Publications

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.

Abstract

Background: Persistent patency of the ductus arteriosus (PDA) has challenged neonatologists for more than 40 years. Controversies persist about the management of PDA in extremely preterm infants. PDA is associated with morbidities, but no therapeutic strategy has resulted in an improved neonatal outcome. Acetaminophen appears to be a promising alternative with possibly fewer adverse effects. The primary objective is to determine whether a prophylactic pharmacological intervention with acetaminophen may increase the survival without severe morbidity at postmenstrual age of 36 weeks.

Methods and analysis: TREOCAPA phase III is a randomized, multicenter, double-blind, stratified, placebo-controlled superiority trial, two arms in a 1:1 ratio performed in 43 NICUs of 14 European countries, evaluating whether the intervention increases the survival without severe morbidity by 10%, from 50% in control arm to 60% in treatment arm, until the age of 36 postmenstrual weeks. To detect this difference, 794 patients were required using a group sequential design. Recruitment has been closed, with 803 patients enrolled. Patients eligible for inclusion are preterm infants with a gestational age between 23 and 28 weeks. In the acetaminophen group, 20 mg/kg loading dose within 12 h after birth, followed by 7.5 mg/kg quarter in die (QID) for 5 days, will be administered to the 27-28 weeks gestational age group, and 25 mg/kg loading dose then 10 mg/kg QID will be administered to the 23-26 weeks gestational age group. The severe morbidities include severe bronchopulmonary dysplasia (BPD grade 3) according to NIH consensus, necrotizing enterocolitis (NEC) of Bell’s stage II or III, intraventricular hemorrhage (IVH) grade III-IV according to Papile classification, or cystic leukomalacia.

Discussion: Whatever the results, the conclusions of this study should be informative for the neonatal scientific community. The results will either confirm the benefit of treatment in increasing survival without severe morbidity, or indicate a worsening of outcomes with prophylactic acetaminophen treatment, or show no difference in the primary outcome. In the latter case, ultrasonographic assessments of ductus arteriosus status on day 7 may help explain the absence of a difference. This could indicate that acetaminophen is ineffective in promoting ductal closure or that early closure of the ductus arteriosus is inconsequential if, despite more frequent closures, there is no associated improvement in outcomes.

Abstract

Background: In France, the infant mortality rate had a long period of decline, but it stopped decreasing after 2010 and then rose. Neonatal mortality is a large part of infant mortality. The aim of this study was thus to describe its main changes, by cause of death and gestational age, and the main changes in socio-spatial distribution, from 2001 to 2017.

Methods: For this purpose, we investigated data on neonatal deaths reported in France from 2001 to 2017. Crude, cause-specific and gestational age-specific neonatal mortality rates were computed and an ecological analysis, according to several contextual factors at commune level, was performed using quasi-Poisson regressions.

Results: The average neonatal mortality rate was 2.42 per 1000 live births in France during the study period, showing an increase from 2011 onwards. This increase was mostly related to perinatal conditions and more births at very low gestational age. Gestational age-specific neonatal mortality rates did not increase during the period. The analysis of socio-spatial factors showed increased mortality rates in large cities, deprived areas and cities with higher percentages of migrants.

Conclusion: This study suggests that a shift in the distribution of gestational age at birth toward low gestational ages may have contributed to the rise in neonatal mortality in France. Furthermore, there is notable spatial heterogeneity in neonatal mortality. Nevertheless, this observation poorly explains the specificity of the high level and recent upsurge in infant mortality in France, in contrast to its European counterparts

Abstract

Background: To measure the association of prematurity and non-preterm low birth weight (LBW) with several long-term health outcomes.

Methods: We selected adult participants from the Constances cohort. Associations between preterm birth (<37 weeks versus ≥37 weeks) and outcomes were measured using modified Poisson regression with adjustment for participant age and parental history. We used the same modeling methods to measure the association between LBW (i.e., <sex-specific 10th percentile) and outcomes in participants born ≥ 37 weeks. We tested for an interaction between exposures and sex.

Results: Among 30,295 participants, preterm birth (5.2%) was associated with (RR[CI95]): obesity (1.25[1.08-1.46]), hypertriglyceridemia (1.23[1.07-1.42]), high LDL-cholesterol (1.16[1.05-1.28]), high blood pressure (HBP) (1.22[1.08-1.36]), metabolic syndrome (1.35[1.06-1.71]), non-alcoholic fatty liver disease (1.26[1.08-1.47]), allergic and atopic symptoms (1.06[1.01-1.12]), and lack of tertiary education (1.11[1.02-1.20]). Women had a significantly higher risk of hypertriglyceridemia and metabolic syndrome. In non-preterm participants, LBW was associated with prediabetes/diabetes (1.30[1.12-1.52]), HBP (1.22[(1.12-1.33]) and lack of tertiary education (1.13[1.07-1.20]), whereas the risk of obesity (0.83[0.73-0.95]) and abdominal obesity (0.84[0.76-0.93]) was reduced.

Conclusion: Preterm birth and non-preterm LBW are both risk factors for several adult outcomes. However, regarding excess fat storage, their long-term effect seems to be in the opposite direction.

Impact statement: Preterm birth is associated with a higher long-term risk of obesity, whereas low birth weight is not. This study improves the understanding of the common idea that low birth weight is associated with a long-term risk of obesity, whereas it might depend on the cause of low birth weight. These findings provide new insights into the difficult distinction between the long-term adverse health effects of preterm birth and low birth weight.