Gilles Cambonie

White matter damage and intraventricular hemorrhage in very preterm infants: the EPIPAGE study☆

OBJECTIVE To evaluate the prevalence of cranial ultrasound abnormalities in very preterm infants as a function of gestational age, plurality, intrauterine growth restriction, and death before discharge. STUDY DESIGN A prospective, population-based cohort of 2667 infants born between 22 and 32 weeks of gestation in 1997 in nine regions of France, transferred to a neonatal intensive care unit, for whom at least one cranial ultrasound scan was available. RESULTS The frequencies of white matter damage (WMD), major WMD, cystic periventricular leukomalacia (PVL), periventricular parenchymal hemorrhagic involvement, and intraventricular hemorrhage with ventricular dilatation were 21%, 8%, 5%, 3%, and 3%, respectively. The risk of WMD increased with decreasing gestational age. Mean age at diagnosis of cystic PVL was older for the most premature infants. Intraventricular hemorrhage with ventricular dilatation was associated with a higher risk of cystic PVL. Intrauterine growth restriction was not associated with a lower prevalence of cystic PVL. CONCLUSION The frequency of WMD is high in very preterm babies and is strongly related to gestational age. The incidence of cystic PVL did not differ between babies with intrauterine growth restriction and babies who were appropriate for gestational age.

Late N-acetylcysteine treatment prevents the deficits induced in the offspring of dams exposed to an immune stress during gestation.

Prenatal infection is a major stressful experience leading to enhanced susceptibility for mental illnesses in humans. We recently reported in rats, that oxidative stress and glutathione (GSH) shortage occurred in fetal male brain after lipopolysaccharide (LPS) to the dams and that these responses might be involved in the neurodevelopmental deficits observed in adolescent offspring. Furthermore, pretreatment with N‐acetylcysteine (NAC) before LPS avoided both delayed synaptic plasticity and mnesic performance deficits. Since NAC is one of the few medications permitted in pregnant women, this study evaluated the ability of NAC to serve as a protective therapy even after the LPS challenge. Pregnant rats received a single ip injection of E. coli LPS, two days before delivery, and were given NAC in their tap water after the LPS. GSH was evaluated at the time of its expected drop in the hippocampus of male fetuses, whereas long‐term potentiation (LTP) in the CA1 area of the hippocampus and spatial memory in the water‐maze were recorded in 28‐day‐old male offspring. Post‐treatment with NAC, four hours after the LPS challenge fully prevented the drop in the GSH hippocampal content. LTP, as well as spatial learning were completely protected. NAC administration at delivery also partially restored the LTP whereas post‐treatment two days later was inefficient. Another set of dams were supplemented with α‐tocopherol prior to LPS exposure, enhancing the α‐tocopherol levels in fetal hippocampus. This treatment did not prevent the LPS‐induced synaptic plasticity impairment. These results point to fetal hippocampal GSH as a major target of the detrimental effects of in utero LPS challenge. The therapeutic window of NAC extends up to birth, suggesting that this drug might be clinically useful even after an immuno‐inflammatory episode.

The complex relationship between smoking in pregnancy and very preterm delivery. Results of the Epipage study.

Objective  To assess the relationship between cigarette smoking during pregnancy and very preterm births, according to the main mechanisms of preterm birth.

Neonatal infection and 5-year neurodevelopmental outcome of very preterm infants.

OBJECTIVE: To determine whether neonatal infections are associated with a higher risk of adverse neurodevelopment at 5 years of age in a population-based cohort of very preterm children. METHODS: We included all live births between 22 and 32 weeks of gestation, from 9 regions in France, in 1997 (EPIPAGE study). Of the 2665 live births, 2277 were eligible for a follow-up evaluation at 5 years of age: 1769 had a medical examination and 1495 underwent cognitive assessment. Cerebral palsy and cognitive impairment were studied as a function of early-onset sepsis (EOS) and late-onset sepsis (LOS), after adjustment for potential confounding factors, in multivariate logistic regression models. RESULTS: A total of 139 (5%) of the 2665 live births included in the study presented with EOS alone (without associated LOS), 752 (28%) had LOS alone (without associated EOS), and 64 (2%) displayed both EOS and LOS. At 5 years of age, the frequency of cerebral palsy was 9% (157 of 1769) and that of cognitive impairment was 12% (177 of 1495). The frequency of cerebral palsy was higher in infants with isolated EOS (odds ratio [OR]: 1.70 [95% confidence interval (CI): 0.84−3.45]) or isolated LOS (OR: 1.71 [95% CI: 1.14−2.56]) than in uninfected infants, and this risk was even higher in cases of combined EOS and LOS (OR: 2.33 [95% CI: 1.02−5.33]). There was no association between neonatal infection and cognitive impairment. CONCLUSIONS: Neonatal infections in these very preterm infants were associated with a higher risk of cerebral palsy at the age of 5 years, particularly in infants presenting with both EOS and LOS.

Special care and school difficulties in 8-year-old very preterm children: the Epipage cohort study.

Objectives To investigate school difficulties, special care and behavioral problems in 8 year-old very preterm (VPT) children. Patient and Methods Longitudinal population-based cohort in nine regions of France of VPT children and a reference group born at 39–40 weeks of gestation (WG). The main outcome measures were information about school, special care and behavioral problems using Strengths and Difficulties Questionnaire from a questionnaire to parents. Results Among the 1439 VPT children, 5% (75/1439) were in a specialised school or class, 18% (259/1439) had repeated a grade in a mainstream class and 77% (1105/1439) were in the appropriate grade-level in mainstream class; these figures were 1% (3/327) , 5% (16/327) and 94% (308/327) , respectively, for the reference group. Also, 15% (221/1435) of VPT children in a mainstream class received support at school versus 5% (16/326) of reference group. More VPT children between the ages of five and eight years received special care (55% (794/1436)) than children born at term (38% (124/325)); more VPT children (21% (292/1387)) had behavioral difficulties than the reference group (11% (35/319)). School difficulties, support at school, special care and behavioral difficulties in VPT children without neuromotor or sensory deficits varied with gestational age, socioeconomic status, and cognitive score at the age of five. Conclusions Most 8-year-old VPT children are in mainstream schools. However, they have a high risk of difficulty in school, with more than half requiring additional support at school and/or special care. Referral to special services has increased between the ages of 5 and 8 years, but remained insufficient for those with borderline cognitive scores.

Clostridium butyricum strains and dysbiosis linked to necrotizing enterocolitis in preterm neonates

BACKGROUND Necrotizing enterocolitis (NEC) is the most common and serious gastrointestinal disorder among preterm neonates. We aimed to assess a specific gut microbiota profile associated with NEC. METHODS Stool samples and clinical data were collected from 4 geographically independent neonatal intensive care units, over a 48-month period. Thirty stool samples from preterm neonates with NEC (n = 15) and controls (n = 15) were analyzed by 16S ribosomal RNA pyrosequencing and culture-based methods. The results led us to develop a specific quantitative polymerase chain reaction (qPCR) assay for Clostridium butyricum, and we tested stool samples from preterm neonates with NEC (n = 93) and controls (n = 270). We sequenced the whole genome of 16 C. butyricum strains, analyzed their phylogenetic relatedness, tested their culture supernatants for cytotoxic activity, and searched for secreted toxins. RESULTS Clostridium butyricum was specifically associated with NEC using molecular and culture-based methods (15/15 vs 2/15; P < .0001) or qPCR (odds ratio, 45.4 [95% confidence interval, 26.2-78.6]; P < .0001). Culture supernatants of C. butyricum strains from preterm neonates with NEC (n = 14) exhibited significant cytotoxic activity (P = .008), and we identified in all a homologue of the β-hemolysin toxin gene shared by Brachyspira hyodysenteriae, the etiologic agent of swine dysentery. The corresponding protein was secreted by a NEC-associated C. butyricum strain. CONCLUSIONS NEC was associated with C. butyricum strains and dysbiosis with an oxidized, acid, and poorly diversified gut microbiota. Our findings highlight the plausible toxigenic mechanism involved in the pathogenesis of NEC.

6 cmH2O continuous positive airway pressure versus conventional oxygen therapy in severe viral bronchiolitis: A randomized trial†

To compare the effects of nasal continuous positive airway pressure (nCPAP) and conventional oxygen therapy on the clinical signs of respiratory distress and the respiratory muscle workload in acute viral bronchiolitis.

High-flow nasal cannula: recommendations for daily practice in pediatrics.

High-flow nasal cannula (HFNC) is a relatively new device for respiratory support. In pediatrics, HFNC use continues to increase as the system is easily set up and is well tolerated by patients. The use of nasal cannula adapted to the infant’s nares size to deliver heated and humidified gas at high flow rates has been associated with improvements in washout of nasopharyngeal dead space, lung mucociliary clearance, and oxygen delivery compared with other oxygen delivery systems. HFNC may also create positive pharyngeal pressure to reduce the work of breathing, which positions the device midway between classical oxygen delivery systems, like the high-concentration face mask and continuous positive airway pressure (CPAP) generators. Currently, most of the studies in the pediatric literature suggest the benefits of HFNC therapy only for moderately severe acute viral bronchiolitis. But, the experience with this device in neonatology and adult intensive care may broaden the pediatric indications to include weaning from invasive ventilation and acute asthma. As for any form of respiratory support, HFNC initiation in patients requires close monitoring, whether it be for pre- or inter-hospital transport or in the emergency department or the pediatric intensive care unit.

Association Between Early Screening for Patent Ductus Arteriosus and In-Hospital Mortality Among Extremely Preterm Infants.

IMPORTANCE There is currently no consensus for the screening and treatment of patent ductus arteriosus (PDA) in extremely preterm infants. Less pharmacological closure and more supportive management have been observed without evidence to support these changes. OBJECTIVE To evaluate the association between early screening echocardiography for PDA and in-hospital mortality. DESIGN, SETTING, AND PARTICIPANTS Comparison of screened and not screened preterm infants enrolled in the EPIPAGE 2 national prospective population-based cohort study that included all preterm infants born at less than 29 weeks of gestation and hospitalized in 68 neonatal intensive care units in France from April through December 2011. Two main analyses were performed to adjust for potential selection bias, one using propensity score matching and one using neonatal unit preference for early screening echocardiography as an instrumental variable. EXPOSURES Early screening echocardiography before day 3 of life. MAIN OUTCOMES AND MEASURES The primary outcome was death between day 3 and discharge. The secondary outcomes were major neonatal morbidities (pulmonary hemorrhage, severe bronchopulmonary dysplasia, severe cerebral lesions, and necrotizing enterocolitis). RESULTS Among the 1513 preterm infants with data available to determine exposure, 847 were screened for PDA and 666 were not; 605 infants from each group could be paired. Exposed infants were treated for PDA more frequently during their hospitalization than nonexposed infants (55.1% vs 43.1%; odds ratio [OR], 1.62 [95% CI, 1.31 to 2.00]; absolute risk reduction [ARR] in events per 100 infants, -12.0 [95% CI, -17.3 to -6.7). Exposed infants had a lower hospital death rate (14.2% vs 18.5% ; OR, 0.73 [95% CI, 0.54 to 0.98]; ARR, 4.3 [95% CI, 0.3 to 8.3]) and a lower rate of pulmonary hemorrhage (5.6% vs 8.9%; OR, 0.60 [95% CI, 0.38 to 0.95]; ARR, 3.3 [95% CI, 0.4 to 6.3]). No differences in rates of necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions were observed. In the overall cohort, instrumental variable analysis yielded an adjusted OR for in-hospital mortality of 0.62 [95% CI, 0.37 to 1.04]. CONCLUSIONS AND RELEVANCE In this national population-based cohort of extremely preterm infants, screening echocardiography before day 3 of life was associated with lower in-hospital mortality and likelihood of pulmonary hemorrhage but not with differences in necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions. However, results of the instrumental variable analysis leave some ambiguity in the interpretation, and longer-term evaluation is needed to provide clarity.

Group B streptococci in milk and late neonatal infections: an analysis of cases in the literature

Background The source for late-onset neonatal infections (LONI) due to group B Streptococcus (GBS) has not been fully explored. We reviewed GBS LONI cases associated with contaminated breast milk to determine whether breast milk was a possible route for neonatal infection. Data sources A PubMed search from January 1977 to March 2013 was performed with MeSH words “Streptococcus agalactiae”, “group B Streptococcus”, “infection”, “milk”, “human”, “late-onset infection” and/or “neonate”; relevant cross references were also reviewed. Results Forty-eight documented cases of GBS LONI matched our search criteria and were retrieved from the literature. When performed, molecular typing identified clonal isolates in the neonate and milk samples taken after LONI in all cases, with the hypervirulent sequence type 17 (ST-17) clone identified in two of these cases. Caesarean delivery combined with the absence of GBS recovery from maternal samples other than milk was noted for four cases. The rate of recurrent infections was high (35%) and, together with the data reviewed, points to a potential role of breast milk in GBS LONI. Conclusions The cases reviewed here, together with the evidence of breast milk transmission for other pathogens, suggest that breast milk, which would account for repeated GBS transmission to the neonate, may favour gut translocation and subsequent LONI. Further investigations are nevertheless needed to study the relative importance of this contamination route compared with persistent postnatal gut colonisation and the dynamics of milk and neonatal gut colonisation.