Publications

Abstract

Numerous mood and behavior disorders have developmental origins resulting from genetic and environmental interactions. Maternal tryptophan hydroxylase 1 (TPH-1)-dependent serotonin (5-HT) depletion alters embryonic brain development, but its long-term impact on adult progeny has never been investigated. Here we demonstrate that adult WT male offspring born to hyposerotonergic Tph1^+/- dams ( ~ 60% deficit) display hyperlocomotion, impaired self-care and an increased anxiety relative to those from WT dams. Concomitantly, norepinephrine (NE) levels and dopamine (DA) turnover are significantly reduced in the mesencephalon and brainstem, whereas monoaminergic cell density is not affected. In the frontal cortex of the offspring, maternal hyposerotonergic status results in significant reduction in DA, NE and 5-HT levels, accompanied by transcriptomic changes, notably in monoaminergic system signaling, synaptic function and plasticity, methylation processes and myelination. Myelination is also impaired as revealed by a reduced thickness of the corpus callosum. Maternal hyposerotonemia thus appears sufficient to affect the phenotype of the adult WT progeny. TPH-1-dependent 5-HT deficit during pregnancy could be considered as a risk factor for neurodevelopmental disorders in the offspring.

Abstract

Introduction: Preeclampsia is a hypertensive disorder of pregnancy associated with placental dysfunction. Optoacoustic imaging enables non-invasive, real-time assessment of placental oxygen saturation. This study aimed to evaluate placental oxygenation and its response to hypoxia in the STOX1A mouse model of preeclampsia.

Methods: Two groups were studied: STOX1A pregnancies (wild-type females crossed with transgenic STOX1A males) and controls (wild-type crosses). Blood pressure and urinary albumin-to-creatinine ratio were monitored during gestation. Placental oxygen saturation was assessed by multispectral optoacoustic imaging between embryonic days 15.5 and 17.5 under normoxia and hypoxia. Delta oxygen saturation and desaturation kinetics were analyzed using sigmoid curve fitting.

Results: Thirty-one placentas from seventeen control pregnancies and twenty-nine placentas from twenty STOX1A pregnancies were analyzed. The STOX1A group showed increased blood pressure and albuminuria compared to controls (mean systolic blood pressure change at embryonic day 17.5: +21.2 ± 11 mmHg versus -8.4 ± 3.7 mmHg, p = 0.006; albumin-to-creatinine ratio fold-change: 3.91 [2.52-17.14] versus 0.86 [0.43-2.49], p = 0.033). Placental baseline oxygen saturation was similar between groups (70.1 ± 5.3 percent versus 70.0 ± 6.9 percent, p = 0.96). No significant differences were observed in delta oxygen saturation (17.0 ± 6.9 percent versus 16.1 ± 7.1 percent, p = 0.61) or desaturation rate (8.6 ± 6.0 versus 7.9 ± 6.1, p = 0.43) during hypoxia.

Discussion: Despite a confirmed preeclamptic phenotype, placental oxygenation and adaptation to maternal hypoxia were preserved in the STOX1A model, suggesting maintained placental resilience in late gestation.

Keywords: Mouse model; Optoacoustic imaging; Placental oxygenation; Preeclampsia.

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No abstract available

Abstract

Aim: Neonatal resuscitation follows national or regional guidelines, but uptake varies in clinical practice. This study aimed to examine variations in reported delivery room practices for infants < 29 weeks’ gestation across neonatal units in 12 networks of the International Network for Evaluating Outcomes in Neonates.

Methods: An online pre-piloted survey was sent to 608 neonatal units across 12 networks. Responses, based on 2022-2023 practices, were categorized as very frequent (90%-100%), often (50%-89%), sometimes (10%-49%), rarely (1%-9%), and never, and summarized as frequency of units per network.

Results: Overall, 382 units (63%) responded (37%-100% within network). Active resuscitation at 22, 23 and 24 weeks was reported as ‘very frequent/often’ by 22%, 53% and 76% of units, with variation. Delayed cord clamping, cord milking, and resuscitation with intact cord were ‘very frequent/often’ in 47%, 27% and 7% of units. Japan reported 75% cord milking. For initial respiratory support, 86% reported oxygen concentration < 40%. Intubation at birth for infants 27-28 weeks was uncommon except in Japan. Surfactant delivery room use was reported by 24% of units.

Conclusions: Delivery room management of very preterm infants varies across networks. Future studies should analyse the impact of reported delivery room practices on neonatal outcomes.

Keywords: delivery room; infant; intensive care units; neonatal premature; questionnaires; resuscitation; surveys.

Abstract

The objective of this study is to evaluate whether non-emergency red blood cell transfusions (RBCT) is associated with neurologic outcomes in preterm infants born at 27-31 weeks of gestation. This analysis used data from the Etude Epidémiologique sur les Petits Ages Gestationnels (EPIPAGE-2), a French nationwide prospective cohort. Infants born at 27-31 weeks and surviving to 5½ years were included, excluding those with emergency RBCT indications. Neurologic outcomes, defined as moderate or severe disabilities, a composite of motor, neurosensory, and cognitive disabilities, were assessed at 5½ years with standardized scales. Behavioral difficulties were evaluated using parental questionnaires. Transfused and non-transfused infants were matched 1:1 using propensity scores. Statistical analyses included odds ratios (ORs) and mean differences. Of the 2182 infants included (656 transfused, 1526 non-transfused), 1062 were matched (531 per group). In the unmatched cohort, RBCT exposure was significantly associated with the composite outcome of moderate to severe neurological disabilities (OR, 1.40; 95%CI, 1.04-1.87). Cognitive impairment and developmental coordination disorders were significantly increased with RBCT (OR, 1.40; 95%CI, 1.07-1.81 and OR, 1.44; 95%CI, 1.06-1.96), respectively. After adjustment using the propensity score, RBCTs were not significantly associated with any individual outcome: cerebral palsy, overall cognitive deficiency, coordination disorders, behavioral difficulties, or moderate-to-severe neurological disabilities. Only the association with cognitive performance relating to working memory persisted (mean difference, – 2.3; 95%CI, – 4.2 to – 0.5).

Conclusion: After controlling for potential confounders, non-emergency RBCTs in preterm infants born at 27-31 weeks were not significantly associated with long-term neurologic outcomes but reduced working memory warrants further investigation.

Trial registration: NCT03078439.

What is known: • Red blood cell transfusions (RBCTs) are frequently administered to preterm infants and have been associated with adverse neonatal outcomes in observational studies. • The long-term neurodevelopmental consequences of RBCT exposure remain uncertain because transfused infants are generally sicker and more immature, making confounding difficult to address.

What is new: • In a large nationwide cohort of preterm infants born at 27-31 weeks’ gestation, non-emergency RBCT exposure was associated with poorer neurodevelopmental outcomes in unadjusted analyses but not after propensity score matching.A modest reduction in working memory performance persisted after adjustment, suggesting a potential domain-specific effect that warrants further investigation.

Keywords: Disabilities; Infants; Red blood cell transfusion; neurological outcome.

Abstract

Perinatal brain injury (PBI) is a major predictor of neurological disability. Commonly associated with prematurity, infection, stroke, hypoxia-ischemia, hemorrhage, and/or toxin exposure, PBI triggers acute and persistent systemic inflammation. There are many stages of vulnerability to PBI during development including pregnancy, birth – term and preterm, and neonatal age. The vulnerable stages can compound inflammation through injury to the placental-fetal-brain axis, adaptive and innate immune system development, neural-immune communication, and central nervous system maturation. Neonates exhibit unique inflammatory signatures and lasting neural-immune responses to various etiologies. Chronic immune dysregulation and priming to a secondary, later-in-life immune challenge defines different forms of PBI while shaping the neonatal and adult immune response with long-term changes. Immunomodulated changes impact regulatory, helper and innate T cells, neutrophils, natural killer cells and immune responsiveness. The major routes of persistent and compounding inflammation in PBI are perinatal neural-immune interactions, cytokine influx, and glial crosstalk. Most treatments are not administered long enough or in the optimal time window to combat sustained inflammation in tertiary and quaternary phases of PBI pathophysiology and are ineffective in reducing neonatal mortality and morbidity and promoting functional recovery. Indeed, persistent systemic and central inflammation is a likely explanation for failed recovery of PBI after the resolution of acute insults. We propose attenuating persistent inflammation and normalizing systemic immune reactivity as key to reducing the functional impact of PBI throughout the lifespan through various avenues including therapeutic treatment, gut microbiome modulation, and novel immunomodulation from preclinical research.

Keywords: Immunology; Inflammation; Neonatology; Neurology; Neuroscience; Pediatrics.

Abstract

Random-effects meta-analysis typically assumes a normal distribution for the underlying effects of the studies. However, under certain conditions, this assumption may not be the most appropriate. Simulation studies comparing several alternative random-effects models have found small differences in bias but larger differences in coverage probabilities and precision. To investigate the impact of using different meta-analysis models, we used a meta-analysis of 58 cohort studies comparing the cognitive functioning between preterm- and term-born children. We compared the results between seven different random-effects models based on: asymmetric distributions, mixtures of distributions and Dirichlet process (DP) prior. Sensitivity analysis using variations of the seven main models was also performed. While estimates for mean treatment effect were similar across models, the between-study variance estimates were identical. Asymmetric distribution models indicated studies with extreme effects and a left-shifted random-effects distribution while mixture models were less informative. DP models revealed clusters of studies with similar characteristics, suggesting that the observed heterogeneity may be partially explained by certain methodological and clinical characteristics of the studies. Overall, our study highlights that applying various meta-analysis models might not affect materially the summary estimates but may provide better insights into the underlying effects’ distribution and the explanation of between-study variance.

Keywords: Bayesian meta-analysis; heterogeneous treatment effects; semi-parametric models; synthesis of observational data.

Abstract

Precise regulation of uterine immunity is required to support fundamental processes including reproduction and pathogen protection. How the local milieu and constitutive stressors, including the cervicovaginal microbiota, shape the delicate balance underlying uterine immunity is poorly understood. Here, we found that the cervicovaginal microbiota promotes both local immunity and the immunoregulatory activity of interferon lambdas (IFN-λ) in the uterus. Using murine models, we found a keystone role for IFN-λ in constraining the immune tone of this compartment, more specifically of innate lymphoid cells and Th17 cells. Conversely, in the context of pregnancy, IFN-λ promotes antibacterial responses at maternal-fetal barriers, and as a result controlling fetal and neonatal transmission. Collectively, this work demonstrates how IFN-λ integrates microbial signals under both steady state and pregnancy conditions thereby orchestrating key functions of the uterine immune system, namely immunoregulation and antibacterial protection

Abstract

Objectives: The primary objective was to describe probiotic exposure in a nationwide cohort of very preterm infants cared for in neonatal intensive care units (NICUs) in France. Secondary outcomes were to describe prescription practices across centers and associated clinical outcomes.

Methods: This retrospective multicentre study included 18,146 infants born at less than 32 weeks of gestation and admitted to NICUs using the same Computer Prescribing Order Entry-Clinical Decision Support system, Logipren®, between January 2019 and December 2023. Linear and logistic regression assessed the association between probiotic exposure and several outcomes, adjusted for sex, gestational age, intrauterine growth restriction, and center-specific effects.

Results: The rate of probiotic exposure in the study cohort was 14.3%, and significantly decreased from 16.2% to 12.7% over the study period. Prescribing practices were highly heterogeneous in terms of: choice of probiotic strains, timing of initiation, duration of treatment, dosing regimens, and pharmaceutical formulations. Limosilactobacillus reuteri DSM 17938 (65.6%) was most frequently used, followed by Lacticaseibacillus (L.) rhamnosus lcr35 (30.0%) and L. rhamnosus GG ATCC 53103 (4.5%). Only one center prescribed the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN)-recommended combination (Bifidobacterium (B.) infantis Bb-02, B. lactis Bb-12, and Streptococcus thermophilus TH-4). After multivariate analysis, mortality was significantly lower in the probiotic group (5.2% vs. 7.4%; adjusted odds ratio: 0.20, 95% confidence interval [0.15-0.26]).

Conclusions: Probiotic use in French NICUs remains limited and practice patterns are heterogeneous, with minimal adherence to ESPGHAN recommendations. These results underscore the need for standardized national guidelines and prospective trials.

Keywords: critical care; enteral nutrition; mortality; prescription; supplemental food.