Publications

Abstract

Introduction: In preterm pre-labor rupture of membranes (PPROM) before 34 weeks, expectant management is preferred in the absence of infection to reduce neonatal morbidity. Outpatient management (OM) has emerged as a potential alternative to prolonged hospitalization, but selection criteria remain ill-defined. Our objective was to evaluate latency between PPROM and delivery, and obstetric and neonatal outcomes before and after the implementation of an OM protocol and its subsequent extensions.

Material and methods: We included all women with PPROM before 34 weeks admitted between January 1, 2011, and December 31, 2021. Two periods were compared: Period A (January 2011-April 2013), when all patients were hospitalized until delivery, and Period B (May 2013-December 2021), when eligible patients were offered OM. Period B was subdivided into three phases (B1-B3) reflecting progressive expansion of eligibility criteria-from stable singleton pregnancies with cephalic presentation and normal amniotic fluid (B1), to inclusion of twins and shorter stabilization periods (B2), and finally cases with oligohydramnios or non-cephalic presentations (B3). The primary outcome was latency period (days between PPROM and delivery). Secondary outcomes included obstetric and neonatal complications. Comparisons were made between Periods A and B and across OM subperiods.

Results: A total of 539 patients were included: 145 in Period A and 394 in Period B, of whom 126 (32%) received OM. Mean gestational age at PPROM was similar between periods (28.9 ± 3.1 vs. 28.9 ± 3.3 weeks; p = 0.94), as were latency (median 7 [3-17] days vs. 8 [2-21]; p = 0.66) and gestational age at delivery (30.8 ± 3.3 vs. 30.9 ± 3.8 weeks; p = 0.62). Early neonatal bacterial infection was significantly lower in Period B (24.2% vs. 34.5%; p = 0.01). OM use increased steadily from B1 to B3 without prolonging latency or worsening outcomes.

Conclusion: Following OM protocol implementation, one-third of eligible women with PPROM before 34 weeks were managed at home. Outpatient care, even with broadened eligibility, appeared safe, did not increase maternal or neonatal morbidity, and may reduce early neonatal infections without extending latency.

Keywords: home monitoring; latency period; neonatal outcomes; obstetric complications; outpatient management (OM); preterm premature rupture of membranes (PPROM)

Abstract

Objective: Early-onset neonatal sepsis due to ascending infection is a potentially preventable complication of preterm premature rupture of membranes. Our objective was to determine whether the analysis of bacteria from vaginal swab samples is predictive of the risk of early-onset neonatal sepsis in preterm premature rupture of membranes.

Study design: In a prospective 3-center observational cohort, patients with preterm premature rupture of membranes were enrolled between 22 and 36 weeks of gestation + 6 days. Vaginal swab samples at delivery were analyzed using 2 different approaches, classical bacterial cultures and shotgun metagenomic sequencing analysis. A metagenomics score was constructed combining the characterization of the vaginal microbiome and the presence of pathogens and the optimal cutoff to predict early-onset neonatal sepsis was tested on a receiver operating curve.

Results: Five hundred sixty-three preterm premature rupture of membranes cases were enrolled, with 646 live-born neonates. Preterm premature rupture of membranes occurred<32 weeks of gestation in 41.9% and deliveries were<34 weeks of gestation in 41.0%. The incidence of early-onset neonatal sepsis was 29/646 (4.5%). When considering all central and peripheral microbiological samples available for 26 neonates, the main pathogens isolated were Escherichia coli in 14 cases (53.8%), other gram-negatives in 5 (19.2%), strict anaerobes in 3 (11.5%); there was a single case (3.8%) each with Group B Streptococcus, Streptococcus anginosus, Staphylococcus aureus, and Ureaplasma urealyticum. We studied the prediction of early-onset neonatal sepsis among 272 mothers and their 310 neonates (20 early-onset neonatal sepsis, 6.4%) with both culture and metagenomic data available. A culture positive for a major or intermediate pathogen in the vaginal sample at delivery had a sensitivity of 80.0% (95% confidence interval=56.3-94.3) and a specificity of 37.9% (95% confidence interval=32.3-43.8), adjusted odds ratio of 1.6 (95% confidence interval [0.5-5.0]) to predict early-onset neonatal sepsis. The presence of E. coli was associated with an early-onset neonatal sepsis risk of 10.6% vs 4.9%, in the absence of E. coli (P=0.07). The metagenomics score was highly associated with early-onset neonatal sepsis, with an area under the receiver operating curve of 0.75 (95% confidence interval, 0.61-0.90). At the optimal cutoff value, sensitivity was 70% (95% confidence interval, 64%% to 95%), specificity was 85% (95% confidence interval, 81%% to 89%). A metagenomics score greater than 40 was associated with a significantly increased risk of early-onset neonatal sepsis with an adjusted odds ratio of 8.9 (95% confidence interval [3.5; 22.3]) in multivariate analysis adjusted for latency period and gestational age, P<0.001.

Conclusion: In preterm premature rupture of membranes, conventional microbial culture of maternal vaginal samples was associated with early-onset neonatal sepsis, but its predictive values remain insufficient to guide perinatal care. Metagenomic microbial signatures improved predictive values. This opens the perspective for a rapid point-of-care test.

Keywords: Nugent score; ascending-route infection; bacterial culture; early-onset neonatal sepsis; metagenomics; pregnancy, preterm premature rupture of membranes (PPROM); vaginal microbiota; vaginal swab sampling.

Abstract

Background: Bronchopulmonary dysplasia (BPD) is the most common morbidity of very preterm (VPT) infants born < 32 weeks’ gestation with lifelong consequences. Studies document wide variation between regions and units in BPD prevalence.

Research question: Which unit-level factors contribute to the variation in BPD prevalence among VPT infants in European neonatal units?

Study design and methods: Analyses were conducted using the prospective population-based Effective Perinatal Intensive Care in Europe (EPICE) cohort in 19 regions in 11 European countries. We compared prevalence of moderate/severe BPD among VPT infants without severe congenital anomalies in neonatal units with ≥ 40 annual VPT admissions (83 units and 5,285 infants). Unit prevalence was adjusted for individual risk factors using standardized morbidity rates. Spearman correlation and multilevel logistic regression were used to assess associations of BPD with unit-level variables: unit mortality rates, first week oxygen saturation targets, proportion of infants ventilated within the first 24 hours, unit practice of postnatal corticosteroid use for hypotension or BPD prevention, and unit volume.

Results: Unadjusted BPD prevalence ranged from 2% to 47% (median, 13%) between units and was 8% to 42% (median, 17%) after adjustment and standardization. Oxygen saturation targets, proportion of initial mechanical ventilation, and postnatal corticosteroid use partly explained the between-unit variability (proportional change of variance: 25%, 5%, and 17%, respectively), leaving 53% unexplained. Risk-adjusted in-hospital mortality (range, 8%-21%) and patient volume were not correlated with BPD prevalence.

Interpretation: Our results show that large variability in BPD prevalence exists between European units, which was only partially explained by patient characteristics. Our findings suggest that improving respiratory management for VPT infants could be beneficial for reducing BPD prevalence. The association of unit postnatal corticosteroid use practice with BPD requires further investigation.

Keywords: bronchopulmonary dysplasia; chronic lung disease; cohort study; mechanical ventilation; mortality; oxygen saturation target; postnatal steroids; practice variations; very preterm.

Abstract

Objective: The Dat’AIDS score was developed to predict 5-year mortality risk in people living with HIV aged 60 and older. However, its validity in people living with HIV aged 70 years and older needed confirmation.

Methods: This was a multicentre prospective cohort study in the Dat’AIDS French cohort. We calculated the Dat’AIDS score and Veterans Aging Cohort Study (VACS) indices 1.0 and 2.0 in people living with HIV aged 70 or older, at their first medical visit between 01/06/2014 and 31/12/2017. Participants were followed until 31 December 2019 (before the COVID-19 era). Discrimination and calibration of the Dat’AIDS score were assessed using Harrell’s C-statistic and comparisons of predicted versus observed survival probabilities. The comparison of the discriminative capacity of the Dat’AIDS score with the VACS indices was performed.

Results: A total of 1330 participants (75.5% male, median age: 73.7 years, median time since HIV diagnosis: 21.7 years, median time under combination antiretroviral therapy (cART): 19.9 years, median CD4 cell count: 553 cells/μL, HIV-1 RNA ≤50 copies/mL: 88.7%) were included. Overall, 221 (16.6%) deaths were recorded during 5598 patient-years of follow-up. The Dat’AIDS score showed good discrimination (C-statistic: 0.72; 95% confidence interval [CI; 0.68-0.75]). Calibration was good except for the moderate-risk group (5% difference). The Dat’AIDS score showed better discrimination than VACS 1.0 and 2.0 with albumin, aspartate aminotransferase (AST) and alanine transaminase (ALT) normal value imputation (C-statistic: 0.72 vs. 0.69 for both) and was similar to VACS 2.0 without imputation (0.72 vs. 0.71), that could be calculated in 99.1%, 98.6% and 34.0%, respectively.

Conclusions: The Dat’AIDS score showed good discrimination and calibration in people living with HIV aged 70 years and older, providing an easy and valuable tool for clinical decision-making and research.

Keywords: DAT’AIDS; HIV infection; aged; cohort; validation study

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