Publications by authors named "Máximo Vento"

268 Publications

Oxygen saturation and heart rate in healthy term and late preterm infants with delayed cord clamping.

Pediatr Res 2022 Jan 7. Epub 2022 Jan 7.

Neonatal Research Group, Health Research Institute and University and Polytechnic Hospital La Fe, Valencia, Spain.

Blood oxygen in the fetus is substantially lower than in the newborn infant. In the minutes after birth, arterial oxygen saturation rises from around 50-60% to 90-95%. Initial respiratory efforts generate negative trans-thoracic pressures that drive liquid from the airways into the lung interstitium facilitating lung aeration, blood oxygenation, and pulmonary artery vasodilatation. Consequently, intra- (foramen ovale) and extra-cardiac (ductus arteriosus) shunting changes and the sequential circulation switches to a parallel pulmonary and systemic circulation. Delaying cord clamping preserves blood flow through the ascending vena cava, thus increasing right and left ventricular preload. Recently published reference ranges have suggested that delayed cord clamping positively influenced the fetal-to-neonatal transition. Oxygen saturation in babies with delayed cord clamping plateaus significantly earlier to values of 85-90% than in babies with immediate cord clamping. Delayed cord clamping may also contribute to fewer episodes of brady-or-tachycardia in the first minutes after birth, but data from randomized trials are awaited. IMPACT: Delaying cord clamping during fetal to neonatal transition contributes to a significantly earlier plateauing of oxygen saturation and fewer episodes of brady-and/or-tachycardia in the first minutes after birth. We provide updated information regarding the changes in SpO and HR during postnatal adaptation of term and late preterm infants receiving delayed compared with immediate cord clamping. Nomograms in newborn infants with delayed cord clamping will provide valuable reference ranges to establish target SpO and HR in the first minutes after birth.
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http://dx.doi.org/10.1038/s41390-021-01805-yDOI Listing
January 2022

A UPLC-MS/MS method for the determination of oxidative stress biomarkers in amniotic fluid.

Free Radic Biol Med 2022 Feb 28;179:164-169. Epub 2021 Dec 28.

Neonatal Research Group, Health Research Institute La Fe, Valencia, Spain; Division of Neonatology, University & Polytechnic Hospital La Fe, Valencia, Spain. Electronic address:

Oxidative stress in the fetal period is associated with preterm birth as well as short and long-term adverse clinical outcomes. Here, an Ultra-Performance Liquid Chromatography-tandem Mass Spectrometry (UPLC-MS/MS) method for the simultaneous quantification of biomarkers of oxidative stress-derived damage to proteins and DNA in amniotic fluid (AF) samples is presented. Appropriate accuracy and precision levels, as well as sensitivity with limits of detection in the low nanomolar (<2 nM) range were achieved. The analytical method was applied to a set of AF samples and reference ranges of the biomarker panel are presented. Median concentrations of biomarkers of protein oxidation (ortho-, 3-chloro-, and 3-nitrotyrosine) and their precursors (para-tyrosine and phenylalanine) ranged between 0.6 and 3 nM and 23 and 30 μM, respectively, while levels of a biomarker of DNA-oxidation (8-hydroxydeoxyguanosine, 8OHdG) and its precursor (2'-deoxyguanosine) were found to be 0.18 and 3 nM, respectively. Detection frequencies of all metabolites were 100% with exception of 3-chlorotyrosine (3Cl-Tyr) and 8OHdG, that were only detected in 8% of samples. The developed method may be applied in research studies focusing on oxidative stress-related complications during pregnancy.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.12.310DOI Listing
February 2022

Higher versus Lower Oxygen Concentration during Respiratory Support in the Delivery Room in Extremely Preterm Infants: A Pilot Feasibility Study.

Children (Basel) 2021 Oct 20;8(11). Epub 2021 Oct 20.

Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, Alberta Health Services, Edmonton, AB T5H 3V9, Canada.

Background: Optimal starting oxygen concentration for delivery room resuscitation of extremely preterm infants (<29 weeks) remains unknown, with recommendations of 21-30% based on uncertain evidence. Individual patient randomized trials designed to answer this question have been hampered by poor enrolment.

Hypothesis: It is feasible to compare 30% vs. 60% starting oxygen for delivery room resuscitation of extremely preterm infants using a change in local hospital policy and deferred consent approach.

Study Design: Prospective, single-center, feasibility study, with each starting oxygen concentration used for two months for all eligible infants.

Population: Infants born at 23 + 0-28 + 6 weeks' gestation who received delivery room resuscitation. Study interventions: Initial oxygen at 30% or 60%, increasing by 10-20% every minute for heart rate < 100 bpm, or increase to 100% for chest compressions.

Primary Outcome: Feasibility, defined by (i) achieving difference in cumulative supplied oxygen concentration between groups, and (ii) post-intervention rate consent >50%.

Results: Thirty-four infants were born during a 4-month period; consent was obtained in 63%. Thirty ( = 12, 30% group; = 18, 60% group) were analyzed, including limited data from eight who died or were transferred before parents could be approached. Median cumulative oxygen concentrations were significantly different between the two groups in the first 5 min.

Conclusion: Randomized control trial of 30% or 60% oxygen at the initiation of resuscitation of extremely preterm neonates with deferred consent is feasible.

Trial Registration: Clinicaltrials.gov NCT03706586.
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http://dx.doi.org/10.3390/children8110942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625238PMC
October 2021

Clinical and immunological aspects of microRNAs in neonatal sepsis.

Biomed Pharmacother 2022 Jan 19;145:112444. Epub 2021 Nov 19.

Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, Valencia, Spain; INCLIVA Health Research Institute, Mixed Unit for Rare Diseases INCLIVA-CIPF, Valencia, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain. Electronic address:

Neonatal sepsis constitutes a highly relevant public health challenge and is the most common cause of infant morbidity and mortality worldwide. Recent studies have demonstrated that during infection epigenetic changes may occur leading to reprogramming of gene expression. Post-transcriptional regulation by short non-coding RNAs (e.g., microRNAs) have recently acquired special relevance because of their role in the regulation of the pathophysiology of sepsis and their potential clinical use as biomarkers. ~22-nucleotide of microRNAs are not only involved in regulating multiple relevant cellular and molecular functions, such as immune cell function and inflammatory response, but have also been proposed as good candidates as biomarkers in sepsis. Nevertheless, establishing clinical practice guidelines based on microRNA patterns as biomarkers for diagnosis and prognosis in neonatal sepsis has yet to be achieved. Given their differential expression across tissues in neonates, the release of specific microRNAs to blood and their expression pattern can differ compared to sepsis in adult patients. Further in-depth research is necessary to fully understand the biological relevance of microRNAs and assess their potential use in clinical settings. This review provides a general overview of microRNAs, their structure, function and biogenesis before exploring their potential clinical interest as diagnostic and prognostic biomarkers of neonatal sepsis. An important part of the review is focused on immune and inflammatory aspects of selected microRNAs that may become biomarkers for clinical use and therapeutic intervention.
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http://dx.doi.org/10.1016/j.biopha.2021.112444DOI Listing
January 2022

Five-minute Apgar score and outcomes in neonates of 24-28 weeks' gestation.

Arch Dis Child Fetal Neonatal Ed 2021 Nov 15. Epub 2021 Nov 15.

Division of Neonatology and Pediatrics, Ospedale Versilia, Viareggio, Azienda USL Toscana Nord Ovest, Italy.

Objectives: To assess associations between 5 min Apgar score and mortality and severe neurological injury (SNI) and to report test characteristics in preterm neonates.

Design, Setting And Patients: Retrospective cohort study of neonates 24 to 28 weeks' gestation born between 2007 and 2016 and admitted to neonatal units in 11 high-income countries.

Exposure: 5 min Apgar score.

Main Outcome Measures: In-hospital mortality and SNI defined as grade 3 or 4 periventricular/intraventricular haemorrhage or periventricular leukomalacia. Outcome rates were calculated for each Apgar score and compared after adjustment. The diagnostic characteristics and ORs for each value from 0 versus 1-10 to 0-9 versus 10, with 1-point increments were calculated.

Results: Among 92 412 included neonates, as 5 min Apgar score increased from 0 to 10, mortality decreased from 60% to 8%. However, no clear increasing or decreasing pattern was identified for SNI. There was an increase in sensitivity and decrease in specificity for both mortality and SNI associated with increasing scores. The Apgar score alone had an area under the curve of 0.64 for predicting mortality, which increased to 0.73 with the addition of gestational age.

Conclusions: In neonates of 24-28 weeks' gestation admitted to neonatal units, higher 5 min Apgar score was associated with lower mortality in a graded manner, while the association with SNI remained relatively constant at all scores. Among survivors, low Apgar scores did not predict SNI.
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http://dx.doi.org/10.1136/archdischild-2021-322230DOI Listing
November 2021

Attentional biases towards emotional scenes in autism spectrum condition: An eye-tracking study.

Res Dev Disabil 2022 Jan 12;120:104124. Epub 2021 Nov 12.

Department of Personality, Evaluation, and Psychological Treatments, University of Valencia, Valencia, Spain; La Fe University and Polytechnic Hospital, Department of Psychiatry, Valencia, Spain; Neonatal Research Group, La Fe Health Research Institute, Valencia, Spain. Electronic address:

Background: Different attentional processing of emotional information may underlie social impairments in Autism Spectrum Condition (ASC). It has been hypothesized that individuals with ASC show hypersensitivity to threat, which may be related to an avoidance behaviour. However, research on the attentional processing of emotional information in autism is inconclusive.

Aim: To examine the attentional processing biases of 27 children with ASC and 25 typically developed (TD) participants.

Methods And Procedures: The initial orienting of attention, the attentional engagement, and the attentional maintenance to complex emotional scenes in competition (happy, neutral, threatening, sad) were assessed in a 20-second eye-tracking based free-viewing task.

Outcomes And Results: i) children with ASC showed an initial orienting bias towards threatening stimuli; ii) TD children demonstrated an attentional engagement and maintenance bias towards threat, while children with ASC did not; and iii) in children with ASC, attentional problems and somatic complaints were associated with higher initial orienting and with higher attentional maintenance towards threat, respectively.

Conclusions And Implications: These results suggest that a perceived threat induces an early overwhelming response in autism, giving rise to an avoidance behaviour. The findings endorse affective information processing theories and shed light on the mechanisms underlying social disturbances in ASC.
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http://dx.doi.org/10.1016/j.ridd.2021.104124DOI Listing
January 2022

Seeking biomarkers that predict neurodevelopmental impairment in preterm infants.

EBioMedicine 2021 Nov 28;73:103657. Epub 2021 Oct 28.

Health Research Institute La Fe, Valencia, Spain; Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2021.103657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577321PMC
November 2021

Neurodevelopmental outcomes of preterm infants after randomisation to initial resuscitation with lower (FiO 0.3) or higher (FiO 0.6) initial oxygen levels. An individual patient meta-analysis.

Arch Dis Child Fetal Neonatal Ed 2021 Nov 1. Epub 2021 Nov 1.

La Fe Health Research Institute, La Fe University and Polytechnic Hospital, Valencia, Spain.

Objective: To determine the effects of lower (≤0.3) versus higher (≥0.6) initial fractional inspired oxygen (FiO) for resuscitation on death and/or neurodevelopmental impairment (NDI) in infants <32 weeks' gestation.

Design: Meta-analysis of individual patient data from three randomised controlled trials.

Setting: Neonatal intensive care units.

Patients: 543 children <32 weeks' gestation.

Intervention: Randomisation at birth to resuscitation with lower (≤0.3) or higher (≥0.6) initial FiO.

Outcome Measures: Primary: death and/or NDI at 2 years of age.Secondary: post-hoc non-randomised observational analysis of death/NDI according to 5-minute oxygen saturation (SpO) below or at/above 80%.

Results: By 2 years of age, 46 of 543 (10%) children had died. Of the 497 survivors, 84 (17%) were lost to follow-up. Bayley Scale of Infant Development (third edition) assessments were conducted on 377 children. Initial FiO was not associated with difference in death and/or disability (difference (95% CI) -0.2%, -7% to 7%, p=0.96) or with cognitive scores <85 (2%, -5% to 9%, p=0.5). Five-minute SpO >80% was associated with decreased disability/death (14%, 7% to 21%) and cognitive scores >85 (10%, 3% to 18%, p=0.01). Multinomial regression analysis noted decreased death with 5-minute SpO ≥80% (odds (95% CI) 09.62, 0.98 to 0.96) and gestation (0.52, 0.41 to 0.65), relative to children without death or NDI.

Conclusion: Initial FiO was not associated with difference in risk of disability/death at 2 years in infants <32 weeks' gestation but CIs were wide. Substantial benefit or harm cannot be excluded. Larger randomised studies accounting for patient differences, for example, gestation and gender are urgently needed.
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http://dx.doi.org/10.1136/archdischild-2021-321565DOI Listing
November 2021

Mother's Bed Incline and Desaturation Episodes in Healthy Term Newborns during Early Skin-to-Skin Contact: A Multicenter Randomized Controlled Trial.

Neonatology 2021 25;118(6):702-709. Epub 2021 Oct 25.

Department of Neonatology, Health Research Institute Imas12, Complutense University, Madrid, Spain.

Introduction: Early skin-to-skin contact (ESSC) is associated with rare, sudden, unexpected postnatal collapse episodes. Placing the newborn in ESSC closer to an upright position may reduce the risk of airway obstruction and improve respiratory mechanics. This study assessed whether a greater inclination of the mother's bed during ESSC would reduce the proportion of healthy term newborns (HTNs) who experienced episodes of pulse oximeter saturation (SpO2) <91%.

Methods: We conducted a multicenter randomized controlled trial comparing the effect of the mother's bed incline, 45° versus 15°, on desaturation in HTNs during ESSC. Before delivery on 1,271 dyads, randomization was conducted, and stringent criteria to select healthy mothers and term newborns were monitored until after birth. Preductal SpO2 was continuously monitored between 10 min and 2 h after birth. The primary outcome was the occurrence of at least one episode of SpO2 <91%.

Results: 254 (20%) mother-infant dyads were eligible for analysis (45°, n = 126; 15°, n = 128). Overall, 57% (95% confidence interval [CI]: 51%-63%) of newborns showed episodes of SpO2 <91%. The proportion of infants with SpO2 <91% episodes was 52% in 45° and 62% in 15° (relative risk: 0.80; 95% CI: 0.6-1.07).

Conclusions: We did not show that a high mother bed inclination during ESSC led to significantly fewer HTNs who experienced episodes of SpO2 <91%. Desaturation episodes from 10 min to 2 h after birth occurred in more than half of HTNs.
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http://dx.doi.org/10.1159/000519387DOI Listing
October 2021

A Reductive Metabolic Switch Protects Infants with Transposition of Great Arteries Undergoing Atrial Septostomy against Oxidative Stress.

Antioxidants (Basel) 2021 Sep 22;10(10). Epub 2021 Sep 22.

Neonatal Research Unit, Health Research Institute Hospital La Fe, Avenida Fernando Abril Martorell 106, 46026 Valencia, Spain.

Transposition of the great arteries (TGA) is one of the most common cyanotic congenital heart diseases requiring neonatal surgical intervention. Parallel circulations that result in impaired cerebral oxygen delivery already in utero may lead to brain damage and long-term neurodevelopmental delay. Balloon atrial septostomy (BAS) is often employed to mix deoxygenated and oxygenated blood at the atrial level. However, BAS causes a sudden increase in arterial blood oxygenation and oxidative stress. We studied changes in oxygen saturation as well as metabolic profiles of plasma samples from nine newborn infants suffering from TGA before and until 48 h after undergoing BAS. The plasma metabolome clearly changed over time and alterations of four metabolic pathways, including the pentose phosphate pathway, were linked to changes in the cerebral tissue oxygen extraction. In contrast, no changes in levels of lipid peroxidation biomarkers over time were observed. These observations suggest that metabolic adaptations buffer the free radical burst triggered by re-oxygenation, thereby avoiding structural damage at the macromolecular level. This study enhances our understanding of the complex response of infants with TGA to changes in oxygenation induced by BAS.
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http://dx.doi.org/10.3390/antiox10101502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8532647PMC
September 2021

High Oxygen Does Not Increase Reperfusion Injury Assessed with Lipid Peroxidation Biomarkers after Cardiac Arrest: A Post Hoc Analysis of the COMACARE Trial.

J Clin Med 2021 Sep 17;10(18). Epub 2021 Sep 17.

Department of Emergency Care and Services, University of Helsinki and Helsinki University Hospital, 00029 Helsinki, Finland.

The products of polyunsaturated fatty acid peroxidation are considered reliable biomarkers of oxidative injury in vivo. We investigated ischemia-reperfusion-related oxidative injury by determining the levels of lipid peroxidation biomarkers (isoprostane, isofuran, neuroprostane, and neurofuran) after cardiac arrest and tested the associations between the biomarkers and different arterial oxygen tensions (PaO). We utilized blood samples collected during the COMACARE trial (NCT02698917). In the trial, 123 patients resuscitated from out-of-hospital cardiac arrest were treated with a 10-15 kPa or 20-25 kPa PaO target during the initial 36 h in the intensive care unit. We measured the biomarker levels at admission, and 24, 48, and 72 h thereafter. We compared biomarker levels in the intervention groups and in groups that differed in oxygen exposure prior to randomization. Blood samples for biomarker determination were available for 112 patients. All four biomarker levels peaked at 24 h; the increase appeared greater in younger patients and in patients without bystander-initiated life support. No association between the lipid peroxidation biomarkers and oxygen exposure either before or after randomization was found. Increases in the biomarker levels during the first 24 h in intensive care suggest continuing oxidative stress, but the clinical relevance of this remains unresolved.
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http://dx.doi.org/10.3390/jcm10184226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471647PMC
September 2021

NAC and Vitamin D Improve CNS and Plasma Oxidative Stress in Neonatal HIE and Are Associated with Favorable Long-Term Outcomes.

Antioxidants (Basel) 2021 Aug 25;10(9). Epub 2021 Aug 25.

Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, USA.

N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate ( = 14) or severe HIE ( = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24-48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.
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http://dx.doi.org/10.3390/antiox10091344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466838PMC
August 2021

Cumulative life stressors and stress response to threatened preterm labour as birth date predictors.

Arch Gynecol Obstet 2021 Sep 21. Epub 2021 Sep 21.

Neonatal Research Unit, Health Research Institute La Fe, Av Fernando Abril Martorell, 106, 46026, Valencia, Spain.

Purpose: Preterm birth represents one of the main causes of neonatal morbimortality and a risk factor for neurodevelopmental disorders. Appropriate predictive methods for preterm birth outcome, which consequently would facilitate prevention programs, are needed. We aim to predict birth date in women with a threatened preterm labour (TPL) based on stress response to TPL diagnosis, cumulative life stressors, and relevant obstetric variables.

Methods: A prospective cohort of 157 pregnant women with TPL diagnosis between 24 and 31 weeks gestation formed the study sample. To estimate the stress response to TPL, maternal salivary cortisol, α-amylase levels, along with anxiety and depression symptoms were measured. To determine cumulative life stressors, previous traumas, social support, and family functioning were registered. Then, linear regression models were used to examine the effect of potential predictors of birth date.

Results: Lower family adaptation, higher Body Mass Index (BMI), higher cortisol levels and TPL diagnosis week were the main predictors of birth date. Gestational week at TPL diagnosis showed a non-linear interaction with cortisol levels: TPL women with middle- and high-cortisol levels before 29 weeks of gestation went into imminent labour.

Conclusion: A combination of stress response to TPL diagnosis (salivary cortisol) and cumulative life stressors (family adaptation) together with obstetric factors (TPL gestational week and BMI) was the best birth date predictor. Therefore, a psychosocial therapeutic intervention program aimed to increase family adaptation and decrease cortisol levels at TPL diagnosis as well as losing weight, may prevent preterm birth in symptomatic women.
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http://dx.doi.org/10.1007/s00404-021-06251-zDOI Listing
September 2021

Oxygen for the delivery room respiratory support of moderate-to-late preterm infants. An international survey of clinical practice from 21 countries.

Acta Paediatr 2021 12 12;110(12):3261-3268. Epub 2021 Sep 12.

Faculty of Medicine, School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.

Aim: The aim of this study was to determine clinician opinion regarding oxygen management in moderate-late preterm resuscitation.

Methods: An anonymous online questionnaire was distributed through email/social messaging platforms to neonatologists in 21 countries (October 2020-March 2021) via REDCap.

Results: Of the 695 respondents, 69% had access to oxygen blenders and 90% had pulse oximeters. Respondents from high-income countries were more likely to have oxygen blenders than those from middle-income countries (72% vs. 66%). Most initiated respiratory support with FiO 0.21 (43%) or 0.3 (36%) but only 45% titrated FiO to target SpO . Most (89%) considered heart rate as a more important indicator of response than SpO . Almost all (96%) supported the need for well-designed trials to examine oxygenation in moderate-late preterm resuscitation.

Conclusion: Most clinicians resuscitated moderate-late preterm infants with lower initial FiO but some cannot/will not target SpO or titrate FiO . Most consider heart rate as a more important indicator of infant response than SpO .Large and robust clinical trials examining oxygen use for moderate-late preterm resuscitation, including long-term neurodevelopmental outcomes, are supported amongst clinicians.
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http://dx.doi.org/10.1111/apa.16091DOI Listing
December 2021

miRNomic Signature in Very Low Birth-Weight Neonates Discriminates Late-Onset Gram-Positive Sepsis from Controls.

Diagnostics (Basel) 2021 Jul 31;11(8). Epub 2021 Jul 31.

Division of Neonatology, University & Polytechnic Hospital La Fe, 46026 Valencia, Spain.

Background And Objectives: Neonatal sepsis is a serious condition with a high rate of mortality and morbidity. Currently, the gold standard for sepsis diagnosis is a positive blood culture, which takes 48-72 h to yield results. We hypothesized that identifying differentially expressed miRNA pattern in neonates with late-onset Gram-positive sepsis would help with an earlier diagnosis and therapy.

Methods: This is a prospective observational study in newborn infants with late-onset Gram positive bacterial sepsis and non-septic controls. Complementary to blood culture, an aliquot of 0.5 mL of blood was used to determine small non-coding RNA expression profiling using the GeneChip miRNA 4.0 Array.

Results: A total of 11 very low birth-weight neonates with late-onset Gram-positive sepsis and 16 controls were analyzed. Further, 217 differentially expressed miRNAs were obtained between both groups. Subsequently, a combined analysis was performed with these miRNAs and 4297 differentially expressed genes. We identified 33 miRNAs that regulate our mRNAs, and the most relevant biological processes are associated with the immune system and the inflammatory response.

Conclusions: The miRNA profiling in very low birth-weight neonates distinguishes late-onset Gram-positive sepsis versus control neonates.
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http://dx.doi.org/10.3390/diagnostics11081389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391178PMC
July 2021

Outcomes of delivery room resuscitation of bradycardic preterm infants: A retrospective cohort study of randomised trials of high vs low initial oxygen concentration and an individual patient data analysis.

Resuscitation 2021 10 20;167:209-217. Epub 2021 Aug 20.

Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain.

Objective: To determine whether hospital mortality (primary outcome) is associated with duration of bradycardia without chest compressions during delivery room (DR) resuscitation in a retrospective cohort study of randomized controlled trials (RCTs) in preterm infants assigned low versus high initial oxygen concentration.

Methods: Medline and EMBASE were searched from 01/01/1990 to 12/01/2020. RCTs of low vs high initial oxygen concentration which recorded serial heart rate (HR) and oxygen saturation (SpO) during resuscitation of infants <32 weeks gestational age were eligible. Individual patient level data were requested from the authors. Newborns receiving chest compressions in the DR and those with no recorded HR in the first 2 min after birth were excluded. Prolonged bradycardia (PB) was defined as HR < 100 bpm for ≥2 min. Individual patient data analysis and pooled data analysis were conducted.

Results: Data were collected from 720 infants in 8 RCTs. Neonates with PB had higher odds of hospital death before [OR 3.8 (95% CI 1.5, 9.3)] and after [OR 1.7 (1.2, 2.5)] adjusting for potential confounders. Bradycardia occurred in 58% infants, while 38% had PB. Infants with bradycardia were more premature and had lower birth weights. The incidence of bradycardia in infants resuscitated with low (≤30%) and high (≥60%) oxygen was similar. Neonates with both, PB and SpO < 80% at 5 min after birth had higher odds of hospital mortality. [OR 18.6 (4.3, 79.7)].

Conclusion: In preterm infants who did not receive chest compressions in the DR, prolonged bradycardia is associated with hospital mortality.
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http://dx.doi.org/10.1016/j.resuscitation.2021.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603874PMC
October 2021

Do Levels of Lipid Peroxidation Biomarkers Reflect the Degree of Brain Injury in Newborns?

Antioxid Redox Signal 2021 Dec;35(17):1467-1475

Neonatal Research Group, Health Research Institute Hospital La Fe, Valencia, Spain.

The pathogenesis and progression of hypoxic-ischemic encephalopathy (HIE), a major cause of severe neurological disability and mortality in the perinatal period, are shaped by the interplay of multiple processes, including inflammation, oxidative stress, and excitotoxicity. We conducted a longitudinal study to determine biomarkers of oxidative stress and inflammation in noninvasive urine samples of newborns with moderate/severe HIE ( = 51), employing liquid chromatography-mass spectrometry. We noted that levels of several biomarkers of oxidative stress increased over time, demonstrating the ongoing propagation of oxidative injury. Prostaglandins, in contrast, showed a decreasing trend in their concentration profiles over time, which probably reflects their mediation in pathogenic mechanisms, including the inflammatory response. Statistically significant differences in the levels of oxidative stress of neonates with distinct brain lesion patterns, as detected with magnetic resonance imaging (MRI), were observed, revealing an increase of lipid peroxidation biomarkers in newborns with cerebral lesions (MRI score of 1 compared with scores of 0 and 2). Moreover, a gender-dependent study showed no statistically significant differences in biomarker concentrations between male and female infants. Our observation leads to the hypothesis that monitoring of noninvasive lipid peroxidation biomarkers could aid in diagnosis and prediction of long-term outcomes as a complementary tool to standard exploration. 35, 1467-1475.
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http://dx.doi.org/10.1089/ars.2021.0168DOI Listing
December 2021

Non-invasive monitoring of saliva can be used to identify oxidative stress biomarkers in preterm and term newborn infants.

Acta Paediatr 2021 12 25;110(12):3255-3260. Epub 2021 Aug 25.

Neonatal Research Unit, Health Research Institute La Fe, Valencia, Spain.

Aim: The aim of this study was to appraise the feasibility and reproducibility of applying a validated analytical method to determine salivary oxidative stress biomarkers in newborn infants.

Methods: Prospective observational single-centre study was carried out in level III neonatal intensive care unit. Eligible patients were preterm infants and healthy full-term newborn infants. Salivary samples were analysed in the chromatographic system.

Results: A total of 23 premature newborn infants and 13 full-term newborns were included. We analysed salivary levels of oxidative stress biomarkers for 5-F isoprostane, 15-E isoprostane, prostaglandin E and prostaglandin F2α. The multivariate predictive model showed a positive association between female and 5-F isoprostonae, and between female sex and prostglandin F2α. In addition, we found a positive association between gestational age and levels of prostaglandin E . Furthermore, in the premature group, we found a positive association between the inspired fraction of oxygen and levels of prostaglandin G .

Conclusion: We identified and determined lipid peroxidation biomarkers in term and preterm newborn infants' saliva using specific and validated mass spectrometry technology.
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http://dx.doi.org/10.1111/apa.16073DOI Listing
December 2021

A multi-centre randomised controlled trial of respiratory function monitoring during stabilisation of very preterm infants at birth.

Resuscitation 2021 10 22;167:317-325. Epub 2021 Jul 22.

Division of Neonatology, Department of Paediatrics, Leiden University Medical Centre, Leiden, the Netherlands. Electronic address:

Aim: To determine whether the use of a respiratory function monitor (RFM) during PPV of extremely preterm infants at birth, compared with no RFM, leads to an increase in percentage of inflations with an expiratory tidal volume (Vte) within a predefined target range.

Methods: Unmasked, randomised clinical trial conducted October 2013 - May 2019 in 7 neonatal intensive care units in 6 countries. Very preterm infants (24-27 weeks of gestation) receiving PPV at birth were randomised to have a RFM screen visible or not. The primary outcome was the median proportion of inflations during manual PPV (face mask or intubated) within the target range (Vte 4-8 mL/kg). There were 42 other prespecified monitor measurements and clinical outcomes.

Results: Among 288 infants randomised (median (IQR) gestational age 26 (25-27) weeks), a total number of 51,352 inflations were analysed. The median (IQR) percentage of inflations within the target range in the RFM visible group was 30.0 (18.0-42.2)% vs 30.2 (14.8-43.1)% in the RFM non-visible group (p = 0.721). There were no differences in other respiratory function measurements, oxygen saturation, heart rate or FiO. There were no differences in clinical outcomes, except for the incidence of intraventricular haemorrhage (all grades) and/or cystic periventricular leukomalacia (visible RFM: 26.7% vs non-visible RFM: 39.0%; RR 0.71 (0.68-0.97); p = 0.028).

Conclusion: In very preterm infants receiving PPV at birth, the use of a RFM, compared to no RFM as guidance for tidal volume delivery, did not increase the percentage of inflations in a predefined target range.

Trial Registration: Dutch Trial Register NTR4104, clinicaltrials.gov NCT03256578.
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http://dx.doi.org/10.1016/j.resuscitation.2021.07.012DOI Listing
October 2021

Use of near infrared spectroscopy in neonatal gastric perforation.

An Pediatr (Engl Ed) 2021 Jul 5. Epub 2021 Jul 5.

Unidad de Investigación Neonatal, Instituto de Investigación Sanitaria La Fe, Valencia, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.anpede.2021.06.004DOI Listing
July 2021

Oxidative stress biomarkers in the preterm infant.

Adv Clin Chem 2021 17;102:127-189. Epub 2020 Dec 17.

Health Research Institute La Fe, Valencia, Spain; Maternal & Child Health and Development Research Network-Red SAMID Health Research, Spain. Electronic address:

Oxidative stress (OS) plays a key role in the pathophysiology of preterm infants. Accurate assessment of OS remains an analytical challenge that has been partially addressed during the last few decades. A plethora of approaches have been developed to assess preterm biofluids to demonstrate a link postnatally with preterm OS, giving rise to a set of widely employed biomarkers. However, the vast number of different analytic methods and lack of standardization hampers reliable comparison of OS-related biomarkers. In this chapter, we discuss approaches for the study of OS in prematurity with respect to methodologic considerations, the metabolic source of different biomarkers and their role in clinical studies.
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http://dx.doi.org/10.1016/bs.acc.2020.08.011DOI Listing
August 2021

Preventive bundle approach decreases the incidence of ventilator-associated pneumonia in newborn infants.

J Perinatol 2021 06 25;41(6):1467-1473. Epub 2021 May 25.

Neonatal Research Group, Health Research Institute La Fe, Valencia, Spain.

Objective: We hypothesized that the implementation of evidence-based interventions shaping a bundle approach could significantly reduce the incidence of ventilator-associated pneumonia (VAP) in the neonatal intensive care unit.

Study Design: We conducted a prospective observational cohort study including neonates undergoing mechanical ventilation >48 h. VAP rate and endotracheal intubation ratio were compared before (pre-period) and after (post-period) applying VAP prevention bundle strategies.

Result: One hundred seventy-four neonates were included in pre-period (30 months) and 106 in post-period (17 months). Demographic characteristics were comparable and device use ratios were similar. Twenty-eight VAP episodes were diagnosed, 25 in the first period and 3 after the implementation of prevention bundle. This represents a reduction in the incidence rate from 11.79 to 1.93 episodes/1000 ventilator days (p < 0.01).

Conclusion: The implementation of an educational evidence-based program using a bundle approach to prevent VAP has shown a statistically significant reduction in its incidence density.
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http://dx.doi.org/10.1038/s41372-021-01086-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147910PMC
June 2021

Noninvasive monitoring of evolving urinary metabolic patterns in neonatal encephalopathy.

Pediatr Res 2021 May 5. Epub 2021 May 5.

Neonatal Research Group, Health Research Institute La Fe, Valencia, Spain.

Background: Infants with moderate and severe neonatal encephalopathy (NE) frequently suffer from long-term adverse outcomes. We hypothesize that the urinary metabolome of newborns with NE reflects the evolution of injury patterns observed with magnetic resonance imaging (MRI).

Methods: Eligible patients were newborn infants with perinatal asphyxia evolving to NE and qualifying for therapeutic hypothermia (TH) included in the HYPOTOP trial. MRI was employed for characterizing brain injury. Urine samples of 55 infants were collected before, during, and after TH. Metabolic profiles of samples were recorded employing three complementary mass spectrometry-based assays, and the alteration of detected metabolic features between groups was assessed.

Results: The longitudinal assessment revealed significant perturbations of the urinary metabolome. After 24 h of TH, a stable disease pattern evolved characterized by the alterations of 4-8% of metabolic features related to lipid metabolism, metabolism of cofactors and vitamins, glycan biosynthesis and metabolism, amino acid metabolism, and nucleotide metabolism. Characteristic metabolomic fingerprints were observed for different MRI injury patterns.

Conclusions: This study shows the potential of urinary metabolic profiles for the noninvasive monitoring of brain injury of infants with NE during TH.

Impact: A comprehensive approach for the study of the urinary metabolome was employed involving a semi-targeted capillary electrophoresis-time-of-flight mass spectrometry (TOFMS) assay, an untargeted ultra-performance liquid chromatography (UPLC)-quadrupole TOFMS assay, and a targeted UPLC-tandem MS-based method for the quantification of amino acids. The longitudinal study of the urinary metabolome identified dynamic metabolic changes between birth and until 96 h after the initiation of TH. The identification of altered metabolic pathways in newborns with pathologic MRI outcomes might offer the possibility of developing noninvasive monitoring approaches for personalized adjustment of the treatment and for supporting early outcome prediction.
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http://dx.doi.org/10.1038/s41390-021-01553-zDOI Listing
May 2021

[Use of near infrared spectroscopy in neonatal gastric perforation].

An Pediatr (Engl Ed) 2021 Apr 12. Epub 2021 Apr 12.

Unidad de Investigación Neonatal, Instituto de Investigación Sanitaria La Fe, Valencia, España. Electronic address:

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http://dx.doi.org/10.1016/j.anpedi.2021.01.018DOI Listing
April 2021

Potential Value of Maternal Oxygen Supplementation.

JAMA Pediatr 2021 07;175(7):749-750

Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain.

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http://dx.doi.org/10.1001/jamapediatrics.2021.0364DOI Listing
July 2021

National protocol led to significant improvements in follow-up programmes for very low birth weight or very preterm infants.

Acta Paediatr 2021 08 8;110(8):2357-2358. Epub 2021 Apr 8.

Division of Neonatology, Health Research Institute i + 12, University Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain.

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http://dx.doi.org/10.1111/apa.15864DOI Listing
August 2021

Transcriptome profiles discriminate between Gram-positive and Gram-negative sepsis in preterm neonates.

Pediatr Res 2021 Mar 25. Epub 2021 Mar 25.

Department of Physiology, School of Medicine, University of Valencia, Valencia, Spain.

Background: Genome-wide expression profiles have been previously employed as clinical research diagnostic tools for newborn sepsis. We aimed to determine if transcriptomic profiles could discriminate between Gram-positive and Gram-negative bacterial sepsis in preterm infants.

Methods: Prospective, observational, double-cohort study was conducted in very low birth weight infants with clinical signs and culture-positive sepsis. Blood samples were collected when clinical signs became apparent. Total RNA was processed for transcriptomic analysis. Results were validated by both reverse-transcription polymerase chain reaction and a mathematical model.

Results: We included 25 septic preterm infants, 17 with Gram-positive and 8 with Gram-negative bacteria. The principal component analysis identified these two clusters of patients. We performed a predictive model based on 21 genes that showed an area under the receiver-operating characteristic curve of 1. Eight genes were overexpressed in Gram-positive septic infants: CD37, CSK, MAN2B2, MGAT1, MOB3A, MYO9B, SH2D3C, and TEP1. The most significantly overexpressed pathways were related to metabolic and immunomodulating responses that translated into an equilibrium between pro- and anti-inflammatory responses.

Conclusions: The transcriptomic profile allowed identification of whether the causative agent was Gram-positive or Gram-negative bacteria. The overexpression of genes such as CD37 and CSK, which control cytokine production and cell survival, could explain the better clinical outcome in sepsis caused by Gram-positive bacteria.

Impact: Transcriptomic profiles not only enable an early diagnosis of sepsis in very low birth weight infants but also discriminate between Gram-positive and Gram-negative bacteria as causative agents. The overexpression of some genes related to cytokine production and cell survival could explain the better clinical outcome in sepsis caused by Gram-positive bacteria, and could lead us to a future, targeted therapy.
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http://dx.doi.org/10.1038/s41390-021-01444-3DOI Listing
March 2021

Environmental Exposure during Pregnancy: Influence on Prenatal Development and Early Life: A Comprehensive Review.

Fetal Diagn Ther 2021 18;48(4):245-257. Epub 2021 Mar 18.

Neonatal Research Group, Health Research Institute La Fe, University and Polytechnic Hospital La Fe, Valencia, Spain.

Preconception and prenatal exposure to environmental contaminants may affect future health. Pregnancy and early life are critical sensitive windows of susceptibility. The aim of this review was to summarize current evidence on the toxic effects of environment exposure during pregnancy, the neonatal period, and childhood. Alcohol use is related to foetal alcohol spectrum disorders, foetal alcohol syndrome being its most extreme form. Smoking is associated with placental abnormalities, preterm birth, stillbirth, or impaired growth and development, as well as with intellectual impairment, obesity, and cardiovascular diseases later in life. Negative birth outcomes have been linked to the use of drugs of abuse. Pregnant and lactating women are exposed to endocrine-disrupting chemicals and heavy metals present in foodstuffs, which may alter hormones in the body. Prenatal exposure to these compounds has been associated with pre-eclampsia and intrauterine growth restriction, preterm birth, and thyroid function. Metals can accumulate in the placenta, causing foetal growth restriction. Evidence on the effects of air pollutants on pregnancy is constantly growing, for example, preterm birth, foetal growth restriction, increased uterine vascular resistance, impaired placental vascularization, increased gestational diabetes, and reduced telomere length. The advantages of breastfeeding outweigh any risks from contaminants. However, it is important to assess health outcomes of toxic exposures via breastfeeding. Initial studies suggest an association between pre-eclampsia and environmental noise, particularly with early-onset pre-eclampsia. There is rising evidence of the negative effects of environmental contaminants following exposure during pregnancy and breastfeeding, which should be considered a major public health issue.
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http://dx.doi.org/10.1159/000514884DOI Listing
November 2021

Early signs of autism in infants whose mothers suffered from a threatened preterm labour: a 30-month prospective follow-up study.

Eur Child Adolesc Psychiatry 2021 Mar 10. Epub 2021 Mar 10.

Neonatal Research Group, Health Research Institute La Fe, Avenida Fernando Abril Martorell 106, Valencia, 46026, Spain.

Infants born after a threatened preterm labour (TPL infants) are at high risk of autism spectrum disorder (ASD). Studying this population may provide insight on the pathophysiological underpinnings of this condition. This study aimed to (i) ascertain the presence and autistic symptom load in TPL infants aged age 30 months relative to non-TPL infants, regardless of preterm birth; (ii) explore the association between early (at 6 months) psychomotor development and temperament features with the autistic symptom load of TPL infants at age 30 months and (iii) examine the association among perinatal risk factors for ASD development with the autistic symptom load of TPL infants at age 30 months. A group of 111 mother-infant pairs recruited at TPL diagnosis and a group of 47 healthy mother-infant controls completed the follow-up. Irrespective of preterm birth, TPL infants showed higher autistic symptom load at age 30 months than non-TPL infants. TPL infants presented poorer communication and problem-solving skills, reduced smiling and laughter, and greater vocal reactivity at age 6 months, predicting higher autistic symptom load at age 30 months. Higher levels of anxiety symptoms in TPL mothers after a TPL diagnosis also predicted higher autistic symptom load for the infants at age 30 months. These results suggest that TPL infants may be an undescribed cluster, with features that differentiate them from other "at-risk" populations. These findings support the need for routine assessment of TPL infants and screening of anxiety symptoms in mothers.
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http://dx.doi.org/10.1007/s00787-021-01749-yDOI Listing
March 2021

Oxygen saturation (SpO2) targeting for newborn infants at delivery: Are we reaching for an impossible unknown?

Semin Fetal Neonatal Med 2021 04 24;26(2):101220. Epub 2021 Feb 24.

School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia; Department of Newborn Care, The Royal Hospital for Women, Randwick, NSW, Australia. Electronic address:

For more than 200 years, pure oxygen was given ad libitum to newborn infants requiring resuscitation. Due to oxidative stress and injury concerns, a paradigm shift towards using "less" oxygen, including air (21% oxygen) instead of pure (100%) oxygen, occurred about twenty years ago. A decade later, clinicians were advised to adjust fractional inspired oxygen (FiO) to target oxygen saturations (SpO) that were derived from spontaneously breathing, healthy, mature infants. Whether these recommendations are achievable, beneficial, harmful or redundant is uncertain. The underlying pathology leading to resuscitation varies between infants and may considerably alter an infant's response to supplemental oxygen. In this review, we summarize available evidence for the use of SpO monitoring at delivery for newborn infants, elucidate existing knowledge and service gaps, and suggest future research recommendations that will lead to the safest clinical strategies for this standard and important practice.
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http://dx.doi.org/10.1016/j.siny.2021.101220DOI Listing
April 2021
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