Publications

Abstract

This study analyzed the longitudinal evolution of intestinal microbiota in very preterm neonates (PN) during and after their hospitalization. The bacterial 16S rRNA gene sequencing approach was applied for the analysis of fecal samples (n = 1,307) from 596 PN. Samples were collected at one week after birth, at one month, at the neonatal intensive care unit discharge, and at 3.5 years of age. Over time, the intestinal microbiota of the infants matured progressively, with increasing alpha diversity and decreasing beta diversity. Based on a Dirichlet multinomial mixture clustering approach (DMM), during hospitalization, infants progressed among ten different clusters. At 3.5 years of age, only three clusters were identified. The influence of the gestational age, the neonatal antibiotic administration, and the maternal antibiotic therapy during delivery on the gut microbiota varied over time and depended on the sampling period. Preconceptional maternal body mass index (BMI) was associated with the gut microbiota of infants during the hospitalization period and at 3.5 years of age. Infants with a lower gestational age or those born by Cesarean section shifted between clusters more frequently. Using PICRUSt2, the inferred metabolic pathways revealed a change in the functional capacities of the intestinal microbiota over time. We found that preconceptional maternal BMI was the only consistent perinatal factor influencing the development of the gut microbiota over time. After hospital discharge, infants exhibited a transition toward a microbiota community similar to that of adults by 3.5 years of age, in accordance with the functional metabolic pathways of the gut microbiota.IMPORTANCEThis study is among the very few reports analyzing the gut microbiota development in very preterm infants over time in a large, multicenter population of 596 children from a well-described nationwide birth cohort, with a follow-up until the age of 3.5 years. The maturation of the intestinal microbiota was confirmed to occur over time, with increased alpha diversity and decreased beta diversity. Specifically, 13 microbiota clusters were identified during the hospitalization period, while and only three clusters were observed at 3.5 years. Infants born prematurely or via Cesarean section exhibited a less stable microbiota, frequently shifting clusters. A number of perinatal factors were identified as influencing the development of the microbiota. Among these, the preconceptional maternal BMI emerged as the only consistent factor up to 3.5 years. The metabolic pathways of the microbiota evolved over time, in accordance with the maturation of the gut microbiota.

Abstract

Background : data on preschool neurodevelopment of preterm infants according to the duration of their neonatal exposure to opioids with/without midazolam is limited. We aimed to assess neurodevelopment outcome in children aged five years, born very preterm (24–31 weeks), according to exposure to these drugs.

Methods : secondary analysis from the French prospective cohort study EPIPAGE-2 (Etude Epidémiologique sur les Petits Ages Gestationnels, 2011). Exposure to opioids with/without midazolam was classified as none, ≤7 or >7 days. Percentages were weighted to account for the study design. The primary outcome was moderate/severe neurodevelopmental disabilities (NDD). Analyses were conducted using logistic regression and adjusted for perinatal confounders.

Findings: among 3117 survivors, 1165 (35.9%) were exposed (762/1165 (68.0%) ≤7 days, 403/1165 (32.0%) >7 days). Of these 49.5% received opioids only, 41.4% opioids and midazolam, and 9.1% midazolam only. Moderate/severe NDD occurred in 17.8%, 18.9%, and 31.7% in the unexposed, exposed ≤7 days, and exposed >7 days groups, respectively. After adjustment for baseline confounders, only exposure >7 days was associated with increased rates of moderate/severe NDD (adjusted odds ratio 2.07; 95% CI 1.32–3.26). After additional adjustment for severe neonatal morbidities no significant association was found between any duration of exposure and NDD.

Interpretation:Exposure to opioids with/without midazolam >7 days might be associated with a higher prevalence of moderate/severe NDD at five years in very preterm born children but severe neonatal morbidities are a major modulator of this association.

Abstract

Background: Persistent patency of the ductus arteriosus (PDA) has challenged neonatologists for more than 40 years. Controversies persist about the management of PDA in extremely preterm infants. PDA is associated with morbidities, but no therapeutic strategy has resulted in an improved neonatal outcome. Acetaminophen appears to be a promising alternative with possibly fewer adverse effects. The primary objective is to determine whether a prophylactic pharmacological intervention with acetaminophen may increase the survival without severe morbidity at postmenstrual age of 36 weeks.

Methods and analysis: TREOCAPA phase III is a randomized, multicenter, double-blind, stratified, placebo-controlled superiority trial, two arms in a 1:1 ratio performed in 43 NICUs of 14 European countries, evaluating whether the intervention increases the survival without severe morbidity by 10%, from 50% in control arm to 60% in treatment arm, until the age of 36 postmenstrual weeks. To detect this difference, 794 patients were required using a group sequential design. Recruitment has been closed, with 803 patients enrolled. Patients eligible for inclusion are preterm infants with a gestational age between 23 and 28 weeks. In the acetaminophen group, 20 mg/kg loading dose within 12 h after birth, followed by 7.5 mg/kg quarter in die (QID) for 5 days, will be administered to the 27-28 weeks gestational age group, and 25 mg/kg loading dose then 10 mg/kg QID will be administered to the 23-26 weeks gestational age group. The severe morbidities include severe bronchopulmonary dysplasia (BPD grade 3) according to NIH consensus, necrotizing enterocolitis (NEC) of Bell’s stage II or III, intraventricular hemorrhage (IVH) grade III-IV according to Papile classification, or cystic leukomalacia.

Discussion: Whatever the results, the conclusions of this study should be informative for the neonatal scientific community. The results will either confirm the benefit of treatment in increasing survival without severe morbidity, or indicate a worsening of outcomes with prophylactic acetaminophen treatment, or show no difference in the primary outcome. In the latter case, ultrasonographic assessments of ductus arteriosus status on day 7 may help explain the absence of a difference. This could indicate that acetaminophen is ineffective in promoting ductal closure or that early closure of the ductus arteriosus is inconsequential if, despite more frequent closures, there is no associated improvement in outcomes.

Abstract

Background: In France, the infant mortality rate had a long period of decline, but it stopped decreasing after 2010 and then rose. Neonatal mortality is a large part of infant mortality. The aim of this study was thus to describe its main changes, by cause of death and gestational age, and the main changes in socio-spatial distribution, from 2001 to 2017.

Methods: For this purpose, we investigated data on neonatal deaths reported in France from 2001 to 2017. Crude, cause-specific and gestational age-specific neonatal mortality rates were computed and an ecological analysis, according to several contextual factors at commune level, was performed using quasi-Poisson regressions.

Results: The average neonatal mortality rate was 2.42 per 1000 live births in France during the study period, showing an increase from 2011 onwards. This increase was mostly related to perinatal conditions and more births at very low gestational age. Gestational age-specific neonatal mortality rates did not increase during the period. The analysis of socio-spatial factors showed increased mortality rates in large cities, deprived areas and cities with higher percentages of migrants.

Conclusion: This study suggests that a shift in the distribution of gestational age at birth toward low gestational ages may have contributed to the rise in neonatal mortality in France. Furthermore, there is notable spatial heterogeneity in neonatal mortality. Nevertheless, this observation poorly explains the specificity of the high level and recent upsurge in infant mortality in France, in contrast to its European counterparts

Abstract

Background: To measure the association of prematurity and non-preterm low birth weight (LBW) with several long-term health outcomes.

Methods: We selected adult participants from the Constances cohort. Associations between preterm birth (<37 weeks versus ≥37 weeks) and outcomes were measured using modified Poisson regression with adjustment for participant age and parental history. We used the same modeling methods to measure the association between LBW (i.e., <sex-specific 10th percentile) and outcomes in participants born ≥ 37 weeks. We tested for an interaction between exposures and sex.

Results: Among 30,295 participants, preterm birth (5.2%) was associated with (RR[CI95]): obesity (1.25[1.08-1.46]), hypertriglyceridemia (1.23[1.07-1.42]), high LDL-cholesterol (1.16[1.05-1.28]), high blood pressure (HBP) (1.22[1.08-1.36]), metabolic syndrome (1.35[1.06-1.71]), non-alcoholic fatty liver disease (1.26[1.08-1.47]), allergic and atopic symptoms (1.06[1.01-1.12]), and lack of tertiary education (1.11[1.02-1.20]). Women had a significantly higher risk of hypertriglyceridemia and metabolic syndrome. In non-preterm participants, LBW was associated with prediabetes/diabetes (1.30[1.12-1.52]), HBP (1.22[(1.12-1.33]) and lack of tertiary education (1.13[1.07-1.20]), whereas the risk of obesity (0.83[0.73-0.95]) and abdominal obesity (0.84[0.76-0.93]) was reduced.

Conclusion: Preterm birth and non-preterm LBW are both risk factors for several adult outcomes. However, regarding excess fat storage, their long-term effect seems to be in the opposite direction.

Impact statement: Preterm birth is associated with a higher long-term risk of obesity, whereas low birth weight is not. This study improves the understanding of the common idea that low birth weight is associated with a long-term risk of obesity, whereas it might depend on the cause of low birth weight. These findings provide new insights into the difficult distinction between the long-term adverse health effects of preterm birth and low birth weight.

ABSTRACT

Background: The relationship between maternal obesity and childhood cognitive development remains unclear. Prior stu
ies did not adjust for important confounders, and preterm infants are a developmentally distinct group that remains scarcely
examined.
Objectives: To determine whether maternal prepregnancy body mass index (BMI) is associated with offspring intelligence quo-
tient (IQ) up to 5 years and whether this relationship varies with gestational age.
Methods: Data from two French birth cohorts, EDEN (all gestational ages) and EPIPAGE-2 (preterm children born between 24
and 34 weeks of gestation), were used for this study. Maternal prepregnancy weight and height were used to calculate prepreg-
nancy BMI. The Wechsler Preschool and Primary Scale of Intelligence was used to assess child IQ around 5 years. Multivariable
models were adjusted for confounders, including socioeconomic status and paternal BMI.
Results: Analytical cohorts included 1100 children from EDEN and 2629 from EPIPAGE-2. Lower intellectual functioning
(full-scale IQ < 85) was observed in 8.1% of children in EDEN and 19.6% in EPIPAGE-2. The prevalence of maternal obesity was
13.6% (EDEN) and 21.3% (EPIPAGE-2) among children with lower intellectual functioning compared to 8.9% (EDEN) and 12.9%

Abstract

Background : in France, the infant mortality rate had a long period of decline, but it stopped decreasing after 2010 and then rose. Neonatal mortality is a large part of infant mortality. The aim of this study was thus to describe its main changes, by cause of death and gestational age, and the main changes in socio-spatial distribution, from 2001 to 2017.

Methods: for this purpose, we investigated data on neonatal deaths reported in France from 2001 to 2017. Crude, cause-specific and gestational age-specific neonatal mortality rates were computed and an ecological analysis, according to several contextual factors at commune level, was performed using quasi-Poisson regressions.

Results : the average neonatal mortality rate was 2.42 per 1000 live births in France during the study period, showing an increase from 2011 onwards. This increase was mostly related to perinatal conditions and more births at very low gestational age. Gestational age-specific neonatal mortality rates did not increase during the period. The analysis of socio-spatial factors showed increased mortality rates in large cities, deprived areas and cities with higher percentages of migrants.

Conclusion : this study suggests that a shift in the distribution of gestational age at birth toward low gestational ages may have contributed to the rise in neonatal mortality in France. Furthermore, there is notable spatial heterogeneity in neonatal mortality. Nevertheless, this observation poorly explains the specificity of the high level and recent upsurge in infant mortality in France, in contrast to its European counterparts

Abstract

Background: Recent studies have shown growing evidence that brain function is closely synchronised with global physiological parameters. Heart rate is linked to various cognitive processes and a strong correlation between neuronal activity and breathing has been demonstrated. These findings highlight the significance of monitoring these key physiological parameters during neuroimaging as they provide valuable insights into the overall brain function. Today, in neuroimaging, assessing these parameters requires additional cumbersome devices or implanted electrodes. Here we demonstrate that ultrasonic neurofunctional imaging data alone is sufficient to extract these parameters.

Methods: In this work, we performed ultrafast ultrasound imaging in male rodents and human neonates, and we extracted heart and breathing rates from local tissue motion assessed by raw ultrasound data processing. Such « Physio-fUS » automatically selects two specific and optimal brain regions with pulsatile tissue signals to monitor such parameters.

Findings: We validated the correspondence of these periodic signals with heart and breathing rates assessed using gold-standard electrodes in anaesthetised rodents. We extracted heart and breathing rates in sleeping rats and heart rate in rats moving freely in an arena. We also validated Physio-fUS imaging in sleeping human newborns using conventional ECG.

Interpretation: We show the potential of fUS imaging as an integrative tool for simultaneously monitoring physiological parameters during neurofunctional imaging. Beyond the technological improvement, it could enhance our understanding of the link between breathing, heart rate and neurovascular activity in preclinical research and clinical functional ultrasound imaging.

Abstract

The European Society for Paediatric Research (ESPR) first developed recommendations for a Neonatology specific European training curriculum in 1998, with updates in 2007 and 2021. The aim of these recommendations was to define a common, European standard of training for national educational programmes for Neonatologists. Following the Union of European Medical Specialists’ (UEMS) framework of European Training Requirements (ETR), and similar to the American Board of Pediatrics (ABP) recommendations, graduates of training programmes conforming to the ETR will be eligible throughout Europe for recognition of equality of training, and with that should be enabled to freedom-of-movement. This concept also accounts for neonatal specialists. We therefore present the pan-European work on the ETR Neonatology in its third iteration (ETR III), summarising the basic requirements for contemporary training programmes, trainers, and training centres in neonatology. We highlight the European School of Neonatology (ESN) as a comprehensive online educational platform which provides the theoretical and practical background to satisfy the ETR-III. Lastly, we introduce the European Board of Neonatal & Child Health Research (EBNCHR) as a committee dedicated to gaining acceptance for the concept of harmonising education and training in Neonatology and recognising Neonatology as a Paediatric subspecialty in every European Union member state. IMPACT: Neonatology currently is not uniformly recognised as a Paediatric subspecialty throughout the 27 European countries. Hence, training in Neonatology formerly followed no commonly agreed standard throughout the European Union (EU). To ensure a minimum standard of care, an agreed minimum standard of training is required. The European Society for Paediatric Research (ESPR) has led on generating an EU-accredited, pan-European Syllabus for Neonatal training in Europe, the European Training Requirements (ETR) in Neonatology (2021). This article presents the ETR Neonatology from commissioning to accreditation and discusses means of how high-grade post-graduate education, aligned with the ETR can be achieved by practitioners.

Abstract

Acute community-acquired pneumonia (CAP) during pregnancy is a frequently encountered and potentially severe condition. CAP incidence and ecology are unchanged during pregnancy as compared with the overall young adult population. Risk factors specifically identified in pregnant women include advanced gestational age, asthma, anemia and repeated courses of corticosteroid therapy for fetal lung maturation. The clinical presentation of CAP is not altered during pregnancy. Key points in the pregnant host encompass: (i) reduced maternal tolerance to hypoxia, due to physiological adaptations during pregnancy; (ii) heightened severity of some infections, notably viral pneumonias such as influenza, varicella or SARS-CoV-2 pneumonia; (iii) potentially deleterious fetal repercussions of infection and maternal hypoxia, with an increased risk of premature delivery and prematurity; (iv) the need for specific attention to the risk of fetal irradiation in the performance of possibly repeated radiological examinations and (v) therapeutic specificities arising from the possible embryo-fetal toxicity of certain anti-infectious agents. CAP prevention is premised on compliance with universal hygiene measures and on vaccination, which guarantees protection against severe forms of pneumonia not only in the mother (Streptococcus pneumoniae, seasonal flu, chickenpox, COVID-19), but also in the child during the first few months of life (whooping cough, RSV