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Objective: To describe prenatal decision‐making processes and birth plans in pregnancies amenable to planning perinatal palliative care. Design: Multicentre prospective observational study. Setting: Nine Multidisciplinary Centres for Prenatal Diagnosis of the Paris‐Ile‐de‐France region. Population: All cases of major and incurable fetal anomaly eligible for TOP where limitation of life‐sustaining treatments for the neonate was discussed in the prenatal period between 2015 and 2016. Methods: Cases of congenital defects amenable to perinatal palliative care were prospectively included in each centre. Prenatal diagnosis, decision‐making process, type of birth plan, birth characteristics, pregnancy and neonatal outcome were collected prospectively and anonymously. Main outcome measure: Final decision reached following discussions in the antenatal period. Results: We identified 736 continuing pregnancies with a diagnosis of a severe fetal condition eligible for TOP. Perinatal palliative care was considered in 102/736 (13.9%) pregnancies (106 infants); discussions were multidisciplinary in 99/106 (93.4%) cases. Prenatal birth plans involved life‐sustaining treatment limitation and comfort care in 73/736 (9.9%) of the pregnancies. The main reason for planning palliative care at birth was short‐term inevitable death in 39 cases (53.4%). In all, 76/106 (71.7%) infants were born alive, and 18/106 (17%) infants were alive at last follow‐up, including four with a perinatal palliative care birth plan. Conclusions: Only a small proportion of severe and incurable fetal disorders were potentially amenable to limitation of life‐sustaining interventions. Perinatal palliative care may not be considered a universal alternative to termination of pregnancy. Perinatal palliative care is planned in 10% of continuing pregnancies with a major and incurable fetal condition eligible for TOP. Perinatal palliative care is planned in 10% of continuing pregnancies with a major and incurable fetal condition eligible for TOP. [ABSTRACT FROM AUTHOR]

Aim: Our aims were to describe the neurodevelopment of infants with congenital gastrointestinal malformations at 2 years of age and to investigate the association between developmental delay and complex trajectories., Methods: We conducted a retrospective cohort study. Infants operated on for oesophageal atresia, abdominal wall defects, intestinal malformation, congenital diaphragmatic hernia and anorectal malformation were analysed. Neurodevelopment was assessed using the Ages and Stages Questionnaire at 24 months. The primary outcome was the presence of developmental delay, defined as ASQ-24 months of total score ≤ 185., Results: Of 118 patients, 11 (9%) had an ASQ-24 months ≤185. Factors associated with an ASQ-24 months ≤185 were earlier gestational age (p = 0.045), longer invasive ventilation (p = 0.046), longer parenteral nutrition (p = 0.043) and ≥2 hospitalisations in the first 2 years (p = 0.022). They had a significantly longer stay in the neonatal intensive care unit and subsequent hospitalisations (p = 0.007). After adjustment for prematurity and breastfeeding, this association remained statistically significant., Conclusion: Nine per cent of children with a gastrointestinal malformation show a developmental delay at the age of two. A prolonged stay in the neonatal intensive care unit and subsequent hospitalisations are associated with an increased risk of neurodevelopmental disorders, while breastfeeding may have a protective effect., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Importance: In low- and middle-income countries (LMICs), neonatal bacterial infections are mainly caused by Enterobacterales species and Staphylococcus aureus, which are also the leading causes of mortality directly attributable to antimicrobial resistance. As bacterial colonization often precedes infection, better knowledge of colonization is crucial to prevent antibiotic-resistant neonatal sepsis., Objective: To synthesize current evidence on the prevalence of and factors associated with colonization with third-generation cephalosporin-resistant Enterobacterales (3GCRE), carbapenem-resistant Enterobacterales (CRE), and methicillin-resistant S aureus (MRSA) during the first 3 months of life in LMICs., Data Sources: PubMed, Scopus, Web of Science, and the World Health Organization Global Index Medicus were searched for articles published from January 1, 2000, through July 29, 2024., Study Selection: Included studies were conducted in LMICs and reported prevalence rates or factors associated with colonization with 3GCRE, CRE, or MRSA in neonates and infants up to 3 months of age. Outbreak reports were excluded., Data Extraction and Synthesis: Data extraction and risk-of-bias assessment using a Joanna Briggs Institute tool were performed by 2 independent reviewers. Pooled prevalence for each pathogen was computed using a random-effects model. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline., Main Outcomes and Measures: Prevalence of and factors associated with 3GCRE, CRE, and MRSA colonization., Results: Of the 3147 articles identified in the search, 67 studies (51 for 3GCRE and CRE and 16 for MRSA) including 17 152 individuals were eligible. The pooled prevalence of 3GCRE colonization was 30.2% (95% CI, 21.4%-40.7%; τ2 = 1.48; I2 = 95.1%), varying from 18.2% (95% CI, 10.8%-29.1%) in nonhospitalized individuals to 48.2% (95% CI, 36.4%-60.2%) in hospitalized individuals. The prevalence of CRE colonization was 2.6% (95% CI, 0.7%-8.8%; τ2 = 7.79; I2 = 95.6%), while it was 2.7% (95% CI, 1.0%-6.7%; τ2 = 2.58; I2 = 93.5%) for MRSA. Increased risk of colonization with 3GCRE was associated with hospital birth (odds ratio [OR], 1.87; 95% CI, 1.33-2.64), neonatal antibiotic use (OR, 2.96; 95% CI, 1.43-6.11), and prolonged rupture of membranes (OR, 3.86; 95% CI, 2.19-6.84)., Conclusions and Relevance: In this systematic review and meta-analysis of antibiotic-resistant pathogen carriage in individuals aged 0 to 3 months, the pooled prevalence was substantial despite a limited exposure period. Although high heterogeneity between studies limited extrapolation of results, the findings highlight the need for further investigation to identify transmission routes and to design targeted and effective preventive measures.

Very preterm infants are at high risk of growth failure. Poor weight gain is a prominent risk factor for retinopathy of prematurity (ROP) and optimizing nutrition could potentially promote growth and reduce ROP. Most infants at risk of ROP need parenteral nutrition initially and studies of enhanced parenteral provision of lipids and amino acids have suggested a beneficial effect on ROP. Higher amino acid intake was associated with lower incidence of hyperglycemia, a risk factor for ROP. For very preterm infants, providing unpasteurized fortified raw maternal breast milk appears to have a dose-dependent preventive effect on ROP. These infants become deficient in arachidonic acid (ArA) and docosahexaenoic acid (DHA) after birth when the maternal supply is lost. Earlier studies have investigated the impact of omega-3 fatty acids on ROP with mixed results. In a recent study, early enteral supplementation of ArA 100 mg/kg/d and DHA 50 mg/kg/d until term equivalent age reduced the incidence of severe ROP by 50%. IMPACT: Previous reviews of nutritional interventions to prevent morbidities in preterm infants have mainly addressed bronchopulmonary dysplasia, brain lesions and neurodevelopmental outcome. This review focusses on ROP. Neonatal enteral supplementation with arachidonic acid and docosahexaenoic acid, at levels similar to the fetal accretion rate, has been found to reduce severe ROP by 50% in randomized controlled trials., (© 2024. The Author(s).)

Dehydration and malnutrition are common in infants with severe epidermolysis bullosa (EB), but their nutritional needs have been poorly studied. The principal aim was to assess the nutritional status, fluid and electrolyte balance, and nutritional intake of newborns with EB during the first month of life and estimate their needs during this period. This was a retrospective study over an eight-year period. Inclusion criteria were neonates with confirmed EB admitted to our neonatal referral unit during the first month of life. Exclusion criteria were hospitalisations <7 days. Twenty-seven patients with EB (mean [min-max] gestational age = 39 weeks [33; 41]; birth weight = 2986 g [1982; 4150]), were included. Four patients (15%) had hyponatraemia < 135 mmol/L at admission (age at admission = 4.8 days +/- 2.6 [2; 7]). Sixteen patients (59%) had a sodium deficit -requiring fluid and sodium intake well above recommendations from the World Health Organisation (WHO). The risk of hyponatraemia was significantly higher in infants with the greatest body surface area affected but did not appear to be related to EB subtype. Caloric and protein intake were well above the WHO's recommendations, preventing acquired growth restriction. The rate of sodium deficit in neonates with EB is high and related to the significance of skin exudate. The administration of nutrient intake greater than that recommended helps to prevent acquired growth restriction. We propose recommendations for nutritional intake and monitoring in neonates with EB in the first month of life.

To characterize the neonatal hemodynamic profiles in recipients born after twin-to-twin transfusion syndrome (TTTS) treated with fetoscopic selective laser coagulation (FSLC). Retrospective analysis during the first month of life of recipient twins. Of the 480 newborns born during an 11-year period, 138 recipient twins with prenatal FSLC were classified into four groups: no hemodynamic impairment (NoHI, n = 102, 74%), isolated high blood pressure (HighBP, n = 18, 13%), right ventricular outflow tract obstruction (RVOTO, n = 10, 7%), and cardiac failure (CF, n = 8, 6%). The time (median (IQR)) between FSLC and birth was significantly shorter in the HighBP (36 days (23-54)) and CF (44 days (18-54)) groups than in the RVOTO (91 days (68-112)) and NoHi (82 days (62-104)) groups (p < 0.001).     Conclusion: Four distinct and well-characterized groups of recipients were identified based on their hemodynamics. High blood pressure and heart failure occurred in approximately 20% of the infants and were associated with a time between laser coagulation and birth of less than 2 months. What is Known: • Twin-to-twin transfusion syndrome (TTTS) is characterized by a hemodynamic imbalance that leads to high fetal and neonatal mortality if left untreated. One-third of recipient twins born without prenatal fetoscopic laser coagulation (FSLC) develop a life-threatening cardiac failure. What is New: • Four distinct groups of recipient twins with prenatal FSLC have been identified based on their hemodynamics. High blood pressure and cardiac failure occurred in 20% of the infants and were associated with an interval between FSLC and birth of less than 2 months., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: Transcatheter closure of the patent ductus arteriosus (TCPDA) is increasingly used in preterm infants as an alternative to surgical ligation. However, clinically ill preterm infants are at risk of contrast nephropathy due to the angiography contrast agents used during the procedure., Methods: We performed a single-centre before-and-after comparative study in VLBW infants to compare the kinetics of serum creatinine during the first 4 days after TCPDA with or without angiography., Results: 69 patients were included and divided into two groups: TCPDA with (contrast+; n = 37) and without (contrast-, n = 32) use of contrast agent. The median dose [range] of contrast agent was 1.0 mL/kg [0.6-2.4 mL/kg]. The change in serum creatinine level between day 2 to 4 after TCPCA and baseline decreased in the contrast- group (-17% [-46%; 18%]), while it increased in the contrast+ group (7% [-24%; 202%] p = 0.002). Comparison of blood urea levels between groups showed similar significant differences. The change in serum creatinine between day 2 to 4 and baseline was significantly correlated with the dose of contrast agent (r 2  = 0.682; p < 0.001)., Conclusion: The use of contrast agents during TCPDA can potentially harm the renal function of very preterm infants. Therefore, we advise minimising or avoiding the use of contrast agents., (© 2024 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objective: To describe the growth trajectory of children with congenital diaphragmatic hernia (CDH) during the first year, to assess the risk factors for growth failure (GF) at 1 year and to determine nutritional intakes at discharge required for early optimal growth., Design: Single-centre retrospective cohort study based on data from a structured follow-up programme., Setting and Patients: All neonates with CDH (2013-2019) alive at discharge and followed up to age 1., Interventions: None., Main Outcome Measures: Weight-for-age z-score (WAZ) at birth, 3, 6 and 12 months of age; risk factors for GF at age 1; energy and protein intake of infants achieving early optimal growth., Results: Sixty-three of 65 neonates who were alive at discharge were included. Seven (11%) had GF at 1 year and 3 (4.8%) had a gastrostomy tube. The mean WAZ decreased in the first 3 months before catching up at 1 year (-0.6±0.78). Children with a severe form or born preterm experienced a deeper loss (from -1.5 to -2 z-scores) with late and limited catch-up. The median energy intake required to achieve positive or null weight growth velocity differed significantly according to CDH severity, ranging from 100 kcal/kg/day (postnatal forms) to 139 kcal/kg/day (severe prenatal forms) (p=0.009)., Conclusions: Growth patterns of CDH infants suggest that nutritional risk stratification and feeding practices may influence growth outcomes. Our results support individualised and active nutritional management based on CDH severity, with energy requirements as high as 140% of recommended intakes for healthy term infants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The transmission risk of SARS-CoV-2 within hospitals can exceed that in the general community because of more frequent close proximity interactions (CPIs). However, epidemic risk across wards is still poorly described. We measured CPIs directly using wearable sensors given to all present in a clinical ward over a 36-h period, across 15 wards in three hospitals in April-June 2020. Data were collected from 2114 participants and combined with a simple transmission model describing the arrival of a single index case to the ward to estimate the risk of an outbreak. Estimated epidemic risk ranged four-fold, from 0.12 secondary infections per day in an adult emergency to 0.49 per day in general paediatrics. The risk presented by an index case in a patient varied 20-fold across wards. Using simulation, we assessed the potential impact on outbreak risk of targeting the most connected individuals for prevention. We found that targeting those with the highest cumulative contact hours was most impactful (20% reduction for 5% of the population targeted), and on average resources were better spent targeting patients. This study reveals patterns of interactions between individuals in hospital during a pandemic and opens new routes for research into airborne nosocomial risk., (© 2024. The Author(s).)

Background: The management of posterior urethral valve (PUV) in neonates requires close monitoring in the intensive care unit because of the risk of post-obstructive diuresis (POD). Our aim was to describe the incidence and factors associated with POD in newborns treated for PUV., Methods: Retrospective analysis of the medical records of all neonates who underwent surgical intervention for PUV in our neonatal intensive care unit between January 2014 and April 2021., Results: Of the 40 patients included, 15 (37.5%) had POD defined by urine output > 6 ml.kg -1 .h -1 during the first 24 h following urinary tract obstruction relief. At prenatal ultrasound examinations, oligohydramnios was more common in the group with POD than in the group without (53.3% vs. 8%, p = 0.002). Preterm birth was more frequent in neonates with POD (66.7% vs. 8%; p < 0.001). Median serum creatinine (212 [137-246] vs. 95 [77-125] µmol.l -1 ; p < 0.001) and urea (8.5 [5.2-12.2] vs. 4.1 [3.5-4.7] mmol.l -1 ; p < 0.001) concentrations on the day of obstruction relief were significantly higher in the group with POD than in the group without. After adjustment for prematurity, logistic regression models confirmed correlation between the occurrence of POD and the severity of the consequences of urethral obstruction (i.e., oligohydramnios and serum creatinine levels; ß = 2.90 [0.88; 5.36], p = 0.013 and ß = 0.014 [0.003; 0.031], p = 0.034, respectively)., Conclusions: In neonates, POD is common after the relief of PUV-related obstruction. Our findings may help to identify patients at highest risk. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Aim: Preterm children are highly vulnerable to sensorial impairments through Retinopathy Of Prematurity (ROP). The objective was to determine whether some cases of ROP requiring surgery could be secondary to deficiencies in care pathways., Methods: Descriptive study of neonatal characteristics and the screening/treatment pathways of children treated for stage ≥4A ROP from 2009 to 2020 in a referral unit in France., Results: Twenty-five preterm children (44 eyes) were included: median gestational age was 25 weeks, and median birthweight was 700 grams. Eighty-four per cent had received at least one fundus examination, 50% of which were completed on time. At the time of retinal detachment diagnosis, only 36% of the children had received laser or anti-vascular endothelial growth factor (VEGF) intra-vitreal injection. ROP stage was only reported in 8%, and the zone or type was reported in 16% of the files., Conclusion: The risk of blindness and the effectiveness of laser or anti-VEGF treatment highlight the need to enhance screening and treatment practices in France., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Maternal-neonatal listeriosis is a rare and serious infection. The long-term outcome of surviving infants with early-onset or late-onset listeriosis remains unknown. We aimed to determine the long-term neurological and neurodevelopmental outcome of neonatal listeriosis., Methods: In this prospective, matched, observational cohort study, we evaluated children born with microbiologically confirmed maternal-neonatal listeriosis in the French MONALISA cohort. At age 5 years, children underwent neurological and neurodevelopmental assessments of sensory deficits, executive function, adaptive behaviour, and cognitive and motor coordination function. The cognitive domain was assessed using the French version of the Wechsler Preschool and Primary Scale of Intelligence, fourth edition, and scored by Full Scale Intelligence Quotient (FSIQ). The motor domain was assessed by physical examination designed to screen for cerebral palsy and developmental coordination disorder. Executive functioning was assessed using the statue and inhibition subtests of Neuropsychological Assessment, second version. The sensory domain was assessed by parental interview, medical report, and clinical assessment. Adaptive behaviour was measured using the Vineland-II behaviour scale from parent-reported assessments of functional communication, socialisation, daily living, and motor skills. Results were compared with gestational age-matched children from two national prospective cohorts: EPIPAGE-2 (preterm infants) and ELFE (term infants from a general population of infants >32 weeks gestation). This study is registered with ClinicalTrials.gov (NCT02580812)., Findings: Of 59 children who were alive and eligible to participate in the study, 53 (median age 5 years, IQR 5-6) were enrolled for neurodevelopmental assessments between Oct 26, 2016, and Oct 29, 2019. Of 53 children, 31 (58%) had been born preterm, 22 (42%) had early-onset systemic infection, 18 (34%) had early-onset non-systemic infection, and six (11%) had late-onset systemic infection, all with meningitis. 29 (66%) of 44 children, in whom neurodevelopmental disabilities scores were available, developed at least one disability; eight (18%) children had severe neurodevelopmental disabilities. Of four children with late-onset infection and in whom neurodevelopmental disabilities scores were available, three developed at least one neurodevelopmental disability. Neurological and neurodevelopmental outcomes of children with neonatal listeriosis did not differ from those of gestational age-matched control children without infection (relative risk [RR] of at least one disability 0·99 [95% CI 0·65-1·51; p=0·97]; RR of FSIQ less than -1 SD 0·92 [0·54-1·54; p=0·74])., Interpretation: These results highlight the burden of persistent disability and dominant contribution of prematurity to long-term outcomes in children born with neonatal listeriosis. The findings support the implementation of systematic long-term screening and provision of tailored education and special needs support., Funding: Institut Pasteur, Inserm, French Public Health Agency, Contrat de Recherche Clinique, and Assistance Publique-Hôpitaux de Paris., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Few studies on neonatal severe bacterial infection are available in LMICs. Data are needed in these countries to prioritize interventions and decrease neonatal infections which are a primary cause of neonatal mortality. The BIRDY project (Bacterial Infections and Antimicrobial Drug Resistant among Young Children) was initially conducted in Madagascar, Senegal and Cambodia (BIRDY 1, 2012-2018), and continued in Madagascar only (BIRDY 2, 2018-2021). We present here the BIRDY 2 project whose objectives were (1) to estimate the incidence of neonatal severe bacterial infections and compare these findings with those obtained in BIRDY 1, (2) to identify determinants associated with severe bacterial infection and (3) to specify the antibiotic resistance pattern of bacteria in newborns., Methods: The BIRDY 2 study was a prospective community-based mother and child cohort, both in urban and semi-rural areas. All pregnant women in the study areas were identified and enrolled. Their newborns were actively and passively followed-up from birth to 3 months. Data on clinical symptoms developed by the children and laboratory results of all clinical samples investigated were collected. A Cox proportional hazards model was performed to identify risk factors associated with possible severe bacterial infection., Findings: A total of 53 possible severe bacterial infection and 6 confirmed severe bacterial infection episodes were identified among the 511 neonates followed-up, with more than half occurring in the first 3 days. For the first month period, the incidence of confirmed severe bacterial infection was 11.7 per 1,000 live births indicating a 1.3 -fold decrease compared to BIRDY 1 in Madagascar (p = 0.50) and the incidence of possible severe bacterial infection was 76.3, indicating a 2.6-fold decrease compared to BIRDY 1 in Madagascar (p < 0.001). The 6 severe bacterial infection confirmed by blood culture included 5 Enterobacterales and one Enterococcus faecium. The 5 Enterobacterales were extended-spectrum β-lactamases (ESBL) producers and were resistant to quinolones and gentamicin. Enterococcus faecium was sensitive to vancomycin but resistant to amoxicillin and to gentamicin. These pathogns were classified as multidrug-resistant bacteria and were resistant to antibiotics recommended in WHO guidelines for neonatal sepsis. However, they remained susceptible to carbapenem. Fetid amniotic fluid, need for resuscitation at birth and low birth weight were associated with early onset possible severe bacterial infection., Conclusion: Our results suggest that the incidence of severe bacterial infection is still high in the community of Madagascar, even if it seems lower when compared to BIRDY 1 estimates, and that existing neonatal sepsis treatment guidelines may no longer be appropriate in Madagascar. These results motivate to further strengthen actions for the prevention, early diagnosis and case management during the first 3 days of life., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Antibiotic resistance is a global public health issue, particularly in low- and middle-income countries (LMICs), where antibiotics required to treat resistant infections are not affordable. LMICs also bear a disproportionately high burden of bacterial diseases, particularly among children, and resistance jeopardizes progress made in these areas. Although outpatient antibiotic use is a major driver of antibiotic resistance, data on inappropriate antibiotic prescribing in LMICs are scarce at the community level, where the majority of prescribing occurs. Here, we aimed to characterize inappropriate antibiotic prescribing among young outpatient children and to identify its determinants in 3 LMICs., Methods and Findings: We used data from a prospective, community-based mother-and-child cohort (BIRDY, 2012 to 2018) conducted across urban and rural sites in Madagascar, Senegal, and Cambodia. Children were included at birth and followed-up for 3 to 24 months. Data from all outpatient consultations and antibiotics prescriptions were recorded. We defined inappropriate prescriptions as antibiotics prescribed for a health event determined not to require antibiotic therapy (antibiotic duration, dosage, and formulation were not considered). Antibiotic appropriateness was determined a posteriori using a classification algorithm developed according to international clinical guidelines. We used mixed logistic analyses to investigate risk factors for antibiotic prescription during consultations in which children were determined not to require antibiotics. Among the 2,719 children included in this analysis, there were 11,762 outpatient consultations over the follow-up period, of which 3,448 resulted in antibiotic prescription. Overall, 76.5% of consultations resulting in antibiotic prescription were determined not to require antibiotics, ranging from 71.5% in Madagascar to 83.3% in Cambodia. Among the 10,416 consultations (88.6%) determined not to require antibiotic therapy, 25.3% (n = 2,639) nonetheless resulted in antibiotic prescription. This proportion was much lower in Madagascar (15.6%) than in Cambodia (57.0%) or Senegal (57.2%) (p < 0.001). Among the consultations determined not to require antibiotics, in both Cambodia and Madagascar the diagnoses accounting for the greatest absolute share of inappropriate prescribing were rhinopharyngitis (59.0% of associated consultations in Cambodia, 7.9% in Madagascar) and gastroenteritis without evidence of blood in the stool (61.6% and 24.6%, respectively). In Senegal, uncomplicated bronchiolitis accounted for the greatest number of inappropriate prescriptions (84.4% of associated consultations). Across all inappropriate prescriptions, the most frequently prescribed antibiotic was amoxicillin in Cambodia and Madagascar (42.1% and 29.2%, respectively) and cefixime in Senegal (31.2%). Covariates associated with an increased risk of inappropriate prescription include patient age greater than 3 months (adjusted odds ratios (aOR) with 95% confidence interval (95% CI) ranged across countries from 1.91 [1.63, 2.25] to 5.25 [3.85, 7.15], p < 0.001) and living in rural as opposed to urban settings (aOR ranged across countries from 1.83 [1.57, 2.14] to 4.40 [2.34, 8.28], p < 0.001). Diagnosis with a higher severity score was also associated with an increased risk of inappropriate prescription (aOR = 2.00 [1.75, 2.30] for moderately severe, 3.10 [2.47, 3.91] for most severe, p < 0.001), as was consultation during the rainy season (aOR = 1.32 [1.19, 1.47], p < 0.001). The main limitation of our study is the lack of bacteriological documentation, which may have resulted in some diagnosis misclassification and possible overestimation of inappropriate antibiotic prescription., Conclusion: In this study, we observed extensive inappropriate antibiotic prescribing among pediatric outpatients in Madagascar, Senegal, and Cambodia. Despite great intercountry heterogeneity in prescribing practices, we identified common risk factors for inappropriate prescription. This underscores the importance of implementing local programs to optimize antibiotic prescribing at the community level in LMICs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ardillon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The exact timing, causes, and circumstances of stillbirth and neonatal mortality in low- and middle-income countries (LMICs) remain poorly described, especially for antenatal stillbirths and deaths occurring at home. We aimed to provide reliable estimates of the incidence of stillbirth and neonatal death in three LMICs (Madagascar, Cambodia and Senegal) and to identify their main causes and associated risk factors., Methods: This study is based on data from an international, multicentric, prospective, longitudinal, community-based mother-infant cohort. We included pregnant mothers and prospectively followed up their children in the community. Stillbirths and deaths were systematically reported; information across healthcare settings was collected and verbal autopsies were performed to document the circumstances and timing of death., Results: Among the 4436 pregnancies and 4334 live births, the peripartum period and the first day of life were the key periods of mortality. The estimated incidence of stillbirth was 11 per 1000 total births in Cambodia, 15 per 1000 in Madagascar, and 12 per 1000 in Senegal. We estimated neonatal mortality at 18 per 1000 live births in Cambodia, 24 per 1000 in Madagascar, and 23 per 1000 in Senegal. Based on ultrasound biometric data, 16.1% of infants in Madagascar were born prematurely, where 42% of deliveries and 33% of deaths occurred outside healthcare facilities. Risk factors associated with neonatal death were mainly related to delivery or to events that newborns faced during the first week of life., Conclusions: These findings underscore the immediate need to improve care for and monitoring of children at birth and during early life to decrease infant mortality. Surveillance of stillbirth and neonatal mortality and their causes should be improved to mitigate this burden in LMICs., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2023 by the Journal of Global Health. All rights reserved.)

Background: Vaccination reduces mortality from infectious disease, which is the leading cause of death in children under 5 and bears a particularly high burden in low- and middle-income countries. The Global Vaccine Action Plan (2011-2020) has set a target of 90% vaccine coverage for all vaccines included in national immunization programs by 2020. The objectives of this study were to estimate vaccine coverage among children in Madagascar, Cambodia, and Senegal and to identify the risk factors associated with incomplete vaccination., Methods: Using data from a community-based prospective cohort that included all newborn of some areas from 2012 to 2018 in these 3 countries, vaccine coverage was estimated for BCG, hepatitis B, oral polio, pentavalent (targeting diphtheria, tetanus, pertussis, hepatitis B, and Haemophilus influenzae type b), and measles vaccines. Risk factor analysis was performed with logistic regression models to identify correlates of incomplete vaccination., Results: A total of 3606 children were followed up, and vaccine coverage was below the 90% threshold for most vaccines in all countries. Coverage was higher for vaccines recommended at birth and at 6 weeks, while a decrease in coverage for subsequent doses was observed for vaccines requiring several doses (23-47 points). Low birth weight (<2500 g) was an important risk factor for nonvaccination for vaccines recommended at birth in all 3 countries (adjusted odds ratio [95% confidence interval] ranging from 1.93 [1.11-3.38] to 4.28 [1.85-9.37])., Conclusions: Vaccine coverage for common childhood vaccines was lower than World Health Organization recommendations, and multidisciplinary approaches may help to improve vaccine coverage and timeliness., Competing Interests: Conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Long-term digestive, respiratory, and neurological morbidity is significant in children who have undergone surgery for esophageal atresia (EA), especially after staged repair for long-gap EA. Risk factors for morbidity after primary repair (non-long-gap populations) have been less documented. We investigated peri- and neonatal factors associated with unfavorable outcomes in children 2 years after primary esophageal anastomosis. This was a single-center retrospective study, based on neonatal, surgical, and pediatric records of children born between December 1, 2002, and December 31, 2018, and followed up to age 2 years. The primary endpoint was unfavorable outcome at 2 years of age, defined by death or survival with severe respiratory, digestive, or neurologic morbidity. Univariate analyses followed by logistic regression analyses were performed to identify the peri- and neonatal risk factors of unfavorable outcomes among survivors at discharge. A total of 150 neonates were included (mean birth weight 2520 ± 718 g, associated malformations 61%); at age 2, 45 (30%) had one or more severe morbidities and 11 had died during the neonatal stay and 2 after discharge (8.7% deaths). In multivariate analyses of the 139 survivors at discharge, duration of ventilatory support (invasive and non-invasive) for more than 8 days (OR 3.74; CI95% [1.68-8.60]; p = 0.001) and achievement of full oral feeding before hospital discharge (OR 0.20; CI95% [0.06-0.56]; p = 0.003) were independently associated with adverse outcome after adjustment for sex, preterm birth, associated heart defect, any surgical complication, and the occurrence of more than one nosocomial infections during the neonatal stay., Conclusions: Post-operative ventilation and feeding management strategies may represent an opportunity for quality-of-care improvement to positively impact long-term outcomes after primary esophageal atresia repair., What Is Known: • Children operated on for esophageal atresia experience long-term digestive, respiratory, and neurologic morbidity, especially after multiple-stage esophageal repair. • Exclusive oral feeding at discharge is associated with a decreased risk of medical complications in the first years of life, in studies including all types of esophageal atresia repair. Outcomes of children after primary repair (non-long gap populations) have been less documented., What Is New: • In our retrospective cohort of children with one-stage esophageal atresia repair, ventilatory support for more than 8 days and inability to achieve full oral feeding before hospital discharge in the neonatal period were independently associated with adverse digestive, respiratory, and neurologic outcomes at 2 years in survivors. • Both these factors are potentially modifiable, representing an opportunity for quality-of-care improvement to positively impact long-term outcomes. These results might also help identify children at risk of unfavorable evolution, to customize a multi-disciplinary follow-up program., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Early treatment of neonatal diabetes with sulfonylureas has been proven to produce marked improvements of neurodevelopment, beside the demonstrated efficacy on glycemic control. Several barriers still prevent an early treatment in preterm babies including the limited availability of suitable galenic form of glibenclamide. We adopted oral glibenclamide suspension (Amglidia) for the early treatment of neonatal diabetes due to an homozygous variant of KCNJ11 gene c.10C>T [p.Arg4Cys] in an extremely preterm infant born at 26 + 2 weeks' of gestational age. After ~6 weeks of insulin treatment with a low glucose intake (4.5 g/kg/day), the infant was switched to Amglidia 6 mg/ml diluted in maternal milk, via nasogastric tube (0.2 mg/kg/day) progressively reduced to 0.01 mg/kg/day (after ~3 months). While on glibenclamide, the patient exhibited a mean daily growth of 11 g/kg/day. The treatment was suspended at month 6 of birth (weight 4.9 kg [5th-10th centile], M3 of c.a.) for normalization of glucose profile. During the treatment, the patient exhibited a stable glucose profile within the range of 4-8 mmol/L in the absence of hypo or hyperglycemic episodes with 2-3 blood glucose tests per day. The patient was diagnosed with retinopathy of prematurity Stade II in Zone II without plus disease at 32 weeks, with progressive regression and complete retinal vascularization at 6 months of birth. Amglidia could be regarded as the specific treatment for neonatal diabetes even in preterm babies due to its beneficial effect on the metabolic and neurodevelopmental side., Competing Interests: Michel Polak has been the scientific advisor for the AMGLIDIA development, none for the others. The other authors declare that they have no conflict of interest., (© 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: This paper’s intent is to describe the neonatal hemodynamic characteristics of recipient twins of monochorionic pregnancies complicated with twin-to-twin transfusion syndrome (TTTS), born without prenatal fetoscopic selective laser coagulation (FSLC). Methods: Retrospective analysis of hemodynamic characteristics was performed during the first five days of life of recipient twins from untreated TTTS. Results: Forty-two recipient twins were included and divided into three groups: no hemodynamic impairment (NoHI) (n = 15, 36%), isolated high blood pressure (HighBP) (n = 12, 28%), and cardiac failure group (CF) (n = 15, 36%). Patients of both CF and HighBP groups had high systolic blood pressure during the first 12 h of life and ventricular hypertrophy at early echocardiography. Cardiac failure occurred at a median age of 14 h (IQR = 6−24) and was followed by a drop in systolic and diastolic blood pressure. Acute kidney injury was more frequent (93% vs. 25%, p < 0.001) and severe (p <0.001) in the CF group than in the HighBP group. The mortality rate in the CF group was 40%. Factors associated with CF were twin anemia-polycythemia sequence (p = 0.012), very preterm birth (p = 0.040), and polycythemia (p = 0.002). Conclusion: One-third of recipient twins born without prenatal FSLC developed life-threatening cardiac failure during the first 24 h of life.

Background: Children in low- and middle-income countries are particularly vulnerable in the months following an initial health event (IHE), with increased risk of mortality caused mostly by infectious diseases. Due to exposure to a wide range of environmental stressors, hospitalization in itself might increase child vulnerability at discharge. The goal of this study was to disentangle the role of hospitalization on the risk of subsequent infection., Methods: Data from a prospective, longitudinal, international, multicenter mother-and-child cohort were analysed. The main outcome assessed was the risk of subsequent infection within 3 months of initial care at hospital or primary healthcare facilities. First, risk factors for being hospitalized for the IHE (Step 1) and for having a subsequent infection (Step 2) were identified. Then, inpatients were matched with outpatients using propensity scores, considering the risk factors identified in Step 1. Finally, adjusted on the risk factors identified in Step 2, Cox regression models were performed on the matched data set to estimate the effect of hospitalization at the IHE on the risk of subsequent infection., Results: Among the 1312 children presenting an IHE, 210 (16%) had a subsequent infection, mainly lower-respiratory infections. Although hospitalization did not increase the risk of subsequent diarrhoea or unspecified sepsis, inpatients were 1.7 (95% Confidence Intervals [1.0-2.8]) times more likely to develop a subsequent lower-respiratory infection than comparable outpatients., Conclusion: For the first time, our findings suggest that hospitalization might increase the risk of subsequent lower-respiratory infection adjusted on severity and symptoms at IHE. This highlights the need for robust longitudinal follow-up of at-risk children and the importance of investigating underlying mechanisms driving vulnerability to infection., (© The Author(s) 2022; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

We report the 51/2 year prevalence of visual and oculomotor impairments in preterm children born at 24−34 weeks’ gestation (WG) using the population-based cohort study EPIPAGE-2, set in France, 2011. The main outcomes were imputed prevalence of refractive errors (REs), strabismus, and binocular visual acuity (VA). Children were clinically assessed by specially trained pediatricians. The population was also analyzed in terms of cerebral palsy at 51/2 years (no CP, stage 1, stage 2, or stage 3−5) and retinopathy of prematurity in the neonatal period (no ROP, stage 1 or 2, or severe ROP). Among the 4441 children included, 2718 (weighted percentage 58.7%) were clinically assessed. REs were reported in 43.1% (95% confidence interval 37.6−48.4), 35.2% (32.7−37.6), and 28.4% (25.0−31.8) of children born at 24−26, 27−31, and 32−34 WG (p < 0.01), respectively; strabismus rates were 19.5% (14.6−24.4), 14.8% (12.9−16.7), and 8.3% (6.2−10.4) (p < 0.001), respectively. Moderate/severe visual deficiencies (VA < 3.2/10) were present in 1.7% (0.2−3.3) of children born at 24−26 WG, and in less than 1% in other groups. A suboptimal VA 5/10−6.3/10 was measured in 40.6% (35.3−45.8) of children born at 24−26 WG, 35.8% (33.5−38.1) at 27−31 WG, and 33.7% (30.4−37.0) at 32−34 WG. CP and ROP were associated with strabismus and RE. The association between CP and VA was strong, while it was not observed for ROP. In this large cohort of preterm-born children, we found a high prevalence of RE and strabismus regardless of WG, supporting the need for specific attention in this population. High prevalence of suboptimal VA could be challenging for these children at the age of reading and writing acquisition.

Background: Listeriosis is caused by the foodborne pathogen Listeria monocytogenes. It can present as a maternal-neonatal infection. We implemented a nationwide prospective cohort and analyzed the features of neonatal listeriosis., Methods: We studied all neonates born alive from mothers with microbiologically proven maternal-neonatal listeriosis enrolled from November 2009 to December 2017. We analyzed presentation, neonatal outcome at discharge, and predictors of severe presentation and outcome., Results: We studied 189 infants; 133 of 189 (70%) had abnormal clinical status at birth, including acute respiratory distress in 106 of 189 (56%). There were 132 of 189 (70%) infants who developed early-onset listeriosis and 12 of 189 (6%) who developed late-onset listeriosis; all presented with acute meningitis. There were 17 of 189 (9%) infants who had major adverse outcomes: 3%, (5 of 189) death; 6% (12 of 189), severe brain injury; and 2% (3 of 189), severe bronchopulmonary dysplasia. Fifteen of 17 infants were born <34 weeks of gestation (P < .0001 vs infants born ≥34 weeks of gestation). Maternal antimicrobial treatment ≥1 day before delivery was associated with a significant decrease in presentation severity for the infant, resulting in significantly fewer inotropic drugs, fluid resuscitation, and mechanical ventilation requirement (odds ratio, 0.23; 95% confidence interval, 0.09-0.51; P < .0001)., Conclusions: Antenatal maternal antimicrobial treatment is associated with reduced neonatal listeriosis severity, justifying the prescription of preemptive maternal antimicrobial therapy when maternal-fetal listeriosis is suspected. Neonatal outcome is better than reported earlier, and its major determinant is gestational age at birth., Clinical Trials Registration: NCT01520597., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background : Aminoglycosides are the most prescribed antibiotics in neonatal intensive care units (NICU). Reducing exposure to antibiotics in the NICU is highly desirable, particularly through benchmarking methods. Methods: Description of aminoglycosides prescriptions in 23 French NICU using the same computerized system over a 4-year period (2017-2020). A benchmarking program of antibiotics prescription was associated. Results: The population included 53,818 patients. Exposition rates to gentamicin and amikacin were 31.7% ( n = 17,049) and 9.1% ( n = 4894), respectively. Among neonates exposed to gentamicin, 90.4% of gentamicin and 77.6% of amikacin treatments were started within the 1st week of life. Among neonates exposed to amikacin, 77.6% started amikacin within the 1st week. The average daily dose of gentamicin at first prescription increased over the study period from 3.9 in 2017 to 4.4 mg/kg/d in 2020 ( p < 0.0001). Conversely, the corresponding amikacin daily doses decreased from 13.0 in 2017 to 12.3 mg/kg/d in 2020 ( p = 0.001). The time interval between the first 2 doses of gentamicin was mainly distributed in 3 values during the first week of life: 49.4% at 24 h, 26.4% at 36 h, and 22.9% at 48 h. At first amikacin prescription, the time interval was distributed in 4 categories: 48% at 24 h, 4.1% at 30 h, 8.5% at 36 h, and 37.1% at 48 h. As compared to literature guidelines, the rates of overdose and underdose in gentamicin (1.5% and 2.7%) and amikacin (0.3% and 1.0%). They significantly decreased for gentamicin over the study period. In multivariate analysis, the factors significantly associated with GENT overdose were the year of admission, prematurity, length of stay, and duration of the treatment. Conclusion: This prescription strategy ensured a low rate of overdose and underdose, and some benefits of the benchmarking program is suggested.

Objective: To describe a postnatal series of patients with arthrogryposis multiplex congenita by the causal mechanisms involved., Methods: In this single-center study, the local data warehouse was used to identify patients with arthrogryposis multiplex congenita. Patients were classified into different etiologic groups., Results: Of 82 patients included, the most frequent cause of arthrogryposis multiplex congenita was a neuromuscular disorder (39%), including skeletal muscle (n = 19), neuromuscular junction (n = 3), and peripheral nerve (n = 11) involvement. In other subgroups, 19 patients (23%) were classified by disorders in the central nervous system, 5 (6%) in connective tissue, 7 (8.5%) had mixed mechanisms, and 18 (22%) could not be classified. Contractures topography was not associated with a causal mechanism. Cerebral magnetic resonance imaging (MRI), electroneuromyography, and muscle biopsy were the most conclusive investigations. Metabolic investigations were normal in all the patients tested. Targeted or whole exome sequencing diagnostic rates were 51% and 71%, respectively. Thirty-three percent of patients died (early death occurred in patients with polyhydramnios, prematurity, and ventilatory dependency)., Discussion: The benefits of a precise diagnosis in the neonatal period include more tailored management of arthrogryposis multiplex congenita and better genetic information.

Background: Severe bacterial infections (SBIs) are a leading cause of neonatal deaths in low- and middle-income countries (LMICs). However, most data came from hospitals, which do not include neonates who did not seek care or were treated outside the hospital. Studies from the community are scarce, and few among those available were conducted with high-quality microbiological techniques. The burden of SBI at the community level is therefore largely unknown. We aimed here to describe the incidence, etiology, risk factors, and antibiotic resistance profiles of community-acquired neonatal SBI in 3 LMICs., Methods and Findings: The BIRDY study is a prospective multicentric community-based mother and child cohort study and was conducted in both urban and rural areas in Madagascar (2012 to 2018), Cambodia (2014 to 2018), and Senegal (2014 to 2018). All pregnant women within a geographically defined population were identified and enrolled. Their neonates were actively followed from birth to 28 days to document all episodes of SBI. A total of 3,858 pregnant women (2,273 (58.9%) in Madagascar, 814 (21.1%) in Cambodia, and 771 (20.0%) in Senegal) were enrolled in the study, and, of these, 31.2% were primigravidae. Women enrolled in the urban sites represented 39.6% (900/2,273), 45.5% (370/814), and 61.9% (477/771), and those enrolled in the rural sites represented 60.4% (1,373/2,273), 54.5% (444/814), and 38.1% (294/771) of the total in Madagascar, Cambodia, and Senegal, respectively. Among the 3,688 recruited newborns, 49.6% were male and 8.7% were low birth weight (LBW). The incidence of possible severe bacterial infection (pSBI; clinical diagnosis based on WHO guidelines of the Integrated Management of Childhood Illness) was 196.3 [95% confidence interval (CI) 176.5 to 218.2], 110.1 [88.3 to 137.3], and 78.3 [59.5 to 103] per 1,000 live births in Madagascar, Cambodia, and Senegal, respectively. The incidence of pSBI differed between urban and rural sites in all study countries. In Madagascar, we estimated an incidence of 161.0 pSBI per 1,000 live births [133.5 to 194] in the urban site and 219.0 [192.6 to 249.1] pSBI per 1,000 live births in the rural site (p = 0.008). In Cambodia, estimated incidences were 141.1 [105.4 to 189.0] and 85.3 [61.0 to 119.4] pSBI per 1,000 live births in urban and rural sites, respectively (p = 0.025), while in Senegal, we estimated 103.6 [76.0 to 141.2] pSBI and 41.5 [23.0 to 75.0] pSBI per 1,000 live births in urban and rural sites, respectively (p = 0.006). The incidences of culture-confirmed SBI were 15.2 [10.6 to 21.8], 6.5 [2.7 to 15.6], and 10.2 [4.8 to 21.3] per 1,000 live births in Madagascar, Cambodia, and Senegal, respectively, with no difference between urban and rural sites in each country. The great majority of early-onset infections occurred during the first 3 days of life (72.7%). The 3 main pathogens isolated were Klebsiella spp. (11/45, 24.4%), Escherichia coli (10/45, 22.2%), and Staphylococcus spp. (11/45, 24.4%). Among the 13 gram-positive isolates, 5 were resistant to gentamicin, and, among the 29 gram-negative isolates, 13 were resistant to gentamicin, with only 1 E. coli out of 10 sensitive to ampicillin. Almost one-third of the isolates were resistant to both first-line drugs recommended for the management of neonatal sepsis (ampicillin and gentamicin). Overall, 38 deaths occurred among neonates with SBI (possible and culture-confirmed SBI together). LBW and foul-smelling amniotic fluid at delivery were common risk factors for early pSBI in all 3 countries. A main limitation of the study was the lack of samples from a significant proportion of infants with pBSI including 35 neonatal deaths. Without these samples, bacterial infection and resistance profiles could not be confirmed., Conclusions: In this study, we observed a high incidence of neonatal SBI, particularly in the first 3 days of life, in the community of 3 LMICs. The current treatment for the management of neonatal infection is hindered by antimicrobial resistance. Our findings suggest that microbiological diagnosis of SBI remains a challenge in these settings and support more research on causes of neonatal death and the implementation of early interventions (e.g., follow-up of at-risk newborns during the first days of life) to decrease the burden of neonatal SBI and associated mortality and help achieve Sustainable Development Goal 3., Competing Interests: The authors have declared that no competing interests exist.

Diabetic retinopathy (DR) remains a major cause of vision loss, due to macular edema, retinal ischemia and death of retinal neurons. We previously demonstrated that acute administration of glibenclamide into the vitreous, or given orally at a non-hypoglycemic dose, protected the structure and the function of the retina in three animal models that each mimic aspects of diabetic retinopathy in humans. In this pilot study, we investigated whether one year of chronic oral glibenclamide, in a non-hypoglycemic regimen (Amglidia ® , 0.4 mg/kg, Ammtek/Nordic Pharma, 5 d/week), could alleviate the retinopathy that develops in the Goto-Kakizaki (GK) rat. In vivo, retinal function was assessed by electroretinography (ERG), retinal thickness by optical coherence tomography (OCT) and retinal perfusion by fluorescein and indocyanin green angiographies. The integrity of the retinal pigment epithelium (RPE) that constitutes the outer retinal barrier was evaluated by quantitative analysis of the RPE morphology on flat-mounted fundus ex vivo. Oral glibenclamide did not significantly reduce the Hb1Ac levels but still improved retinal function, as witnessed by the reduction in scotopic implicit times, limited diabetes-induced neuroretinal thickening and the extension of ischemic areas, and it improved the capillary coverage. These results indicate that low doses of oral glibenclamide could still be beneficial for the prevention of type 2 diabetic retinopathy. Whether the retinas ofpatients treated specifically with glibenclamideare less at risk of developing diabetic complications remains to be demonstrated.

Sulfonylureas, widely used as hypoglycemic agents in adults with type 2 diabetes, have neuroprotective effects in preclinical models of central nervous system injury, and in children with neuropsychomotor impairments linked to neonatal diabetes secondary to ATP-sensitive potassium channel mutations. In the human and rodent retina, we show that the glibenclamide-activated channel sulfonylurea receptor 1 (SUR1) is expressed in the retina and enriched in the macula; we also show that it colocalizes with the potassium channel Kir6.2, and with the cation channel transporter TRPM4. Glibenclamide (glyburide), administered at doses that did not decrease the glycemia, or injected directly into the eye, protected the structure and the function of the retina in various models of retinal injury that recapitulate the pathogenic neurodegenerative events in the diabetic retina. The downregulation of SUR1 using a siRNA suppressed the neuroprotective effects of glibenclamide on excitotoxic stress-induced cell death. The glibenclamide effects include the transcriptional regulation of antioxidant and neuroprotective genes. Ocular glibenclamide could be repurposed for diabetic retinopathy., (Copyright © 2020. Published by Elsevier Inc.)

Background: Hyperglycemia in preterm infants may be associated with severe retinopathy of prematurity (ROP) and other morbidities. However, it is uncertain which concentration of blood glucose is associated with increased risk of tissue damage, with little consensus on the cutoff level to treat hyperglycemia. The objective of our study was to examine the association between hyperglycemia and severe ROP in premature infants., Methods and Findings: In 2 independent, monocentric cohorts of preterm infants born at <30 weeks' gestation (Nantes University Hospital, 2006-2016, primary, and Lyon-HFME University Hospital, 2009-2017, validation), we first analyzed the association between severe (stage 3 or higher) ROP and 2 markers of glucose exposure between birth and day 21-maximum value of glycemia (MaxGly1-21) and mean of daily maximum values of glycemia (MeanMaxGly1-21)-using logistic regression models. In both the primary (n = 863 infants, mean gestational age 27.5 ± 1.4 weeks, boys 52.5%; 38 with severe ROP; 54,083 glucose measurements) and the validation cohort (n = 316 infants, mean gestational age 27.4 ± 1.4 weeks, boys 51.3%), MaxGly1-21 and MeanMaxGly1-21 were significantly associated with an increased risk of severe ROP: odds ratio (OR) 1.21 (95% CI 1.14-1.27, p < 0.001) and OR 1.70 (95% CI 1.48-1.94, p < 0.001), respectively, in the primary cohort and OR 1.17 (95% CI 1.05-1.32, p = 0.008) and OR 1.53 (95% CI 1.20-1.95, p < 0.001), respectively, in the validation cohort. These associations remained significant after adjustment for confounders in both cohorts. Second, we identified optimal cutoff values of duration of exposure above each concentration of glycemia between 7 and 13 mmol/l using receiver operating characteristic curve analyses in the primary cohort. Optimal cutoff values for predicting stage 3 or higher ROP were 9, 6, 5, 3, 2, 2, and 1 days above a glycemic threshold of 7, 8, 9, 10, 11, 12, and 13 mmol/l, respectively. Severe exposure was defined as at least 1 exposure above 1 of the optimal cutoffs. Severe ROP was significantly more common in infants with severe exposure in both the primary (10.9% versus 0.6%, p < 0.001) and validation (5.2% versus 0.9%, p = 0.030) cohorts. Finally, we analyzed the association between insulin therapy and severe ROP in a national population-based prospectively recruited cohort (EPIPAGE-2, 2011, n = 1,441, mean gestational age 27.3 ± 1.4, boys 52.5%) using propensity score weighting. Insulin use was significantly associated with severe ROP in overall cohort crude analyses (OR 2.51 [95% CI 1.13-5.58], p = 0.024). Adjustment for inverse propensity score (gestational age, sex, birth weight percentile, multiple birth, spontaneous preterm birth, main pregnancy complications, surfactant therapy, duration of oxygen exposure between birth and day 28, digestive state at day 7, caloric intake at day 7, and highest glycemia during the first week) and duration of oxygen therapy had a large but not significant effect on the association between insulin treatment and severe ROP (OR 0.40 [95% CI 0.13-1.24], p = 0.106). Limitations of this study include its observational nature and, despite the large number of patients included compared to earlier similar studies, the lack of power to analyze the association between insulin use and retinopathy., Conclusions: In this study, we observed that exposure to high glucose concentration is an independent risk factor for severe ROP, and we identified cutoff levels that are significantly associated with increased risk. The clinical impact of avoiding exceeding these thresholds to prevent ROP deserves further evaluation., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To define characteristics of Klebsiella pneumoniae isolated from carriage and infections in mothers and their neonates belonging to a paediatric cohort in Madagascar., Methods: A total of 2000 mothers and their 2001 neonates were included. For each mother, vaginal and stool samples were collected at the birth. Additionally, upon suspicion of infection, samples were collected from suspected infected body sites in 121 neonates. Genomic sequences of all isolated K. pneumoniae were used for phylogenetic analyses and to investigate the genomic content of antimicrobial resistance genes, virulence genes and plasmid replicon types., Results: Five percent (n = 101) of mothers were K. pneumoniae positive. Of 251 collected K. pneumoniae isolates, 102 (40.6%) were from mothers and 149 (59.3%) were from neonates. A total of 49 (19.5%; all from infants except 1) isolates were from infected body sites. MLST identified 108 different STs distributed over the six K. pneumoniae phylogroups Kp1 to Kp6. We found 65 (25.8%) ESBL producers and a total of 101 (40.2%) MDR isolates. The most common ESBL gene was blaCTX-M-15 (in 99.3% of isolates expressing ESBL). One isolate co-harboured blaCTX-M-15 and blaNDM-1 genes. Three isolates from infected body sites belonged to hypervirulent-associated ST23 (n = 1) and ST25 (n = 2). We observed two cases of mother-to-child transmission and sustained K. pneumoniae carriage was identified in 10 neonates, with identical isolates observed longitudinally over the course of 18 to 115 days., Conclusions: This study revealed substantial genetic diversity and a high rate of antimicrobial resistance among K. pneumoniae isolated from both carriage and infections in Madagascar., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The aim of the study was to assess zinc status of newborns with parenteral nutrition with or without a small bowel stoma, to determine the incidence of zinc deficit, and to determine the clinical factors associated with plasma zinc levels., Methods: Monocentric cohort study including all liveborn infants receiving zinc parenteral intake at 500 μg · kg · day and who benefited from at least 1 plasma zinc assessment during hospitalization., Results: Sixty-eight dosages of zinc were performed in 50 newborns, divided into 3 groups (no stoma = 26, jejunostomy = 11, ileostomy = 13). Thirty-seven of the 50 infants were born preterm. The mean ± standard deviation plasma zinc was 14.9 ± 4.3 μmol/L and was similar among the 3 groups. Sixty-four percent, 3%, and 34% of zinc values were within, below, and above the normal range, respectively. In infants with jejunostomy, only 1 plasma zinc value (5%) was below the reference range. Plasma zinc levels were negatively correlated with stoma output (r = -0.449; P = 0.013). In contrast to patients with limited intestinal losses (ie, no stoma and ileostomy groups) no association between zinc levels and postmenstrual age was observed in infants with a jejunostomy suggesting that 500 μg · kg · day was adequate not only in preterm infants but also in term infants with a jejunostomy., Conclusion: Plasma zinc levels decrease significantly with the increase of stoma output volume of newborns with small bowel stoma. Zinc deficit was prevented in newborns with a small bowel stoma receiving of 500 μg · kg · day of parenteral zinc.

Objectives: The primary objective of this study is to determine the current level of patient medication exposure in Level 3 Neonatal Wards (L3NW). The secondary objective is to evaluate in the first month of life the rate of medication prescription not cited in the Summary of Product Characteristics (SmPC). A database containing all the medication prescriptions is collected as part of a prescription benchmarking program in the L3NW., Material and Methods: The research is a two-year observational cohort study (2017-2018) with retrospective analysis of medications prescribed in 29 French L3NW. Seventeen L3NW are present since the beginning of the study and 12 have been progressively included. All neonatal units used the same computerized system of prescription, and all prescription data were completely de-identified within each hospital before being stored in a common data warehouse., Results: The study population includes 27,382 newborns. Two hundred and sixty-one different medications (International Nonproprietary Names, INN) were prescribed. Twelve INN (including paracetamol) were prescribed for at least 10% of patients, 55 for less than 10% but at least 1% and 194 to less than 1%. The lowest gestational ages (GA) were exposed to the greatest number of medications (18.0 below 28 weeks of gestation (WG) to 4.1 above 36 WG) (p<0.0001). In addition, 69.2% of the 351 different combinations of an medication INN and a route of administration have no indication for the first month of life according to the French SmPC. Ninety-five percent of premature infants with GA less than 32 weeks received at least one medication not cited in SmPC., Conclusion: Neonates remain therapeutic orphans. The consequences of polypharmacy in L3NW should be quickly assessed, especially in the most immature infants., Competing Interests: Dr Beatrice Gouyon (1st author) was in charge of the B-PEN program (Benchmarking of Prescription in Neonatology) in the research center (CEPOI) from 2012 to 2016. Her employer was the University Hospital of La Reunion. Then Dr B. Gouyon left the CEPOI to take the lead of a new start-up (LogipremF comp.) responsible for the development of the prescription software Logipren and its implementation in the NICUs of the B-PEN network. This change of affiliation has been contracted with the University Hospital of La Réunion, after authorization from the “Commission de Déontologie de la Fonction Publique” was obtained. Dr B. Gouyon remained closely involved in the research project issued from the B-PEN database particularly in setting of the data warehouse, treatment of data and writing of this manuscript. Pr J-B. Gouyon (the corresponding author) has no function, no shares, no role, nor any financial relationship in and with the LogipremF company. Additionally, he has no other competing interests. As a corresponding author and to the best of my knowledge, other authors have no potential conflicts of interest. This does not alter our adherence to all PLOS ONE policies on sharing data and materials.

Severe bacterial infections are a leading cause of death among neonates in low-income countries, which harbor several factors leading to emergence and spread of multidrug-resistant bacteria. Low-income countries should prioritize interventions to decrease neonatal infections; however, data are scarce, specifically from the community. To assess incidence, etiologies, and antimicrobial drug-resistance patterns of neonatal infections, during 2012-2014, we conducted a community-based prospective investigation of 981 newborns in rural and urban areas of Madagascar. The incidence of culture-confirmed severe neonatal infections was high: 17.7 cases/1,000 live births. Most (75%) occurred during the first week of life. The most common (81%) bacteria isolated were gram-negative. The incidence rate for multidrug-resistant neonatal infection was 7.7 cases/1,000 live births. In Madagascar, interventions to improve prevention, early diagnosis, and management of bacterial infections in neonates should be prioritized.

Objectives: Few studies have evaluated long-term diaphragmatic function in congenital diaphragmatic hernia (CDH). The aim of our cross-sectional study was to assess diaphragmatic function in infants and young children with CDH after surgical repair., Methods: All the patients with CDH repair followed in our centre between February 2014 and January 2016 were enrolled. Patients with a postnatal diagnosis after 1 month of life were excluded. Breathing pattern and diaphragmatic function were assessed using esophageal and gastric (Pgas) pressure recording after surgery, or at 1 or 5 years of age., Results: Twenty-eight patients (24 left-sided CDH, 6 with diaphragmatic patch) were included. Twelve patients were assessed before hospital discharge (Y0), 6 around the age of 1 year (Y1) and 10 around the age of 5 years (Y5). Mean antenatal estimated pulmonary volume (VLA) was 42 ± 10% (n = 23). Diaphragmatic strength, assessed by transdiaphragmatic pressure during crying/sniff, was low at Y0 (47 ± 18 cmH2O, n = 12) and within normality at Y5 (81 ± 15 cmH2O, n = 7). Diaphragmatic dysfunction, assessed by Pgas during crying/sniff, was present at Y0 (-58 ± 22 cmH2O, n = 12) and Y1 (-53 ± 36 cmH2O, n = 5) and still present at Y5 (3 ± 9 cmH2O, n = 7) but to a lesser extent. The diaphragmatic tension time index (TTdi), which estimates diaphragmatic endurance, was high at Y0 (0.10 ± 0.04, n = 11) and within normality at Y5 (0.03 ± 0.01, n = 6). VLA correlated with neonatal TTdi (r = -0.961, P < 0.001)., Conclusions: Infants with CDH have diaphragmatic dysfunction in the neonatal period, which correlates with VLa and normalizes with age. Future longitudinal studies should assess the role of CDH side, size of diaphragmatic defect and patch repair.

In low and middle income countries (LMICs), where the burden of neonatal sepsis is the highest, the spread of extended spectrum beta-lactamase-producing enterobacteriaceae (ESBL-PE) in the community, potentially contributing to the neonatal mortality, is a public health concern. Data regarding the acquisition of ESBL-PE during the neonatal period are scarce. The routes of transmission are not well defined and particularly the possible key role played by pregnant women. This study aimed to understand the neonatal acquisition of ESBL-PE in the community in Madagascar. The study was conducted in urban and semi-rural areas. Newborns were included at birth and followed-up during their first month of life. Maternal stool samples at delivery and six stool samples in each infant were collected to screen for ESBL-PE. A Cox proportional hazards model was performed to identify factors associated with the first ESBL-PE acquisition. The incidence rate of ESBL-PE acquisition was 10.4 cases/1000 newborn-days [95% CI: 8.0-13.4 cases per 1000 newborn-days]. Of the 83 ESBL-PE isolates identified, Escherichia coli was the most frequent species (n = 28, 34.1%), followed by Klebsiella pneumoniae (n = 20, 24.4%). Cox multivariate analysis showed that independent risk factors for ESBL-PE acquisition were low birth weight (adjusted Hazard-ratio (aHR) = 2.7, 95% CI [1.2; 5.9]), cesarean-section, (aHR = 3.4, 95% CI [1.7; 7.1]) and maternal use of antibiotics at delivery (aHR = 2.2, 95% CI [1.1; 4.5]). Our results confirm that mothers play a significant role in the neonatal acquisition of ESBL-PE. In LMICs, public health interventions during pregnancy should be reinforced to avoid unnecessary caesarean section, unnecessary antibiotic use at delivery and low birth weight newborns.