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Periodic Report Summary 3 - EARLYNUTRITION (Long-term effects of early nutrition on later health)

Project Context and Objectives:
Increasing evidence, most recently from the EU FP6 Project EARNEST, but also from many other investigators, demonstrates that early nutrition and lifestyle have long-term effects on later health and the risk of common non-communicable diseases (known as “developmental or metabolic programming”). Because of the increasing public health importance and the trans-generational nature of the problem, obesity and associated disorders are the focus of the project ‘EarlyNutrition’, running from 2012-2017 with a total budget of 11.12 million Euros, including a contribution by the European Commission of 8.96 Million Euros. This project brings together 36 partners from academia, industry and the SME sector from 12 European countries, the USA and Australia forming a strong multi-disciplinary team of international leaders in the field which achieves balance and complementarity.
The EarlyNutrition project explores the three current key hypotheses on likely causes and pathways to prevention of early life origins of obesity (specifically adiposity) and associated disorders. It brings together extraordinary expertise and study populations of 470,000 individuals to investigate:
1) the fuel mediated ‘in utero’ hypothesis which suggests that intrauterine exposure to an excess of fuels, most notably glucose, causes permanent changes of the fetus that lead to obesity in postnatal life;
2) the accelerated postnatal weight gain hypothesis which proposes an association between rapid weight gain in infancy and an increased risk of later obesity and adverse outcomes; and
3) the mismatch hypothesis which suggests that experiencing a developmental ‘mismatch’ between a sub-optimal perinatal and an obesogenic childhood environment is related to a particular predisposition to obesity and corresponding co-morbidities.
EarlyNutrition will provide the scientific foundations for evidence based recommendations for optimal early nutrition that incorporate long-term health outcomes, with a focus on obesity and related disorders. Evidence is produced from animal and placental studies (Theme 1), prospective cohort studies (Theme 2), and randomised controlled trials in pregnant women and infants (Theme 3). Theme 4 covers scientific strategic integration, recommendation development and dissemination, including systematic reviews and behaviour change approaches. Four target groups are studied: women before pregnancy, pregnant women, infants and young children.
Scientific and technical expertise in placental biology, epigenetics and metabolomics provides understanding at the cellular and molecular level of the relationships between early life nutrition and the risk of later obesity and adiposity. This, in turn will help refine strategies for intervention in early life to prevent obesity. The project’s impact comprises definitive evidence on early nutrition effects on health, enhanced EU and global policies, major economic benefits through obesity prevention and value-added nutritional products, and practical recommendations on optimal nutrition in the four target groups. Wide dissemination is achieved through active engagement with stakeholders.

Project Results:
Theme 1 explores the mechanisms for programming of obesity. The hypothesis that maternal obesity alters human/animal placental mRNA expression was not proven, but placental lipid metabolism in lipid droplets was modified. Technical issues delayed placental fatty acid transfer studies, and the approach to modelling placental fatty acid transfer in lean and obese women has been refined. Completed dietary/exercise intervention studies in obese pregnant rodents showed proof of principle that interventions can reduce obesity and some related disorders. Metabolomic profiling of pregnant womens’ blood samples led to the first characterisation of metabolite profiles in pregnancy and identification of obesity-related metabolic ‘signatures’, potential targets to prevent programming of obesity. Novel sex differences in the metabolome and time needed for re-analyses led to some delays. Technical delays hampered one epigenetic study, but many hundreds of samples have been processed to better address the molecular mechanisms which may underlie developmental programming of obesity, with some emerging and very interesting preliminary data.

Theme 2 is investigating early nutrition programming through follow-up of prospective mother-offspring cohorts. We have compiled the world’s largest meta-analysis (39 studies) of gestational weight gain, body composition and smoking in relation to offspring adiposity/co-morbidities. A new publication demonstrated that a greater number of modifiable early life risk factors associates with large differences in childhood adiposity/obesity risk, with major policy implications. Long term follow-up found no relation between long-chain omega-3 fatty acid intake in pregnancy and adolescent adiposity or early type-2 diabetes. Analyses of growth velocities have shown independent influences on childhood adiposity of high velocities of both prenatal and early infancy soft tissue accretion, but also novel evidence for interaction between faltering of fetal growth and an obesogenic childhood environment. Nutritional analysis of breast milk composition in 597 samples from women in 5 European countries, has shown many new findings, including correlations between pre-pregnancy weight and milk insulin/IGF-II levels.

Theme 3 combines infant and childhood follow up studies and three randomized trials investigating pre- or postnatal interventions. The follow-up studies are progressing. In the CHOP study (WP12) examination of the subjects at age 11 years has already been completed, with a higher follow-up rate than anticipated. Childhood follow-up from the three maternal prenatal intervention studies is either complete (LIMIT) or ongoing (ROLO, UPBEAT)(WP11) and the first meta-analysis of infants is underway. The AMELIE trial (WP14) had already been completed. During the current period data have been evaluated and a manuscript has been submitted and accepted for publication. In the NIGO study (WP11) a markedly unequal recruitment rate in the two study centres prompted us to change the study sites, which is currently implemented and expected to improve and speed-up recruitment considerably. After the delayed start the PROTEUS study (WP13) has progressed very well and has successfully recruited subjects. Current estimate is that the inclusion has reached the target number of subjects summer 2016, while the intervention period will add another 6 months from the time of last inclusion.The data safety and monitoring board found no indications that the study formula is not safe.
In summary there was impressive progress in Theme 3. Considering the enormous amount of data generated and the delays in two of the intervention studies Theme 3 would greatly benefit from an extension of the project duration by 6 months.

Theme 4 involves a number of tasks including collating information on current and developing new recommendations on optimised nutrition for women prior to pregnancy, pregnant women and infants and children, which take into account the effects of early nutrition on later health. Successful progress has been seen. The review of current guidelines has been completed. The first draft of the recommendations for all four target groups have been prepared. Additionally, the analyses of the various datasets will be described and a synthesis will be made to provide a summary of similarities and differences between the main influences on diet, dietary behaviours and physical activity across EU countries.
Strong dissemination has been achieved on all deliverables and publications. Every opportunity has been used to spread the combined expertise within the consortium to other members of the consortium and to external individuals. Practical workshops have been organized and the e-learning platform ENeA is continuing to grow.

In Theme 5, all databases had been developed and deployed in the first half of the project, except one because of delay in finalizing the study protocol. In the current reporting period, the last database was deployed. All databases have been successfully used to collect data of these studies.

Potential Impact:
Project EarlyNutrition will lead to a better understanding of the impact of early nutritional programming on health during childhood, adolescence and adults in specific subgroups of the population. Furthermore, research in the project will help to identify the nutritional needs of women of childbearing age in Europe. The results should lead to recommendations on optimized nutrition before and during pregnancy, during the breast feeding period and during the early life of infants, with special reference to later health development of offspring. Most current recommendations for pregnant women, particularly obese women, and for young children do not take into account the long-term health consequences of nutrition. EarlyNutrition will systematically review the evidence, draw conclusions and formulate recommendations on optimized nutrition before and during pregnancy, during the breastfeeding period and childhood with special reference to later health development of offspring. Barriers to change will be explored in research investigating driving forces of consumer preferences and behaviour to ensure the suitability and user-friendliness of the recommendations.
For the scientific community, EarlyNutrition will produce better evidence for the impact of lasting effects of "Early Nutrition Programming" on health, well-being and performance, with a focus on obesity and associated disorders. It will provide further clarification of the causative maternal/offspring exposures, effect sizes, key processes and mechanisms regulating programming, will confirm or refute key concepts related to programming, such as the roles of accelerated foetal and/or infant growth and "mismatch" in the programming of obesity susceptibility, and will define new interventions to reverse the obesity epidemic. It will contribute towards a better understanding of the impact of early nutritional programming on health during infancy, childhood, adolescence and in pregnant women. It will provide further evidence towards identifying the nutritional needs of women in Europe before and during pregnancy, based on a better understanding of the long-term consequences in their offspring. A “database toolkit” and standardized approaches to describe key exposures (including dietary patterns) and outcomes, and harmonized methodologies e.g. for assessing outcomes, sample collection and handling, analytical approaches, data management and evaluation, will improve and enhance future intervention studies and facilitate collaboration as well as comparison of results from different studies and meta-analyses of results.
The wider societal implications of project EarlyNutrition are to strengthen the evidence for effective ways of reducing the susceptibility to obesity and its associated disorders, which could lead to future generations with a reduced propensity to gain excessive amounts of weight. The policy recommendations arising out of the project will therefore contribute to the primary prevention of obesity and its associated disorders, metabolic syndrome, diabetes, cardiovascular disease, asthma and certain cancers. This will help to reverse the increasing rates of obesity seen across all European countries.
More information about the project can be found on .

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