Publications

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.

Abstract

Background: Long-term effects of Skin-to-Skin Contact (SSC) on neurodevelopmental outcome for preterm children are still debated. We aimed to evaluate associations between SSC, cognition and behavior at 5 years among children born at 24-31 weeks of gestation.

Methods: In this secondary analysis of the French Etude Epidémiologique sur les Petits Ages Gestationnels (EPIPAGE-2), a nationwide prospective population-based cohort study conducted in all neonatal units across 25 French regions from Mar 28, 2011, to Dec 31, 2011, we examined preterm-born children divided into two groups based on exposure to skin-to-skin contact (SSC) during the first week of life. Outcomes at 5 years included full-scale intelligence quotient (FSIQ; Wechsler Preschool and Primary Scale of Intelligence, 4th edition) and behavioural difficulties (Strengths and Difficulties Questionnaire, SDQ), using a contemporaneous group of term-born children from the ELFE cohort as a reference. The ELFE cohort enrolled participants during four inclusion periods in 2011: Apr 01-04, 2011; Jun 27-Jul 04, 2011; Sep 27-Oct 04, 2011; and Nov 28-Dec 05, 2011. Included children were born at 24-31 weeks of gestation, remained in the same neonatal unit during the first week of life, were alive at 7 days, had no severe cerebral malformations or decisions to limit/withhold care, and had data on SSC exposure. Results are given after multiple imputation using propensity score methods with inverse probability of treatment weighting approach.

Findings: Of 3669 live-born preterm children, 2726 children were eligible and 2666 included with SSC information during the first week of life available; 2561 survived to 5 years (1328 boys (51.8%). Among survivors, 1581 received SSC during the first week of whom 987 had full follow-up assessment; 980 were not exposed of whom 558 had full follow-up assessment. SSC exposure increased with gestational age (21.7% at 24 weeks to 78.0% at 31 weeks), with variability across neonatal units (range 5%-100%). Compared with non-exposed children, exposed children had higher FSIQ scores (mean difference +2.3, 95% CI [+0.3 to 4.3], p = 0.024) and were more likely to score ≥-1 standard deviation (odds ratio 1.33, 95% CI [1.04-1.70], p = 0.023). There was no significant difference in SDQ scores between groups (mean difference -0.3, 95% CI [-1.1 to 0.5], p = 0.42 and score ≥90th percentile odds ratio 0.92 [0.64; 1.33], p = 0.66).

Interpretation: While the duration of SSC the first week of life and SSC beyond the first week were not accounted for, our findings suggest that SSC during the first week of life may be associated with an increased likelihood of higher FSIQ at 5 years. These results point to a potential neuroprotective role of SSC during this early sensitive postnatal period and highlight important areas for improvement. Variability in SCC implementation across units deserves attention and further research is needed to explore dose-response relationships and timing effects.

Funding: The National Research Agency (via the French Equipex Program of Investments in the Future); the French Institute of Public Health Research/Institute for Public Health and its partners at the French Health Ministry; the National Institute of Cancer; the National Institute of Health and Medical Research; the National Solidarity Fund for Autonomy; and the PremUP Foundation.

Abstract

Objective: To investigate the magnitude and evolution of inequalities in neonatal mortality rates by using area based socioeconomic indices in France.

Design: National population based study.

Setting: For 2015-20, data from the French National Health Data System (Système National des Données de Santé, SNDS). For 2001-08, neonatal death certificates and aggregate vital statistics data by municipality of residence.

Participants: Live births with a gestational age ≥22 completed weeks to a mother residing in metropolitan France, 2015-20 (4 293 403 live births and 10 869 neonatal deaths), compared with a 2001-08 study (6 202 918 live births and 14 851 neonatal deaths).

Main outcome measures: Differences in neonatal mortality rate (death before day 28 of life) according to the socioeconomic characteristics of the mother’s municipality of residence. Comparison with data from a 2001-08 study to assess changes in socioeconomic inequalities and their contribution to the increase in neonatal mortality rate.

Results: The neonatal mortality rate was 2.53 per 1000 live births in 2015-20. Five indicators, previously associated with perinatal mortality, were combined into a perinatal French deprivation index (P-FDep) for the main analysis. P-FDep was categorised into five equal groups (deprivation groups 1-5) for comparison with other research and into 10 equal groups (deprivation groups 1-10) for more granular analyses, with group 1 being the least and group 5 (or group 10) the most deprived group. The rate in the most deprived compared with the least deprived group for P-FDep was 1.71 (95% confidence interval 1.60 to 1.83) times higher, based on the analysis of deprivation groups 1-5. A mortality gradient existed across the groups, translating into 2496 excess deaths (23.3%) when the rate in the least deprived group was applied to all areas. The gradient was more marked when deprivation groups 1-10 were used (relative risk 1.88, 95% CI 1.71 to 2.07 for the highest to the lowest deprived group). Compared with 2001-08 (neonatal mortality rate 2.39 per 1000), the rate remained constant in the least deprived areas, but worsened in the most deprived areas (+10.1% and +11.7% for groups 4 and 5, respectively), increasing the relative risks between the highest and lowest groups, which were 1.54 (95% CI 1.46 to 1.62) for deprivation groups 1-5 and 1.67 (1.55 to 1.79) for deprivation groups 1-10, in 2001-08.

Conclusions: In this study, the socioeconomic level of the mother’s place of residence was strongly associated with the neonatal mortality rate. The data showed that inequalities have widened, contributing to the increase in the neonatal mortality rate.

Abstract

Mother’s own milk is the preferred source of nutrition for preterm infants due to its beneficial compounds, including human milk oligosaccharides (HMOs). HMOs support microbiota and immune development, but their effect on the preterm brain remains unstudied. Here, we examined the therapeutic potential of HMOs and short-chain galacto- and long-chain fructo-oligosaccharides (scGOS/lcFOS) in a preclinical model for encephalopathy of prematurity. Pregnant Wistar rats were injected with 10 μg/kg lipopolysaccharides at embryonic day 20, and pups were exposed to hypoxia (8% O₂, 140 min) at postnatal day (P)4 (fetal inflammation and postnatal hypoxia; FIPH). From P1, FIPH-pups of both sexes were treated intragastrically with HMOs, scGOS/lcFOS (9:1), or water. Transcriptomic analysis of CD11b/c + microglia was performed at P6, while immunohistochemical, microbial and short-chain fatty acid (SCFA) analyses were performed at P20. Decreased cortical myelin in FIPH animals was rescued exclusively by HMOs. Furthermore, both HMOs and scGOS/lcFOS treatments normalized reduced parvalbumin+ interneuron numbers in the hippocampus, potentially through promoting beneficial bacteria, including Lactobacillus and Bifidobacterium, and cecal acetic acid content. Interestingly, treatment with HMOs more effectively restored FIPH-induced upregulation of microglial genes associated with immune activation and normalized persistent activated microglial morphology in FIPH-males. HMOs supplementation holds promise to improve neurodevelopmental outcomes following preterm birth.

Abstract

Functional ultrasound (fUS) is a promising imaging method for evaluating brain function in animals and human neonates. fUS images local cerebral blood volume changes to map brain activity. One application of fUS imaging is the quantification of functional connectivity (FC), which characterizes the strength of the connections between functionally connected brain areas. fUS-FC enables characterization of important cerebral alterations in pathological animal models, with potential for translation into identification of biomarkers of neurodevelopmental disorders. However, the sensitivity of fUS to signal sources other than cerebral activity, such as motion artifacts, cardiac pulsatility, anesthesia (if present), and respiration, limits its capacity to distinguish milder cerebral alterations. Here, we show that using canonical correlation analysis (CCA) preprocessing and dynamic functional connectivity analysis, we can efficiently decouple noise signals from the fUS-FC signal. We use this method to characterize the effects of a mild perinatal inflammation on FC in mice. The inflammation mouse model showed lower occurrence of states of high FC between the cortex, hippocampus, thalamus, and cerebellum as compared with controls, while connectivity states limited either to intracortical connections or to ventral pathways were more often observed in the inflammation model. These important differences could not be distinguished using other preprocessing techniques that we compared, such as global signal regression, highlighting the advantage of canonical correlation analysis for preprocessing fUS data. CCA preprocessing is applicable to a wide variety of fUS imaging experimental situations, from anesthetized to awake animal studies, or for neonatal, perinatal, or neurodevelopmental imaging. Beyond fUS imaging, this method can also be applied to FC data from any neuroimaging modality when the sources of noise can be spatially identified.

Abstract

The European Society for Paediatric Research (ESPR) first developed recommendations for a Neonatology specific European training curriculum in 1998, with updates in 2007 and 2021. The aim of these recommendations was to define a common, European standard of training for national educational programmes for Neonatologists. Following the Union of European Medical Specialists’ (UEMS) framework of European Training Requirements (ETR), and similar to the American Board of Pediatrics (ABP) recommendations, graduates of training programmes conforming to the ETR will be eligible throughout Europe for recognition of equality of training, and with that should be enabled to freedom-of-movement. This concept also accounts for neonatal specialists. We therefore present the pan-European work on the ETR Neonatology in its third iteration (ETR III), summarising the basic requirements for contemporary training programmes, trainers, and training centres in neonatology. We highlight the European School of Neonatology (ESN) as a comprehensive online educational platform which provides the theoretical and practical background to satisfy the ETR-III. Lastly, we introduce the European Board of Neonatal & Child Health Research (EBNCHR) as a committee dedicated to gaining acceptance for the concept of harmonising education and training in Neonatology and recognising Neonatology as a Paediatric subspecialty in every European Union member state. IMPACT: Neonatology currently is not uniformly recognised as a Paediatric subspecialty throughout the 27 European countries. Hence, training in Neonatology formerly followed no commonly agreed standard throughout the European Union (EU). To ensure a minimum standard of care, an agreed minimum standard of training is required. The European Society for Paediatric Research (ESPR) has led on generating an EU-accredited, pan-European Syllabus for Neonatal training in Europe, the European Training Requirements (ETR) in Neonatology (2021). This article presents the ETR Neonatology from commissioning to accreditation and discusses means of how high-grade post-graduate education, aligned with the ETR can be achieved by practitioners.

Abstract

Aim: To investigate whether treatment with inhaled nitric oxide is associated with cognitive performance at age 5-6 years in preterm-born children.

Methods: We analysed preterm children from two large European cohort studies, the German Neonatal Network (GNN) (N = 3606) and the French EPIPAGE-2 cohort (N = 2579) admitted to neonatal care and followed up at age 5-6 years. Both cohorts had recorded data on iNO treatment. General cognitive ability was tested with IQ tests. Classification and Regression trees analysis was used to identify prenatal, perinatal and neonatal, clinical and social-environmental predictors of IQ.

Results: In both cohorts, treatment with inhaled nitric oxide was not associated with IQ at age 5-6 years. Analysis identified maternal educational level, gestational age at discharge from hospital, intraventricular haemorrhage and maternal country of birth as important factors associated with IQ scores.

Conclusion: Treatment with inhaled nitric oxide was neither negatively nor positively associated with IQ at age 5-6 years. Neonatal and brain health, as well as socioeconomic factors are important for cognitive performance in early childhood.

Abstract

Preeclampsia is a common and severe pregnancy-related disease associated with failed remodeling of the uterine spiral arteries by the placenta, which can lead to maternal and fetal mortality. Currently, there are limited strategies for early intervention of preeclampsia, primarily relying on long-term use of low-dose aspirin, which cannot reverse the pathological changes in the placenta. In this study, we propose the potential of using rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, for early intervention of preeclampsia. We conducted a literature review of the mechanisms of PPARγ in preeclampsia-related research over the past few decades and evaluated the toxicity and practical outcome of rosiglitazone in clinical applications, providing feasibility for conducting clinical trials of rosiglitazone in the treatment of preeclampsia.

Abstract

Background: Patent ductus arteriosus is a common complication of extreme prematurity. Prophylactic treatment with indomethacin or ibuprofen has shown efficacy on ductus closure but without reducing mortality and morbidity. Prophylactic treatment by paracetamol could be a safer alternative.

Objective: The aim was to build a pharmacokinetic-pharmacodynamic (PKPD) model describing the effect of paracetamol on the time-course of the ductus arteriosus diameter.

Methods: Extremely preterm neonates of 23-26 weeks of gestational age were recruited within 12 h after birth and were treated with prophylactic intravenous paracetamol for 5 days (two dose levels: 20 mg/kg followed by 7.5 mg/kg or 25 mg/kg followed by 10 mg/kg every 6 h). The diameter of ductus arteriosus was determined by echocardiography performed daily until day 7. The PKPD model was built using an I_max model with effect compartment and exponential disease progression model. Concentrations of paracetamol in the effect compartment were simulated with different doses over time for 500 virtual patients.

Results: A total of 29 extremely preterm neonates with median birth weight of 800 g (IQR: 670-860) were included in the study. Between-subject variability was estimated on transfer rate constant between the central compartment and the effect compartment (ke₀) and maximum drug inhibition (I_max) parameters. Two subpopulations with different I_max values were identified: 99% for a first subpopulation of 10 patients and 42% for the second subpopulation of 19 patients. A negative effect of maximum fraction of inspired oxygen (FiO₂) used during transfer to intensive care unit and a positive effect of intubation and ventilation during treatment were significant on ke₀. Simulations showed that both dose levels generally enabled patients to reach the concentration needed to achieve 95% of maximal inhibition by the end of treatment. However, the second dose level enabled more than 90% of patients to reach this inhibition threshold as early as day one.

Conclusion: The relationship between paracetamol and the time-course of ductus arteriosus diameter has been described in extremely preterm neonates. Intravenous paracetamol treatment with a loading dose of 25 mg/kg within 12 h after birth followed by 10 mg/kg every 6 h appears to be effective to accelerate time to ductus closure with limited benefit of a further dose increase.

Abstract

Hypoxic-ischemic encephalopathy (HIE) is a major cause of morbidity and mortality in newborns resulting in motor and cognitive impairment. Therapeutic hypothermia is the only treatment approved for HIE. Consequently, there is a critical requirement for additional treatments for hypoxic-ischemic (HI) brain injury because hypothermia is only partially protective. Pharmacological therapeutics are as yet not available to treat HIE. Therefore, we developed a novel trisubstituted purine-derivative drug (BRT_002) to attenuate HI related brain injury. The safety of BRT_002 was confirmed by treating adult rats with BRT_002 (100 ​mg/kg) for 7 days. Postnatal day-7 rats exposed to sham surgery or carotid ligation and 8% FiO₂ for 90 ​min were given BRT_002 (30 ​mg/kg) or placebo intraperitoneally (IP) immediately, 24, and 48 ​h after the induction of HI. Pharmacokinetic studies revealed suitable systemic and brain exposure to BRT_002. Treatment with BRT_002 reduced neuropathological infarct volumes in the neonatal rats. Bioinformatics analyses of proteomic data identified upregulation of Agrin, Zyxin and Syt5 (p ​< ​0.05) in both brain hemispheres in the male and female neonatal rats after treatment with BRT_002. BRT_002 also augmented mitochondrial respiration and produced metabolic changes in mouse neurons exposed to oxygen-glucose deprivation in vitro. Protein-protein interactions suggest that Syt5 interacts with major participants required to attenuate injury and/or facilitate parenchymal brain repair through Fblim1 that include Agrin, Zyxin, Vegfa, Vwf and mitochondrial targets. Our study provides preclinical findings that could serve as a foundation for future clinical trials of this novel purine derivative for the treatment of newborns exposed to HIE.