Association between gut microbiota at 3.5 years of age and body mass index at 5 years: results from two French nationwide birth cohorts.

BACKGROUND/OBJECTIVES: The relationship between gut microbiota and changes in body mass index (BMI) or pediatric overweight in early life remains unclear, and information regarding the preterm population is scarce. This study aimed to investigate how the gut microbiota at 3.5 years of age is associated with (1) later BMI at 5 years, and (2) BMI z-score variations between 2 and 5 years in children from two French nationwide birth cohorts. SUBJECTS/METHODS: Bacterial 16S rRNA gene sequencing was performed to profile the gut microbiota at 3.5 years of age in preterm children (n = 143, EPIPAGE 2 cohort) and late preterm/full-term children (n = 369, ELFE cohort). The predicted abundances of metabolic functions were computed using PICRUSt2. Anthropometric measurements were collected at 2 and 5 years of age during medical examinations or retrieved from children's health records. Statistical analyses included multivariable linear and logistic regressions, random forest variable selection, and MiRKAT. RESULTS: The Firmicutes to Bacteroidetes (F/B) ratio at 3.5 years was positively associated with the BMI z-score at 5 years. Several genera were positively ([Eubacterium] hallii group, Fusicatenibacter, and [Eubacterium] ventriosum group) or negatively (Eggerthella, Colidextribacter, and Ruminococcaceae CAG-352) associated with the BMI z-scores at 5 years. Some genera were also associated with variations in the BMI z-scores between 2 and 5 years of age. Predicted metabolic functions, including steroid hormone biosynthesis, biotin metabolism, glycosaminoglycan degradation, and amino sugar and nucleotide sugar metabolism, were associated with lower BMI z-scores at 5 years. The unsaturated fatty acids biosynthesis pathway was associated with higher BMI z-scores. CONCLUSIONS: These findings indicate that the gut microbiota at 3.5 years is associated with later BMI during childhood, independent of preterm or term birth, suggesting that changes in the gut microbiota that may predispose to adult obesity begin in early childhood.

Clinical Chorioamnionitis and Neurodevelopment at 5 Years of Age in Children Born Preterm: The EPIPAGE-2 Cohort Study.

OBJECTIVE: To assess the association between clinical chorioamnionitis and neurodevelopmental disorders at 5 years of age in children born preterm. STUDY DESIGN: EPIPAGE 2 is a national, population-based cohort study of children born before 35 weeks of gestation in France in 2011. We included infants born alive between 240/7 and 346/7 weeks after preterm labor or preterm premature rupture of membranes. Clinical chorioamnionitis was defined as maternal fever before labor (>37.8°C) with ≥2 of the following criteria: maternal tachycardia, hyperleukocytosis, uterine contractions, purulent amniotic fluid, or fetal tachycardia. The primary outcome was a composite, including cerebral palsy, coordination disorders, cognitive disorders, sensory disorders, or behavioral disorders. We also analyzed each of these disorders separately as secondary outcomes. We performed a multivariable analysis using logistic regression models. We accounted for the nonindependence of twins and missing data by generalized estimating equation models and multiple imputations, respectively. RESULTS: Among 2927 children alive at 5 years of age, 124 (3%) were born in a context of clinical chorioamnionitis. Overall, 8.2% and 9.6% of children exposed and unexposed, respectively, to clinical chorioamnionitis had moderate-to-severe neurodevelopmental disorders. After multiple imputations and multivariable analysis, clinical chorioamnionitis was not associated with the occurrence of moderate-to-severe neurodevelopmental disorders (aOR, 0.9; 95% CI, 0.5-1.8). CONCLUSIONS: We did not find any association between clinical chorioamnionitis and neurodevelopmental disorders at 5 years of age in children born at <35 weeks of gestation after preterm labor or preterm premature rupture of membrane.

Long-term health in individuals born preterm or with low birth weight: A cohort study.

BACKGROUND: To measure the association of prematurity and non-preterm low birth weight (LBW) with several long-term health outcomes. METHODS: We selected adult participants from the Constances cohort. Associations between preterm birth (<37 weeks versus ≥37 weeks) and outcomes were measured using modified Poisson regression with adjustment for participant age and parental history. We used the same modeling methods to measure the association between LBW (i.e.,

Five-year outcomes for extremely preterm babies with active perinatal management: A clinical prediction model.

OBJECTIVE: To develop and validate a clinical prediction model for outcomes at 5 years of age for children born extremely preterm and receiving active perinatal management. DESIGN: The EPIPAGE-2 national prospective cohort. SETTING: France, 2011. POPULATION: Live-born neonates between 24+0 and 26+6 weeks of gestation who received active perinatal management (i.e. birth in a tertiary-level hospital, with antenatal steroids and resuscitation at birth). METHODS: A prediction model using logistic modelling, including gestational age, small-for gestational-age (SGA) status and sex, was developed. Model performance was assessed through calibration and discrimination, with bootstrap internal validation. MAIN OUTCOME MEASURES: Survival without moderate or severe neurodevelopmental disability (NDD) at 5 years. RESULTS: Among the 557 neonates included, 401 (72%) survived to 5 years, of which 59% survived without NDD (95% CI 54% to 63%). Predicted rates of survival without NDD ranged from 45% (95% CI 33% to 57%), to 56% (95% CI 49% to 64%) to 64% (95% CI 57% to 70%) for neonates born at 24, 25 and 26 weeks of gestation, respectively. Predicted rates of survival without NDD were 47% (95% CI 18% to 76%) and 62% (95% CI 49% to 76%) for SGA and non-SGA children, respectively. The model showed good calibration (calibration slope 0.85, 95% CI 0.54 to 1.16; calibration-in-the-large -0.0123, 95% CI -0.25 to 0.23) and modest discrimination (C-index 0.59, 95% CI 0.53 to 0.65). CONCLUSIONS: A simple prediction model using three factors easily known antenatally may help doctors and families in their decision-making for extremely preterm neonates receiving active perinatal management.

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

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

Gestational age, maternal smoking, neurological lesion and retinopathy predict strabismus at age 5.5 in preterm children.

AIM: Prematurity is a risk factor for strabismus, but the roles of intermediate factors like retinopathy of prematurity (ROP) and neurological lesions are less understood. We aimed to identify neonatal risk factors for strabismus at age 5.5 in preterm children. METHODS: Data were extracted from the étude épidémiologique sur les petits âges gestationnels 2 cohort, a French prospective population-based study of preterm children born in 2011 with gestational age of 34 weeks or less. Strabismus was recorded during a medical interview at 5.5 years. Using a directed acyclic graph, intermediate and confounding factors were identified. Total and direct effects of gestational age on strabismus risk were analysed using generalised estimating equation. RESULTS: Among 2419 children assessed, 274 (52.6% male) presented strabismus at 5.5 years. The direct effect of gestational age remained significant after adjustment (p < 0.001). In the complete imputed model: maternal smoking during pregnancy (odds ratio, OR 1.8; 95% confident interval, 95% CI 1.3-2.6), neonatal severe cerebral lesions (OR 2.9, 95% CI 1.8-4.6) and severe ROP (OR 4.2, 95% CI 1.9-9.0) were independent risk factors. CONCLUSION: Special attention is needed regarding strabismus screening at age 5.5 in preterm children, even without severe cerebral lesions and ROP. Smoking cessation during pregnancy should be encouraged.

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.

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.

Timing of antenatal corticosteroids and survival without neurologic disabilities at 5½ years in children born before 35 weeks of gestation.

BACKGROUND: The efficacy of antenatal corticosteroids for neonatal preterm complications wanes beyond 7 days after treatment. The neurodevelopmental effects of longer treatment-to-birth intervals have not been adequately evaluated. OBJECTIVE: This study aimed to assess the impact of antenatal corticosteroid timing on survival without moderate or severe neurologic disabilities at 5½ years. STUDY DESIGN: This was a secondary analysis of the EPIPAGE-2 study, a national population-based cohort (France) that recruited neonates in 2011 and followed them up at 5½ years (results first reported in 2021). Participants were children born alive between 24+0 and 34+6 weeks, with a complete corticosteroid course, delivery >48 hours after the first injection, and neither limitation of care decided before birth nor severe congenital malformation. The study included 2613 children, 2427 of whom were alive at 5½ years; 71.9% (1739/2427) had a neurologic assessment at this age; 1537 had a clinical examination (complete for 1532), and 202 were assessed with a postal questionnaire. Exposure was defined as the interval between the first injection of the last antenatal corticosteroid course and delivery in days, studied in 2 categories (days 3-7 and after day 7), in 4 categories (days 3-7, 8-14, 15-21, and after day 21), and continuously in days. The main outcome was survival at 5½ years without moderate/severe neurologic disabilities, defined as moderate/severe cerebral palsy, or unilateral or bilateral blindness or deafness, or Full-Scale Intelligence Quotient 2 standard deviations below the mean. A multivariate analysis with a generalized estimated equation logistic regression model assessed the statistical association between the main outcomes and the interval from the first corticosteroid injection of the last course to birth. Multivariate analyses were adjusted for potential confounders, defined with a directed acyclic graph: gestational age in days, number of corticosteroid courses, multiple pregnancy, and cause of prematurity in 5 categories. Because neurologic follow-up was complete in only 63.2% of cases (1532/2427), the analyses used imputed data. RESULTS: Among 2613 children, 186 died between birth and 5½ years. Overall survival was 96.6% (95% confidence interval, 95.9-97.0), and survival without moderate or severe neurologic disabilities was 86.0% (95% confidence interval, 84.7-87.0). Survival without moderate or severe neurologic disabilities was lower after day 7 (85.0%) than during the interval from day 3 to day 7 (87.0%) (adjusted odds ratio, 0.70; 95% confidence interval, 0.54-0.89). CONCLUSION: The association of a >7-day interval between antenatal corticosteroid administration and birth with a lower rate of survival without moderate or severe neurologic disabilities among children aged 5½ years emphasizes the importance of better targeting women at risk of preterm delivery to optimize the timing and thus benefits of treatment.

Tocolysis after preterm prelabor rupture of membranes and 5-year outcomes: a population-based cohort study.

BACKGROUND: The administration of tocolytics after preterm prelabor rupture of membranes remains a controversial practice. In theory, reducing uterine contractility should delay delivery and allow for optimal antenatal management, thereby reducing the risks for prematurity and adverse consequences over the life course. However, tocolysis may be associated with neonatal death or long-term adverse neurodevelopmental outcomes, mainly related to prolonged fetal exposure to intrauterine infection or inflammation. In a previous study, we showed that tocolysis administration was not associated with short-term benefits. There are currently no data available to evaluate the impact of tocolysis on neurodevelopmental outcomes in school-aged children born prematurely in this clinical setting. OBJECTIVE: This study aimed to investigate whether tocolysis administered after preterm prelabor rupture of membranes is associated with neurodevelopmental outcomes at 5.5 years of age. STUDY DESIGN: We used data from a prospective, population-based cohort study of preterm births recruited in 2011 (referred to as the EPIPAGE-2 study) and for whom the results of a comprehensive medical and neurodevelopmental assessment of the infant at age 5.5 years were available. We included pregnant individuals with preterm prelabor rupture of membranes at 24 to 32 weeks' gestation in singleton pregnancies with a live fetus at the time of rupture, birth at 24 to 34 weeks' gestation, and participation of the infant in an assessment at 5.5 years of age. Exposure was the administration of any tocolytic treatment after preterm prelabor rupture of membranes. The main outcome was survival without moderate to severe neurodevelopmental disabilities at 5.5 years of age. Secondary outcomes included survival without any neurodevelopmental disabilities, cerebral palsy, full-scale intelligence quotient, developmental coordination disorders, and behavioral difficulties. A propensity-score analysis was used to minimize the indication bias in the estimation of the treatment effect on outcomes. RESULTS: Overall, 596 of 803 pregnant individuals (73.4%) received tocolytics after preterm prelabor rupture of membranes. At the 5.5-year follow-up, 82.7% and 82.5% of the children in the tocolysis and no tocolysis groups, respectively, were alive without moderate to severe neurodevelopmental disabilities; 52.7% and 51.1%, respectively, were alive without any neurodevelopmental disabilities. After applying multiple imputations and inverse probability of treatment weighting, we found no association between the exposure to tocolytics and survival without moderate to severe neurodevelopmental disabilities (odds ratio, 0.93; 95% confidence interval, 0.55-1.60), survival without any neurodevelopmental disabilities (odds ratio, 1.02; 95% confidence interval, 0.65-1.61), or any of the other outcomes. CONCLUSION: There was no difference in the neurodevelopmental outcomes at age 5.5 years among children with and without antenatal exposure to tocolysis after preterm prelabor rupture of membranes. To date, the health benefits of tocolytics remain unproven, both in the short- and long-term.

Early skin-to-skin contact and risk of late-onset-sepsis in very and extremely preterm infants.

BACKGROUND: To evaluate the association between exposure to early skin-to-skin contact (SSC) and incidence of late-onset sepsis (LOS) in extremely and very preterm infants. METHODS: Observational study using the national population-based EPIPAGE-2 cohort in 2011. A propensity score for SSC exposure was used to match infants with and without exposure to SSC before day 4 of life and binomial log regression used to estimate risk ratios and CIs in the matched cohort. The primary outcome was at least one episode of LOS during hospitalization. Secondary outcomes were the occurrence of any late-onset neonatal infection (LONI), LOS with Staphylococcus or Staphylococcus aureus, incidence of LOS and LONI per 1000 central venous catheter days. RESULTS: Among the 3422 included infants, 919 were exposed to early SSC. The risk ratio (RR) for LOS was 0.86 (95% CI, 0.67-1.10), for LONI was 1.00 (95% CI, 0.83-1.21), and for LOS with Coagulase-negative Staphylococcus or Staphylococcus aureus infection was 0.91 (95% CI, 0.68-1.21) and 0.77 (95% CI, 0.31-1.87). The incidence RR for LOS per-catheter day was 0.87 (95% CI, 0.64-1.18). CONCLUSION: Early SSC exposure was not associated with LOS or LONI risk. Thus, their prevention should not be a barrier to a wider use of SSC. IMPACT: Kangaroo Mother Care decreased neonatal infection rates in middle-income countries. Skin-to-skin contact is beneficial for vulnerable preterm infants but barriers exist to its implementation. In a large population-based study using a propensity score methods, we found that skin-to-skin contact before day 4 of life was not associated with a decreased risk of late-onset-sepsis in very and extremely preterm infants. Early skin-to-skin contact was not associated with an increased risk of any late-onset-neonatal-infection, in particular with staphylococcus. The fear of neonatal infection should not be a barrier to a wider use of early skin-to-skin contact in this population.

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.

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.

Longitudinal impact of psychosocial status on children's mental health in the context of COVID-19 pandemic restrictions.

Emerging research suggests that the prevalence of child and adolescent mental health problems has increased considerably during the COVID-19 crisis. However, there have been few longitudinal studies on children's mental health issues according to their social determinants in this context, especially in Europe. Our aim was to investigate the association between family socioeconomic status (SES) and children' mental health during the period of school closure due to COVID-19. Longitudinal data came from 4575 children aged 8-9 years old in 2020 and participating in the ELFE population-based birth cohort that focuses on children's health, development and socialization. Parents completed the Strengths and Difficulties Questionnaire (SDQ) when children were (a) 5 years of age and (b) 9 years of age, which corresponded to the period of school closure due to the COVID-19 pandemic in France. We retrieved data from the ELFE cohort collected on children from birth to age 5 years (birth, 1 year, 2 years, 3,5 years and 5 years). Socioeconomic status (SES) was measured based on information obtained when the child was 5 years old. Data were analyzed using multinomial logistic regression models. Children's elevated levels of symptoms of Attention-deficit/Hyperactivity disorder (ADHD) during the period of school closure were significantly associated with prior low family SES (aOR 1.26, 95% CI 1.08-1.48). Children's elevated symptoms of hyperactivity/inattention and of emotional symptoms were associated with decline in income during the COVID crisis (respectively, aOR 1.38, 95% CI 1.16-1.63 and aOR 1.23, 95% CI 1.01-1.51). Moreover, when testing interactions, a low prior SES was significantly associated with a higher risk of emotional symptoms aOR 1.54 (1.07-2.21), only for children whose families experienced a decline in income, while gender, parental separation and prior mental health difficulties were not associated. This study underlines the impact of the financial crisis related to the COVID-19 epidemic on children's mental health. Both pre-existing family SES before lockdown and more proximal financial difficulties during the COVID crisis were negatively associated with children's psychological difficulties during the period of school closure. The pandemic appears to exacerbate mental health problems in deprived children whose families suffer from financial difficulties.

Early Antibiotic Exposure and Adverse Outcomes in Very Preterm Infants at Low Risk of Early-Onset Sepsis: The EPIPAGE-2 Cohort Study.

OBJECTIVE: To assess the association between early empirical antibiotics and neonatal adverse outcomes in very preterm infants without risk factors for early-onset sepsis (EOS). STUDY DESIGN: This is a secondary analysis of the EPIPAGE-2 study, a prospective national population-based cohort that included all liveborn infants at 22-31 completed weeks of gestation in France in 2011. Infants at high risk of EOS (ie, born after preterm labor or preterm premature rupture of membranes or from a mother who had clinical chorioamnionitis or had received antibiotics during the last 72 hours) were excluded. Early antibiotic exposure was defined as antibiotic therapy started at day 0 or day 1 of life, irrespective of the duration and type of antibiotics. We compared treated and untreated patients using inverse probability of treatment weighting based on estimated propensity scores. RESULTS: Among 648 very preterm infants at low risk of EOS, 173 (26.2%) had received early antibiotic treatment. Early antibiotic exposure was not associated with death or late-onset sepsis or necrotizing enterocolitis (OR, 1.04; 95% CI, 0.72-1.50); however, it was associated with higher odds of severe cerebral lesions (OR, 2.71; 95% CI, 1.25-5.86) and moderate-severe bronchopulmonary dysplasia (BPD) (OR, 2.30; 95% CI, 1.21-4.38). CONCLUSIONS: Early empirical antibiotic therapy administrated in very preterm infants at low risk of EOS was associated with a higher risk of severe cerebral lesions and moderate-severe BPD.

Neurodevelopment at 5 years of age for preterm-born children according to mode of conception: a cohort study.

BACKGROUND: Preterm delivery is a risk factor for suboptimal neurodevelopment. Pregnancies conceived after medically assisted reproduction-which includes in vitro fertilization, with or without intracytoplasmic insemination, and induction of ovulation followed by intrauterine insemination or timed intercourse-have a higher risk of preterm delivery. Few studies have evaluated the outcome at >2 years of age of such preterm-born children. OBJECTIVE: To evaluate neurodevelopmental outcome at 5½ years of age of children born preterm according to the mode of conception (spontaneous vs medically assisted reproduction). STUDY DESIGN: A total of 4349 children born between 24 and 34 weeks of gestation who survived to 5½ years of age in the 2011 French prospective national cohort study "EPIPAGE-2" were included: 814 in the medically assisted reproduction group (433 by in vitro fertilization, with or without intracytoplasmic insemination, and 381 by induction of ovulation) and 3535 in the spontaneously conceived group. The studied neurodevelopmental outcomes were sensory (hearing and vision) impairments, cerebral palsy, cognition, and developmental coordination disorders. Multivariate analyses were performed with generalized estimating equation models adjusted for gestational age, antenatal steroids, and social characteristics. All analyses were performed following multiple imputation. Sensitivity analyses were performed with the populations of singletons and cases with complete data. RESULTS: No differences in cerebral palsy (adjusted odds ratio, 1.00; 95% confidence interval, 0.67-1.49), neurodevelopmental impairment (adjusted odds ratio, 1.09; 95% confidence interval, 0.82-1.45), or developmental coordination disorders (adjusted odds ratio, 0.75; 95% confidence interval, 0.50-1.12) were found between children born following medically assisted reproduction and children born following spontaneous conception after adjustment for sociodemographic factors. For proportions of children with an intelligence quotient below 1 and 2 standard deviations, there were no differences between those born after medically assisted reproduction and those born after spontaneous pregnancy (respectively, adjusted odds ratio, 0.99; 95% confidence interval, 0.80-1.23 and adjusted odds ratio, 1.14; 95% confidence interval, 0.83-1.56). In subgroup analyses, no differences were observed between children born following induction of ovulation or in vitro fertilization and those conceived spontaneously. Sensitivity analyses were consistent with the main results. CONCLUSION: In this cohort of preterm-born children, there was no evidence of an impact of the mode of conception on neurodevelopmental outcomes at 5½ years of age.

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.

Birth outcomes between 22 and 26 weeks' gestation in national population-based cohorts from Sweden, England and France.

AIM: We investigated the timing of survival differences and effects on morbidity for foetuses alive at maternal admission to hospital delivered at 22 to 26 weeks' gestational age (GA). METHODS: Data from the EXPRESS (Sweden, 2004-07), EPICure-2 (England, 2006) and EPIPAGE-2 (France, 2011) cohorts were harmonised. Survival, stratified by GA, was analysed to 112 days using Kaplan-Meier analyses and Cox regression adjusted for population and pregnancy characteristics; neonatal morbidities, survival to discharge and follow-up and outcomes at 2-3 years of age were compared. RESULTS: Among 769 EXPRESS, 2310 EPICure-2 and 1359 EPIPAGE-2 foetuses, 112-day survival was, respectively, 28.2%, 10.8% and 0.5% at 22-23 weeks' GA; 68.5%, 40.0% and 23.6% at 24 weeks; 80.5%, 64.8% and 56.9% at 25 weeks; and 86.6%, 77.1% and 74.4% at 26 weeks. Deaths were most marked in EPIPAGE-2 before 1 day at 22-23 and 24 weeks GA. At 25 weeks, survival varied before 28 days; differences at 26 weeks were minimal. Cox analyses were consistent with the Kaplan-Meier analyses. Variations in morbidities were not clearly associated with survival. CONCLUSION: Differences in survival and morbidity outcomes for extremely preterm births are evident despite adjustment for background characteristics. No clear relationship was identified between early mortality and later patterns of morbidity.

Association of Continuous Opioids and/or Midazolam During Early Mechanical Ventilation with Survival and Sensorimotor Outcomes at Age 2 Years in Premature Infants: Results from the French Prospective National EPIPAGE 2 Cohort.

OBJECTIVE: To evaluate the association of early continuous infusions of opioids and/or midazolam with survival and sensorimotor outcomes at age 2 years in very premature infants who were ventilated. STUDY DESIGN: This national observational study included premature infants born before 32 weeks of gestation intubated within 1 hour after birth and still intubated at 24 hours from the French EPIPAGE 2 cohort. Infants only treated with bolus were excluded. Treated infants received continuous opioid and/or midazolam infusion started before 7 days of life and before the first extubation. Naive infants did not receive these treatments before the first extubation, or received them after the first week of life, or never received them. This study compared treated (n = 450) vs naive (n = 472) infants by using inverse probability of treatment weighting after multiple imputation in chained equations. The primary outcomes were survival and survival without moderate or severe neuromotor or sensory impairment at age 2 years. RESULTS: Survival at age 2 years was significantly higher in the treated group (92.5% vs 87.9%, risk difference, 4.7%; 95% CI, 0.3-9.1; P = .037), but treated and naive infants did not significantly differ for survival without moderate or severe neuromotor or sensory impairment (86.6% vs 81.3%; risk difference, 5.3%; 95% CI -0.3 to 11.0; P = .063). These results were confirmed by sensitivity analyses using 5 alternative models. CONCLUSIONS: Continuous opioid and/or midazolam infusions in very premature infants during initial mechanical ventilation that continued past 24 hours of life were associated with improved survival without any difference in moderate or severe sensorimotor impairments at age 2 years.