Open research questions in Neonatal Respiratory Health Research

What the literature leaves open

• In the pre-discharge mortality network, favorable estimates were less certain because mortality events were sparse and several 95% credible intervals (CrIs) were wide.

  Efficacy of pharmacologic therapies for reducing bronchopulmonary dysplasia and mortality in preterm infants: a network meta-analysis · 2026 · DOI

• Objective Extracorporeal membrane oxygenation (ECMO) serves as a vital rescue therapy for neonates with refractory cardiopulmonary failure, yet domestic clinical data regarding ECMO use in preterm infants remain scarce.

  Application of extracorporeal membrane oxygenation in respiratory and circulatory support of preterm infants: a multicenter retrospective study in China · 2026 · DOI

• Limited evidence-based guidelines are available for transcatheter PDA closure in premature infants in general and for bedside PDA closure specifically.

  Expert consensus on bedside transcatheter closure of patent ductus arteriosus in extremely low birth weight infants · 2026 · DOI

• Many confounding variables could have impacted these results; however, this information fills an important gap in literature and can help to assure providers that the current practice of utilising caffeine citrate in neonates with ductal-dependent CHD is not associated with a statistically significant increased frequency of sustained tachycardia at the University of Florida.

  Safety of caffeine citrate in neonates with Congenital Heart Disease receiving continuous infusions of alprostadil · 2026 · DOI

• However, this study did have a large sample size and addressed a clinically significant gap in the literature for the neonates with ductal-dependent CHD.

  Safety of caffeine citrate in neonates with Congenital Heart Disease receiving continuous infusions of alprostadil · 2026 · DOI

• Future research should focus more on refined and individualized analysis, relying on human lung organoids and standardized large animal models, combined with single-cell spatial multi-omics to analyze the cross-regulation pathways of gas signaling, establish unified detection standards, and develop targeted pulmonary sustained-release drug delivery systems. The complete dose-effect relationship has not been systematically clarified, and there is a lack of a unified in vivo monitoring method.

  The molecular mechanisms of gas signaling molecules in bronchopulmonary dysplasia related lung injury · 2026 · DOI

• The use of transcutaneous pacing (TCP) in the delivery room has rarely been reported in neonates with CCHB, and extracorporeal membrane oxygenation (ECMO) during neonatal intensive care has sporadically been described.

  Delivery-room transcutaneous pacing and ECMO support in the NICU for a preterm neonate with congenital complete heart block · 2026 · DOI

• Several limitations of this systematic review and the underlying evidence base should be acknowledged. First, the review protocol was not prospectively registered, and the full multi-database search strategy was not published (only a representative MEDLINE string is provided in the Appendices), which may limit reproducibility. Second, the absence of neonatal-specific safety standards for vibration, noise, or thermal conditions during transport means that all threshold comparisons in the included studies rely on adult occupational health benchmarks; these thresholds were not developed for immature neonatal physiology, may not represent meaningful clinical risk thresholds for this population, and may either over- or underestimate true physiological risk. Third, the methodological heterogeneity of included studies, spanning experimental bench studies, large-scale observational datasets, and small feasibility pilots, precluded formal meta-analysis and limits the precision of comparative synthesis. Fourth, most included studies were conducted in high-income settings with well-resourced transport services; findings may not be generalisable to low- and middle-income countries where transport conditions, incubator quality, and team expertise differ substantially. Fifth, several included studies [18,21] were rated as high overall risk of bias due to small convenience samples, which constrains confidence in their specific effect estimates. Sixth, no included study provided direct longitudinal data linking quantified transport stressor exposure to long-term neurodevelopmental outcomes, leaving the most clinically important causal question unanswered. Future prospective studies with individual-level stressor measurement, linked to neurodevelopmental follow-up, are essential to close this gap. 2026 Damra et al. Cureus 18(6): e111621.

  Physiological Impact of Environmental Stressors During Neonatal Transport: A Systematic Review of Clinical and Biophysical Outcomes · 2026 · DOI

• • The relationship between ventilator-derived carbon dioxide transport and effective arterial CO2 elimination during HFOV with volume guarantee remains incompletely understood.

  Ventilatory efficiency during high-frequency oscillatory ventilation with volume guarantee in preterm infants · 2026 · DOI

• This study has several limitations. First, patient enrolment was based on voluntary clinician participation, resulting in disproportionate representation across countries and creating potential for selection bias. The uneven geographic distribution of patients may also reflect underlying influences such as ethnicity, genetic background, or local environmental exposures, although these factors remain uncertain. Second, due to its retrospective design, some clinical data were incomplete. Longitudinal follow-up was not available for all patients at the predefined time points, primarily due to young patient age or loss to follow-up. Consequently, it is not possible to determine whether patients who were lost to follow-up became asymptomatic or if the information is simply missing. This limitation affects our ability to fully characterize long-term outcomes. In addition, parameters were not assessed continuously but only during scheduled follow-up visits, resulting in further gaps in the dataset. Third, because of the observational design, treatment decisions were not standardized and reflect local practices, so these data should not be interpreted as evidence of efficacy or as uniform recommendations. Finally, follow-up CT scans were evaluated by radiologists at the participating centers, and possible variability in radiological interpretation across sites represents an additional limitation. Despite these limitations, this study presents the most comprehensive analysis of treatment strategies in the largest PTI/NEHI cohort reported to date. It also provides the most robust longitudinal clinical dataset available in the literature. INTERPRETATION Management of PTI/NEHI varies considerably across Europe, highlighting the lack of standardized, evidencebased protocols for this rare condition. Supportive measures and inhaled therapies remain the most commonly employed interventions. Systemic glucocorticoid therapy is also relatively frequent; however, its use declined over time. Although most children demonstrate gradual clinical improvement, a subset experience persistent respiratory symptoms, growth impairment, or functional abnormalities that extend into adolescence or beyond. These findings underscore the importance of long-term follow-up. Pulmonary function tests and lung 13 ultrasound may provide useful, non-invasive modalities for longitudinal assessment in these patients. Despite broad collaboration within the European network, not all centers were able to contribute patients, reflecting the inherent challenges of conducting research in rare diseases. Overall, our report underscores the need for well-designed studies to establish standardized management protocols for PTI/NEHI.

  Management and Long-Term Outcomes of Persistent Tachypnea of Infancy/Neuroendocrine Cell Hyperplasia of Infancy: A European Multicenter Retrospective Study. · 2026 · DOI

• The heterogeneity of the included studies in terms of study design, newborn populations, timing definitions for DCC, and reported results is a significant limitation of www.

  CLINICAL OUTCOMES OF DELAYED CORD CLAMPING IN NEWBORNS: A SYSTEMATIC REVIEW · 2026 · DOI

• The strengths of the study include its comprehensive geographic representation, large sample size, and use of a validated measurement tool (AQ-KNDS). The stratified sampling technique ensured representation across Upper Egypt, Lower Egypt, and remote areas, minimizing biases related to population density. However, limitations were noted, including the cross-sectional design, which restricted causal inferences, and reliance on self-reported data, which may have introduced recall or social desirability bias. Moreover, the study built on a quantitative analysis and did not explore the underlying reasons for poor maternal knowledge, such as cultural beliefs, social barriers, or misconceptions. Future research using qualitative methods could better understand these factors.

  Assessing maternal knowledge of neonatal danger signs in Egypt: a cross-sectional study · 2026 · DOI

• First, early dexamethasone (<7 days) should be avoided except perhaps in the most extreme circumstances where mortality risk is near-certain without intervention, given the high-certainty evidence of CP harm and lack of evidence for net benefit (Doyle et al.

  Association Between Postnatal Steroid Use and Long-term Neurodevelopmental Impairment : A Systematic Review · 2026 · DOI

• Uncertainty about whether specific light parameters (quality and spectral composition) are critical for immature neonatal circadian systems versus mature systems where wavelengths between 446-477 nanometers are optimal.

  Effectiveness of combined versus single circadian interventions in neonatal and pediatric intensive care units: a systematic review with meta-analysis · 2026 · DOI

• INTRODUCTION: Currently, there is no consensus regarding analgesic premedication before the surfactant administration by less invasive surfactant application (LISA) procedure.

  Premedication with Fentanyl for Less Invasive Surfactant Application (LISA): A Randomized Controlled Trial · 2022 · DOI

• The main problems in the management of newborns with PH are the lack of standardization of echocardiographic parameters for newborns, the lack of a single decision on timing and the need for PH screening in the population of premature infants, lack of controlled studies and development of a single therapeutic strategy for premature infants and patients of gestational age; and the lack of clear criteria for inclusion in the National Register of PH patients.

  PROBLEMS AND MANAGEMENT RESERVES OF NEWBORNS WITH PULMONARY HYPERTENSION · 2020 · DOI

• Conclusions Given the limited evidence available to support the practice of feeding neonates in the NICU by mouth while on CPAP or HFNC, and the potential for adverse respiratory events related to the underlying respiratory disease, the authors urge caution with this practice, and highlight the urgent need for further research in this area.

  Noninvasive Respiratory Support and Feeding in the Neonate · 2017 · DOI

• Although in the past 20 years no studies have shown clear results about the efficacy of exogenous surfactant treatment in paediatric Acute Respiratory Distress Syndrome (ARDS), many of them were able to point out and better define very important aspects of this treatment like dosage, timing, ways of administration and usage of different types of surfactant (natural and synthetic).

  Exogenous Surfactant Treatment in Children with ARDS · 2013 · DOI

• BACKGROUND: The physiological basis underlying the decline in the incidence of sudden infant death syndrome (SIDS) associated with changing the sleep position from prone to supine remains unknown.

  Effects of the supine and prone position on diaphragm thickness in healthy term infants · 2000 · DOI

• According to ERC guidelines from 2025, respiratory support should be started with a PEEP of 6 cmH2O, but the evidence is limited.

  High versus low PEEP in the delivery room: a preimplementation and postimplementation cohort study · 2026 · DOI

• By anchoring neonatal drug dosing in empirically derived physiology rather than adult extrapolation, these models have the potential to transform dosing practice and advance pharmacoequity for one of the most vulnerable and historically understudied populations.

  Developmental age and clinical illness drive in vivo variability of CYP1A2 ontogeny and caffeine metabolism in preterm neonates · 2026 · DOI

• Safety and efficacy of sacubitril/valsartan in pediatric heart failure populations, particularly in neonates, requires validation through larger multicenter trials.

  Novel and Precision Therapies in Neonatal Heart Failure · 2026 · DOI

• Ventricular assist device outcomes in infants and children with stage 1 single ventricle palliation require ongoing investigation and data collection.

  Novel and Precision Therapies in Neonatal Heart Failure · 2026 · DOI

• Long-term neurodevelopmental follow-up should be prioritized, as while immediate physiological changes are encouraging, the ultimate goal of circadian interventions is to optimize long-term outcomes for this vulnerable population.

  Effectiveness of combined versus single circadian interventions in neonatal and pediatric intensive care units: a systematic review with meta-analysis · 2026 · DOI

• Studies should incorporate objective circadian biomarkers such as melatonin rhythms, cortisol profiles, or actigraphy to verify that interventions actually achieve circadian alignment rather than relying solely on clinical outcomes.

  Effectiveness of combined versus single circadian interventions in neonatal and pediatric intensive care units: a systematic review with meta-analysis · 2026 · DOI

Most-cited papers in Neonatal Respiratory Health Research

• Longitudinal Growth of Hospitalized Very Low Birth Weight Infants · PEDIATRICS · 1999 · 669 citations
• Optimizing Care and Outcome for Late-Preterm (Near-Term) Infants: A Summary of the Workshop Sponsored by the National Institute of Child Health and Human Development · PEDIATRICS · 2006 · 544 citations
• Neonatal Abstinence Syndrome · PEDIATRICS · 2014 · 502 citations
• Pulmonary Artery Hypertension in Formerly Premature Infants With Bronchopulmonary Dysplasia: Clinical Features and Outcomes in the Surfactant Era · PEDIATRICS · 2007 · 483 citations
• Early Dexamethasone Therapy in Preterm Infants: A Follow-up Study · PEDIATRICS · 1998 · 324 citations
• Causes of apparent life threatening events in infants: a systematic review · Archives of Disease in Childhood · 2004 · 157 citations
• Sudden infant death syndrome · Canadian Medical Association Journal · 2006 · 157 citations
• Is antenatal steroid treatment effective in preterm IUGR fetuses? · Acta Obstetricia Et Gynecologica Scandinavica · 2009 · 54 citations
• High-risk Factors of Respiratory Distress Syndrome in Term Neonates: A Retrospective Case-control Study · Balkan Medical Journal · 2014 · 46 citations
• The changing epidemiology of infantile hypertrophic pyloric stenosis in Scotland · Archives of Disease in Childhood · 2008 · 43 citations

Most recent work

• Effect of Prone Positioning on Ventilation in Preterm Neonates – A Randomized Controlled Trial: Correspondence · The Indian Journal of Pediatrics · 2026
• Perinatal Factors and Postnatal Growth Trajectories as Determinants of School-Age Pulmonary Function in Preterm Infants · Neonatal Medicine · 2026
• Cardiac Interventions in Neonates: State of the Art · The Indian Journal of Pediatrics · 2026
• Global estimates of mortality in newborn babies, children, and adolescents · BMJ · 2026
• Effectiveness of combined versus single circadian interventions in neonatal and pediatric intensive care units: a systematic review with meta-analysis · Frontiers in Neurology · 2026
• Model Informed “Therapeutic Window” of Dexamethasone by Quantitatively Balancing the Fetal Lung Maturation and Neurotoxicity in Pregnant Rats: An Insight Study for Clinical Precision Medicine · 2026
• Novel and Precision Therapies in Neonatal Heart Failure · Current Treatment Options in Pediatrics · 2026
• Clinical and biological impact of caffeine therapy in premature infants with apnea of prematurity: a prospective observational study · Frontiers in Medicine · 2026
• Pattern and Predictors of Bronchopulmonary Dysplasia in Preterm Infants in New South Wales, Australia: A Population‐Based Cohort Study · Acta Paediatrica · 2026
• Risk factors for bronchopulmonary dysplasia among preterm infants born before thirty-two weeks of gestation in Palestinian private hospitals · World Journal of Clinical Pediatrics · 2026

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