Pao2 and Mortality in Neonatal Extracorporeal Membrane Oxygenation: Retrospective Analysis of the Extracorporeal Life Support Organization Registry, 2015-2020.

OBJECTIVES: Extracorporeal life support can lead to rapid reversal of hypoxemia but the benefits and harms of different oxygenation targets in severely ill patients are unclear. Our primary objective was to investigate the association between the Pao2 after extracorporeal membrane oxygenation (ECMO) initiation and mortality in neonates treated for respiratory failure. DESIGN: Retrospective analysis of the Extracorporeal Life Support Organization (ELSO) Registry data, 2015-2020. PATIENTS: Newborns supported by ECMO for respiratory indication were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pao2 24 hours after ECMO initiation (H24 Pao2) was reported. The primary outcome was 28-day mortality. We identified 3533 newborns (median age 1 d [interquartile range (IQR), 1-3]; median weight 3.2 kg [IQR, 2.8-3.6]) from 198 ELSO centers, who were placed on ECMO. By 28 days of life, 731 (20.7%) had died. The median H24 Pao2 was 85 mm Hg (IQR, 60-142). We found that both hypoxia (Pao2 < 60 mm Hg) and moderate hyperoxia (Pao2 201-300 mm Hg) were associated with greater adjusted odds ratio (aOR [95% CI]) of 28-day mortality, respectively: aOR 1.44 (95% CI, 1.08-1.93), p = 0.016, and aOR 1.49 (95% CI, 1.01-2.19), p value equals to 0.045. CONCLUSIONS: Early hypoxia or moderate hyperoxia after ECMO initiation are each associated with greater odds of 28-day mortality among neonates requiring ECMO for respiratory failure.

Post-ligation cardiac syndrome after surgical versus transcatheter closure of patent ductus arteriosus in low body weight premature infants: a multicenter retrospective cohort study.

Transcatheter patent ductus arteriosus (PDA) closure is a safe and effective alternative to surgical ligation in low-body-weight infants. Post-ligation cardiac syndrome (PLCS) is defined as severe hemodynamic and respiratory collapse within 24 h of PDA closure, requiring initiation or an increase of an inotropic agent by > 20% of preligation dosing and an absolute increase of at least 20% in ventilation parameters compared with the preoperative value. Whilst PLCS is routinely observed after surgery, its incidence remains poorly described following transcatheter closure. This study aimed to compare the incidence of PLCS after surgical versus transcatheter closure of PDA in low-body-weight premature infants. Propensity scores were used to compare surgical (N = 78) and transcatheter (N = 76) groups of preterm infants who underwent PDA closure at a procedural weight less than 2000 g in two tertiary institutions between 2009 and 2021. The primary outcome was the incidence of PLCS. Secondary outcomes included overall mortality before discharge, risk factors for PLCS, and post-procedural complications. Procedural success was 100% in both groups. After matching, transcatheter group experienced no PLCS vs 15% in the surgical group (p = 0.012). Furthermore, overall mortality (2% vs 17%; p = 0.03) and major complications (2% vs 23%; p = 0.002) were higher in the surgical group. Surgery (100% vs 47%; p < 0.01), gestation age (25 ± 1 vs 26 ± 2 weeks, p < 0.05) and inotropic support before closure (90% vs 29%; p < 0.001) were associated with PLCS occurrence.          Conclusion: Transcatheter PDA closure may be equally effective but safer than surgical PDA closure in low-body-weight premature infants. What is Known: • Post-ligation cardiac syndrome is a serious and common complication of surgical closure of the ductus arteriosus in preterm infants. • Transcatheter closure of preterm ductus arteriosus is a safe and effective technique that is becoming more and more common worldwide. What is New: • Device closure is safer than surgical ligation for patent ductus arteriosus closure in preterm infants and may be the first-line non-pharmacological therapeutic option in this indication in experienced teams. • Our findings should encourage neonatologists and pediatric cardiologists to start and/or strengthen a durable interventional program for transcatheter PDA closure in premature infants.

Prophylactic Intravenous Acetaminophen in Extremely Premature Infants: Minimum Effective Dose Research by Bayesian Approach.

BACKGROUND: Patent ductus arteriosus (PDA) in preterm infants is associated with increased morbidities and mortality. Prophylactic treatment with cyclooxygenase inhibitors, as indomethacin or ibuprofen, failed to demonstrate significant clinical benefits. Acetaminophen may represent an alternative treatment option. OBJECTIVE: This study evaluated the minimum effective dose of prophylactic acetaminophen to close the ductus and assessed the safety and tolerability profile in extremely preterm infants at 23-26 weeks of gestation. METHODS: A dose finding trial with Bayesian continual reassessment method was performed in a multicenter study with premature infants hospitalized in neonatal intensive care unit. Infants of 23-26 weeks of gestation and post-natal age ≤ 12 h were enrolled. Four intravenous acetaminophen dose levels were predefined. The primary outcome was the ductus arteriosus closing at two consecutive echocardiographies or at day 7. The main secondary objectives included the safety of acetaminophen on hemodynamics and biological hepatic function. RESULTS: A total of 29 patients were analyzed sequentially for the primary analysis with 20 infants assigned to the first dose level followed by 9 infants to the second dose level. No further dose level increase was necessary. The posterior probabilities of success, estimated from the Bayesian logistic model, were 46.1% [95% probability interval (PI), 24.9-63.9] and 67.6% (95% PI, 51.5-77.9) for dose level 1 and 2, respectively. A closing or closed pattern was observed among 19 patients at the end of treatment [65.5% (95% confidence interval (CI), 45.7-82.0)]. No change in alanine aminotransferase values was observed during treatment. A significant decrease in aspartate aminotransferase values was observed with postnatal age. No change in systolic and diastolic blood pressures was observed during treatment. CONCLUSIONS: Minimum effective dose to close the ductus was 25 mg/kg loading dose then 10 mg/kg/6 h for 5 days in extremely preterm infants. Acetaminophen was well tolerated in this study following these doses. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04459117.

Association between gut microbiota at 3.5 years of age and body mass index at 5 years: results from two French nationwide birth cohorts.

BACKGROUND/OBJECTIVES: The relationship between gut microbiota and changes in body mass index (BMI) or pediatric overweight in early life remains unclear, and information regarding the preterm population is scarce. This study aimed to investigate how the gut microbiota at 3.5 years of age is associated with (1) later BMI at 5 years, and (2) BMI z-score variations between 2 and 5 years in children from two French nationwide birth cohorts. SUBJECTS/METHODS: Bacterial 16S rRNA gene sequencing was performed to profile the gut microbiota at 3.5 years of age in preterm children (n = 143, EPIPAGE 2 cohort) and late preterm/full-term children (n = 369, ELFE cohort). The predicted abundances of metabolic functions were computed using PICRUSt2. Anthropometric measurements were collected at 2 and 5 years of age during medical examinations or retrieved from children's health records. Statistical analyses included multivariable linear and logistic regressions, random forest variable selection, and MiRKAT. RESULTS: The Firmicutes to Bacteroidetes (F/B) ratio at 3.5 years was positively associated with the BMI z-score at 5 years. Several genera were positively ([Eubacterium] hallii group, Fusicatenibacter, and [Eubacterium] ventriosum group) or negatively (Eggerthella, Colidextribacter, and Ruminococcaceae CAG-352) associated with the BMI z-scores at 5 years. Some genera were also associated with variations in the BMI z-scores between 2 and 5 years of age. Predicted metabolic functions, including steroid hormone biosynthesis, biotin metabolism, glycosaminoglycan degradation, and amino sugar and nucleotide sugar metabolism, were associated with lower BMI z-scores at 5 years. The unsaturated fatty acids biosynthesis pathway was associated with higher BMI z-scores. CONCLUSIONS: These findings indicate that the gut microbiota at 3.5 years is associated with later BMI during childhood, independent of preterm or term birth, suggesting that changes in the gut microbiota that may predispose to adult obesity begin in early childhood.

High Amino Acid Intake in Early Life Is Associated With Systolic but Not Diastolic Arterial Hypertension at 5 Years of Age in Children Born Very Preterm.

BACKGROUND: The life course of individuals born very premature is a topic of increasing concern. The association between high early amino acid intake and later high blood pressure (HBP) in preterm neonates is debated. METHODS AND RESULTS: In a national, prospective, population-based birth cohort, EPIPAGE-2 (Etude Epidémiologique sur Petits Ages Gestationnels), we assessed blood pressure at 5 years. Eligible infants were those born between 24 and 29 weeks of gestation. Infants were distributed in 2 groups of 717 infants matched on propensity score on whether or not they were exposed to high amino acid intake (>3.5 g/kg per day at day 7); 455 control term infants were also enrolled. A value ≥95th percentile of reference values for age and height defined systolic or diastolic HBP. Blood pressure at 5 years of age was assessed for 389 and 385 children in the exposed and nonexposed groups, respectively. Rates (in percent) of systolic and diastolic HBP were 18.0% (95% CI, 14.5%-22.2%), 13.3% (95% CI, 10.3%-17.0%), 8.5% (95% CI, 6.5%-11.1%), and 9.0% (95% CI, 6.6%-12.3%), 10.2% (95% CI, 7.5%-13.6%), and 5.4% (95% CI, 3.8%-7.6%) in exposed, nonexposed, and term-born groups, respectively. Exposure to high early amino acid intake and maximal serum creatinine (by 50 µmol/L) between day 3 and day 7 were 2 independent risk factors for systolic HBP (adjusted odds ratio [aOR], 1.60 [95% CI, 1.05-2.43] and aOR, 1.59 [95% CI, 1.12-2.26], respectively) but not for diastolic HBP (aOR, 0.84 [95% CI, 0.50-1.39] and aOR, 1.09 [95% CI, 0.71-1.67], respectively). After adjustment for 5-year weight Z score, the aOR between high early amino acid intake and systolic HBP was 1.50 [95% CI, 0.98-2.30]. CONCLUSIONS: These results suggest that mechanisms of childhood systolic HBP involve neonatal renal challenge by high amino acid intake or dysfunction.

Occurrence of Neonatal Necrotizing Enterocolitis in Premature Neonates and Gut Microbiota: A Case-Control Prospective Multicenter Study.

BACKGROUND: Necrotizing enterocolitis (NEC) is still one of the leading causes of neonatal death. The present study reports the data from a French case-control prospective multicenter study. METHODS: A total of 146 preterm neonates (PNs) with or without NEC were included. Bacterial 16S rRNA gene sequencing was performed on stool samples (n = 103). Specific culture media were used to isolate Escherichia coli, Clostridium butyricum, and Clostridium neonatale, and strains were phenotypically characterized. RESULTS: The gut microbiota of PNs was dominated by Firmicutes and Proteobacteria, and five enterotypes were identified. The microbiota composition was similar between NEC cases and PN controls. However, differences were observed in the relative abundance of Lactobacillus genus, which was significantly lower in the NEC group, whereas that of the Clostridium cluster III was significantly higher (p < 0.05). Within enterotypes, several phylotypes were significantly more abundant in NEC cases (p < 0.05). Regarding perinatal factors, a statistical association was found between the gut microbiota and cesarean delivery and antifungal therapy. In NEC cases and PN controls, the carriage rates and virulence genes of uropathogenic E. coli were equivalent based on culture. No correlation was found between E. coli, C. butyricum, and C. neonatale carriages, beta-lactam resistance, and antibiotic treatment. CONCLUSIONS: At disease onset, our data support a microbiota dysbiosis between NEC and control infants at the genus level. In addition, it provides valuable information on bacterial antimicrobial susceptibility.

Cow's milk-based infant formula supplements in breastfed infants and primary prevention of cow's milk allergy: A commentary of the Committee on Nutrition of the French Society of Pediatrics.

The role of nutritional interventions for the primary prevention of cow's milk allergy (CMA) remains debated as well as the role of early introduction of allergenic foods, which is largely encouraged from the beginning of complementary feeding. Considering the introduction of cow's milk protein (CMP), current recommendations suggest avoidance of any cow's milk formula (CMF) supplements in breastfed infants in the maternity ward. By contrast, based on poor evidence, some authors support systematic supplements of CMP in breastfed children at risk of allergy from the first week of life. The Committee on Nutrition of the French Society of Pediatrics considers that such a proposal requires more clinical studies and mainly randomized and placebo-controlled clinical trials before becoming a recommendation.

Cognitive Training for Visuospatial Processing in Children Aged 5½ to 6 Years Born Very Preterm With Working Memory Dysfunction: A Randomized Clinical Trial.

Importance: Compared with term-born peers, children born very preterm generally perform poorly in executive functions, particularly in working memory and inhibition. By taking advantage of neuroplasticity, computerized cognitive training of working memory in those children could improve visuospatial processing by boosting visual inhibition via working memory. Objective: To evaluate the long-term effect of cognitive working memory training on visuospatial processing in children aged 5½ to 6 years born very preterm who have working memory impairment. Design, Setting, and Participants: This multicenter (18 French university hospitals), open-label randomized clinical trial with 2 parallel groups (EPIREMED) was conducted from November 2016 to April 2018, with the last follow-up during August 2019. Eligible children from the EPIPAGE 2 cohort were aged 5½ to 6 years, were born between 24 and 34 weeks' gestation, and had a global intelligence quotient greater than 70 and a working memory index less than 85. Data were analyzed from February to December 2020. Intervention: Children were randomized 1:1 to standard care management and a working memory cognitive training program (Cogmed software) for 8 weeks (25 sessions) (intervention) or to standard management (control). Main Outcomes and Measures: The primary outcome was the visuospatial index score from the Wechsler Preschool and Primary Scale of Intelligence, 4th Edition. Secondary outcomes were working memory, intellectual functioning, executive and attention processes, language skills, behavior, quality of life, and schooling. Neurobehavioral assessments were performed at inclusion and after finishing training at 6 months (intermeditate assessment; secondary outcomes) and at 16 months (final assessment; primary outcome). Results: There were 169 children randomized, with a mean (SD) age of 5 years 11 months (2 months); 91 (54%) were female. Of the participants, 84 were in the intervention group (57 of whom [68%] completed at least 15 cognitive training sessions) and 85 were in the control group. The posttraining visuospatial index score was not different between groups at a mean (SD) of 3.0 (1.8) months (difference, -0.6 points; 95% CI, -4.7 to 3.5 points) or 12.9 (2.6) months (difference, 0.1 points; 95% CI, -5.4 to 5.1 points). The working memory index score in the intervention group significantly improved from baseline at the intermediate time point (difference, 4.7 points; 95% CI, 1.2-8.1 points), but this improvement was not maintained at the final assessment. Conclusions and Relevance: This randomized clinical trial found no lasting effect of a cognitive training program on visuospatial processing in children aged 5½ to 6 years with working memory disorders who were born very preterm. The findings suggest that this training has limited long-term benefits for improving executive function. Transient benefits seemed to be associated with the developmental state of executive functions. Trial Registration: ClinicalTrials.gov Identifier: NCT02757794.

Assessing of executive functions in daily life in preterm children aged 3-4 years old from the "Behavior Rating Inventory of Executive Function-Preschool version" questionnaire.

Background: Executive functions (EFs) are a set of neuropsychological skills permitting solving problems in a new situation by regulating action, behavior, and emotional response. As cerebral maturation remains vulnerable in preterm children, a higher risk of developing cognitive disorders including EFs exist compared to term children. Aims: The aim of this study was to estimate the incidence of preschool EF impairments through proxy reports in children born preterm before 34 weeks of gestational age using the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P) version. Secondary aims were to report neonatal, child, or socioeconomic factors associated with EF disorders. Results: Parents of 357 children born preterm aged 3-4 years old completed the BRIEF-P version. Impairment in EFs was clinically significant for 13.5% of preterm children (n = 47; 95% CI = 0.10-0.18) compared to 5.1% in term children. A low parental socioeconomic level was significantly associated with impaired parent-rated EF (19.1% vs. 5.3%, p = 0.003). Conclusions: Proxy reports of EF impairment are about twice as frequent as in term children. EF difficulties are not related to neonatal or child severity factors in contrast with the parental socioeconomic level. Using a parent-rated questionnaire may be a useful and easy tool to identify early the daily life impact of EF disorders on clinical follow-up of preterm children.This study was recorded in the Clinical Trials Register under identifier NCT03700463.

Pulmonary hypertension among preterm infants born at 22 through 32 weeks gestation in France: Prevalence, survival, morbidity and management in the EPIPAGE-2 cohort study.

OBJECTIVE: To determine the prevalence, short-term prognosis and pharmacologic management of pulmonary hypertension (PH) among very preterm infants born before 32 weeks gestation (WG). STUDY DESIGN: In the EPIPAGE-2 French national prospective population-based cohort of preterm infants born in 2011, those presenting with PH were identified and prevalence was estimated using multiple imputation. The primary outcome was survival without severe morbidity at discharge and was compared between infants with or without PH after adjusting for confounders, using generalized estimating equations models. Subgroup analysis was performed according to gestational age (GA) groups. RESULTS: Among 3383 eligible infants, 3222 were analyzed. The prevalence of PH was 6.0 % (95 % CI, 5.2-6.9), 14.5 % in infants born at 22-27+6 WG vs 2.7 % in infants born at 28-31+6 WG (P < .001). The primary outcome (survival without severe morbidity at discharge) occurred in 30.2 % of infants with PH vs 80.2 % of infants without PH (P < .001). Adjusted incidence rate ratios for survival without severe morbidity among infants with PH were 0.42 (0.32-0.57) and 0.52 (0.39-0.69) in infants born at 22-27+6 weeks gestation and those born at 28-31+6 weeks, respectively. Among infants with PH, 92.2 % (95 % CI, 87.7-95.2) received sedation and/or analgesia, 63.5 % (95 % CI, 56.6-69.9) received inhaled NO and 57.6 % (95 % CI, 50.9-64.0) received hemodynamic treatments. CONCLUSION: In this population-based cohort of very preterm infants, the prevalence of PH was 6 %. PH was associated with a significant decrease of survival without severe morbidity in this population.

Assisted reproductive techniques do not impact late neurodevelopmental outcomes of preterm children.

Objective: Assisted reproductive technology (ART) increases the rate of preterm births, though few studies have analyzed outcomes for these infants. No data are available on 4-year-old children born prematurely after ART. The objective was to investigate whether ART affect the neurodevelopmental outcomes at 4 years in preterm infants born before 34 weeks of gestational age (GA). Methods and results: A total of 166 ART and 679 naturally conceived preterm infants born before 34 weeks GA between 2013 and 2015 enrolled in the Loire Infant Follow-up Team were included. Neurodevelopment was assessed at 4 years using the age and stage questionnaire (ASQ) and the need for therapy services. The association between the socio-economic and perinatal characteristics and non-optimal neurodevelopment at 4 years was estimated. After adjustment, the ART preterm group remained significantly associated with a lower risk of having at least two domains in difficulty at ASQ: adjusted odds ratio (aOR) 0.34, 95% confidence interval (CI) (0.13-0.88), p = 0.027. The factors independently associated with non-optimal neurodevelopment at 4 years were male gender, low socio-economic level, and 25-30 weeks of GA at birth. The need for therapy services was similar between groups (p = 0.079). The long-term neurodevelopmental outcomes of preterm children born after ART are very similar, or even better than that of the spontaneously conceived children.

Assessing Behavioral Disorders with SDQ in Very Preterm Children at 5 Years of Age in LIFT Cohort.

BACKGROUND: Preterm-born children are at risk of behavioral disorders and the systematic assessment of these disorders remains a challenge. Questions remain about the accuracy of self-reported parent questionnaires and the real everyday life behavior of the child. AIM: To evaluate the association between SDQ reported by parents in the preterm and behavioral difficulties in the everyday school life environment reported by teacher. METHODS: All children born before 33 weeks and who followed-up in the LIFT (Loire Infant Follow-up team) network were included. The Strengths and Difficulties Parental Questionnaire (SDQ), completed at 5 years, was used to check for behavioral difficulties and identified three groups: "normal", "borderline" and "abnormal". Then, the SDQ results were compared to the Global School Adaptation Score (GSA) at 5 years. RESULTS: Out of the 1825 children followed in the cohort at the age of 5, 1397 questionnaires were analyzed. A total of 11.1% of children had an abnormal score, and 9.7% had a borderline score. Male gender and a lower birth weight z-score were significantly associated with the "abnormal SDQ" group. There is a significant relationship between the probability of being in the "abnormal SDQ" group at 5 years and with difficulty in global school adaptation at 5 years, as well as an SDQ borderline score in the preterm (p < 0.001). CONCLUSIONS: SDQ abnormal and borderline scores are associated with behavioral difficulties in the classroom and everyday life behavior. In preterm children, one should be alerted even by a borderline SDQ score.

Excessive workload and insufficient night-shift remuneration are key elements of dissatisfaction at work for French neonatologists.

AIM: Neonatologists are exposed to ethical issues and unplanned emergencies that require 24-h in-house coverage. These elements may affect quality of life at work, which we surveyed. METHODS: This was a self-administered, voluntary and anonymous cross-sectional survey of French neonatologists. An online questionnaire was sent to members of the French Society of Neonatology from June to October 2022. RESULTS: Of approximately 1500 possible responses, 721 were analysed, with a response rate of 48%. Respondents were mostly women (77%), aged 35-50 years (50%), and hospital practitioners (63%). Reported weekly working time was over 50 h for 80%. Among the 650 neonatologists with on-call duty, 47% worked ≥5 shifts per month. For 80% of practitioners, on-call duty was perceived to have a negative impact on personal life; 49% indicated having sleep disorders. The mean satisfaction score at work was 5.7 ± 1.7 on a scale of 0-10. The main reasons for dissatisfaction were excessive working hours and insufficient remuneration for on-call duty. CONCLUSION: This first evaluation of the quality of life at work of French neonatologists showed high workload. The working conditions and specificities of NICU activity may have significant consequences for their mental health.

Early Life Factors Influencing Children Gut Microbiota at 3.5 Years from Two French Birth Cohorts.

Early life gut microbiota-influencing factors may play an important role in programming individuals long-term health and substantial efforts have been devoted into studying the development of the gut microbiota in relation to early life events. This study aimed to examine in a single study, the persistence of associations between 20 factors occurring in the early life and the gut microbiota at 3.5 years of 798 children from two French nationwide birth cohorts, EPIPAGE 2 (very preterm children) and ELFE (late preterm and full-term children). Gut microbiota profiling was assessed using 16S rRNA gene sequencing-based method. Upon thorough adjustment of confounding factors, we demonstrated that gestational age was one of the factors most associated with gut microbiota differences with a noticeable imprint of prematurity at 3.5 years of age. Children born by cesarean section harbored lower richness and diversity and a different overall gut microbiota composition independently of preterm status. Children who had ever received human milk were associated with a Prevotella-driven enterotype (P_type) compared to those who had never received human milk. Living with a sibling was associated with higher diversity. Children with siblings and those attending daycare centers were associated with a P_type enterotype. Maternal factors including the country of birth and preconception maternal body mass index were associated with some microbiota characteristics: children born to overweight or obese mothers showed increased gut microbiota richness. This study reveals that multiple exposures operating from early life imprint the gut microbiota at 3.5 years that is a pivotal age when the gut microbiota acquires many of its adult characteristics.

Neonatal necrotizing enterocolitis: Clostridium butyricum and Clostridium neonatale fermentation metabolism and enteropathogenicity.

Bacterial colonization in the gut plays a pivotal role in neonatal necrotizing enterocolitis (NEC) development, but the relationship between bacteria and NEC remains unclear. In this study, we aimed to elucidate whether bacterial butyrate end-fermentation metabolites participate in the development of NEC lesions and confirm the enteropathogenicity of Clostridium butyricum and Clostridium neonatale in NEC. First, we produced C.butyricum and C.neonatale strains impaired in butyrate production by genetically inactivating the hbd gene encoding ß-hydroxybutyryl-CoA dehydrogenase that produces end-fermentation metabolites. Second, we evaluated the enteropathogenicty of the hbd-knockout strains in a gnotobiotic quail model of NEC. The analyses showed that animals harboring these strains had significantly fewer and less intense intestinal lesions than those harboring the respective wild-type strains. In the absence of specific biological markers of NEC, the data provide original and new mechanistic insights into the disease pathophysiology, a necessary step for developing potential novel therapies.

Association Between Early Change in Arterial Carbon Dioxide Tension and Outcomes in Neonates Treated by Extracorporeal Membrane Oxygenation.

The primary objective was to investigate the association between partial pressure of carbon dioxide (PaCO 2 ) change after extracorporeal membrane oxygenation (ECMO) initiation and neurologic outcome in neonates treated for respiratory failure. A retrospective analysis of the Extracorporeal Life Support Organization (ELSO) database including newborns supported by ECMO for respiratory indication during 2015-2020. The closest Pre-ECMO (Pre-ECMO PaCO 2 ) and at 24 hours after ECMO initiation (H24 PaCO 2 ) PaCO 2 values allowed to calculate the relative change in PaCO 2 (Rel Δ PaCO 2 = [H24 PaCO 2 - Pre-ECMO PaCO 2 ]/Pre-ECMO PaCO 2 ). The primary outcome was the onset of any acute neurologic event (ANE), defined as cerebral bleeding, ischemic stroke, clinical or electrical seizure, or brain death during ECMO. We included 3,583 newborns (median age 1 day [interquartile range {IQR}, 1-3], median weight 3.2 kg [IQR, 2.8-3.6]) from 198 ELSO centers. The median Rel Δ PaCO 2 value was -29.9% [IQR, -46.2 to -8.5]. Six hundred nine (17%) of them had ANE (405 cerebral bleedings, 111 ischemic strokes, 225 seizures, and 6 brain deaths). Patients with a decrease of PaCO 2 > 50% were more likely to develop ANE than others (odds ratio [OR] 1.78, 95% confidence interval [CI], 1.31-2.42, p < 0.001). This was still observed after adjustment for all clinically relevant confounding factors (adjusted OR 1.94, 95% CI, 1.29-2.92, p = 0.001). A significant decrease in PaCO 2 after ECMO start is associated with ANE among neonates requiring ECMO for respiratory failure. Cautious PaCO 2 decrease should be considered after start of ECMO therapy.

Implementation of a centralized pharmacovigilance system in academic pan-European clinical trials: Experience from EU-Response and conect4children consortia.

Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk-benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors.

Nutri-Score: Its Benefits and Limitations in Children's Feeding.

Reducing the burden of noncommunicable diseases (NCDs) is one of the top priorities of public health policies worldwide. One of the recognized means of achieving this objective is to improve the diet quality. The Nutri-Score (N-S) is a [five-color-A, B, C, D, E letters] front-of-pack labeling logo intended to help consumers quickly identify the healthier prepackaged foods within a food category. Available studies have shown that the N-S is an efficient tool to achieve this aim in terms of consumers' awareness, perception, understanding, and purchasing and that its use may help to reduce the prevalence of NCDs. The N-S is currently implemented on a voluntary basis in 7 European countries and a discussion is underway within the European Commission to achieve a harmonized mandatory label. However, no study on the putative impact of the N-S on children's dietary patterns and health is available. The N-S is not applicable to infants' and young children's formulas and to specific baby foods, the compositions of which are already laid down in European Union regulations. The N-S does not replace age-appropriate dietary guidelines. As children consume an increasing number of adult type and processed foods, the relevance of the N-S for children should be evaluated considering the children's high specific requirements, especially in younger children. This is especially necessary for fitting fat and iron requirements, whereas protein-rich foods should be better framed. Moreover, efforts should be made to inform on how to use the N-S and in education on healthy diets.

Preventing Respiratory Syncytial Virus in Children in France: A Narrative Review of the Importance of a Reinforced Partnership Between Parents, Healthcare Professionals, and Public Health Authorities.

The highly contagious respiratory syncytial virus (RSV) is responsible for up to approximately 50,000 hospitalisations during each RSV season in children aged under 5 years in France, with the burden greatest in infants younger than 1 year who were born at term. There is a need for a strategy to universally protect young children from RSV infection, and thereby reduce the pressure that RSV places every year on RSV-infected children, their parents, and French healthcare systems. Potential strategies currently undergoing clinical investigation include passive immunisation via maternal vaccination or administration of long-acting monoclonal antibodies at or soon after birth, followed by vaccination later in infancy or childhood. An ongoing partnership and collaboration between parents, public health authorities, and frontline primary healthcare will need to be reinforced once these new RSV prevention strategies are available, to facilitate their use and ensure that all children receive adequate protection from the start of their first RSV season.