Prolonged hospitalization signature and early antibiotic effects on the nasopharyngeal resistome in preterm infants.

Respiratory pathogens, commonly colonizing nasopharynx, are among the leading causes of death due to antimicrobial resistance. Yet, antibiotic resistance determinants within nasopharyngeal microbial communities remain poorly understood. In this prospective cohort study, we investigate the nasopharynx resistome development in preterm infants, assess early antibiotic impact on its trajectory, and explore its association with clinical covariates using shotgun metagenomics. Our findings reveal widespread nasopharyngeal carriage of antibiotic resistance genes (ARGs) with resistomes undergoing transient changes, including increased ARG diversity, abundance, and composition alterations due to early antibiotic exposure. ARGs associated with the critical nosocomial pathogen Serratia marcescens persist up to 8-10 months of age, representing a long-lasting hospitalization signature. The nasopharyngeal resistome strongly correlates with microbiome composition, with inter-individual differences and postnatal age explaining most of the variation. Our report on the collateral effects of antibiotics and prolonged hospitalization underscores the urgency of further studies focused on this relatively unexplored reservoir of pathogens and ARGs.

Initial Oxygen Concentration for the Resuscitation of Infants Born at Less Than 32 Weeks' Gestation: A Systematic Review and Individual Participant Data Network Meta-Analysis.

Importance: Resuscitation with lower fractional inspired oxygen (FiO2) reduces mortality in term and near-term infants but the impact of this practice on very preterm infants is unclear. Objective: To evaluate the relative effectiveness of initial FiO2 on reducing mortality, severe morbidities, and oxygen saturations (SpO2) in preterm infants born at less than 32 weeks' gestation using network meta-analysis (NMA) of individual participant data (IPD). Data Sources: MEDLINE, Embase, CENTRAL, CINAHL, ClinicalTrials.gov, and WHO ICTRP from 1980 to October 10, 2023. Study Selection: Eligible studies were randomized clinical trials enrolling infants born at less than 32 weeks' gestation comparing at least 2 initial oxygen concentrations for delivery room resuscitation, defined as either low (≤0.3), intermediate (0.5-0.65), or high (≥0.90) FiO2. Data Extraction and Synthesis: Investigators from eligible studies were invited to provide IPD. Data were processed and checked for quality and integrity. One-stage contrast-based bayesian IPD-NMA was performed with noninformative priors and random effects and adjusted for key covariates. Main Outcomes and Measures: The primary outcome was all-cause mortality at hospital discharge. Secondary outcomes were morbidities of prematurity and SpO2 at 5 minutes. Results: IPD were provided for 1055 infants from 12 of the 13 eligible studies (2005-2019). Resuscitation with high (≥0.90) initial FiO2 was associated with significantly reduced mortality compared to low (≤0.3) (odds ratio [OR], 0.45; 95% credible interval [CrI], 0.23-0.86; low certainty) and intermediate (0.5-0.65) FiO2 (OR, 0.34; 95% CrI, 0.11-0.99; very low certainty). High initial FiO2 had a 97% probability of ranking first to reduce mortality. The effects on other morbidities were inconclusive. Conclusions and Relevance: High initial FiO2 (≥0.90) may be associated with reduced mortality in preterm infants born at less than 32 weeks' gestation compared to low initial FiO2 (low certainty). High initial FiO2 is possibly associated with reduced mortality compared to intermediate initial FiO2 (very low certainty) but more evidence is required.

Newborns at risk of COVID-19, the story continues.

After more than 4 years of the SARS-CoV-2 pandemic, a great deal of knowledge on how this virus affects pregnant women, the fetus and the newborn has accumulated. Guidelines for mode of delivery, cord clamping, skin to skin, breastfeeding, and rooming-in have become uniform across the world. Vaccination has considerably improved outcomes, but hesitancy amongst pregnant patients and the emergence of variants remain challenged and SARS-CoV-2 positivity during pregnancy continues to be associated with an increased risk of maternal complications, premature delivery and higher neonatal mortality and morbidity. An emerging body of data now exists on the effect of SARS-CoV-2 in pregnancy on early neonatal outcomes, medical education in obstetrics and pediatrics, and longer-term developmental outcomes. In this article, we review the development in this field since our last review.

Correction: Nerdrum Aagaard et al. Significance of Neonatal Heart Rate in the Delivery Room-A Review. Children2023, 10, 1551.

In the original publication [...].

Extrauterine Growth Restriction: Need for an Accurate Definition.

Neonates show considerable variation in growth that can be recognized through serial measurements of basic variables such as weight, length, and head circumference. If possible, measurement of subcutaneous and total body fat mass can also be useful. These biometric measurements at birth may be influenced by demographics, maternal and paternal anthropometrics, maternal metabolism, preconceptional nutritional status, and placental health. Subsequent growth may depend on optimal feeding, total caloric intake, total metabolic activity, genetic makeup, postnatal morbidities, medications, and environmental conditions. For premature infants, these factors become even more important; poor in utero growth can be an important reason for spontaneous or induced preterm delivery. Later, many infants who have had intrauterine growth restriction (IUGR) and are born small for gestational age (SGA) continue to show suboptimal growth below the 10th percentile, a condition that has been defined as extrauterine growth restriction (EUGR) or postnatal growth restriction (PNGR). More importantly, a subset of these growth-restricted infants may also be at high risk of abnormal neurodevelopmental outcomes. There is a need for well-defined criteria to recognize EUGR/PNGR, so that correctional steps can be instituted in a timely fashion.

Significance of Neonatal Heart Rate in the Delivery Room-A Review.

BACKGROUND: Heart rate (HR) is considered the main vital sign in newborns during perinatal transition, with a threshold of 100 beats per minute (bpm), below which, intervention is recommended. However, recent changes in delivery room management, including delayed cord clamping, are likely to have influenced normal HR transition. OBJECTIVE: To summarize the updated knowledge about the factors, including measurement methods, that influence HR in newborn infants immediately after birth. Additionally, this paper provides an overview of delivery room HR as a prognostic indicator in different subgroups of newborns. METHODS: We searched PubMed, EMBASE, and Google Scholar with the terms infant, heart rate, delivery room, resuscitation, pulse oximetry, and electrocardiogram. RESULTS: Seven studies that described HR values in newborn infants immediately after birth were included. Pulse oximetry-derived HR percentiles after immediate cord clamping may not be applicable to the current practice of delayed cord clamping and the increasing use of delivery room electrocardiograms. Mask ventilation may adversely affect HR, particularly in premature and non-asphyxiated infants. Prolonged bradycardia is a negative prognostic factor, especially if combined with hypoxemia in infants <32 weeks of gestation. CONCLUSIONS: HR assessment in the delivery room remains important. However, the cardiopulmonary transition is affected by delayed cord clamping, gestational age, and underlying conditions.

Searching for evidence in neonatology.

Evidence-based medicine has changed clinical practice by incorporating data from randomised controlled trials (RCTs). While some biases in RCTs are well recognised, we discuss some less acknowledged. Selection bias may arise in the consent stage. Industry-funded studies more often report a positive outcome. Post-hoc changes of outcome measures and other mis-reporting lowers the reliability of outcome data. Finally, even the GRADE system retains subjectivity. CONCLUSION: Moving from "intuition" into "evidence-based" medicine involves grappling with several pitfalls. These pose challenges for authors, editors, reviewers, and readers. All require vigilance before drawing conclusions from presented data.

Gene expression in the intestine of newborn piglets after hypoxia-reoxygenation.

BACKGROUND: In preterm infants, intestinal hypoxia may partly contribute to the pathophysiology of necrotizing enterocolitis through changes in gene expression. Splanchnic hypoxia can be detected with monitoring of regional splanchnic oxygen saturation (rsSO2). Using a piglet model of asphyxia, we aimed to correlate changes in rsSO2 to gene expression. METHODS: Forty-two newborn piglets were randomized to control or intervention groups. Intervention groups were subjected to hypoxia until they were acidotic and hypotensive. Next, they were reoxygenated for 30 min according to randomization, i.e., 21% O2, 100% O2, or 100% O2 for 3 min followed by 21% O2, and observed for 9 h. We continuously measured rsSO2 and calculated mean rsSO2 and variability of rsSO2 (rsCoVar = SD/mean). Samples of terminal ileum were analyzed for mRNA expression of selected genes related to inflammation, erythropoiesis, fatty acid metabolism, and apoptosis. RESULTS: The expression of selected genes was not significantly different between control and intervention groups. No associations between mean rsSO2 and gene expression were observed. However, lower rsCoVar was associated with the upregulation of apoptotic genes and the downregulation of inflammatory genes (P < 0.05). CONCLUSION: Our study suggests that hypoxia and reoxygenation cause reduced vascular adaptability, which seems to be associated with the upregulation of apoptosis and downregulation of inflammation. IMPACT: Our results provide important insight into the (patho)physiological significance of changes in the variability of rsSO2. Our findings may advance future research and clinical practice regarding resuscitation strategies of preterm infants.

Ending Preventable Neonatal Deaths: Multicountry Evidence to Inform Accelerated Progress to the Sustainable Development Goal by 2030.

INTRODUCTION: The Sustainable Development Goal (SDG) 3.2 aims for every country to reach a neonatal mortality rate (NMR) of ≤12/1,000 live births by 2030. More than 60 countries are off track, and 2.3 million newborns still die each year. Urgent action is needed, but varies by context, notably mortality level. METHODS: We applied a five-phase NMR transition model based on national analyses for 195 UN member states: I (NMR >45), II (30-<45), III (15-<30), IV (5-<15), and V (<5). We analyzed data over the last century from selected countries to inform strategies to reach SDG3.2. We also undertook impact analyses for packages of care using the Lives Saved Tool software. RESULTS: An NMR of <15/1,000 requires firstly wide-scale access to maternity care and hospital care for small and sick newborns, including skilled nurses and doctors, safe oxygen use, and respiratory support, such as CPAP. Neonatal mortality could be reduced to the SDG target of ≤12/1,000 with further scale-up of small and sick newborn care. To reduce neonatal mortality further, more investment is required in infrastructure, device bundles (e.g., phototherapy, ventilation), and careful attention to infection prevention. To reach phase V (NMR <5), which is closer to ending preventable newborn deaths, additional technologies and therapies such as mechanical ventilation and surfactant replacement therapy are needed, as well as higher staffing ratios. CONCLUSIONS: Learning from high-income country is important, including what not to do. Introduction of new technologies should be according to the country's phase. Early focus on disability-free survival and family involvement is also crucial.

A Narrative Review of the Rationale for Conducting Neonatal Emergency Studies with a Waived or Deferred Consent Approach.

Emergency research studies are high-stakes studies that are usually performed on the sickest patients, where many patients or guardians have no opportunity to provide full informed consent prior to participation. Many emergency studies self-select healthier patients who can be informed ahead of time about the study process. Unfortunately, results from such participants may not be informative for the future care of sicker patients. This inevitably creates waste and perpetuates uninformed care and continued harm to future patients. The waiver or deferred consent process is an alternative model that may be used to enroll sick patients who are unable to give prospective consent to participate in a study. However, this process generates vastly different stakeholder views which have the potential to create irreversible impediments to research and knowledge. In studies involving newborn infants, consent must be sought from a parent or guardian, and this adds another layer of complexity to already fraught situations if the infant is very sick. In this manuscript, we discuss reasons why consent waiver or deferred consent processes are vital for some types of neonatal research, especially those occurring at and around the time of birth. We provide a framework for conducting neonatal emergency research under consent waiver that will ensure the patient's best interests without compromising ethical, beneficial, and informative knowledge acquisition to improve the future care of sick newborn infants.

Umbilical cord blood acid-base analysis at birth and long-term neurodevelopmental outcomes in children: a systematic review and meta-analysis.

BACKGROUND: Umbilical cord blood acid-base sampling is routinely performed at many hospitals. Recent studies have questioned this practice and the association of acidosis with cerebral palsy. OBJECTIVE: To investigate the associations between the results of umbilical cord blood acid-base analysis at birth and long-term neurodevelopmental outcomes and mortality in children. SEARCH STRATEGY: We searched six databases using the search strategy: umbilical cord AND outcomes. SELECTION CRITERIA: Randomised controlled trials, cohorts and case-control studies from high-income countries that investigated the association between umbilical cord blood analysis and neurodevelopmental outcomes and mortality from 1 year after birth in children born at term. DATA COLLECTION AND ANALYSIS: We critically assessed the included studies, extracted data and conducted meta-analyses comparing adverse outcomes between children with and without acidosis, and the mean proportions of adverse outcomes. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations approach. MAIN RESULTS: We have very low confidence in the following findings: acidosis was associated with higher cognitive development scores compared with non-acidosis (mean difference 5.18, 95% CI 0.84-9.52; n = two studies). Children with acidosis also showed a tendency towards higher risk of death (relative risk [RR] 5.72, 95% CI 0.90-36.27; n = four studies) and CP (RR 3.40, 95% CI 0.86-13.39; n = four studies), although this was not statistically significant. The proportion of children with CP was 2.39/1000 across the studies, assessed as high certainty evidence. CONCLUSION: Due to low certainty of evidence, the associations between umbilical cord blood gas analysis at delivery and long-term neurodevelopmental outcomes in children remains unclear.

Long Non-Coding RNAs in Hypoxia and Oxidative Stress: Novel Insights Investigating a Piglet Model of Perinatal Asphyxia.

Birth asphyxia is the leading cause of death and disability in young children worldwide. Long non-coding RNAs (lncRNAs) may provide novel targets and intervention strategies due to their regulatory potential, as demonstrated in various diseases and conditions. We investigated cardinal lncRNAs involved in oxidative stress, hypoxia, apoptosis, and DNA damage using a piglet model of perinatal asphyxia. A total of 42 newborn piglets were randomized into 4 study arms: (1) hypoxia-normoxic reoxygenation, (2) hypoxia-3 min of hyperoxic reoxygenation, (3) hypoxia-30 min of hyperoxic reoxygenation, and (4) sham-operated controls. The expression of lncRNAs BDNF-AS, H19, MALAT1, ANRIL, TUG1, and PANDA, together with the related target genes VEGFA, BDNF, TP53, HIF1α, and TNFα, was assessed in the cortex, the hippocampus, the white matter, and the cerebellum using qPCR and Droplet Digital PCR. Exposure to hypoxia-reoxygenation significantly altered the transcription levels of BDNF-AS, H19, MALAT1, and ANRIL. BDNF-AS levels were significantly enhanced after both hypoxia and subsequent hyperoxic reoxygenation, 8% and 100% O2, respectively. Our observations suggest an emerging role for lncRNAs as part of the molecular response to hypoxia-induced damages during perinatal asphyxia. A better understanding of the regulatory properties of BDNF-AS and other lncRNAs may reveal novel targets and intervention strategies in the future.

European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update.

Respiratory distress syndrome (RDS) care pathways evolve slowly as new evidence emerges. We report the sixth version of "European Guidelines for the Management of RDS" by a panel of experienced European neonatologists and an expert perinatal obstetrician based on available literature up to end of 2022. Optimising outcome for babies with RDS includes prediction of risk of preterm delivery, appropriate maternal transfer to a perinatal centre, and appropriate and timely use of antenatal steroids. Evidence-based lung-protective management includes initiation of non-invasive respiratory support from birth, judicious use of oxygen, early surfactant administration, caffeine therapy, and avoidance of intubation and mechanical ventilation where possible. Methods of ongoing non-invasive respiratory support have been further refined and may help reduce chronic lung disease. As technology for delivering mechanical ventilation improves, the risk of causing lung injury should decrease, although minimising time spent on mechanical ventilation by targeted use of postnatal corticosteroids remains essential. The general care of infants with RDS is also reviewed, including emphasis on appropriate cardiovascular support and judicious use of antibiotics as being important determinants of best outcome. We would like to dedicate this guideline to the memory of Professor Henry Halliday who died on November 12, 2022.These updated guidelines contain evidence from recent Cochrane reviews and medical literature since 2019. Strength of evidence supporting recommendations has been evaluated using the GRADE system. There are changes to some of the previous recommendations as well as some changes to the strength of evidence supporting recommendations that have not changed. This guideline has been endorsed by the European Society for Paediatric Research (ESPR) and the Union of European Neonatal and Perinatal Societies (UENPS).

A Piglet Perinatal Asphyxia Model to Study Cardiac Injury and Hemodynamics after Cardiac Arrest, Resuscitation, and the Return of Spontaneous Circulation.

Neonatal piglets have been extensively used as translational models for perinatal asphyxia. In 2007, we adapted a well-established piglet asphyxia model by introducing cardiac arrest. This enabled us to study the impact of severe asphyxia on key outcomes, including the time taken for the return of spontaneous circulation (ROSC), as well as the effect of chest compressions according to alternative protocols for cardiopulmonary resuscitation. Due to the anatomical and physiological similarities between piglets and human neonates, piglets serve as good models in studies of cardiopulmonary resuscitation and hemodynamic monitoring. In fact, this cardiac arrest model has provided evidence for guideline development through research on resuscitation protocols, pathophysiology, biomarkers, and novel methods for hemodynamic monitoring. Notably, the incidental finding that a substantial fraction of piglets have pulseless electrical activity (PEA) during cardiac arrest may increase the applicability of the model (i.e., it may be used to study pathophysiology extending beyond the perinatal period). However, the model generation is technically challenging and requires various skill sets, dedicated personnel, and a fine balance of the measures, including the surgical protocols and the use of sedatives/analgesics, to ensure a reasonable rate of survival. In this paper, the protocol is described in detail, as well as experiences with adaptations to the protocol over the years.

Oxygenation of the newborn. The impact of one molecule on newborn lives.

Hypoxanthine is a purine metabolite which increases during hypoxia and therefore is an indicator of this condition. Further, when hypoxanthine is oxidized to uric acid in the presence of xanthine oxidase, oxygen radicals are generated. This was the theoretical basis for suggesting and studying, beginning in the 1990s, resuscitation of newborn infants with air instead of the traditional 100% O2. These studies demonstrated a 30% reduction in mortality when resuscitation of term and near term infants was carried out with air compared to pure oxygen. The mechanism for this is not fully understood, however the hypoxanthine -xanthine oxidase system increases oxidative stress and plays a role in regulation of the perinatal circulation. Further, hyperoxic resuscitation inhibits mitochondrial function, and one reason may be that genes involved in ATP production are down-regulated. Thus, the study of one single molecule, hypoxanthine, has contributed to the global prevention of an estimated 2-500,000 annual infant deaths.

Is the increasing prevalence of labor induction accompanied by changes in pregnancy outcomes? An observational study of all singleton births at gestational weeks 37-42 in Norway during 1999-2019.

INTRODUCTION: Induction of labor is often performed to prevent adverse perinatal and maternal outcomes, and has become increasingly common. We studied whether changes in prevalence of labor induction in gestational weeks 37-42 weeks were accompanied by changes in adverse pregnancy outcomes or mode of delivery. MATERIAL AND METHODS: We used data from the Medical Birth Registry of Norway, and included all singleton births in gestational weeks 37-42 in Norway, 1999-2019 (n = 1 127 945). We calculated the prevalence of labor induction and outcome measures according to year of birth. We repeated these calculations for each gestational week at birth. RESULTS: The prevalence of labor induction increased from 9.7% to 25.9%, and the increase was particularly high in gestational week 41. A modest decline in fetal deaths was observed in all gestational weeks, except gestational week 41. The overall decline was from 0.18% in 1999-2004 to 0.13% during 2015-2019. There were no overall changes in other perinatal outcomes. The prevalence of postpartum hemorrhage ≥500 ml increased from 11.4% in 1999 to 30.1% in 2019, and operative deliveries increased slightly. The prevalence of acute cesarean section increased from 6.5% to 9.3%, whereas vacuum and/or forceps assisted deliveries increased from 7.8% to 10.4%. CONCLUSIONS: A high increase in labor inductions was accompanied by a modest decline in fetal deaths, but no decline in other adverse perinatal outcomes. In settings where the prevalence of adverse perinatal outcomes is low, the beneficial effect of increased use of labor induction may not outweigh the side effects or the costs.