Publications

Abstract

Objective: To examine associations between a 5-min Apgar score < 7 and severe neonatal outcomes in very preterm (VPT) infants and how results are impacted by variations in assigning Apgar scores within an international context.

Design: Prospective observational population-based cohort study.

Setting: Eleven structurally and organisationally diverse countries across Europe.

Population: In total, 7900 liveborn VPT infants from the EPICE-SHIPS study.

Methods: Descriptive statistics, logistic regression, modified Poisson regression.

Main outcome measures: Associations between 5-min Apgar scores < 7 and adverse neonatal outcomes were estimated with adjustments for perinatal characteristics. We tested for interactions by country-level prevalence of an Apgar score < 7, grouped into low (14%-16%), medium (19%-22%) and high (28%-40%).

Results: 20.2% of infants had 5-min Apgar score < 7 with rates of 14%-40% across countries. A score < 7 increased risks of in-hospital mortality, intraventricular haemorrhage (IVH), cystic periventricular leukomalacia (cPVL), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD) and length of hospital stay (LHS), but not necrotising enterocolitis or late-onset infection (LOI). No interactions with country group were detected for mortality, cPVL and ROP, while associations with IVH, BPD and LHS were restricted to countries with lower prevalence of scores < 7.

Conclusions: Significant differences exist in the prevalence of low Apgar scores across countries. Their interactions with adverse outcomes demand caution when using the Apgar score in prognostic models for clinical care and research without local validation. More broadly, our findings emphasise the importance of accounting for country-specific effects in clinical assessment scores.

Abstract

Long-term outcomes of preterm children are one of the major challenges in neonatology. Neurodevelopmental disorders are common in these children. Severe motor, cognitive or neurosensory disorders mainly affect the most immature children. Minor difficulties are present in more than a third of children, whatever their gestational age. School integration is frequently affected, and recourse to developmental support is important. A combination of certain factors should alert caregivers to the risk of neurodevelopmental disorders. These include male gender, small for gestational age, high-grade intraventricular hemorrhage, cystic periventricular leukomalacia or bronchopulmonary dysplasia. Early identification of neurodevelopmental disorders makes it possible to provide support for children and their families and to take advantage of the cerebral plasticity of the developing brain.

Keywords: prematurity.

Abstract

Objective: Pediatric traumatic brain injury (TBI) is a leading cause of death and disability in infants, whose neurodevelopmental consequences currently lack effective treatment. Since TBI is associated with neuroinflammation, modulation of the post-injury neuroinflammatory response is a promising strategy. Oxytocin is suggested to possess anti-inflammatory properties, and seems to play a role in clinical interventions that improve brain development in neonates. However, the underlying mechanisms remain unclear, as does its applicability to acute brain injury.

Methods: Here, we assess the effects of chemogenetic activation of oxytocinergic neurons on acute neuroinflammation and on long-term brain development after TBI in postnatal day 7 (P7) male mice. Immunohistochemistry, RNA sequencing, ex-vivo MRI-diffusion tensor imaging, in-vivo functional ultrasound imaging and behavioral assays are used for assessment. Oxytocinergic neurons were chemogenetically activated daily between P7 and P10.

Results: We show that chemogenetic activation of oxytocinergic neurons mitigates the acute neuroinflammatory response to TBI 24 h post-injury, where it reduces the expression of inflammation-related genes, and promotes brain repair and development gene pathways in microglia. In the long-term, early-life oxytocinergic neuron activation improves subcortical and cortical white matter damage after TBI, prevents hyperactivity and loss of social behavior, and restores TBI-induced alterations in resting-state functional connectivity of the isocortex. These effects were found 35 days after the last treatment session.

Conclusions: Our findings enhance the understanding of neuroinflammation modulation by oxytocin, reveal its long-term effects, and support intervention associated with endogenous oxytocin release as a promising neuroprotective strategy in pediatric TBI

No abstract available

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.