A population pharmacokinetic model for sertraline in women during the perinatal period-A contribution from the ConcePTION project.

AIMS: Sertraline is frequently prescribed for mental health conditions in both pregnant and breastfeeding women. According to the limited available data, only small amounts of sertraline are transferred into human milk, yet with a large amount of unexplained interindividual variability. This study aimed to develop a population pharmacokinetic (popPK) model to describe the pharmacokinetics of sertraline during the perinatal period and explain interindividual variability. METHODS: Pregnant women treated with sertraline were enrolled in the multicenter prospective cohort SSRI-Breast Milk study. A popPK model for sertraline maternal plasma and breast milk concentrations was developed and allowed estimating the milk-to-plasma ratio (MPR). An additional fetal compartment allowed cord blood concentrations to be described. Several covariates were tested for significance. Ultimately, model-based simulations allowed infant drug exposure through placenta and breast milk under various conditions to be predicted. RESULTS: Thirty-eight women treated with sertraline were included in the study and provided 89 maternal plasma, 29 cord blood and 107 breast milk samples. Sertraline clearance was reduced by 42% in CYP2C19 poor metabolizers compared to other phenotypes. Doubling milk fat content increased the MPR by 95%. Simulations suggested a median daily infant dosage of 6.9 µg kg-1 after a 50 mg maternal daily dose, representing 0.95% of the weight-adjusted maternal dose. Median cord blood concentrations could range from 3.29 to 33.23 ng mL-1 after maternal daily doses between 25 and 150 mg. CONCLUSIONS: Infant exposure to sertraline, influenced by CYP2C19 phenotype and breast milk fat content, remains low, providing reassurance regarding the use of sertraline during pregnancy and breastfeeding.

Growth charts for use at birth and in the neonatal period: Recommendations of the French Neonatal Society.

INTRODUCTION: The use of different growth charts can lead to confusion in discussions between professionals. There are obstetric charts (of fetal growth) and neonatal charts (of measurements at birth and of postnatal growth). These charts can be descriptive (derived from an unselected population) or prescriptive (derived from of a population at low risk and with optimal conditions for growth). OBJECTIVES: (1) To describe available charts for infants at birth and in the neonatal period and compare them, and (2) to recommend one or more charts for use in neonatology in France. METHODS: Bibliographic research was conducted on MEDLINE and completed by the guidelines of professional societies. RESULTS: Antenatal information about fetal growth restriction or fetuses identified as small-for-gestational-age using Intrauterine charts must be integrated into the identification of newborns at risk, but the use of Intrauterine charts to evaluate birthweight is not recommended to allow consistency with postnatal charts used in neonatal practice. Z-score variations using the updated Fenton postnatal charts are the most appropriate for the assessment of birthweight and postnatal growth for infants born preterm. These charts are sex-specific, include the three measurements (length, weight, and head circumference) and enable longitudinal follow-up of growth up to 50 weeks of corrected age and are linked to the World Health Organization charts at term. The French Audipog charts, although are individualized, accessible online and can be used in maternity units to evaluate birthweight for term infants, but do not allow the follow-up of postnatal growth, while Fenton charts may be used to evaluate birthweight and postnatal growth in the first month for hospitalized term infants. CONCLUSION: The updated Fenton charts are the neonatal charts that best suit the objectives of pediatricians in France for monitoring the growth of preterm newborns. The use of the Audipog charts at term remains an alternative in maternity wards, while Fenton charts can be used for hospitalized term newborns.

Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial.

BACKGROUND: Antenatal 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. METHODS: We 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. FINDINGS: Between 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. INTERPRETATION: Because 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. FUNDING: French Ministry of Health.

Circumstances, causes and timing of death in extremely preterm infants admitted to NICU: The EPIPAGE-2 study.

AIM: To describe the circumstances, causes and timing of death in extremely preterm infants. METHODS: We included from the EPIPAGE-2 study infants born at 24-26 weeks in 2011 admitted to neonatal intensive care units (NICU). Vital status and circumstances of death were used to define three groups of infants: alive at discharge, death with or without withholding or withdrawing life-sustaining treatment (WWLST). The main cause of death was classified as respiratory disease, necrotizing enterocolitis, infection, central nervous system (CNS) injury, other or unknown. RESULTS: Among 768 infants admitted to NICU, 224 died among which 89 died without WWLST and 135 with WWLST. The main causes of death were respiratory disease (38%), CNS injury (30%) and infection (12%). Among the infants who died with WWLST, CNS injury was the main cause of death (47%), whereas respiratory disease (56%) and infection (20%) were the main causes in case of death without WWLST. Half (51%) of all deaths occurred within the first 7 days of life, and 35% occurred within 8 and 28 days. CONCLUSION: The death of extremely preterm infants in NICU is a complex phenomenon in which the circumstances and causes of death are intertwined.

High-frequency oscillatory ventilation versus conventional ventilation in the respiratory management of term neonates with a congenital diaphragmatic hernia: a retrospective cohort study.

Conventional mechanical ventilation (CMV) has been recommended as the first-line mode of respiratory support for neonates born with a congenital diaphragmatic hernia (CDH). However, older studies suggested that protective high-frequency oscillatory ventilation (HFOV) with low-mean airway pressure (MAP) may limit lung injury. We aimed to compare low-MAP HFOV with CMV in neonates with CDH in terms of patient outcomes. This retrospective cohort study was conducted in two French neonatal intensive care units: center 1 mainly used CMV, and center 2 mainly used HFOV with a low MAP. All term neonates with CDH born between 2010 and 2018 in these two centers were included. The primary outcome was the duration of oxygen therapy. Secondary outcomes were survival and duration of mechanical ventilation. A total of 170 patients (105 in center 1, 65 in center 2) were included. In center 2, 96% of patients were ventilated with HFOV versus 19% in center 1. After adjustment for perinatal data, there was no significant difference regarding duration of oxygen therapy (SHR 0.83, 95% CI [0.55-1.23], p = 0.35) or survival (HR 1.73, 95% CI [0.64-4.64], p = 0.28). Center 2 patients required longer mechanical ventilation and sedation. CONCLUSION: First-line mode of mechanical ventilation was not associated with the duration of oxygen therapy or survival in neonates with CDH. WHAT IS KNOWN: • Recommendations were given in favour of using the conventional mechanical ventilation in first intention in neonates with a congenital diaphragmatic hernia, since High frequency oscillation (HFO) has been associated with a higher morbidity. WHAT IS NEW: • No differences between HFO and conventional mechanical ventilation were observed concerning the length of oxygen supply and the survival..

Minimum evidence-based care in intrauterine growth-restricted fetuses and neonatal prognosis.

BACKGROUND: Introduction: There is clear evidence that fetuses with intrauterine growth restriction (IUGR) do not receive the minimum evidence-based care during their antenatal management. OBJECTIVE: Considering that optimal management of IUGR may reduce neonatal morbi-mortality in IUGR, the objective of the present study was to evaluate the impact of antenatal management of IUGR according to the recommendations of the French college of gynecologists and obstetricians (CNGOF) on the neonatal prognosis of IUGR fetuses. STUDY DESIGN: From a historical cohort of 31,052 children, born at the Femme Mère Enfant hospital (Lyon, France) between January 1, 2011 and December 31, 2017, we selected the population of IUGR fetuses. The minimum evidence-based care (MEC) in the antenatal management of fetuses with IUGR was defined according to the CNGOF recommendations and neonatal prognosis of early and late IUGR fetuses were assessed based on the whether or not they received MEC. The neonatal prognosis was defined according to a composite criterion that included neonatal morbidity and mortality. RESULTS: A total of 1020 fetuses with IUGR were studied. The application of MEC showed an improvement in the neonatal prognosis of early-onset IUGR (p = 0.003), and an improvement in the neonatal prognosis of IUGR born before 32 weeks (p = 0.030). Multivariate analysis confirmed the results showing an increase in neonatal morbi-mortality in early-onset IUGR in the absence of MEC with OR 1.79 (95% CI 1.01-3.19). CONCLUSION: Diagnosed IUGR with MEC had a better neonatal prognosis when born before 32 weeks. Regardless of the birth term, MEC improved the neonatal prognosis of fetuses with early IUGR. Improvement in the rate of MEC during antenatal management has a significant impact on neonatal prognosis.

Neurodevelopmental Outcomes after Premedication with Atropine/Propofol vs Atropine/Atracurium/Sufentanil for Neonatal Intubation: 2-Year Follow-Up of a Randomized Clinical Trial.

This study followed 173 newborn infants in the PREmedication Trial for Tracheal Intubation of the NEOnate multicenter, double-blind, randomized controlled trial of atropine-propofol vs atropine-atracurium-sufentanil for premedication before nonemergency intubation. At 2 years of corrected age, there was no significant difference between the groups in death or risk of neurodevelopmental delay assessed with the Ages and Stages Questionnaire. Trial registration Clinicaltrials.gov: NCT01490580.

Persistent microbial contamination of incubators despite disinfection.

BACKGROUND: In neonatal intensive care units (NICUs), hygiene and disinfection measures are pivotal to protect neonates from nosocomial infections. This study aimed to evaluate the efficacy of the classical incubators disinfection procedure and to follow-up neonates housed in the incubators for the development of late-onset sepsis (LOS). METHODS: In a tertiary NICU, 20 incubators were monitored for bacterial contamination at three times: before disinfection, after disinfection, and 24 h after turning on and housing a new neonate. Clinical data of neonates housed in these incubators were retrieved from the medical records. RESULTS: All 20 incubators were contaminated at the 3 times of the study, mainly on mattresses and balances. Coagulase-negative Staphylococci, Enterococcus, and Bacillus-resisted disinfection while enterobacteria and Staphylococcus aureus were eradicated. After 24 h, the bacterial colonisation was similar to the one observed before disinfection. The bacteria isolated on incubators were also found on the caregivers' hands. During the study, two preterm neonates developed a LOS involving a bacterial species that has been previously isolated in their incubator. CONCLUSION: Pathogenic contaminants persist on incubators despite disinfection and represent a risk for subsequent infection in preterm neonates. Improvements are needed concerning both the disinfection process and incubator design. IMPACT: Procedures of disinfection that are usually recommended in NICUs do not allow for totally eradicating bacteria from incubators. Preterm neonates are housed in incubators colonised with potentially pathogenic bacteria. The control of nosocomial infections in NICUs requires further researches concerning mechanisms of bacterial persistence and ways to fight against environmental colonisation.

Characteristics of the delayed respiratory syncytial virus epidemic, 2020/2021, Rhône Loire, France.

The Rhône-Loire metropolitan areas' 2020/21 respiratory syncytial virus (RSV) epidemic was delayed following the implementation of non-pharmaceutical interventions (NPI), compared with previous seasons. Very severe lower respiratory tract infection incidence among infants ≤ 3 months decreased twofold, the proportion of cases among children aged > 3 months to 5 years increased, and cases among adults > 65 years were markedly reduced. NPI appeared to reduce the RSV burden among at-risk groups, and should be promoted to minimise impact of future RSV outbreaks.

Thresholds of glycemia, insulin therapy, and risk for severe retinopathy in premature infants: A cohort study.

BACKGROUND: Hyperglycemia in preterm infants may be associated with severe retinopathy of prematurity (ROP) and other morbidities. However, it is uncertain which concentration of blood glucose is associated with increased risk of tissue damage, with little consensus on the cutoff level to treat hyperglycemia. The objective of our study was to examine the association between hyperglycemia and severe ROP in premature infants. METHODS AND FINDINGS: In 2 independent, monocentric cohorts of preterm infants born at <30 weeks' gestation (Nantes University Hospital, 2006-2016, primary, and Lyon-HFME University Hospital, 2009-2017, validation), we first analyzed the association between severe (stage 3 or higher) ROP and 2 markers of glucose exposure between birth and day 21-maximum value of glycemia (MaxGly1-21) and mean of daily maximum values of glycemia (MeanMaxGly1-21)-using logistic regression models. In both the primary (n = 863 infants, mean gestational age 27.5 ± 1.4 weeks, boys 52.5%; 38 with severe ROP; 54,083 glucose measurements) and the validation cohort (n = 316 infants, mean gestational age 27.4 ± 1.4 weeks, boys 51.3%), MaxGly1-21 and MeanMaxGly1-21 were significantly associated with an increased risk of severe ROP: odds ratio (OR) 1.21 (95% CI 1.14-1.27, p < 0.001) and OR 1.70 (95% CI 1.48-1.94, p < 0.001), respectively, in the primary cohort and OR 1.17 (95% CI 1.05-1.32, p = 0.008) and OR 1.53 (95% CI 1.20-1.95, p < 0.001), respectively, in the validation cohort. These associations remained significant after adjustment for confounders in both cohorts. Second, we identified optimal cutoff values of duration of exposure above each concentration of glycemia between 7 and 13 mmol/l using receiver operating characteristic curve analyses in the primary cohort. Optimal cutoff values for predicting stage 3 or higher ROP were 9, 6, 5, 3, 2, 2, and 1 days above a glycemic threshold of 7, 8, 9, 10, 11, 12, and 13 mmol/l, respectively. Severe exposure was defined as at least 1 exposure above 1 of the optimal cutoffs. Severe ROP was significantly more common in infants with severe exposure in both the primary (10.9% versus 0.6%, p < 0.001) and validation (5.2% versus 0.9%, p = 0.030) cohorts. Finally, we analyzed the association between insulin therapy and severe ROP in a national population-based prospectively recruited cohort (EPIPAGE-2, 2011, n = 1,441, mean gestational age 27.3 ± 1.4, boys 52.5%) using propensity score weighting. Insulin use was significantly associated with severe ROP in overall cohort crude analyses (OR 2.51 [95% CI 1.13-5.58], p = 0.024). Adjustment for inverse propensity score (gestational age, sex, birth weight percentile, multiple birth, spontaneous preterm birth, main pregnancy complications, surfactant therapy, duration of oxygen exposure between birth and day 28, digestive state at day 7, caloric intake at day 7, and highest glycemia during the first week) and duration of oxygen therapy had a large but not significant effect on the association between insulin treatment and severe ROP (OR 0.40 [95% CI 0.13-1.24], p = 0.106). Limitations of this study include its observational nature and, despite the large number of patients included compared to earlier similar studies, the lack of power to analyze the association between insulin use and retinopathy. CONCLUSIONS: In this study, we observed that exposure to high glucose concentration is an independent risk factor for severe ROP, and we identified cutoff levels that are significantly associated with increased risk. The clinical impact of avoiding exceeding these thresholds to prevent ROP deserves further evaluation.

A population pharmacokinetic model for escitalopram and its major metabolite in depressive patients during the perinatal period: Prediction of infant drug exposure through breast milk.

BACKGROUND AND OBJECTIVES: Escitalopram (SCIT) is frequently prescribed to breastfeeding women. Available information on SCIT excretion into breast milk is based on heterogeneous and incomplete data. A population pharmacokinetic model that aimed to better characterize maternal and infant exposure to SCIT and its metabolite was developed. METHODS: The study population was composed of women treated by SCIT or racemic citalopram and enrolled in the multicenter prospective cohort study SSRI-Breast Milk study (ClinicalTrial.gov NCT01796132). A joint structural model was first built for SCIT and S-desmethylcitalopram (SDCIT) in plasma using NONMEM and the milk-to-plasma ratio (MPR) was estimated by adding the drug breast milk concentrations. The effect of different influential covariates was tested and the average drug exposure with variability through breastfeeding was predicted under various conditions by simulation. RESULTS: The study enrolled 33 patients treated with SCIT or racemic citalopram who provided 80 blood and 104 milk samples. Mean MPR for both parent drug and metabolite was 1.9. Increased milk fat content was significantly associated with an increased drug transfer into breast milk (+28% for SCIT and +18% for SDCIT when fat amount doubles from 3.1 to 6.2 g/100 mL). Simulations suggested that an exclusively breastfed infant would ingest daily through breast milk 3.3% of the weight-adjusted maternal SCIT dose on average. CONCLUSION: The moderate between-subject variability in milk concentration of SCIT and the limited exposure to escitalopram through breast milk observed provide reassurance for treated mothers of breastfed healthy infants.

Enterobacter cloacae colonisation and infection in a neonatal intensive care unit: retrospective investigation of preventive measures implemented after a multiclonal outbreak.

BACKGROUND: Enterobacter cloacae species is responsible for nosocomial outbreaks in vulnerable patients in neonatal intensive care units (NICU). The environment can constitute the reservoir and source of infection in NICUs. Herein we report the impact of preventive measures implemented after an Enterobacter cloacae outbreak inside a NICU. METHODS: This retrospective study was conducted in one level 3 NICU in Lyon, France, over a 6 year-period (2012-2018). After an outbreak of Enterobacter cloacae infections in hospitalized neonates in 2013, several measures were implemented including intensive biocleaning and education of medical staff. Clinical and microbiological characteristics of infected patients and evolution of colonization/infection with Enterobacter spp. in this NICU were retrieved. Moreover, whole genome sequencing was performed on 6 outbreak strains. RESULTS: Enterobacter spp. was isolated in 469 patients and 30 patients developed an infection including 2 meningitis and 12 fatal cases. Preventive measures and education of medical staff were not associated with a significant decrease in patient colonisation but led to a persistent decreased use of cephalosporin in the NICU. Infection strains were genetically diverse, supporting the hypothesis of multiple hygiene defects rather than the diffusion of a single clone. CONCLUSIONS: Grouped cases of infections inside one setting are not necessarily related to a single-clone outbreak and could reveal other environmental and organisational problematics. The fight against implementation and transmission of Enterobacter spp. in NICUs remains a major challenge.

Health-related quality of life during pregnancy: A repeated measures study of changes from the first trimester to birth.

INTRODUCTION: The objective was to evaluate the quality of life of pregnant women with a full-term birth from the first trimester to the 9th month using the EQ5D-3L questionnaire, comparing physiological, simple pathological, or complex pathological pregnancies. MATERIAL AND METHODS: A prospective cohort of 500 pregnant women over the age of 18 was monitored between 2015 and 2017 at the Toulouse University Hospital (France). The data were collected monthly with an online report. Given that the decrease in quality of life was not linear during pregnancy, unadjusted and adjusted piecewise linear regression models were performed, considering 3 periods of time during pregnancy: 3-4, 4-8, and 8-9 months. The 5 dimensions of the EQ5D-Index and perceived health status were also analyzed. RESULTS: In total, 1847 questionnaires were collected. Between the 4th and 8th months, the quality of life was lower for pathological pregnancies (P < 0.001) than for physiological ones and decreased over time for each type of pregnancy (physiological: -0.08 points per month, P < 0.001; simple pathological: -0.12 points per month, P < 0.001; complex pathological: -0.11 points per month, P < 0.001). Interestingly, the perceived health status was lower at the 9th month than at the 3rd month of pregnancy, for physiological pregnancies (mean difference = -10.5 points, P < 0.001), pathological pregnancies (mean difference = -10.0 points, P < 0.002), and for complex pathological pregnancies (mean difference = -7.8 points, P = 0.058). CONCLUSIONS: In our population, the quality of life decreased between the 4th and 8th months, and decreased to a greater degree in a pathological pregnancy.

No neurodevelopmental benefit of cerebral oximetry in the first randomised trial (SafeBoosC II) in preterm infants during the first days of life.

AIM: Cerebral hypoxia has been associated with neurodevelopmental impairment. We studied whether reducing cerebral hypoxia in extremely preterm infants during the first 72 hours of life affected neurological outcomes at two years of corrected age. METHODS: In 2012-2013, the phase II randomised Safeguarding the Brains of our smallest Children trial compared visible cerebral near-infrared spectroscopy (NIRS) monitoring in an intervention group and blinded NIRS monitoring in a control group. Cerebral hypoxia was significantly reduced in the intervention group. We followed up 115 survivors from eight European centres at two years of corrected age, by conducting a medical examination and assessing their neurodevelopment with the Bayley Scales of Infant and Toddler Development, Second or Third Edition, and the parental Ages and Stages Questionnaire (ASQ). RESULTS: There were no differences between the intervention (n = 65) and control (n = 50) groups with regard to the mean mental developmental index (89.6 ± 19.5 versus 88.4 ± 14.7, p = 0.77), ASQ score (215 ± 58 versus 213 ± 58, p = 0.88) and the number of children with moderate-to-severe neurodevelopmental impairment (10 versus six, p = 0.58). CONCLUSION: Cerebral NIRS monitoring was not associated with long-term benefits or harm with regard to neurodevelopmental outcome at two years of corrected age.

Effect of Atropine With Propofol vs Atropine With Atracurium and Sufentanil on Oxygen Desaturation in Neonates Requiring Nonemergency Intubation: A Randomized Clinical Trial.

Importance: Propofol or a combination of a synthetic opioid and muscle relaxant are both recommended for premedication before neonatal intubation but have yet to be compared. Objective: To compare prolonged desaturation during neonatal nasotracheal intubation after premedication with atropine-propofol vs atropine-atracurium-sufentanil treatment. Design, Setting, and Participants: Multicenter, double-blind, randomized clinical trial (2012-2016) in 6 NICUs in France that included 173 neonates requiring nonemergency intubation. The study was interrupted due to expired study kits and lack of funding. Interventions: Eighty-nine participants were randomly assigned to the atropine-propofol group and 82 to the atropine-atracurium-sufentanil group before nasotracheal intubation. Main Outcomes and Measures: The primary outcome was prolonged desaturation (Spo2 <80% lasting > 60 seconds), using intention-to-treat analysis using mixed models. Secondary outcomes assessed the characteristics of the procedure and its tolerance. Results: Of 173 neonates randomized (mean gestational age, 30.6 weeks; mean birth weight, 1502 g; 71 girls), 171 (99%) completed the trial. Of 89 infants, 53 (59.6%) in the atropine-propofol group vs 54 of 82 (65.9%) in the atropine-atracurium-sufentanil group achieved the primary outcome (adjusted RD, -6.4; 95% CI, -21.0 to 8.1; P = .38). The atropine-propofol group had a longer mean procedure duration than did the atropine-atracurium-sufentanil group (adjusted RD, 1.7 minutes; 95% CI, 0.1-3.3 minutes; P = .04); a less frequent excellent quality of sedation rate, 51.7% (45 of 87) vs 92.6% (75 of 81; P < .001); a shorter median time to respiratory recovery, 14 minutes (IQR, 8-34 minutes) vs 33 minutes (IQR, 15-56 minutes; P = .002), and shorter median time to limb movement recovery, 18 minutes (IQR, 10-43 minutes) vs 36 minutes (IQR, 19-65 minutes; P = .003). In the 60 minutes after inclusion, Spo2 was preserved significantly better in the atropine-propofol group (time × treatment interaction P = .02). Of the atropine-propofol group 20.6% had head ultrasound scans that showed worsening intracranial hemorrhaging (any or increased intraventricular hemorrhage) in the 7 days after randomization vs 17.6% in the atropine-atracurium-sufentanil group (adjusted RD, 1.2; 95% CI, -13.1 to 15.5, P = .87). Severe adverse events occurred in 11% of the atropine-propofol group and in 20% of the atropine-atracurium-sufentanil group. Conclusions and Relevance: Among neonates undergoing nonemergency nasotracheal intubation, the frequency of prolonged desaturation did not differ significantly between atropine used with propofol or atropine used with atracurium and sufentanil. However, the study may have been underpowered to detect a clinically important difference, and further research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01490580, EudraCT number: 2009-014885-25.

Brain injury in the international multicenter randomized SafeBoosC phase II feasibility trial: cranial ultrasound and magnetic resonance imaging assessments.

BACKGROUND: Abnormal cerebral perfusion during the first days of life in preterm infants is associated with higher grades of intraventricular hemorrhages and lower developmental score. In SafeBoosC II, we obtained a significant reduction of cerebral hypoxia by monitoring cerebral oxygenation in combination with a treatment guideline. Here, we describe (i) difference in brain injury between groups, (ii) feasibility of serial cranial ultrasound (cUS) and magnetic resonance imaging (MRI), (iii) local and central cUS assessment. METHODS: Hundred and sixty-six extremely preterm infants were included. cUS was scheduled for day 1, 4, 7, 14, and 35 and at term-equivalent age (TEA). cUS was assessed locally (unblinded) and centrally (blinded). MRI at TEA was assessed centrally (blinded). Brain injury classification: no, mild/moderate, or severe. RESULTS: Severe brain injury did not differ significantly between groups: cUS (experimental 10/80, control 18/77, P = 0.32) and MRI (5/46 vs. 3/38, P = 0.72). Kappa values for local and central readers were moderate-to-good for severe and poor-to-moderate for mild/moderate injuries. At TEA, cUS and MRI were assessed in 72 and 64%, respectively. CONCLUSION: There was no difference in severe brain injury between groups. Acquiring cUS and MRI according the standard operating procedures must be improved for future trials. Whether monitoring cerebral oxygenation during the first 72 h of life prevents brain injury should be evaluated in larger multicenter trials.

The SafeBoosC II randomized trial: treatment guided by near-infrared spectroscopy reduces cerebral hypoxia without changing early biomarkers of brain injury.

BACKGROUND: The SafeBoosC phase II multicentre randomized clinical trial investigated the benefits and harms of monitoring cerebral oxygenation by near-infrared spectroscopy (NIRS) combined with an evidence-based treatment guideline vs. no NIRS data and treatment as usual in the control group during the first 72 h of life. The trial demonstrated a significant reduction in the burden of cerebral hypoxia in the experimental group. We now report the blindly assessed and analyzed treatment effects on electroencephalographic (EEG) outcomes (burst rate and spectral edge frequency 95% (SEF95)) and blood biomarkers of brain injury (S100ß, brain fatty acid-binding protein, and neuroketal). METHODS: One hundred and sixty-six extremely preterm infants were randomized to either experimental or control group. EEG was recorded at 64 h of age and blood samples were collected at 6 and 64 h of age. RESULTS: One hundred and thirty-three EEGs were evaluated. The two groups did not differ regarding burst rates (experimental 7.2 vs. control 7.7 burst/min) or SEF95 (experimental 18.1 vs. control 18.0 Hz). The two groups did not differ regarding blood S100ß, brain fatty acid-binding protein, and neuroketal concentrations at 6 and 64 h (n = 123 participants). CONCLUSION: Treatment guided by NIRS reduced the cerebral burden of hypoxia without affecting EEG or the selected blood biomarkers.

Translating Neurodevelopmental Care Policies Into Practice: The Experience of Neonatal ICUs in France-The EPIPAGE-2 Cohort Study.

OBJECTIVES: To describe the implementation of neurodevelopmental care for newborn preterm infants in neonatal ICUs in France in 2011, analyze changes since 2004, and investigate factors associated with practice. DESIGN: Prospective national cohort study of all births before 32 weeks of gestation. SETTING: Twenty-five French regions. PARTICIPANTS: All neonatal ICUs (n = 66); neonates surviving at discharge (n = 3,005). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Neurodevelopmental care policies and practices were assessed by structured questionnaires. Proportions of neonates initiating kangaroo care during the first week of life and those whose mothers expressed breast milk were measured as neurodevelopmental care practices. Multilevel logistic regression analyses were used to investigate relationships between kangaroo care or breast-feeding practices and unit policies, taking into account potential confounders. Free visiting policies, bed availability for parents, and kangaroo care encouragement significantly improved between 2004 and 2011 but with large variabilities between units. Kangaroo care initiation varied from 39% for neonates in the most restrictive units to 68% in less restrictive ones (p < 0.001). Individual factors associated with kangaroo care initiation were gestational age (odds ratio, 5.79; 95% CI, 4.49-7.48 for babies born at 27-31 wk compared with babies born at 23-26 wk) and, to a lesser extent, single pregnancy, birthweight above the 10th centile, and mother's employment before pregnancy. At unit level, policies and training in neurodevelopmental care significantly influenced kangaroo care initiation (odds ratio, 3.5; 95% CI, 1.8-7.0 for Newborn Individualized Developmental Care and Assessment Program implementation compared with no training). Breast milk expression by mothers was greater in units with full-time availability professionals trained for breast-feeding support (60% vs 73%; p < 0.0001). CONCLUSIONS: Dissemination of neurodevelopmental practices occurred between 2004 and 2011, but large variabilities between units persist. Practices increased in units with supportive policies. Specific neurodevelopmental care training with multifaceted interventions strengthened the implementation of policies.