Optimizing the care of very preterm infants: A collective European initiative

“Effective Perinatal Intensive Care in Europe: translating knowledge into evidence-based practice”, is the theme that will bring together the 12 institutions taking part in the EPICE project – Effective Perinatal Intensive Care in Europe – a European project funded by the EU 7th Framework Program “Health”, coordinated by Inserm. This meeting organised in Paris from the 25th to the 27th of October, will be the opportunity to mark the end of inclusions for a cohort of over 8000 very preterm infants and to provide feedback on preliminary results of the project, launched in 2011.

Changing practices in obstetric and neonatal units

The EPICE project, set up 18 months ago, collects data from 19 European regions (shown in orange on the map) in order to identify the factors that promote the use of evidence-based medicine in the care of very preterm infants.

 “The need to set up a European research project arose from the observation that mortality and morbidity rates for very preterm infants can vary by a factor greater than two between European regions”, states Jennifer Zeitlin, coordinator of the EPICE project and Researcher at Inserm (Unit 953 “Epidemiological Research Unit on Perinatal Health and Women’s and Children’s Health”).

Very preterm infants born before 32 weeks of gestation (the 8th month of pregnancy) represent between 1 and 2% of all births. They have a higher risk of mortality and long term neurological and developmental impairments than full term infants.

The EPICE project thus aims to improve the survival and long-term health of these children by ensuring that medical knowledge is translated into effective care. The project results will provide scientific knowledge on which to base intervention strategies to improve the use of evidence based medicine. It will also build a methodological and conceptual framework for future scientific work on the effectiveness of intervention strategies.

Promoting evidence-based medicine

The development of evidence-based clinical-practice guidelines is one of the most promising and cost-effective tools for improving the quality of care The EPICE project researchers are studying a large range of interventions, in order to identify the factors that promote their dissemination in everyday clinical practice.

“The aim is to learn from the experiences of high performing neonatal units in Europe and to use what we learn to improve the care offered to very preterm infants”

explains Jennifer Zeitlin.

19 medical interventions have been selected based on their clinical importance, the solidity of the evidence base and the feasibility of collecting data. These interventions concern such aspects as:

– The use of antenatal corticosteroids to promote lung maturation prior to a very preterm delivery,

– The transfer of pregnant women before delivery to specialised centres with a neonatal intensive care unit (level III units),

– The restriction of post-natal corticosteroid use,

– Promotion of breastfeeding.

Since March 2011, two epidemiological studies have been running in parallel: the first is a cohort study of more than 8000 very preterm infants (between 180 and 1500 depending on the country); the second focuses on the maternity hospitals and neonatal units that care for these infants.

– The cohort study will provide data about the care of very preterm infants and their health from birth to discharge home. These data will be completed with information about health and development at 2 years of age by means of a questionnaire sent to the family.

– Questionnaires given to the medical teams of 261 maternity hospitals and neonatal units collect data on the characteristics of the units, their organization and protocols for use of selected medical interventions and procedures.

The project’s multidisciplinary team has expertise in obstetrics, neonatal medicine, epidemiology and health services research. By grouping and reinforcing national research initiatives, this project enhances cooperation and excellence in Europe.

Why is “evidence-based medecine” necessary?

Evidence-based medecine improves the quality of health care. It is defined by the solidity of the evidence proving the beneficial effects of a practice, its advantages and any risks involved in the treatment. It helps health professionals to select treatments and practices already proven to be effective.

For further information:


“Effective Perinatal Intensive Care in Europe: translating knowledge into evidence-based practice”

The EPICE project is dedicated to the medical care of very preterm infants born before 32 weeks of gestation, in eleven European countries. The aim of the project is to assess practices in order to improve health care for this population of high risk babies.

The EPICE project was launched in 2011 and has been supported by the European Union (FP7) for five years. It is coordinated by Inserm, just like 27 other European “health” projects. The project involves 12 partners and 6 associate partners, based in 11 European countries.

The 12 partners:

Inserm (coordinator), France

SPE, Belgium

Hvidore Hospital, Denmark

Universitas Tartuensis, Estonia

Philipps Universität Marburg, Germany

Bambino Gesu Ospedale Pediatrico, Italy

Laziosanita Agenzia Di Sanita Pubblica, Italy

Radboud University Nijmegen Medical Centre, the Netherlands

Poznan University of Medical Sciences, Poland

U.Porto, Portugal

University of Leicester, United Kingdom

Karolinska Institutet, Sweden

EPICE in France

The EPICE project in France is part of a national study entitled EPIPAGE 2 (an epidemiological study on very preterm babies). It is a cohort study of very preterm infants, launched in 2011 in the 22 regions of mainland France and the French overseas departments. The study will monitor over 6000 premature children up to the age of 11 to 12. Three regions in France: Ile-de-France, Nord-Pas-de-Calais and Bourgogne participate in EPICE project.

The EPIPAGE 2 project is managed by the Inserm unit 953 (“Epidemiological research into perinatal health and the health of women and infants”), in collaboration with team 2, from UMRS 1027, directed by Dr Catherine Arnaud (Perinatal epidemiology, handicap of child and health of adolescents.

For further information on this study: (Head of studies: Pierre-Yves Ancel, Inserm U953)


Founded in 1964, the French National Health and Medical Research Institute (Inserm) is a public science and technology institute, jointly supervised by the French Ministry of Higher Education and Research and the Ministry of Health.

The mission of its scientists is to study all diseases, from the most common to the most rare, through their work in biological, medical and public health research.

With a budget of 905 million euros in 2011, Inserm supports more than 300 laboratories across France. In total, the teams include nearly 13,000 researchers, engineers, technicians and administrative staff, etc.

Inserm is a member of the National Alliance for Life and Health Sciences, founded in April 2009 with CNRS, Inserm, the CEA, INRA, INRIA, the IRD, the Pasteur Institute, the Conference of University Presidents – Conférence des Présidents d’Université (CPU) and the Conference of Chairmen of The Regional and University Hospital Centres – Conférence des directeurs généraux de centres hospitaliers régionaux et universitaires. This alliance forms part of the policy to reform the research system by better coordinating the parts played by those involved and by strengthening the position of French research in this field through a concerted plan.

Inserm is Europe’s leading European project instigator, with 28 projects coordinated by the Institute as part of the FP7 scheme.

Job strain and coronary heart disease linked

The most recent studies on the connection between ischemic cardiovascular disease and job strain have been affected by many types of bias, such as the methodology used, the definition of stress and the number of cases studied. This has led to different risk values. To find out more, French researchers at Inserm and Université Versailles Saint Quentin joined a large European consortium called IPD-WORK Consortium, which brings together thirteen cohorts in Europe. Following a far-reaching analysis of nearly 200,000 people in Europe, researchers have now confirmed that job strain and cardiovascular accidents are related. Studies show that the risk of heart attack is 23% higher in persons exposed to stress than in those who are not. Stress prevention could reduce this risk.

Result published in The Lancet on Friday September 14, 2012

In recent years, studies have investigated the role played by various psychological factors (including personality, cognition and stress) in cardiovascular diseases. The main focus has been on psychological stress, especially job strain, which combines high demand in the workplace with low control. It emerged from earlier studies that job strain could multiply the risk of coronary events by two. Other research suggests a much slighter risk. The European IPD-WORK Consortium (Individual-Participant-Data Meta-analysis in Working Populations) was set up in 2008 to investigate this topic further.

Study of 13 cohorts totalling nearly 200,000 participants

The consortium brings together thirteen European cohorts, including the French GAZEL cohort, which is made up of 20,000 EDF-GDF employees who have been monitored since 1989. Inserm researchers Marcel Goldberg, Archana Singh Manoux and Marie Zins, from Inserm unit 1018 “Research Centre for Epidemiology and Public Health” and Université Versailles Saint Quentin, have contributed to the most extensive analysis ever carried out on the relation between job strain and the onset of coronary events.

The specific feature of this analysis is that it incorporates the personal data of 193,473 participants in the European cohorts, thus allowing research teams to pinpoint the relation between job strain and risks over a large number of cases.

Seven national cohorts set up between 1985 and 2006 were studied. The countries concerned were Belgium, Denmark, Finland, France, Netherlands, Switzerland and the United Kingdom.

The study population had an average age of 42.3 years, with as many women as men. Questionnaires focusing on work-related psychosocial aspects were used to assess job strain. Among the points considered were job demand, the excessive workloads of some individuals, the conflicting demands made of them and the limited amount of time in which they were expected to complete their tasks.

The proportion of individuals exposed to job strain ranged from 12.5% to 22.3% according to previous studies. It represented 15.3% of this large study population.

At the same time, researchers identified 2,358 coronary events among the 200,000 individuals over an average monitoring period of seven years.

The importance of stress prevention

After analysing the data,

the results obtained from the 13 European cohorts show that the risk of heart attack is 23% higher in persons exposed to stress at work than in those who are not”

explains Marcel Goldberg, a professor at Université de Versailles Saint Quentin and researcher at Inserm.

The results are practically the same after allowing for the participants’ lifestyles, age, gender, socioeconomic status and geographical distribution.

Taking the population as a whole (stressed and unstressed), the researchers consider that job strain can lead to a slight, but not negligible, increase in the risk of heart attack: “In our study, 3.4% of the heart attacks reported among the 200,000 individuals can be explained by job strain. Of the 100,000 to 120,000 heart attacks occurring in France every year, that would represent roughly 3,400 to 4,000 accidents attributable to this risk factor,” Marcel Goldberg explains.

The European research team suggests reducing this risk by stepping up measures to prevent work-related stress. Preventive measures in this area could also positively affect other risk factors, such as tobacco and alcohol consumption, which recent studies have shown to be partly stress-related.

The neurological bases of anxiety disorders

On June 18th, a one-day scientific symposium in Paris entitled “Neurobiological basis of Anxiety disorders”, got together scientists from 6 of the partners of DEVANX (1) , a European project coordinated by Inserm and launched in 2008. It was an opportunity to take stock of what knowledge has been acquired about the neurological basis of anxiety disorders.

Over the last few years, great progress has been made in our knowledge of brain circuits and the key molecules involved in the manifestations of anxiety. The use of animal models has greatly contributed to our understanding. In mice, it was possible to observe behavioral changes that occurred in situations of emotional conflict, for example how the animal chose between exploring new avenues (curiosity) and withdrawal (fear). It allowed us to describe the way in which the animal acts in a situation of learned fear: how the animal learns to associate a neutral environment with potential danger.

Serotonin and GABA are the 2 main molecules that act as “messengers” (or neurotransmitters) between the neurons involved in states of anxiety. And these are the common targets for “anxiolytic” drugs.

However, the exact role played by these molecules and their interactions with the environment are still unknown. Genetics and the new information gained about brain plasticity need to be integrated into our constantly growing understanding of the mechanisms involved. Patricia Gaspar and Laurence Lanfumey, Research directors at Inserm and coordinators of the DEVANX project, have worked with their colleagues to study the neurobiological bases of anxiety from different angles.

1. Pharmacological aspects

The GABAb receptors present in neurons are targeted by new molecules that work in a completely different way from conventional anxiolytics (benzodiazepines), that act on the GABAa receptors. By finding out more about the structure and the function of GABAb receptors and their interactions with the serotoninergic system, we can propose new therapeutic targets.

A particular example is Benny Bettler’s team, a member of the DEVANX consortium in Switzerland. They demonstrated that GABAb receptors are heterodimers (a combination of two different receptor subunits) that possess partner proteins capable of modifying their binding properties. The pharmacological properties of GABAb receptors vary depending on how the partner proteins are organized. From a therapeutic point of view, positive modulation of these receptors represents a possible strategy for developing new anxiolytics. John Cryan, a partner of the DEVANX consortium in Ireland, has shown that inhibiting GABAb receptors can reduce depressive behavior. Working along the same lines, Laurence Lanfumey’s team in Paris studied the connection between GABAb receptors and the serotoninergic system.

© Gassmann et Bettler, 2012

GABAB receptor subunits: GABAB1a, GABAB1b and GABAB2

These subunits are receptors with seven transmembrane domains bound to the G proteins via the GABAB2 .subunit. The difference between the GABAB1a and GABAB1b subunits is that there are two terminal domains (sushi-domains) on the GABAB1a subunit.

2. The part played by serotonin

In people who suffer from depression, panic attacks, anxiety disorders or phobias, administering drugs that increase the serotonin level reduces these pathologies.

However we know very little about the initial cause of this lack of serotonin that causes the disorders. That is the reason why the researchers need different animal models to discover and analyze the different situations of a brain that is “depleted” of serotonin.

Serotonin is involved in numerous physiological functions: sleep/wake rhythms, impulsivity, appetite, pain, sexual behavior and anxiety. Its action is mediated by around fifteen different receptor sub-types.

The serotoninergic system is a multiple system: it is present in the central nervous system (in the Raphe nuclei of the brain) and in the peripheral nervous system (in the enterochromaffin cells of the digestive tract).

The way in which neurons “specialize” into serotonin neurons is controlled by different molecular factors, depending on their location, and does not all happen at the same time in the course of development.

One of the studies carried out by the genetics specialists as part of the DEVANX project aimed at conditionally targeting the production of serotonin at a given time and in a given location. For example, Dusan Bartsch’s team, a DEVANX partner in Mannheim, produced genetically modified mouse models that allowed them to reduce the serotonin at different times during the life of the mice, by creating models known as inductable models (in which the elimination of a gene could be induced by administering a drug). Patricia Gaspar’s team in Paris characterized mutations in which only part of the serotoninergic neurons was affected (mutation of a Pet-1 transcription factor). In these mice, the team noted that spontaneous anxiety was reduced, but that their fear conditioning was increased. Therefore, the lack of serotonin in the central nervous system could mean that the subjects more easily associate neutral situations with a panic reaction.

3. Other circuits involved: Fear circuits

By linking the research into fear with the latest neurobehavioral findings, it was possible to combine the approaches.

It is becoming more and more evident that it is the normal neuron circuits specialized in dealing with fear that are pathologically affected or amplified in anxiety disorders. So it is very important to understand and analyze how these circuits function in “real situations” in animal models. The end purpose is to find a way of “deconditioning” certain brain circuits that have been abnormally or over-activated.

The new approaches to physiology on the knockout animal, combined with pharmacogenetic research, have made for progress in this field. For example, Agnés Gruart’s laboratory in Sevilla, one of the partners of the DEVANX project, has recorded different neurons from the hippocampal circuits in different fear learning situations and observed the effect of modifying the message conveyed by GABAb and serotonin. Cornelius Gross’s team from EMBL in Rome has shown that we can use serotoninergic receptors (5-HT1A) expressed in different areas of the brain in order to temporarily deactivate highly specific neuron circuits. This allowed them to identify the hippocampal and amygdala circuits involved in the generalization of fear.

Research into anxiety disorders, as in numerous fields of neurosciences, is now using integrated approaches that require multiple fields of knowledge. Molecular studies now need to be integrated into the whole animal context that expresses behavior patterns as similar as possible to physiological situations, while still being strictly controlled as experiments. Genetic tools now provide us with unequalled power for researching into a determined molecule function, or a molecular assembly within a given circuit and a precise time slot. This type of approach will continue to develop in the years to come, with the coming of tools that will allow us to activate or deactivate certain selected neuron circuits.

By solving these intertwined elementary processes step by step, we should at last find the explanation to the mechanisms underlying pathological anxiety disorders.

(1) DEVANX: “Serotonin and GABA-B receptors in anxiety: From developmental risk factors to treatment”, a project funded by the European Commission and launched in 2008. Partners involved: Inserm (coordinator), University College Cork, Ireland, European Molecular Biology Laboratory, Italy/Germany, Central Institute of Mental Health, Mannheim, Germany, Universitaet Basel, Switzerland, Universidad Pablo de Olavide, Spain

Why do the different people’s bodies react differently to a high-fat diet?

A diet rich in greasy foods causes an imbalance in our gut flora. The composition of the gut flora seems to determine the way in which the body develops certain metabolic disorders such as diabetes, regardless of any genetic modification, gender, age or specific diet. This has recently been demonstrated by Rémy Burcelin and Matteo Serino, researchers from the Inserm unit 1048 “Institute of Metabolic and cardiovascular diseases (I2MC)”. It is believed that nutritional additives such as gluco-oligosaccharides and dietary fibers that target the gut microbiota could prevent the development of metabolic disorders. These results have been published in the review Gut of April 2012

Gut flora, otherwise knows as gut microbiota, are the bacteria that live in our digestive tract. There are roughly one thousand different species of bacteria, that are nourished partly by what we eat. Each person has their own specific gut flora and metabolism and these differ according to our dietary habits. Previous studies in mice have shown that a high-fat diet is capable of causing an imbalance in the gut flora, thus causing metabolic diseases such as diabetes or obesity.

Rémy Burcelin’s research team (Inserm unit 1048, Université Toulouse III – Paul Sabatier) spent three months studying how a fatty (1) diet affected the gut flora of male mice of the same age, all with the same genetic background. Most of the mice developed diabetes while remaining thin, whereas some remained thin but did not develop diabetes. Why is this so?

In order to confirm the theory that gut flora affects the way in which our body reacts to a high-fat diet, the research team looked at the microbial profile of different types of mice (thin and diabetic and thin and non-diabetic, which indicates two phenotypes). They showed that there was a difference in the quantities of gut bacteria between diabetic and non-diabetic mice. The thin but diabetic mice presented a flora composed mainly of “bacteroidetes” type bacteria, unlike the thin and non-diabetic mice that presented a flora composed mainly of “firmicutes“ type bacteria.

So is gut flora the cause or the result of metabolic disorders? To find the answer to this question, Rémy Burcelin’s team directly modified the gut flora of a group of mice by adding dietary fibers and gluco-oligosaccharides to their high-fat diet. “By adding these fibers, we modulated most of the physiological characteristics. The metabolism of the mice that we treated with these fibers was similar to that of the thin, non-diabetic mice. But the gut flora of the mice treated with fibers changed greatly compared to that of the other phenotypes observed”, says Matteo Serino.

This project was partly sponsored by the “Florinflam” research program financed by the National Research Agency (ANR) and the FLORINASH research program financed by the EU 7th Framework Programme (FP7). The FLORINASH project (Prevention and treatment of non-alcoholic fatty liver disease) was coordinated by Inserm under the auspices of Rémy Burcelin, Inserm research director, and was contributed to by 6 partners from 4 European countries.