The FHU PREMA project focuses on 2 main objectives: “Improvement of Knowledge” on prematurity and “Improvement of Care” provided to pregnant women and to babies born preterm:
- The first objective is to develop projects on the mechanisms and causes of preterm birth or delivery and on the short- and long-term harmful consequences.
- The second objective is to focus research on innovation and on the development of diagnostic tools and new therapeutic approaches. Dedicated research platforms are used to evaluate new procedures, therapies, devices, and digital solutions. Collaboration with the Research Development Institute (IRD) gives access to cohorts in Africa and the opportunity to test the applicability of FHU PREMA’s innovations to low-income countries.
- Cross-functional projects : The dissemination of effective and relevant practices in France and elsewhere is part of the objective to improve the health of premature newborns.
With regard to teaching, FHU PREMA aims to develop teaching programs for professionals and educational tools for the general public. FHU PREMA teams have already developed innovative programs with high-fidelity simulation techniques and MOOC. The objective is now to develop new ways of using communication technologies to disseminate knowledge.
Axis 1: Improving knowledge in prematurity. Coordination: C. POYART.
Social inequalities in health (E. Azria & P. Sauvegrain).
Social inequalities in perinatal health are increasingly well documented and many studies have shown associations between social exposure and adverse perinatal outcomes. However, mechanisms of these inequalities are poorly studied and understood. Furthermore, very few interventions to reduce their magnitude have so far been proposed and tested.
Our objectives are to advance in the understanding of these inequalities and, based on the mechanisms identified, to build interventions to be implemented and tested within the framework. Among these mechanisms, differentiated care (i.e. care provided in a different way according to the social category without medical basis) probably plays an important role. In the continuity of the ANR project “Migrants and differential care in the perinatal period: Effects of implicit bias (BiP)”, we will develop this research program based on mixed methodological approaches by extending the approach to social exposures other than migration and to aspects of perinatal care other than those currently studied.
Determinants and consequences of placental dysfunction in a context of malaria (A. Garcia).
In endemic areas, malaria in pregnancy is a main cause of fetal growth restriction and preterm delivery. Placental inflammation due to the accumulation of infected red blood cells in the placenta through adhesion to the chondroitin sulphate A is one of the key underlying pathophysiological mechanisms. However, abnormal placental functions and trophoblast differentiation related to malaria have not been explored so far.
Our current project (FIND funded) aims to identify biomarkers of placental alterations (PlGF, sFlt-1, hPL) that are related to malaria by a Luminex approach, and whether variations in the level of these markers are predictive of poor birth outcomes. We will use plasmas collected during the RECIPAL project (ANR-13-JSV1-0004), which followed 411 Beninese pregnant women until delivery, with repeated measurements of malaria indicators and longitudinal fetal growth assessment.
Intestinal microbiota and necrotizing enterocolitis (NEC) (F. Barbut & J. Aires).
NEC is one of the most severe and life-threatening gastrointestinal diseases among preterm neonates that still accounts for substantial morbidity and mortality in neonatal intensive care units. We showed the key role of nutrition strategies and microbiota in the increase risk of NEC (PMID: 28659297).
Taking advantage of our collection strains and fecal samples (ClosNEC study, ANR-13-PRTS-0018), our project relies on providing mechanistic data on the inflammatory process of NEC and identifies host and/or microbial specific metabolic biomarkers of NEC. Identifying metabolites as potential biomarkers will support nutritional interventions to modulate the gut microbiota and/or its metabolic functional activity. We have previously identified two specific strains that could potentially be used for the prevention of severe gastrointestinal diseases in very preterm infants. The pharmaceutical development of these strains and their testing in clinical settings will be considered.
10-year outcome of very preterm children (EPIPAGE 10Y) (P.Y. Ancel).
Preterm birth interrupts the development and maturation of many organs during a critical growth period. It is crucial to understand mechanisms of long-term risks of outcomes to guide preventive measures to preserve organ function across the lifespan. EPIPAGE 2 is a national prospective cohort of preterm births occurring between 22 and 34 WG (4441 children followed up) (EQUIPEX ANR-11-EQPX-0038, PMID: 25621457). To address the key research questions, a comprehensive survey will be organized at 10 years of age.
The objectives are to evaluate cognitive development, to measure anthropometric characteristics, sensory-motor abilities, heart rate and arterial blood pressure, and respiratory function, and to collect data on quality of life, behavior and personality development. A linkage with the National Health Insurance Database and with national assessments in secondary schools will be conducted. This project, supported by the FHU leaders, is the subject of a funding request under the Future Investment Program.
Axis 2: Improving the care of pregnant women and preterm infants. Coordination: F. GOFFINET
Promoting single embryo transfer (eSET) after In Vitro Fertilization (IVF) (C. Patrat & P. Santulli),
We promote single embryo transfer (eSET) after In Vitro Fertilization (IVF) by defining new criteria of embryo choice, while ensuring high pregnancy rates and babies’ health. Although most babies conceived by IVF appear healthy, they are at increased risk of adverse perinatal outcomes, particularly premature birth, as compared to naturally-conceived children (PMID: 30753453). IVF is associated with a high rate of multiple pregnancies thus contributing massively to preterm deliveries. By developing tools to select the embryos with the highest probability of implantation we will promote eSET and therefore reduce multiple pregnancies.
Machine learning algorithms, associated with a physical model of morphogenesis, will be developed from human embryo development kinetics and applied in our IVF routinely practice (collaboration with J.L. Maitre, Institut Curie). This approach will be supplemented by the status of embryo ploidy, after trophectoderm biopsy or indirectly in the culture medium and will be tested in national randomized control trial (PHRC submitted). Finally, correlation analyses of metabolomic profiles of follicular fluid, using nuclear magnetic resonance (NMR), and ART outcomes will optimize embryo selection criteria (Collaboration with the metabolomic platform – MetaboParis-Santé – Sesame Project).
Preeclampsia bed-side test (V. Tsatsaris & J. Guibourdenche).
Preeclampsia is a disease specific to pregnancy due to placental dysfunction and the release into the maternal circulation of several factors responsible for endothelial dysfunction. We were among the first to describe the role of PlGF and sFlt-1 in the pathophysiology of preeclampsia and their potential utility as biomarkers (PMID:14602804). They are excellent markers for the prediction of preeclampsia and severe maternal or fetal outcomes. However, their use is limited in clinical practice since they are not available rapidly in obstetrical emergency units.
The challenge is to create a highly sensitive PoC test, available in each obstetric emergency unit, for a rapid assay of PlGF in whole blood. This project will be developed with an industrial partnership (Biosynex). The collaboration with UMR 168 will allow the development of an automated microfluidic device based on combination of droplets and fluidized bed in order to obtain a quantitative measurement of very low PlGF concentrations (below 12pg/mL). Multiplexing will allow simultaneous testing of other new relevant markers to improve risk assessment (i.e. sLIFR recently patented by P6.2).
Vaccines to prevent and treat maternal-fetal infection (D. Skurnik & O. Launay).
Preterm birth is associated with a significant increase of severe neonatal bacterial infections caused by Group B Streptococcus, E. coli K1 and even Staphylococcus aureus. PREMA will be an outstanding opportunity to advance toward preventing (active vaccination) and treating (passive vaccination using human monoclonal antibodies) these infections.
Our aim is to develop a collaborative work between teams working on the preclinical side of the antibacterial vaccine development from discovery, using high-throughput sequencing, to in vitro and relevant in vivo models, including antigens expressed by all the major pathogens (PMID:26747103), to the Vaccinology Center (Odile Launay) which will use the most promising targets from the preclinical studies to demonstrate the proof of concept of efficacy, and finally to industrial partners that will help to bring these new compounds into the market. We will take advantage of the expertise of the Streptococci National Reference Center (C. Poyart, https://cnrstrep. fr).
PREMEX Trial (F. Goffinet & P.H. Jarreau).
Extreme preterm infants born between 22 and 26 WG (3500/year in France) are at very high risk for neonatal death, severe morbidity and disability. Survival in France remains low with substantial variability in practices depending on the place of birth, with active care ranging from 22% to 61%. Moreover, survival in France was 10 to 50% lower than in the US, UK, Japan and Sweden (PMID: 25621457). In 2015 a highly formalized protocol was introduced in the DHU to standardize the perinatal management of extreme prematurity and a pilot study showed an improvement in the morbidity-free survival of the extremely preterm infants.
The objective of the PREMEX trial is to evaluate in 20 French perinatal networks the impact of this new organization of care on survival without severe neonatal morbidity and neurodevelopmental outcome children at 2 years old. This stepped wedge randomized trial will include 2100 extremely preterm infants. Funding will be requested from the Ministry of Health PREPS (950 k €) and the study could take place in 2020- 2024.
Our objective is to create at Bichat Hospital (APHP) a unit for the evaluation of innovative digital tools in pregnant women (Digital Medical Hub-PREG, D. Luton & M.P. d’Ortho). We will evaluate mobile devices/apps in comparison with gold standard measurements.
The use of bigdata in perinatology is emerging. We recently obtained a database from the National Health Data System (SNDS) with medical and administrative information on 5.1 million pregnancies (2012-2016). This database will serve to investigate at the national level the relation between diseases/practices and prematurity, for example, the real impact of ART procedures on preterm deliveries (J.M. Treluyer).
We will also develop new educational approaches to professionals and the general public (P.F. Ceccaldi) in collaboration with Simforhealth and Medusims.
Regarding the management of patients, we will develop common medical protocols and harmonize information for parents. We will perform inter-hospital morbidity/mortality reviews jointly with clinicians from all the FHU medical units.
Finally, we will particularly encourage and support the involvement of midwives in MSc/PhD programs as well as in clinical research projects Midwifery Research (A. Chantry).
We will establish an active collaboration with patient associations (C. Le Ray). They will participate to the design and follow-up of the research projects and the hosting of the Word Prematurity Day in France every Nov 17th.