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

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

Validity of a Delphi consensus definition of growth restriction in the newborn for identifying neonatal morbidity.

BACKGROUND: Small for gestational age is defined as a birthweight below a birthweight percentile threshold, usually the 10th percentile, with the third or fifth percentile used to identify severe small for gestational age. Small for gestational age is used as a proxy for growth restriction in the newborn, but small-for-gestational-age newborns can be physiologically small and healthy. In addition, this definition excludes growth-restricted newborns who have weights more than the 10th percentile. To address these limits, a Delphi study developed a new consensus definition of growth restriction in newborns on the basis of neonatal anthropometric and clinical parameters, but it has not been evaluated. OBJECTIVE: To assess the prevalence of growth restriction in the newborn according to the Delphi consensus definition and to investigate associated morbidity risks compared with definitions of Small for gestational age using birthweight percentile thresholds. STUDY DESIGN: Data come from the 2016 and 2021 French National Perinatal Surveys, which include all births ≥22 weeks and/or with birthweights ≥500 g in all maternity units in France over 1 week. Data are collected from medical records and interviews with mothers after the delivery. The study population included 23,897 liveborn singleton births. The Delphi consensus definition of growth restriction was birthweight less than third percentile or at least 3 of the following criteria: birthweight, head circumference or length <10th percentile, antenatal diagnosis of growth restriction, or maternal hypertension. A composite of neonatal morbidity at birth, defined as 5-minute Apgar score <7, cord arterial pH <7.10, resuscitation and/or neonatal admission, was compared using the Delphi definition and usual birthweight percentile thresholds for defining small for gestational age using the following birthweight percentile groups: less than a third, third to fourth, and fifth to ninth percentiles. Relative risks were adjusted for maternal characteristics (age, parity, body mass index, smoking, educational level, preexisting hypertension and diabetes, and study year) and then for the consensus definition and birthweight percentile groups. Multiple imputation by chained equations was used to impute missing data. Analyses were carried out in the overall sample and among term and preterm newborns separately. RESULTS: We identified that 4.9% (95% confidence intervals, 4.6-5.2) of newborns had growth restriction. Of these infants, 29.7% experienced morbidity, yielding an adjusted relative risk of 2.5 (95% confidence intervals, 2.2-2.7) compared with newborns without growth restriction. Compared with birthweight ≥10th percentile, morbidity risks were higher for low birthweight percentiles (less than third percentile: adjusted relative risk, 3.3 [95% confidence intervals, 3.0-3.7]; third to fourth percentile: relative risk, 1.4 [95% confidence intervals, 1.1-1.7]; fifth to ninth percentile: relative risk, 1.4 [95% confidence intervals, 1.2-1.6]). In adjusted models including the definition of growth restriction and birthweight percentile groups and excluding birthweights less than third percentile, which are included in both definitions, morbidity risks remained higher for birthweights at the third to fourth percentile (adjusted relative risk, 1.4 [95% confidence intervals, 1.1-1.7]) and fifth to ninth percentile (adjusted relative risk, 1.4 [95% confidence intervals, 1.2-1.6]), but not for the Delphi definition of growth restriction (adjusted relative risk, 0.9 [95% confidence intervals, 0.7-1.2]). Similar patterns were found for term and preterm newborns. CONCLUSION: The Delphi consensus definition of growth restriction did not identify more newborns with morbidity than definitions of small for gestational age on the basis of birthweight percentiles. These findings illustrate the importance of evaluating the results of Delphi consensus studies before their adoption in clinical practice.

[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.

Identifying Newborns with Hypoxic-Ischemic Encephalopathy in Hospital Discharge Data: A Validation Study.

Hospital discharge databases (HDDs) are increasingly used for research on health of newborns. Linkage between a French population-based cohort of newborns with hypoxic-ischemic encephalopathy (HIE) and national HDD showed that the HIE ICD-10 code was not accurately reported. Our results suggest that HDD should not be used for research on neonatal HIE without prior validation of HIE ICD-10 codes.

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.

Which fetal growth charts should be used in France? Position of the French College of Obstetricians and Gynecologists (CNGOF).

OBJECTIVE: To assess which fetal growth charts best describe intrauterine growth in France defined as the ability to classify 10% of fetuses below the 10th percentile (small for gestational age [SGA]) and above the 90th percentile (large for gestational age [LGA]) in the second and third trimesters. METHODS: We analyzed five studies on fetal ultrasound measurements using three French data sources. Two studies used second and third trimester ultrasound data from a nationwide birth cohort in 2011 (the ELFE study, N = 13 197 and N = 7747); one study used third trimester ultrasound data from on a nationwide cross-sectional study (the 2016 French National Perinatal Survey, N = 9940); and the last two studies were from the "Flash study" 2014 which prospectively collected ultrasound data from routine visits in the second and third trimesters (N = 4858 and N = 3522). For each study, we reported the percentage of measurements below the 10th percentile or above the 90th percentile, using French, Hadlock's, WHO and Intergrowth (IG) charts. RESULTS: WHO classified 4.7% and 16.3% of fetuses as having an estimated fetal weight (EFW) <10th and >90th percentiles in the second trimester compared to 3.3% and 34.7% with IG. The percentage of fetuses in the third trimester with an EFW <10th and >90th percentiles, ranged from 9.1% to 9.4% and from 8.0% to 11.1%, respectively, for WHO, and from 3.9% to 4.1% and from 17.3% to 21.6%, respectively, for IG. The WHO and IG charts for head circumference were very similar and performed well. Compared to the WHO charts, the French and Hadlock's charts deviated more frequently from the target percentiles values for EFW and biometric measures. CONCLUSION: It is recommended to use the WHO charts for the assessment of EFW and ultrasound biometric measurements in France (strong recommendation; low quality of evidence).

Screening for small for gestational age infants in early vs late third-trimester ultrasonography: a randomized trial.

BACKGROUND: Recent studies have demonstrated that a routine third-trimester ultrasound scan may improve the detection of small for gestational age infants when compared with clinically indicated ultrasound scans but with no reported reduction in severe perinatal morbidity. Establishing the optimal gestational age for the third-trimester examination necessitates evaluation of the ability to detect small for gestational age infants and to predict maternal and perinatal outcomes. Intrauterine growth restriction most often corresponds with small for gestational age infants associated with pathologic growth patterns. OBJECTIVE: This study aimed to assess the performance of routine early ultrasound scans vs late ultrasound scans during the third trimester of pregnancy to identify small for gestational age infants and fetuses with intrauterine growth restriction. STUDY DESIGN: This was an open-label, randomized, parallel trial conducted in Upper Normandy, France, from 2012 to 2015. The study eligibility criteria were heathy, nulliparous women older than 18 years with gestational age determined using the crown-rump length at the first trimester routine scan and with no fetal malformation or suspected small for gestational age fetus at the routine second trimester scan. Pregnant women were randomly assigned to a third-trimester scan group at 31 weeks gestational age ±6 days (early ultrasound scan) or at 35 weeks gestational age ±6 days (late ultrasound scan). The primary outcome of this trial was the ability of a third trimester scan to predict small for gestational age infants (customized birth weight <10th percentile) and intrauterine growth restriction (customized birth weight

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.

Serial plotting of symphysis-fundal height and estimated fetal weight to improve the antenatal detection of infants small for gestational age: A cluster randomised trial.

OBJECTIVE: To assess whether standardised longitudinal reporting of growth monitoring information improves antenatal detection of infants who are small for gestational age (SGA), compared with usual care. DESIGN: Cluster-randomised controlled trial. SETTING: Sixteen French level-3 units in 2018-2019. POPULATION: Singleton pregnancies. METHODS: The intervention consisted of the serial plotting of symphysis-fundal height (SFH) and estimated fetal weight (EFW) measurements on customised growth charts using a software program, compared with standard antenatal care. We estimated relative risks (RR) adjusted for known risk factors for fetal growth restriction (FGR). MAIN OUTCOME MEASURES: The primary outcome was antenatal detection of FGR among SGA births (with birthweights below the tenth centile of French customised curves), defined as the mention of suspected FGR in medical records and either referral ultrasounds for growth monitoring or indicated delivery for FGR. Secondary outcomes were false-positive rates, mode of delivery, perinatal morbidity and mortality, and number of antenatal visits and ultrasounds. RESULTS: In total, seven intervention clusters (n = 4349) and eight control clusters (n = 4943) were analysed, after the exclusion of one intervention centre for a major deviation in protocol. SGA births represented 613 (14.1%) and 626 (12.7%) of all births, respectively. The rates of antenatal detection of FGR among SGA births were 40.0% in the intervention arm versus 37.1% in the control arm (crude RR 1.08, 95% CI 0.87-1.34; adj RR 1.09, 95% CI 0.88-1.35). No benefits of the intervention were detected in the analyses of secondary outcomes. CONCLUSIONS: Serial plotting of SFH and EFW measurements on customised growth charts did not improve the antenatal detection of FGR among SGA births.

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.

World Health Organization fetal growth charts applied in a French birth cohort.

OBJECTIVE: To evaluate the applicability of World Health Organization (WHO) fetal growth charts for abdominal circumference (AC), femur length (FL) and estimated fetal weight (EFW) at the second and third trimester ultrasounds in a French birth cohort. MATERIALS AND METHODS: Using the ELFE cohort of live births after 33 weeks' gestation in France in 2011, we selected 7747 singletons with fetal biometric measurements at the second (20-25 weeks) and third (30-35 weeks) trimester routine ultrasounds. We calculated proportions of fetuses <3rd and <10th percentiles and >90th and >97th percentiles for AC, FL and EFW using WHO charts and two international (Intergrowth and Hadlock) and two national (Salomon and CFEF) charts. Analyses were also carried out in a subsample of 4427 low-risk births. RESULTS: WHO charts classified 2,3% and 8-10% of fetuses <3rd and <10th percentiles respectively, for AC and FL in the second and third trimesters and EFW in the third trimester. Similarly, about 3 and 10% of fetuses had AC, FL and EFW >97th and >90th percentile in both trimesters. Hadlock and CFEF charts also provided a good fit for third-trimester EFW <10th percentile. For most measures, Intergrowth yielded low proportions <3rd and <10th percentile, and high proportions >90th and >97th percentiles. Proportions were slightly lower for low-risk pregnancies. CONCLUSION: WHO charts provided a good description of the distribution of French fetal biometric measures. Further research is needed to assess the impact of using WHO charts on obstetrical management and perinatal outcomes.

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.

Unisex vs sex-specific estimated fetal weight charts for fetal growth monitoring: a population-based study.

BACKGROUND: In contrast with birthweight or other growth charts, a feature of most intrauterine charts is that they are not differentiated by sex. Differences in weight by sex during pregnancy are considered to be relatively minor; however, small systematic differences may affect the sensitivity and specificity of screening for fetuses with growth restriction. OBJECTIVE: To assess differences between unisex and sex-specific estimated fetal weight charts at the third-trimester ultrasound with regard to the sex ratio of fetuses detected with an estimated fetal weight <10th percentile and subsequent detection of small-for-gestational-age newborns with morbidity at birth. STUDY DESIGN: The study included 9940 singleton live births from a French population-based study in 2016. Main outcomes were an estimated fetal weight <10th percentile at the routine third-trimester ultrasound between 30 and 35 weeks of gestation, and small for gestational age infants (birthweight <10th percentile) with neonatal morbidity (Apgar score <7 at 5 minutes and/or resuscitation in delivery room and/or admission to a neonatal unit). We used 2 charts with unisex and sex-specific options: the World Health Organization international standard chart and a customized chart for fetal sex based on Gardosi's gestation-related optimal weight model adapted to the French population (Epopé). Hadlock's unisex chart, commonly used in clinical care and research, was also included to provide an external reference. We compared the proportions of female and male fetuses with an estimated fetal weight <10th percentile and the sensitivity and specificity of such estimated fetal weight for predicting small-for-gestational-age newborns with morbidity when using unisex vs sex-specific charts, overall and by sex. RESULTS: Among all singleton births, there were 51.6% males and 48.4% females. Males faced higher risks of being small-for-gestational-age with morbidity at birth (2.4% vs 1.8%; P=.031). Using the World Health Organization unisex chart, 6.9% of males and 9.9% of females had an estimated fetal weight <10th percentile vs 9.9% of males and 7.1% of females with the sex-specific chart; these proportions were 3.5% and 4.6% and 4.3% and 2.7%, respectively, for the Epopé. Proportions of estimated fetal weight <10th percentile using Hadlock's chart were slightly higher than those obtained using the unisex World Health Organization chart (7.5% of males and 10.6% of females), but the difference of about 3% was the same. The sensitivity of an estimated fetal weight <10th percentile for identifying small-for-gestational-age newborns with morbidity differed for males and females by type of chart; unisex charts detected more small-for-gestational-age females with morbidity and sex-specific charts detected more small-for-gestational-age males with morbidity, but the overall sensitivity was the same (49.1% for the World Health Organization chart and Hadlock's chart and 34.9% for the Epopé chart). CONCLUSION: This study suggests that the use of sex-specific charts instead of unisex charts would reduce sex bias in intrauterine growth screening during the third trimester of pregnancy. Prospective studies are needed to assess the effects of using sex-specific charts rather than unisex charts on obstetrical management and outcomes.

Biostatistics Disruptive Acculturation Through Serious Gaming: A New Hope.

Biostatistics is one of the transversal subjects that all future doctors must acquire and master. Nonetheless, it is a subject that has the reputation of being difficult, which has not been able to be corrected even with the application of new pedagogical methods such as blended learning. We address this problem with our acculturative and disruptive approach in the form of a serious game scenario in clinical research that integrates biostatistics with our R4Web adapted tools. Our approach was launched in 2008 for the second year of medical school. Here we describe this LOE scenario for serious game including the biostatistics disruptive acculturation task and present its new international version.

Propofol versus placebo (with rescue with ketamine) before less invasive surfactant administration: study protocol for a multicenter, double-blind, placebo controlled trial (PROLISA).

BACKGROUND: One major limitation for less invasive surfactant administration (LISA) is the difficulty in providing sedation before this procedure and the competitive risk of respiratory depression versus avoidance of intubation for most sedative or analgesic drugs used in this context. The objective of this study is to compare the need for mechanical ventilation within 72 h of life following premedication with propofol, versus placebo (rescue with ketamine), for the LISA procedure in preterm neonates born before 32 weeks gestational age (wGA). METHODS: ProLISA is a phase III, non-inferiority, multicenter, double blind, randomized, placebo controlled trial designed according to the SPIRIT Statement. Neonates born before 32 wGA in 12 geographically dispersed Neonatal Intensive Care Units in France needing surfactant will be included from September 2019 to September 2022. A sample of 542 patients is needed. The neonate is randomized to the intervention (propofol) or control placebo group. Open label rescue treatment with ketamine is possible in both groups if FANS (Faceless Acute Neonatal pain Scale) is ≥6. To guide drug administration, FANS is scored before attempting laryngoscopy. Once an adequate score has been obtained, LISA is performed according to a standardized protocol. The primary outcome is the need for mechanical ventilation within 72 h of life. Secondary outcomes are tolerance of the procedure, pain evaluation, hemodynamic and neurologic parameters after the intervention, morbidities before discharge and neurodevelopmental assessment at 2 years of age. DISCUSSION: This paper describes the first multicenter, double-blind, randomized, placebo-controlled trial on this topic and will provide crucial information to support implementation of the LISA procedure. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04016246. Registered 06 June 2019, N°EUDRACT: 2018-002876-41.

Nebulized hypertonic saline 3% for 1 versus 3 days in hospitalized bronchiolitis: a blinded non-inferiority randomized controlled trial.

BACKGROUND: The use and optimal duration of treatment with nebulized hypertonic saline (HS) in infants hospitalized for acute bronchiolitis is unclear. The objective was to compare the efficacy of 1 versus 3 days of nebulized 3% HS at 72 h of treatment. We conducted a blinded non-inferiority randomized controlled trial including infants aged less than 12 months old, hospitalized for a moderate bronchiolitis. METHODS: Nebulisations of 3% HS for 1 day were followed by either the continuation of 3% HS (HS3d group) or switched to 0.9% normal isotonic saline (HS1d group) for 2 days Randomization was performed according to a predefined list with a 1:1 ratio, obtained with a random generator number with blocks.. Main outcome was mean Wang clinical severity score (CSS) after 72 h of treatment. RESULTS: One hundred sixteen infants (HS1d n = 59 and HS3d n = 57), were included over two epidemic seasons from 2014 to 2016, but recruitement did not reach the planned sample size. The difference for the Wang CSS score in the HS3d vs HS1d group was 0.71 [IC 90% 0.1; 1.3], above the precluded value of 0.4 set in the protocol defining the non-inferiority of shorter treatment duration. Clinical remission was more rapidly obtained in the HS3d than in HS1d (2.3 ± 1.6 vs 2.9 ± 1.4 days, p = 0.04), with a non-significant tendency for less need of nutritional support and supplemental oxygen in HS3d group. Clinical worsening and treatment intolerance were similar in the 2 groups. CONCLUSIONS: Despite being underpowered, results seem not to be in favour of reducing the duration of nebulised HS treatment from 3 to 1 day in acute moderate bronchiolitis. TRIAL REGISTRATION: Clinical trials NCT02538458, October 2014.