Publications

Abstract

To assess the short-term safety of doxapram for treating apnea of prematurity. This is a retrospective and bicenter study. Eligible children were born before 28 weeks of gestation from January 1, 2020 to December 31, 2021. The association between doxapram treatment and gastrointestinal events was assessed with logistic regression models with adjustment for the main confounding factors: center, sex, intra-uterine growth restriction and gestational age. The main outcome measures are gastrointestinal events (necrotizing enterocolitis or feeding intolerance), the adverse effects of doxapram most frequently reported in the literature. The population consisted of 268 children; 113 (42.2%) received doxapram. As compared with children who did not receive doxapram, those who did had lower gestational age at birth (25.4 vs 26.3 weeks), lower birth weight and more evidence of greater clinical respiratory severity. Doxapram treatment was not associated with increased risk of gastrointestinal events (30.1% and 29.7% in the treated and untreated groups; odds ratio 1.3, 95% CI 0.7-2.4, p = 0.43). More children in the treated than untreated group had high blood pressure (25.7% vs 6.5%).

Conclusion: In children born before 28 weeks of gestation, doxapram treatment for apnea of prematurity was not associated with the occurrence of gastrointestinal events.

What is known: • Doxapram is a well-known second-line treatment for apnea of prematurity. It is a central nervous stimulant that can be used in refractory apnea of prematurity despite continuous positive airway pressure and optimal caffeine therapy. However, its use varies among countries and centers, probably because of suspected adverse effects. Studies suggest that this drug may have potential side effects such as digestive events (necrotizing enterocolitis).

What is new: • We present reassuring data on the digestive safety of doxapram. Use of this drug was not associated with increased rates of digestive events in preterm infants born before 28 weeks of gestation.

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: 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

Abstract

Objective: To study perinatal outcomes for newborns with early, isolated, severe FGR, for whom initial active management was considered unreasonable or impossible at an obstetric-pediatric assessment and to identify the determinants associated with a course that made active management reasonable.

Material and methods: This retrospective observational single-center study occurred in a level-3 university hospital maternity unit. It included all pregnancies with a singleton fetus presenting isolated FGR <3rd percentile at 23 weeks or more of gestation with an obstetric-pediatric assessment (OPA) initially unfavorable to active management. The main outcome measure was perinatal mortality. Characteristics of the women and pregnancies were compared between the groups « OPA became favorable » versus « OPA remained unfavorable ».

Results: Among the 80 cases included, 48 (60%) of the children died, 38 (47.5%) before birth, 2 (2.5%) in the delivery room, and 8 (10%) in the NICU. Overall, the OPA for 32 (40%) became favorable. There were 44 (91.7%) perinatal deaths when the OPA remained unfavorable versus 4 (12.5%) when it became favorable (P<0.001). The median gestational age at the first OPA (25 weeks) did not differ between the groups. The patients in the OPA became favorable group had initially abnormal uterine Doppler findings less often (56.2% vs 85.4%, P=0.001), absent diastole or reverse flow umbilical artery less often (9.4% vs 33.3%, P=0.0016), less preeclampsia (6.2% vs 31.2%, P=0.009) and a higher estimated fetal weight (520 [491-546] g vs 487 [449-523] g, P=0.005).

Conclusion: In fetuses with early severe FGR, the risk of perinatal death was very high when the initial OPA was unfavorable. Initial OPA without preeclampsia and umbilical reverse diastolic flow were associated with higher probability that the OPA became favorable.

Abstract

Aim: Healthcare givers are exposed to stress and therefore are at risk of the development of pathologies. We aimed to provide recommendations regarding psychosocial risks such as stress, moral distress, burnout syndrome or secondary stress syndrome in neonatal care units to best support neonatal healthcare givers.

Methods: We searched PubMed for articles published from 1 January 2017 to 1 December 2023 by using the keywords burnout OR (moral and distress) AND neonatal unit. Recommendations were developed after internal and external review by a multidisciplinary group including 15 professionals and parent representatives.

Results: We identified 207 studies and developed 15 recommendations based on 118 eligible studies. Recommendations to support neonatology healthcare givers were developed for the individual level, the collective or department level to organise the environment, the training of the team with communication sessions and team cohesion; and the institutional level to respect and organise working time.

Conclusion: Psychosocial risks have consequences for the neonatal healthcare givers themselves and possibly those being cared for. To date, prevention, screening and treatment have been insufficiently developed and explored. In this context, an overall institutional review of the chosen care model is needed.

Abstract

The short-term respiratory consequences of small for gestational (SGA) are only partially known. Our aim was to compare the early respiratory features between SGA and appropriate for gestational age (AGA) in very preterm infants. We conducted a secondary analysis of the French prospective EPIPAGE-2 cohort. Eligible children were those born alive before 32 weeks’ gestation. The exposed group consisted of children with SGA. The unexposed group consisted of AGA children. SGA and AGA children were randomly matched in a ratio of 1:1 on the same gestational age and sex. Primary outcomes were age at final extubation and age at weaning from any respiratory support. Among 3.964 very preterm from the EPIPAGE2 cohort, 1123 SGA and 1123 AGA very preterm children were included in the study. The median gestational age was 30.0 weeks (interquartile range 28.0-31.0) in both groups. The median birthweight was 1440 g (1138-1680) in the AGA group and 1000 g (780-1184) in the SGA group. Invasive mechanical ventilation was less common in the SGA than in the AGA group: 68.6% (770/1123) versus 72.0% (808/1062), odds ratio 0.85 (95% CI [0.72-1.00]). In cases of mechanical ventilation, median age at final extubation was 4 days (1-23) and 2 days (1-9) in the SGA and AGA groups. Median postmenstrual age at weaning from any respiratory support was 33.4 weeks (31.7-35.9) in the SGA group and 32.4 weeks (31.4-34.3) in the AGA group.

Conclusion: SGA is associated with delayed extubation and respiratory support weaning.

What is known: • Small for gestational age concerns more than 30% of very preterm children. • The condition is strongly associated with increased neonatal mortality and morbidity, including bronchopulmonary dysplasia.

What is new: • Small for gestational age is associated with delayed extubation and respiratory support weaning in very preterm children. • Shortening invasive mechanical ventilation as much as possible is a crucial issue in this population to try to reduce the risk of bronchopulmonary dysplasia.

Abstract

Prophylactic administration of low-dose hydrocortisone, at replacement dosage, targets inability of extremely low gestational age neonates (ELGANs) to respond to postnatal stress due to adrenal glands immaturity and is intended to prevent serious complications such as death and bronchopulmonary dysplasia (BPD). Increasing evidence from systematic reviews shows that prophylactic hydrocortisone reduces pre-discharge mortality, improves survival without BPD, favors patent ductus arteriosus (PDA) closure, and may have beneficial effects on cardiovascular stability and urine output. In contrast, an increased risk of spontaneous intestinal perforation when prophylactic hydrocortisone is combined with indomethacin and late-onset sepsis, particularly in infants of 24-25 weeks of gestation, have been reported as major adverse events. No significant negative impact on long-term neurodevelopmental outcomes following prophylactic hydrocortisone exposure was observed. Recent real-world data, despite their intrinsic methodological limitations, generally confirm the benefits observed in clinical trials, even with additional potential benefits and without increased adverse events. Ongoing challenges and questions discussed in this invited review relate to the best population to treat, optimal timing and duration of treatment, and potential barriers to implementation due to evolving knowledge and guidelines. IMPACT STATEMENT: Prophylactic low-dose hydrocortisone improves survival without BPD in infants born extremely preterm. Recent real-world data generally confirm the benefits observed in clinical trials, even with additional potential benefits and without increased adverse events. Unanswered questions remain about optimal timing and duration of treatment, and potential barriers to implementation due to evolving knowledge and guidelines.

Abstract

Aim: Infants born very preterm spend their early postnatal life in a neonatal intensive care unit, where irregular and unpredictable sounds replace the structured and familiar intrauterine auditory environment. Music interventions may contribute to alleviate these deleterious effects by reducing stress and providing a form of environmental enrichment.

Material and methods: This was an ancillary study as part of a blinded randomised controlled clinical trial entitled the effect of music on preterm infant’s brain development. It measured the impact of music listening on the autonomic nervous system (ANS), we assessed heart rate variability (HRV) through high-resolution recordings of heart rate monitoring, at three specific postmenstrual ages in premature infants.

Results: From 29 included subjects, 18 were assessed for complete HRV dataset, including nine assigned to the music intervention and nine to the control group. Postmenstrual age appeared to be the main factor influencing HRV from 33 weeks to term equivalent age. Further analyses did not reveal any detectable effect of music intervention on ANS response.

Conclusion: This study found that ANS responses were not modified by recorded music intervention in very preterm infants during wakefulness or sleep onset. Further research is warranted to explore other factors influencing ANS development in this population.

Keywords: autonomic nervous system; heart rate variability; music intervention; neonatal intensive care unit; preterm infants.