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

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

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.

Abstract

The aim of this study is to assess the use of centrally and femorally inserted central catheters (CICCs and FICCs, respectively) in French neonatal intensive care units (NICUs) and to describe associated clinical practices. We conducted a national cross-sectional survey targeting all level III or higher NICUs in France. A link to an online questionnaire was sent to one member of the medical team in each unit between September and December 2024. CICCs were defined as central catheters inserted via the brachiocephalic or the internal jugular vein, and FICCs as central catheters inserted via the common femoral vein. All 65 NICUs participated in the survey. Of these, 45 (69.2%) reported performing CICC or FICC placements. Specifically, 35 (53.8%), 39 (60.0%), and 37 (56.9%) units performed insertions via the brachiocephalic vein, internal jugular vein, and common femoral vein, respectively. In most units, CICC/FICCs were used most frequently (n = 20) or systematically (n = 18) as a second-line option after an epicutaneo-caval catheter had been considered. In units that use CICC/FICCs, placement was performed by a NICU physician in 39 (86.7%) of them. In most cases, the catheter was placed under conscious sedation when feasible. The median minimum patient weight [interquartile range] considered suitable for central catheter placement was 1500 [800-2000] grams for brachiocephalic catheters, 1500 [900-2000] grams for internal jugular catheters, and 1650 [800-2000] grams for common femoral catheters. Very small caliber catheters (1 or 2 French in diameter) and a modified Seldinger insertion technique were used in 23 and 17 units, respectively.

Conclusion: CICC/FICCs use is part of clinical practice in most French NICUs, mainly as a second-line option. Indications for use, placement techniques, and maintenance protocols vary across units.

What is known: • Previous studies from specialized centers have shown that centrally and femorally inserted central catheters (CICC/FICCs) can be safely inserted in neonates. •It is still unclear to what extent these practices have been implemented in neonatal intensive care units.

What is new: • CICC/FICCs are now part of clinical practice in the majority of French NICUs. • The median minimum weight for CICC/FICC insertion was approximately 1500 g, indicating that their use has extended to smaller, more vulnerable infants. Very small-diameter catheters combined with a modified insertion technique enhance compatibility with neonatal vasculature.

Abstract

Objective: To assess the association between histological chorioamnionitis without maternal clinical symptoms and neurodevelopmental disabilities at age 5 years in children born very preterm.

Design: French national prospective population-based cohort study, EPIPAGE-2 (Etude épidémiologique sur les petits âges gestationnels).

Setting: All births from 22 to 34 weeks of gestational age in France in 2011 were eligible.

Population: Infants born alive between 24⁺⁰ and 31⁺⁶ weeks following preterm labour (PTL) or preterm premature rupture of membranes (PPROMs).

Exposure: Histological chorioamnionitis without maternal clinical symptoms, also called isolated histological chorioamnionitis, was defined as the presence of neutrophils in the chorionic plate, excluding clinical chorioamnionitis.

Main outcome measures: Neurodevelopmental disabilities, a composite outcome including cerebral palsy, developmental coordination disorders, sensory impairment, developmental cognitive deficiencies or behavioural difficulties. These assessments were comprehensive, standardised and conducted by trained neuropsychologists and paediatricians at age 5 years.

Results: Among 1296 children alive at 5 years of age, 486 (36.3%) were born in a context of isolated histological chorioamnionitis. Overall, 47% vs 33.6% of children exposed and not exposed to isolated histological chorioamnionitis had mild neurodevelopmental disabilities, and 13.8% vs 13.3% had moderate-to-severe neurodevelopmental disabilities. After multiple imputation and multivariable analysis, isolated histological chorioamnionitis was found not to be associated with the occurrence of mild or moderate-to-severe neurodevelopmental disabilities (adjusted OR: 1.0, 95% CI: 0.7 to 1.4 and 0.9, 0.6 to 1.2).

Conclusion: We did not find any association between isolated histological chorioamnionitis and neurodevelopmental disabilities at age 5 years in children born very preterm after PTL or PPROM.