Abstract
Objective: To assess the association between histological chorioamnionitis without maternal clinical symptoms and neurodevelopmental disabilities at age 5 years in children born very preterm.
Design: French national prospective population-based cohort study, EPIPAGE-2 (Etude épidémiologique sur les petits âges gestationnels).
Setting: All births from 22 to 34 weeks of gestational age in France in 2011 were eligible.
Population: Infants born alive between 24+0 and 31+6 weeks following preterm labour (PTL) or preterm premature rupture of membranes (PPROMs).
Exposure: Histological chorioamnionitis without maternal clinical symptoms, also called isolated histological chorioamnionitis, was defined as the presence of neutrophils in the chorionic plate, excluding clinical chorioamnionitis.
Main outcome measures: Neurodevelopmental disabilities, a composite outcome including cerebral palsy, developmental coordination disorders, sensory impairment, developmental cognitive deficiencies or behavioural difficulties. These assessments were comprehensive, standardised and conducted by trained neuropsychologists and paediatricians at age 5 years.
Results: Among 1296 children alive at 5 years of age, 486 (36.3%) were born in a context of isolated histological chorioamnionitis. Overall, 47% vs 33.6% of children exposed and not exposed to isolated histological chorioamnionitis had mild neurodevelopmental disabilities, and 13.8% vs 13.3% had moderate-to-severe neurodevelopmental disabilities. After multiple imputation and multivariable analysis, isolated histological chorioamnionitis was found not to be associated with the occurrence of mild or moderate-to-severe neurodevelopmental disabilities (adjusted OR: 1.0, 95% CI: 0.7 to 1.4 and 0.9, 0.6 to 1.2).
Conclusion: We did not find any association between isolated histological chorioamnionitis and neurodevelopmental disabilities at age 5 years in children born very preterm after PTL or PPROM.
Abstract
Objective: The objective is to investigate the prevalence of underweight and overweight and obesity (OWOB) and associated risk factors among 5-year-old children born very preterm (VPT).
Design: Multinational area-based cohort study of children born VPT.
Setting: 19 regions in 11 European countries.
Patients: Children born before 32 weeks of gestational age in 2011-2012 and followed up at 5 years of age.
Main outcome measures: Body mass index (BMI) at 5 years of age was classified into underweight and OWOB using International Obesity Task Force references, and associations with sociodemographic, perinatal and neonatal risk factors were assessed using multinomial logistic regression. Data came from medical records during the neonatal hospitalisation and parental questionnaires at 5 years of age. Models accounted for missing data and attrition by using multiple imputation by chained equations and inverse probability weighting.
Results: 27.6% of children were underweight and 10.8% were OWOB. Younger maternal age was associated with lower risks of underweight, while low maternal education, household unemployment and non-European maternal country of birth were associated with having OWOB. Fetal growth restriction, receiving postnatal steroids and bronchopulmonary dysplasia were associated with underweight, and fetal growth restriction, male sex and multiple birth were negatively associated with OWOB.
Conclusions: 38% of children born VPT had suboptimal BMI at 5 years, principally due to being underweight, with differing risk factors for underweight and OWOB. These results raise questions about underlying mechanisms and the growth trajectories and metabolic outcomes of underweight children, in light of high prevalence and association with clinical risk.
Abstract
Importance: Controversies persist about management of the ductus arteriosus by nonsteroidal anti-inflammatory drugs in extremely preterm infants. Acetaminophen (paracetamol) appears to be a promising alternative with possibly fewer adverse effects.
Objective: To evaluate whether prophylactic intravenous acetaminophen started within 12 hours of birth increases survival without neonatal severe morbidities at 36 weeks’ postmenstrual age.
Design, setting, and participants: A double-blind, randomized, placebo-controlled clinical trial was conducted among preterm infants born between 23 weeks 0 days and 28 weeks 6 days of gestation in 43 neonatal intensive care units of 14 European countries between October 2020 (October 2021 for infants born at 23-26 weeks’ gestation, after the phase 2 study identified the optimal dose of acetaminophen) and April 2024. Data analysis was conducted from January to June 2025.
Intervention: In the acetaminophen group, patients born at 27 to 28 weeks’ gestation received a 20-mg/kg loading dose of acetaminophen followed by 7.5 mg/kg every 6 hours for 5 days, and patients born at 23 to 26 weeks’ gestation received a 25-mg/kg loading dose of acetaminophen followed by 10 mg/kg every 6 hours for 5 days. In the placebo group, isotonic sodium chloride was administered.
Main outcomes and measures: The primary outcome was survival without neonatal morbidity evaluated at 36 weeks’ postmenstrual age. The secondary exploratory outcome was ductus arteriosus closure, assessed by echocardiography on day 7.
Results: A total of 778 patients (median [IQR] gestational age, 26 [25-27] weeks; 375 [48.2%] female) were included in the study, with 391 in the acetaminophen group and 387 in the placebo group. Survival without severe morbidities at 36 weeks’ postmenstrual age occurred in 259 infants (66.2%) in the acetaminophen group and 246 (63.6%) in the placebo group (absolute risk difference [ARD], 2.7 [95% CI, -4.0 to 9.3] percentage points; relative risk [RR], 1.04 [95% CI, 0.94 to 1.16]). The ductus arteriosus was considered closed on day 7 in 264 of 371 infants (71.2%) assigned to acetaminophen and 191 of 366 infants (52.2%) assigned to placebo (ARD, 19.0 [95% CI, 12.0 to 25.7] percentage points; RR, 1.36 [95% CI, 1.21 to 1.53]). In the safety analysis, adverse events were not different except for a higher cholestasis rate in the acetaminophen group (25 of 392 infants [6.4%]) vs the placebo group (10 of 386 infants [2.6%]) (ARD, 3.8 [95% CI, 0.9 to 6.9]) percentage points.
Conclusions and relevance: This study found that prophylactic acetaminophen treatment for patent ductus arteriosus did not increase survival without neonatal morbidities.
Abstract
Antibodies are central to immune defenses. Despite advances in understanding the mechanisms of antibody generation, a comprehensive model of how intrinsic and external factors shape human humoral responses to viruses has been lacking. Here we apply phage immunoprecipitation sequencing to investigate the effects of demographic factors-including 108 lifestyle and health-related variables-and genetic variation on antibody reactivity to over 97,000 viral peptides in 1,212 healthy adults. We demonstrate that age, sex and continent of birth extensively affect not only the viruses but also the specific viral epitopes targeted by the antibody repertoire. Notably, we find that antibodies against rapidly evolving epitopes of influenza A virus decrease with age, whereas immunoreactivity to conserved epitopes increases. Furthermore, we identify strong associations between antibodies against 34 viruses and genetic variants at HLA, FUT2, IGH and IGK loci, some of which increase autoimmune disease risk. These findings offer a valuable resource for understanding the factors affecting antibody-mediated immunity, laying the groundwork for optimizing vaccine strategies.
Abstract
Immune responsiveness at barrier surfaces is tailored to the exposures of each tissue. In the oral mucosa, mechanisms by which a permeable epithelium coexists with diverse microbiota and maintains integrity during inflammatory pathology remain poorly understood. We compile a multiomics spatial map of this exposed mucosal microenvironment and uncover remarkable immune zonation with organization that is preserved even during inflammatory disease. At the tooth interface, we identify a dynamic epithelium underlined by a layer of neutrophils and a zone of antigen-presenting cell-lymphocyte aggregates. During disease, inflammatory zones expand and organize into immature tertiary lymphoid structures, suggesting local antibody production. Location-specific transcriptomes support a role for the stromal compartment in the spatial organization of immunity. This preserved immune zonation meets the demands for continuous protection of this vulnerable interface and suggests unique tissue-specific wiring of immunity at the human oral mucosal barrier.
Abstract
Background: To estimate the association between very preterm birth combined with the presence of a congenital anomaly and economic costs during the fifth year of life in Europe.
Methods: An economic analysis was embedded within a population-based prospective cohort study, including all infants born between 22 + 0 and 31 + 6 weeks’ gestation in 2011-2012 in 19 regions across 11 European countries. Economic costs (€, 2022 prices) during the fifth year of life were estimated for children born very preterm with (n = 313) and without (n = 3374) a congenital anomaly, and by severity of congenital anomaly. Multilevel generalised linear models explored factors associated with economic costs by anomaly severity.
Results: Total mean societal costs during the fifth year of life were significantly higher among very preterm children born before 32 weeks with a congenital anomaly than those without (unadjusted mean cost difference: €2760, p = 0.02). A multilevel model including socioeconomic, clinical characteristics, and complications of preterm birth, showed that total mean societal costs were €3281 higher for children born before 32 weeks with congenital anomalies compared to those without (p < 0.001).
Conclusion: Very preterm birth combined with the presence of a congenital anomaly generates significant economic costs on health and social care systems in Europe.
Impact: Very preterm birth combined with the presence of a congenital anomaly is associated with increased health and social service costs and increased societal costs during the fifth year of life. Additional severe neonatal morbidity is independently associated with increased costs in this population. Very preterm birth together with a congenital anomaly creates substantial economic burdens for health and social care systems and families five years after birth.
Abstract
Background: Preterm birth is the leading cause of death in children under five years of age worldwide. The association between preterm birth and long-term outcomes is vaguely known. In very preterm infants, the gut microbiome is highly variable and impacted by the neonatal intensive care unit environment. Our objective was to better understand the crosstalk between the gut microbiome and the host at one month of age in very preterm infants and its impact on neurological outcomes at two years of age. We performed a multi-omics analysis of fecal samples collected in 2011 from 73 very preterm French infants at one month of age, grouped according to their neurodevelopment assessed at two years of age using the Ages & Stages questionnaire. Multi-omics profiling and integrative analyses were performed between 2022 and 2023, including fecal microbiome, metabolome, and host transcriptome characterization using 16 S rRNA gene sequencing, LC-MS, and mRNA sequencing, respectively.
Results: The gut microbiome of very preterm infants at one month is mostly driven by either Escherichia or Staphylococcus, which are differentially associated with host immune markers (CAMP), metabolomic pathways, notably the energy pathway due to the presence of various nicotinamide adenine dinucleotides (NAD+) and two-year neurodevelopmental outcomes.
Conclusion: The gut microbiome at one month of age could be a noninvasive biomarker of gut immaturity and metabolic defects. Escherichia and Staphylococcus proportions were found to be the best indicators of physiological maturity and immaturity, respectively. Escherichia may help the process of intestinal maturation in preterm infants through specific metabolites production and is associated with a better neurodevelopment.
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.