Publications

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.

Abstract

Intestinal immunity defends against enteric pathogens, mediates symbiotic relationships with the resident microbiota, and provides tolerance to food antigens, safeguarding critical nutrient absorption and barrier functions of this mucosal tissue. Despite the abundance of tissue resident activated T cells, their contributions to these various roles remain poorly understood. Here, we identify a dominant population of IL-10 producing, T-bet-expressing Tr1 T cells, residing in the small intestinal lamina propria at homeostasis. Remarkably, these intestinal Tr1 cells emerge at the time of weaning and accumulate independently of the microbiota displaying similar abundance, function, and TCR repertoire under germ-free conditions. Instead, the small intestinal T-bet⁺ Tr1 program is driven and shaped by dietary antigens, and accumulates in a cDC1-IL-27-dependent manner. Upon activation, these cells robustly express IL-10 and multiple inhibitory receptors, establishing a distinct suppressive profile. Altogether, this work uncovers a previously unappreciated dominant player in homeostatic small intestinal immunity with the potential to play critical suppressive roles in this tissue, raising important implications for the understanding of immune regulation in the intestine.

Abstract

Background: To assess whether administering hydrocortisone in the perinatal period is associated with subsequent adverse cardiovascular outcomes.

Methods: The children/adolescents enrolled in the PREMILOC trial underwent resting blood pressure (BP) measurement, tonometry evaluation (pulse wave velocity (PWV), aortic systolic BP), continuous BP and ECG measurements (supine and standing), and ambulatory BP monitoring. Heart rate variability (HRV) indices, baroreflex sensitivity (BRS), and orthostatic systolic BP (SBP) response were calculated.

Results: Fifty-two subjects (median [25th; 75th percentile] birth weight: 892 g [750; 982]; gestational age: 26⁺³ [25⁺¹; 27⁺⁴]; age at assessment: 11.7 years [10.5; 12.7]; z-score of body mass index: 0.23 [-0.65; 1.27]; 27 girls) who received hydrocortisone (n = 28) or placebo (n = 24) were enrolled. The PWV was not different (hydrocortisone: 4.84 m/s [4.40; 5.48] vs. placebo: 5.00 m/s [4.48; 5.34], p = 0.969), and similar results were observed for HRV and BP measurements. Overweight/obese children (n = 17) vs. other children (n = 35) were characterized by higher office SBP, lower supine descending BRS, and higher orthostatic SBP response.

Conclusion: Early hydrocortisone administration after extremely preterm birth in a randomized trial is not associated with detrimental cardiovascular indices in children/adolescents, while overweight/obesity is already associated with cardiovascular morbidity. The study has been registered, ClinicalTrials.gov ID NCT05451264: https://clinicaltrials.gov/study/NCT05451264?cond=NCT05451264&rank=1 .

Impact: A meta-analysis on the effects of early postnatal administration of corticosteroids concluded that the hypertensive risk was increased in infants, but that long-term studies should be carried out. We show that early hydrocortisone administration after extremely preterm birth in a randomized trial is not associated with detrimental cardiovascular indices in children/adolescents, at least in one center of the trial Thus, our study suggests that early markers of the risk of hypertension are not altered by hydrocortisone.

Abstract

Introduction: Children born preterm often have anatomical and functional visual abnormalities, even in the absence of retinopathy of prematurity. This includes suboptimal visual acuity (VA), defined as binocular VA between 5-6.3/10 and 8/10. We examine relationships between suboptimal VA and neurodevelopment in children born preterm.

Methods: Secondary analysis of the French EPIPAGE-2 cohort with children born between 24+0 weeks and 31+6 weeks of gestation, eligible for follow-up at 5.5 years. Children were classified into three VA groups: 5-6.3/10, 8/10 and 10/10 as reference group. Neurodevelopment was assessed with the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition, the Movement Assessment Battery for Children-II (MABC-2) and the Strengths and Difficulties Questionnaire (SDQ). Comparisons between groups were adjusted for neonatal and socioeconomic characteristics using generalised estimating equations models.

Results: Among 1787 included children, 62% had suboptimal VA. Compared with the 10/10 VA group, the mean full-scale IQ decreased by -3.09 (95 % CI -4.75 to -1.42) and -4.97 (95 % CI -6.47 to -3.46) points, the mean MABC-2 total score by -0.66 (95 % CI -0.71 to -0.61) and -1.06 (95 % CI -1.09 to -1.00), and the mean total SDQ scores increased by 0.40 (95 % CI -0.16 to 0.94) and 0.60 (95 % CI 0.10 to 1.1) in groups with VA groups at 8/10 and 5-6.3/10, respectively.

Discussion: In this French population-based cohort of children born preterm, suboptimal VA was frequent and associated with increased risk of neurodevelopmental difficulties. A comprehensive neurodevelopmental and neurovisual assessment is warranted in children born preterm with suboptimal VA.

Abstract

Cesarean delivery is a common route of delivery before term, but the benefits or harms for preterm infants are still unknown. This review aimed to gather information on the current epidemiology of preterm cesarean delivery using data from international collaborations and on neonatal outcomes concerning the mode of delivery. Of note, 4 obstetrical scenarios were reviewed: preterm births with cephalic or noncephalic fetal presentations, preterm preeclampsia, and preterm birth of multiple pregnancies. In addition, cesarean delivery for preterm birth and its association with later child health was briefly discussed. In Europe, the highest cesarean delivery rates were reported in very preterm births (66%) and moderately preterm births (58%), with marked between-country variations. Among very preterm infants, international cesarean delivery rates averaged 70% at 28 to 31 weeks of gestation, with declining and more variable rates at lower gestational ages, especially at 22 and 23 weeks of gestation. In moderate preterm births (32-33 weeks of gestation) and late preterm births (34-36 weeks of gestation), country-specific cesarean delivery rates mirrored practice in the full-term population. In low-risk, singletons in cephalic position, primary cesarean delivery before term has been associated with a higher risk of neonatal respiratory morbidity than vaginal delivery, particularly among moderate-late preterm infants. However, preterm cesarean delivery for breech presentation (singleton and multiple pregnancies with the first fetus in noncephalic presentation) has been associated with lower neonatal mortality than vaginal delivery, particularly among very extremely preterm infants. The literature provided no clear and consistent support for the neonatal benefits of cesarean delivery vs a trial of induction of labor in preterm preeclampsia. The same was true for twin pregnancies, except for monoamniotic twin pregnancies that were recommended for primary cesarean delivery in moderately preterm gestations. There are associations between preterm cesarean delivery and adverse childhood health outcomes, but causality has not been established. With the exception of moderate and late preterm births, in which unnecessary, policy-dictated cesarean delivery could be reduced, there are usually strong medical indications for cesarean delivery in very or extremely preterm gestations. In such situations, the immediate benefits for the infant of increased chances of survival without severe neonatal morbidity should outweigh any long-term health issues. In conclusion, there is insufficient evidence to support routine delivery of preterm infants by cesarean delivery except for breech presentation, maternal or fetal emergencies, and monoamniotic twins.

Abstract

Background: Lower gestational age (GA) is linked to higher mortality and morbidity. Long-term health and developmental difficulties of individuals born moderate (MPT, 32-33 GA) and late (LPT, 34-36 GA) preterm, and early term (ET, 37-38 GA) are less explored than those of their very preterm peers.

Objectives: To test how being born MPT, LPT, or ET affects health and development at age 10, compared to full-term (FT, 39-40 GA) births.

Methods: Data from two ongoing French nationwide birth cohorts, initiated in 2011, were collected at 10 years via telephone interview (n = 8372) and home visit (n = 6418). Weighting procedures accounted for study design, non-inclusion, and participation. Outcome-wide regressions (modified Poisson, linear), adjusted for socioeconomic situation and pregnancy complications, were used to calculate adjusted relative risks (aRR) and beta-coefficients (β).

Results: No increased risk of asthma/atopy was observed for our MPT, LPT, and ET populations, except for allergic rhinitis in MPT. Strabismus was more prevalent among MPT, LPT, and ET (2.3%-3.0%) than FT (1.3%), corresponding to aRR of 1.99 (95% CI 0.91, 4.39), 1.67 (95% CI 0.85, 3.28), and 2.18 (95% CI 1.37, 3.47), respectively. MPT and LPT had increased risk of balance problems, with aRR of 1.63 (95% CI 0.81, 3.32) and 1.80 (95% CI 1.14, 2.82), respectively. MPT scored on average lower on the WISC-V full-scale IQ Matrix β -0.6 (95% CI -1.17, -0.11) and performance IQ Puzzle β -0.7 (95% CI -1.23, -0.26) subtests, compared to FT, and had an increased risk of dental malposition, aRR 1.42 (95% CI 1.15, 1.75).

Conclusions: While most outcomes (respiratory, anthropometry, cardiometabolic) did not differ between MPT, LPT, ET, and their FT peers, others, including strabismus, were more prevalent among preterm and ET. Some outcomes were specific to MPT, including lower WISC-V average scores and dental issues.

No abstract available

Abstract

Every year, 15 million babies are born preterm, putting them at increased risk of encephalopathy of prematurity (EoP). EoP is characterized by microglia-induced neuroinflammation, which can aggravate injury mechanisms leading to neuronal disorders, myelination delay, and subsequent functional consequences. While effective neuroprotective strategies in the preterm brain remain elusive, interventions such as skin-to-skin, developmental care, and music therapy have a positive impact on newborn brain development, potentially related to the oxytocinergic system. Endogenous oxytocin is recognized as a regulator of maternal-child social bonding, but its neuroprotective effect in the injured brain remains to be elucidated. Here, we investigated the effects of chemogenetic activation of oxytocinergic neurons on the neural correlates of EoP. Using a well-established mouse model of systemic interleukin-1β to induce EoP, we showed that neonatal chemogenetic activation of oxytocinergic neurons has anti-inflammatory effects in microglia, improving microstructural development of the corpus callosum and motor cortex, and rescuing typical social behavior. These neuroprotective effects were more pronounced in females, who showed a greater reduction in microgliosis and improved social behavior compared to males. This study provides a biological explanation for how developmental care and early interventions, linked to the oxytocinergic system, may induce neuroprotection in the developing brain.