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.

[Medium and long-term health outcome of children conceived through in vitro fertilization]. / Conséquences de la fécondation in vitro sur la santé des enfants à moyen et long termes.

MEDIUM AND LONG-TERM HEALTH OUTCOME OF CHILDREN CONCEIVED THROUGH IN VITRO FERTILIZATION. Numerous studies have been carried out in children conceived by in vitro fertilization (IVF) focusing on the occurrence of various alterations in their health. It appears that if children can sometimes be affected by health problems, without a particular type predominating, nevertheless their incidence is relatively moderate and not much greater than in naturally conceived children. The alterations observed in children are not necessarily attributable to IVF insofar as infertile couples may be more at risk of transmitting to their children factors responsible for health disturbances. The mechanisms involved in the occurrence of the observed alterations are poorly understood. If disruptions of epigenetic regulations are most often mentioned, research is still needed to clarify them.

CONSÉQUENCES DE LA FÉCONDATION IN VITRO SUR LA SANTÉ DES ENFANTS À MOYEN ET À LONG TERMES. De nombreuses études ont été menées chez les enfants conçus par fécondation in vitro (FIV), s'intéressant à la survenue de différentes altérations de leur santé. Il en ressort que si les enfants peuvent être parfois atteints de troubles de la santé, sans qu'un type particulier prédomine, leur incidence est néanmoins relativement modérée et pas beaucoup plus importante que chez les enfants conçus naturellement. Les altérations observées chez les enfants ne sont pas forcément imputables à la FIV dans la mesure où les couples infertiles peuvent être plus à risque de transmettre à leurs enfants des facteurs responsables de perturbations de santé. Les mécanismes impliqués dans la survenue des altérations observées sont mal connus. Si des perturbations de régulations épigénétiques sont le plus souvent évoquées, des recherches sont encore nécessaires pour les préciser.

On punctate white matter lesions in preterm infants: Is ultrasound diagnosis feasible?

OBJECTIVES: To observe hyperechoic nodular or punctate white matter lesions (HNPL) in a population of preterm infants using routine cranial ultrasound (cUS), to describe the characteristics of HNPL, and to compare them with punctate white matter lesions (PWML) detected in magnetic resonance imaging (MRI). DESIGN: Retrospective observational single-center cohort study. SETTING: Level 2B neonatal unit in France. PATIENTS: 307 infants born <33 weeks gestation undergoing routine cUS with a total of 961 cUS performed. MAIN OUTCOME MEASURES: Description of lesions (HNPL/PWML): presence or absence, number, size, location, and structural distribution. RESULTS: Among the 307 included infants, 63 (20.5%) had at least one cerebral lesion, with 453 HNPL for 63 infants. HNPL were numerous (more than three in 66.6% of cases), primarily grouped in clusters (76.2%), located near the lateral ventricles (96.8%), and measuring more than 2 mm (79%). HNPL were diagnosed on day 29 on average and persisted until term. Overall, 43 MRI were performed in 307 infants, on average 18.9 days after last cUS, in 21 of those the indication was presence of HPNL on cUS. Of these 21 MRI, 14/21 presented 118 PWML compared to 173 HNPL on cUS. In the remaining MRI (7/21), no PWML were detected compared to 47 HNPL on cUS. CONCLUSIONS: In our population of 307 preterm infants, cUS allowed the diagnosis of HNPL, with a large similarity to PWML in MRI and a better sensitivity. But in the absence of data on inter-observer variability, we cannot exclude overdiagnosis of HNPL.

Cognitive Training for Visuospatial Processing in Children Aged 5½ to 6 Years Born Very Preterm With Working Memory Dysfunction: A Randomized Clinical Trial.

Importance: Compared with term-born peers, children born very preterm generally perform poorly in executive functions, particularly in working memory and inhibition. By taking advantage of neuroplasticity, computerized cognitive training of working memory in those children could improve visuospatial processing by boosting visual inhibition via working memory. Objective: To evaluate the long-term effect of cognitive working memory training on visuospatial processing in children aged 5½ to 6 years born very preterm who have working memory impairment. Design, Setting, and Participants: This multicenter (18 French university hospitals), open-label randomized clinical trial with 2 parallel groups (EPIREMED) was conducted from November 2016 to April 2018, with the last follow-up during August 2019. Eligible children from the EPIPAGE 2 cohort were aged 5½ to 6 years, were born between 24 and 34 weeks' gestation, and had a global intelligence quotient greater than 70 and a working memory index less than 85. Data were analyzed from February to December 2020. Intervention: Children were randomized 1:1 to standard care management and a working memory cognitive training program (Cogmed software) for 8 weeks (25 sessions) (intervention) or to standard management (control). Main Outcomes and Measures: The primary outcome was the visuospatial index score from the Wechsler Preschool and Primary Scale of Intelligence, 4th Edition. Secondary outcomes were working memory, intellectual functioning, executive and attention processes, language skills, behavior, quality of life, and schooling. Neurobehavioral assessments were performed at inclusion and after finishing training at 6 months (intermeditate assessment; secondary outcomes) and at 16 months (final assessment; primary outcome). Results: There were 169 children randomized, with a mean (SD) age of 5 years 11 months (2 months); 91 (54%) were female. Of the participants, 84 were in the intervention group (57 of whom [68%] completed at least 15 cognitive training sessions) and 85 were in the control group. The posttraining visuospatial index score was not different between groups at a mean (SD) of 3.0 (1.8) months (difference, -0.6 points; 95% CI, -4.7 to 3.5 points) or 12.9 (2.6) months (difference, 0.1 points; 95% CI, -5.4 to 5.1 points). The working memory index score in the intervention group significantly improved from baseline at the intermediate time point (difference, 4.7 points; 95% CI, 1.2-8.1 points), but this improvement was not maintained at the final assessment. Conclusions and Relevance: This randomized clinical trial found no lasting effect of a cognitive training program on visuospatial processing in children aged 5½ to 6 years with working memory disorders who were born very preterm. The findings suggest that this training has limited long-term benefits for improving executive function. Transient benefits seemed to be associated with the developmental state of executive functions. Trial Registration: ClinicalTrials.gov Identifier: NCT02757794.

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.

Infant exposure to Fluvoxamine through placenta and human milk: a case series - A contribution from the ConcePTION project.

Introduction: Fluvoxamine is widely used to treat depression during pregnancy and lactation. However, limited data are available on its transfer to the fetus or in human milk. This case series provides additional information on the infant exposure to fluvoxamine during pregnancy and lactation. Case presentation: Two women, aged 38 and 34 years, diagnosed with depression were treated with 50 mg fluvoxamine during pregnancy and lactation. At delivery a paired maternal and cord blood sample was collected for each woman. The first mother exclusively breastfed her child for 4 months and gave one foremilk and one hindmilk sample at 2 days and 4 weeks post-partum, whereas the second mother did not breastfeed. Results: The cord to plasma concentration ratios were 0.62 and 0.48, respectively. At 2 weeks post-partum, relative infant doses (RID) were 0.47 and 0.57% based on fluvoxamine concentrations in foremilk and hindmilk, respectively. At 4 weeks post-partum, the RIDs were 0.35 and 0.90%, respectively. The child from the first mother was born healthy and showed a normal development at the 6th, 18th and 36th month follow-ups. One of the twins from the second woman was hospitalized for hypoglycemia that was attributed to gestational diabetes and low birth weight. The second one was born healthy. Conclusion: These results suggest a minimal exposure to fluvoxamine during lactation which is in accordance with previously published data. Larger clinical and pharmacokinetic studies assessing the long-term safety of this drug during lactation and the variability of its exposure through breastmilk are warranted.

Performance of 11 Host Biomarkers Alone or in Combination in the Diagnosis of Late-Onset Sepsis in Hospitalized Neonates: The Prospective EMERAUDE Study.

Despite the high prevalence of late-onset sepsis (LOS) in neonatal intensive care units, a reliable diagnosis remains difficult. This prospective, multicenter cohort study aimed to identify biomarkers early to rule out the diagnosis of LOS in 230 neonates ≥7 days of life with signs of suspected LOS. Blood levels of eleven protein biomarkers (PCT, IL-10, IL-6, NGAL, IP-10, PTX3, CD14, LBP, IL-27, gelsolin, and calprotectin) were measured. Patients received standard of care blinded to biomarker results, and an independent adjudication committee blinded to biomarker results assigned each patient to either infected, not infected, or unclassified groups. Performances of biomarkers were assessed considering a sensitivity of at least 0.898. The adjudication committee classified 22% of patients as infected and all of these received antibiotics. A total of 27% of the not infected group also received antibiotics. The best biomarkers alone were IL-6, IL-10, and NGAL with an area under the curve (95% confidence interval) of 0.864 (0.798-0.929), 0.845 (0.777-0.914), and 0.829 (0.760-0.898), respectively. The best combinations of up to four biomarkers were PCT/IL-10, PTX3/NGAL, and PTX3/NGAL/gelsolin. The best models of biomarkers could have identified not infected patients early on and avoided up to 64% of unjustified antibiotics. At the onset of clinical suspicion of LOS, additional biomarkers could help the clinician in identifying non-infected patients.

Neurodevelopmental Outcome at Two Years for Preterm Infants With Intraventricular Hemorrhage: A Case-Control Study.

BACKGROUND: High-grade intraventricular hemorrhage (IVH), including grade III and grade IV IVH, is known to impact neurodevelopmental outcome of preterm infants, but prognosis remains difficult to establish due to confounding factors and significant variations in the reported outcomes. The aim of this study was to compare the neurodevelopmental outcome of preterm infants with or without severe IVH. METHODS: A retrospective case-control study was conducted including preterm infants with gestational age <32 weeks hospitalized between 2009 and 2017 in a level III neonatal intensive care unit. This study included 73 cases with high-grade IVH and 73 controls who were matched to cases, based on the same gestational age, birth weight, sex, and year of birth. The neurodevelopmental outcome was compared at two years of age corrected for prematurity between cases and controls. Neurodevelopmental impairment was defined as cerebral palsy, hearing deficiency, visual impairment, or developmental delay. Multivariate analysis was used to identify whether high-grade IVH was an independent risk factor for neurodevelopmental impairment. RESULTS: In univariate analysis, high-grade IVH was associated with death or poor neurodevelopmental outcome at two years of age corrected for prematurity (odds ratio [OR], 16.3; 95% confidence interval [CI], 5.93 to 57.8; P < 0.001), and this association remained significant after adjusting for confounding factors including neonatal infection and bronchopulmonary dysplasia in multivariate analysis (OR, 8.71; 95% CI, 2.48 to 38.09; P = 0.002). CONCLUSIONS: This study highlights the impact of high-grade IVH as an independent risk factor of poor neurodevelopmental outcomes in very preterm infants and suggests that early interventions could improve the prognosis of these infants.

Respiratory physiology during NAVA ventilation in neonates born with a congenital diaphragmatic hernia: The "NAVA-diaph" pilot study.

BACKGROUND: Neurally adjusted ventilatory assist (NAVA) is a ventilatory mode that delivers synchronized ventilation, proportional to the electrical activity of the diaphragm (EAdi). Although it has been proposed in infants with a congenital diaphragmatic hernia (CDH), the diaphragmatic defect and the surgical repair could alter the physiology of the diaphragm. AIM: To evaluate, in a pilot study, the relationship between the respiratory drive (EAdi) and the respiratory effort in neonates with CDH during the postsurgical period under either NAVA ventilation or conventional ventilation (CV). METHODS: This prospective physiological study included eight neonates admitted to a neonatal intensive care unit with a diagnosis of CDH. EAdi, esophageal, gastric, and transdiaphragmatic pressure, as well as clinical parameters, were recorded during NAVA and CV (synchronized intermittent mandatory pressure ventilation) in the postsurgical period. RESULTS: EAdi was detectable and there was a correlation between the ΔEAdi (maximal - minimal values) and the transdiaphragmatic pressure (r = 0.26, 95% confidence interval [CI] [0.222; 0.299]). There was no significant difference in terms of clinical or physiological parameters during NAVA compared to CV, including work of breathing. CONCLUSION: Respiratory drive and effort were correlated in infants with CDH and therefore NAVA is a suitable proportional mode in this population. EAdi can also be used to monitor the diaphragm for individualized support.

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.

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

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

Risk Factors of Very Severe RSV Infections in a Multicenter Cohort of Very Preterm and Extreme Preterm Babies Receiving or Not Palivizumab.

Introduction: Preterm infants are at risk of lower respiratory tract infections (LRTI), including Respiratory Syncytial Virus (RSV) associated bronchiolitis, for which palivizumab prophylaxis can be proposed. Our aim was to determine risk factors of very severe RSV disease in children born before 34 weeks of gestation. Methods: Among 2,101 infants born before 34 weeks of gestation in 3 maternity wards between 2012 and 2017, the laboratory confirmed RSV-infected patients requiring hospitalization before 12 months of corrected age were retrospectively included. We collected data about the neonatal period, the palivizumab prophylaxis and the hospitalization for a RSV-related LRTI. LRTI was considered as very severe (VS-LRTI) when patients required invasive or non-invasive positive pressure ventilation. Results: Among 86 included patients, 31 met the criteria of VS-LRTI. The VS-LRTI patients had a higher birth gestational age and weight but less heart disease and bronchopulmonary dysplasia. They received palivizumab prophylaxis less frequently than the other patients but the difference was not significant. At the onset of infection, VS-LRTI patients had a younger corrected age for prematurity and presented more frequently with apnea, bradycardia, life-threatening event, hemodynamic failure, hypercapnia. Using logistic regression, the main factor associated with VS-LRTI was a younger corrected age for prematurity at the onset of infection [Odd ratio for each month of corrected age = 0.77 (0.62; 0.93), p = 0.012]. Conclusion: Infants at the highest risk of VS-LRTI were infants with a younger corrected age for prematurity. Therefore, a better targeting of infants requiring palivizumab prophylaxis and early interventions at hospital discharge could limit VS-LRTI in these infants.

Identifying the Target Population for Primary Respiratory Syncytial Virus Two-Step Prevention in Infants: Normative Outcome of Hospitalisation Assessment for Newborns (NOHAN).

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute respiratory infection- related hospitalisations in infants (RSVh). Most of these infants are younger than 6 months old with no known risk factors. An efficient RSVh prevention program should address both mothers and infants, relying on Non-Pharmaceutical (NPI) and Pharmaceutical Interventions (PI). This study aimed at identifying the target population for these two interventions. METHODS: Laboratory-confirmed RSV-infected infants hospitalised during the first 6 months of life were enrolled from the Hospices Civils de Lyon birth cohort (2014 to 2018). Clinical variables related to pregnancy and birth (sex, month of birth, birth weight, gestational age, parity) were used for descriptive epidemiology, multivariate logistic regression, and predictive score development. RESULTS: Overall, 616 cases of RSVh in 45,648 infants were identified. Being born before the epidemic season, prematurity, and multiparity were independent predictors of RSVh. Infants born in January or June to August with prematurity and multiparity, and those born in September or December with only one other risk factor (prematurity or multiparity) were identified as moderate-risk, identifying the mothers as candidates for a first-level NPI prevention program. Infants born in September or December with prematurity and multiparity, and those born in October or November were identified as high-risk, identifying the mothers and infants as candidates for a second-level (NPI and PI) intervention. CONCLUSIONS: It is possible to determine predictors of RSVh at birth, allowing early enrollment of the target population in a two-level RSV prevention intervention.

Early cerebral hypoxia in extremely preterm infants and neurodevelopmental impairment at 2 year of age: A post hoc analysis of the SafeBoosC II trial.

BACKGROUND: The SafeBoosC II, randomised clinical trial, showed that the burden of cerebral hypoxia was reduced with the combination of near infrared spectroscopy and a treatment guideline in extremely preterm infants during the first 72 hours after birth. We have previously reported that a high burden of cerebral hypoxia was associated with cerebral haemorrhage and EEG suppression towards the end of the 72-hour intervention period, regardless of allocation. In this study we describe the associations between the burden of cerebral hypoxia and the 2-year outcome. METHODS: Cerebral oxygenation was continuously monitored from 3 to 72 hours after birth in 166 extremely preterm infants. At 2 years of age 114 of 133 surviving children participated in the follow-up program: medical examination, Bayley II or III test and the parental Ages and Stages Questionnaire. The infants were classified according to the burden of hypoxia: within the first three quartiles (n = 86, low burden) or within in the 4th quartile (n = 28, high burden). All analyses were conducted post hoc. RESULTS: There were no statistically significant differences between the quantitative assessments of neurodevelopment in the groups of infants with the low burden of cerebral hypoxia versus the group of infants with the high burden of cerebral hypoxia. The infants in the high hypoxia burden group had a higher-though again not statistically significant-rate of cerebral palsy (OR 2.14 (0.33-13.78)) and severe developmental impairment (OR 4.74 (0.74-30.49). CONCLUSIONS: The burden of cerebral hypoxia was not significantly associated with impaired 2-year neurodevelopmental outcome in this post-hoc analysis of a feasibility trial.

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

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

Fetal growth restriction: underdiagnosed condition with non-optimal screening.

BACKGROUND: Fetal Growth restriction (FGR) is the pathological failure of a fetus to reach its biologically determined growth potential. Detection of FGR fetuses is a universally agreed key objective of antenatal care. Antenatal detection of FGR has undeniable benefits, juggling between intensive fetal surveillance and optimized timing of delivery; it reduces adverse perinatal outcomes by up to four-fold. However, FGR is still widely underdiagnosed. We aimed to identify the prevalence of FGR diagnosis in our wards and study the impact of the 2013 published French guidelines on the detection rate of FGR. The secondary objective aimed to highlight the factors of suboptimal screening in the population of non-diagnosed FGR fetuses and emphasize the screening method that led to antenatal diagnosis of FGR. MATERIALS AND METHODS: We conducted a retrospective study at a single tertiary maternity center in Lyon-France, the Femme Mère Enfant Hospital, including the exhaustive population of FGR born after 24 + 0 weeks of gestation from 1 January 2011 to 31 December 2017. FGR was defined combining the neonatal and antenatal consensus-based definitions for early and late FGR in absence of congenital anomalies, excluding small for gestational age fetuses. For all FGR fetuses, we compared the antenatal detection rate of FGR during 2011-2013 to 2015-2017, since the French guidelines were published in December 2013. When FGR fetuses underwent an antenatal diagnosis of FGR, we retrospectively collected the characteristics that led to the diagnosis. When fetuses were not diagnosed as FGR, we retrospectively reviewed the implementation of the recommended screening method, enabling to evaluate whether screening was optimal or not. Statistical analysis was performed in July 2018, and statistical significance was regarded as a p-value <.05. RESULTS: Over the seven-year period, and among 31,052 newborns, 1020 (3.3%) infants were identified as FGR and met the inclusion criteria. The detection rate of FGR was similar before and after publication of the French Guidelines related to FGR in 2013. Indeed, 50.8% (201/395) FGR were diagnosed between 2011 and 2013 versus 52.6% (245/465) between 2015 and 2017 (p = .59). In the population of non-diagnosed FGR infants, screening was suboptimal in 80%. Symphysis-fundal height (SFH) was not measured in 10.7%, with no difference before and after 2014 (7.3 versus 11.8% p = .11). Ultrasound examination for fetal biometry had not been prescribed in spite of abnormal SFH in 47.7% of undiagnosed FGR infants. Diagnosis has been missed in 11.5% of infants because of misinterpretation of the estimated fetal weight's centile. CONCLUSION: FGR is widely underdiagnosed. However, the limited performances can partially be explained by the regular misuse of screening method in clinical practice. Despite the systematic third trimester ultrasound screening, the detection rate of FGR was similar to the one reported in the medical literature. The timing of routine third trimester ultrasound in low-risk women may be rethought.

Fatal Neonatal DOLK-CDG as a Rare Form of Syndromic Ichthyosis.

Neonatal collodion baby or ichthyosis can pose a diagnostic challenge, and in many cases, only additional organ involvement or the course of the disease will help differentiate between non-syndromic and syndromic forms. Skin abnormalities are described in about 20% of the congenital disorders of glycosylation (CDG). Among those, some rare CDG forms constitute a special group among the syndromic ichthyoses and can initially misdirect the diagnosis towards non-syndromic genodermatosis. DOLK-CDG is such a rare subtype, resulting from a defect in dolichol kinase, in which the congenital skin phenotype (often ichthyosis) is later associated with variable extracutaneous features such as dilatative cardiomyopathy, epilepsy, microcephaly, visual impairment, and hypoglycemia and may lead to a fatal course. We report two neonatal cases of lethal ichthyosis from the same family, with distal digital constrictions and a progressive course leading to multi-organ failure and death. Postmortem trio whole-exome sequencing revealed the compound heterozygous variants NM_014908.3: c.1342G>A, p.(Gly448Arg) and NM_014908.3: c.1558A>G, p.(Thr520Ala) in the DOLK gene in the first affected child, which were confirmed in the affected sibling. Reduced staining with anti-α-Dystroglycan antibody was observed in frozen heart tissue of the second child as an expression of reduced O-mannosylation due to the dolichol kinase deficiency. In addition to the detailed dermatopathological changes, both cases presented hepatic and extrahepatic hemosiderosis on histological examination. Our patients represent an early and fatal form of DOLK-CDG with a striking presentation at birth resembling severe collodion baby. Both cases emphasize the phenotypic variability of glycosylation disorders and the importance to broaden the differential diagnosis of ichthyosis and to actively search for organ involvement in neonates with ichthyosis.

Association Between Early Amino Acid Intake and Full-Scale IQ at Age 5 Years Among Infants Born at Less Than 30 Weeks' Gestation.

Importance: An international expert committee recently revised its recommendations on amino acid intake for very preterm infants, suggesting that more than 3.50 g/kg/d should be administered only to preterm infants in clinical trials. However, the optimal amino acid intake during the first week after birth in these infants is unknown. Objective: To evaluate the association between early amino acid intake and cognitive outcomes at age 5 years. Design, Setting, and Participants: Using the EPIPAGE-2 (Epidemiologic Study on Small-for-Gestational-Age Children-Follow-up at Five and a Half Years) cohort, a nationwide prospective population-based cohort study conducted at 63 neonatal intensive care units in France, a propensity score-matched analysis was performed comparing infants born at less than 30 weeks' gestation who had high amino acid intake (3.51-4.50 g/kg/d) at 7 days after birth with infants who did not. Participants were recruited between April 1 and December 31, 2011, and followed up from September 1, 2016, to December 31, 2017. Full-scale IQ (FSIQ) was assessed at age 5 years. A confirmatory analysis used neonatal intensive care unit preference for high early amino acid intake as an instrumental variable to account for unmeasured confounding. Statistical analysis was performed from January 15 to May 15, 2021. Exposures: Amino acid intake at 7 days after birth. Main Outcomes and Measures: The primary outcome was an FSIQ score greater than -1 SD (ie, ≥93 points) at age 5 years. A complementary analysis was performed to explore the association between amino acid intake at day 7 as a continuous variable and FSIQ score at age 5 years. Data from cerebral magnetic resonance imaging at term were available for a subgroup of preterm infants who participated in the EPIRMEX (Cerebral Abnormalities Detected by MRI, Realized at the Age of Term and the Emergence of Executive Functions) ancillary study. Results: Among 1789 preterm infants (929 boys [51.9%]; mean [SD] gestational age, 27.17 [1.50] weeks) with data available to determine exposure to amino acid intake of 3.51 to 4.50 g/kg/d at 7 days after birth, 938 infants were exposed, and 851 infants were not; 717 infants from each group could be paired. The primary outcome was known in 396 of 646 exposed infants and 379 of 644 nonexposed infants who were alive at age 5 years and was observed more frequently among exposed vs nonexposed infants (243 infants [61.4%] vs 206 infants [54.4%], respectively; odds ratio [OR], 1.33 [95% CI, 1.00-1.71]; absolute risk increase in events [ie, the likelihood of having an FSIQ score >-1 SD at age 5 years] per 100 infants, 7.01 [95% CI, 0.06-13.87]; P = .048). In the matched cohort, correlation was found between amino acid intake per 1.00 g/kg/d at day 7 and FSIQ score at age 5 years (n = 775; ß = 2.43 per 1-point increase in FSIQ; 95% CI, 0.27-4.59; P = .03), white matter area (n = 134; ß = 144 per mm2; 95% CI, 3-285 per mm2; P = .045), anisotropy of the corpus callosum (n = 50; ß = 0.018; 95% CI, 0.016-0.021; P < .001), left superior longitudinal fasciculus (n = 42; ß = 0.018; 95% CI, 0.010-0.025; P < .001), and right superior longitudinal fasciculus (n = 42; ß = 0.014 [95% CI, 0.005-0.024; P = .003) based on magnetic resonance imaging at term. Confirmatory and sensitivity analyses confirmed these results. For example, the adjusted OR for the association between the exposure and the primary outcome was 1.30 (95% CI, 1.16-1.46) using the instrumental variable approach among 978 participants in the overall cohort, and the adjusted OR was 1.35 (95% CI, 1.05-1.75) using multiple imputations among 1290 participants in the matched cohort. Conclusions and Relevance: In this cohort study, high amino acid intake at 7 days after birth was associated with an increased likelihood of an FSIQ score greater than -1 SD at age 5 years. Well-designed randomized studies with long-term follow-up are needed to confirm the benefit of this nutritional approach.