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International audience; BackgroundAntenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, reports of growth and neurodevelopmental dose-related side-effects suggest that the current dose (12 mg plus 12 mg, 24 h apart) might be too high. We therefore investigated whether a half dose would be non-inferior to the current full dose for preventing respiratory distress syndrome.MethodsWe designed a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial in 37 level 3 referral perinatal centres in France. Eligible participants were pregnant women aged 18 years or older with a singleton fetus at risk of preterm delivery and already treated with the first injection of antenatal betamethasone (11·4 mg) before 32 weeks’ gestation. We used a computer-generated code producing permuted blocks of varying sizes to randomly assign (1:1) women to receive either a placebo (half-dose group) or a second 11·4 mg betamethasone injection (full-dose group) 24 h later. Randomisation was stratified by gestational age (before or after 28 weeks). Participants, clinicians, and study staff were masked to the treatment allocation. The primary outcome was the need for exogenous intratracheal surfactant within 48 h after birth. Non-inferiority would be shown if the higher limit of the 95% CI for the between-group difference between the half-dose and full-dose groups in the primary endpoint was less than 4 percentage points (corresponding to a maximum relative risk of 1·20). Four interim analyses monitoring the primary and the secondary safety outcomes were done during the study period, using a sequential data analysis method that provided futility and non-inferiority stopping rules and checked for type I and II errors. Interim analyses were done in the intention-to-treat population. This trial was registered with ClinicalTrials.gov, NCT02897076.FindingsBetween Jan 2, 2017, and Oct 9, 2019, 3244 women were randomly assigned to the half-dose (n=1620 [49·9%]) or the full-dose group (n=1624 [50·1%]); 48 women withdrew consent, 30 fetuses were stillborn, 16 neonates were lost to follow-up, and 9 neonates died before evaluation, so that 3141 neonates remained for analysis. In the intention-to-treat analysis, the primary outcome occurred in 313 (20·0%) of 1567 neonates in the half-dose group and 276 (17·5%) of 1574 neonates in the full-dose group (risk difference 2·4%, 95% CI –0·3 to 5·2); thus non-inferiority was not shown. The per-protocol analysis also did not show non-inferiority (risk difference 2·2%, 95% CI –0·6 to 5·1). No between-group differences appeared in the rates of neonatal death, grade 3–4 intraventricular haemorrhage, stage ≥2 necrotising enterocolitis, severe retinopathy of prematurity, or bronchopulmonary dysplasia.InterpretationBecause non-inferiority of the half-dose compared with the full-dose regimen was not shown, our results do not support practice changes towards antenatal betamethasone dose reduction.

Thermal instability is harmful on the newborn infant. We sought to draw up practical guidelines on maintaining homeothermy alongside skin-to-skin contact.A systematic analysis of the literature identified relevant studies between 2000 and 2021 in the PubMed database. Selected publications were evaluated, and their level of evidence were graded, in order to underpin the development of clinical guidelines.We identified 7 meta-analyses and 64 clinical studies with a focus on newborn infants homeothermy. Skin-to-skin contact is the easiest and most rapidly implementable method to prevent body heat loss. Alongside skin-to-skin contact, monitoring the newborn infant's body temperature with a target of 37.0°C is essential. For newborn infants32 weeks of gestation, a skullcap and a polyethylene bag should be used in the delivery room or during transport. To limit water loss, inhaled gases humidification and warming is recommended, and preterm infants weighing less than 1600 g should be nursed in a closed, convective incubator. With regard to incubators, there are no clear benefits for single vs. double-wall incubators as well as for air vs. skin servo control.Alongside skin-to-skin contact, a bundle of practical guidelines could improve the maintenance of homeothermy in the newborn infant.

Mesenchymal stromal cells (MSCs) are widely used in preclinical and clinical research. Despite minimal criteria to define MSCs provided by the International Society for Cell and Gene Therapy (ISCT), concerns have been raised about inconsistent descriptions of cell products used. To address the question “How are MSCs currently defined and characterized?” we conducted a scoping review on original MSC preclinical and clinical studies published over a 3-month period. Selected studies identified from a systematic search of MEDLINE and Embase were categorized as follows: Clinical, Animal, Biology, or Biomaterial studies. Data were extracted from a randomly selected subsample of studies. We extracted information, including epidemiological characteristics of studies, study design, ISCT criteria, and MSC characterization and culture condition. A total of 1053 articles were included and among them, 318 articles were analyzed. Overall, 18% of the articles explicitly referred to the ISCT minimal criteria for MSC. MSC characteristics and culture conditions were inconstantly reported (eg, viability assay reported in only 18% of the articles). Only 20% of documents reported at least 1 functional assay. Clinical studies showed inconsistent completeness in reporting relevant information on the MSC characterization and cell manufacturing processes. These results suggest that further development and implementation of a consensus definition of MSCs and reporting guidelines are needed to enhance rigor, reproducibility, and transparency in MSC research.

RationaleHuman lung development has been mainly described in morphologic studies and the potential underlying molecular mechanisms were extrapolated from animal models. Therefore, there is a need to gather knowledge from native human lung tissue. In this study we describe changes at a single-cell level in human fetal lungs during the pseudoglandular stage.MethodsWe report the cellular composition, cell trajectories and cell-to-cell communication in developing human lungs with single-nuclei RNA sequencing (snRNA-seq) on 23,251 nuclei isolated from nine human fetuses with gestational ages between 14 to 19 weeks of gestation.ResultsWe identified nine different cell types, including a rare pulmonary neuroendocrine cells population. For each cell type, marker genes are reported, and selected marker genes are used for spatial validation with fluorescent RNA in situ hybridization. Enrichment and developmental trajectory analysis provide insight into molecular mechanisms and signaling pathways within individual cell clusters according to gestational age. Lastly, ligand-receptor analysis highlights determinants of cell-to-cell communication among the different cell types through the pseudoglandular stage, including general developmental pathways (NOTCH and TGFB), as well as more specific pathways involved in vasculogenesis, neurogenesis, and immune system regulation.ConclusionThese findings provide a clinically relevant background for research hypotheses generation in projects studying normal or impaired lung development and help to develop and validate surrogate models to study human lung development, such as human lung organoids.TAKE HOME MESSAGEUsing a single-cell transcriptomic approach (single-nuclei RNA sequencing), we describe here, for the first time, the cellular landscape, cell developmental trajectories, and cell-to-cell communication in the developing human lung during the pseudoglandular stage.

During late lung development, alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such as development. Here, we use MULTI-seq to generate scRNA-seq profiles of over 66,000 cells from 36 mice during normal or impaired lung development secondary to hyperoxia with validation of some of the findings in lungs from BPD patients. We observe dynamic populations of cells, including several rare cell types and putative progenitors. Hyperoxia exposure, which mimics the BPD phenotype, alters the composition of all cellular compartments, particularly alveolar epithelium, stromal fibroblasts, capillary endothelium and macrophage populations. Pathway analysis and predicted dynamic cellular crosstalk suggest inflammatory signaling as the main driver of hyperoxia-induced changes. Our data provides a single-cell view of cellular changes associated with late lung development in health and disease., It is unclear how changes in gene expression are induced by changes in oxygen levels during late lung development. Here, the authors provide data from MULTI-seq scRNAseq in mice showing exposure to higher oxygen levels affects cell fates, especially for alveolarisation, and define gene/cell signatures of impaired lung development under hyperoxia.

Cell‐based therapies hold promise to substantially curb complications from extreme preterm birth, the main cause of death in children below the age of 5 years. Exciting preclinical studies in experimental neonatal lung injury have provided the impetus for the initiation of early phase clinical trials in extreme preterm infants at risk of developing bronchopulmonary dysplasia. Clinical translation of promising therapies, however, is slow and often fails. In the adult population, results of clinical trials so far have not matched the enticing preclinical data. The neonatal field has experienced many hard‐earned lessons with the implementation of oxygen therapy or postnatal steroids. Here we briefly summarize the preclinical data that have permitted the initiation of early phase clinical trials of cell‐based therapies in extreme preterm infants and describe the INCuBAToR concept (Innovative Neonatal Cellular Therapy for Bronchopulmonary Dysplasia: Accelerating Translation of Research), an evidence‐based approach to mitigate the risk of translating advanced therapies into this vulnerable patient population. The INCuBAToR addresses several of the shortcomings at the preclinical and the clinical stage that usually contribute to the failure of clinical translation through (a) systematic reviews of preclinical and clinical studies, (b) integrated knowledge transfer through engaging important stakeholders early on, (c) early economic evaluation to determine if a novel therapy is viable, and (d) retrospective and prospective studies to define and test ideal eligibility criteria to optimize clinical trial design. The INCuBAToR concept can be applied to any novel therapy in order to enhance the likelihood of success of clinical translation in a timely, transparent, rigorous, and evidence‐based fashion., The INCuBAToR is a framework built into the classical clinical translation pathway from laboratory discovery to human trials. It is designed to mitigate the risk of translating cell therapies into the clinic by providing an evidence‐based approach. Systematic reviews, integrated knowledge translation, early economic evaluation, and retro‐ and prospective observational cohort studies can substantially enhance success of the clinical translation.

Phosphoglucomutase 3 (PGM3) deficiency is a rare congenital disorder of glycosylation. Most of patients with autosomal recessive hypomorphic mutations in PGM3 encoding for phosphoglucomutase 3 present with eczema, skin and lung infections, elevated serum IgE, as well as neurological and skeletal features. A few PGM3-deficient patients suffer from a more severe disease with nearly absent T cells and severe skeletal dysplasia. We performed targeted next-generation sequencing on two kindred to identify the underlying genetic etiology of a severe combined immunodeficiency with developmental defect. We report here two novel homozygous missense variants (p.Gly359Asp and p.Met423Thr) in PGM3 identified in three patients from two unrelated kindreds with severe combined immunodeficiency, neurological impairment, and skeletal dysplasia. Both variants segregated with the disease in the two families. They were predicted to be deleterious by in silico analysis. PGM3 enzymatic activity was found to be severely impaired in primary fibroblasts and Epstein-Barr virus immortalized B cells from the kindred carrying the p.Met423Thr variant. Our findings support the pathogenicity of these two novel variants in severe PGM3 deficiency.

IntroductionDespite being more than two decades of research, Mesenchymal Stromal Cell (MSC) treatments are still struggling to cross the translational gap. Two key issues that likely contribute to these failures are i) the lack of clear definition for MSC and ii) poor quality of reporting in MSC clinical studies. To address these issues, we propose a modified Delphi study to establish a consensus definition for MSC and clinical reporting guidelines for MSC.Methods and analysisWe will conduct a three-round international modified Delphi Survey. Findings from a recent scoping review examining how MSC are defined and reported in preclinical and clinical studies were used to draft the initial survey for round one of our Delphi. Participants will include a ‘core group’ of individuals as well as researchers whose work was captured in our scoping review. The core group will include stakeholders from different research fields including developmental biology, translational science, research methods, regulatory practices, scholarly journal editing, and industry. The first two survey rounds will be online, and the final round will take place in person. Each participant will be asked to rate their agreement on potential MSC definition characteristics and reporting items using a Likert scale. After each round, we will analyse data to determine which items have reached consensus for inclusion/exclusion, and then develop a revised questionnaire for any new items, or items that did not reach consensus.Ethics and disseminationThis study received ethical approval from the Ottawa Health Research Network Research Ethics Board. To support the dissemination of our findings, we will use an evidence-based ‘integrated knowledge translation’ approach to engage knowledge users from the inception of the research. This will allow us to develop a tailored end-of-project knowledge translation plan to support and ensure dissemination and implementation of the Delphi results.Strengths and limitations of this studyWe proposed to address the current limitations in MSC experimental and clinical research with a rigorous and methodological consensus building method (Delphi method) that will allow for structured communication on controversial issues.To support dissemination and implementation of our results, we will engage stakeholders and end-users from the inception of the project – such as patient partners – and will develop a tailored end of project knowledge translation plan (integrated knowledge translation approach) in order to overcome historical issues related to community uptake.To address the main limitations of a Delphi method (e.g., lack of participation, no in-person interaction or information exchange), we use a modified Delphi survey with a Core group of stakeholders and a face-to-face meeting.

ObjectiveTo describe the effectiveness of the Neonatal Life Support (NLS) course in terms of attendees’ knowledge, perceived self-efficacy, and clinical applicability.MethodsWe conducted an electronic survey of NLS course attendees (NLS+ group). The survey had six themes: i) demographic characteristics; ii) NLS clinical applicability; iii) attendee’s perceived proficiency at neonatal resuscitation; iv) attendee’s perceived experience of fluency, security, and quality of care during neonatal resuscitation; v) knowledge (multiple-choice questions); and vi) perceived personal and professional impact of the NLS course. A control group (NLS−) was recruited via our regional perinatal network. The survey data were analysed anonymously. Multiple linear regression analysis examined the following: NLS course, job tenure, maternity level, and profession.ResultsThe survey completion rate was 62% (200/323) for the NLS+ group. Among participants, 84% had participated in neonatal resuscitation since their course. The scores for positive perceived experience for neonatal resuscitation (fluency, security, and quality of care delivered) were higher in the NLS+ group than the NLS− group (p < 0.006). After adjustment, the independent factors associated with a higher positive perceived experience were the NLS course, work in tertiary level maternity ward, and job tenure > 5 years. The multiple-choice questions score (n = 10) was 8.2 ± 1.3 (NLS+) vs. 6.7 ± 1.5 (NLS−) (p < 0.0001). NLS course, medical degree, and work in a tertiary level maternity ward were independently associated with higher knowledge scores.ConclusionThe NLS course was associated with better knowledge of, and a positive perceived experience regarding, neonatal resuscitation.

Primary Subject area Neonatal-Perinatal Medicine Background Each year, thousands of newborns are transported by air or ground ambulance to receive specialized medical care. For neurologically immature and physiologically compromised infants, especially preterm infants, the noise and vibration exposure during transport are high despite preventative measures, and may be an important contributor to brain injury risk. Objectives To develop a new tool to investigate vibrations during neonatal transport and mitigation strategies. Design/Methods Proof of concept study including 3 steps: 1) Characterization of the vibrations during transport. Accelerometer sensors placed on different layers of the Neonatal Patient Transport System (NPTS) (neonate manikin, mattress, incubator, deck, stretcher, and vehicle floor) with a variety of ambulance on road tests performed to capture data. 2) Experimentation - A shaker table was used to develop a standardized test environment. Vibration testing was performed, with the entire NPTS mounted on the shaker table. 3) Mitigation - Shaker table tests were repeated using different configurations of mattress and harness types on manikins with different bodyweights. Results 1) Characterization: Road transport exposed the manikin’s head to vibrations that exceeded adult standards. Examining the frequency spectra of the accelerometer signals across different layers of the NPTS suggests that two interfaces, stretcher/vehicle floor and incubator/deck, may be critical for intervention to mitigate the vibrations, as they both showed the highest gains in vibration power. 2) Experimentation: Comparison between the on-road and shaker table tests showed that the shaker table was able to reproduce on-road transportation with acceptable fidelity. The shaker table setup can serve as a standardized environment to explore the impact of several NPTS design variables on vibrations transmitted to the patient. 3) Mitigations: Different mattresses were shown to influence the vibrations experienced by the manikin. The head restraint harness type showed an amplitude reduction of the peak frequency component for all experiment types and for most mattress types compared to a standard 5-point harness. Conclusion Our study demonstrated that: i) vibrations during neonatal transport can exceed adult standards; ii) acceptable fidelity simulation of road conditions can be achieved using a shaker table system; and iii) the most effective approach for vibration mitigation should consider the whole NTPS, instead of focusing solely on the isolette.

The chronic lung disease bronchopulmonary dysplasia (BPD) is the most common complication in preterm infants. It is characterized by alveolar hypoplasia and dysmorphic vasculature. Changes in cellular composition and gene expression underlying the development of BPD are not fully understood. Here we created a detailed temporal map of normal and aberrant late lung development using single-cell RNA sequencing on lung cells from 36 mice at postnatal days (P) 3, 7 and 14. BPD was mimicked by exposure to hyperoxia (85% O2). The MULTI-seq labeling was used in order to minimize experimental bias and increase the reproducibility. A total of 66.200 cells were analyzed throughout three crucial time points of late lung development, across which we identified 1 mesothelial, 5 epithelial, 6 stromal, 5 endothelial, 8 myeloid and 9 lymphoid cell clusters. All cell compartments followed developmental trajectories and hyperoxic exposure impaired the composition and expression patterns in all compartments. Specifically, hyperoxia impaired epithelial surfactant homeostasis and halted fibroblasts maturation. The number of capillary endothelial cells was significantly reduced, suggesting that hyperoxia impairs endothelial maturation at a critical stage of capillary development. Hyperoxia altered lung macrophage populations by reducing the number of homeostatic alveolar macrophages and diminishing the proliferating macrophages. Additionally, we identified the effector cells of the innate immune response, thought to orchestrate pivotal processes resulting in lung impairment. Understanding the temporal changes on transcriptional level provides new means to study the pathogenesis and novel therapies for BPD.

Surfactant protein B (SP-B) deficiency is an autosomal recessive disorder that impairs surfactant homeostasis and manifests as lethal respiratory distress. A compelling argument exists for gene therapy to treat this disease, as de novo protein synthesis of SP-B in alveolar type 2 epithelial cells is required for proper surfactant production. Here we report a rationally designed adeno-associated virus (AAV) 6 capsid that demonstrates efficiency in lung epithelial cell transduction based on imaging and flow cytometry analysis. Intratracheal administration of this vector delivering murine or human proSFTPB cDNA into SP-B deficient mice restores surfactant homeostasis, prevents lung injury, and improves lung physiology. Untreated SP-B deficient mice develop fatal respiratory distress within two days. Gene therapy results in an improvement in median survival to greater than 200 days. This vector also transduces human lung tissue, demonstrating its potential for clinical translation against this lethal disease., Surfactant protein B (SP-B) deficiency is a genetic lung disease that results in lethal respiratory distress within months of birth. Here, the authors describe a gene therapy strategy using a rationally designed AAV6 capsid that restores surfactant homeostasis, prevents lung injury, and improves survival in a mouse model of SP-B deficiency.

ObjectiveTo determine whether the use of nasal, high-frequency percussive ventilation (nHFPV) to manage neonatal respiratory distress decreases the regional cerebral oxygen saturation (rScO2) below that afforded by nasal continuous positive airway pressure (nCPAP).DesignMonocentric, prospective, randomized, monocentric, open-label, non-inferiority crossover trial.PatientsNewborns of gestational age (GA) ≥ 33 weeks exhibiting persistent respiratory distress after 10 min of life (Silverman score ≥ 4).InterventionnHFPV and nCPAP, in succession and in random order.Main outcome measureMean rScO2, as revealed by near-infrared spectroscopy (NIRS) performed over the last 5 min of each ventilation mode. To show that nHFPV was not inferior to nCPAP, our a priori calculations required that the lower boundary of the bilateral 95% confidence interval (CI) of the difference between the mean rScO2 values of each ventilation mode should exceed –5.ResultsForty-nine newborns were randomized and 46 were analyzed. The mean (± standard deviation [SD]) GA and birth weight were 36.4 ± 1.9 weeks and 2,718 ± 497 g. The diagnosis was transient tachypnea in 65% of cases and respiratory distress syndrome in 35%. The mean rScO2 difference during the last 5 min of each ventilation mode (nHFPV minus nCPAP) was – 0.7 ± 5.4% (95% CI –2.25; 0.95). Neither a period effect nor a period-treatment interaction was evident. The mean transcutaneous carbon dioxide values (n = 26) for nCPAP and nHFPV were 7.1 ± 4.8 and 7.9 ± 5.1 kPa, respectively. No harmful or unintentional effect was observed.ConclusionIn our study on newborns of GA ≥ 33 weeks treated for respiratory distress, cerebral oxygenation via nHFPV was not inferior to nCPAP.What is already known on the topicNon-invasive high-frequency ventilation is feasible in preterm newborns and seems to improve ventilation compared to nasal CPAP.We previously showed that nasal high-frequency percussive ventilation (nHFPV) was more efficient that nCPAP for respiratory distress management in newborns of gestational age (GA) ≥ 35 weeks.The impact of mechanical ventilation, especially high-frequency modes, on cerebral blood flow in neonates is of concern.What this study addsnHFPV was well-tolerated and non-inferior to nasal CPAP as measured by rScO2 levels when used to manage respiratory distress at birth in newborns of GA ≥ 33 weeks.

During late lung development alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such as development. Here, we use MULTI-seq to generate scRNA-seq profiles of over 66,000 cells from 36 mice during normal or impaired lung development secondary to hyperoxia. We observed dynamic populations of cells, including several rare cell types and putative progenitors. Hyperoxia exposure, which mimics the BPD phenotype, alters the composition of all cellular compartments, particularly alveolar epithelium, capillary endothelium and macrophage populations. We identified several BPD-associated signatures, including Pdgfra in fibroblasts, Activin A in capillary endothelial cells, and Csf1-Csf1r and Ccl2-Ccr2 signaling in macrophages and neutrophils. Our data provides a novel single-cell view of cellular changes associated with late lung development in health and in disease.

IntroductionDespite being more than two decades of research, mesenchymal stromal cell (MSC) treatments are still struggling to cross the translational gap. Two key issues that likely contribute to these failures are (1) the lack of clear definition for MSC and (2) poor quality of reporting in MSC clinical studies. To address these issues, we propose a modified Delphi study to establish a consensus definition for MSC and reporting guidelines for clinical trials of MSC therapy.Methods and analysisWe will conduct a three-round international modified Delphi survey. Findings from a recent scoping review examining how MSCs are defined and reported in preclinical and clinical studies were used to draft the initial survey for round 1 of our Delphi. Participants will include a ‘core group’ of individuals as well as researchers whose work was captured in our scoping review. The core group will include stakeholders from different research fields including developmental biology, translational science, research methods, regulatory practices, scholarly journal editing and industry. The first two survey rounds will be online, and the final round will take place in person. Each participant will be asked to rate their agreement on potential MSC definition characteristics and reporting items using a Likert scale. After each round, we will analyse the data to determine which items have reached consensus for inclusion/exclusion, and then develop a revised questionnaire for any new items, or items that did not reach consensus.Ethics and disseminationThis study received ethical approval from the Ottawa Health Research Network Research Ethics Board. To support the dissemination of our findings, we will use an evidence-based ‘integrated knowledge translation’ approach to engage knowledge users from the inception of the research. This will allow us to develop a tailored end-of-project knowledge translation plan to support and ensure dissemination and implementation of the Delphi results.

We sought to establish guidelines for hygiene care in newborns based on a systematic review of the literature and grading of evidence using the Groupe de Reflexion et d'Evaluation de l'Environement des Nouveau-nes (GREEN) methodology. We examined 45 articles and 4 reports from safety agencies. These studies recommend a tub bath (rather than a sponge bath) for full-term infants and a swaddle bath for preterm newborns. They also recommend against daily cleansing of preterm infants. The literature emphasized that hygiene care must consider the clinical state of the newborn, including the level of awareness and behavioral responses. Hospitalized newborns treated with topical agents may also experience high exposure to potentially harmful excipients of interest. Caregivers should therefore be aware of the excipients present in the different products they use. In high-resource countries, the available data do not support the use of protective topical agents for preterm infants. Conclusions: We recommend individualization of hygiene care for newborns. There is increasing concern regarding the safety of excipients in topical agents that are used in neonatology. A multidisciplinary approach should be used to identify an approach that requires lower levels of excipients and alternative excipients.What is known:center dot Hygiene care is one of the most basic and widespread types of care received by healthy and sick newborns worldwide.center dot There is no current guideline on hygiene for preterm or hospitalized term newborn.What is new:center dot The French Group of Reflection and Evaluation of the environment of Newborns (GREEN) provided here guidelines based on the current body of evidence.center dot Caregivers should be aware of the many issues related to hygiene care of newborns including newborns' behavioral responses to hygiene care, exposition to excipients of interest, and the potential risk of protective topical agents in a preterm infant. provided here guidelines based on the current body of evidence.center dot Caregivers should be aware of the many issues related to hygiene care of newborns including newborns' possible behavioral responses to hygiene care, exposition to excipients of interest and the potential risk of protective topical agents in a preterm infant.

Resume L’incidence des evenements thromboemboliques veineux en pediatrie differe selon qu’il s’agit de nouveau-nes ou d’enfants plus grands. La genese d’une thrombose veineuse profonde est possible par l’intervention de trois facteurs : la paroi du vaisseau, le flux sanguin et la composition du sang circulant. La presence d’un catheter central constitue une des causes majeures d’apparition d’une thrombose veineuse profonde dans la population des enfants hospitalises en reanimation pediatrique. Nous n’evoquerons pas dans ce travail les particularites de l’embolie pulmonaire ni ne detaillerons la prise en charge specifique des maladies congenitales de l’hemostase a l’origine des evenements thrombotiques chez l’enfant. Nous allons developper les principaux facteurs de risque d’apparition d’une thrombose veineuse chez l’enfant, les elements du diagnostic biologique et d’imagerie et les grands principes de prise en charge therapeutique (curative et preventive).

Background & Aim The chronic lung disease bronchopulmonary dysplasia (BPD) is the most severe complication of prematurity. BPD occurs following ventilator treatment with supplemental oxygen for acute respiratory failure, and early inflammation. The hallmarks of the lung pathology are arrested lung development including fewer and larger alveoli with less septation, thickening of alveolar septa and impaired development of the capillary network. These changes may lead to life-long respiratory morbidity including asthma, reduced exercise capacity, early onset emphysema and pulmonary hypertension. Currently, there is no treatment for BPD. Mesenchymal stromal cells derived from the umbilical cord (UC-MSCs) improve lung structure and function in experimental BPD, and early phase clinical trials are underway. However, the optimal UC-MSC donor remains to be determined. The aim of this project is to compare healing effects of UC-MSC donors in hyperoxia-induced experimental BPD. Methods, Results & Conclusion UC-MSCs derived from 5 human donors (1st term delivery [TMSC], 2nd term delivery [T2MSC], preterm delivery [PMSC], preterm delivery with preeclampsia [PPMSC], preterm delivery with chorioamnionitis [PCMSC]) were administered intratracheally at postnatal day (P) 4 in rat pups exposed to 85% oxygen from P0 to P14. At P21, survival, lung function (flexivent), lung structure (mean linear intercept), right ventricular hypertrophy (Fulton index), as well as lung vasculature at P35 (microCT) were assessed. Treatment with UC-MSCs increased survival in hyperoxia-exposed developing pups. In addition, TMSC, PMSC, PPMSC and PCMSC, but not T2MSC, improved lung compliance, lung growth and attenuated pulmonary hypertension when compared to control hyperoxic pups. Thus, donor source impacts beneficial effects of UC-MSCs in a rat BPD model. In the future, understanding the differences at the transcriptomic level between UC-MSC donors might improve the identification of the optimal MSC source for treatment of complications of extreme prematurity, the number one killer of infants below the age of 5.

Objective: Identify measures to diagnose, prevent, and treat genital herpes infection during pregnancy and childbirth as well as neonatal herpes infection. Materials and methods: Bibliographic search from the Medline and Cochrane Library databases and review of international clinical practice guidelines. Results: Genital herpes lesions are most often due to HSV-2 (LE2). The risk of HSV seroconversion during pregnancy is 1-5% (LE2). Genital herpes lesions during pregnancy in a woman with a history of genital herpes is a recurrence. In this situation, there is no need for virologic confirmation (Grade B). In pregnant women with genital lesions who report they have not previously had genital herpes, virological confirmation by PCR and identifying the specific IgG type is necessary (professional consensus). A first episode of genital herpes during pregnancy should be treated with aciclovir (200 mg 5 times daily) or valaciclovir (1000 mg twice daily) for 5-10 days (Grade C), and recurrent herpes during pregnancy with aciclovir (200 mg 5 times daily) or valaciclovir (500 mg twice daily) (Grade C). The risk of neonatal herpes is estimated at between 25% and 44% if a non primary and primary first genital herpes episode is ongoing at delivery (LE2) and 1% for a recurrence (LE3). Antiviral prophylaxis should be offered to women with either a first or recurrent episode of genital herpes during pregnancy from 36 weeks of gestation until delivery (Grade B). Routine prophylaxis is not recommended for women with a history of genital herpes but no recurrence during pregnancy (professional consensus). A cesarean delivery is recommended if a first episode of genital herpes is suspected (or confirmed) at the onset of labor (Grade B) or if it occured less than 6 weeks before delivery (professional consensus) or in the event of premature rupture of the membranes at term. When a recurrence of genital herpes is underway at the onset of labor, cesarean delivery is most likely to be considered when the membranes are intact and vaginal delivery in cases of prolonged rupture of membranes (professional consensus). Neonatal herpes is rare and mainly due to HSV-1 (LE3). In most cases of neonatal herpes, mothers have no history of genital herpes (LE3). When neonatal herpes is suspected, various samples (blood and cerebrospinal fluid) for HSV PCR must be taken to confirm the diagnosis (professional consensus). Any newborn with suspected neonatal herpes should be treated with intravenous acyclovir (20 mg/kg 3 times daily) (grade A) before the PCR results are available (professional consensus). The duration of the treatment depends on the clinical form (professional consensus) CONCLUSION: There is no formal evidence that it is possible to reduce the risk of neonatal herpes in genital herpes during pregnancy. However, appropriate care can reduce the symptoms associated with herpes and the risk of recurrence at term, as well as cesarean rate because of herpes lesions. Keywords: First episode of genital herpes; Mode of delivery; Prophylactic treatment; Recurrence.

International audience; Objectives To describe a population choosing to continue with their pregnancy despite being eligible to receive a medical termination of pregnancy (TOP). Methods Nine-year retrospective study of data (01/01/2006 to 31/12/2014) from three French prenatal diagnostic centers describing the perinatal outcomes of these pregnancies. Pregnancies were classified according to etiology and severity of its fetal pathology. Several perinatal parameters were described: maternal characteristics, parental prenatal choices and information on the pregnancy and neonatal outcomes. These parameters were classified in function of the severity of fetal pathology according to the classification proposed by Dommergues et al. (Prenatal Diagnosis 30(6):531-539, 2010) Results Overall, 155 pregnancies were continued; 140 have been included in our study. Pregnancy outcomes consisted of four TOPs (2.9%); 20 in utero deaths (14.3%); 110 live births (78.6%) of which 55.4% were still alive at 2 years old as the most recent information; and 6 (4.2%) with unknown outcomes. In 27 cases, perinatal palliative care was requested (an increase of 37% over 9 years). 36.4% of cases were classified as having a high mortality risk; 19.3% with a severe handicap risk; 11.4% with a risk of isolated intellectual disability; and 32.9% with an uncertain prognosis. The parental decisions to choose perinatal palliative care were significantly higher within the high mortality risk group as compared to other severity groups (p

Background Meconium aspiration syndrome (MAS) remains a frequent cause of morbidity and mortality in term newborns. Our objective was to compare two modes of high-frequency ventilation, high-frequency oscillation (HFOV), and high-frequency percussive ventilation (HFPV) with conventional mechanical ventilation (CMV) in a piglet model of MAS. Methods Fifteen newborn piglets were anesthetized, paralyzed, and intubated. Following the instillation of a 3 ml/kg solution of meconium diluted to 30%, the piglets were randomized to one of three groups: high-frequency oscillation (HFOV; Sensormedics®), HFPV (Percussionaire®), or CMV (Siemens®). Animals were ventilated for 6 hr to maintain arterial blood gases within a normal range, that is, pH 7.35–7.45, PaO2 10–16 kPa, PaCO2 4–6.6 kPa. Arterial blood gas measurements, dynCrs and dynRrs, ventilator settings, and vital signs (heart rate, arterial blood pressure, transcutaneous pulse oxygen saturation, and temperature) were collected at 30, 60, 90, 120, 180, 240, 300, and 360 min after meconium instillation. Oxygenation index (OI) ([(fraction of inspired oxygen)(mean airway pressure)(100)]/PaO2), mean airway pressure, dynamic lung function, secretions cleared and histological alterations were studied in all groups. Results Mean airway pressure and OI were significantly lower in the CV and HFPV groups compared to the HFOV group (P

Objective To determine whether nasal high frequency percussive ventilation (NHFPV) would decrease duration of transient tachypnea of the newborn (TTN) compared to nasal continuous positive airway pressure (NCPAP) in newborn infants. Methods A prospective, unmasked, randomized, controlled clinical trial was conducted in 46 eligible newborn infants who were hospitalized for TTN in the University Hospital of Bordeaux (France) between 2007 and 2009. Infants born by cesarian section ≥37 GA, ≥2,000g with diagnosis of TTN and with a transcutaneous saturation

Meconium aspiration syndrome (MAS) remains a frequent cause of morbidity and mortality in term newborns. Our objective was to compare two modes of high-frequency ventilation, high-frequency oscillation (HFOV), and high-frequency percussive ventilation (HFPV) with conventional mechanical ventilation (CMV) in a piglet model of MAS.Fifteen newborn piglets were anesthetized, paralyzed, and intubated. Following the instillation of a 3 ml/kg solution of meconium diluted to 30%, the piglets were randomized to one of three groups: high-frequency oscillation (HFOV; Sensormedics®), HFPV (Percussionaire®), or CMV (Siemens®). Animals were ventilated for 6 hr to maintain arterial blood gases within a normal range, that is, pH 7.35-7.45, PaO(2) 10-16 kPa, PaCO(2) 4-6.6 kPa. Arterial blood gas measurements, dynCrs and dynRrs, ventilator settings, and vital signs (heart rate, arterial blood pressure, transcutaneous pulse oxygen saturation, and temperature) were collected at 30, 60, 90, 120, 180, 240, 300, and 360 min after meconium instillation. Oxygenation index (OI) ([(fraction of inspired oxygen)(mean airway pressure)(100)]/PaO(2) ), mean airway pressure, dynamic lung function, secretions cleared and histological alterations were studied in all groups.Mean airway pressure and OI were significantly lower in the CV and HFPV groups compared to the HFOV group (P 0.05). There was no significant difference between groups regarding lung function, amount of secretions and histological alterations.In our model of MAS in piglets, whilst effective gas exchange with a lower mean airway pressure was possible with both CMV and HFPV compared with HFOV there was no apparent difference in lung histology or secretions.

To determine whether nasal high frequency percussive ventilation (NHFPV) would decrease duration of transient tachypnea of the newborn (TTN) compared to nasal continuous positive airway pressure (NCPAP) in newborn infants.A prospective, unmasked, randomized, controlled clinical trial was conducted in 46 eligible newborn infants who were hospitalized for TTN in the University Hospital of Bordeaux (France) between 2007 and 2009. Infants born by cesarian section ≥37 GA, ≥2,000 g with diagnosis of TTN and with a transcutaneous saturation90% at 20 min after birth were eligible. Infants were randomized to either NHFPV or NCPAP. The primary endpoint was a reduction of the duration of TTN. Secondary endpoints were the duration of oxygen therapy and the minimal level required to obtain a saturation between 90% and 96% integrated into an index which included a time factor: [(FiO2 -21)/time of O2 therapy].In the NHFPV group the duration of TTN was half the time of NCPAP group (105 min ± 20 and 377 min ± 150, respectively; P 0.0001). There was a significant decrease in duration of oxygen supplementation in the NHFPV group (6.3 min ± 3.3) compared to the NCPAP group (19.1 min ± 8.1; P 0.001), and a significant decrease in level of oxygen supplementation [(FiO2 -0.21)/time of O2 therapy] in the NHFPV group (0.29 min(-1) ± 0.16) compared to the NCPAP group (0.46 min(-1) ± 0.50; P 0.001). There was no complication and NHFPV was as well tolerated as NCPAP.NHFPV is well tolerated and more effective than NCPAP in treatment of TTN. NHFPV might be a novel and safe tool to manage TTN. Pediatr Pulmonol.

Background: Meconium aspiration syndrome (MAS) induces respiratory distress in an infant born through meconium-stained amniotic fluid whose symptoms cannot be explained otherwise. It is a frequent source of morbi-mortality in term neonates and there is no consensus regarding respiratory support modalities. Aim: To compare two modes of high frequency ventilation (high frequency oscillation ventilation HFOV and high frequency percussive ventilation HFPV) to a conventional ventilator (CV) in a piglet model of MAS. Methods: After instillation of a 3ml/kg solution of meconium diluted to 30%, 15 piglets were randomized to one of three groups: HFOV (Sensormedics 3100A), HFPV (VDR-3c Bird Percussionaire) and CV (Siemens Servo-D). We adjusted ventilator settings to maintain the arterial blood gas within a target window during the 6 hours of ventilation. The oxygenation index OI ([(fraction of inspired oxygen)(mean airway pressure)(100)]/PaO2), mean airway pressure, dynamic lung function, amount of secretions cleared and histological alterations were studied in all groups. Results: Mean airway pressure was significantly lower in the CV and HFPV groups compared with the HFOV group (p < 0.05). The oxygen index was higher during HFOV compared with CV and HFPV (p < 0.05). There was no significant difference between groups regarding lung function, amount of secretions and histological alterations. Conclusion: CV and HFPV devices are as effective as HFOV for the respiratory support in a piglet model of MAS.

Background Preterm prelabor rupture of membranes (PPROM) before 34 weeks of gestation complicates 1% of pregnancies and accounts for one-third of preterm births. International guidelines recommend expectant management, along with antenatal steroids before 34 weeks and antibiotics. Up-to-date evidence about the risks and benefits of administering tocolysis after PPROM, however, is lacking. In theory, reducing uterine contractility could delay delivery and reduce the risks of prematurity and its adverse short- and long-term consequences, but it might also prolong fetal exposure to inflammation, infection, and acute obstetric complications, potentially associated with neonatal death or long-term sequelae. The primary objective of this study is to assess whether short-term (48 h) tocolysis reduces perinatal mortality/morbidity in PPROM at 22 to 33 completed weeks of gestation. Methods A randomized, double-blind, placebo-controlled, superiority trial will be performed in 29 French maternity units. Women with PPROM between 220/7 and 336/7 weeks of gestation, a singleton pregnancy, and no condition contraindicating expectant management will be randomized to receive a 48-hour oral treatment by either nifedipine or placebo (1:1 ratio). The primary outcome will be the occurrence of perinatal mortality/morbidity, a composite outcome including fetal death, neonatal death, or severe neonatal morbidity before discharge. If we assume an alpha-risk of 0.05 and beta-risk of 0.20 (i.e., a statistical power of 80%), 702 women (351 per arm) are required to show a reduction of the primary endpoint from 35% (placebo group) to 25% (nifedipine group). We plan to increase the required number of subjects by 20%, to replace any patients who leave the study early. The total number of subjects required is thus 850. Data will be analyzed by the intention-to-treat principle. Discussion This trial will inform practices and policies worldwide. Optimized prenatal management to improve the prognosis of infants born preterm could benefit about 50,000 women in the European Union and 40,000 in the United States each year. Trial registration ClinicalTrials.gov identifier: NCT03976063 (registration date June 5, 2019).

Introduction : l’objectif était de réaliser un état des lieux des connaissances et des pratiques concernant l’allaitement maternel (AM) au Centre Hospitalier Universitaire (CHU) de Bordeaux. Ce travail était préalable à l’élaboration d’une formation continue ciblée et adaptée aux professions accompagnant les mères et leur enfant (dyade M-E). Méthode : un questionnaire était élaboré à partir d’une revue exhaustive de la littérature sur 8 thèmes prédéfinis par le groupe de travail « Allaitement » du CHU : bénéfices de l’AM, idées reçues, méthodes de recueil du lait maternel (LM), peau à peau, bouts de sein, insuffisances de lactation, conservation et don du LM, généralités. Pour chacun, le questionnaire comprenait des questions de connaissances et des questions déclaratives sur les pratiques. Il était adressé aux soignants des unités impliquées dans la prise en charge des dyades M-E (néonatologie et maternité). Résultats : trente-neuf articles ont été retenus pour élaborer le questionnaire. Trois cent vingt-trois personnes ont répondu à l’enquête (taux de réponse de 63%). Concernant les connaissances théoriques, le taux moyen de bonnes réponses variait entre 45% (insuffisances de lactation) et 88% (conservation du LM) en néonatologie, et 43% (insuffisances de lactation) et 79% (conservation du LM) à la maternité. L’évaluation des pratiques montrait des variations selon les services, les professions, et la nature des soins apportés aux dyades M-E. Conclusion : notre étude a objectivé des disparités sur les connaissances et les pratiques des soignants du CHU. L’analyse de celles-ci permettra la mise en place d’une formation continue adaptée afin d’harmoniser les pratiques dans l’accompagnement de l’AM.