Reevaluating the FDA's warning against the use of probiotics in preterm neonates: A societal statement by ESPGHAN and EFCNI.

The recent advisory issued by the United States Food and Drug Administration, cautioning against the routine administration of probiotics in preterm neonates, has sparked a lively debate within the scientific community. This commentary presents a perspective from members of the Special Interest Group on Gut Microbiota and Modifications within the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and other authors who contributed to the ESPGHAN position paper on probiotics for preterm infants, as well as representatives from the European Foundation for the Care of Newborn Infants. We advocate for a more nuanced and supportive approach to the use of certain probiotics in this vulnerable population, balancing the demonstrated benefits and risks.

Antenatal Ureaplasma Infection Causes Colonic Mucus Barrier Defects: Implications for Intestinal Pathologies.

Chorioamnionitis is a risk factor for necrotizing enterocolitis (NEC). Ureaplasma parvum (UP) is clinically the most isolated microorganism in chorioamnionitis, but its pathogenicity remains debated. Chorioamnionitis is associated with ileal barrier changes, but colonic barrier alterations, including those of the mucus barrier, remain under-investigated, despite their importance in NEC pathophysiology. Therefore, in this study, the hypothesis that antenatal UP exposure disturbs colonic mucus barrier integrity, thereby potentially contributing to NEC pathogenesis, was investigated. In an established ovine chorioamnionitis model, lambs were intra-amniotically exposed to UP or saline for 7 d from 122 to 129 d gestational age. Thereafter, colonic mucus layer thickness and functional integrity, underlying mechanisms, including endoplasmic reticulum (ER) stress and redox status, and cellular morphology by transmission electron microscopy were studied. The clinical significance of the experimental findings was verified by examining colon samples from NEC patients and controls. UP-exposed lambs have a thicker but dysfunctional colonic mucus layer in which bacteria-sized beads reach the intestinal epithelium, indicating undesired bacterial contact with the epithelium. This is paralleled by disturbed goblet cell MUC2 folding, pro-apoptotic ER stress and signs of mitochondrial dysfunction in the colonic epithelium. Importantly, the colonic epithelium from human NEC patients showed comparable mitochondrial aberrations, indicating that NEC-associated intestinal barrier injury already occurs during chorioamnionitis. This study underlines the pathogenic potential of UP during pregnancy; it demonstrates that antenatal UP infection leads to severe colonic mucus barrier deficits, providing a mechanistic link between antenatal infections and postnatal NEC development.

Reassessing and Extending the European Standards of Care for Newborn Health: How to Keep Reference Standards in Line with Current Evidence.

The European Standards of Care for Newborn Health (ESCNH) were launched in 2018. After three years, the first standards were reassessed and revised to align with current evidence. Moreover, new standards regarding emerging topics were developed. The aim of this paper is to outline the approach adopted for reassessing, revising and developing new standards for the ESCNH. We established a systematic approach to reassess the ESCNH including a public and an expert consultation. The public consultation was open to all stakeholders for feedback whereas the expert consultation followed a targeted consultation method. For developing new standards, a similar process to the original development was implemented. Overall, 20 standards were reassessed and six standards were developed. For the revision process, 23 experts were involved in the targeted consultation method and 253 questionnaires were completed via the open consultation. We demonstrated a systematic approach to update and extend reference standards, which can be applied by other developers of standards. Thereby, we highlighted that including a public and an expert consultation is crucial to improve quality and to ensure that all stakeholder perspectives are integrated.

ResQ Family: Respiratory Syncytial Virus (RSV) Infection in Infants and Quality of Life of Families-Study Protocol of a Multi-Country Family Cohort Study.

(1) Respiratory syncytial virus (RSV) infection in infants not only affects the child itself, but also their families. Nevertheless, information on the overall impact is scarce. A comprehensive caregiver-specific approach covering essential (health) dimensions and relevant stakeholders was initiated under the ResQ Family study conducted in Germany, France, Italy and Sweden. The primary objective is to investigate the health-related quality of life of parents and/or caregivers of children (<24 months) hospitalised for RSV. (2) Each participant completes an online questionnaire disseminated via social media and printed material in hospitals. Using the PedsQLTM FIM as well as further self-designed questions, parent and patient characteristics as well as potential stressors and preventive factors are recorded at baseline and after six weeks. Multivariate regression models with health-related quality of life as main outcome parameter will be conducted. (3) The study is currently in the recruitment process. A full analysis will be performed once the data collection phase is complete. First results are to be expected in late 2023. (4) Publishing the results in the form of scientific papers but also non-scientific (information) material will help us raise awareness for RSV and the importance of prevention among healthcare professionals, patient representatives and decision-makers.

Noninvasive Mechanical Ventilation with Average Volume-Assured Pressure Support versus BiPAP S/T in De Novo Hypoxemic Respiratory Failure.

Background: Bilevel positive airway pressure in spontaneous/time and average volume-assured pressure support (BiPAP·S/T-AVAPS) could maintain an adequate tidal volume by reducing the patient's inspiratory effort; however, this ventilatory strategy has not been compared with other ventilatory modes, especially the conventional BiPAP S/T mode, when noninvasive mechanical ventilation (NIMV) is used. The primary objective of this study was to determine the rate of success and failure of the use of BiPAP·S/T-AVAPS versus BiPAP·S/T alone in patients with mild-to-moderate "de novo" hypoxemic respiratory failure. Methods: This was a matched-cohort study. Subjects with mild-to-moderate de novo hypoxemic respiratory failure were divided into two groups according to the ventilatory strategy used. The subjects in the BiPAP·S/T group were paired with those in the BiPAP·S/T-AVAPS group. Results: A total of 58 subjects were studied. Twenty-nine subjects in the BiPAP·S/T group were paired with 29 subjects in the BiPAP·S/T-AVAPS group. Twenty patients (34.5%) presented with "failure of NIMV," while 38 (65.5%) patients did not. In addition, 13 (22.4%) patients died, while 45 (77.6%) recovered. No differences were found in the percentage of intubation (P=0.44) and mortality (P=0.1). Conclusion: The BiPAP S/T-AVAPS ventilator mode was not superior to the BiPAP·S/T mode. A high mortality rate was observed in patients with NIMV failure in both modes. This trial is registered with https://doi.org/10.1186/ISRCTN17904857.

Novel mRNA therapy restores GALT protein and enzyme activity in a zebrafish model of classic galactosemia.

Messenger RNA (mRNA) has emerged as a novel therapeutic approach for inborn errors of metabolism. Classic galactosemia (CG) is an inborn error of galactose metabolism caused by a severe deficiency of galactose-1-phosphate:uridylyltransferase (GALT) activity leading to neonatal illness and chronic impairments affecting the brain and female gonads. In this proof of concept study, we used our zebrafish model for CG to evaluate the potential of human GALT mRNA (hGALT mRNA) packaged in two different lipid nanoparticles to restore GALT expression and activity at early stages of development. Both one cell-stage and intravenous single-dose injections resulted in hGALT protein expression and enzyme activity in the CG zebrafish (galt knockout) at 5 days post fertilization (dpf). Moreover, the levels of galactose-1-phosphate (Gal-1-P) and galactonate, metabolites that accumulate because of the deficiency, showed a decreasing trend. LNP-packaged mRNA was effectively translated and processed in the CG zebrafish without signs of toxicity. This study shows that mRNA therapy restores GALT protein and enzyme activity in the CG zebrafish model, and that the zebrafish is a suitable system to test this approach. Further studies are warranted to assess whether repeated injections safely mitigate the chronic impairments of this disease.

Parents' experiences regarding neonatal care during the COVID-19 pandemic: country-specific findings of a multinational survey.

OBJECTIVES: The COVID-19 pandemic has disrupted healthcare systems, challenging neonatal care provision globally. Curtailed visitation policies are known to negatively affect the medical and emotional care of sick, preterm and low birth weight infants, compromising the achievement of the 2030 Development Agenda. Focusing on infant and family-centred developmental care (IFCDC), we explored parents' experiences of the disruptions affecting newborns in need of special or intensive care during the first year of the pandemic. DESIGN: Cross-sectional study using an electronic, web-based questionnaire. SETTING: Multicountry online-survey. METHODS: Data were collected between August and November 2020 using a pretested online, multilingual questionnaire. The target group consisted of parents of preterm, sick or low birth weight infants born during the first year of the COVID-19 pandemic and who received special/intensive care. The analysis followed a descriptive quantitative approach. RESULTS: In total, 1148 participants from 12 countries (Australia, Brazil, Canada, China, France, Italy, Mexico, New Zealand, Poland, Sweden, Turkey and Ukraine) were eligible for analysis. We identified significant country-specific differences, showing that the application of IFCDC is less prone to disruptions in some countries than in others. For example, parental presence was affected: 27% of the total respondents indicated that no one was allowed to be present with the infant receiving special/intensive care. In Australia, Canada, France, New Zealand and Sweden, both the mother and the father (in more than 90% of cases) were allowed access to the newborn, whereas participants indicated that no one was allowed to be present in China (52%), Poland (39%), Turkey (49%) and Ukraine (32%). CONCLUSIONS: The application of IFCDC during the COVID-19 pandemic differs between countries. There is an urgent need to reconsider separation policies and to strengthen the IFCDC approach worldwide to ensure that the 2030 Development Agenda is achieved.

Apnea-Hypopnea Index in Chronic Obstructive Pulmonary Disease Exacerbation Requiring Noninvasive Mechanical Ventilation with Average Volume-Assured Pressure Support.

INTRODUCTION: This study intends to determine the Apnea-Hypopnea Index in patients hospitalized with acute hypercapnic respiratory failure from chronic obstructive pulmonary disease exacerbation, who require noninvasive ventilation with average volume-assured pressure support (AVAPS), as well as describes the clinical characteristics of these patients. MATERIALS AND METHODS: We designed a single-center prospective study. The coexistence of Apnea-Hypopnea Index and clinical, gasometric, spirometric, respiratory polygraphy, and ventilatory characteristics were determined. The clinical characteristics found were categorized and compared according to the Apnea-Hypopnea Index (AHI) < 5, AHI 5-15, and AHI >15. A p value <0.05 was considered statistically significant. RESULTS: During the study period, a total of 100 patients were admitted to the ICU with a diagnosis of acute hypercapnic respiratory failure due to COPD exacerbation. 72 patients presented with acute respiratory failure and fulfilled criteria for ventilatory support. Within them, 24 received invasive mechanical ventilation and 48 NIV. After applying the inclusion criteria for this study, 30 patients were eligible. An AHI >5 was present in 24 of the 30 patients recruited (80%). Neck circumference (cm), Epworth scale, and Mallampati score evidenced significant differences when compared to the patient's AHI <5, AHI 5-15, and AHI >15 (p < 0.05). Furthermore, patients with an AHI >5 had longer hospital admissions, prolonged periods on mechanical ventilation, and a higher percentage of intubation rates. CONCLUSION: Apnea-Hypopnea Index and chronic obstructive pulmonary disease exacerbation are a frequent association found in patients with acute hypercapnic respiratory failure and COPD exacerbations that require NIV. This association could be a determining factor in the response to NIV, especially when AVAPS is used as a ventilatory strategy.

Neonatal care during the COVID-19 pandemic - a global survey of parents' experiences regarding infant and family-centred developmental care.

BACKGROUND: The COVID-19 pandemic restrictions affect provision and quality of neonatal care. This global study explores parents' experiences regarding the impact of the restrictions on key characteristics of infant and family-centred developmental care (IFCDC) during the first year of the pandemic. METHODS: For this cross-sectional study, a pre-tested online survey with 52 questions and translated into 23 languages was used to collect data between August and November 2020. Parents of sick or preterm infants born during the pandemic and receiving special/intensive care were eligible for participation. Data analysis included descriptive statistics and statistical testing based on different levels of restrictive measures. FINDINGS: In total, 2103 participants from 56 countries provided interpretable data. Fifty-two percent of respondents were not allowed to have another person present during birth. Percentages increased with the extent of restrictions in the respondents' country of residence (p = 0·002). Twenty-one percent of total respondents indicated that no-one was allowed to be present with the infant receiving special/intensive care. The frequency (p < 0·001) and duration (p = 0·001) of permitted presence largely depended on the extent of restrictions. The more restrictive the policy measures were, the more the respondents worried about the pandemic situation during pregnancy and after birth. INTERPRETATION: COVID-19 related restrictions severely challenged evidence-based cornerstones of IFCDC, such as separating parents/ legal guardians and their newborns. Our findings must therefore be considered by public health experts and policy makers alike to reduce unnecessary suffering, calling for a zero separation policy. FUNDING: EFCNI received an earmarked donation by Novartis Pharma AG in support of this study.

Antenatal and Perioperative Mechanisms of Global Neurological Injury in Congenital Heart Disease.

Congenital heart defects (CHD) is one of the most common types of birth defects. Thanks to advances in surgical techniques and intensive care, the majority of children with severe forms of CHD survive into adulthood. However, this increase in survival comes with a cost. CHD survivors have neurological functioning at the bottom of the normal range. A large spectrum of central nervous system dysmaturation leads to the deficits seen in critical CHD. The heart develops early during gestation, and CHD has a profound effect on fetal brain development for the remainder of gestation. Term infants with critical CHD are born with an immature brain, which is highly susceptible to hypoxic-ischemic injuries. Perioperative blood flow disturbances due to the CHD and the use of cardiopulmonary bypass or circulatory arrest during surgery cause additional neurological injuries. Innate patient factors, such as genetic syndromes and preterm birth, and postoperative complications play a larger role in neurological injury than perioperative factors. Strategies to reduce the disability burden in critical CHD survivors are urgently needed.

Modes and strategies for providing conventional mechanical ventilation in neonates.

Neonatal respiratory failure is a common and serious clinical problem which in a considerable proportion of infants requires invasive mechanical ventilation. The basic goal of mechanical ventilation is to restore lung function while limiting ventilator-induced lung injury, which is considered an important risk factor in the development of bronchopulmonary dysplasia (BPD). Over the last decades, new conventional mechanical ventilation (CMV) modalities have been introduced in clinical practice, aiming to assist clinicians in providing lung protective ventilation strategies. These modalities use more sophisticated techniques to improve patient-ventilator interaction and transfer control of ventilation from the operator to the patient. Knowledge on how these new modalities work and how they interact with lung physiology is essential for optimal and safe use. In this review, we will discuss some important basic lung physiological aspects for applying CMV, the basic principles of the old and new CMV modalities, and the evidence to support their use in daily clinical practice.

Parents' ratings of post-discharge healthcare for their children born very preterm and their suggestions for improvement: a European cohort study.

BACKGROUND: Follow-up of very preterm infants is essential for reducing risks of health and developmental problems and relies on parental engagement. We investigated parents' perceptions of post-discharge healthcare for their children born very preterm in a European multi-country cohort study. METHODS: Data come from a 5-year follow-up of an area-based cohort of births <32 weeks' gestation in 19 regions from 11 European countries. Perinatal data were collected from medical records and 5-year data from parent-report questionnaires. Parents rated post-discharge care related to their children's preterm birth (poor/fair/good/excellent) and provided free-text suggestions for improvements. We analyzed sociodemographic and medical factors associated with poor/fair ratings, using inverse probability weights to adjust for attrition bias, and assessed free-text responses using thematic analysis. RESULTS: Questionnaires were returned for 3635 children (53.8% response rate). Care was rated as poor/fair for 14.2% [from 6.1% (France) to 31.6% (Denmark)]; rates were higher when children had health or developmental problems (e.g. cerebral palsy (34.4%) or epilepsy (36.9%)). From 971 responses, 4 themes and 25 subthemes concerning care improvement were identified. CONCLUSIONS: Parents' experiences provide guidance for improving very preterm children's post-discharge care; this is a priority for children with health and developmental problems as parental dissatisfaction was high. IMPACT: In a European population-based very preterm birth cohort, parents rated post-discharge healthcare as poor or fair for 14.2% of children, with a wide variation (6.1-31.6%) between countries. Dissatisfaction was reported in over one-third of cases when children had health or developmental difficulties, such as epilepsy or cerebral palsy. Parents' free-text suggestions for improving preterm-related post-discharge healthcare were similar across countries; these focused primarily on better communication with parents and better coordination of care. Parents' lived experiences are a valuable resource for understanding where care improvements are needed and should be included in future research.

European Standards of Care for Newborn Health-A project protocol.

AIM: Among children who receive hospital care, preterm infants are Europe's largest group, whose numbers are continually increasing. Currently, no pan-European standards of care for preterm or critically ill infants are available, except for a few specific topics, and practices vary widely in different regions. METHODS: The European Foundation for the Care of Newborn Infants (EFCNI) has initiated a transdisciplinary collaboration project to provide agreed standards for high-quality perinatal and neonatal care, whose implementation will ensure fairer and more equitable care across Europe. This will improve care for these vulnerable infants and their families, ameliorate the long-term conditions found in preterm and critically ill infants and enhance the quality of family life of affected families. More than 220 experts-healthcare professionals, patient representatives and other relevant stakeholders-have come together for the first time to develop a broad reference guidance in neonatology and associated fields. RESULTS: Ninety-six standards on 11 overarching topic areas were developed and endorsed. CONCLUSION: This reference framework serves as a basis for the development of binding national standards for high-quality care. A robust translation and implementation strategy is facilitated, with the goal of improved health outcomes following preterm birth all around Europe.

A comparison of four different models of acute respiratory distress syndrome in sheep.

BACKGROUND: Acute respiratory distress syndrome (ARDS) can have various causes. The study objective was to investigate whether different pathophysiologic models of ARDS would show different respiratory, cardiovascular and inflammatory outcomes. METHODS: We performed a prospective, randomized study in 27 ventilated ewes inducing ARDS using three different techniques to mimic the pulmonary causes of ARDS (ARDSp): warm saline lavage (n = 6), intratracheal hydrochloric acid (HCl; n = 6), intratracheal albumin (n = 10), and one technique to mimic an extrapulmonary cause of ARDS (ARDSexp): intravenous lipopolysaccharide (LPS iv; n = 5). ARDS was defined when PaO2 was < 15 kPa (112 mmHg) when ventilated with PEEP 10 cm H2O and FiO2 = 1.0. The effects on gas exchange were investigated by calculating the oxygenation index (OI) and the ventilation efficacy index (VEI) every 30 min for a period of 4 h. Post mortem lung lavage was performed to obtain broncho-alveolar lavage fluid (BALF) to assess lung injury and inflammation. Lung injury and inflammation were assessed by measuring the total number and differentiation of leukocytes, the concentration of protein and disaturated phospholipids, and interleukine-6 and -8 in the BALF. Histology of the lung was evaluated by measuring the mean alveolar size, alveolar wall thickness and the lung injury score system by Matute-Bello et al., as markers of lung injury. The concentration of interleukin-6 was determined in plasma, as a marker of systematic inflammation. RESULTS: The OI and VEI were most affected in the LPS iv group and thereafter the HCl group, after meeting the ARDS criteria. Diastolic blood pressure was lowest in the LPS iv group. There were no significant differences found in the total number and differentiation of leukocytes, the concentration of protein and disaturated phospholipids, or interleukin-8 in the BALF, histology of the lung and the lung injury score. IL-6 in BALF and plasma was highest in the LPS iv group, but no significant differences were found between the other groups. It took a significantly longer period of time to meet the ARDS criteria in the LPS iv group. CONCLUSIONS: The LPS model caused the most severe pulmonary and cardiovascular insufficiency. Surprisingly, there were limited significant differences in lung injury and inflammatory markers, despite the different pathophysiological models, when the clinical definition of ARDS was applied.

Lower versus Traditional Treatment Threshold for Neonatal Hypoglycemia.

BACKGROUND: Worldwide, many newborns who are preterm, small or large for gestational age, or born to mothers with diabetes are screened for hypoglycemia, with a goal of preventing brain injury. However, there is no consensus on a treatment threshold that is safe but also avoids overtreatment. METHODS: In a multicenter, randomized, noninferiority trial involving 689 otherwise healthy newborns born at 35 weeks of gestation or later and identified as being at risk for hypoglycemia, we compared two threshold values for treatment of asymptomatic moderate hypoglycemia. We sought to determine whether a management strategy that used a lower threshold (treatment administered at a glucose concentration of <36 mg per deciliter [2.0 mmol per liter]) would be noninferior to a traditional threshold (treatment at a glucose concentration of <47 mg per deciliter [2.6 mmol per liter]) with respect to psychomotor development at 18 months, assessed with the Bayley Scales of Infant and Toddler Development, third edition, Dutch version (Bayley-III-NL; scores range from 50 to 150 [mean {±SD}, 100±15]), with higher scores indicating more advanced development and 7.5 points (one half the SD) representing a clinically important difference). The lower threshold would be considered noninferior if scores were less than 7.5 points lower than scores in the traditional-threshold group. RESULTS: Bayley-III-NL scores were assessed in 287 of the 348 children (82.5%) in the lower-threshold group and in 295 of the 341 children (86.5%) in the traditional-threshold group. Cognitive and motor outcome scores were similar in the two groups (mean scores [±SE], 102.9±0.7 [cognitive] and 104.6±0.7 [motor] in the lower-threshold group and 102.2±0.7 [cognitive] and 104.9±0.7 [motor] in the traditional-threshold group). The prespecified inferiority limit was not crossed. The mean glucose concentration was 57±0.4 mg per deciliter (3.2±0.02 mmol per liter) in the lower-threshold group and 61±0.5 mg per deciliter (3.4±0.03 mmol per liter) in the traditional-threshold group. Fewer and less severe hypoglycemic episodes occurred in the traditional-threshold group, but that group had more invasive diagnostic and treatment interventions. Serious adverse events in the lower-threshold group included convulsions (during normoglycemia) in one newborn and one death. CONCLUSIONS: In otherwise healthy newborns with asymptomatic moderate hypoglycemia, a lower glucose treatment threshold (36 mg per deciliter) was noninferior to a traditional threshold (47 mg per deciliter) with regard to psychomotor development at 18 months. (Funded by the Netherlands Organization for Health Research and Development; HypoEXIT Current Controlled Trials number, ISRCTN79705768.).