Screening preterm-born infants for autistic traits may help to identify social communication difficulties at five years of age.

AIM: This study compared neurodevelopmental screening questionnaires completed when preterm-born children reached 2 years of corrected age with social communication skills at 5.5 years of age. METHODS: Eligible subjects were born in 2011 at 24-34 weeks of gestation, participated in a French population-based epidemiological study and were free of motor and sensory impairment at 2 years of corrected age. The Ages and Stages Questionnaire (ASQ) and the Modified Checklist for Autism in Toddlers (M-CHAT) were used at 2 years and the Social Communication Questionnaire (SCQ) at 5.5 years of age. RESULTS: We focused on 2119 children. At 2 years of corrected age, the M-CHAT showed autistic traits in 20.7%, 18.5% and 18.2% of the children born at 24-26, 27-31 and 32-34 weeks of gestation, respectively (p = 0.7). At 5.5 years of age, 12.6%, 12.7% and 9.6% risked social communication difficulties, with an SCQ score ≥90th percentile (p = 0.2). A positive M-CHAT score at 2 years was associated with higher risks of social communication difficulties at 5.5 years of age (odds ratio 3.46, 95% confidence interval 2.04-5.86, p < 0.001). Stratifying ASQ scores produced similar results. CONCLUSION: Using parental neurodevelopmental screening questionnaires for preterm-born children helped to identify the risk of later social communication difficulties.

Consequences of General Anesthesia in Infancy on Behavior and Brain Structure.

BACKGROUND: One in 7 children will need general anesthesia (GA) before the age of 3. Brain toxicity of anesthetics is controversial. Our objective was to clarify whether exposure of GA to the developing brain could lead to lasting behavioral and structural brain changes. METHODS: A first study was performed in mice. The behaviors (fear conditioning, Y-maze, and actimetry) and brain anatomy (high-resolution magnetic resonance imaging) of 6- to 8-week-old Swiss mice exposed or not exposed to GA from 4 to 10 days old were evaluated. A second study was a complementary analysis from the preexisting APprentissages EXécutifs et cerveau chez les enfants d'âge scolaire (APEX) cohort to assess the replicability of our data in humans. The behaviors (behavior rating inventory of executive function, emotional control, and working memory score, Backward Digit Span, and Raven 36) and brain anatomy (high-resolution magnetic resonance imaging) were compared in 102 children 9 to 10 years of age exposed or not exposed to a single GA (surgery) during infancy. RESULTS: The animal study revealed chronic exacerbated fear behavior in the adult mice (95% confidence interval [CI], 4-80; P = .03) exposed to postnatal GA; this was associated with an 11% (95% CI, 7.5-14.5) reduction of the periaqueductal gray matter (P = .046). The study in humans suggested lower emotional control (95% CI, 0.33-9.10; P = .06) and a 6.1% (95% CI, 4.3-7.8) reduction in the posterior part of the right inferior frontal gyrus (P = .019) in the children who had been exposed to a single GA procedure. CONCLUSIONS: The preclinical and clinical findings of these independent studies suggest lasting effects of early life exposure to anesthetics on later emotional control behaviors and brain structures.

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.

Neurobehavioral Phenotype and Dysexecutive Syndrome of Preterm Children: Comorbidity or Trigger? An Update.

Premature birth is a worldwide public health priority. One in ten children is born before 37 weeks of gestational age and, in developed countries, survival rates without major neonatal morbidity are increasing. Although severe sequelae associated with these births have decreased, their neurobehavioral difficulties, often associated in multiple fields, remain stable but still widespread. These neurobehavioral difficulties hamper the normal development of academic achievements and societal integration and intensify the children's needs for rehabilitation during their preschool and academic years. Severe sequelae increase when gestational age decreases. This is even truer if the socio-cultural background is impeded by low income, education and language skills as compared with defined averages. However, moderate and/or minor neurocognitive and/or behavioral difficulties are almost identical for a moderate or a late preterm birth. Obtaining a better clinical description of neurobehavioral characteristics of those pretermly born, once they reach preschool age, is essential to detect behavioral issues as well as early specific cognitive difficulties (working memory, planning, inhibition, language expression and reception, attention and fine motor skills, etc.). Such information would provide a better understanding of the executive functions' role in brain connectivity, neurodevelopment and neuroanatomical correlation with premature encephalopathy.

The forest, the trees, and the leaves in preterm children: the impact of prematurity on a visual search task containing three-level hierarchical stimuli.

Very preterm (VPT; < 33 gestational weeks) children are at risk of developing visuospatial deficits, including local/global attention deficits. They are also more likely to develop poorer inhibitory control. Here, we investigated, using the same stimuli, the potential local/global attention and inhibitory control deficits of VPT children using three levels compound stimuli (global, intermediate, and local levels), more ecological than the ones used in a classic global/local task (Navon task). We compared the results from 22 VPT children to those of a control group of 21 children to investigate (1) how VPT children processed compound stimuli with three-level information and (2) how inhibitory control in a visual task differs between VPT and control children. The results revealed that VPT children had no difficulty processing information presented at the local level. By contrast, VPT children were impaired when considering the intermediate and global levels of processing in comparison to control children. Finally, a reduced efficiency in VPT children in inhibiting visual distractors was evidenced for the conditions with a larger number of distractors. These results are discussed in terms of neurodevelopmental disorders of both dorsal stream (global visual processing) and prefrontal regions (inhibitory control) in VPT children. Given the central role of visuospatial and inhibitory control in day-to-day situations, the present results provide important clues for pedagogical implications regarding the organization of visual information presented to VPT children.

Complex and subtle structural changes in prefrontal cortex induced by inhibitory control training from childhood to adolescence.

A number of training interventions have been designed to improve executive functions and inhibitory control (IC) across the lifespan. Surprisingly, no study has investigated the structural neuroplasticity induced by IC training from childhood to late adolescence, a developmental period characterized by IC efficiency improvement and protracted maturation of prefrontal cortex (PFC) subregions involved in IC. The aim of the present study was to investigate the behavioral and structural changes induced by a 5-week computerized and adaptive IC training in school-aged children (10-year-olds) and in adolescents (16-year-olds). Sixty-four children and 59 adolescents were randomly assigned to an IC (i.e. Color-Word Stroop and Stop-Signal tasks) or an active control (AC) (knowledge- and vocabulary-based tasks) training group. In the pre- and posttraining sessions, participants performed the Color-Word Stroop and Stop-signal tasks, and an anatomical resonance imaging (MRI) was acquired for each of them. Children's IC efficiency improved from the pre- to the posttraining session in boys but not in girls. In adolescents, IC efficiency did not improve after IC training. Similar to the neuroplastic mechanisms observed during brain maturation, we observed IC training-related changes in cortical thickness and cortical surface area in several PFC subregions (e.g. the pars opercularis, triangularis, and orbitalis of the inferior frontal gyri) that were age- and gender-specific. Because no correction for multiple comparisons was applied, the results of our study provide only preliminary evidence of the complex structural neuroplastic mechanisms at the root of behavioral changes in IC efficiency from pre- to posttraining in school-aged children and adolescents.

Perceived maternal information on premature infant's pain during hospitalization: the French EPIPAGE-2 national cohort study.

BACKGROUND: Parents of preterm neonates wish greater involvement in pain management; little is known about factors associated with this involvement. We aim to describe perceived maternal information on infants' pain during hospitalization (PMIP), to study associations between PMIP and mothers' attitudes during painful procedures, and to identify individual and contextual factors associated with PMIP. METHODS: Analyses of questionnaires from the French national cohort study of preterm neonates, EPIPAGE-2. PMIP was derived from mothers' answers to questions about information perceived on both pain assessment and management. RESULTS: Among 3056 eligible neonates born before 32 weeks, 1974, with available maternal reports, were included in the study. PMIP was classified as "sufficient," "little, not sufficient," or "insufficient, or none" for 22.7, 45.9, and 31.3% of neonates, respectively. Mothers reporting PMIP as "sufficient" were more frequently present and more likely comforting their child during painful procedures. Factors independently associated with "sufficient" PMIP were high maternal education, gestational age <29 weeks, daily maternal visits, perception of high team support, and implementation of the neonatal and individualized developmental care and assessment program. CONCLUSION: Perceived maternal information on premature infants' pain reported as sufficient increased maternal involvement during painful procedures and was associated with some units' policies.

Association of Language Skills with Other Developmental Domains in Extremely, Very, and Moderately Preterm Children: EPIPAGE 2 Cohort Study.

OBJECTIVE: To analyze language skills in children born at 24-34 weeks of gestation at 2 years of corrected age and the association between language and other developmental domains. STUDY DESIGN: We included 2424 children (64% of the eligible population) from the French population-based EPIPAGE 2 cohort study. At 2 years' corrected age, children were screened with the French short version of the MacArthur-Bates Communication Developmental Inventories and the Ages and Stages Questionnaire completed by parents. RESULTS: Small lexicon size, <10th percentile of the calibration sample (ie, 28 words in a list of 100) was observed in 135 of 300 children (45%) born at 23-26 weeks, 484 of 1513 (32%) born at 27-31 weeks, and 165 of 611 (27%) born at 32-34 weeks of gestation. Small lexicon size was associated with 2 other language measures: word combination use and the Ages and Stages Questionnaire communication domain score. It was also significantly associated with the Ages and Stages Questionnaire score below the threshold in the other developmental domains (gross motor function, fine motor function, problem solving skills, and personal social skills) for all gestational age groups, after adjustment for potential confounders. Overall, 46% of children with a small lexicon size had ≥1 of these domains below the threshold, as compared with only 22% of children without a small lexicon size. CONCLUSIONS: These results highlight the usefulness of the MacArthur-Bates Communication Developmental Inventories in preterm children, especially those who do not participate in specialized follow-up. A small lexicon size points to developmental difficulties in language and increased risk for other developmental and neurobehavioral functions.

One-Year Outcome for Congenital Diaphragmatic Hernia: Results From the French National Register.

OBJECTIVE: To evaluate the status of congenital diaphragmatic hernia (CDH) management in France and to assess predictors of adverse outcomes. STUDY DESIGN: We reviewed the first-year outcome of all cases of CDH reported to the French National Register in 2011. RESULTS: A total of 158 cases were included. Of these, 83% (131) were prenatally diagnosed, with a mortality rate of 39% (44 of 112) for live born infants with a known outcome at hospital discharge. Mortality increased to 47% (60 of 128) including those with termination of pregnancy and fetal loss. This contrasts with the 7% (2 of 27) mortality rate of the patients diagnosed postnatally (P = .002). Mortality worsened with 1 prenatal marker of CDH severity (OR 3.38 [1.30-8.83] P = .013) and worsened further with 2 markers (OR 20.64 [5.29-80.62] P < .001). Classic postnatal risk factors of mortality such as side of hernia (nonleft P = .001), prematurity (P < .001), low birth weight (P = .002), and size of the defect (P < .001) were confirmed. Of the 141 live births (114 prenatal and 27 postnatal diagnosis) with known outcomes, 93 (67%) survived to hospital discharge, 68 (60%) with a prenatal diagnosis and 25 (93%) with a postnatal diagnosis. The median time to hospital discharge was 34 days (IQR, 19.25-62). Of these survivors, 71 (76%) were followed up for 1 year. CONCLUSIONS: Despite advances in management of CDH, mortality was high and associated with prenatal risk factors. Postnatally, severe persistent pulmonary hypertension was difficult to predict and presented persistent challenges in management.

Experience in the management of eighty-two newborns with congenital diaphragmatic hernia treated with high-frequency oscillatory ventilation and delayed surgery without the use of extracorporeal membrane oxygenation.

The aim of this study is to analyze neonatal outcome of isolated congenital diaphragmatic hernia and to identify prenatal and postnatal prognosis-related factors. A retrospective single institution series from January 2000 to November 2005 of isolated congenital diaphragmatic hernia neonates was reviewed. Respiratory-care strategy was early high-frequency oscillatory ventilation, nitric oxide in pulmonary hypertension, and delayed surgery after respiratory and hemodynamic stabilization. Survival rate at 1 month was 65.9%. None of the prenatal factors were predictive of neonatal outcome, except an intra-abdominal stomach in left diaphragmatic hernia. Preoperative pulmonary hypertension was more severe in the nonsurvivor group and was predictive of length of ventilation in the survivors. During the first 48 hours of life, the best oxygenation index above 13 and the best PaCO2 above 45 were predictive of poor outcome. When treating isolated congenital diaphragmatic hernia with early high-frequency ventilation and delayed surgery but excluding extracorporeal membrane oxygenation, survival rates compare favorably with other reported series, and the respiratory morbidity is low.

Prenatal prognosis in isolated congenital diaphragmatic hernia.

OBJECTIVE: A monocentric retrospective study of 79 neonates with isolated diaphragmatic hernia antenatally diagnosed was performed to identify prenatal parameters that may characterize the severity of the disease. STUDY DESIGN: Postnatal treatment protocol included early high frequency ventilation, inhaled nitric oxide, and delayed surgery. Postnatal survival rate was 63.3%. RESULTS: Age at diagnosis, polyhydramnios, and left ventricle/right ventricle index were not related with survival. None of the 9 left diaphragmatic hernias with intraabdominal stomach died. Neonatal mortality was significantly related with the side of the defect, intrathoracic position of the liver, the ratio of fetal lung area to head circumference value, and fetal lung volume ratio measured by resonance magnetic imaging. CONCLUSION: No prenatal factor alone firmly predicts neonatal outcome. Clinicians should help stratify the severity of the disease and compare accurately different postnatal therapeutic strategies.