemic damage in neonates with hypoxic-ischemic encephalopathy. However, the predictive value of cTnI in assessing mortality in neonatal asphyxia remains obscure. This retrospective study aims to analyze the relationship between cTnI levels in blood serum with gestational age, birth weight, gender, delivery type, electrocardiography, echocardiography, Apgar scores, length of hospital stay, and mortality in asphyxiated neonates. METHODS: This study included 164 full-term neonates with evidence of asphyxia. Myocardial markers, electrocardiography, and echocardiography were assessed in the first 24 hours after birth in neonates with asphyxia. The length of hospital stay and short-term outcome were assessed. RESULTS: There were no statistically significant correlations found between cTnI concentrations and traditional markers of asphyxia, length of hospitalization or mode of delivery. However, high cTnI levels were significant predictors of mortality in neonates with birth asphyxia. CONCLUSIONS: This study highlights the significance of monitoring cardiac injury in asphyxiated neonates. Serum cTnI levels measured at 24 hours after birth are likely to have significant predictive value for assessing mortality in neonates with birth asphyxia.