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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.
Abstract
Early microscopic-scale pericyte dysfunction contributes to the initial stages of many neurological diseases and represents a strong candidate target for therapeutic intervention. A non-invasive imaging modality able to image microvascular alterations induced by pericyte dysfunction is needed. In addition, the development of pericyte-focused therapies remains challenging due to the lack of early biomarkers of disease progression. Here we show that cerebral microvascular alterations induced by pericyte dysfunction can be characterized non-invasively in mice using functional ultrasound localization microscopy (fULM). Depletion of endothelial endoglin in adult mice as a model of hereditary haemorrhagic telangiectasia, leads to pericyte detachment in the arteriole-capillary transition (ACT) zone. Imaging reveals that arteriolar capillaries have irregular shapes, increased diameters, reduced blood speed and neurovascular uncoupling mainly localized in the ACT zone. Transforming growth factor-β signalling activator C381 restores pericyte coverage and neurovascular response. Our study underscores the potential of fULM in characterizing early microvascular alterations. As super-resolution ultrasound transitions to the clinic, our data support its future use in monitoring pericyte-focused therapies in humans.
Abstract
Importance: In randomized trials, early prophylactic hydrocortisone improved survival without bronchopulmonary dysplasia (BPD) with few adverse effects in extremely preterm infants. Large scale implementation data are needed to evaluate clinical effects and safety.
Objective: To examine the association between early prophylactic hydrocortisone and survival without BPD at 36 weeks’ postmenstrual age (PMA) in extremely preterm infants in Sweden after guideline implementation and to assess treatment safety.
Design, setting, and participants: A national historical cohort study with prospectively collected data from the Swedish Neonatal Quality register from 4 Swedish centers where hydrocortisone prophylaxis was implemented. The study included infants born between 22 and 27 weeks’ gestation between 2018 and 2023. Infants were divided into exposed and nonexposed groups according to the intention-to-treat principle.
Exposure: Hydrocortisone, 1 mg/kg/d, for the first 7 days of life, followed by 0.5 mg/kg/d from days 8 through 10.
Main outcomes and measures: The primary outcome was survival without BPD at 36 weeks’ PMA. A predefined statistical analysis plan with logistic regression was used to calculate unadjusted and adjusted odds ratios.
Results: Among 1106 infants (median [IQR] gestational age, 25 weeks, 6 days [24 weeks, 3 days to 27 weeks]; median [IQR] birth weight, 780 [610-964] g), 474 received hydrocortisone prophylaxis and 632 did not. Survival without BPD occurred in 154 of 474 exposed (32.5%) and 185 of 632 nonexposed (29.3%) infants (adjusted odds ratio, 1.62; 95% CI, 1.16-2.27). BPD occurred in 233 exposed (49.2%) and 345 nonexposed (54.6%) infants (adjusted odds ratio, 0.65; 95% CI, 0.49-0.86). Death before 36 weeks’ PMA occurred in 87 exposed (18.4%) and 102 nonexposed (16.1%) infants. Late-onset bacterial infection was more common in exposed infants, but not significant after adjustment. No other severe neonatal morbidities differed significantly between the 2 groups.
Conclusions and relevance: In this cohort study of extremely preterm infants, the introduction of prophylactic hydrocortisone was associated with increased survival without BPD, after adjusting for covariates. There was no significant increase in severe neonatal morbidities, except that late-onset bacterial infection was more common in the exposed group before adjustments.
Abstract
Background: Very preterm birth (<32 weeks gestation, VP), immigrant background, and language barriers are all independently associated with a high risk for mental health problems in childhood, but research has neglected the long-term development of immigrant children born VP. We assessed whether behavioural and socio-emotional problems of 5-year-old children born VP growing up across different language contexts in the European Union are associated with an immigrant background and linguistic distance of families’ mother tongue (L1) to the host countries’ official languages.
Methods: Data are from a population-based cohort including all VP births in 2011/12 in 11 European countries; a total of 3,067 children were followed up at 2 and 5 years of age. Behavioural and socio-emotional difficulties were assessed using the parent-reported Strengths and Difficulties Questionnaire (SDQ).
Results: Mixed-effects models showed that a larger linguistic distance of children’s L1 to the host countries’ official language was associated with higher SDQ total scores (0.02 [0.01, 0.03]), after adjusting for a wide range of social risks, biological, and perinatal clinical factors.
Conclusion: Language barriers in the form of linguistic distance between VP children’s L1 and countries’ official languages play a critically important role for the behavioural and socio-emotional development of immigrant children born VP.
Impact: Immigrant children born very preterm across Europe face systemic inequalities such as language barriers. Language barriers can be operationalised as a continuous linguistic distance score between children’s mother tongues and countries’ official languages. Linguistic distance plays an important role for the behavioural and socio-emotional development of immigrant children born VP. Research, policy, and practice need to better account for language barriers to increase equity in health and education.
Abstract
Objective: Existing predictive models for bronchopulmonary dysplasia (BPD) often lack external validation, limiting their clinical use. This study aimed to externally validate recent BPD prediction models using baseline variables, in a population-based cohort.
Design: This was an external validation study conducted on data collected from 2014 to 2021.
Setting: This was a retrospective, multicentre, population-level cohort with prospectively collected data.
Participants: Extremely low gestational age neonates recorded in the SwissNeoNet registry across all nine level III neonatal care units in Switzerland (n=1748) were included.
Interventions: Recent BPD prediction models estimating the risk of BPD or death at 36 weeks postmenstrual age, based on predictors available within the first 24 hours of life.
Main outcome measures: The primary outcome was survival without BPD. A systematic literature search identified five eligible models, which were externally validated and recalibrated for the Swiss cohort. The most performant model was further optimised to improve local applicability.
Results: Among 693 screened studies, five models based solely on perinatal variables were included. Without recalibration, models showed fair discrimination (area under the curve (AUC) 0.70-0.76) but variable calibration (observed/expected (O/E) 0.58-0.80). After recalibration, AUCs ranged from 0.69 to 0.76, and calibration improved (O/E 0.58-1.61). The optimised version of the best-performing model demonstrated improved calibration (O/E 1.03) and was validated in the Swiss population.
Conclusion: By comparing and externally validating existing BPD prediction models, we propose an optimised model using baseline variables at birth, enhancing its applicability to both the Swiss population and similar clinical contexts.
Abstract
Background: The characteristics of listeriosis in children beyond the neonatal period are unknown.
Methods: MONALISA is a prospective cohort study of listeriosis in France. All children aged 1 month to 18 years with microbiologically confirmed infection were enrolled.
Findings: We included 48 children among the 1,646 MONALISA patients (3%): 29/48 (60%) with neurolisteriosis, 12/48 (25%) with bacteremia, 6/48 (13%) with abdominal infection (gastroenteritis [n = 4] and appendicitis [n = 2]), and 1 with skin abscess. The median age was 4 years (interquartile range [IQR]: 25-75, range: 1-10), 23 were male (23/48, 48%), and 16 (16/48, 33%) reported at least one past medical event: 8/12 (67%) of those with bacteremia but only 8/29 (28%) of those with neurolisteriosis (p = 0.034) and none of the seven children with other forms. Diarrhea was reported in 21/48 children (44%) and was equally distributed among the different forms. Neurolisteriosis presented as meningoencephalitis (13/29, 45%) or isolated meningitis (16/29, 55%). Twenty-three children with neurolisteriosis presented without known immunosuppression (23/29, 79%), including 20 of the 22 children younger than 5 years (90%). Fourteen patients (14/48, 29%) required intensive care unit management. There were four in-hospital deaths (4/48, 8%), two attributed to listeriosis. All surviving children with neurolisteriosis recovered without permanent disability.
Conclusion: Listeriosis in children has specificities: neurolisteriosis in younger children most often occurs in the absence of immunosuppression and often presents as isolated meningitis, abdominal forms are more common than in adults, and the outcome is much better than in adults.
Funding: This work was funded by Institut Pasteur, INSERM, Santé Publique France, and Program Hospitalier de Recherche Clinique.
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.