Disclosure: L. Martinerie: None. I. Hani: None. L. Guyon: None. N. Cherradi: None. T. Vu: None. J. Perrot: None. T. Rajkumar: None. E. Pussard: None. P. Boileau: None. R. Brillet: None. J. Guegan: None. J. Bouligand: None. P. Kamenicky: None. M. Lombes: None. S. Viengchareun: None. Aldosterone regulates sodium homeostasis by binding to the Mineralocorticoid Receptor (MR). We previously identified a critical temporal window during renal development when MR expression is low, explaining the physiological sodium losses observed in newborns at birth. However, the molecular mechanisms governing MR expression remain unclear. Here, we report the involvement of two microRNAs (miRNAs), miR-409-3p and miR-431-5p, in regulating MR expression during early renal development. Using miRNA sequencing, we identified these miRNAs as upregulated on postnatal day 0 (D0) compared to day 8 (D8). RT-qPCR validated their differential expression, while luciferase reporter assays confirmed their functional interaction with MR transcripts. Functional studies using miRNA mimics and inhibitors revealed that miR-409-3p and miR-431-5p modulate MR expression and signaling in primary renal cell cultures. Specifically, their increased expression at D0 destabilizes MR transcripts and decreases MR expression and signaling, while their decreased expression at D8 leads to MR stabilization and enhanced mineralocorticoid signaling. Notably, digital droplet PCR (ddPCR) analysis of neonatal urine samples from the PREMALDO cohort demonstrated that these miRNAs are highly expressed at birth but decrease gradually postnatally. To explore the broader regulatory network, we performed RNA sequencing to identify differentially expressed genes (DEGs) between D0 and D8. Cross-referencing DEGs with the predicted targets of miR-409-3p and miR-431-5p yielded 83 differentially expressed target genes. Functional annotation of these genes highlighted significant enrichment in pathways related to kidney development, sodium transport and homeostasis. Our findings identify miR-409-3p and miR-431-5p as key regulators of MR expression and mineralocorticoid signaling during renal development. These miRNAs could serve as potential predictive and non-invasive biomarkers of renal maturity and mineralocorticoid signaling efficiency in premature infants. Presentation: Monday, July 14, 2025

BACKGROUND:Accurately targeting newborns suspected of early-onset bacterial neonatal infection (EONI) and optimizing the administration of antibiotics is challenging. French clinical guidelines (HAS/SFN) on the management of newborns over 34 weeks at risk of EONI were deployed in September 2017. OBJECTIVE:Our objective was to assess their implementation 3 years later in the Paris area, representing approximately 180,000 births. METHODS AND SETTINGS:We conducted an observational study in all maternity units of the Ile-de-France region from July 2020 to January 2021. We sent a self-administered questionnaire on the application of the new guidelines by email addressed to a pediatrician in each maternity unit. RESULTS:Out of the 80 maternity units in the Ile-de-France region, 78 participated. Among the participating units, 40 (51 %) reported applying the new clinical guidelines fully, 28 (36 %) partially, while 10 (13 %) reported not applying them. Among participants, 45 (66 %) maternity units found the implementation of the clinical guidelines feasible, and nearly 80 % of them observed that applying them resulted in fewer additional tests, such as blood samples or peripheral bacteriological tests. Only 35 % of maternity units no longer collect gastric fluid sample, even though this practice is no longer recommended. Among the difficulties identified by the 10 centers that reported not implementing the guidelines were a lack of equipment, insufficient numbers of competent personnel, and insufficient time to train relevant professionals. CONCLUSION:Three years after the publication of the French clinical guidelines (HAS/SFN) on the management of newborns over 34 weeks at risk of EONI, this study showed that over 85 % of responding maternity units in the Ile-de-France region reported have implemented the guidelines either fully or partially.

Four indicators of severe neonatal morbidity (SNM) (intraventricular hemorrhage stages 3–4, retinopathy of prematurity (ROP) stage 3, severe bronchopulmonary dysplasia (BPD), and/or necrotizing enterocolitis) are well-known to be associated with poor infancy outcome after very preterm birth. Practice changes according to recent guidelines were implemented after medical team restructuration. We hypothesized that these changes may have improved overall survival and SNM-free survival in extremely preterm infants (EPI). We conducted a monocentric, retrospective, uncontrolled before-after study at our neonatal intensive care unit including all inborn alive neonates with gestational age less than 28 weeks during two periods (period 1 2016–2017, period 2 2019–2020). We compared the global and SNM-free survival rates before and after changes were implemented. Clinical, ventilatory, and nutritional data were also collected for comparison. We included 163 EPI (76 for period 1, 87 for period 2). Twenty-five patients deceased before home discharge in each group. The median duration of invasive ventilation was shorter during period 2 (4 vs 17 days, p < 0.01). Patients of period 2 had an earlier exclusive enteral nutrition (20 vs 34 days, p < 0.01). The composite endpoint of “death or SNM” was lower during period 2 (40.2

To describe the circumstances, causes and timing of death in extremely preterm infants. 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. 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. The death of extremely preterm infants in NICU is a complex phenomenon in which the circumstances and causes of death are intertwined.

Very low birth weight (VLBW) neonates present a high risk of metabolic bone disease (MBD). Our main objective was to determine the easiest way to make an early diagnosis of this disease by identifying surrogate biomarkers before any radiological signs occurred. We conducted in our NICU a 6-month observational prospective study, with inclusion of all singleton VLBW neonates. We collected clinical and biological data, and nutritional intakes during hospitalization. We defined biological MBD (bMBD) as alkaline phosphatase (ALP) levels superior to 600 UI/L at day of life 30 (DOL30) and performed a case–control analysis. Nine out of 30 patients (30

Plasticity in developmental programming has evolved in order to provide the best chances of survival and reproductive success to the organism under changing environments. Environmental conditions that are experienced in early life can profoundly influence human biology and long-term health. Developmental origins of health and disease and life-history transitions are purported to use placental, nutritional, and endocrine cues for setting long-term biological, mental, and behavioral strategies in response to local ecological and/or social conditions. The window of developmental plasticity extends from preconception to early childhood and involves epigenetic responses to environmental changes, which exert their effects during life-history phase transitions. These epigenetic responses influence development, cell- and tissue-specific gene expression, and sexual dimorphism, and, in exceptional cases, could be transmitted transgenerationally. Translational epigenetic research in child health is a reiterative process that ranges from research in the basic sciences, preclinical research, and pediatric clinical research. Identifying the epigenetic consequences of fetal programming creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and the development of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs.

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.

Objective To compare different antibiotic prophylaxis administered after preterm premature rupture of membranes to determine whether any were associated with differences in obstetric and/or neonatal outcomes and/or neurodevelopmental outcomes at 2 years of corrected age. Design Prospective, nationwide, population-based EPIPAGE-2 cohort study of preterm infants. Setting France, 2011. Sample We included 492 women with a singleton pregnancy and a diagnosis of preterm premature rupture of membranes at 24-31 weeks. Exclusion criteria were contraindication to expectant management or indication for antibiotic therapy other than preterm premature rupture of membranes. Antibiotic prophylaxis was categorised as amoxicillin (n = 345), macrolide (n = 30), third-generation cephalosporin (n = 45) or any combinations covering Streptococcus agalactiae and >90% of Escherichia coli (n = 72), initiated within 24 hours after preterm premature rupture of membranes. Methods Population-averaged robust Poisson models. Main Outcome Measures Survival at discharge without severe neonatal morbidity, 2-year neurodevelopment. Results With amoxicillin, macrolide, third-generation cephalosporin and combinations, 78.5%, 83.9%, 93.6% and 86.0% of neonates were discharged alive without severe morbidity. The administration of third-generation cephalosporin or any E. coli-targeting combinations was associated with improved survival without severe morbidity (adjusted risk ratio 1.25 [95% confidence interval 1.08-1.45] and 1.10 [95 % confidence interval 1.01-1.20], respectively) compared with amoxicillin. We evidenced no increase in neonatal sepsis related to third-generation cephalosporin-resistant pathogen. Conclusion In preterm premature rupture of membranes at 24-31 weeks, antibiotic prophylaxis based on third-generation cephalosporin may be associated with improved survival without severe neonatal morbidity when compared with amoxicillin, with no evidence of increase in neonatal sepsis related to third-generation cephalosporin-resistant pathogen.

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

Glucose homeostasis is a real challenge for extremely preterm infants (EPIs) who have both limited substrate availability and immature glucose metabolism regulation. In the first days of life, EPIs frequently develop transient glucose intolerance, which has a complex pathophysiology that associates unregulated gluconeogenesis, immature insulin secretion, and peripheral insulin resistance. In this population, glucocorticoid therapy is frequently administrated to prevent severe bronchopulmonary dysplasia. During this treatment, glucose intolerance classically increases and may lead to hyperglycemia. We report a case of neonatal hypoglycemia that was concomitant to a glucocorticoids administration, and that led to a congenital hyperinsulinism diagnosis in an EPI with a heterozygous ABCC8 variant. The variant was inherited from his mother, who had developed monogenic onset diabetes of the youth (MODY) at the age of 23. ABCC8 encodes a beta-cell potassium channel unit and causes congenital hyperinsulinism or MODY depending on the mutation location. Moreover, some mutations have been observed in the same patient to cause both hyperinsulinism in infancy and MODY in adulthood. In our case, the baby showed repeated and severe hypoglycemias, which were undoubtedly time-associated with the betamethasone intravenous administration. This hyperinsulinism was transient, and the infant has not yet developed diabetes at three years of age. We take the opportunity presented by this unusual clinical presentation to provide a review of the literature, suggesting new insights regarding the pathophysiology of the beta-pancreatic cells' insulin secretion: glucocorticoids may potentiate basal insulin secretion in patients with ABCC8 mutation.

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

Background Early-onset neonatal sepsis (EOS) is a rare condition but an important cause of severe morbidity and mortality in neonates. Methods This is a prospective observational study in neonates born at ≥34 weeks of gestation (WG). The primary endpoint was EOS, defined by isolation of pathogenic species from blood culture and/or cerebrospinal fluid culture within 72 hours after birth. Data on EOS were collected exhaustively from all maternity wards in Paris area (April 2019–March 2021). Results 108 EOS were recorded (annual incidence, 0.32 per 1000 live births; 95% CI 0.26 to 0.38). In term infants, the most frequent pathogens were group B Streptococcus (GBS) (n=47) and Escherichia coli (n=20); in late preterm infants, the most frequent pathogens were E. coli (n=15) and GBS (n=7). Fifteen meningitis cases were diagnosed. Five E. coli strains (14%) were resistant to both amoxicillin and gentamicin, which is an empiric treatment for EOS. Of the 54 infants with GBS infections, 35 were born from mothers with negative GBS prepartum screening test and 8 from mothers with no screening. Two deaths were reported, both in term infants ( Proteus mirabilis and E. coli ). Conclusion In neonates ≥34 WG born in the Paris area, GBS was twice as frequent as E. coli in term infants. EOS was six times more frequent in late preterm than in term infants and was due to E. coli in 60% of cases. Prevention of GBS EOS and empiric antibiotic treatment of EOS could be improved.

Neonates have never been reported to be symptomatic when affected with a low affinity β-globin variants. We describe here an isolated cyanosis in a full-term neonate who inherited Hb Saint Mandé variant from his father. He exhibited a low oxygen saturation with no sign of pulmonary disease since birth. The risk for the hemoglobinopathy was known but the medical staff initially supposed that there was no reason for clinical impact because of high proportion of HbF. Pediatricians may be aware of the possibility of such conditions to avoid unnecessary investigations and treatment, even in the first days of life.

We report a case of late-onset sepsis caused by Salmonella Typhi in a one-month old preterm infant hospitalised in our neonatal unit. An investigation of the index case was undertaken to identify the source of contamination. The patient made a complete recovery.

Preterm birth is associated with immaturity of several crucial physiological functions notably those prevailing in the lung and kidney. Recently, a steroid secretion deficiency was identified in very preterm neonates, associated with a partial yet transient deficiency in 11β-hydroxylase activity, sustaining cortisol synthesis. However, the P450c11β enzyme is expressed in preterm adrenal glands, we hypothesized an inhibition of cortisol production by adrenomedullin (ADM), a peptide highly produced in neonates and whose effect on steroidogenesis remains poorly known. We studied the effects of ADM on three models: 104 cord-blood samples of the PREMALDO neonate cohort, genetically targeted mice overexpressing ADM, and two human adrenocortical cell lines (H295R and HAC15 cells). Mid-regional-proADM (MR-proADM) quantification in cord-blood samples showed strong negative correlation with gestational age ( P = 0.0004), cortisol production ( P < 0.0001), and 11β-hydroxylase activity index ( P < 0.0001). Mean MR-proADM was higher in very preterm than in term neonates (1.12 vs 0.60 nmol/L, P < 0.0001). ADM-overexpression mice revealed a lower 11β-hydroxylase activity index ( P < 0.05). Otherwise, aldosterone levels measured by LC-MS/MS were higher in ADM-overexpression mice (0.83 vs 0.46 ng/mL, P < 0.05). More importantly, the negative relationship between adrenal ADM expression and aldosterone production found in control was lacking in the ADM-overexpression mice. Finally, LC-MS/MS and gene expression studies on H295R and HAC15 cells revealed an ADM-induced inhibition of both cortisol secretion in cell supernatants and CYP11B1 expression. Collectively, our results converge toward an inhibitory effect of ADM on glucocorticoid synthesis in humans and should be considered to explain the steroid secretion deficiency observed at birth in premature newborns.

To describe the frequency and nature of premedication practices for neonatal tracheal intubation (TI) in 2011; to identify independent risk factors for the absence of premedication; to compare data with those from 2005 and to confront observed practices with current recommendations. Data concerning TI performed in neonates during the first 14 days of their admission to participating neonatal/pediatric intensive care units were prospectively collected at the bedside. This study was part of the Epidemiology of Procedural Pain in Neonates study (EPIPPAIN 2) conducted in 16 tertiary care units in the region of Paris, France, in 2011. Multivariate analysis was used to identify factors associated with premedication use and multilevel analysis to identify center effect. Results were compared with those of the EPIPPAIN 1 study, conducted in 2005 with a similar design, and to a current guidance for the clinician for this procedure. One hundred and twenty-one intubations carried out in 121 patients were analyzed. The specific premedication rate was 47% and drugs used included mainly propofol (26%), sufentanil (24%), and ketamine (12%). Three factors were associated with the use of a specific premedication: nonemergent TI (Odds ratio (OR) [95% CI]: 5.3 [1.49-20.80]), existence of a specific written protocol in the ward (OR [95% CI]:4.80 [2.12-11.57]), and the absence of a nonspecific concurrent analgesia infusion before TI (OR [95% CI]: 3.41 [1.46-8.45]). No center effect was observed. The specific premedication rate was lower than the 56% rate observed in 2005. The drugs used were more homogenous and consistent with the current recommendations than in 2005, especially in centers with a specific written protocol. Premedication use prior to neonatal TI was low, even for nonemergent procedures. Scientific consensus, implementation of international or national recommendations, and local written protocols are urgently needed to improve premedication practices for neonatal intubation.

Objective: To investigate the impact of fetal growth restriction (FGR) on hormonal regulation of post-natal growth and glucose metabolism [via insulin and growth hormone (GH)/Insulin-like Growth factor 1 (IGF1) axis pathways] in small for gestational age (SGA) neonates. Methods: We conducted a monocentric observational prospective comparative study on 73 singleton babies born with a weight inferior to 2,000 g. We analyzed auxological (weight, height and head circumference), and hormonal (GH, IGF1, and insulin plasma concentrations) data comparing SGA and appropriate for gestational age (AGA) neonates, between day 1 and 60. Results: One third (23/73) of the neonates were SGA. Twenty-five percent (18/73) required insulin for idiopathic hyperglycemia of prematurity and were smaller in weight and head circumference at discharge. In the SGA group compared with the AGA group, GH plasma concentrations were higher at day 3 (70.1 vs. 38.0 mIU/L) and IGF1 plasma concentrations were higher at day 10 (29.0 vs. 18.7 ng/ml). Conclusions: SGA neonates displayed resistance to GH and IGF1, concomitant to insulin resistance. This could partially explain the initial defective catch-up growth and, later in life, the higher prevalence of metabolic syndrome in this population.