losartan-potassium and Asphyxia-Neonatorum

Neonatal encephalopathy (NE), most commonly a result of the disruption of cerebral oxygen delivery, is the leading cause of neurologic disability in term neonates. Given the key role of free radicals in brain injury development following hypoxia-ischemia-reperfusion, several oxidative biomarkers have been explored in preclinical and clinical models of NE. Among these, antioxidant enzyme activity, uric acid excretion, nitric oxide, malondialdehyde, and non-protein-bound iron have shown promising results as possible predictors of NE severity and outcome. Owing to high costs and technical complexity, however, their routine use in clinical practice is still limited. Several strategies aimed at reducing free radical production or upregulating physiological scavengers have been proposed for NE. Room-air resuscitation has proved to reduce oxidative stress following perinatal asphyxia and is now universally adopted. A number of medications endowed with antioxidant properties, such as melatonin, erythropoietin, allopurinol, or N-acetylcysteine, have also shown potential neuroprotective effects in perinatal asphyxia; nevertheless, further evidence is needed before these antioxidant approaches could be implemented as standard care.

Topics: Acetylcysteine; Allopurinol; Animals; Antioxidants; Asphyxia Neonatorum; Biomarkers; Brain Injuries; Clinical Trials as Topic; DNA; Erythropoietin; Free Radicals; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Malondialdehyde; Melatonin; Nitric Oxide; Oxidative Stress; Prostaglandins; Proteins; Uric Acid

Perinatal asphyxia is characterized by oxygen deprivation and lack of perfusion in the perinatal period, leading to hypoxic-ischemic encephalopathy and sequelae such as cerebral palsy, mental retardation, cerebral visual impairment, epilepsy and learning disabilities. On cellular level PA is associated with a decrease in oxygen and glucose leading to ATP depletion and a compromised mitochondrial function. Upon reoxygenation and reperfusion, the renewed availability of oxygen gives rise to not only restoration of cell function, but also to the activation of multiple detrimental biochemical pathways, leading to secondary energy failure and ultimately, cell death. The formation of reactive oxygen species, nitric oxide and peroxynitrite plays a central role in the development of subsequent neurological damage. In this review we give insight into the pathophysiology of perinatal asphyxia, discuss its clinical relevance and summarize current neuroprotective strategies related to therapeutic hypothermia, ischemic postconditioning and pharmacological interventions. The review will also focus on the possible neuroprotective actions and molecular mechanisms of the selective neuronal and inducible nitric oxide synthase inhibitor 2-iminobiotin that may represent a novel therapeutic agent for the treatment of hypoxic-ischemic encephalopathy, both in combination with therapeutic hypothermia in middle- and high-income countries, as well as stand-alone treatment in low-income countries.

Topics: Allopurinol; Asphyxia Neonatorum; Biotin; Cerebral Palsy; Clinical Trials as Topic; Epilepsy; Erythropoietin; Female; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Intellectual Disability; Ischemic Postconditioning; Melatonin; Neuroprotective Agents; Pregnancy; Reactive Nitrogen Species; Reactive Oxygen Species

Perinatal asphyxia-induced brain injury may present as hypoxic-ischemic encephalopathy in the neonatal period, and disability including cerebral palsy in the long term. The brain injury is secondary to both the hypoxic-ischemic event and the reoxygenation-reperfusion following resuscitation. Early events in the cascade of brain injury can be classified as either inflammation or oxidative stress through the generation of free radicals. The objective of this paper is to present efforts that have been made to limit the oxidative stress associated with hypoxic-ischemic encephalopathy. In the acute phase of ischemia/hypoxia and reperfusion/reoxygenation, the outcomes of asphyxiated infants can be improved by optimizing the initial delivery room stabilization. Interventions include limiting oxygen exposure, and shortening the time to return of spontaneous circulation through improved methods for supporting hemodynamics and ventilation. Allopurinol, melatonin, noble gases such as xenon and argon, and magnesium administration also target the acute injury phase. Therapeutic hypothermia, N-acetylcysteine2-iminobiotin, remote ischemic postconditioning, cannabinoids and doxycycline target the subacute phase. Erythropoietin, mesenchymal stem cells, topiramate and memantine could potentially limit injury in the repair phase after asphyxia. To limit the injurious biochemical processes during the different stages of brain injury, determination of the stage of injury in any particular infant remains essential. Currently, therapeutic hypothermia is the only established treatment in the subacute phase of asphyxia-induced brain injury. The effects and side effects of oxidative stress reducing/limiting medications may however be difficult to predict in infants during therapeutic hypothermia. Future neuroprotection in asphyxiated infants may indeed include a combination of therapies. Challenges include timing, dosing and administration route for each neuroprotectant.

Topics: Acetylcysteine; Allopurinol; Argon; Asphyxia Neonatorum; Cannabinoids; Erythropoietin; Female; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Magnesium Sulfate; Melatonin; Neuroprotective Agents; Oxidative Stress; Pregnancy; Treatment Outcome; Xenon

Hypoxic ischemic encephalopathy (HIE) is one of the leading causes of neonatal mortality in developing countries and leads to some form of neuro-developmental disability in latter part of life.. The aim of this study is to evaluate the role of erythropoietin (EPO) in neuroprotection for term newborn having HIE.. The literature search was done for various trials by searching the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of science, Scopus, Index Copernicus, and other database.. A total of nine studies fulfilled inclusion criteria. EPO has shown to cause reduction in death and disability, better long-term neuro-developmental outcome, improvement in EEG, and reduction in risk of cerebral palsy.. EPO treatment has neuroprotective effects against moderate/severe HIE and improves long-term behavioral neurological developments in neonates.

Topics: Asphyxia Neonatorum; Cerebral Palsy; Developmental Disabilities; Erythropoietin; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Neuroprotective Agents; Randomized Controlled Trials as Topic; Term Birth; Treatment Outcome

Intrapartum-related events are the third leading cause of childhood mortality worldwide and result in one million neurodisabled survivors each year. Infants exposed to a perinatal insult typically present with neonatal encephalopathy (NE). The contribution of pure hypoxia-ischaemia (HI) to NE has been debated; over the last decade, the sensitising effect of inflammation in the aetiology of NE and neurodisability is recognised. Therapeutic hypothermia is standard care for NE in high-income countries; however, its benefit in encephalopathic babies with sepsis or in those born following chorioamnionitis is unclear. It is now recognised that the phases of brain injury extend into a tertiary phase, which lasts for weeks to years after the initial insult and opens up new possibilities for therapy.There has been a recent focus on understanding endogenous neuroprotection and how to boost it or to supplement its effectors therapeutically once damage to the brain has occurred as in NE. In this review, we focus on strategies that can augment the body's own endogenous neuroprotection. We discuss in particular remote ischaemic postconditioning whereby endogenous brain tolerance can be activated through hypoxia/reperfusion stimuli started immediately after the index hypoxic-ischaemic insult. Therapeutic hypothermia, melatonin, erythropoietin and cannabinoids are examples of ways we can supplement the endogenous response to HI to obtain its full neuroprotective potential. Achieving the correct balance of interventions at the correct time in relation to the nature and stage of injury will be a significant challenge in the next decade.

Topics: Asphyxia Neonatorum; Brain; Cannabinoids; Erythropoietin; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Melatonin; Neuroprotection; Neuroprotective Agents

Perinatal asphyxia can cause serious illness or death. By taking steps in the «latent phase», which occurs 6-24 hours after the hypoxic event, the neurological damage caused by perinatal asphyxia can be limited. We wish to present a selection of such measures that are either established treatment today or that appear promising.. We searched in the Medline and Cochrane Library databases for options for treating perinatal asphyxia.. An overwhelming number of potential treatments were identified. From among them we selected 44 indexed, peer-reviewed original articles in English on strategies for neuroprotective treatment after perinatal asphyxia. The treatments target different cellular mechanisms that cause neurological damage following perinatal asphyxia. In randomised clinical trials, only hypothermia treatment has improved the long-term outcome for newborns with perinatal asphyxia. Xenon gas, erythropoeitin and allopurinol are undergoing clinical testing.. The efficacy of xenon gas, erythropoeitin and allopurinol in combination with the established treatment form of hypothermia must be studied more closely. Antioxidants, stem cell treatment and DNA repair mechanisms can pave the way for new opportunities in the future.

Topics: Allopurinol; Anesthetics, Inhalation; Asphyxia Neonatorum; Combined Modality Therapy; Erythropoietin; Free Radical Scavengers; Humans; Hypothermia, Induced; Infant, Newborn; Neuroprotective Agents; Time Factors; Xenon

Advances in the care of high-risk newborn babies have contributed to reduced mortality rates for premature and term births, but the surviving neonates often have increased neurological morbidity. Therapies aimed at reducing the neurological sequelae of birth asphyxia at term have brought hypothermia treatment into the realm of standard care. However, this therapy does not provide complete protection from neurological complications and a need to develop adjunctive therapies for improved neurological outcomes remains. In addition, the care of neurologically impaired neonates, regardless of their gestational age, clearly requires a focused approach to avoid further injury to the brain and to optimize the neurodevelopmental status of the newborn baby at discharge from hospital. This focused approach includes, but is not limited to, monitoring of the patient's brain with amplitude-integrated and continuous video EEG, prevention of infection, developmentally appropriate care, and family support. Provision of dedicated neurocritical care to newborn babies requires a collaborative effort between neonatologists and neurologists, training in neonatal neurology for nurses and future generations of care providers, and the recognition that common neonatal medical problems and intensive care have an effect on the developing brain.

Topics: Anesthetics, Inhalation; Anticonvulsants; Antioxidants; Asphyxia Neonatorum; Electroencephalography; Erythropoietin; Humans; Hypothermia, Induced; Infant, Newborn; Intensive Care, Neonatal; Monitoring, Physiologic; Nervous System Diseases; Neuroprotective Agents; Seizures; Xenon

Topics: Adaptation, Physiological; Arginine Vasopressin; Asphyxia Neonatorum; beta-Endorphin; Catecholamines; Erythropoietin; Fetal Blood; Humans; Infant, Newborn; Stress, Physiological

Perinatal asphyxia, more appropriately known as hypoxic-ischemic encephalopathy (HIE), is a condition characterized by clinical and laboratory evidence of acute or sub-acute brain injury resulting from systemic hypoxemia and/or reduced cerebral blood flow. HIE is a common and devastating clinical condition in resource-poor countries with poor treatment outcome. This paper describes the protocol for an ongoing study that aims to evaluate the neuroprotective effects of Erythropoietin (EPO) as compared to routine care in the management of moderate to severe HIE among term infants.. This study is a double-blind randomized controlled trial that will be conducted in the neonatal wards of the Lagos University Teaching Hospital (LUTH), Lagos, Nigeria, over a two-year period after ethical approvals and consents. One hundred and twenty-eight term newborns (≥ 37 weeks gestation) diagnosed with moderate/ severe HIE at admission will be allocated by randomization to receive either EPO or normal saline. All the participants will be offered standard care according to the unit protocol for HIE. Baseline investigations and close monitoring of the babies are done until discharge. Participants are followed up for 2 years to monitor their outcome (death or neurological development) using standard instruments.. Previous trials had shown that EPO confers neuroprotective benefits and improve neurological and behavioral outcome in infants with HIE both singly or as an adjuvant to therapeutic hypothermia. This study hypothesized that administering EPO to newborns with moderate /severe HIE can positively influence their clinical and neurological outcomes and will provide evidence to either support or disprove the usefulness of Erythropoietin as a sole agent in the treatment of HIE, especially in resource-limited environment with the highest burden of the disease.. The study has been registered with the Pan African Clinical trials registry on the 2nd of December 2018, with registration number PACTR201812814507775.

Topics: Asphyxia Neonatorum; Brain Injuries; Cerebrovascular Circulation; Double-Blind Method; Erythropoietin; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Neuroprotection; Neuroprotective Agents; Nigeria; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic

Erythropoietin (EPO) is neuroprotective after asphyxia in animal studies. The efficacy and safety of EPO monotherapy in term neonates with hypoxic ischemic encephalopathy (HIE) is uncertain.. Hundred term neonates with moderate or severe HIE were randomized by random permuted block algorithm to receive either EPO 500 U kg. Death or moderate or severe disability occurred in 40% of neonates in the treatment group vs 70% in the placebo group (risk ratio, 0.57; 95% confidence interval (CI) 0.38 to 0.85; P=0.003). Death occurred in 16% of patients in both the groups (risk ratio, 1.0; 95% CI 0.33 to 2.9; P=0.61). The risk of cerebral palsy was lower among survivors in the treatment group (risk ratio, 0.52; 95% CI 0.25 to 1.03; P=0.04) and lesser number of babies were on anticonvulsants at assessment (risk ratio, 0.47; 95% CI 0.20 to 1.01; P=0.03). Neonatal brain magnetic resonance imaging showed more abnormalities in the placebo group (relative risk, 0.66; 95% CI 0.42 to 1.03; P=0.04)). Improvement in other neurological outcomes was not significant.. EPO monotherapy reduces the risk of death or disability in term neonates with moderate or severe encephalopathy.

Topics: Asphyxia Neonatorum; Brain; Cerebral Palsy; Double-Blind Method; Erythropoietin; Female; Humans; Hypoxia-Ischemia, Brain; India; Infant; Infant, Newborn; Longitudinal Studies; Magnetic Resonance Imaging; Male; Prospective Studies; Severity of Illness Index; Term Birth

The aim of this study was to compare two neuroprotective strategies to supportive care in the treatment of perinatal asphyxia.. A total of 67 term newborns with perinatal asphyxia were included and randomized into three groups: one group received supportive treatment; another group received a single dose of 40 mg/kg phenobarbital; and the third received three daily doses of 1000 IU/kg erythropoietin. The following parameters were analyzed: gestational age, birthweight, Apgar scores, cord blood pH, total serum antioxidant status (TAS), superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA). The newborns were included in the follow-up program and examined up to 18 months of age.. TAS was higher in the erythropoietin group than in the other groups. SOD and GPx were lower for infants treated with phenobarbital or erythropoietin compared to control infants. MDA was lower in the erythropoietin group compared to the other groups, although the difference was not statistically significant (P > 0.05). The mortality rate was lower in the phenobarbital and erythropoietin groups (both 4.6%) than in the control group (17.4%). Long-term neurologic follow up showed a high incidence of sequelae in the control group compared to the phenobarbital and erythropoietin groups. Follow-up results were better in the phenobarbital group than in the erythropoietin group for motor and cognitive function at 3 and 6 months and worse for expressive language. At 18 months, however, the differences between these two groups were not significant.. High-dose phenobarbital or erythropoietin along with supportive treatment has a positive influence on the outcome of newborns with perinatal asphyxia. Phenobarbital has the advantage of low cost and simplicity.

Topics: Asphyxia Neonatorum; Birth Weight; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Gestational Age; Hematinics; Humans; Hypnotics and Sedatives; Infant, Newborn; Injections, Intravenous; Injections, Subcutaneous; Male; Oxidative Stress; Phenobarbital; Prospective Studies; Recombinant Proteins; Treatment Outcome

The goal was to examine biochemical, neurophysiologic, anatomic, and clinical changes associated with erythropoietin administration to neonates with hypoxic-ischemic encephalopathy (HIE).. We conducted a prospective case-control study with 45 neonates in 3 groups, a normal healthy group (N = 15), a HIE-erythropoietin group (N = 15; infants with mild/moderate HIE who received human recombinant erythropoietin, 2500 IU/kg, subcutaneously, daily for 5 days), and a HIE-control group (N = 15; did not receive erythropoietin). Serum concentrations of nitric oxide (NO) were measured at enrollment for the normal healthy neonates and at enrollment and after 2 weeks for the 2 HIE groups. The 2 HIE groups underwent electroencephalography at enrollment and at 2 to 3 weeks. Brain MRI was performed at 3 weeks. Neurologic evaluations and Denver Developmental Screening Test II assessments were performed at 6 months.. Compared with normal healthy neonates, the 2 HIE groups had greater blood NO concentrations (P < .001). At enrollment, the 2 HIE groups did not differ in clinical severity, seizure incidence, NO concentrations, or electroencephalographic findings. At 2 weeks of age, electroencephalographic backgrounds improved significantly (P = .01) and NO concentrations decreased (P < .001) in the HIE-erythropoietin group, compared with the HIE-control group; MRI findings did not differ between groups. At 6 months of age, infants in the HIE-erythropoietin group had fewer neurologic (P = .03) and developmental (P = .03) abnormalities.. This study demonstrates the feasibility of early administration of human recombinant erythropoietin to term neonates with HIE, to protect against encephalopathy.

Topics: Asphyxia Neonatorum; Brain; Case-Control Studies; Dose-Response Relationship, Drug; Electroencephalography; Erythropoietin; Female; Follow-Up Studies; Humans; Hypoxia-Ischemia, Brain; Infant; Infant, Newborn; Injections, Subcutaneous; Magnetic Resonance Imaging; Male; Neurologic Examination; Nitric Oxide; Prospective Studies; Recombinant Proteins

The purpose of this study was to evaluate the efficacy and safety of erythropoietin in neonatal hypoxic-ischemic encephalopathy (HIE), by using a randomized, prospective study design.. A total of 167 term infants with moderate/severe HIE were assigned randomly to receive either erythropoietin (N = 83) or conventional treatment (N = 84). Recombinant human erythropoietin, at either 300 U/kg (N = 52) or 500 U/kg (N = 31), was administered every other day for 2 weeks, starting <48 hours after birth. The primary outcome was death or disability. Neurodevelopmental outcomes were assessed at 18 months of age.. Complete outcome data were available for 153 infants. Nine patients dropped out during treatment, and 5 patients were lost to follow-up monitoring. Death or moderate/severe disability occurred for 35 (43.8%) of 80 infants in the control group and 18 (24.6%) of 73 infants in the erythropoietin group (P = .017) at 18 months. The primary outcomes were not different between the 2 erythropoietin doses. Subgroup analyses indicated that erythropoietin improved long-term outcomes only for infants with moderate HIE (P = .001) and not those with severe HIE (P = .227). No negative hematopoietic side effects were observed.. Repeated, low-dose, recombinant human erythropoietin treatment reduced the risk of disability for infants with moderate HIE, without apparent side effects.

Topics: Asphyxia Neonatorum; Brain Damage, Chronic; China; Developmental Disabilities; Disability Evaluation; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Follow-Up Studies; Humans; Hypoxia-Ischemia, Brain; Infant; Infant, Newborn; Infusions, Intravenous; Injections, Subcutaneous; Intensive Care Units, Neonatal; Male; Neurologic Examination; Prospective Studies; Psychomotor Disorders; Recombinant Proteins

We aimed to study the haematopoietic response in normal and acidotic deliveries following vaginal and abdominal delivery and to compare this to the surrogate markers of perinatal acidosis. Blood gas analyses, complete blood pictures and erythropoietin assays were performed on umbilical or early neonatal blood samples. Placental sections were examined for the presence of nucleated red blood cells. Perinatal clinical risk factors and major neonatal outcomes were collected. The control population was 78 deliveries where the cord arterial pH was > 7.10. Controls born after labour were compared to those born prior to the onset of labour and to 14 acidotic infants born after labour. Nucleated red blood cells did not increase with labour in the control groups but were significantly higher (p < 0.05) in the acidotic group. Erythropoietin did not significantly change with either labour or acidosis. The predictive values from nucleated red blood cell counts were higher than those from low Apgar scores, atypical cardiotocograph traces, meconium-stained amniotic fluid, erythropoietin and the presence of nucleated red blood cells in placental sections. Nucleated red blood cell counts may be a useful surrogate marker of acidosis where blood gas analysis is unavailable. Further studies are required to examine the timing of the increase of erythropoiesis to help define the onset of the stimulus.

Topics: Acidosis; Asphyxia Neonatorum; Blood Gas Analysis; Chi-Square Distribution; Delivery, Obstetric; Erythrocyte Count; Erythropoietin; Female; Fetal Blood; Fetal Diseases; Fetal Monitoring; Hematopoiesis; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Obstetric Labor Complications; Pregnancy; Pregnancy Outcome; Probability; Reference Values; Sensitivity and Specificity

We previously reported that erythropoietin (Epo) is present in human cerebrospinal fluid (CSF). It is not known whether CSF Epo concentrations change under conditions of CNS injury or, if so, whether this change reflects loss of blood-brain barrier integrity or increased CNS Epo synthesis. We hypothesized that CSF Epo increases in conditions of neural injury including hypoxia, meningitis, and intraventricular hemorrhage (IVH) and that CSF Epo concentrations are independent of plasma Epo concentrations. To test these hypotheses, Epo concentrations were measured in 122 paired CSF and blood samples obtained from neonates and children categorized as follows: 16, asphyxia; 31, meningitis; 11, IVH; 41, controls. Twelve infants treated with recombinant Epo (rEpo) and 11 additional samples from children with miscellaneous neurologic problems were also evaluated. CSF and plasma Epo concentrations were significantly higher in asphyxiated infants than in controls (225.0+/-155.0 versus 4.5+/-0.5 mU/mL; mean +/- SEM, p < 0.05, respectively, in CSF; 1806.7+/-1254 versus 5.2+/-0.5, p < 0.05 in plasma). Neonates with IVH had higher CSF Epo concentrations than controls (p < 0.01) but did not have higher plasma Epo concentrations than controls. Patients with meningitis did not have elevated CSF or plasma Epo concentrations. There was no correlation between CSF and plasma Epo concentrations in infants treated with rEpo. We conclude that Epo is selectively increased in the CSF by hypoxia, less so by IVH, and not at all by meningitis. rEpo treatment does not elevate CSF Epo. These findings suggest that rEpo does not cross the blood-brain barrier and that hypoxia induces increased CNS synthesis of Epo.

Topics: Asphyxia Neonatorum; Brain Injuries; Cerebral Ventricles; Erythropoietin; Female; Humans; Infant, Newborn; Intracranial Hemorrhages; Linear Models; Meningitis; Postpartum Hemorrhage; Pregnancy

Cord blood pH, lactate, hypoxanthine, and erythropoietin levels have all been used as markers of either acute or chronic asphyxia. We sought to determine whether these index values were significantly different in infants with or without meconium-stained amniotic fluid.. Fifty-six pregnant women in spontaneous labor at term were divided into two groups on the basis of the presence or absence of meconium-stained amniotic fluid. All meconium-stained fluid was centrifuged, and the volume percentage of particulate matter (i.e., meconium) was recorded. Umbilical artery blood and mixed arterial and venous cord blood were obtained at each delivery. Lactate, hypoxanthine, and erythropoietin levels were measured. Statistical analysis included Student t test and rank sum statistics where appropriate. Normal and Spearman correlation coefficients were also used.. There were no significant differences in mean umbilical artery pH (7.26 +/- 0.06 vs 7.25 +/- 0.10), lactate levels (32.8 +/- 10 mg/dl vs 30.4 +/- 14.2 mg/dl), and hypoxanthine levels (13.4 +/- 6.7 mumol/L vs 14.0 +/- 6.0 mumol/L) in newborns with meconium (n = 28) compared with controls (n = 28). Erythropoietin levels were significantly greater in newborns with meconium (median 39.5 mIU/ml vs 26.8 mIU/ml, p = 0.039). There was no correlation between the amount of particulate matter and any marker of asphyxia.. There was no correlation between markers of acute asphyxia (i.e., umbilical artery blood pH, lactate, or hypoxanthine) and meconium. However, erythropoietin levels were significantly elevated in newborns with meconium-stained amniotic fluid. This latter marker may better correlate with chronic asphyxia.

Topics: Acute Disease; Adolescent; Adult; Amniotic Fluid; Asphyxia Neonatorum; Biomarkers; Chronic Disease; Erythropoietin; Female; Fetal Blood; Humans; Hydrogen-Ion Concentration; Hypoxanthines; Infant, Newborn; Lactates; Meconium

There is a critical need for development of physiological biomarkers in infants with birth asphyxia to identify the physiologic response to therapies in real time. This is an ancillary single site study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (Wu et al., 2022 [1]) to measure neurovascular coupling (NVC) non-invasively during an ongoing blinded randomized trial.. Neonates who randomized in the HEAL enrolled at a single-center Level III Neonatal Intensive Care Unit were recruited between 2017 and 2019. Neurodevelopmental impairment was blinded and defined as any of the following: cognitive score <90 on Bayley Scales of Infant Toddler Development, third edition (BSID-III), Gross Motor Function Classification Score (GMFCS) ≥1.. All twenty-seven neonates enrolled in HEAL were recruited and 3 died before complete recording. The rank-based analysis of covariance models demonstrated lack of difference in NVC between the two groups (Epo versus Placebo) that was consistent with the observed lack of effect on neurodevelopmental outcomes.. We demonstrate no difference in neurovascular coupling after Epo administration. These findings are consistent with overall negative trial results. Physiological biomarkers can help elucidate mechanisms of neuroprotective therapies in real time in future trials.

Topics: Asphyxia; Asphyxia Neonatorum; Biomarkers; Erythropoietin; Humans; Hypoxia-Ischemia, Brain; Infant; Infant, Newborn; Neuroprotection; Neurovascular Coupling

High-dose human recombinant erythropoietin (rEPO) is a promising potential neuroprotective treatment in preterm and full-term neonates with hypoxic-ischemic encephalopathy (HIE). There are limited data on the pharmacokinetics of high-dose rEPO in neonates. We examined the effects of body weight, gestation age, global asphyxia, cerebral ischemia, hypothermia and exogenous rEPO on the pharmacokinetics of high-dose rEPO in fetal sheep. Near-term fetal sheep on gestation day 129 (0.87 gestation) (full term 147 days) received sham-ischemia (

Topics: Animals; Asphyxia Neonatorum; Birth Weight; Body Weight; Combined Modality Therapy; Dose-Response Relationship, Drug; Embryonic Development; Erythropoietin; Female; Fetus; Gestational Age; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Infusions, Intravenous; Injections, Intravenous; Models, Biological; Neuroprotective Agents; Recombinant Proteins; Sheep; Species Specificity

Topics: Asphyxia; Asphyxia Neonatorum; Brain Diseases; Erythropoietin; Female; Humans; Infant, Newborn; Pregnancy

Topics: Asphyxia; Asphyxia Neonatorum; Erythropoietin; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn

Topics: Asphyxia; Asphyxia Neonatorum; Brain Diseases; Erythropoietin; Female; Humans; Infant, Newborn; Pregnancy

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.. 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.. 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.. 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.. 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.

Topics: Asphyxia Neonatorum; Biomarkers; Erythropoietin; Female; Fetal Blood; Glycopeptides; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Male; Parturition; Predictive Value of Tests; Retrospective Studies; S100 Calcium Binding Protein beta Subunit; Up-Regulation

Cerebral palsy (CP) is the most common motor disability in childhood, with a worldwide prevalence of 1.5-4/1,000 live births. Hypoxic-ischemic encephalopathy (HIE) contributes to the burden of CP, but the long-term neuropathological findings of this association remain limited.. Thirty-four term Macaca nemestrina macaques were included in this long-term neuropathological study: 9 control animals delivered by cesarean section and 25 animals with perinatal asphyxia delivered by cesarean section after 15-18 min of umbilical cord occlusion (UCO). UCO animals were randomized to saline (n = 11), therapeutic hypothermia (TH; n = 6), or TH + erythropoietin (Epo; n = 8). Epo was given on days 1, 2, 3, and 7. Animals had serial developmental assessments and underwent magnetic resonance imaging with diffusion tensor imaging at 9 months of age followed by necropsy. Histology and immunohistochemical (IHC) staining of brain and brainstem sections were performed.. All UCO animals demonstrated and met the standard diagnostic criteria for human neonates with moderate-to-severe HIE. Four animals developed moderate-to-severe CP (3 UCO and 1 UCO + TH), 9 had mild CP (2 UCO, 3 UCO + TH, 3 UCO + TH + Epo, and 1 control), and 2 UCO animals died. None of the animals treated with TH + Epo died, had moderate-to-severe CP, or demonstrated signs of long-term neuropathological toxicity. Compared to animals grouped together as having no CP (no-CP; controls and mild CP only), animals with CP (moderate and severe) demonstrated decreased fractional anisotropy of multiple white-matter tracts including the corpus callosum and internal capsule, when using Tract-Based Spatial Statistics (TBSS). Animals with CP had decreased staining for cortical neurons and increased brainstem glial scarring compared to animals without CP. The cerebellar cell density of the internal granular layer and white matter was decreased in CP animals compared to that in control animals without CP.. In this nonhuman primate HIE model, animals treated with TH + Epo had less brain pathology noted on TBSS and IHC staining, which supports the long-term safety of TH + Epo in the setting of HIE. Animals that developed CP showed white-matter changes noted on TBSS, subtle histopathological changes in both the white and gray matter, and brainstem injury that correlated with CP severity. This HIE model may lend itself to further study of the relationship between brainstem injury and CP.

Topics: Animals; Animals, Newborn; Asphyxia Neonatorum; Cerebral Palsy; Disease Models, Animal; Erythropoietin; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Macaca nemestrina; Random Allocation

Infants with neonatal encephalopathy (NE) of hypoxic-ischaemic origin are at risk of oxidative and ischaemia-reperfusion injury, which may induce abnormal inflammatory responses involving excessive cytokine production and release in serum and cerebrospinal fluid (CSF). Systemic inflammation is found in infants with NE, and we therefore were interested in cytokines associated with hypoxia, including vascular endothelial growth factor (VEGF) and erythropoietin (Epo).. To investigate the relationship between Epo, VEGF levels, brain injury and outcome in a group of term infants exposed to perinatal asphyxia (PA) compared to controls.. Serum and CSF biomarkers associated with hypoxia (VEGF, Epo) were serially measured using multiplex immunoassays over days 1-4 in term infants exposed to PA including infants with NE and controls. Results were compared to severity of encephalopathy, MR brain imaging and mortality.. Ninety-four infants had 247 serum samples collected (n = 12 controls, 82 exposed to PA with 34 CSF samples), and 4 infants died. Controls had significantly lower serum Epo levels on days 1 and 2 compared to those exposed to PA (p = 0.02). Grade II/III NE was significantly associated with elevated day 2 Epo and decreased day 1 VEGF (p < 0.05; day 2 Epo AUC = 0.74, cut-off 10.05 IU/ml). Elevated serum Epo was associated with severely abnormal MRI. Mortality was associated with elevated day 3 Epo and decreased day 1 VEGF. CSF levels were all after hypothermia and were not significantly associated with outcome.. Serum Epo and VEGF may be markers of severity of hypoxia-ischaemia and brain injury as they are closely related to hypoxic exposure.

Topics: Asphyxia Neonatorum; Biomarkers; Brain; Case-Control Studies; Erythropoietin; Female; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Ireland; Magnetic Resonance Imaging; Male; Severity of Illness Index; Tertiary Care Centers; Vascular Endothelial Growth Factor A

Biomarkers that indicate the severity of hypoxic-ischemic brain injury and response to treatment and that predict neurodevelopmental outcomes are urgently needed to improve the care of affected neonates. We hypothesize that sequentially obtained plasma metabolomes will provide indicators of brain injury and repair, allowing for the prediction of neurodevelopmental outcomes. A total of 33 Macaca nemestrina underwent 0, 15 or 18 min of in utero umbilical cord occlusion (UCO) to induce hypoxic-ischemic encephalopathy and were then delivered by hysterotomy, resuscitated and stabilized. Serial blood samples were obtained at baseline (cord blood) and at 0.1, 24, 48, and 72 h of age. Treatment groups included nonasphyxiated controls (n = 7), untreated UCO (n = 11), UCO + hypothermia (HT; n = 6), and UCO + HT + erythropoietin (n = 9). Metabolites were extracted and analyzed using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry and quantified by PARAFAC (parallel factor analysis). Using nontargeted discovery-based methods, we identified 63 metabolites as potential biomarkers. The changes in metabolite concentrations were characterized and compared between treatment groups. Further comparison determined that 8 metabolites (arachidonic acid, butanoic acid, citric acid, fumaric acid, lactate, malate, propanoic acid, and succinic acid) correlated with early and/or long-term neurodevelopmental outcomes. The combined outcomes of death or cerebral palsy correlated with citric acid, fumaric acid, lactate, and propanoic acid. This change in circulating metabolome after UCO may reflect cellular metabolism and biochemical changes in response to the severity of brain injury and have potential to predict neurodevelopmental outcomes.

Topics: Animals; Animals, Newborn; Apgar Score; Asphyxia Neonatorum; Biomarkers; Cerebral Palsy; Disease Models, Animal; Erythropoietin; Female; Hypothermia; Hypoxia-Ischemia, Brain; Macaca nemestrina; Male; Metabolome; Umbilical Cord

Topics: Asphyxia Neonatorum; Erythropoietin; Female; Humans; Male; Phenobarbital

The aims of this study were to determine which of the two biomarkers of renal injury, kidney injury molecule-1 or cystatin C, is more sensitive and to evaluate whether erythropoietin protects kidneys injured by perinatal asphyxia.. Animals were split into three groups designated as follows: AE, pups that survived perinatal asphyxia and subsequently received 2.5 μg (0.1 ml) of darbepoetin-α (i.p.); A, the pups that survived perinatal asphyxia and received 0.1 ml of 0.9% NaCl; and C, control group. The pups were killed at different ages of life (6 h, 24 h, 48 h, 7 d, and 14 d of age; 10 rats in each subgroup). Immunohistopathological evaluation of kidneys was performed.. At 48 h and on days 7 and 14, absolute injury scores were significantly lower in group AE as measured by both biomarkers. Cystatin C expression was the most intensive 6 h after the hypoxic event (average value of absolute injury score was 2.82) and declined over time. Expression of kidney injury molecule-1 was less intensive, with the average value of absolute injury score being 2.02 at 6 h and 2.105 at 24 h; the peak value (2.155) was recorded 48 h after the hypoxic event.. Erythropoietin has a protective effect on hypoxic kidneys. Cystatin C is more sensitive as an early biomarker of acute kidney injury in comparison with kidney injury molecule-1.

Topics: Animals; Animals, Newborn; Asphyxia Neonatorum; Biomarkers; Cell Adhesion Molecules; Cystatin C; Darbepoetin alfa; Erythropoietin; Female; Hypoxia; Kidney; Male; Rats; Rats, Wistar; Time Factors; Treatment Outcome

Evaluation of neuroprotective effects of hypothermia, erythropoietin and their simultaneous use after perinatal asphyxia in newborn rats.. Hysterectomy was performed to Wistar female rats on the last day of gestation. Perinatal asphyxia was induced by submersion of uterus containing pups in saline for 15 min. After resuscitation, pups were randomized into 4 groups, 15 animals in each: G1 - asphyxia; G2 - asphyxia + hypothermia (rectal temperature 33 °C for 1 h); G3 - asphyxia + erythropoietin (Darbepoetin-α 2.5 μg, intraperitoneally) and G4 - asphyxia + erythropoietin + hypothermia. Pups were sacrificed on 7th day of life and histopathological analysis of hippocampus was performed.. Measure of damage to dorsal, ventral and entire hippocampus was significantly lower in groups G2, G3 and G4 than in group G1 (p ~ 0.00; respectively). Measure of damage to hippocampus in group G4 was significantly lower than in group G2 (p = 0.029).. This study demonstrates that simultaneous use of hypothermia and erythropoietin has more expressed neuroprotective effects than sole use of hypothermia after perinatal asphyxia in newborn rats.

Topics: Animals; Animals, Newborn; Asphyxia Neonatorum; Brain Diseases; Combined Modality Therapy; Disease Models, Animal; Erythropoietin; Female; Hippocampus; Hypothermia, Induced; Neurons; Neuroprotective Agents; Pregnancy; Rats; Rats, Wistar

To study the effects of erythropoietin (EPO) on cardiomyocyte apoptosis and endoplasmic reticulum stress (ERS)-related proteins, glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP), in neonatal rats with asphyxia.. A total of 120 newborn Sprague-Dawley rats (7 days old) were randomly divided into sham-operated (n=40), asphyxia (n=40) and EPO-treated asphyxia groups (n=40). A neonatal rat model of normobaric asphyxia was established in the asphyxia and EPO-treated asphyxia groups. The rats in the EPO-treated asphyxia group received intraperitoneal injection of recombinant human erythropoietin (500 U/mL) immediately after the model was established, while the other two groups received the same volume of normal saline (0.9%). Heart blood and myocardial tissue samples were collected from 8 rats in each group at 2, 6, 12, 24 or 48 hours after the model was established. Serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels were measured; cardiomyocyte apoptosis was evaluated, and expression of myocardial GRP78 and CHOP was measured.. Compared with the sham-operated and EPO-treated asphyxia groups, the asphyxia group had significantly increased serum CK and LDH levels, number of apoptotic cells, and expression of myocardial GRP78 and CHOP at each time point (P<0.01), and all the indices were significantly higher in the EPO-treated asphyxia group than in the sham-operated group (P<0.01). At 24 hours after asphyxia, the expression of myocardial CHOP was positively correlated with the myocardial apoptosis index (r=0.944, P<0.01).. EPO exerts a protective effect on the myocardium of neonatal rats with hypoxic-ischemic injury by regulating ERS-related proteins GRP78 and CHOP and reducing cardiomyocyte apoptosis.

Topics: Animals; Animals, Newborn; Apoptosis; Asphyxia Neonatorum; Creatine Kinase; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Erythropoietin; Heat-Shock Proteins; L-Lactate Dehydrogenase; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Transcription Factor CHOP

The aim of this study was to determine the effects of erythropoietin (EPO), moderate hypothermia, and a combination thereof on the kidneys of newborn rats damaged during perinatal asphyxia. An animal model of perinatal asphyxia (Wistar rats) was used in which after birth, newborn rats were divided into four groups of 15 animals each: G1, rats exposed only to asphyxia; G2, rats exposed to asphyxia and hypothermia (rectal temperature 32°C) and which received EPO (darbepoetin alpha) intraperitoneally; G3, rats exposed to asphyxia and hypothermia; G4, rats exposed to asphyxia and which received EPO. The rats were sacrificed on the 7th day of life and histopathological evaluation of kidneys was performed. Damage to the proximal tubules was significantly higher in group G1 rats than in groups G2, G3, and G4 rats (p < 0.01). Damage to the distal tubules was found only in group G1 rats. Histological changes in the proximal tubules were more prominent than in the distal tubules (p < 0.01). The immature glomeruli zone was less expressed in group G4 rats than in groups G1, G2, and G3 rats (p < 0.01). Based on these results, we conclude that EPO and hypothermia, as well as the combination thereof, have a protective effect on rats' kidneys damaged during perinatal asphyxia.

Topics: Acute Kidney Injury; Animals; Animals, Newborn; Asphyxia Neonatorum; Combined Modality Therapy; Cytoprotection; Darbepoetin alfa; Disease Models, Animal; Erythropoietin; Female; Humans; Hypothermia, Induced; Infant, Newborn; Kidney; Kidney Glomerulus; Kidney Tubules; Male; Protective Agents; Rats; Rats, Wistar; Time Factors

The objective was to explain the discrepancy in the development of hypoxic ischemic brain injury (HIE) in some asphyxiated newborns rather than others. Forty newborns were classified according to their cerebrospinal neuron-specific-enolase (CSF-NSE) levels on their 5th-day of life; group 1 with low-NSE (n = 25). The remaining 15 newborns had high-NSE and were further divided into a group with no HIE (n = 10, group 2) and another with HIE (n = 5, group 3). CSF-NSE, total-hydroperoxide (TH), biological-antioxidant-potentials (BAPs), 12 cytokines and erythropoietin (EPO) were measured. The TH/BAP gave the oxidative-stress-index (OSI). The BAPs of serial dilutions of three types of EPO were tested. CSF-NSE and TH and mean OSIs were higher in group 3. IL-8 and mean BAPs were higher in group 2 than in group 1. EPO was less detected in group 3. Serial EPO dilutions correlated with their BAPs. Compensatory antioxidants and IL-8 elevation could be protective of perinatal asphyxic brain injury. Antioxidative effect of EPO could be neuroprotective.

Topics: Antioxidants; Asialoglycoproteins; Asphyxia Neonatorum; Erythropoietin; Female; Humans; Hydrogen Peroxide; Hypoxia, Brain; Infant, Newborn; Interleukin-8; Male; Oxidative Stress; Phosphopyruvate Hydratase; Recombinant Proteins; Up-Regulation

Topics: Animals; Asphyxia Neonatorum; Combined Modality Therapy; Erythropoietin; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Magnesium Sulfate; Melatonin; Neuroprotective Agents; Recombinant Proteins

Oxygen toxicity has been identified as a risk factor for adverse neurological outcome in survivors of preterm birth. In infant rodent brains, hyperoxia induces disseminated apoptotic neurodegeneration. Because a tissue-protective effect has been observed for recombinant erythropoietin (rEpo), widely used in neonatal medicine for its hematopoietic effect, we examined the effect of rEpo on hyperoxia-induced brain damage.. Six-day-old C57Bl/6 mice or Wistar rats were exposed to hyperoxia (80% O(2)) or normoxia for 24 hours and received rEpo or normal saline injections intraperitoneally. The amount of degenerating cells in their brains was determined by DeOlmos cupric silver staining. Changes of their brain proteome were determined through two-dimensional electrophoresis and mass spectrometry. Western blot, enzyme activity assays and real-time polymerase chain reaction were performed for further analysis of candidate proteins.. Systemic treatment with 20,000 IE/kg rEpo significantly reduced hyperoxia-induced apoptosis and caspase-2, -3, and -8 activity in the brains of infant rodents. In parallel, rEpo inhibited most brain proteome changes observed in infant mice when hyperoxia was applied exclusively. Furthermore, brain proteome changes after a single systemic rEpo treatment point toward a number of mechanisms through which rEpo may generate its protective effect against oxygen toxicity. These include reduction of oxidative stress and restoration of hyperoxia-induced increased levels of proapoptotic factors, as well as decreased levels of neurotrophins.. These findings are highly relevant from a clinical perspective because oxygen administration to neonates is often inevitable, and rEpo may serve as an adjunctive neuroprotective therapy.

Topics: Animals; Apoptosis; Asphyxia Neonatorum; Brain; Caspases; Cell Death; Disease Models, Animal; Erythropoietin; Humans; Hyperoxia; Infant, Newborn; Mice; Mice, Inbred C57BL; Nerve Degeneration; Neurons; Neuroprotective Agents; Oxidative Stress; Oxygen; Oxygen Inhalation Therapy; Proteome; Rats; Rats, Wistar

Erythropoietin (EPO) prevents neuronal damage following ischemic, metabolic and excitotoxic stress. Recent studies have shown that EPO plays a significant role in the developing brain. The present study investigates the effect of EPO administration on hypoxic-ischemic brain injury and the possibility that its neuroprotective action may be associated with anti-apoptotic activity. Seven-day-old rats were treated with EPO (2000 U/kg) and subjected to a modified Levine procedure. EPO administration before the hypoxic-ischemic insult significantly reduces the severity of brain damage and improved the short-term functional brain recovery. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and DNA electrophoresis displayed no evidence of DNA fragmentation in EPO-treated animals. These results suggest that EPO might protect the neonatal rat brain by anti-apoptotic mechanisms.

Topics: Animals; Animals, Newborn; Asphyxia Neonatorum; Brain; Disease Models, Animal; DNA Fragmentation; Erythropoietin; Female; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Male; Neuroprotective Agents; Rats; Rats, Wistar; Reflex

To investigate the cause of fetal asphyxia of mothers with intrahepatic cholestasis of pregnancy (ICP).. The cord plasma erythropoietin (EPO) concentrations were measured in 37 infants of mothers with ICP and 46 control infants after elective cesarean section. Furthermore, the transfer of oxygen across the placental membranes in ICP group (n = 7) were compared with controls (n = 8) by dual perfusion of the human placental lobule in vitro.. The oxygen transfer across the placental membrane in ICP was similar to the controls (P < 0.05). However cord venous EPO was lower in infants delivered by elective cesarean section from women with ICP (13.58 +/- 8.88 IU/L, P < 0.05) than that in control infants (20.43 +/- 14.15 IU/L).. The transfer of oxygen across the placental membrane in ICP may be normal. The lower cord venous EPO value in ICP may be mainly responsible for the fetal asphyxia.

Topics: Adult; Asphyxia Neonatorum; Cholestasis, Intrahepatic; Erythropoietin; Female; Fetal Blood; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications

To assess a correlation between the erythropoietin (Epo) level in umbilical blood during delivery and three "classical" markers of hypoxia: the Apgar score, pH in the umbilical artery and lactate concentration.. The above parameters were assessed in 109 deliveries divided into three groups-normal deliveries, deliveries with neonatal pathology at term and premature deliveries.. Based on calculation of Spearman correlations which seemed most suitable with regard to the nature of the experimental data no significant relations were found between Epo and any of the mentioned parameters, while the mutual correlations between the Apgar score, pH of the umbilical artery and lactate were highly significant.. Epo is an independent marker of foetal hypoxia and supplementation of "classical" markers by this examination could be an asset to the evaluation of the prognosis of postnatal development.

Topics: Asphyxia Neonatorum; Biomarkers; Erythropoietin; Fetal Hypoxia; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Umbilical Arteries

To assess the immediate postnatal changes of serum immunoreactive erythropoietin (EP) in infants born after acute or chronic fetal hypoxia, and to estimate the rate of EP disappearance, we studied EP concentration, measured by double-antibody radioimmunoassay, in cord venous plasma and in serum at a mean age of 8 hours in a control group (n = 9) and in three patient groups: (1) infants with polycythemia (n = 10), (2) infants born to mothers with preeclampsia of pregnancy, without (n = 22) or with (n = 11) acidosis at birth, and (3) infants with acute birth asphyxia (n = 19), seven of whom had postnatal hypoxia. In all patient groups, cord venous EP was elevated in comparison with values in control infants. No change was found in EP level between birth and 8 hours in control infants (geometric mean in cord and 8-hour sample: 20 and 16 mU/ml, not significant) or in acutely asphyxiated infants with postnatal hypoxia (122 and 72 mU/ml, not significant), whereas the EP level decreased in all other groups: infants with polycythemia (123 to 24 mU/ml, p less than 0.001), nonacidotic infants (78 to 26 mU/ml, p less than 0.001) and acidotic infants (176 to 38 mU/ml, p less than 0.001) of the preeclampsia group, and acutely asphyxiated infants without postnatal hypoxia (58 to 30 mU/ml, p less than 0.001). The mean (+/- SD) half-time of EP disappearance was 2.6 +/- 0.5 hours in infants with polycythemia and 3.7 +/- 0.9 hours in infants of the preeclampsia group.

Topics: Acidosis; Apgar Score; Asphyxia Neonatorum; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Polycythemia; Pre-Eclampsia; Pregnancy; Time Factors

To assess the value of cord plasma arginine vasopressin (AVP), erythropoietin (EP), and hypoxanthine (HX) as indices of asphyxia, we studied 62 infants of mothers with preeclampsia, 34 acutely asphyxiated infants, with 5-min Apgar score less than or equal to 6 and/or umbilical arterial pH less than or equal to 7.05, and 38 control infants. Umbilical arterial AVP in the asphyxia group (geometric mean; 95% confidence interval: 180; 92-350 pg/ml) was higher than in the control group (23; 8-66, p = 0.002) and correlated with umbilical arterial pH (r = -0.447, p = 0.028). AVP levels in the preeclampsia group did not differ from controls. Cord venous EP was higher in infants delivered by elective cesarean section from women with severe preeclampsia (115; 75-177 mU/ml, p less than 0.001) than in control infants (23; 18-27); in the whole group EP correlated with pH (r = -0.493, p less than 0.001). EP in the asphyxia group was similar (46; 35-65) to controls (40; 33-47) and did not correlate with pH. Cord arterial HX in the preeclampsia group was similar to controls (12.3; 9.5-16.0 mumol/liter), but elevated in the asphyxia group (23.7; 17.6-31.8, p = 0.001), in which HX correlated with pH (r = 0.558, p = 0.008) and AVP (r = 0.588, p = 0.005). EP did not correlate with AVP or HX in any group, nor did any of the variables correlate with the Apgar score. We conclude that cord plasma AVP and HX reflect acute asphyxia, whereas EP is elevated after more prolonged hypoxia.

Topics: Apgar Score; Asphyxia Neonatorum; Erythropoietin; Female; Fetal Blood; Humans; Hydrogen-Ion Concentration; Hypoxanthine; Hypoxanthines; Infant, Newborn; Male; Pre-Eclampsia; Pregnancy; Vasopressins

For an assessment of whether cord plasma arginine vasopressin, erythropoietin, and hypoxanthine concentrations are predictors of perinatal brain damage, these concentrations were measured in 62 infants born after preeclampsia of pregnancy, 31 acutely asphyxiated infants, and 38 control infants. Follow-up at 2 years included neurologic examination and the determination of a Bayley mental score. Clear abnormality (death, cerebral palsy, or developmental delay) was found in four infants in the preeclampsia group and five in the asphyxia group; slight abnormality was found in 12 and 6 infants, respectively; and no abnormality was found in the remainder. Neither arginine vasopressin values nor hypoxanthine values predicted adverse outcome in either study group. A high erythropoietin level was found in infants born after preeclampsia regardless of outcome: normal outcome (geometric mean (GM), 102; 95% confidence interval [CI], 69 to 153 mU/ml), slightly abnormal outcome (GM, 100; 95% CI, 37 to 270 mU/ml) or clearly abnormal outcome (GM, 84; 95% CI, 19 to 378 mU/ml). However, asphyxiated infants with clearly abnormal outcome had higher erythropoietin values (GM, 67; 95% CI, 33 to 137 mU/ml; p less than 0.05) than the normal infants (GM, 37; 95% CI, 23 to 59 mU/ml). We conclude that a high erythropoietin level after normal pregnancy, but not after preeclampsia, indicates an increased risk for cerebral palsy or death.

Topics: Arginine Vasopressin; Asphyxia Neonatorum; Brain Damage, Chronic; Cerebral Palsy; Erythropoietin; Female; Fetal Blood; Humans; Hypoxanthine; Hypoxanthines; Infant, Newborn; Male; Pre-Eclampsia; Pregnancy; Prognosis

Topics: Asphyxia Neonatorum; Erythropoietin; Female; Gestational Age; Humans; Hypoxia; Infant, Newborn; Infant, Premature; Iron Isotopes; Male; Pregnancy; Respiratory Distress Syndrome, Newborn; Umbilical Cord

Topics: Animals; Asphyxia Neonatorum; Blood; Epoetin Alfa; Erythroblastosis, Fetal; Erythropoietin; Fetal Blood; Fetus; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; Mice; Research; Umbilical Cord