Publications

Abstract

Trophoblast fusion into the multinucleated syncytiotrophoblast (SCT) appears as an inescapable feature of placentation in mammals and other viviparous species. The trophoblast cells underlying the syncytium are considered a reservoir for the restoration of the aging peripheric structure. The transition from trophoblasts to SCTs has to be tightly regulated, and could be altered by genetic anomalies or environmental exposure. The resulting defective placental function could be one of the causes of the major placental diseases, such as preeclampsia (PE) and Intra-Uterine Growth Restriction (IUGR). This review attempts to take stock of the current knowledge about fusion mechanisms and their deregulations

Abstract

Background : data on preschool neurodevelopment of preterm infants according to the duration of their neonatal exposure to opioids with/without midazolam is limited. We aimed to assess neurodevelopment outcome in children aged five years, born very preterm (24–31 weeks), according to exposure to these drugs.

Methods : secondary analysis from the French prospective cohort study EPIPAGE-2 (Etude Epidémiologique sur les Petits Ages Gestationnels, 2011). Exposure to opioids with/without midazolam was classified as none, ≤7 or >7 days. Percentages were weighted to account for the study design. The primary outcome was moderate/severe neurodevelopmental disabilities (NDD). Analyses were conducted using logistic regression and adjusted for perinatal confounders.

Findings : among 3117 survivors, 1165 (35.9%) were exposed (762/1165 (68.0%) ≤7 days, 403/1165 (32.0%) >7 days). Of these 49.5% received opioids only, 41.4% opioids and midazolam, and 9.1% midazolam only. Moderate/severe NDD occurred in 17.8%, 18.9%, and 31.7% in the unexposed, exposed ≤7 days, and exposed >7 days groups, respectively. After adjustment for baseline confounders, only exposure >7 days was associated with increased rates of moderate/severe NDD (adjusted odds ratio 2.07; 95% CI 1.32–3.26). After additional adjustment for severe neonatal morbidities no significant association was found between any duration of exposure and NDD.

Interpretation : exposure to opioids with/without midazolam >7 days might be associated with a higher prevalence of moderate/severe NDD at five years in very preterm born children but severe neonatal morbidities are a major modulator of this association.

Abstract

Respiratory syncytial virus (RSV) is a leading cause of infant morbidity. France has implemented a national campaign using nirsevimab to prevent RSV-related infections in infants. This study assessed its effectiveness in preventing hospitalization due to bronchiolitis in emergency department (ED). This retrospective study was conducted among six pediatric EDs in the Greater Paris area, France, and included infants aged < 3 months with a clinical diagnosis of bronchiolitis during the 2023-2024 RSV epidemic season. The primary outcome was hospitalization after the ED visits. The association with nirsevimab immunization was assessed using a multiple logistic model adjusted for potential confounding factors, with missing data handled using random forest imputation. Secondary analyses examined the risk of admission to the pediatric intensive care unit (PICU), RSV positivity, and subgroup analyses of prematurity, neonates, and deprivation using the FDep index (area-based measure of social deprivation in France). Between October 2 and December 31, 2023, 739 infants were included in the study. A total of 531 (72%) patients had a documented nirsevimab immunization status, and 402 (54%) were hospitalized following a bronchiolitis diagnosis. Nirsevimab showed 53.5% adjusted effectiveness in reducing hospitalizations (95% CI 34.1-67.3). Sensitivity analyses of complete-case data and propensity score matching yielded similar results. Nirsevimab also resulted in 51.1% reduction in PICU admissions (95% CI 10.7-74.3) and 79.6% reduction in RSV positivity (95% CI 68.0-87.1). The protective effect of immunization was consistent for preterm infants, neonates, and deprived groups, though the results were not statistically significant in these smaller subgroups.

Conclusions: Immunization with nirsevimab reduced hospitalization following an ED visit for bronchiolitis among infants aged < 3 months.

What is known: • Nirsevimab reduces the risk of bronchiolitis-related hospitalizations in clinical trials. • Real-world data from the immunization campaign in France remain limited.

What is new: • Nirsevimab showed 53.5% (95% CI 34.1-67.3) adjusted effectiveness in reducing hospitalizations for all-cause bronchiolitis in infants aged < 3 months in emergency departments. • Analyses included social deprivation and highlighted potential disparities in immunization access.

Keywords: Bronchiolitis; Immunization; Nirsevimab; Pediatric; RSV

Abstract

To assess the short-term safety of doxapram for treating apnea of prematurity. This is a retrospective and bicenter study. Eligible children were born before 28 weeks of gestation from January 1, 2020 to December 31, 2021. The association between doxapram treatment and gastrointestinal events was assessed with logistic regression models with adjustment for the main confounding factors: center, sex, intra-uterine growth restriction and gestational age. The main outcome measures are gastrointestinal events (necrotizing enterocolitis or feeding intolerance), the adverse effects of doxapram most frequently reported in the literature. The population consisted of 268 children; 113 (42.2%) received doxapram. As compared with children who did not receive doxapram, those who did had lower gestational age at birth (25.4 vs 26.3 weeks), lower birth weight and more evidence of greater clinical respiratory severity. Doxapram treatment was not associated with increased risk of gastrointestinal events (30.1% and 29.7% in the treated and untreated groups; odds ratio 1.3, 95% CI 0.7-2.4, p = 0.43). More children in the treated than untreated group had high blood pressure (25.7% vs 6.5%).

Conclusion: In children born before 28 weeks of gestation, doxapram treatment for apnea of prematurity was not associated with the occurrence of gastrointestinal events.

What is known: • Doxapram is a well-known second-line treatment for apnea of prematurity. It is a central nervous stimulant that can be used in refractory apnea of prematurity despite continuous positive airway pressure and optimal caffeine therapy. However, its use varies among countries and centers, probably because of suspected adverse effects. Studies suggest that this drug may have potential side effects such as digestive events (necrotizing enterocolitis).

What is new: • We present reassuring data on the digestive safety of doxapram. Use of this drug was not associated with increased rates of digestive events in preterm infants born before 28 weeks of gestation.

Abstract

Objective: To study perinatal outcomes for newborns with early, isolated, severe FGR, for whom initial active management was considered unreasonable or impossible at an obstetric-pediatric assessment and to identify the determinants associated with a course that made active management reasonable.

Material and methods: This retrospective observational single-center study occurred in a level-3 university hospital maternity unit. It included all pregnancies with a singleton fetus presenting isolated FGR <3rd percentile at 23 weeks or more of gestation with an obstetric-pediatric assessment (OPA) initially unfavorable to active management. The main outcome measure was perinatal mortality. Characteristics of the women and pregnancies were compared between the groups “OPA became favorable” versus “OPA remained unfavorable”.

Results: Among the 80 cases included, 48 (60%) of the children died, 38 (47.5%) before birth, 2 (2.5%) in the delivery room, and 8 (10%) in the NICU. Overall, the OPA for 32 (40%) became favorable. There were 44 (91.7%) perinatal deaths when the OPA remained unfavorable versus 4 (12.5%) when it became favorable (P<0.001). The median gestational age at the first OPA (25 weeks) did not differ between the groups. The patients in the OPA became favorable group had initially abnormal uterine Doppler findings less often (56.2% vs 85.4%, P=0.001), absent diastole or reverse flow umbilical artery less often (9.4% vs 33.3%, P=0.0016), less preeclampsia (6.2% vs 31.2%, P=0.009) and a higher estimated fetal weight (520 [491-546] g vs 487 [449-523] g, P=0.005).

Conclusion: In fetuses with early severe FGR, the risk of perinatal death was very high when the initial OPA was unfavorable. Initial OPA without preeclampsia and umbilical reverse diastolic flow were associated with higher probability that the OPA became favorable.

Abstract

Objective: Extremes of prepregnancy maternal BMI increase neonatal mortality and morbidity at term. They also increase the risk of extremely preterm (EP, i.e., <27 weeks’ gestational age) births. However, the association between maternal BMI and outcomes for EP babies is poorly understood.

Methods: We used a cross-country design, bringing together the following three population-based, prospective, national EP birth cohorts: EXPRESS (Sweden, 2004-2007); EPICure 2 (UK, 2006); and EPIPAGE 2 (France, 2011). We included all singleton births at 22 to 26 weeks’ gestational age with a live fetus at maternal hospital admission. Our exposure was maternal prepregnancy BMI, i.e., underweight, reference, overweight, or obesity. Odds ratios (OR) for survival without severe neonatal morbidity to hospital discharge according to maternal BMI were calculated using logistic regression.

Results: A total of 1396 babies were born to mothers in the reference group, 140 to those with underweight, 719 to those with overweight, 556 to those with obesity, and 445 to those with missing BMI information. There was no difference in survival without major neonatal morbidity (reference, 22%; underweight, 26%, OR, 1.31, 95% CI: 0.82-2.08; overweight, 23%, OR, 1.00, 95% CI: 0.77-1.29; obesity, 19%, OR, 0.94, 95% CI: 0.70-1.25).

Conclusions: No associations were seen between maternal BMI and outcomes for EP babies.

Abstract

The purpose of this study was to compare two initial surgical strategies for spontaneous intestinal perforation (SIP) in a bi-centric cohort of extremely preterm and/or extremely low birthweight infants. Observational, retrospective study including infants born before 28 weeks of gestation and/or with birthweight < 1000 g, born between 2010 and 2020, operated for SIP in two type 3 centers. Infants were attributed to groups according to the surgical technique of the first intervention: primary anastomosis or suturing (PAS) or enterostomy (ES). The primary endpoint was the duration of parenteral nutrition (PN) analyzed using multivariate Cox model. Secondary endpoints included total number of surgeries under general anesthesia, morbidity and mortality at discharge, and outcomes at 2 years. Among 65 included patients, those in the PAS group (n = 46) had a higher median [IQR] CRIB II score than those from the ES group (n = 19) (11.5 [10-13] vs 8 [4-10], p = 0.01) and were more frequently operated in Robert Debré (78% vs 21%, p < 0.001) but had comparable other clinical characteristics at birth and at the time of surgery. As compared to the ES group, infants from the PAS group had a significantly higher probability of NP weaning after adjustment (adjusted hazard ratio 3.05, 95% CI [1.43-6.49]) and a significantly lower median [IQR] number of general anesthesia (1 [1-1] vs 2 [2-2], p < 0.001). At discharge and at age 2, there was no significant difference in outcomes between groups. Conclusion: Initial one-stage surgery for SIP in extremely preterm infants was associated with shorter NP duration and fewer general anesthesia in this study.

Abstract

Recurrence is a rare complication of group B Streptococcus (GBS) neonatal infections. We conducted a retrospective observational study on GBS neonatal invasive infections in France from 2007 to 2021. A total of 1527 cases were reported, of which 36 (2.36%) were recurrent. Recurrence mainly concerned preterm (68%) and low-birth-weight (72%) infants and was associated with the hypervirulent GBS clonal complex 17 (83%; odds ratio, 2.86 [95% confidence interval, 1.18-6.92]). No β-lactam-tolerant strains were identified, and bacterial whole-genome sequencing could not reveal any specific feature associated with recurrence. Large-cohort studies should be undertaken to address the optimal management of these uncommon diseases.

Abstract

This study analyzed the longitudinal evolution of intestinal microbiota in very preterm neonates (PN) during and after their hospitalization. The bacterial 16S rRNA gene sequencing approach was applied for the analysis of fecal samples (n = 1,307) from 596 PN. Samples were collected at one week after birth, at one month, at the neonatal intensive care unit discharge, and at 3.5 years of age. Over time, the intestinal microbiota of the infants matured progressively, with increasing alpha diversity and decreasing beta diversity. Based on a Dirichlet multinomial mixture clustering approach (DMM), during hospitalization, infants progressed among ten different clusters. At 3.5 years of age, only three clusters were identified. The influence of the gestational age, the neonatal antibiotic administration, and the maternal antibiotic therapy during delivery on the gut microbiota varied over time and depended on the sampling period. Preconceptional maternal body mass index (BMI) was associated with the gut microbiota of infants during the hospitalization period and at 3.5 years of age. Infants with a lower gestational age or those born by Cesarean section shifted between clusters more frequently. Using PICRUSt2, the inferred metabolic pathways revealed a change in the functional capacities of the intestinal microbiota over time. We found that preconceptional maternal BMI was the only consistent perinatal factor influencing the development of the gut microbiota over time. After hospital discharge, infants exhibited a transition toward a microbiota community similar to that of adults by 3.5 years of age, in accordance with the functional metabolic pathways of the gut microbiota.IMPORTANCEThis study is among the very few reports analyzing the gut microbiota development in very preterm infants over time in a large, multicenter population of 596 children from a well-described nationwide birth cohort, with a follow-up until the age of 3.5 years. The maturation of the intestinal microbiota was confirmed to occur over time, with increased alpha diversity and decreased beta diversity. Specifically, 13 microbiota clusters were identified during the hospitalization period, while and only three clusters were observed at 3.5 years. Infants born prematurely or via Cesarean section exhibited a less stable microbiota, frequently shifting clusters. A number of perinatal factors were identified as influencing the development of the microbiota. Among these, the preconceptional maternal BMI emerged as the only consistent factor up to 3.5 years. The metabolic pathways of the microbiota evolved over time, in accordance with the maturation of the gut microbiota.

Abstract

Background : data on preschool neurodevelopment of preterm infants according to the duration of their neonatal exposure to opioids with/without midazolam is limited. We aimed to assess neurodevelopment outcome in children aged five years, born very preterm (24–31 weeks), according to exposure to these drugs.

Methods : secondary analysis from the French prospective cohort study EPIPAGE-2 (Etude Epidémiologique sur les Petits Ages Gestationnels, 2011). Exposure to opioids with/without midazolam was classified as none, ≤7 or >7 days. Percentages were weighted to account for the study design. The primary outcome was moderate/severe neurodevelopmental disabilities (NDD). Analyses were conducted using logistic regression and adjusted for perinatal confounders.

Findings: among 3117 survivors, 1165 (35.9%) were exposed (762/1165 (68.0%) ≤7 days, 403/1165 (32.0%) >7 days). Of these 49.5% received opioids only, 41.4% opioids and midazolam, and 9.1% midazolam only. Moderate/severe NDD occurred in 17.8%, 18.9%, and 31.7% in the unexposed, exposed ≤7 days, and exposed >7 days groups, respectively. After adjustment for baseline confounders, only exposure >7 days was associated with increased rates of moderate/severe NDD (adjusted odds ratio 2.07; 95% CI 1.32–3.26). After additional adjustment for severe neonatal morbidities no significant association was found between any duration of exposure and NDD.

Interpretation:Exposure to opioids with/without midazolam >7 days might be associated with a higher prevalence of moderate/severe NDD at five years in very preterm born children but severe neonatal morbidities are a major modulator of this association.