Publications

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.

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.

Abstract

Background: Children born preterm face higher risks of neurodevelopmental difficulties that, with social vulnerabilities, may impair school performance. We described and assessed determinants of receiving school support in preterm-born children in France.

Methods: We used data from the prospective population-based cohort of births before 35 weeks’ gestation in France, EPIPAGE-2, to estimate crude rates and adjusted relative risks (using multivariable, mixed-effects generalized linear models) of receiving school support at age five, by children’s neurodevelopment at five, sociodemographic characteristics, and region.

Results: Out of 3,007 children, 99% attended mainstream school at age five, of whom 9% received school support. Support was more often received by boys (11%; aRR = 1.37) than girls (6%), children born at 24-27 weeks’ gestation (21%; aRR = 2.78 compared to 32-34 weeks), and children with moderate or severe neurodevelopmental impairments (MSNDI: cerebral palsy, cognitive impairment, visual impairment or blindness, and/or hearing impairment or deafness) (39%; aRR = 17.25 compared to none). Receiving support was not associated with sociodemographic characteristics, after adjusting for covariates.

Conclusions: Neurodevelopmental impairment is a key determinant for receiving school support. However, 9% of the cohort and under 40% of children with MSNDI were receiving support, raising questions on whether unmet needs for school support exist in France.

Impact: This study provides an overview of school support received at age five by children born before 35 weeks’ gestation in France, and associated determinants Less than 10% of the total cohort and 40% of children with a moderate or severe neurodevelopmental impairment were receiving school support Cognitive and neurodevelopmental impairments were key determinants for receiving school support, but sociodemographic characteristics were not Our results raise questions about whether unmet needs for school support exist, calling for further research on the support available in schools, decision-making processes for allocating them, and the psychosocial and academic consequences of their provision on children.

Abstract

Objective: To evaluate the occurrence of multiple gestation birth and perinatal adverse outcomes in pregnancies resulting from clomiphene citrate (CC) treatment compared with nonexposed pregnancies.

Design: Nationwide cohort study in a university hospital-based research center.

Subjects: Pregnancies lasting >22 weeks of gestation, in women aged 18-43 years between 2013 and 2019, recorded in the French health data warehouse (Système National des Données de Santé).

Exposure: Pregnancies exposed to CC were assigned to a 1:5 unexposed control cohort on the basis of maternal age, calendar year of childbirth, French social deprivation index, history of hypertension, and history of diabetes. The exclusion criteria were in vitro fertilization/intracytoplasmic sperm injection treatment or gonadotropins within 12 months before pregnancy and pregnancies occurring in women with the dispensing of CC between 12 and 2 months and/or less 11 days before the beginning of the pregnancy.

Main outcome measures: Multiple gestation birth rate and perinatal outcomes.

Results: Of 3,173,013 pregnancies, 32,010 (1%) occurred in women exposed to CC, of whom 31,934 were assigned to 159,670 unexposed control pregnancies. The multiple pregnancy rate was significantly higher in CC-exposed pregnancies (5.2% vs. 1.4%; odds ratio [OR], 3.9; 95% confidence interval [CI], 3.7-4.1) such as twin pregnancies (5.1% vs. 1.4%; OR, 3.9; 95% CI, 3.7-4.1) and triple or more pregnancies (0.13% vs. 0.03%; OR, 4.3; 95% CI, 2.9-6.5) than in the unexposed control cohort. Women exposed to CC presented significantly more adverse obstetric and perinatal outcomes, including stillbirths, premature delivery threats, premature rupture of membranes, gestational diabetes, placenta previa, gravid hypertension, preeclampsia, preterm birth, small for gestational age, and cesarean section rate. After stratification on multiple pregnancy and adjustment on confounders (history of psychiatric disease, obesity, and embryo reduction during pregnancy), exposure to CC remains associated with adverse outcomes in both singleton and multiple pregnancies.

Conclusion: A fourfold risk of multiple gestation births was found in pregnancies exposed to CC, along with perinatal adverse events, even in singletons. Although it remains uncertain whether these adverse events are because of the medication itself or to the treated medical condition, these findings should provide awareness of practitioners and patients about its use. It also underscores the importance of attentively monitoring follicular growth during the treatment process to avoid multiple pregnancies.