Publications

Abstract

Objective: To assess the association between late-onset sepsis (LOS) and neurodevelopmental disorders (NDD) at 5 years of age among children born very preterm.

Methods: We included children from the EPIPAGE-2 cohort study, born before 32 weeks of gestation and followed at 5 years. LOS was defined as one positive blood culture after 72 hours of life, associated with antibiotic therapy ≥5 days. At 5 years, NDD were evaluated as a composite outcome including cerebral palsy, neurosensory impairment and/or coordination, cognitive and behavioural disorders. NDD were categorised as: none, mild or moderate-to-severe disorders. We used multivariable multinomial regressions after multiple imputations of missing data to assess the association between LOS and NDD at 5 years.

Results: Among the 3186 children born very preterm, 697 (20.6%) had at least one episode of LOS and 1927 (60.5%) had a complete assessment at 5 years. Among children who had an LOS, 42.2% had no NDD, 38.2% had mild NDD and 19.6% had moderate-to-severe NDD. The proportion of children with three episodes of LOS was higher in the mild NDD group and in the moderate to severe NDD group than in the none NDD group (1.3% vs 0.6% and 2.8 vs 0.6%, respectively). No association was found between the occurrence of at least one episode of LOS and NDD (mild NDD adjusted OR (aOR) 1.06 (95% CI 0.82 to 1.36); moderate-to-severe NDD aOR 1.18 (95% CI 0.90 to 1.55)).

Conclusion: We found no significant association between LOS and mild, moderate or severe NDD at five in children born very preterm.

Keywords: Child Development; Epidemiology; Follow-Up Studies; Neonatology; Sepsis.

Abstract

Objective: This study assesses whether fetal growth trajectories are associated with neonatal outcomes.

Methods: The study population included 8537 singleton liveborn infants from the 2021 French National Perinatal Survey. Fetal growth trajectories were assessed between second and third trimester routine ultrasounds and between the third trimester ultrasound and birth, and classified for each period as constant (C, fetal weight variation <±1 standard deviation [SD]), accelerated (A, ≥ 1 SD), or declining (D, ≤ -1 SD). Seven combined trajectory groups were defined over both periods: CC, AC, CA, AA, DC, CD, and DD. A composite neonatal outcome included 5-min Apgar score < 7, pH < 7.10, birth resuscitation, neonatal transfer, or death. Adjusted odds ratios (aOR) for potential confounders with 95% confidence intervals (CI) were estimated for the full cohort and by small for gestational age (SGA, birthweight < 10th centile) status.

Results: The fetal trajectory was constant (CC), declining (DC, CD, DD) or accelerated (AC, CA, AA) for 54%, 27%, and 18% of fetuses, respectively. In the overall population, the risk of poor neonatal outcomes was higher in the CD group (aOR, 1.6 [95% CI, 1.3-2.0]) and the DD group (aOR, 2.0 [95% CI, 1.3-3.2]). This risk was also increased in the DD group (aOR, 3.7 [95% CI, 1.8-7.9]) among SGA births and in the CD group (aOR, 1.5 [95% CI, 1.2-2.0]) among non-SGA births.

Conclusion: Declining fetal growth trajectories throughout and during the third trimester of pregnancy were associated with an increased risk of poor neonatal outcomes among both SGA and non-SGA infants.

Keywords: fetal growth restriction; fetal growth trajectories; large for gestational age; neonatal morbidity; small for gestational age.

Abstract

Conventional dendritic cells (cDCs) are key sentinels at epithelial barriers, regulating immunity to microbial pathogens and commensals while preserving tissue integrity. NOTCH2 deficiency in CD11c-expressing cells (Notch2^cKO) disrupts type 2a DC (cDC2a) development, impairs intestinal T_H17 immunity and increases susceptibility to enteropathogenic bacteria. This defect leads to persistent dysbiosis in Notch2^cKO mice, characterized by low-grade inflammation and systemic autoimmune features, including elevated autoantibody titers and renal immune complex deposition. Dysbiosis precedes expansion of highly inflammatory AXL-expressing type 3 DCs (AXL⁺inf-DC3), promoting chronic inflammation and tertiary lymphoid structures driving adaptive immune responses. Notably, dysbiosis is defined by three dominant pathobionts and is transferable to wild-type mice, recapitulating the autoimmune features observed in Notch2^cKO mice. Here these findings identify a microbiota-DC axis linking intestinal pathobionts to systemic autoimmunity, establishing inflammatory DC3 as the cellular bridge between dysbiosis, chronic inflammation and autoimmune pathogenesis.

Abstract

Preterm birth may disrupt maturation of brain networks and functional activity, including theta oscillations that play a key role in early network development. Traditional EEG spectral analyses show marked development of theta power in early infancy, but these approaches mix oscillatory and non-oscillatory activity, limiting insights into the underlying mechanisms. Using spectral parameterization, we assessed the development of aperiodic activity and periodic theta power in very preterm (born before 32 weeks gestational age, GA) and full-term infants, and examined inter-individual variability among preterms. High-density EEG was acquired during active/REM sleep at term-equivalent age (TEA) and 2 months corrected age (2mCA) in preterm (n = 41) and full-term (n = 13) infants. Spectral parameterization allowed extracting metrics of aperiodic activity (offset, exponent) and periodic theta power, globally and across spatial clusters of electrodes. From TEA to 2mCA, offset, exponent, and theta power increased with no differences between preterms and full-terms. At TEA, aperiodic activity metrics were stronger in anterior compared with posterior areas, but this regional landscape shifted by 2mCA due to pronounced changes in posterior areas from TEA to 2mCA. Within preterms, inter-individual variability in EEG metrics at TEA was partly explained by clinical risk factors (male sex, lower GA, being small for GA, and invasive ventilation) and variations in brain microstructure, as assessed with diffusion MRI: higher theta power correlated with more advanced cortical maturation. These findings indicate that EEG spectral parameterization combined with spatial analysis provides a sensitive framework for characterizing early brain maturation and vulnerabilities associated with prematurity.

Keywords: Brain development; Diffusion MRI; Electroencephalography; Prematurity; Spectral parameterization.

Abstract

Antenatal corticosteroids are used to accelerate fetal lung maturation. Recent studies suggest that the current dose may be too high. In the randomized multicenter BETADOSE trial, non-inferiority of the half dose compared to full dose was not shown for surfactant administration. Children with intra-uterine growth restriction have a higher risk of poor respiratory outcomes, including bronchopulmonary dysplasia, compared to those in other indications for antenatal corticosteroids. This post hoc study aims to compare respiratory outcomes between the half-dose and the full-dose groups in very preterm neonates, overall and according to indications for antenatal corticosteroids: inflammatory or vascular context including intra-uterine growth restriction. Eligible neonates were born < 32 weeks among those enrolled in the BETADOSE trial. The primary outcome was the occurrence of bronchopulmonary dysplasia. Multiple analyses adjusted for indications for antenatal corticosteroids, birthweight z-score, and gestational age were used. To account for multiple comparisons, p values were adjusted using the Bonferroni correction for the primary outcome. In the overall population and in the inflammatory context subgroup, there were no significant differences in respiratory outcomes, in particular surfactant use and bronchopulmonary dysplasia. The rate of discharge home with oxygen was higher in the half-dose group in the overall population. In neonates with intra-uterine growth restriction, surfactant use (63% vs 42%, p = 0.02) and bronchopulmonary dysplasia (40% vs 24%, p = 0.04) were more frequent in the half-dose group although no statistically significant difference was observed after correction using the Bonferroni method.

Conclusion: The impact of reducing the dose of antenatal corticosteroids may vary according to the underlying indication for administration. No firm conclusions can be drawn from these findings, which may reflect residual confounding, particularly in the subgroup with intra-uterine growth restriction. As such, this observation should be considered exploratory and further prospective studies are needed.

What is known: • Antenatal corticosteroids are used to accelerate fetal lung maturation. Recent studies question the current dose of betamethasone. The non-inferiority of the half compared to the full dose was not shown regarding the use of surfactant in the BETADOSE trial.

What is new: • Few differences in in-hospital respiratory outcomes were found between the half-dose and the full-dose groups. A trend toward less favorable respiratory outcomes was observed among neonates exposed to the half dose.

Keywords: Antenatal corticosteroids; Bronchopulmonary dysplasia; Intra-uterine growth restriction; Preterm neonates.

Abstract

Over the past decade, new evidence has emerged regarding postnatal corticosteroids use in extremely preterm infants, particularly early prophylactic hydrocortisone. In France, national recommendations published in 2010 address late postnatal corticosteroids use only and do not incorporate the most evidence-based data. We aimed to provide a national overview of prescribing practices in French neonatal intensive care units (NICUs), focusing on prophylactic hydrocortisone. A national survey was conducted between 1 June and 13 August 2024 among all 66 French level III NICUs using a structured online questionnaire. One response per center was gathered. Fifty-five of 66 (83%) NICUs responded. Prophylactic hydrocortisone was used in 33 (60%) centers: 16 (29%) systematically and 17 (31%) selectively. Among users, 21 (64%) targeted the same population as the PREMILOC study. Non-users cited concerns about benefit-risk balance, lack of evidence, and absence of national guidelines. Fear of neurodevelopmental risk was more frequent among non-users (9/22 (41%) vs 1/33 (3%), p < 0.001), while perceived spontaneous intestinal perforation risk did not differ.

Conclusion: Hydrocortisone use in French NICUs remain heterogeneous due to safety concerns and a possible uncertainty about the strength of evidence. These findings underscore the need for updated national guidelines to support harmonized, evidence-based care for ELGANs.

What is known: • Recent evidence supports prophylactic hydrocortisone to improve survival without bronchopulmonary dysplasia in extremely preterm infants. • French national recommendations (2010) address late corticosteroid use (beyond 3 weeks) and do not incorporate recent evidence-based data.

What is new: • This national survey provides the first overview of hydrocortisone use in French NICUs, highlighting heterogeneity in prescribing practices. • It identifies discrepancies between evidence and clinical practice, supporting the need for updated guidelines.

Abstract

Background: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in infants. Nirsevimab, a long-acting monoclonal antibody targeting a conserved epitope on the prefusion F protein (site Φ), has shown high efficacy in clinical trials and early real-world studies. Although widespread resistance has not been reported, concerns remain about the emergence of escape variants, particularly among RSV-B viruses. During the 2024-25 RSV season in France, RSV-B predominated, providing a unique opportunity to examine breakthrough infections with RSV-B and resistance at a large scale. The study aimed to characterise RSV escape from nirsevimab using genotypic and phenotypic methods.

Methods: This POLYRES-2 project was a multicentre, national, observational study conducted in hospital settings (inpatients and outpatients) across France during the 2024-25 RSV season. We included infants aged 1 year or under with a RT-PCR-confirmed RSV infection in routine care, regardless of whether they had received nirsevimab. Infants were identified through hospital virology laboratory databases. Each participating centre was requested to include a balanced number of nirsevimab-exposed and non-exposed infected infants throughout the study period. Clinical data were retrieved from electronic medical records. We compared RSV susceptibility to nirsevimab in infants who received nirsevimab with that in nirsevimab-naive infants. Respiratory samples were sequenced for full-length RSV genomes. To ensure reliability, phylogenetic and mutational analyses were restricted to high-quality sequences with greater than or equal to 90% genome coverage and complete reads across the nirsevimab-binding site. Clinical RSV isolates were tested for neutralisation by nirsevimab. We analysed F candidate substitutions using a fusion inhibition assay. The primary outcomes were presence of resistance-associated substitutions (RASs) in the RSV F protein (site Φ) and phenotypic resistance to nirsevimab.

Findings: Among 1023 RSV-infected infants, 858 (83·9%) had full-length RSV genome sequences: 419 (48·8%) from nirsevimab-treated breakthrough infections (212 [50·6%] RSV-A, 207 [49·4%] RSV-B) and 439 (51·2%) from nirsevimab-naive infants (192 [43·7%] RSV-A, 247 [56·3%] RSV-B). RASs were identified in two of 195 RSV-A breakthrough infections (1·0%) and in 23 of 184 RSV-B breakthrough infections (12·5%). In RSV-A, the only RAS was F:K209E, conferring intermediate resistance. In RSV-B, resistance was more frequent and diverse than in RSV-A: 12 of 23 (52.2%) resistant viruses carried a substitution at residue 208 (F:N208D, F:N208I, F:N208K, F:N208S, or F:N208Y). Additional novel substitutions, including F:I64V/F:K65E, F:K68I, F:L204S, and F:P205S, also mediated resistance. Notably, a resistant RSV-B variant (F:N208S) was detected almost 1 year after prophylaxis. No resistant RSV was detected in nirsevimab-naive infants.

Interpretation: Resistance to nirsevimab in RSV-B can emerge in real-world settings, affecting around 12% of breakthrough infections and showing greater diversity than previously recognised, although the clinical impact remains constrained by available evidence. Detection of resistant variants long after prophylaxis highlights the need for extended genomic surveillance. Integration of clinical and virological data will be essential to sustain the long-term effectiveness of RSV monoclonal antibody programmes.

Funding: This study was supported by a grant from the Agence Nationale de Recherche sur le Sida et les hépatites virales – Maladies Infectieuses Emergentes and the French Ministry of Health and Prevention.

Abstract

Neonatal encephalopathy refers to disturbed neurological function in the neonatal period and has multiple potential aetiologies. A systematic review showed that neonatal encephalopathy, hypoxic-ischaemic encephalopathy, and perinatal asphyxia are often used interchangeably in clinical trials and communications. We aimed to establish an international, consensus-based definition as a preliminary step towards standardising terminology. Findings from a systematic review of definitions guided the creation of a real-time Delphi survey. Three consensus meetings were held to finalise the definition, which was approved by the steering committee. Participants were recruited from a broad range of stakeholder groups, including health-care providers; researchers; parents, family members, guardians, or representatives of children with neonatal encephalopathy; or adults who had neonatal encephalopathy as infants. From Feb 1 to May 31, 2024, the survey received 235 complete and 143 partial responses. Respondents were from 52 countries, with 75 (20%) from low-income and middle-income countries. Although most respondents were health-care workers, 23 (6%) represented parents and caregivers. 62 individuals participated in at least one consensus development meeting. The final definition was organised into primary, secondary, and tertiary domains. The primary domain is as follows: neonatal encephalopathy is a heterogeneous clinical condition characterised by abnormal or impaired brain function with multiple potential causes. It presents with an altered level of consciousness and may include seizures, abnormal primitive and deep tendon reflexes, altered muscle tone, posture or movements, or an abnormal brain-related breathing pattern. Neonatal encephalopathy can be associated with a heightened risk of morbidity and mortality. This Delphi process established a novel consensus definition for neonatal encephalopathy, with contributions from a diverse range of international stakeholders, including families. Adopting consensus-based terminology and definitions will enhance communication among health-care professionals and families, facilitate research and data synthesis, improve the interpretation and application of research findings, and ultimately improve care

Abstract

Objectives: Bacillus cereus sensu lato (s.l.) or B. cereus group increasingly causes severe infections in preterm neonates. However, species-level identification and virulence characterization remain limited. This study aimed to identify B. cereus group species responsible for invasive infections in preterm neonates and to correlate genomic virulence profiles with clinical outcomes.

Methods: We conducted a retrospective, multicentre study across 13 French hospitals (2010-2021), including 40 B. cereus group isolates from blood or cerebrospinal fluid of preterm neonates with invasive infections. Clinical data were extracted from patient records. Whole-genome sequencing (WGS) (Illumina and Oxford Nanopore) with hybrid assemblies enabled species identification using digital DNA-DNA hybridization and average nucleotide identity. Virulence genes were screened against a curated database of 65 virulence genes, and associations with clinical outcomes were analysed.

Results: Forty isolates were analysed, 42.5% (17 of 40) of patients developed septic shock, and 37.5% (15 of 40), died, usually after rapid clinical deterioration. WGS identified seven species, predominantly Bacillus paranthracis (47.5%, 19 of 40) and B. cereus sensu stricto (20%, 8 of 40). Virulence gene content varied by species. The presence of hblCDAB (60%, 9 of 15), nprB (46.5%, 7 of 15), asbABCDEF (80%, 12 of 15), and essC-cereus/esxA (66.7%, 10 of 15) genes correlated with mortality (p 0.00015, 0.002, 0.0027, and 0.02, respectively). B. cereus sensu stricto carried more virulence determinants and was associated with higher mortality than B. paranthracis and other species, at day 7 (p 0.05) and at day 28 (p 0.0065). The cesH gene (60%, 15 of 25) is significantly associated with survival (p 0.007), particularly with B. paranthacis, the predominant species in our cohort.

Conclusions: Invasive B. cereus group infections in preterm neonates are associated with high mortality, particularly in cases due to B. cereus sensu stricto. WGS enables precise species identification and virulence profiling, which are essential insights for diagnostic refinement, outbreak control, and risk stratification in neonatal intensive care settings.

Keywords: Bacillus cereusgroup; Epidemiology; Neonatal infection; Virulence; Whole-genome sequencing.

Abstract

Background: Hypertensive disorders of pregnancy represent a major cause of maternal and fetal morbidity and mortality. Despite primary aldosteronism (PA) being the most common cause of secondary hypertension, there is limited data on pregnancy complications in patients with PA.

Methods: We conducted an international survey across 5 Hypertension Centers in Europe to gather data on maternal and neonatal complications in women diagnosed with PA from 2000 to 2022. We included 102 women aged 18 to 45 years at PA diagnosis who were pregnant either after or <1-year before the diagnosis of PA. The first eligible pregnancy for each patient was included.

Results: Overall, 56% of pregnancies were complicated, with the most frequent complications being maternal preeclampsia (36%), preterm birth (30%), low birth weight (30%), and neonatal intensive care admission (22%). Hypokalemia occurred in 31% of pregnancies. Pregnancies occurring before PA diagnosis presented a poorer blood pressure control and were associated with higher rates of overall, maternal, and fetal/neonatal complications compared with pregnancies in patients with an established PA diagnosis. Independent predictors of complications included uncontrolled blood pressure values during pregnancy (odds ratio [OR], 7.05), undiagnosed PA (OR, 4.37), North/Black African ethnicity (OR, 3.69), a higher body mass index (OR, 1.09), and treatment with a higher number of antihypertensive drugs at PA diagnosis (OR, 2.18).

Conclusions: PA is associated with a high rate of pregnancy-related complications, predominantly preeclampsia. Undiagnosed PA during gestation significantly increases the risk of adverse outcomes. Early identification and optimized hypertension control in women with PA are critical to improve maternal and fetal outcomes.

Keywords: aldosterone; blood pressure; body mass index; hypokalemia; pregnancy.