Publications

Abstract

By interfering with the normal sequence of mechanisms serving the brain maturation, premature birth and related stress can alter perinatal experiences, with potential long-term consequences on a child’s neurodevelopment. The early characterization of brain functioning and maturational changes is thus of critical interest in premature infants who are at high risk of atypical outcomes and could benefit from early diagnosis and dedicated interventions. Using high-density electroencephalography (HD-EEG), we recorded brain activity in extreme and very preterm infants at the equivalent age of pregnancy term (n = 43), and longitudinally 2 months later (n = 33), compared with full-term born infants (n = 14). We characterized the maturation of brain activity by using a dedicated microstate analysis to quantify the spatio-temporal dynamics of the spontaneous transient network activity while controlling for vigilance states. The comparison of premature and full-term infants first showed slower dynamics as well as altered spatio-temporal properties of brain activity in preterm infants. Maturation of functional networks between term-equivalent age and 2 months later in preterms was linked to the emergence of faster dynamics, manifested in part by shorter duration of microstates, as well as an evolution in the spatial organization of the dominant microstates. The inter-individual differences in the temporal dynamics of brain activity at term-equivalent age were further impacted by sex (with slower microstate dynamics in boys) and by gestational age at birth for some microstate dynamics but not by other considered risk factors. This study highlights the potential of the microstate approach to reveal maturational properties of the emerging brain network activity in premature infants.

Abstract

Preeclampsia (PE) is the most threatening pathology of human pregnancy. Placenta from PE patients releases harmful factors that contribute to the exacerbation of the disease. Among these factors is the prokineticin1 (PROK1) and its receptor, PROKR2 that we identified as a mediators of PE. Here we tested the effects of PKRA, an antagonist of PROKR2, on the attenuation of PE symptoms. We used the genetic PE mouse model, STOX1 that overexpresses Stox1 gene in a heterozygosis manner in the placenta. This model allowed exploiting two genotypes of the offspring, those that overexpress the Stox1 gene, and the WT that grow in a PE environment (STE). We characterised the effect PKRA (1 μM) on the attenuation of PE symptoms and compared its effects on STOX1 and STE placentas. We also used STOX1 overexpressing trophoblast cells to decipher the PROK1-underlying mechanism. We demonstrated that (i) antagonisation of PROKR2 attenuated PE-mediated hypertension and proteinuria, (ii) STE placentas and foetuses exhibited better outcomes in response to PKRA, (iii) the secretome of STOX1-trophoblasts impacted the integrity of the fetal vasculature that was attenuated by PKRA treatment. This study demonstrates the direct involvement of the PROK1 in PE and identifies PKRA as a promising therapy for PE.

No abstract available

Abstract

Retinopathy of prematurity (ROP, ORPHA: 90050) is the main cause of visual impairment in preterm infants and the leading preventable cause of childhood blindness in high- and middle-income countries. However, severe stages of the disease remain rare. While screening recommendations for the disease are well-established in France, management of ROP requiring treatment is less standardized, especially since new therapeutic options have been approval on this indication. The management of preterm infants requiring treatment for ROP is complex and involves a multidisciplinary team, including pediatric ophthalmologists, vitreoretinal surgeons, neonatologists, pediatric anesthetists, nurses, and orthoptists, within an adapted structure for premature infants care. There is a genuine need to unify national practices, with a strong demand from physicians involved in ROP care along the country. The objective of this National Diagnostic and Care Protocol (PNDS) is to provide guidelines for diagnostic and management for ROP, and to optimize and harmonize the management of this disease across the country. The main treatment indications, the different treatment modalities including laser photocoagulation, anti-VEGF injections, and vitreoretinal surgery as well as follow-up calendar, are reviewed to establish the best practice recommendations on ROP.

Abstract

Infants born very preterm (below 28 weeks of gestation) are at high risk of developing neurodevelopmental disorders, such as intellectual deficiency, autism spectrum disorders, and attention deficit. Preterm birth often occurs in the context of perinatal systemic inflammation due to chorioamnionitis and postnatal sepsis. In addition, C-section is often performed for very preterm neonates to avoid hypoxia during a vaginal delivery. We have developed and characterized a mouse model based on intraperitoneal injections of IL-1β between postnatal days one and five to reproduce perinatal systemic inflammation. This model replicates several neuropathological, brain imaging, and behavioral deficits observed in preterm infants. We hypothesized that C-sections could synergize with systemic inflammation to induce more severe brain abnormalities. We observed that C-sections significantly exacerbated the deleterious effects of IL-1β on reduced gut microbial diversity, increased levels of circulating peptidoglycans, abnormal microglia/macrophage reactivity, impaired myelination, and reduced functional connectivity in the brain relative to vaginal delivery plus intraperitoneal saline. These data demonstrate the deleterious synergistic effects of C-section and neonatal systemic inflammation on brain maldevelopment and malfunction, two conditions frequently observed in very preterm infants, who are at high risk of developing neurodevelopmental disorders.

Abstract

Background: Very preterm children are at greater risk of academic difficulties (AD). Some of them start school a year earlier than anticipated during pregnancy due to being born preterm. The aim of this study was to analyze the relationship between neurodevelopment, school-entry age, and AD at age seven.

Method: AD were assessed at age seven in children born before 33 weeks of gestation between January 1st, 2007 and December 31, 2014 and enrolled in LIFT cohort. To analyze the relationship between school-entry age and AD, we used generalized equations with adjustment for perinatal, socio-economic factors, and neurodevelopment assessed by Age Stages Questionnaire (ASQ) at 5 years. Moreover, we used Global Scholar Adaptation (GSA) score to evaluate the school adaptation.

Results: 2599 children were in routine schooling. Entering school a year earlier was observed in 597 (23.0 %). AD was known for 1943/2599 (74.8 %). Starting school a year earlier was associated with an increased rate of AD: 35.4 % in the exposed group versus 20.2 % in the non-exposed group, with a relative risk of 1.76 (95 % CI: 1.48; 2.08). Both starting school a year earlier and ASQ at 5 years old were independently associated with the GSA score at age 7: standardized β = -0.15 (95 % CI:-0.10;-0.20) and 0.40 (95 % CI: 0.35; 0.45) respectively.

Conclusion: Starting school a year earlier than anticipated during pregnancy was associated with an increased rate of AD at age 7 in children born very preterm, independently of their neurodevelopment at age 5 assessed by ASQ. Basing school entry age on corrected age seems appropriate to mitigate this risk.

Abstract

Aim: Prematurity is a risk factor for strabismus, but the roles of intermediate factors like retinopathy of prematurity (ROP) and neurological lesions are less understood. We aimed to identify neonatal risk factors for strabismus at age 5.5 in preterm children.

Methods: Data were extracted from the étude épidémiologique sur les petits âges gestationnels 2 cohort, a French prospective population-based study of preterm children born in 2011 with gestational age of 34 weeks or less. Strabismus was recorded during a medical interview at 5.5 years. Using a directed acyclic graph, intermediate and confounding factors were identified. Total and direct effects of gestational age on strabismus risk were analysed using generalised estimating equation.

Results: Among 2419 children assessed, 274 (52.6% male) presented strabismus at 5.5 years. The direct effect of gestational age remained significant after adjustment (p < 0.001). In the complete imputed model: maternal smoking during pregnancy (odds ratio, OR 1.8; 95% confident interval, 95% CI 1.3-2.6), neonatal severe cerebral lesions (OR 2.9, 95% CI 1.8-4.6) and severe ROP (OR 4.2, 95% CI 1.9-9.0) were independent risk factors.

Conclusion: Special attention is needed regarding strabismus screening at age 5.5 in preterm children, even without severe cerebral lesions and ROP. Smoking cessation during pregnancy should be encouraged.

Abstract

Aim: Healthcare givers are exposed to stress and therefore are at risk of the development of pathologies. We aimed to provide recommendations regarding psychosocial risks such as stress, moral distress, burnout syndrome or secondary stress syndrome in neonatal care units to best support neonatal healthcare givers.

Methods: We searched PubMed for articles published from 1 January 2017 to 1 December 2023 by using the keywords burnout OR (moral and distress) AND neonatal unit. Recommendations were developed after internal and external review by a multidisciplinary group including 15 professionals and parent representatives.

Results: We identified 207 studies and developed 15 recommendations based on 118 eligible studies. Recommendations to support neonatology healthcare givers were developed for the individual level, the collective or department level to organise the environment, the training of the team with communication sessions and team cohesion; and the institutional level to respect and organise working time.

Conclusion: Psychosocial risks have consequences for the neonatal healthcare givers themselves and possibly those being cared for. To date, prevention, screening and treatment have been insufficiently developed and explored. In this context, an overall institutional review of the chosen care model is needed.

Abstract

The short-term respiratory consequences of small for gestational (SGA) are only partially known. Our aim was to compare the early respiratory features between SGA and appropriate for gestational age (AGA) in very preterm infants. We conducted a secondary analysis of the French prospective EPIPAGE-2 cohort. Eligible children were those born alive before 32 weeks’ gestation. The exposed group consisted of children with SGA. The unexposed group consisted of AGA children. SGA and AGA children were randomly matched in a ratio of 1:1 on the same gestational age and sex. Primary outcomes were age at final extubation and age at weaning from any respiratory support. Among 3.964 very preterm from the EPIPAGE2 cohort, 1123 SGA and 1123 AGA very preterm children were included in the study. The median gestational age was 30.0 weeks (interquartile range 28.0-31.0) in both groups. The median birthweight was 1440 g (1138-1680) in the AGA group and 1000 g (780-1184) in the SGA group. Invasive mechanical ventilation was less common in the SGA than in the AGA group: 68.6% (770/1123) versus 72.0% (808/1062), odds ratio 0.85 (95% CI [0.72-1.00]). In cases of mechanical ventilation, median age at final extubation was 4 days (1-23) and 2 days (1-9) in the SGA and AGA groups. Median postmenstrual age at weaning from any respiratory support was 33.4 weeks (31.7-35.9) in the SGA group and 32.4 weeks (31.4-34.3) in the AGA group.

Conclusion: SGA is associated with delayed extubation and respiratory support weaning.

What is known: • Small for gestational age concerns more than 30% of very preterm children. • The condition is strongly associated with increased neonatal mortality and morbidity, including bronchopulmonary dysplasia.

What is new: • Small for gestational age is associated with delayed extubation and respiratory support weaning in very preterm children. • Shortening invasive mechanical ventilation as much as possible is a crucial issue in this population to try to reduce the risk of bronchopulmonary dysplasia.

Abstract

Prophylactic administration of low-dose hydrocortisone, at replacement dosage, targets inability of extremely low gestational age neonates (ELGANs) to respond to postnatal stress due to adrenal glands immaturity and is intended to prevent serious complications such as death and bronchopulmonary dysplasia (BPD). Increasing evidence from systematic reviews shows that prophylactic hydrocortisone reduces pre-discharge mortality, improves survival without BPD, favors patent ductus arteriosus (PDA) closure, and may have beneficial effects on cardiovascular stability and urine output. In contrast, an increased risk of spontaneous intestinal perforation when prophylactic hydrocortisone is combined with indomethacin and late-onset sepsis, particularly in infants of 24-25 weeks of gestation, have been reported as major adverse events. No significant negative impact on long-term neurodevelopmental outcomes following prophylactic hydrocortisone exposure was observed. Recent real-world data, despite their intrinsic methodological limitations, generally confirm the benefits observed in clinical trials, even with additional potential benefits and without increased adverse events. Ongoing challenges and questions discussed in this invited review relate to the best population to treat, optimal timing and duration of treatment, and potential barriers to implementation due to evolving knowledge and guidelines. IMPACT STATEMENT: Prophylactic low-dose hydrocortisone improves survival without BPD in infants born extremely preterm. Recent real-world data generally confirm the benefits observed in clinical trials, even with additional potential benefits and without increased adverse events. Unanswered questions remain about optimal timing and duration of treatment, and potential barriers to implementation due to evolving knowledge and guidelines.