Publications

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.

Abstract

Importance: Progress in perinatal care has improved survival for children born very preterm (VPT), but these children remain at higher risk of cognitive impairment compared with children born at term.

Objective: To synthesize cohort studies on childhood cognitive ability following VPT birth to investigate trends over time.

Data sources: All studies from 5 previous meta-analyses of VPT birth and cognition published before 2019 were included, and PubMed, Web of Science, and PsycInfo were searched for new studies published up to June 2024.

Study selection: Studies reporting IQ scores of children (aged <18 years) born VPT (<32 weeks’ gestational age [GA] or birth weight <1500 g) with a term-born comparison group were included.

Data extraction and synthesis: Two reviewers independently selected studies, extracted data, and evaluated study quality using a modified version of the Newcastle-Ottawa Scale. Unique cohorts were identified to avoid duplicate measures from studies on the same children.

Main outcomes and measures: The standardized mean difference (SMD) of IQ scores between VPT-born and term-born children was calculated, and mixed-effects metaregression was used to investigate linear and nonlinear associations between median birth year and the SMD. The main analysis focused on cohorts with IQ measured between 4 and 7 years of age to allow comparison at similar assessment ages. Secondary analyses were conducted in all cohorts using IQ obtained at the latest assessment age.

Results: A total of 257 studies reported data from 131 cohorts of 25 746 individuals born from 1977 to 2016 (15 548 born VPT and 10 198 at term). In the 61 cohorts assessed at age 4 to 7 years (13 842 children born between 1977 and 2014 [8847 born VPT and 4995 at term]; mean [SD] GA, 28.2 [1.7] weeks for the VPT cohorts), IQ was lower for VPT-born children compared with term-born children (SMD = -0.88; 95% CI, -0.97 to -0.79). The linear model showed no association with birth year (β = -0.002; 95% CI,-0.012 to 0.008). Three types of nonlinear models were fit, with no nonlinear associations observed. Adjustment for GA and study characteristics did not change the results (β = -0.001; 95% CI, -0.013 to 0.011). Secondary analysis of 131 cohorts found a similar difference between VPT and term groups (SMD = -0.84; 95% CI, -0.90 to -0.79), with no time trend (β = 0.001; 95% CI, -0.005 to 0.007).

Conclusions and relevance: On average, children born VPT had significantly lower IQ scores than term-born children, and this deficit did not decrease in studies conducted over 4 decades.

Abstract

Objective: The objective is to investigate the prevalence of underweight and overweight and obesity (OWOB) and associated risk factors among 5-year-old children born very preterm (VPT).

Design: Multinational area-based cohort study of children born VPT.

Setting: 19 regions in 11 European countries.

Patients: Children born before 32 weeks of gestational age in 2011-2012 and followed up at 5 years of age.

Main outcome measures: Body mass index (BMI) at 5 years of age was classified into underweight and OWOB using International Obesity Task Force references, and associations with sociodemographic, perinatal and neonatal risk factors were assessed using multinomial logistic regression. Data came from medical records during the neonatal hospitalisation and parental questionnaires at 5 years of age. Models accounted for missing data and attrition by using multiple imputation by chained equations and inverse probability weighting.

Results: 27.6% of children were underweight and 10.8% were OWOB. Younger maternal age was associated with lower risks of underweight, while low maternal education, household unemployment and non-European maternal country of birth were associated with having OWOB. Fetal growth restriction, receiving postnatal steroids and bronchopulmonary dysplasia were associated with underweight, and fetal growth restriction, male sex and multiple birth were negatively associated with OWOB.

Conclusions: 38% of children born VPT had suboptimal BMI at 5 years, principally due to being underweight, with differing risk factors for underweight and OWOB. These results raise questions about underlying mechanisms and the growth trajectories and metabolic outcomes of underweight children, in light of high prevalence and association with clinical risk

Abstract

Objective: To evaluate obstetric and perinatal outcomes of pregnancies among patients with osteogenesis imperfecta using the French National Health Insurance Database.

Methods: We conducted a retrospective cohort study. Pregnancies were identified with an algorithm specifically developed for the French National Health Insurance Database to identify delivery stays using a combination of International Classification of Diseases, Tenth Revision (ICD-10) discharge codes and medical procedures. Exposure was osteogenesis imperfecta status based on the occurrence of ICD-10 code Q780 5 years before conception or during pregnancy. Outcomes included pregnancy, delivery, postpartum, and fetal complications based on hospital discharge data and reimbursements of medical procedures, medical devices, and drugs. Multivariable logistic regression analysis was performed, adjusted for multiple pregnancies per participant with generalized estimating equations.

Results: The cohort included 8,850,969 pregnancies (5,823,322 patients) between January 2012 and December 2023. In total, 408 pregnant individuals (4.6/100,000) were identified with osteogenesis imperfecta. Compared with pregnant individuals without osteogenesis imperfecta, pregnant individuals with osteogenesis imperfecta had increased risks of antepartum hemorrhage (adjusted risk ratio [RR] 1.78, 95% CI, 1.01-3.14), chorioamnionitis (adjusted RR 2.79, 95% CI, 1.17-6.64), malpresentation (adjusted RR 1.65, 95% CI, 1.19-2.30), and preterm delivery (adjusted RR 2.11, 95% CI, 1.62-2.74). Cesarean delivery rates were notably higher in pregnant individuals with osteogenesis imperfecta (adjusted RR 2.59, 95% CI, 2.34-2.88), including among nulliparous individuals (adjusted RR 2.50, 95% CI, 2.22-2.81). Osteogenesis imperfecta was associated with major congenital anomalies (adjusted RR 5.04, 95% CI, 3.97-6.39 overall; adjusted RR 1.67, 95% CI, 1.09-2.56 when osteogenesis imperfecta was excluded from the congenital anomaly definition), especially cardiac anomalies. Postpartum analysis indicated no significant increase in fracture rates compared with prepregnancy periods.

Conclusion: In this nationwide cohort study, osteogenesis imperfecta was associated with both maternal and fetal complications. These findings underscore the need for specialized, multidisciplinary management of pregnancies in patients with osteogenesis imperfecta