Publications

Abstract

Background: To assess rates and factors for disability at 3 following hypoxic-ischemic encephalopathy (HIE).

Methods: Newborns more than 34 weeks with HIE Sarnat grades I to III, mostly treated by hypothermia were included in the population-based cohort LyTONEPAL and followed at 3. Mild, moderate, or severe neurodevelopment was defined on motor, sensorial impairment, epilepsy and neurodevelopmental delay. Main measurement was relative risk ratio (aRRR) and 95% CI of disability, adjusted for birth circumstances and neonatal complications, estimated on complete and imputed cases.

Results: 647 out of 794 newborns survived, and 463 were assessed. Severe, moderate or mild neurodevelopmental impairment was observed in 10.5% (95% CI 7.6-14.1), 11.8% (95% CI 8.7-15.6) and 22.0% (95% CI 17.9-26.6), respectively. Moderate to severe outcome was increased with an abnormal examination at discharge (aRRR=4.22, 95% CI 1.74-10.25) and hypoglycemia (aRR=8.54, 95%CI 1.88-38.73.05) while hypothermia decreased it (aRRR=0.36 95% CI 0.13-0.99). Mild outcome was associated with neonatal infection (aRRR 3.73, 95% CI 1.55-8.98-8.36), while higher gestational age seemed protective (aRRR 0.83, 95% CI 0.69-1.00).

Conclusion: Four in 10 HIE had neurodevelopmental sequelae, half of which were mild. A more immature brain or exposure to neonatal infection seemed to worsen prognosis, irrespective of disease severity.

Trial registration: Clinical trials registry, NCT02676063, ClinicalTrials.gov.

Impact: Follow-up at 3 in a 647 children with HIE Sarnat grades I to III, mostly treated by hypothermia showed impairment of motor, sensorial and learning skills in 44.4%, of which 10.5% and 11.8% were moderate and severe respectively. 45.7% of children have at least one rehabilitation treatment, including 26% of children with favorable outcome. Neonatal infection increased the risk of unfavorable evolution, while more advanced gestational age and hypothermia were protective. In addition to clinical or MRI severity, our data suggest to integrate gestational age and neonatal infection into early prognostic assessment, and extending HIE follow-up to school age.

Abstract

Purpose: The SafeBoosC-III trial compared treatment guided by cerebral oximetry monitoring for the first 72 h after birth with usual care in 1601 extremely preterm infants. Incidence of death or severe brain injury at 36 weeks of postmenstrual age did not differ between the cerebral oximetry and usual care group (relative risk with cerebral oximetry, 1.03; 95% CI 0.90 to 1.18). To assess the probability of clinically important benefit or harm, we conducted secondary analyses in a Bayesian framework.

Methods: Primary analyses used a weakly informative prior assuming a wide range of effects, to assess the probability that treatment guided by cerebral oximetry monitoring carried an a priori defined clinically important benefit or harm (a relative risk below 0.90 or above 1.10) or any benefit or harm (a relative risk differing from 1.0) for death or severe brain injury. Secondary analyses used an evidence-based prior derived from relevant prior trials.

Results: Posterior probabilities of clinically important benefit or harm were 1.5% and 19.2%, respectively. Posterior probabilities of any benefit or harm were 28.7% and 71.3%, respectively. Probabilities derived from secondary analyses using evidence-based priors were consistent with those from the primary analysis.

Conclusion: Treatment guided by cerebral oximetry monitoring during the first 72 h after birth in extremely preterm infants resulted in posterior probabilities of 1.5% for a clinically important benefit and 19.2% for a clinically important harm with respect to the incidence of death or severe brain injury at 36 weeks of postmenstrual age.

Trial registration: ClinicalTrials.gov NCT03770741. Registered on 12 July 2018.

Keywords: Bayesian analysis; Cerebral oximetry; Extremely preterm; Near-infrared spectroscopy; Neonatal intensive care; Randomised clinical trial.

Abstract

As part of the ADVANCE-VAC4PM project, the European Vaccine Initiative (EVI) and La Fondation pour la Recherche Scientifique (FORS) co-hosted a hybrid workshop titled “Strategies for using malaria vaccines to prevent malaria in pregnancy (MiP)”. The event brought together researchers, regulators, civil society, global health experts, and policymakers to discuss the need for MiP vaccines and strategies for their development, evaluation, and implementation. Malaria remains a major global health threat, with sub-Saharan Africa bearing the highest burden. Pregnant women (PW) are highly vulnerable, with an estimated 12.4 million affected in 2023. Beyond maternal health effects, a major cause of the MiP-related disease burden is placental malaria (PM), which can cause significant morbidity in newborns. PM risk is greatest in primigravidae and secundigravidae, as immunity develops over successive pregnancies. As existing malaria control strategies remain insufficient, MiP vaccines have the potential to complement them by eliciting immunity comparable to that seen in multigravidae. To be effective, such a vaccine should provide long-lasting immunity and target adolescent girls and women before their first pregnancy. PM vaccine candidates targeting the VAR2CSA antigen (PRIMVAC and PAMVAC) are in development, and existing malaria vaccines preventing infection are being repurposed to prevent MiP. However, limited awareness of MiP-specific burden, weak pharmacovigilance systems, and vaccine hesitancy may hinder future vaccine implementation. Key recommendations highlighted during the workshop included strengthening communication and community engagement strategies, defining relevant efficacy endpoints for pivotal clinical trials, reinforcing pharmacovigilance systems to support safety and real-world effectiveness studies, and planning for early regulatory alignment. Panel discussions emphasized the importance of stakeholder coordination and reduced-dose schedules to support future MiP vaccine programmatic feasibility. The workshop concluded with a call for sustained collaboration and national investment to ensure that MiP vaccines become a viable and effective component of global malaria prevention efforts.

Keywords: Malaria in pregnancy; Placental malaria; Vaccine development; Vaccine implementation.

The increasingly wide use of low-dose aspirin during pregnancy to prevent preeclampsia, based on recently updated clinical guidelines, raises debates about potential maternal bleeding risks. This population-based study aimed to quantify the risk of hemorrhage complications associated with aspirin exposure. We performed a nationwide exposed/unexposed cohort study using the French National Health Data System (SNDS), analyzing 5,774,333 pregnancies between 2015 and 2022. Exposure was defined as a low-dose aspirin prescription (75-160 mg/day) during pregnancy (2.99% of the cohort). The primary endpoint was a hospital stay for maternal hemorrhage during the 1st, 2nd/3rd trimesters, or the postpartum period. Risk was evaluated using a Cox survival regression. Aspirin exposure was associated with a significantly increased risk of maternal hemorrhage: during the first trimester (Hazard Ratio [HR] 2.87 [95% CI 2.56-3.21]), the second and third trimesters (HR 1.74 [1.65-1.84]), and the post-partum (OR 1.44 [1.32-1.57]). The use of low-dose aspirin during pregnancy is associated with an increased risk of maternal bleeding events. These findings emphasize the need for a precise assessment of pregnant women who will really benefit from low-dose aspirin, to preserve its favorable benefits-risks balance.

Abstract

Nutrition influences host physiological processes, yet how diets reshape host physiology, microbial functions, or host-microbe interactions to promote regeneration remains poorly explored. Here, we show that a ketogenic diet (KD), enriched in fats and low in carbohydrates, reprograms both skin microbial and immune functions to promote tissue repair. KD enhances IL-17A activity in γδ T cells and mucosal-associated invariant T (MAIT) cells, accelerating tissue repair, while KD-induced skin lipidomic alterations enhance both the abundance and metabolic output of Staphylococcus epidermidis. Metatranscriptomic and lipidomic analyses revealed increased riboflavin biosynthesis and sphingomyelinase (Sph)-dependent ceramide production in S. epidermidis under KD conditions. Genetic depletion of microbial ribD, a key enzyme for riboflavin biosynthesis, or of sph compromised the ability of the bacteria to promote tissue repair. Thus, host nutritional status drives tissue regeneration by synergistically rewiring host and microbial functions, providing new insights into how diet can be harnessed to regulate host physiology.

No abstract available

Abstract

Persistent pathological structures, such as tumors, fibrotic nodules, granulomas, microbial biofilms, or protein aggregates, are traditionally viewed as age-related conditions that emerge after reproduction, when natural selection is less effective at eliminating traits expressed late in life. However, some pathologies with robust and organized architectures can arise surprisingly early, challenging this classical perspective. We recently proposed that intra-organismal selection for function, a selective process operating within organisms and acting on non-reproducing entities by favoring structural configurations that enhance stability, robustness, and novelty generation, may play a role in aging. Here, we suggest that this same process can also operate well before the so-called selection shadow (i.e., life stages where natural selection is too weak to purge deleterious mutations). We identify three non-mutually exclusive mechanisms that may promote this early-life action: (i) initial local adaptive benefits, such as improved tissue repair or containment of infection; (ii) limited or context-specific fitness costs, allowing structurally stable but abnormal configurations to persist undetected; and (iii) rapid environmental changes that reshape tissue-level selective landscapes, driven by pollutants, endocrine disruptors, or novel diets. Recognizing early-onset organized pathologies as by-products of eco-evolutionary tissue dynamics, rather than as mere developmental errors, reframes their biological significance and opens new therapeutic avenues. Instead of targeting cells exclusively, future strategies could focus on disrupting the functional architecture of pathological tissues and structures, offering novel means to prevent or control early-life diseases shaped by internal selection forces.

Abstract

The gut microbiota, immune system, and enteric nervous system interact to regulate adult gut physiology. However, the mechanisms establishing gut physiology during development remain unknown. We report that in developing zebrafish, enteroendocrine cells produced interleukin-22 (IL-22) in response to microbial signals before lymphocytes populated the gut. In larvae, IL-22 shaped the gut microbiota, increasing Lactobacillaceae abundance and ghrelin expression to promote gut motility. Impaired motility and ghrelin expression were restored in il22^-/- zebrafish by transfer of microbiota from wild-type zebrafish or by introducing only Lactobacillus plantarum. IL-22-deficient mice also had impaired gut motility and reduced ghrelin expression in early life, indicating a conserved function. Thus, before immune system maturation, enteroendocrine cells regulate early-life gut function by controlling the microbiota through IL-22.

Abstract

Introduction: In women with a history of one extremely preterm birth, the current literature suggests that ultrasound cervical length screening offers a more favorable risk-benefit ratio than history-indicated cerclage. However, some of the women included in previous studies were at a low risk of cervical insufficiency. Therefore, the efficacy of history-indicated cerclage may have been underestimated. Our objective was to compare history-indicated cerclage with ultrasound cervical length screening in women with a history of one second-trimester loss or extremely preterm birth suggestive of cervical insufficiency.

Material and methods: We conducted a retrospective cohort study comparing two centers with different management strategies for women with a history of one second-trimester loss or extremely preterm birth suggestive of cervical insufficiency. This study was conducted from January 1, 2015 to December 31, 2022 in two French tertiary care maternity units. In the first center, women were offered a cerclage in the first trimester (cerclage center). In the second center, women were offered an ultrasound screening with cerclage only for women with cervical shortening (ultrasound center). To target a population at high risk for cervical insufficiency, we included women with a history of one second-trimester loss or spontaneous preterm birth before 28 weeks of gestation. We excluded women who had any of the following complications in their previous pregnancy: bleeding from placenta previa or placental abruption, intrauterine fetal death, or delivery after invasive prenatal testing. We also excluded women with a history of more than one preterm delivery. Our primary outcome was delivery before 34 weeks. A multivariable analysis was performed.

Results: The rate of delivery before 34 weeks was significantly lower in the cerclage center compared with that in the ultrasound center (26/165 (15.8%) vs. 38/149 (25.5%), p = 0.032). After adjusting for confounding factors, history-indicated cerclage was associated with a twofold decreased risk of delivery before 34 weeks compared with ultrasound cervical length screening (aOR 0.46, 95% CI 0.23-0.95).

Conclusions: In women with a history of one second-trimester loss or extremely preterm birth suggestive of cervical insufficiency, history-indicated cerclage is associated with a lower risk of delivery before 34 weeks compared with ultrasound cervical length screening.

Keywords: cervical insufficiency; history‐indicated cerclage; preterm delivery; second‐trimester fetal loss; ultrasound screening of cervical length.

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ), encoded by the PPARG gene on chromosome 3p25.2 in humans, is a ligand-dependent transcription factor that belongs to the nuclear receptor family. In various tissues, PPARγ controls cell differentiation, proliferation, or fusion. Its essential role in the development and functions of the placenta is now well established. To date, the specific functions of its RNA isoforms, encoded by ten exons, in trophoblast biology, including cell fusion and invasion, remain unknown. As translation is mainly regulated by the 5’UTR sequences of mature mRNA, this region was analyzed, and four previously unreported exonic sequences were revealed. Their expressions were confirmed and quantified in villous cytotrophoblasts from term placenta and in chorionic villi from both first-trimester and term placenta. Distinct expression patterns were observed: one exon showed weak expression in placental and chorionic cells, another exhibited stable expression throughout pregnancy, while two exons specific to villous cytotrophoblasts displayed increased expression during the first trimester, suggesting a role in oxygen-responsive mechanisms. Among these, one may be involved in villous trophoblast differentiation. These findings demonstrate that the PPARG gene is composed of 14 exons and is highly regulated depending on cell type and the stage of cell differentiation.

Keywords: 5′UTR exon; PPARG gene; cell-type-specific expression; placenta; pregnancy; trophoblast differentiation.