Publications

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.

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No abstract available

Abstract

Importance: The Apgar score, the first clinical assessment to direct measures to stabilize newborn infants, is also used for risk assessment. Its accuracy in estimating outcomes remains poor among very preterm (VPT) infants.

Objective: To assess the utility of the combined 5-minute Apgar score and umbilical artery pH (UA-pH) for estimating risks of mortality and severe neonatal morbidity among VPT infants.

Design, setting, and participants: This cohort study (Effective Perinatal Intensive Care in Europe [EPICE]) analyzed infants born at less than 32 weeks’ gestation between April 2011 and September 2012 across 11 European countries. All liveborn VPT infants with Apgar scores and UA-pH data were included. Data were analyzed between February and December 2025.

Exposures: Apgar score at 5 minutes and UA-pH. The Apgar score was classified as lower than 7 and 7 or higher, and the UA-pH values were categorized as low (<7.20) and normal (≥7.20). Four groups that combined these 2 measures were defined: Apgar score lower than 7 and low UA-pH; Apgar score lower than 7 and normal UA-pH; Apgar score 7 or higher and low UA-pH; and Apgar score 7 or higher and normal UA-pH.

Main outcomes and measures: Combined outcome of mortality and/or any adverse morbidity (intraventricular hemorrhage [IVH] >grade 2, cystic periventricular leukomalacia, moderate or severe bronchopulmonary dysplasia [BPD], retinopathy of prematurity ≥stage 2, and necrotizing enterocolitis). Modified Poisson regression was used to estimate relative risks (RRs) between the exposure and the combined mortality and morbidity outcome and 3 individual components: mortality, IVH, and BPD. Models were adjusted for perinatal variables associated with Apgar score and UA-pH and adverse neonatal outcomes.

Results: Of 7900 liveborn infants in the EPICE cohort, 4174 (52.8%) had information on Apgar score and UA-pH. These infants included 2249 males (53.9%) and had a median [IQR] gestational age of 29.9 [27.9-31.0] weeks and median [IQR] birth weight of 1240 [960-1520] g. A total of 367 infants (8.8%) had an Apgar score 7 or higher but a low UA-pH, 558 (13.4%) had an Apgar score lower than 7 but a normal UA-pH, and 196 (4.7%) had an Apgar score lower than 7 and a low UA-pH. Infants with an Apgar score lower than 7 had a higher frequency of the combined outcome among those with a normal UA-pH (270 [48.4%] vs 596 [19.5%]) and a low UA-pH (108 [55.1%] vs 596 [19.5%]), with similar adjusted RRs (ARRs; low: 1.4 [95% CI, 1.2-1.7]; normal: 1.4 [95% CI, 1.3-1.6]). For mortality risk, associations were robust for an Apgar score lower than 7 and a low UA-pH (ARR, 2.4; 95% CI, 1.7-3.3) and absent with an Apgar score of 7 or higher and a low UA-pH (ARR, 1.2; 95% CI, 0.8-1.8). IVH risk was increased in all 3 subcategories, including an Apgar score of 7 or higher with a low UA-pH (ARR, 2.0; 95% CI, 1.3-3.0). BPD risk was associated only with an Apgar score lower than 7 and a normal UA-pH (ARR, 1.4; 95% CI, 1.2-1.7).

Conclusions and relevance: In this cohort study of VPT infants, combining information on UA-pH with the 5-minute Apgar score was associated with improved accuracy in estimating the risk of some adverse outcomes-notably mortality and IVH, which occurred soon after birth. These results highlight the importance of exploring the associations of early markers of risk with neonatal mortality and key neonatal morbidities separately.