Respiratory outcomes and survival after unplanned extubation in the NICU: a prospective cohort study from the SEPREVEN trial.

OBJECTIVE: To compare reintubation rates after planned extubation and unplanned extubation (UE) in patients in neonatal intensive care units (NICUs), to analyse risk factors for reintubation after UE and to compare outcomes in patients with and without UE. DESIGN: Prospective, observational study nested in a randomised controlled trial (SEPREVEN/Study on Epidemiology and PRevention of adverse EVEnts in Neonates). Outcomes were expected to be independent of the intervention tested. SETTING: 12 NICUs in France with a 20-month follow-up, starting November 2015. PATIENTS: n=2280 patients with a NICU stay >2 days, postmenstrual age ≤42 weeks on admission. INTERVENTIONS/EXPOSURE: Characteristics of UE (context, timing, sedative administration in the preceding 6 hours, weaning from ventilation at time of UE) and patients. MAIN OUTCOME MEASURES: Healthcare professional-reported UE rates, reintubation/timing after extubation, duration of mechanical ventilation, mortality and bronchopulmonary dysplasia (BPD). RESULTS: There were 162 episodes of UE (139 patients, median gestational age (IQR) 27.3 (25.6-31.7) weeks). Cumulative reintubation rates within 24 hours and 7 days of UE were, respectively, 50.0% and 57.5%, compared with 5.5% and 12.3% after a planned extubation. Independent risk factors for reintubation within 7 days included absence of weaning at the time of UE (HR, 95% CI) and sedatives in the preceding 6 hours (HR 1.93, 95% CI 1.04 to 3.60). Mortality at discharge did not differ between patients with planned extubation or UE. UE was associated with a higher risk of BPD. CONCLUSION: In the SEPREVEN trial, reintubation followed UE in 58% of the cases, compared with 12% after planned extubation. TRIAL REGISTRATION NUMBER: NCT02598609.

[Investigation of a French cohort of neonatal anoxo-ischemic encephalopathy in the era of therapeutic hypothermia: Questions and answers]. / Analyse d'une cohorte française d'encéphalopathies néonatales anoxo-ischémiques à l'ère de l'hypothermie thérapeutique : questions­réponses.

OBJECTIVE: To improve knowledge of neonatal hypoxic-ischemic encephalopathy, a prospective, nationwide, population-based cohort of affected children is being set up between September 2015 and March 2017. METHODS: During this period, 794 cases are collected, with information on pregnancy, delivery, neonatal stay and outcome at the end of hospitalization. Clinical and parental questionnaire follow-up is planned until the child is 4 years old. RESULTS: This article presents the clinical presentation of the newborns included, the analysis of factors associated with short-term outcome at hospital discharge and the organizational factors associated with treatment with therapeutic hypothermia. CONCLUSION: These data illustrate the value of a prospective cohort to analyze the management of anoxo-ischemic encephalopathy in France.

Effect of gestational age on cerebral lesions in neonatal encephalopathy.

OBJECTIVE: To determine the risk on brain lesions according to gestational age (GA) in neonates with neonatal encephalopathy. DESIGN: Secondary analysis of the prospective national French population-based cohort, Long-Term Outcome of NeonataL EncePhALopathy. SETTING: French neonatal intensive care units. PATIENTS: Neonates with moderate or severe neonatal encephalopathy (NE) born at ≥34 weeks' GA (wGA) between September 2015 and March 2017. MAIN OUTCOME MEASURES: The results of MRI performed within the first 12 days were classified in seven injured brain regions: basal ganglia and thalami, white matter (WM), cortex, posterior limb internal capsule, corpus callosum, brainstem and cerebellum. A given infant could have several brain structures affected. Risk of brain lesion according to GA was estimated by crude and adjusted ORs (aOR). RESULTS: MRI was available for 626 (78.8%) of the 794 included infants with NE. WM lesions predominated in preterm compared with term infants. Compared with 39-40 wGA neonates, those born at 34-35 wGA and 37-38 wGA had greater risk of WM lesions after adjusting for perinatal factors (aOR 4.0, 95% CI (1.5 to 10.7) and ORa 2.0, 95% CI (1.1 to 3.5), respectively). CONCLUSION: WM is the main brain structure affected in late-preterm and early-term infants with NE, with fewer WM lesions as GA increases. This finding could help clinicians to estimate prognosis and improve the understanding of the pathophysiology of NE. TRIAL REGISTRATION NUMBER: NCT02676063, ClinicalTrials.gov.

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.

Management of respiratory distress in moderate and late preterm infants: clinical trajectories in the Neobs study.

Management of respiratory distress (RD) in the extremely preterm newborn meets recommendations. Few data are available concerning the management and the clinical course of moderate and late preterms with RD. Clinical course and management among moderate (30-33 weeks (wks) of gestation) and late preterms (34-36 wks) were assessed in the Neobs study, a French neonatal observational cohort study (2018) of preterms with RD in the first 24 h of life. Clinical course was defined as stable (use of non-invasive ventilation (NIV) only), initially severe (initial use of invasive ventilation (IV)), and worsening (switch off IV after NIV support). Surfactant therapy instillation and withdrawal of all ventilator support at 72 h were recorded. Among moderate (n = 279) and late (n = 281) preterms, the clinical course was similar (p < 0.27): stable (82.1 and 86.8%), worsening (11.8% and 9.3%), and initially severe RD (6.1% and 3.9%), respectively. Surfactant was administered more frequently in the moderate versus late preterm groups (28.3% vs 16.7%; p < 0.001). The recommended surfactant dose (200 mg/kg) was administered in 53.3-83.3% of moderate and 42.1-63.2% of late preterms according to the clinical course. Withdrawal of ventilatory support at 72 h was observed in 40.0% and 70.0% of moderate and late preterms, respectively (p < 0.05), and was significantly (p < 0.001) associated with clinical course (the minus proportion among the worsening group). CONCLUSION: While the proportion of clinical course pattern is similar in moderate and late preterm infants, the management of RD varies with gestational age, with late preterm infants being managed later in life and moderate premature infants weaned from ventilation at a later stage. WHAT IS KNOWN: • There is a lack of clear guidance on the management of respiratory distress (RD) in moderate-to-late preterm infants. • Neobs was a multicentre, observational study designed to characterise the real-world management of moderate-to-late preterm infants with RD in France. WHAT IS NEW: • Secondary analyses of Neobs study data found that ventilatory support strategies were dependent on gestational age despite a similar clinical course. • At 30-33 weeks of gestation (wks), infants were more likely to receive non-invasive ventilation at delivery, while 34-36 wks infants were more likely to be managed using a wait-and-see approach.

Early factors associated with continuous positive airway pressure failure in moderate and late preterm infants.

To determine the early factors associated with continuous positive airway pressure (CPAP) failure in moderate-to-late preterm infants (32 + 0/7 to 36 + 6/7 weeks' gestation) from the NEOBS cohort study. The NEOBS study was a multi-center, prospective, observational study in 46 neonatal intensive care units in France, which included preterm and late preterm infants with early neonatal respiratory distress. This analysis included a subset of the NEOBS population who had respiratory distress and required ventilatory support with CPAP within the first 24 h of life. CPAP failure was defined as the need for tracheal intubation within 72 h of CPAP initiation. Maternal and neonatal clinical parameters in the delivery room and clinical data at 3 h of life were analyzed. CPAP failure occurred in 45/375 infants (12%), and compared with infants with CPAP success, they were mostly singletons (82.2% vs. 62.1%; p < 0.01), had a lower Apgar score at 10 min of life (9.1 ± 1.3 vs. 9.6 ± 0.8; p = 0.02), and required a higher fraction of inspired oxygen (FiO2; 34.4 ± 15.9% vs. 22.8 ± 4.1%; p < 0.0001) and a higher FiO2*positive end-expiratory pressure (PEEP) (1.8 ± 0.9 vs. 1.1 ± 0.3; p < 0.0001) at 3 h. FiO2 value of 0.23 (R2 = 0.73) and FiO2*PEEP of 1.50 (R2 = 0.75) best predicted CPAP failure. The risk of respiratory distress and early CPAP failure decreased 0.7 times per 1-week increase in gestational age and increased 1.7 times with every one-point decrease in Apgar score at 10 min and 19 times with FiO2*PEEP > 1.50 (vs. ≤ 1.50) at 3 h (R2 of the overall model = 0.83).  Conclusion: In moderate-to-late preterm infants, the combination of singleton pregnancy, lower Apgar score at 10 min, and FiO2*PEEP > 1.50 at 3 h can predict early CPAP failure with increased accuracy. What is Known: •Respiratory distress syndrome (RSD) represents an unmet medical need in moderate-to-late preterm births and is commonly treated with continuous positive airway pressure (CPAP) to reduce mortality and the need for additional ventilatory support. • Optimal management of RSD is yet to be established, with several studies suggesting that identification of predictive factors for CPAP failure can aid in the prompt treatment of infants likely to experience this failure. What is New: •Secondary analysis of the observational NEOBS study indicated that oxygen requirements during CPAP therapy, especially the product of fraction of inspired oxygen (FiO2) and positive end-expiratory pressure (PEEP), are important factors associated with early CPAP failure in moderate-to-late term preterm infants. •The combination of a singleton pregnancy, low Apgar score at 10 minutes, and high FiO2*PEEP at 3 hours can predict early CPAP failure with increased accuracy, highlighting important areas for future research into the prevention of CPAP failure.

Glycemia and Neonatal Encephalopathy: Outcomes in the LyTONEPAL (Long-Term Outcome of Neonatal Hypoxic EncePhALopathy in the Era of Neuroprotective Treatment With Hypothermia) Cohort.

OBJECTIVES: To assess in newborns with neonatal encephalopathy (NE), presumptively related to a peripartum hypoxic-ischemic event, the frequency of dysglycemia and its association with neonatal adverse outcomes. STUDY DESIGN: We conducted a secondary analysis of LyTONEPAL (Long-Term Outcome of Neonatal hypoxic EncePhALopathy in the era of neuroprotective treatment with hypothermia), a population-based cohort study including 545 patients with moderate-to-severe NE. Newborns were categorized by the glycemia values assessed by routine clinical care during the first 3 days of life: normoglycemic (all glycemia measurements ranged from 2.2 to 8.3 mmol/L), hyperglycemic (at least 1 measurement >8.3 mmol/L), hypoglycemic (at least 1 measurement <2.2 mmol/L), or with glycemic lability (measurements included at least 1 episode of hypoglycemia and 1 episode of hyperglycemia). The primary adverse outcome was a composite outcome defined by death and/or brain lesions on magnetic resonance imaging, regardless of severity or location. RESULTS: In total, 199 newborns were categorized as normoglycemic (36.5%), 74 hypoglycemic (13.6%), 213 hyperglycemic (39.1%), and 59 (10.8%) with glycemic lability, based on the 2593 glycemia measurements collected. The primary adverse outcome was observed in 77 (45.8%) normoglycemic newborns, 37 (59.7%) with hypoglycemia, 137 (67.5%) with hyperglycemia, and 40 (70.2%) with glycemic lability (P < .01). With the normoglycemic group as the reference, the aORs and 95% 95% CIs for the adverse outcome were significantly greater for the group with hyperglycemia (aOR 1.81; 95% CI 1.06-3.11). CONCLUSIONS: Dysglycemia affects nearly two-thirds of newborns with NE and is independently associated with a greater risk of mortality and/or brain lesions on magnetic resonance imaging. TRIAL REGISTRATION: NCT02676063.

Risk factors for unfavorable outcome at discharge of newborns with hypoxic-ischemic encephalopathy in the era of hypothermia.

OBJECTIVE: To re-visit short-term outcomes and associated risk factors of newborns with hypoxic-ischemic encephalopathy (HIE) in an era where hypothermia treatment (HT) is widespread. METHODS: This is a prospective population-based cohort in French neonatal intensive care units (NICU). Neonates born at or after 34 weeks of gestational age with HIE were included; main outcomes were in-hospital death and discharge with abnormal or normal MRI. Associations of early perinatal risk factors, present at birth or at admission to NICU, with these outcomes were studied. RESULTS: A total of 794 newborns were included and HT was administered to 670 (84.4%); 18.3% died and 28.5% and 53.2% survived with abnormal and normal MRI, respectively. Severe neurological status, Apgar score at 5 mn ≤5, lactate at birth ≥11 mMoles/l, and glycemia ≥100 mg/dL at admission were associated with an increased risk of death (relative risk ratios (aRRR) (95% CI) 19.93 (10.00-39.70), 2.89 (1.22-1.62), 3.06 (1.60-5.83), and 2.55 (1.38-4.71), respectively). Neurological status only was associated with survival with abnormal MRI (aRRR (95% CI) 1.76 (1.15-2.68)). CONCLUSION: Despite high use of HT in this cohort, 46.8% died or presented brain lesions. Early neurological and biological examinations were associated with unfavorable outcomes and these criteria could be used to target children who warrant further neuroprotective treatment. TRIAL REGISTRATION: Clinical trial registry, NCT02676063, ClinicalTrials.gov. IMPACT: In this population-based cohort of newborns with HIE where 84% received hypothermia, 46.8% still had an unfavorable evolution (death or survival with abnormal MRI). Risk factors for death were high lactate, low Apgar score, severe early neurological examination, and high glycaemia. While studies have established risk factors for HIE, few have focused on early perinatal factors associated with short-term prognosis. This French population-based cohort updates knowledge about early risk factors for adverse outcomes in the era of widespread cooling. In the future, criteria associated with an unfavorable evolution could be used to target children who would benefit from another neuroprotective strategy with hypothermia.

Healthcare organizational factors associated with delayed therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy: the LyTONEPAL cohort.

Initiation of therapeutic hypothermia (TH) within 6 h of life is a major concern for treating neonatal hypoxic ischemic encephalopathy (HIE). We aimed to determine clinical and healthcare organizational factors associated with delayed TH in a French population-based cohort of neonates with moderate/severe HIE. Time to reach a rectal temperature of 34 °C defines optimal and delayed (within and over 6 h, respectively) TH. Clinical and healthcare organizational factors associated with delayed TH were analysed among neonates born in cooling centres (CCs) and non-cooling centres (non-CCs). Among 629 neonates eligible for TH, 574 received treatment (91.3%). TH was delayed in 29.8% neonates and in 20.3% and 36.2% of those born in CCs and non-CCs, respectively. Neonates with moderate HIE were more exposed to delayed TH in both CCs and non-CCs. After adjustment for HIE severity, maternal and neonatal characteristics and circumstances of birth were not associated with increased risk of delayed TH. However, this risk was 2 to 5 times higher in maternities with < 1999 annual births, when the delay between birth and call for transfer (adjusted odds ratio [aOR] 2.47, 95% confidence interval [CI] [1.03 to 5.96]) or between call for transfer and admission (aOR 6.06, 95%CI [2.60 to 14.12]) was > 3 h and when an undesirable event occurred during transfer (aOR 2.66, 95%CI [1.11 to 6.37].  Conclusion: Increasing early identification of neonates who could benefit from TH and access to TH in non-CCs before transfer are modifiable factors that could improve care of neonates with HIE.  Trial registration: The trial was registered at ClinicalTrials.gov (NCT02676063). What is Known: • International recommendations are to initiate therapeutic hypothermia before 6 h of life in neonates with moderate or severe hypoxic ischemic encephalopathy. What is New: •In this French population-based cohort of infants with hypoxic ischemic encephalopathy, nearly one-third of neonates eligible for treatment did not have access to hypothermia in the therapeutic window of 6 h of life. . • Among infants born in non-cooling centres, healthcare organizational factors involved in delayed care were the small size of maternities (1999 annual births), a time interval of more than 3 h between birth and call for transfer and between call for transfer and admission in neonatology, and the occurrence of an undesirable event during transfer.

Neurodevelopment at two years and appropriate schooling at five years in children born very preterm.

AIM: This single-centre French cohort study evaluated the relationship between standardised assessment at 2 years of corrected age and schooling level at 5 years of age in children born at ≤32 weeks' gestational age. METHODS: This was a single-centre retrospective study of children born preterm between 2010 and 2014 included in a follow-up network. At 5 years of age, the population was divided into 2 groups: (1) 'appropriate schooling', defined as age-appropriate schooling without support, and (2) 'schooling with support'. At 2 years of corrected age, the developmental quotient (DQ) was calculated using the revised Brunet-Lezine test. Neonatal variables and DQ categories were compared between the 2 groups on univariate and multivariate analyses. RESULTS: DQ was available for 251 of the 270 children included (93%), with a median score of 93.0 (IQR [87.0-100.0]), and 171 children (68%) were in the schooling without support group. On multivariate analysis, DQ ≥100 (n = 67) was the only variable that significantly associated with schooling without support (OR = 13.9; 95% CI: 5.5-35.4) at 5 years of age. CONCLUSION: This result may be useful for clinicians in their routine practice and for information given to parents in neonatal follow-up.

An Updated Overview of MRI Injuries in Neonatal Encephalopathy: LyTONEPAL Cohort.

BACKGROUND: Brain magnetic resonance imaging (MRI) is a key tool for the prognostication of encephalic newborns in the context of hypoxic-ischemic events. The purpose of this study was to finely characterize brain injuries in this context. METHODS: We provided a complete, descriptive analysis of the brain MRIs of infants included in the French national, multicentric cohort LyTONEPAL. RESULTS: Among 794 eligible infants, 520 (65.5%) with MRI before 12 days of life, grade II or III encephalopathy and gestational age ≥36 weeks were included. Half of the population had a brain injury (52.4%); MRIs were acquired before 6 days of life among 247 (47.5%) newborns. The basal ganglia (BGT), white matter (WM) and cortex were the three predominant sites of injuries, affecting 33.8% (n = 171), 33.5% (n = 166) and 25.6% (n = 128) of participants, respectively. The thalamus and the periventricular WM were the predominant sublocations. The BGT, posterior limb internal capsule, brainstem and cortical injuries appeared more frequently in the early MRI group than in the late MRI group. CONCLUSION: This study described an overview of brain injuries in hypoxic-ischemic neonatal encephalopathy. The basal ganglia with the thalamus and the WM with periventricular sublocation injuries were predominant. Comprehensive identification of brain injuries in the context of HIE may provide insight into the mechanism and time of occurrence.

Implementation of a Vancomycin Dose-Optimization Protocol in Neonates: Impact on Vancomycin Exposure, Biological Parameters, and Clinical Outcomes.

Vancomycin dosing used in neonates results frequently in insufficient concentrations. A vancomycin dose-optimization protocol consisting of an individualization of loading and maintenance doses (administered during continuous infusion) through a previously validated pharmacokinetic model was implemented in our center. This monocenter retrospective study aimed to compare vancomycin average concentration (Cavg) in the therapeutic range (15 to 25 mg/L) and biological and clinical parameters before and after implementation of this protocol. A total of 60 and 59 courses of vancomycin treatment in 45 and 49 patients were analyzed in groups before and after implementation, respectively. Initial vancomycin Cavg were more frequently in the therapeutic range in the group after implementation (74.6% versus 28.3%, P < 0.001), with 1.6-fold higher Cavg (20.3 [17.0-22.2] mg/L versus 12.9 [11.3-17.0] mg/L, P < 0.001). Considering all Cavg during longitudinal therapeutic drug monitoring (TDM), the frequency of therapeutic Cavg was higher in the group after implementation (74.8% [n = 103] versus 31% [n = 116], P < 0.001). The dose optimization protocol was also associated with a reduced time to obtain a negative blood culture (P < 0.001) and fewer antibiotic switches (P = 0.025), without increasing the frequency of nephrotoxicity. Clinical outcomes also appeared to be improved, with less periventricular leukomalacia (P = 0.021), trended toward less respiratory instability (P = 0.15) and a shorter duration of vasoactive drug use (P = 0.18) for neonates receiving personalized doses of vancomycin. This personalized vancomycin dose protocol improves vancomycin exposure in neonates, with good safety, and suggests an improvement in biological and clinical outcomes.

Prevalence and risk factors of discomfort in infants with severe bronchiolitis.

AIM: The aim of this study was to assess the prevalence of discomfort in infants with severe bronchiolitis supported by noninvasive ventilation and to identify its potential risk factors. METHODS: A single-centre retrospective observational study. Discomfort was assessed using the EDIN (Echelle de Douleur et d'Inconfort du Nouveau-né) scale. RESULTS: Ninety-one infants (median age 34 days [Interquartile IQR 19-55], 52 (57%) boys) were included in our study. Overall, no patient had a mean EDIN score higher than 8 on Days 1, 2 and 3. On Days 1 and 2, patients supported by bilevel positive airway pressure (BiPAP) had a higher EDIN score compared with other patients (3.3 [SD 2.5] versus 2.6 [SD 2.2] on Day 1 and 2.9 (SD 2.1) versus 2.3 (SD 2.2) on Day 2, both p < 0.001). CONCLUSION: Patients with severe bronchiolitis and supported by any type of noninvasive ventilation had a low degree of discomfort during the first 3 days of ICU stay. Patients requiring bilevel noninvasive ventilation appeared to have a higher degree of discomfort, while we found no correlation between the level of discomfort and the degree of respiratory distress.

Patent ductus arteriosus, tracheal ventilation, and the risk of bronchopulmonary dysplasia.

BACKGROUND: An increased risk for bronchopulmonary dysplasia (BPD) exists when moderate-to-large patent ductus arteriosus shunts (hsPDA) persist beyond 14 days. GOAL: To examine the interaction between prolonged exposures to tracheal ventilation (≥10 days) and hsPDA on the incidence of BPD in infants <28 weeks gestation. STUDY DESIGN: Predefined definitions of prolonged ventilation (≥10 days), hsPDA (≥14 days), and BPD (room air challenge test at 36 weeks) were used to analyze deidentified data from the multicenter TRIOCAPI RCT in a secondary analysis of the trial. RESULTS: Among 307 infants who survived >14 days, 41 died before 36 weeks. Among survivors, 93/266 had BPD. The association between BPD and hsPDA depended on the length of intubation. In multivariable analyses, prolonged hsPDA shunts were associated with increased BPD (odds ratio (OR) (95% confidence interval (CI)) = 3.00 (1.58-5.71)) when infants required intubation for ≥10 days. In contrast, there was no significant association between hsPDA exposure and BPD when infants were intubated <10 days (OR (95% CI) = 1.49 (0.98-2.26)). A similar relationship between prolonged hsPDA and length of intubation was found for BPD/death (n = 307): infants intubated ≥10 days: OR (95% CI) = 2.41 (1.47-3.95)); infants intubated <10 days: OR (95% CI) = 1.37 (0.86-2.19)). CONCLUSIONS: Moderate-to-large PDAs were associated with increased risks of BPD and BPD/death-but only when infants required intubation ≥10 days. IMPACT: Infants with a moderate-to-large hsPDA that persist beyond 14 days are only at risk for developing BPD if they also receive prolonged tracheal ventilation for ≥10 days. Infants who receive less ventilatory support (intubation for <10 days) have the same incidence of BPD whether the ductus closes shortly after birth or whether it persists as a moderate-to-large shunt for several weeks. Early PDA closure may be unnecessary in infants who require short durations of intubation since the PDA does not seem to alter the incidence of BPD in infants who require intubation for <10 days.

Cerebral injuries in neonatal encephalopathy treated with hypothermia: French LyTONEPAL cohort.

BACKGROUND: Hypothermia is widely used for infants with hypoxic-ischemic neonatal encephalopathy but its impact remains poorly described at a population level. We aimed to describe brain imaging in infants born at ≥36 weeks' gestation, with moderate/severe encephalopathy treated with hypothermia. METHODS: Descriptive analysis of brain MRI and discharge neurological examination for infants included in the French national multicentric prospective observational cohort LyTONEPAL. RESULTS: Among 575 eligible infants, 479 (83.3%) with MRI before 12 days of life were included. MRI was normal for 48.2% (95% CI 43.7-52.8). Among infants with brain injuries, 62.5% (95% CI 56.2-68.5) had damage to more than one structure, 19.8% (95% CI 15.0-25.3) showed a pattern-associating injuries of basal ganglia/thalami (BGT), white matter (WM) and cortex. Overall, 68.4% (95% CI 62.0-74.3) of infants with normal MRI survived with a normal neurological examination. The rate of death was 15.4% (95% CI 12.3-19.0), predominantly for infants with the combined BGT, cortex, and/or WM injuries. CONCLUSIONS: Among infants with neonatal encephalopathy treated with hypothermia, two-thirds of those with normal MRI survived with a normal neurological examination at discharge. When present, brain injuries often involved more than one structure. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (NCT02676063). IMPACT: In this multicentric cohort of infants with neonatal encephalopathy (LYTONEPAL) two-thirds survived with normal MRI and neurological examination at discharge. In total, 10% of newborns showed a pattern associating injuries of the basal ganglia-thalami, white matter, and cortex, which was correlated with a high risk of death at discharge. The evolution of MRI techniques and sequences in the era of hypothermia calls for a revisiting of imaging protocol in neonatal encephalopathy, especially for the timing. The neurological examination did not give evidence of brain injuries, thus questioning the reproducibility of the clinical exam or the neonatal brain functionality.

Mortality and significant neurosensory impairment in preterm infants: an international comparison.

OBJECTIVE: To compare mortality and rates of significant neurosensory impairment (sNSI) at 18-36 months' corrected age in infants born extremely preterm across three international cohorts. DESIGN: Retrospective analysis of prospectively collected neonatal and follow-up data. SETTING: Three population-based observational cohort studies: the Australian and New Zealand Neonatal Network (ANZNN), the Canadian Neonatal and Follow-up Networks (CNN/CNFUN) and the French cohort Etude (Epidémiologique sur les Petits Ages Gestationnels: EPIPAGE-2). PATIENTS: Extremely preterm neonates of <28 weeks' gestation in year 2011. MAIN OUTCOME MEASURES: Primary outcome was composite of mortality or sNSI defined by cerebral palsy with no independent walking, disabling hearing loss and bilateral blindness. RESULTS: Overall, 3055 infants (ANZNN n=960, CNN/CNFUN n=1019, EPIPAGE-2 n=1076) were included in the study. Primary composite outcome rates were 21.3%, 20.6% and 28.4%; mortality rates were 18.7%, 17.4% and 26.3%; and rates of sNSI among survivors were 4.3%, 5.3% and 3.3% for ANZNN, CNN/CNFUN and EPIPAGE-2, respectively. Adjusted for gestational age and multiple births, EPIPAGE-2 had higher odds of composite outcome compared with ANZNN (OR 1.71, 95% CI 1.38 to 2.13) and CNN/CNFUN (OR 1.72, 95% CI 1.39 to 2.12). EPIPAGE-2 did have a trend of lower odds of sNDI but far short of compensating for the significant increase in mortality odds. These differences may be related to variations in perinatal approach and practices (and not to differences in infants' baseline characteristics). CONCLUSIONS: Composite outcome of mortality or sNSI for extremely preterm infants differed across high-income countries with similar baseline characteristics and access to healthcare.

Neurodevelopmental outcomes at age 5 among children born preterm: EPIPAGE-2 cohort study.

OBJECTIVES: To describe neurodevelopment at age 5 among children born preterm. DESIGN: Population based cohort study, EPIPAGE-2. SETTING: France, 2011. PARTICIPANTS: 4441 children aged 5½ born at 24-26, 27-31, and 32-34 weeks MAIN OUTCOME MEASURES: Severe/moderate neurodevelopmental disabilities, defined as severe/moderate cerebral palsy (Gross Motor Function Classification System (GMFCS) ≥2), or unilateral or bilateral blindness or deafness, or full scale intelligence quotient less than minus two standard deviations (Wechsler Preschool and Primary Scale of Intelligence, 4th edition). Mild neurodevelopmental disabilities, defined as mild cerebral palsy (GMFCS-1), or visual disability ≥3.2/10 and <5/10, or hearing loss <40 dB, or full scale intelligence quotient (minus two to minus one standard deviation) or developmental coordination disorders (Movement Assessment Battery for Children, 2nd edition, total score less than or equal to the fifth centile), or behavioural difficulties (strengths and difficulties questionnaire, total score greater than or equal to the 90th centile), school assistance (mainstream class with support or special school), complex developmental interventions, and parents' concerns about development. The distributions of the scores in contemporary term born children were used as reference. Results are given after multiple imputation as percentages of outcome measures with exact binomial 95% confidence intervals. RESULTS: Among 4441 participants, 3083 (69.4%) children were assessed. Rates of severe/moderate neurodevelopmental disabilities were 28% (95% confidence interval 23.4% to 32.2%), 19% (16.8% to 20.7%), and 12% (9.2% to 14.0%) and of mild disabilities were 38.5% (33.7% to 43.4%), 36% (33.4% to 38.1%), and 34% (30.2% to 37.4%) at 24-26, 27-31, and 32-34 weeks, respectively. Assistance at school was used by 27% (22.9% to 31.7%), 14% (12.1% to 15.9%), and 7% (4.4% to 9.0%) of children at 24-26, 27-31, and 32-34 weeks, respectively. About half of the children born at 24-26 weeks (52% (46.4% to 57.3%)) received at least one developmental intervention which decreased to 26% (21.8% to 29.4%) for those born at 32-34 weeks. Behaviour was the concern most commonly reported by parents. Rates of neurodevelopment disabilities increased as gestational age decreased and were higher in families with low socioeconomic status. CONCLUSIONS: In this large cohort of children born preterm, rates of severe/moderate neurodevelopmental disabilities remained high in each gestational age group. Proportions of children receiving school assistance or complex developmental interventions might have a significant impact on educational and health organisations. Parental concerns about behaviour warrant attention.

Influence of swaddling on tactile manual learning in preterm infants.

BACKGROUND AND AIM: Swaddling is a well-known technique in developmental care programs as there is some evidence that swaddling is an appropriate stress-reducing method for preterm infants in the NICU. However, no experimental study has investigated the influence of swaddling in a learning context. This study aimed to assess the impact of swaddling on tactile manual abilities in preterm infants. METHODS: Two phases were introduced for all infants: habituation (successive presentation of the same object, prism or cylinder in the left hand), followed by discrimination (presentation of a new-shaped object). The infants were assigned to one of the two conditions (swaddled; non-swaddled). RESULTS: Forty preterm infants were included (between 28 and 35 weeks' postconceptional age). First, swaddled and non-swaddled infants exhibited similar tactile habituation abilities. However, all infants needed more time and more trials to habituate to the cylinder than to the prism. Second, they all exhibited an effective discrimination, but the importance of the increase in holding time for the new-shaped object varied according to the habituated-shape and the condition. Moreover, stress intensity was higher in non-swaddled infants during tactile exploration. Finally, infants with greater previous swaddling experience during the week preceding the test took more time and more trials to habituate to the object, regardless of the condition. CONCLUSION: Swaddling preterm infants during sensory learning did not influence the tactile memorization process but would improve the use of their attentional resources. Swaddling seems to provide favorable conditions for sensory learning by improving attention to tactile stimuli. CLINICAL TRIAL REGISTRATION: This trial, EMMASENS, has been registered at www.clinicaltrials.gov (identifier NCT04315428).

Effect of Early Targeted Treatment of Ductus Arteriosus with Ibuprofen on Survival Without Cerebral Palsy at 2 Years in Infants with Extreme Prematurity: A Randomized Clinical Trial.

OBJECTIVE: To examine the effects of early echocardiography-targeted ibuprofen treatment of large patent ductus arteriosus (PDA) on survival without cerebral palsy at 24 months of corrected age. STUDY DESIGN: We enrolled infants born at <28 weeks of gestation with a large PDA on echocardiography at 6-12 hours after birth to ibuprofen or placebo by 12 hours of age in a multicenter, double blind, randomized-controlled trial. Open-label ibuprofen was allowed for prespecified criteria of a hemodynamically significant PDA. The primary outcome was survival without cerebral palsy at 24 months of corrected age. RESULTS: Among 337 enrolled infants, 109 had a small or closed ductus and constituted a reference group; 228 had a large PDA and were randomized. The primary outcome was assessed at 2 years in 108 of 114 (94.7%) and 102 of 114 (89.5%) patients allocated to ibuprofen or placebo, respectively. Survival without cerebral palsy occurred in 77 of 108 (71.3%) after ibuprofen, 73 of 102 (71.6%) after placebo (adjusted relative risk 0.98, 95% CI 0.83-1.16, P = .83), and 77 of 101 (76.2%) in reference group. Infants treated with ibuprofen had a lower incidence of PDA at day 3. Severe pulmonary hemorrhage during the first 3 days occurred in 2 of 114 (1.8%) infants treated with ibuprofen and 9 of 114 (7.9%) infants treated with placebo (adjusted relative risk 0.22, 95% CI 0.05-1.00, P = .05). Open-label rescue treatment with ibuprofen occurred in 62.3% of infants treated with placebo and 17.5% of infants treated with ibuprofen (P < .001), at a median (IQR) age of 4 (3, 5) and 4 (4, 12) days, respectively. CONCLUSIONS: Early echocardiography-targeted ibuprofen treatment of a large PDA did not change the rate of survival without cerebral palsy. TRIAL REGISTRATION: Eudract 2011-003063-30 and ClinicalTrials.gov: NCT01630278.