Publications

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

Background: Prospective data on pregnancies in systemic sclerosis are scarce. We aimed to examine the frequency of adverse pregnancy outcomes and maternal disease progression in systemic sclerosis, as well as the factors that predict these events.

Methods: In this analysis, we studied pregnant women with systemic sclerosis (American College of Rheumatology-European League Against Rheumatism 2013 classification) or with Very Early Diagnosis of Systemic Sclerosis (VEDOSS criteria) included in the GR2 French prospective study. Frequency of composite adverse pregnancy outcomes (preterm birth at 34 weeks or less, placental insufficiency complications, small for gestational age, or fetal or neonatal death) and maternal disease course were the primary objectives. The secondary objectives were to assess other complications related to pregnancy (including delivery outcomes and postpartum complications) and compare these results with outcomes for age-matched controls from the French perinatal survey (ENP) 2016 (ie, general population), and to identify predictive factors associated with composite adverse pregnancy outcomes and maternal disease course using univariate analysis.

Findings: Between May 1, 2014, and Dec 27, 2020, we included 58 pregnancies (in 52 women), with 53 (91·4%) resulting in livebirths. Of the 53 ongoing pregnancies beyond 22 weeks of gestation, 14 (26·4%) had a composite adverse pregnancy outcome, including two (3·8%) preterm deliveries at 34 weeks of gestation or less, 12 (22·6%) placental insufficiency complications (pre-eclampsia or fetal growth restriction), and six (11·3%) small for gestational age. Among the 53 pregnancies, six (11·3%) severe postpartum haemorrhage events occurred. When compared with the 2016 ENP survey results, pre-eclampsia (seven [13·2%] of 53 vs 16 [3·0%] of 530, p=0·0010, preterm birth before 37 weeks of gestation (seven [13·2%] of 53 vs 31 [5·8%] of 530, p=0·047), birthweight of less than 2500 g (11 [21·1%] of 52 vs 23 [4·3%] of 530, p<0·0001), and severe postpartum haemorrhage (six [11·3%] of 53 vs seven [1·4%] of 516, p=0·0001) were more frequent than in the general population. No factors were significantly associated with the composite adverse pregnancy outcome in univariate analysis. Systemic sclerosis or VEDOSS worsened in 23 (39·7%) of 58 pregnancies, mainly during the postpartum period. In the univariate analysis, diffuse cutaneous systemic sclerosis (odds ratio 3·7 [95% CI 1·1-12·4]) and previous cutaneous vascular involvement (3·7 [1·2-11·5]) were associated with maternal disease progression, whereas the presence of anticentromere antibodies was inversely associated with stable disease (0·2 [0·1-0·8]).

Interpretation: Despite 53 (91·4%) of 58 livebirths, systemic sclerosis pregnancies were associated with higher rates of adverse pregnancy outcomes and severe postpartum haemorrhage. Disease worsened in 23 (39·7%) of 58 pregnancies, particularly during the postpartum period, especially in women with diffuse cutaneous systemic sclerosis, previous cutaneous vascular involvement, and antibodies other than anticentromere.

Funding: Lupus France, Association des Sclérodermiques de France, Association Gougerot Sjögren, Association Francophone Contre la Polychondrite Chronique Atrophiante, AFM-Telethon, Société Nationale Française de Médecine Interne, Société Française de Rhumatologie, Cochin Hospital, French Health Ministry, Fondation for Research in Rheumatology, Association Prix Véronique Roualet, Union Chimique Belge.

Abstract

A growing body of epidemiological evidence links maternal exposure to air pollution with an increased risk of adverse pregnancy outcomes, such as preterm birth and low birth weight. Cerium dioxide nanoparticles (CeO₂ NPs or nanoceria) are emerging pollutants, used as additives in diesel fuels and cigarettes for their catalytic properties, and released into the environment. Due to their high surface-to-volume ratio and reactivity, CeO₂ NPs develop a surface coating during combustion, which may incorporate other released fuel-borne chemicals, such as benzo[a]pyrene (BaP), a known carcinogen, mutagen and reprotoxicant, raising concerns about their combined impacts on human health. To better reflect environmental reality, we produced BaP-coated CeO₂ NPs and exposed primary human trophoblasts and chorionic villi. Our findings show that BaP-coated CeO₂ NPs activate the aryl hydrocarbon receptor (AhR) pathway, enhancing trophoblast differentiation and syncytium formation, with effects distinct from those of BaP or CeO₂ NPs alone, or their unbound mixture. Additionally, exposure to CeO₂ NPs alone altered homeostasis of mitochondria, affecting their phenotype and function. While individual exposures or BaP-coated CeO₂ NPs had no detectable impact, parallel co-exposure resulted in a slight but significant reduction in basal respiration. Finally, uncoated CeO₂ NPs altered placental steroidogenesis, increasing estrone level while decreasing dehydroepiandrosterone level, with sex-specific effects. These findings suggest that CeO₂ NPs can influence the biological effects of BaP in the human placenta, including modulating trophoblast differentiation, as well as disrupting mitochondria homeostasis and steroid production, with potential implications for pregnancy outcomes in polluted environments.

Abstract

The mode of delivery in cases of very preterm or extremely preterm breech presentation remains a matter of debate. Available randomized trials are too few and underpowered to provide a definitive answer, and most of the evidence comes from observational, hospital-based or population-based studies, often limited by bias, particularly indication bias. Practices vary widely depending on teams and institutional policies. Analyses from different cohorts, including EPIPAGE 1 and 2, show no clear superiority of planned cesarean section over planned vaginal delivery with respect to neonatal mortality, severe morbidity, or long-term sequelae, although a rare but documented risk of death due to entrapment of the aftercoming head is described, especially in low-birth-weight infants. A meta-analysis published in 2024 reported, for breech singletons, a significant reduction in mortality with cesarean delivery, whether performed or planned, a result largely driven by two retrospective studies with a high risk of bias. These findings highlight the need to balance neonatal risks against maternal complications (and neonatal risks in subsequent pregnancies) related to cesarean section at such an early gestational age, without any delivery mode being clearly recommended.

Abstract

Spontaneous preterm births, particularly those occurring before 32 weeks of gestation, are a major cause of neonatal morbidity. In women with a prior spontaneous preterm birth, the risk of recurrence is estimated at around 30%. Two main preventive strategies are proposed: prophylactic cerclage, performed before 16 weeks, and cervical ultrasound surveillance with ultrasound-indicated cerclage in case of cervical shortening. In the absence of a standardized clinical definition of cervical insufficiency, comparisons between these strategies are limited by three main factors: indication bias, as women at highest risk are more likely to undergo cervical ultrasound monitoring; the lack of a standardized clinical definition of cervical insufficiency, which leads to the inclusion of lower-risk women and dilutes potential benefits; and the relative rarity of the condition, which reduces the statistical power of available studies. Meta-analyses cannot correct for these limitations. The absence of a demonstrated difference despite indication bias suggests that classical cases of cervical insufficiency may benefit more from prophylactic cerclage. Future research should also consider medico-economic and psychological aspects. In conclusion, for women with an isolated history of spontaneous preterm birth, the choice between prophylactic cerclage and ultrasound surveillance should be individualized, taking into account clinical history, patient preferences, and available resources.

Abstract

Preterm birth is a major cause of perinatal morbidity and mortality. In France, about 7% of births occur before 37 weeks of gestation, nearly two-thirds of which are spontaneous. Preterm labor (PTL), defined as the combination of uterine contractions and cervical changes between 22 and 37 weeks, represents the most frequent condition leading to prematurity. However, half of the women hospitalized for PTL ultimately deliver at term, highlighting the need for reliable tools to identify those truly at risk. Transvaginal ultrasound measurement of cervical length is currently the reference exam. Its negative predictive value is excellent, but its positive predictive value remains limited and depends on the threshold used. Other ultrasound parameters, such as internal os funneling or the presence of intra-amniotic sludge, have been investigated, though with variable results. Biomarkers identified in cervicovaginal secretions represent an alternative or complementary approach. Fetal fibronectin, initially assessed qualitatively, is now studied quantitatively, allowing sensitivity or specificity to be adjusted depending on the chosen threshold. PAMG-1 shows higher specificity, but its use is not recommended by most professional societies. Maternal serum biomarkers, particularly those related to inflammation or infection, are also being studied, though only on an exploratory basis. Finally, several algorithms combining clinical data, ultrasound, and biomarkers have shown promising results in predicting the risk of short-term delivery. The challenge remains to optimize the management of PTL by identifying all women at high risk, while limiting the iatrogenic effects of unnecessary hospitalizations.

Abstract

This study presents a summary of the results from two cohorts of children born very preterm, EPIPAGE-2 (Epidemiological Study of Small Gestational Ages) in France, and EPICE-SHIPS (« Effective Perinatal Intensive Care in Europe ») in Europe. In 2011, these two cohorts collected data on very preterm infants and their families between birth and age 10. The survival of very preterm infants has improved over the past 25 years, but with significant differences between countries, particularly for extreme prematurity. At preschool age in France, 28% of children born at 24-26 weeks, 19% of those born at 27-31 weeks, and 12% of children born at 32-34 weeks had moderate to severe impairments, compared with 5% of children born at term. 52% of children born at 24-26 weeks of gestation received specialized care, compared to 33% at 27-31 weeks, 26% at 32-34 weeks, and 25% at term. Among children with moderate to severe disabilities, 30-40% did not receive any specialized care. In Europe, the percentage of children receiving such care varied from 28% to 50% depending on the European region. These cohorts provided original data on the prognosis of children born very preterm, its evolution over time, and the care offered. They helped to redefine certain practices, healthcare organization methods and public health policies. Despite the progress made, these children, who represent only 1% of births, account for 50% of perinatal deaths and 50% of disabilities associated with the perinatal period. Nearly 15 years after EPIPAGE-2 and EPICE, the question arises of re-evaluating the care and prognosis for these children.

Abstract

The aim of this review is to gather the most recent data on the association between intrauterine inflammation and neurodevelopmental disorders in preterm infants. Two major methodological challenges will be emphasized: first, the heterogeneity of definitions of intrauterine inflammation; and second, the heterogeneity of study populations, in which the causes of preterm birth (spontaneous labor, preterm premature rupture of membranes, maternal hypertensive disorders, etc.) are not always distinguished. These elements introduce a risk of confounding bias and partly explain the divergence between studies. In the short term, intrauterine inflammation is associated with an increased risk of early-onset sepsis and necrotizing enterocolitis. However, the effects on respiratory and neurological outcomes are less clear, and whether an association exists remains controversial. In the longer term, in populations homogeneous with respect to the cause of prematurity, clinical chorioamnionitis has been associated with an increased risk of cerebral palsy at 2 years, a risk further amplified when combined with histological chorioamnionitis. However, this risk of cerebral palsy does not appear to persist beyond 5 years, and no major association has been reported on cognitive, sensory, coordination, or behavioral functions. Regarding isolated histological chorioamnionitis, most studies conducted on homogeneous populations do not report an association with neurodevelopmental disorders. Nevertheless, some suggest that severe inflammation, particularly in the presence of a fetal inflammatory response, may increase the risk of neurodevelopmental impairment. In conclusion, while intrauterine inflammation is associated with increased neonatal morbidity, its long-term impact on neurodevelopment appears limited and dependent on the severity of the inflammation. These findings highlight the importance of conducting longitudinal studies on homogeneous populations to refine our understanding of developmental trajectories in preterm infants.

Abstract

Retrospective foreign studies conducted using data from medical-administrative registers have all reported an increase in neonatal mortality and morbidity associated with vaginal delivery, mainly for the second twin. However, these studies suffer from major methodological flaws: lack of comparison according to the planned route of delivery, difficulty in distinguishing extreme prematurity from moderate or late prematurity, lack of adjustment for the most important confounding factors, so that their results do not allow any conclusion regarding a protective effect of cesarean section. Conversely, 3 high-quality French studies, including 2 prospective studies, report no benefit associated with cesarean section in women with preterm labor or premature rupture of membranes. In these 3 studies, even if the differences are not significant, severe neonatal morbidity is lower or survival without severe neonatal morbidity is higher in the planned vaginal delivery group compared to the planned cesarean group. In conclusion, there is no scientific evidence to support any protective effect of elective caesarean section in cases of spontaneous prematurity before 32 weeks of gestation. Therefore, planned vaginal delivery should be the preferred option in France.

Abstract

Extremely premature infants (22-26 weeks) are at high risk of neonatal death, severe morbidity, and disability. The survival of these infants is essentially linked to the obstetrical-pediatric team’s willingness to provide intensive care. Numerous studies show that this increased survival rate in cases of willingness to actively manage them is not accompanied by an increased risk of morbidity and psychomotor delay in the longer term. The great variability in antenatal practices for the management of extremely premature infants reflects the confusion among medical teams who, in the absence of consensus and formalized decision-making processes, end up making management decisions that are at best based on local habits, and at worst on the individual habits of the attending clinician. This variability in practices across centers poses a problem of equity. Thus, in our country, practices and outcomes vary greatly depending on the child’s place of birth. Intensive antenatal care rates for these children vary from 22 to 61% depending on the region. One consequence is a survival rate in France that is much lower than in other countries. Survival in the USA, Great Britain, Japan, Australia, and Sweden is 10 to 50% higher than in France. To improve this situation, new principles have been proposed: administration of corticosteroid therapy independently of treatment, prognostic assessment not based solely on gestational age, and collective decision-making on treatment outside of an emergency setting, and consensus on the information to be provided to parents before informing them and seeking their opinions. This approach requires consistency in care before, during, and after birth and relies on close obstetric-pediatric collaboration. This new organization is being tested in the PREMEX Cluster randomized trial involving 25 perinatal networks in France, the results of which will be available in 2026.