Mortality and neurodevelopmental outcomes at 2 years' corrected age of very preterm infants with necrotising enterocolitis or spontaneous intestinal perforation: The EPIPAGE-2 cohort study.

PURPOSE: The primary objective was to evaluate the impact of necrotising enterocolitis (NEC) and spontaneous intestinal perforation (SIP) on mortality and neurodevelopmental outcomes at 2 years' corrected age (CA) in infants born before 32 weeks' gestation (WG). METHODS: We studied neurodevelopment at 2 years' CA of infants with NEC or SIP who were born before 32 WG from the EPIPAGE-2 cohort study. The primary outcome was death or the presence of moderate-to-severe motor or sensory disability defined by moderate-to-severe cerebral palsy or hearing or visual disability. The secondary outcome was developmental delay defined by a score < 2 SDs below the mean for any of the five domains of the Ages and Stages Questionnaire. RESULTS: At 2 years' CA, 46% of infants with SIP, 34% of infants with NEC, and 14% of control infants died or had a moderate-to-severe sensorimotor disability (p < 0.01). This difference was mainly due to an increase in in-hospital mortality in the infants with SIP or NEC. Developmental delay at 2 years' CA was more frequent for infants with SIP than controls (70.8% vs 44.0%, p = 0.02) but was similar for infants with NEC and controls (49.3% vs 44.0%, p = 0.5). On multivariate analysis, the likelihood of developmental delay was associated with SIP (adjusted odds ratio = 3.0, 95% CI 1.0-9.1) but not NEC as compared with controls. CONCLUSION: NEC and SIP significantly increased the risk of death or sensorimotor disability at 2 years' CA. SIP was also associated with risk of developmental delay at 2 years' CA.

Variations in neonatal mortality of preterm infants with intraparenchymal haemorrhage in Europe: the EPICE cohort.

OBJECTIVE: The aim of this study was to investigate variations in mortality before neonatal intensive care unit (NICU) discharge of infants born preterm with intraparenchymal haemorrhage (IPH) in Europe with a special interest for withdrawing life-sustaining therapy (WLST). DESIGN: Secondary analysis of the Effective Perinatal Intensive Care in Europe (EPICE) cohort, 2011-2012. SETTING: Nineteen regions in 11 European countries. PATIENTS: All infants born between 24+0 and 31+6 weeks' gestational age (GA) with a diagnosis of IPH. MAIN OUTCOME MEASURES: Mortality rate with multivariable analysis after adjustment for GA, antenatal steroids and gender. WLST policies were described among NICUs and within countries. RESULTS: Among 6828 infants born alive between 24+0 and 31+6 weeks' GA and without congenital anomalies admitted to NICUs, IPH was diagnosed in 234 infants (3.4%, 95% CI 3.3% to 3.9%) and 138 of them (59%) died. The median age at death was 6 days (3-13). Mortality rates varied significantly between countries (extremes: 30%-81%; p<0.004) and most infants (69%) died after WLST. After adjustment and with reference to the UK, mortality rates were significantly higher for France, Denmark and the Netherlands, with ORs of 8.8 (95% CI 3.3 to 23.6), 5.9 (95% CI 1.6 to 21.4) and 4.8 (95% CI 1.1 to 8.9). There were variations in WLST between European regions and countries. CONCLUSION: In infants with IPH, rates of death before discharge and death after WLST varied between European countries. These variations in mortality impede studying reliable outcomes in infants with IPH across European countries and encourage reflection of clinical practices of WLST across European units.

Doxapram for apnoea of prematurity and neurodevelopmental outcomes at age 5-6 years.

OBJECTIVE: To assess the long-term neurodevelopmental impact of doxapram for treating apnoea of prematurity. DESIGN: Secondary analysis of the French national cohort study EPIPAGE-2. Recruitment took place in 2011. A standardised neurodevelopmental assessment was performed at age 5-6 years. A 2:1 propensity score matching was used to control for the non-randomised assignment of doxapram treatment. SETTING: Population-based cohort study. PATIENTS: All children born before 32 weeks' gestation alive at age 5-6 years. INTERVENTIONS: Blind and standardised assessment by trained neuropsychologists and paediatricians at age 5-6 years. MAIN OUTCOME MEASURES: Neurodevelopmental outcomes at age 5-6 years assessed by trained paediatricians and neuropsychologists: cerebral palsy, developmental coordination disorders, IQ and behavioural difficulties. A composite criterion for overall neurodevelopmental disabilities was built. RESULTS: The population consisted of 2950 children; 275 (8.6%) received doxapram. Median (IQR) gestational age was 29.4 (27.6-30.9) weeks. At age 5-6 years, complete neurodevelopmental assessment was available for 60.3% (1780 of 2950) of children and partial assessment for 10.6% (314 of 2950). In the initial sample, children receiving doxapram had evidence of greater clinical severity than those not treated. Doxapram treatment was associated with overall neurodevelopmental disabilities of any severity (OR 1.43, 95% CI 1.07 to 1.92, p=0.02). Eight hundred and twenty-one children were included in the 2:1 matched sample. In this sample, perinatal characteristics of both groups were similar and doxapram treatment was not associated with overall neurodevelopmental disabilities (OR 1.09, 95% CI 0.76 to 1.57, p=0.63). CONCLUSIONS: In children born before 32 weeks' gestation, doxapram treatment for apnoea of prematurity was not associated with neurodevelopmental disabilities.

Neurodevelopment and healthcare utilisation at age 5-6 years in bronchopulmonary dysplasia: an EPIPAGE-2 cohort study.

OBJECTIVE: We aimed to study neurodevelopmental outcomes and healthcare utilisation at age 5-6 years in very preterm children with bronchopulmonary dysplasia (BPD). DESIGN: Prospective and national population-based study. SETTING: All the neonatal units in 25 French regions (21 of the 22 metropolitan regions and 4 overseas regions). PATIENTS: Children born before 32 weeks' gestation in 2011. INTERVENTIONS: Blind, comprehensive and standardised assessment by trained neuropsychologists and paediatricians at age 5-6 years. MAIN OUTCOME MEASURES: Overall neurodevelopmental disabilities, behavioural difficulties, developmental coordination disorders, full-scale IQ, cerebral palsy, social interaction disorders, rehospitalisation in the previous 12 months and detailed developmental support. RESULTS: Of the 3186 children included, 413 (11.7%) had BPD. The median gestational age of children with BPD was 27 weeks (IQR 26.0-28.0) and without BPD was 30 weeks (28.0-31.0). At age 5-6 years, 3150 children were alive; 1914 (60.8%) had a complete assessment. BPD was strongly associated with mild, moderate and severe overall neurodevelopmental disabilities (OR 1.49, 95% CI 1.05 to 2.20; 2.20, 1.41 to 3.42 and 2.71, 1.67 to 4.40). BPD was associated with developmental coordination disorders, behavioural difficulties, lower IQ score as well as rehospitalisation in the last 12 months and developmental support. The association between BPD and cerebral palsy was statistically significant before adjustment but not in adjusted analyses. CONCLUSIONS: BPD was strongly and independently associated with many neurodevelopmental disabilities. Improving medical and neurodevelopmental management of BPD in very preterm children should be a priority to reduce its long-term consequences.

Intraventricular Hemorrhage in Very Preterm Children: Mortality and Neurodevelopment at Age 5.

OBJECTIVES: The objectives were to describe mortality and causes of death in children with intraventricular hemorrhage (IVH) and to study neurodevelopmental outcomes. METHODS: The study was a secondary analysis of the French national prospective and population-based cohort EPIPAGE-2. Children were recruited in 2011. A standardized assessment was conducted at age 5. Children born before 32 weeks' gestation and admitted to a NICU were eligible. Exposure was IVH defined by the Papile classification. Main outcomes were mortality, causes of death, and neurodevelopmental outcomes at age 5. RESULTS: Among the 3468 children included, 578 (16.7%) had grade 1 IVH, 424 (12.2%) grade 2 IVH, and 114 (3.3%) grade 3 IVH; 144 (4.1%) had intraparenchymal hemorrhage (IPH). Mortality was 29.7% (36 of 114) for children with grade 3 IVH and 74.4% (109 of 144) for those with IPH; 67.6% (21 of 31) and 88.7% (86 of 97) of deaths, respectively, were because of withholding and withdrawing of life-sustaining treatment. As compared with no IVH, low-grade IVH was not associated with measured neurodevelopmental disabilities at age 5. High-grade IVH was associated with moderate and severe neurodevelopmental disabilities, reduced full-scale IQ, and cerebral palsy. CONCLUSIONS: Rates of neurodevelopmental disabilities at age 5 did not differ between children without IVH and those with low-grade IVH. For high-grade IVH, mortality rate was high, mostly because of withholding and withdrawal of life-sustaining treatment, and we found a strong association with overall neurodevelopmental disabilities in survivors.

Prone-Positioning for Severe Acute Respiratory Distress Syndrome Requiring Extracorporeal Membrane Oxygenation.

OBJECTIVES: To determine the characteristics and outcomes of patients prone-positioned during extracorporeal membrane oxygenation for severe acute respiratory distress syndrome and lung CT pattern associated with improved respiratory system static compliance after that intervention. DESIGN: Retrospective, single-center study over 8 years. SETTINGS: Twenty-six bed ICU in a tertiary center. MEASUREMENTS AND MAIN RESULTS: A propensity score-matched analysis compared patients with prone-positioning during extracorporeal membrane oxygenation and those without. An increase of the static compliance greater than or equal to 3 mL/cm H2O after 16 hours of prone-positioning defined prone-positioning responders. The primary outcome was the time to successful extracorporeal membrane oxygenation weaning within 90 days of postextracorporeal membrane oxygenation start, with death as a competing risk. Among 298 venovenous extracorporeal membrane oxygenation-treated adults with severe acute respiratory distress syndrome, 64 were prone-positioning extracorporeal membrane oxygenation. Although both propensity score-matched groups had similar extracorporeal membrane oxygenation durations, prone-positioning extracorporeal membrane oxygenation patients' 90-day probability of being weaned-off extracorporeal membrane oxygenation and alive was higher (0.75 vs 0.54, p = 0.03; subdistribution hazard ratio [95% CI], 1.54 [1.05-2.58]) and 90-day mortality was lower (20% vs 42%, p < 0.01) than that for no prone-positioning extracorporeal membrane oxygenation patients. Extracorporeal membrane oxygenation-related complications were comparable for the two groups. Patients without improved static compliance had higher percentages of nonaerated or poorly aerated ventral and medial-ventral lung regions (p = 0.047). CONCLUSIONS: Prone-positioning during venovenous extracorporeal membrane oxygenation was safe and effective and was associated with a higher probability of surviving and being weaned-off extracorporeal membrane oxygenation at 90 days. Patients with greater normally aerated lung tissue in the ventral and medial-ventral regions on quantitative lung CT-scan performed before prone-positioning are more likely to improve their static compliance after that procedure during extracorporeal membrane oxygenation.

Bronchopulmonary Dysplasia and Risk of Developmental Delay: An EPIPAGE-2 Cohort Study.

BACKGROUND: Overall and respiratory management of preterm children are constantly evolving, which might have changed both the pathophysiology and neurodevelopmental consequences of bronchopulmonary dysplasia (BPD). OBJECTIVES: The objective of this study is to determine whether the previously shown association between BPD and risk of developmental delay persists. METHODS: The study population was children born before 32 weeks' gestation from the French prospective cohort EPIPAGE-2. The exposure was BPD assessed at 36 weeks' postmenstrual age. The main outcome was risk of developmental delay defined by an Age & Stages Questionnaires (ASQ) score below threshold at 24 months' corrected age. RESULTS: The analyzed population included 2,706 children. Among those with available ASQ score, 196/1,587 had BPD and 671/1,587 had an ASQ score below threshold. BPD was associated with an ASQ score below threshold (odds ratio 1.52, 95% confidence interval 1.11-2.08; p = 0.008). CONCLUSIONS: BPD was strongly associated with risk of developmental delay.

CRISPR Typing Increases the Discriminatory Power of Streptococcus agalactiae Typing Methods.

We explored the relevance of a Clustered regularly interspaced short palindromic repeats (CRISPR)-based genotyping tool for Streptococcus agalactiae typing and we compared this method to current molecular methods [multi locus sequence typing (MLST) and capsular typing]. To this effect, we developed two CRISPR marker schemes (using 94 or 25 markers, respectively). Among the 255 S. agalactiae isolates tested, 229 CRISPR profiles were obtained. The 94 and 25 markers made it possible to efficiently separate isolates with a high diversity index (0.9947 and 0.9267, respectively), highlighting a high discriminatory power, superior to that of both capsular typing and MLST (diversity index of 0.9017 for MLST). This method has the advantage of being correlated with MLST [through analysis of the terminal direct repeat (TDR) and ancestral spacers] and to possess a high discriminatory power (through analysis of the leader-end spacers recently acquired, which are the witnesses of genetic mobile elements encountered by the bacteria). Furthermore, this "one-shot" approach presents the benefit of much-reduced time and cost in comparison with MLST. On the basis of these data, we propose that this method could become a reference method for group B Streptococcus (GBS) typing.

Occurrence and severity of acute respiratory infections during the first year among very preterm infants: an Epipage-2 cohort analysis.

This study aims to describe the incidence of acute respiratory infections (ARI) during the first year in infants born before 32 weeks' gestation, and to analyze and study the risk factors as well as factors associated with oxygen requirement among infants with an ARI, in the palivizumab era. This study included 2571 infants from a nationwide French population-based cohort (Epipage 2). ARI at 1-year corrected age was identified by parental questionnaires. Risk and severity factors included those already known, and detailed information about neonatal morbidities. ARI occurred in 52.2% (n = 1349) of infants. Oxygen therapy was used in 33.2% (n = 391) of infants with an ARI. Risk factors for AII were male sex, bronchopulmonary dysplasia, presence of siblings at home, and childcare in the community together with incomplete treatment palivizumab. Mechanical ventilation in the neonatal period, bronchopulmonary dysplasia, and discharge between October and March were associated with more frequent oxygen requirement. No other factors describing neonatal morbidities were associated with risk of ARI or oxygen requirement.Conclusion: ARIs are still very common during the first year of life of very preterm children, and oxygen therapy is frequently needed. Educational strategies are needed in all families with a very preterm infant. What is Known: • Acute respiratory infections (ARIs) are the first cause of rehospitalizations in preterm children, with bronchopulmonary dysplasia being the main risk factor. • Palivizumab prophylaxis has proven its effect against severe RSV infections, but it is not universal. What is New: • No factor describing neonatal morbidity, except BPD, was associated with ARI occurrence or severity. • BPD and discharge during RSV season were the only factors associated with O2 requirement during ARI.

Burnout among paediatric residents during the COVID-19 outbreak in France.

The primary objective of the study was to assess the prevalence of burnout among paediatric residents during the coronavirus disease 2019 (COVID-19) outbreak in France. The secondary objective was to identify risk factors associated with burnout in this population. In a nationwide, cross-sectional survey, a questionnaire was e-mailed to all paediatric residents in France in the first week of May 2020. The prevalence of burnout was assessed with the validated French-language version of the Maslach Burnout Inventory - Human Services Survey. The questionnaire also contained items on the residents' sociodemographic characteristics and professional situation. Three hundred and forty paediatric residents completed the questionnaire. The median age was 27 (interquartile range 25-28) and 285 (83.8%, 95% confidence interval (CI) [79.5-87.6]) of the residents were women. The prevalence of burnout was 37.4%, 95%CI [32.2-42.7]. There was no association between burnout and exposure to the consequences of COVID-19, which may be related to the low incidence of severe COVID-19 among children. In contrast, the hours worked per week and the anxiety scores were significantly associated with burnout.Conclusion: The level of burnout among French paediatric residents is a matter of concern for residents, and cannot be ascribed to the COVID-19 outbreak. Preventive actions should be implemented, with a reduction in working hours and support programs to help manage work-related anxiety. What is Known: • Burnout is a concern for both residents and the patients they care for. • Natural disasters disrupt the health care organizations and increase the burnout rate. What is New: • The prevalence of burnout among paediatric residents in France is 37.4%, 95%CI [32.2-42.7]. • COVID-19 outbreak is not associated with burnout in this population but anxiety and working hours per week might be modifiable risk factors.

Full compliance with Respiratory syncytial virus prophylaxis was associated with fewer respiratory-related hospital admissions in preterm children: A cohort study.

AIM: Although well documented in randomised trials, the efficacy of prophylaxis against respiratory syncytial virus (RSV) in real-word conditions is less studied. The objective was to assess the impact of partial versus full RSV prophylaxis for acute respiratory infections (ARIs) and ARI-related hospital admissions in preterm children. METHODS: This study included children born preterm in 2011 in France who were eligible for RSV prophylaxis and received at least one palivizumab dose from October 2011 to March 2012. Full prophylaxis was defined as receiving at least one palivizumab dose for each month of RSV exposure in the community. Children with full and partial prophylaxis were matched, and odds of ARIs and ARI-related hospital admission were compared by logistic regression. RESULTS: Full prophylaxis concerned 861/1083 (80%) children. As compared with full prophylaxis, partial prophylaxis was not associated with ARI occurrence (odds ratio OR 1.3, 95% confidence interval CI 0.9-1.9) but was significantly associated with ARI-related hospital admission during the RSV epidemic (OR 1.9, 95% CI 1.2-2.9). CONCLUSION: During the 2011-2012 RSV epidemic, hospital admission rates were higher for preterm children with partial than full RSV prophylaxis. Improving compliance could help alleviate the burden of RSV on healthcare systems.