Do Lower Levels of Fetal Hemoglobin in Preterm Infants Relate to Oxidative Stress?

Fetal hemoglobin (HbF) has a higher affinity to oxygen than adult hemoglobin, allowing for a slower oxygen transfer to peripheral tissue, creating a microenvironment conducive to adequate fetal development in utero. However, most preterm infants receive packed red blood cell transfusions from adult donors leading to a drastic nonphysiological descent of circulating HbF. We hypothesized that this drop could enhance oxygen delivery to peripheral tissues generating a hyperoxic pro-oxidant environment. To investigate this, we assessed differences in oxidative stress biomarkers determined in urine samples in a cohort of 56 preterm infants born <32 weeks' gestation. Median oxidative stress biomarkers were compared between patients with circulating HbF above or below median HbF levels using Wilcoxon rank sum test. Oxidative stress biomarkers were significantly higher in the group of patients with lower levels of HbF. This study provides the initial evidence indicating elevated levels of oxidative stress biomarkers in preterm neonates with lower HbF levels. Based on the results, we hypothesize that HbF may contribute to preventing free radical-associated conditions during the newborn period. Antioxid. Redox Signal. 40, 453-459.

Preterm-related posthemorrhagic hydrocephalus: Review of our institutional series with a long-term follow-up.

INTRODUCTION: Preterm-related posthemorrhagic hydrocephalus is a major cause of neurological impairment and a common indication for a ventriculoperitoneal shunt in infants that are prone to diverse complications. Protocols of diagnosis and treatment are in continuous evolution and require evaluation of their results. OBJECTIVE: To review the clinical characteristics and results of a series of preterm-related posthemorrhagic hydrocephalus needing a definitive shunt from 1982 to 2020 in our institution. As a secondary objective we evaluated the safety of the changes in our protocol of treatment from 2015. METHODS: Retrospective review, clinical investigation. RESULTS: 133 patients were implanted a shunt in the study period. Shunt infection was diagnosed in 15 patients. Proximal shunt obstruction as the first complication was diagnosed in 30% of cases at one year, 37% at two years and 46% at five years. 61 patients developed very small or collapsed ventricles at last follow-up. Two thirds of our patients achieved normal neurological development or mild impairment. Changes in protocol did not significantly modify clinical results although improvement in most outcomes was observed. Mean follow-up was over nine years. CONCLUSIONS: Clinical outcomes are comparable to previous reported data. Changes in protocol proved to be safe and improved our results. Programmable shunts can be used safely in preterm patients although they may not prevent tendency towards ventricular collapse, which is very common after long follow-up.

Quantitative Evaluation of Neonatal Brain Elasticity Using Shear Wave Elastography.

OBJECTIVES: To demonstrate the feasibility of 2-dimensional brain ultrasound shear wave elastography (SWE) and to define the average elasticity values of the gray and white matter in term neonates. METHODS: This work was a prospective observational single-center study including 55 healthy term neonates consecutively recruited in the maternity ward between the second and third postnatal days. All were successfully evaluated with a cerebral SWE examination performed with a multifrequency 4-9-MHz transducer. Bilateral sagittal planes of the thalamus and corona radiata were used to measure stiffness using a quantitative SWE method. Several elastograms with 5 to 15 nonoverlapping areas were obtained from the 2 different anatomic locations. The 5 most central measurements were averaged as representative values. RESULTS: The 55 neonates ranged from 37 to 40 weeks' gestation. The estimated mean velocity values of the thalamus (1.17 m/s; 95% confidence interval, 1.13, 1.22 m/s) and corona radiata (1.60 m/s; 95% confidence interval, 1.57, 1.64 m/s) were statistically different (P < .001). There was no significant influence of laterality, gestational age, cephalic perimeter, sex, length, or type of delivery on the stiffness measurements. CONCLUSIONS: Brain ultrasound SWE is feasible and allows measurements of neonatal brain elasticity. The elasticity of the thalamus and corona radiata at the frontal white matter in healthy term neonates is different. The knowledge of normal SWE ranges in term neonates allows comparative studies under pathologic conditions.

Metabolic adaptation and neuroprotection differ in the retina and choroid in a piglet model of acute postnatal hypoxia.

BACKGROUND: Hypoxic-ischemic insults to the neonatal brain may cause neurodevelopmental disorders. Vulnerability of different areas of the neural tissue to hypoxic-ischemic stress might be explained by either heterogeneous sensitivity to oxygen or neuroprotective capability. Our understanding of regional heterogeneity is still incomplete in terms of metabolic reconfiguration and/or activation of neuroprotective mechanisms. METHODS: We studied, by western blotting, reverse-transcriptase PCR, and tandem mass spectrometry, the response of retina and choroid at protein, gene, and metabolic levels during hypoxia in a piglet model of acute postnatal hypoxia. RESULTS: We evidenced a metabolic shift towards glycolysis in choroid after hypoxia while retina experienced a dramatic energy stress with decreased mitochondrial metabolites. Hypoxia-inducible transcription factor-1α (HIF-1α) was not stabilized in retina during hypoxia, supported by a deficient signaling from v-akt murine thymoma viral oncogene (AKT) and ERK1/2, and unchanged glutathione redox status. In retina, but not in choroid, phosphorylation of p65 (NF-κB) and increased transcription of target genes may have a major role during hypoxic stress. CONCLUSION: We showed that the retina engages a distinct pattern of signaling and transcriptional events than observed in the choroid. Retina and choroid may reflect regional sensitivity to hypoxia. While prolonged and intense hypoxia may jeopardize retinal cell survival, choroid sets up a different pattern of response, which promotes adaptation to these adverse conditions.

Oxygen in the delivery room.

Immediately after birth the newly born infant aerates the lungs, diminishes pulmonary vascular resistance, and initiates gas exchange. However, under certain circumstances this process will not be adequately accomplished. Asphyxia is characterized by periods of hypoxia and ischemia leading frequently to hypoxic ischemic encephalopathy. The mainstay of newborn resuscitation resides in the establishment of a functional residual capacity and an adequate oxygenation. Recent guidelines have established guidelines which provide counsel on the use of oxygen in term infants. However, preterm oxygenation in the delivery room (DR) has only been defined very vaguely. Herewith, we will address available information regarding the use of oxygen supplementation in the DR both in term and preterm babies for a satisfactory postnatal adaptation.

Oxygen saturation after birth in preterm infants treated with continuous positive airway pressure and air: assessment of gender differences and comparison with a published nomogram.

AIMS: The goal of the study was to compare preductal SpO2 in the first 10 min after birth in preterm infants treated with non-invasive continuous positive airway pressure (CPAP) and air with a published nomogram of preductal SpO2 in preterm infants who received no medical intervention, and to examine gender differences. DESIGN: Prospective observational study. PATIENTS AND METHODS: We enrolled infants of ≤32 weeks gestation who were spontaneously breathing with heart rate >100 bpm, and treated with face mask CPAP and air during postnatal stabilisation. SpO2 limits were targeted at ≥75% at 5 min and ≥85% at 10 min and heart rate at >100 bpm. FIO2 was titrated against SpO2. Preductal SpO2, airway pressure and FIO2 were recorded with a data acquisition system from birth until stabilisation. Babies receiving supplemental oxygen (>21%), positive pressure ventilation, were intubated and/or received chest compressions or drugs were excluded. RESULTS: Measurements were obtained in 102 babies with median gestational age of 29 (range: 24-31) weeks. Median SpO2 was significantly higher in the observational group than in the reference range at 3 min (82% (CI 71% to 85%) vs 76% (CI 67% to 83%); p<0.05), at 4 min (87% (CI 81% to 90%) vs 81% (CI 72% to 88%); p<0.05), at 5 min (92% (CI 88% to 95%) vs 86% (CI 80% to 92%); p<0.05), at 6 min (94% (CI 90% to 97%) vs 90% (CI 81% to 95%); p<0.05), at 7 min (95% (CI 92% to 97%) vs 92% (CI 85% to 95%); p<0.05), at 8 min (96% (CI 93% to 98%) vs 92% (CI 87% to 96%); p<0.05) and at 9 min (97% (CI 92% to 99%) vs 93% (CI 87% to 96%); p<0.05). Female babies achieved targeted SpO2 significantly earlier than male babies. CONCLUSIONS: Preterm babies receiving CPAP and air and especially female subjects achieve reference oxygen saturation more rapidly than spontaneously breathing preterm babies without respiratory aid.

Oxygen saturation targets for preterm infants in the delivery room.

Fetal life evolves in a low oxygen milieu as compared to the extra-uterine. In the fetal to neonatal transition rapid changes in the oxygen content of the newly born infant occur within a brief period of time. Delivery room care givers should be aware of the slow transition regarding oxygenation, and supply oxygen as needed trying to avoid damage caused by hyper-and-hypoxia. In this regard, titrating oxygen inspiratory fraction against oxygen saturation as measured by pulse oximetry following recent nomogram ranges is a valid method.

Expression of aquaporins early in human pregnancy.

BACKGROUND: Aquaporins (AQPs) constitute a family of channel proteins implicated in transmembrane water transport. Thirteen different AQPs (AQP0-12) have been described but their precise biologic function still remains unclear. AQPs 1, 3, 4, 8, and 9 expression has been described in human chorion, amnion and placenta; however, AQP4 is the only that has been identified in the first trimester of human pregnancy. OBJECTIVE: To assess multiplicity of AQPs expression from 10th to 14th week gestation. POPULATION AND METHODS: Chorionic villi samples (CVS) collected in pregnant women for prenatal diagnosis were analysed by real time-PCR to assess cDNA expression of AQPs 1, 2, 3, 4, 5, 6, 7, 8, 9, and 11, and compared with AQPs expression in placentas from normal term pregnancies. RESULTS: 26 CVS corresponding to 26 pregnant women (age: 32.7±4.5 years; gestational age: 12.4±0.9 weeks) and 10 placental samples corresponding to normal term pregnancies were analysed. In CVS karyotype was normal in 16 cases, trisomy in 6 cases, mosaicism in 1 and unknown in 1. We found high mRNA expression for AQPs 1, 3, 9 and 11, low for AQPs 4, 5, and 8, and non-detectable for AQPs 2, 6, and 7 in chorionic villi. CONCLUSIONS: This is the first study systematically assessing the expression of a multiplicity of AQPs in chorionic villi samples between 10th and 14th weeks of gestation. High expression of AQP11 has been identified for the first time in early stages of human pregnancy. Chromosomal abnormalities did not alter AQPs' expression.

The use and misuse of oxygen during the neonatal period.

This article describes aerobic metabolism, oxygen free radicals, antioxidant defenses, oxidative stress, inflammatory response and redox signaling, the fetal to neonatal transition, arterial oxygen saturation, oxygen administration in the delivery room, oxygen during neonatal care in the NICU, evolving oxygen needs in the first few weeks of life, and complications that can occur when infants go home from the hospital on oxygen.

Antenatal steroids and antioxidant enzyme activity in preterm infants: influence of gender and timing.

Antenatal steroids have improved the survival of preterm infants; however, the mechanism of action is not fully understood. We aimed to establish an association between antenatal steroids and antioxidant activity and postnatal oxidative stress. In a prospective cohort study, extremely preterm neonates receiving antenatal steroids (CORT) or not (NOCORT) were enrolled. An association between antenatal steroids and activities of antioxidant enzymes and glutathione cycle enzymes in cord blood was found. In addition, reduced oxidative stress (GSH/GSSG ratio, CORT vs. NOCORT, 35.68 + or - 12.20 vs. 28.38 + or - 9.92; p < 0.01) and, decreased oxidation of proteins (ortho-tyrosine/phenylalanine ratio, CORT vs. NOCORT, 8.66 + or - 2.45 vs. 12.55 + or - 4.41; p < 0.01) and DNA (8oxodG/2dG ratio, CORT vs. NOCORT, 6.73 + or - 2.18 vs. 9.53 + or - 3.83; p < 0.01) also was found. Antenatal steroids were associated with reduced oxygen supplementation, mechanical ventilation, and conditions such as bronchopulmonary dysplasia, intra-periventricular hemorrhage, or retinopathy of prematurity. The maximal effectiveness was when steroids were administered 2-4 days before delivery. Female preterm infants had less oxidative stress and increased antioxidant activity and better clinical outcomes than did male infants, independent of receiving or not antenatal steroids. Antenatal steroids are accompanied by a reduction in postnatal oxidative-stress-derived conditions and increased antioxidant enzyme activity. Both these effects seem to be influenced by specific timing and female gender.

Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease.

OBJECTIVE: The goal was to reduce adverse pulmonary adverse outcomes, oxidative stress, and inflammation in neonates of 24 to 28 weeks of gestation initially resuscitated with fractions of inspired oxygen of 30% or 90%. METHODS: Randomized assignment to receive 30% (N = 37) or 90% (N = 41) oxygen was performed. Targeted oxygen saturation values were 75% at 5 minutes and 85% at 10 minutes. Blood oxidized glutathione (GSSG)/reduced glutathione ratio and urinary o-tyrosine, 8-oxo-dihydroxyguanosine, and isoprostane levels, isofuran elimination, and plasma interleukin 8 and tumor necrosis factor alpha levels were determined. RESULTS: The low-oxygen group needed fewer days of oxygen supplementation (6 vs 22 days; P < .01) and fewer days of mechanical ventilation (13 vs 27 days; P < .01) and had a lower incidence of bronchopulmonary dysplasia at discharge (15.4% vs 31.7%; P < .05). GSSG/reduced glutathione x 100 ratios at day 1 and 3 were significantly higher in the high-oxygen group (day 1: high-oxygen group: 13.36 +/- 5.25; low-oxygen group: 8.46 +/- 3.87; P < .01; day 3: high-oxygen group: 8.87 +/- 4.40; low-oxygen group: 6.97 +/- 3.11; P < .05). Urinary markers of oxidative stress were increased significantly in the high-oxygen group, compared with the low-oxygen group, in the first week after birth. GSSG levels on day 3 and urinary isofuran, o-tyrosine, and 8-hydroxy-2'-deoxyguanosine levels on day 7 were correlated significantly with development of chronic lung disease. CONCLUSIONS: Resuscitation of preterm neonates with 30% oxygen causes less oxidative stress, inflammation, need for oxygen, and risk of bronchopulmonary dysplasia.

Human milk enhances antioxidant defenses against hydroxyl radical aggression in preterm infants.

BACKGROUND: Preterm infants endowed with an immature antioxidant defense system are prone to oxidative stress. Hydroxyl radicals are very aggressive reactive oxygen species that lack specific antioxidants. These radicals cannot be measured directly, but oxidation byproducts of DNA or phenylalanine in urine are reliable markers of their activity. Human milk has a higher antioxidant capacity than formula. OBJECTIVE: We hypothesized that oxidative stress associated with prematurity could be diminished by feeding human milk. DESIGN: We recruited a cohort of stable preterm infants who lacked perinatal conditions associated with oxidative stress; were not receiving prooxidant or antioxidant drugs, vitamins, or minerals before recruitment; and were fed exclusively human milk (HM group) or preterm formula (PTF group). Collected urine was analyzed for oxidative bases of DNA [8-hydroxy-2'-deoxyguanosine (8-oxodG)/2'-deoxyguanosine (2dG) ratio] and oxidative derivatives of phenylalanine [ortho-tyrosine (o-Tyr)/Phe ratio] by HPLC coupled to tandem mass spectrometry. Healthy term newborn infants served as control subjects. RESULTS: Both preterm groups eliminated greater amounts of metabolites than did the control group. However, the PTF group eliminated significantly (P < 0.02) higher amounts of 8-oxodG (8-oxodG/2dG ratio: 10.46 +/- 3.26) than did the HM group (8-oxodG/2dG ratio: 9.05 +/- 2.19) and significantly (P < 0.01) higher amounts of o-Tyr (o-Tyr/Phe ratio: 14.90 +/- 3.75) than did the HM group (o-Tyr/Phe ratio: 12.53 +/- 3.49). When data were lumped together independently of the type of feeding received, a significant correlation was established between the 8-oxodG/2dG and o-Tyr/Phe ratios in urine, dependent on gestational age and birth weight. CONCLUSION: Prematurity is associated with protracted oxidative stress, and human milk is partially protective.

Consequences of neonatal resuscitation with supplemental oxygen.

There has been considerable controversy surrounding the optimal inspired oxygen concentration for resuscitation of term and preterm infants. We have developed a rat pup model to quantify both physiologic and biochemical parameters associated with normoxic vs. hyperoxic resuscitation. We have confirmed existing human data that hyperoxic resuscitation of rat pups is associated with a significant delay in onset of spontaneous respiratory efforts. Both 40% and 100% inspired oxygen delayed onset of respiratory activity when compared to 21% oxygen. We have also documented, in the rat pup model, that hyperoxic resuscitation is associated with reduced levels of glutathione at 24 hours post resuscitation. The implications of these and other findings for human infants are that term asphyxiated babies can be safely resuscitated in 21% oxygen and that supplementary oxygen can be reserved for non-responders. In contrast, resuscitation of extremely low gestational age infants does appear to require an initial low inspired oxygen concentration (eg, 30%) with subsequent pulse oximetry titration to optimize oxygenation status.

Achievement of targeted saturation values in extremely low gestational age neonates resuscitated with low or high oxygen concentrations: a prospective, randomized trial.

OBJECTIVE: Extremely low gestational age neonates have very low oxygen saturation in utero and an immature antioxidant defense system. Abrupt increases in oxygen saturation after birth may cause oxidative stress. We compared achievement of a targeted oxygen saturation of 85% at 10 minutes of life when resuscitation was initiated with low or high fractions of inspired oxygen and levels were adjusted according to preductal pulse oxygen saturation values. METHODS: A prospective, randomized, clinical trial was performed in 2 level III neonatal referral units. Patients of < or = 28 weeks of gestation who required active resuscitation were randomly assigned to the low-oxygen group (fraction of inspired oxygen: 30%) or the high-oxygen group (fraction of inspired oxygen: 90%). Every 60 to 90 seconds, the fraction of inspired oxygen was increased in 10% steps if bradycardia occurred (< 100 beats per minute) or was decreased in similar steps if pulse oxygen saturation reached values of > 85%. Preductal pulse oxygen saturation was continuously monitored. RESULTS: The fraction of inspired oxygen in the low-oxygen group was increased stepwise to 45% and that in the high-oxygen group was reduced to 45% to reach a stable pulse oxygen saturation of approximately 85% at 5 to 7 minutes in both groups. No differences in oxygen saturation in minute-to-minute registers were found independent of the initial fraction of inspired oxygen used 4 minutes after cord clamping. No differences in mortality rates in the early neonatal period were detected. CONCLUSIONS: Resuscitation can be safely initiated for extremely low gestational age neonates with a low fraction of inspired oxygen (approximately 30%), which then should be adjusted to the infant's needs, reducing the oxygen load to the neonate.

Resuscitation of hypoxic newborn piglets with oxygen induces a dose-dependent increase in markers of oxidation.

Newborn resuscitation with pure oxygen may be associated with long-term detrimental effects. Due to the change in attitude toward use of less oxygen upon resuscitation, there is a need to study effects of intermediate hyperoxia. The aim was to study dose-response correlation between inspiratory fraction of oxygen used for resuscitation and urinary markers of oxidative damage to DNA and amino acids. Hypoxemia was induced in newborn piglets following a standardized model; they were resuscitated for 15 min with either 21%, 40%, 60% or 100% oxygen and observed for 1 h. Urine samples were collected. Urinary elimination of 8-hydroxy-2'-deoxyguanosine (8-oxo-dG), 2'deoxyguanosine (2dG), ortho-tyrosine (o-Tyr) and phenylalanine (Phe) were determined by HPLC and tandem mass spectrometry (HPLC-MS/MS). Quotient of 8-oxo-dG/2dG and o-Tyr/Phe ratios were significantly and dose-dependant higher in piglets resuscitated with supplementary oxygen. 8-oxodG/dG: Mean (SD) 5.76 (1.81) versus 22.44 (12.55) p < 0.01 and o-Tyr/Phe: 19.07 (10.7) versus 148.7 (59.8)for 21% versus 100%, p < 0.001. Hypoxia and subsequent resuscitation for 15 min with graded inspiratory fraction of oxygen causes increased oxidative stress and a dose-dependant oxidation of DNA and Phenylalanine. The increase in the hydroxyl attack may lead to a pro-oxidative status and risk for genetic instability.