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Vitamin D And LIfestyle Intervention for Gestational Diabetes Mellitus (GDM) Prevention

Periodic Report Summary 3 - DALI (Vitamin D And LIfestyle Intervention for Gestational Diabetes Mellitus (GDM) Prevention)

Project Context and Objectives:
DALI represents a collaborative research effort of 11 academic and 2 industrial partners (SMEs) from 11 European countries. It focuses on gestational diabetes mellitus (GDM), a problem of increasing significance in the decades to come.
Europe is facing an unprecedented threat from Type 2 diabetes (T2D) with associated human suffering and economic burden of enormous and rapidly growing proportions. While T2D is traditionally associated with sedentary lifestyle and unhealthy diet, the currently observed growth in developed countries is greater than expected from lifestyle changes alone. Evidence is accumulating that GDM is a more important contributor to these epidemics than previously recognized. Firstly, women with past GDM comprise up to 31% of parous women with T2D; secondly, intrauterine exposure to hyperglycaemia through GDM predisposes for diabetes and obesity: so called "fuel mediated teratogenesis". If GDM is acting as the "accumulator" behind the T2D epidemic, strategies to arrest this inter-generational transmission are urgently needed. However, there is a shortage of evidence about how to proceed, which the DALI project will address with the goal to pave the way for a pan-European strategy to prevent GDM.
To this end DALI will use an exploratory trial approach to develop the best intervention for preventing gestational diabetes mellitus. Three interventions will be tested either singly or in combination: coaching for dietary changes and/or changes in physical activity and/or vitamin D supplementation. Behavioral models have informed the strategies that motivate for lifestyle changes. DALI will concurrently use the trial data, samples and cohorts to increase the understanding of the patho-physiological mechanisms leading to enhanced diabetes and obesity risk to mother and baby. Building upon the expertise of members of the Diabetes in Pregnancy Study Group Europe (DPSG), and joined by behavioral researchers and health economists, DALI is designed to collate the evidence around the epidemiology of GDM in Europe, to promote pan-European standards and measures for GDM and identify suitable preventive measures against GDM.

Description of the project objectives
Specific objectives of the DALI-project, which are also reflected in the respective work-package structure, include:
• To obtain information on GDM prevalence in Europe for the first pan-European epidemiological study (Epidemiology)
o Description of national approaches to screening and diagnosing GDM across Europe
o Assessment of the prevalence of GDM locally and in obese women
o To identify the best available measures to prevent GDM in pregnancy (Prevention)
§ Evaluation of GDM diagnostic maternal measures and fetal measures
§ Comparison of the impact of increased physical activity, enhanced nutrition and Vitamin D supplementation either alone or in combination on maternal glucose tolerance, maternal weight gain and insulin sensitivity
§ Evaluation of barriers and promoters of uptake in life style changes
§ Understanding whether the trial results in less weight gain, lower fasting glucose and/or lower insulin resistance in one or more intervention groups
§ Understanding the effect of the intervention on the fetus with a focus on fetal hypoxia, blood vessel characteristics and growth in utero
§ Determining the effect of fetal sex on intervention success and the path physiology in utero
§ To provide a cost-benefit calculation of GDM prevention (Societal impact)
• Completion of a cost and quality of life calculation for GDM
• Completion of an economic evaluation of DALI preventive strategies
• Development of a decision tree to estimate cost-effectiveness of prevention strategies
• To establish a pan-European cohort of mother-offspring pairs for future analyses with a central biobank and data base (Sustainability)
o Creation of a comprehensive internet-based data base
o Creation of a physical store of placental tissue, maternal and cord blood (serum, DNA)

Project Results:
Because of the delay of some deliverables in reporting periods 1 and 2, the main objectives of this period from months 37-54 were to continue recruiting women into the main trial and to execute the intervention.
Specifically, the following work was carried out during the reporting period:
1) To continue executing the full trial (WP5). This included:
• Enhancing study recruitment procedures
• Monitoring the trial progress by analyzing the weekly reports from all sites sent to the coordination site
• Implementation of a training programme for new coaches
• Training workshops for lifestyle coaches and for nurses taking mother/baby measurements
• Upgrading the PDA system
• Completing the site visits to ensure that study procedures are complied with
• Obtaining ethical approvals for the vitamin D trial.
• 652 women have consented, for the lifestyle limb of whom 451 have been randomized, with others excluded for various reasons (eg gestation, BMI criteria, co-morbidities). 350 women completed the trial (had their babies) and 92 have developed GDM so far (others have dropped out for a number of reasons including withdrawal of consent)..
• 125 women have consented for the Vitamin D limb of whom 89 have been randomized. 13 have completed the trial and 11 have developed GDM so far

2) The biobank has begun receiving and storing samples from trial sites (WP7). Email interaction with laboratory personnel at sites and the biobank has helped clarifying unclear procedures. The DALI database has been continuously improved based upon feedback (email, telephone) on the beta versions, and is now in use in the main trial. Data are being entered. Laboratory analyses have begun. The transfer of data from first laboratory analyses has been technically implemented and laboratory results have been continuously entered into the database.
3) To continue informing the public about the DALI project (WP8). A manuscript describing the design of the DALI trial was published in BMC Pregnancy and Childbirth. DALI was presented to the public by press releases, press clippings and media interviews at several partner sites. Several free papers have been/or are to be presented as posters or oral presentations at national/international meetings. The final DALI meeting including the recommendation meeting (WP8) is being discussed and planned
4) To continue managing the project on a daily basis (WP9).
Regular meetings in person or telephone facilitated refinements of the protocols. Main issues at the partner sites have been how to improve recruitment, and lack of weekly reporting of recruitment. These issues have been a major topic of continuous discussion.
The sponsor has worked with the vitamin D supplier and the trial sites on details of distribution. Vitamin D and placebo was distributed to the sites. Upcoming problems with the vitamin D trial in some countries have been continuously dealt with by the sponsor and support provided.

Potential Impact:
DALI represents a comprehensive research programme, which will provide a better understanding of GDM. This will allow the development of effective preventive measures, which could hold significant potential in having a key impact on curbing T2D prevalence. One finding from the pilot raises the question whether screening for GDM in obese women should be earlier: we will review this with the data from the main trial.
The development, testing and exploratory trials of the interventions (physical activity, nutrition, both, Vitamin D supplementation) is designed to provide the most cost-effective intervention to prevent GDM for entry into a full RCT. The next step should therefore be funding for a full trial. In view of the pace at which the diabetes and obesity epidemics are progressing, and the likely accumulator effect of GDM and obesity in pregnancy, we are well aware of the need for prompt action in terms of policy and clinical service development in this area. DALI will provide the tools, the methods and an understanding of the numbers needed for the full trial of whatever intervention is assessed as "the best". Once these are in place, as long as multiple centres are recruited into this next step, such a trial could be undertaken with 6-12 months set up/recruitment and probably just 6-12 months of the actual trial. This is particularly the case as the intervention period is only 6-7 months long. With such a disseminated trial and with the confidence from the careful design of DALI and the subsequent full trial, adoption of the intervention into services itself will be easier. After DALI, assuming that at least one intervention is efficacious in reducing GDM risk, a range of international, national and local policy initiatives would be needed to promote the funding and creation of "GDM prevention services". This would represent a significant improvement in health care provision for those at risk of GDM.
Although the tools and approach will have been developed for women at risk of GDM, an important component of care for those women with GDM already is diet and physical activity. We suspect that the programme developed will be of significant benefit for services for women with GDM and could result in less women requiring additional treatment (e.g. insulin therapy).
Data generated in the trial can be used for answering many additional questions. For instance, it would be possible to assess the impact of different degrees of weight gain in obese women on mother and baby and the subsequent dissemination is likely to have a major impact on policy development for the pre-conception and antenatal health care of women. Furthermore, DALI expects to discover a range of GDM phenotypes. The ability to link detailed maternal measures with characterization of insulin sensitivity and insulin resistance in a relatively large number of women, with the impact of different forms of lifestyle change, weight loss and Vitamin D supplementation is likely to allow a detailed phenotypic classification. On this basis it is expected that in the future GDM treatment will be applied in a more personalized manner. And finally, by starting early in pregnancy, including a range of ultrasonographic and other fetal anthropometric, metabolic and rheological measures and relating this to detailed measures of the maternal metabolic milieu (with DNA available for future use), this study will allow a greater understanding of the effects of the maternal milieu on fetal programming including epigenetic mechanisms. Again, the potential to find a change in the fetus with maternal interventions has rarely been studied and could open up new avenues for research and subsequent translation of knowledge into clinical practice.
The study design not only allows for epidemiological data collection regarding what is known about the prevalence of GDM in Europe, but will also look at how the current systems for screening and diagnosing GDM operate. We expect to use these data to generate a discussion document to help move Europe to adopt common standards, based on the best evidence, for screening for and diagnosing GDM. Having a single set of criteria for GDM across the EU would be an important step to a quality initiative in the management of GDM including monitoring, audit and inter-centre and international benchmarking.
The database and biobank, which will be established in DALI for the mother/offspring pairs, will make the project relevant beyond its actual duration and could form the basis of wider, pan-European studies or follow-up cohorts of both mother and child from the present studies. This would allow conclusions about offspring development in relation to the intervention. Moreover, the medium to long term impact of the intervention on maternal development of life-style diseases can be assessed within a longer timeframe than in most studies worldwide. A plan for follow up of mothers and babies is under development, and some sites (eg UK) have already begun a programme (with ethics approval) to maintain contact.

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