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Genomic and lifestyle predictors of foetal outcome relevant to diabetes and obesity and their relevance to prevention strategies in South Asian peoples.

Final Report Summary - GIFTS (Genomic and lifestyle predictors of foetal outcome relevant to diabetes and obesity and their relevance to prevention strategies in South Asian peoples.)

Executive Summary:

GIFTS is an acronym for Genomic and lifestyle predictors of foetal outcome relevant to diabetes and obesity and their relevance to South Asian people. Diabetes and obesity are disorders caused by the combination of inherited factors in the genes and a changing environment that involves choosing lifestyles known to aggravate a tendency to put on weight, make poor food choices and exercising less – these are all aggravated by poverty and a rapidly changing lifestyle. In South Asians this has led to an epidemic of diabetes whether they reside in their home countries or in Europe.
Current diabetes/obesity prevention strategies are focused on adult life and target over-nutrition with interventions designed to reduce obesity in high-risk adults. However, for many population groups across the globe, such strategies ignore many key principles that underlie the increasing global prevalence of these diseases, which include a key determinant of nutritional deficiencies driven by poverty and rapid ‘westernization’. These conditions are of particular importance during pregnancy and may affect the early developmental stages of baby growth when environmental insults may interact with the genetic risk to program the developing baby to later become overweight and develop diabetes and related disorders.
The GIFTS program of work is therefore aimed at pregnancy and early childhood. There were 3 main areas of investigation broken down by work packages (WPs):
1. Baseline studies in pregnancy, pilot randomized clinical trials in pregnancy and outcome studies in early life (WP2-4)
2. Genomic and biomarker studies (WP 5-7)
3. Post Intervention: Understanding societal attitudes towards diabetes prevention and antenatal care, the affordability of interventions and the dissemination of information (WP 8-11)
The primary goal of the GIFTS program has been reached “to enhance understanding of the convergence of genetic and environmental factors involved in developing diabetes and obesity, and their transmission through parent child units”. The outcomes of the GIFTS project, once published, will provide invaluable information to assist in creating measures to prevent diabetes and obesity in people of South Asian origin. Some of the early headlines are itemised below:
• Deficiencies in pregnancy of vitamin D and vitamin B12 is a significant problem.
• In Bangladesh and Pakistan there is the dual problem of pregnant women being either underweight or overweight whereas in Europe the predominant problem in pregnant South Asians is being overweight
• Based on the Maternal Child Health Intervention (MCH), executed in Dhaka, it is difficult to design an RCT (randomised control trial) to prevent diabetes in the pregnant mother and her offspring and it seems unlikely that one size will fit all in all settings. Furthermore, epigenetics cannot be used to predict outcomes of maternal interventions in the MCH trial. However, in a rural setting in a developing country women’s participatory groups may offer beneficial effects on infant health.
• Recruitment of pregnant women and to follow the women up to delivery has proven to be most difficult in developing nations (Bangladesh and Pakistan), but especially in the immigrant communities in Europe.
• Preliminary evidence might suggest that genetic risk scores might predict fetal outcomes and determine important aetiological biochemical processes.
• In London and Oslo, personal, family and societal attitudes play a very important part in the acceptance of South Asian women for acceptable interventions in pregnancy to prevent future disease and models of care available to minimise risks in pregnancy.
• An online resource has been developed to help health professionals learn more about diabetes prevention strategies in pregnancy.

Project Context and Objectives:

The GIFTS project has been established to improve diabetes prevention and obesity in people of South Asian origin, by targeting pregnancy and early life programming. Although a strong genetic component to diabetes and obesity exists, it is becoming increasingly clear that the rapidly rising prevalence of diabetes and obesity is due to adaptation to a changing environment. The epicentre of the ‘diabetes epidemic’ is in South Asia and this is reflected in the migrant populations in Europe. Current prevention strategies are focused on adult life and target over-nutrition in high-risk adults. However, for many population groups, these strategies ignore many key principles that underlie the increasing global prevalence of these diseases. A substantial portion of the South Asian people, living in their home countries experience nutrition deprivation, while after migration to Europe, may encounter nutritional abundance resulting in imbalance during their life course. These conditions are of particular importance during foetal and early developmental stages, where environmental insults may interact with genetic risk to induce ‘foetal programming’ of adult metabolic disease. Prior to GIFTS, few groups have targeted early life programming as an opportunity for the prevention of diabetes/obesity in childhood and subsequent adult life and there are limited guidelines on this topic.

GIFTS has brought together a unique group of investigators from South Asia (India, Bangladesh and Pakistan) and Europe (UK, Norway, Germany and Finland) with SMEs of complementary expertise (Germany and Spain) combining prevention strategies, state-of-the-art genomics, social sciences and public health that focus on these early life predictors of disease. The major objective behind this collaborative and multi-disciplinary approach is to combine knowledge on lifestyle, nutrition and genomics to both inform public health policy through guideline development, and to design a large-scale pragmatic intervention to prevent obesity and diabetes in South Asian populations, aimed at early life and taking into account multi-generational effects.

Three key objectives of the program were:

• Use of results generated by GIFTS to inform public health policy via guideline development in Europe and South Asia.

• Dissemination of key outputs to stake holders in diabetes prevention, including healthcare professionals and South Asian communities.

• Use of the results and expertise gained from GIFTS to design a large-scale pragmatic intervention for diabetes prevention in people of South Asian origin.

Specific objectives, which will allow the key objectives to be achieved, are as follows:

• To enhance understanding of the early life determinants of diabetes, obesity and metabolic syndrome in people of South Asian origin, which give rise to variation in disease prevalence.

• To study family trios of South Asians, both in their native countries and migrant populations across Europe, to allow identification of early life determinants of growth and development with the final aim to decrease future risk of disease

• To utilise the epidemiological, nutritional, genomic and societal data arising from the project to generate hypotheses to reduce risks of metabolic diseases.

• To learn from pilot intervention and prevention strategies in South Asia, combined with qualitative studies investigating barriers to equitable healthcare access, and understand how outcomes may be translated directly into clinical care across widely differing settings.

• Establish an international consortium based on understanding the early life determinants of diabetes, obesity and metabolic syndrome. Aim for strong co-operation and adoption of common protocols across different geographic regions within this consortium.

• Maximise opportunities for success by leveraging existing infrastructure and promoting interdisciplinary research by world class experts in Europe and Asia.

GIFTS has been divided into 11 work packages (WP), which have been grouped into four major components:

1) Co-ordination and Management (WP1)

2) Lifestyle and Nutrition from Pre-conception to Early Childhood (WP2-4)

3) Characterisation of Gene and Environment Interactions (WP5-7)

4) Clinical Translation of the Findings of GIFTS Programme (WP8-11)

The scientific and technical results generated by each work package are presented in the following section.

Project Results:
Scientific and Technical Results

Milestone 1 and Milestone 2
Comparative lifestyle and nutrition in different communities living in South Asia and Europe, and acceptability and feasibility of trial methods and health economic analysis
WP2 – Baseline data
The link between suboptimum foetal growth and a higher risk of cardio-metabolic disease such as cardiovascular disease, hypertension, insulin resistance syndrome or type 2 diabetes have been demonstrated in several populations and age groups. The factors that modulate the growth of the foetus and permanently program its metabolism may be the key to effective prevention of these chronic diseases in adult life. Thus there is an urgent need to assess the potential contribution of impaired foetal growth and growth in early infancy to cardiometabolic risk in adults, and to identify in what ways this increased risk can be mitigated; this is particularly pertinent to South Asian populations. The aim of WP2 was to explore the range of reversible lifestyle and nutritional risk factors in pregnant mothers and their newborns, relevant to future metabolic diseases in South Asians living in Europe and in their home countries.
Data analysis and results
Baseline data were collected on South Asian women and their newborns in Dhaka, Karachi, Bangladesh, London and Oslo (Oslo data is still to be processed). The data included:
• Routine clinical data and measurements.
• Foetal measurements and cord blood and placenta sampling.
• Biochemical assays of metabolic and nutritional status.
• Health, lifestyle and dietary questionnaires.

The primary analysis in WP2 has been to characterise the metabolic and nutritional status of women recruited and the phenotypes of their offspring at birth.
Baseline characteristics of the pregnant women
Women recruited to the GIFTS study varied between study sites with regard to age and BMI, with the oldest women with highest BMI being in the UK and the youngest with lowest BMI in Bangladesh. Systolic blood pressure differences also existed between the 3 study groups and were higher in the UK, consistent with the age and BMI of the women. In the Bangladeshi study group, nearly 1/3rd of women were underweight, compared to 21.9% of the Pakistani group and only 3% in the UK study.
Metabolic and nutritional parameters measured in women recruited to GIFTS WP2
Women studied in WP2 had varied nutritional and metabolic parameters, with women in Bangladesh having the highest levels of serum folate and vitamin B12. Further investigation is ongoing to determine whether this is due to differences in dietary intake, supplementation, or assay variation. Women in the UK had the highest levels of vitamin D and were more hyperglycaemic.
Characteristics of the offspring born to women recruited to GIFTS WP2
Babies born to women in the UK were delivered earlier (at 38.5 weeks gestation) compared to those in Bangladesh, likely reflecting variation in obstetric practice. Despite these deliveries being at an earlier gestational age, babies born in the UK were heavier than their Bangladeshi and Pakistani counterparts, with higher birth length and skinfolds compared to Pakistani babies. Interestingly, the abdominal circumference of Pakistani babies was higher than that in the UK, suggesting greater central adiposity.
Analysis of the data from WP2 is ongoing and includes biochemical assay comparison, correction of birth measurements for gestational age at delivery and the identification of maternal determinants of birth weight and anthropometric measures. Evaluation of the observational data is also underway. The characteristics of the mothers and offspring recruited and studied have been characterised using simple descriptive statistics, and analysis is currently being performed to make comparisons between those recruited in Pakistan, Bangladesh and London.
Future Work
This work package has enabled us to identify the prevalence of nutritional deficiencies and adverse metabolic health in people of South Asian origin in the UK, Bangladesh and Pakistan. It has also informed the subsequent intervention in WP3 and provided an important test of the recruitment, sample collection and analysis protocols. The high prevalence of micronutrient deficiencies provides an important insight to feed back to those delivering healthcare to women in pregnancy so that strategies to prevent and treat them can be implemented.
The data from WP2 will also be integrated into the WP6 and WP7 studies, in which genomic and epigenomic associations with micronutrient status and metabolic health are being investigated. These studies should, through Mendelian randomisation, identify causal pathways in determining birthweight, and identify potential epigenetic signatures of fetal programming.
We are currently preparing the feasibility of 4 manuscripts for publication from WP2: three manuscripts describing country-specific prevalence of micronutrient deficiencies and adverse metabolic health in pregnancy; and one manuscript combining the data collected from all 3 WP2 sites that analyse the combined dataset to identify nutritional and metabolic determinants of birth phenotype in babies of South Asian ethnicity.

WP3 – Pilot intervention in India and Bangladesh
Pilot intervention in India
Previous studies have suggested a role of 1-C metabolism in the development of diabetes. Researchers at King Edward Memorial Hospital, (Pune, India) therefore commenced an interventional study (Pune Rural Intervention in Young Adults; PRIYA) to investigate whether micronutrient supplementation before and during pregnancy reduces the programming of diabetes in the next generation; this has been partially funded by the Indian Council of Medical Research (ICMR) and Medical Research Council (MRC), UK.
In this context, GIFTS funds were used to study the mechanisms by which 1-C metabolism may be linked to nutritional foetal programming by using the methionine challenge test (MCT). As maternal 1-C metabolism is influenced by a number of nutrients, MCT provides a comprehensive view of different metabolic pathways.
An initial pilot study was carried out to test and standardise the methods in performing the MCT. A subsequent study was carried out to assess the efficiency of micronutrient supplementation towards improving one carbon metabolism among B12 deficient subjects. The MCT test was done at baseline and repeated after micronutrient supplementation, providing crucial information on the reversibility of metabolic derangements by nutrient supplementation. The participants were randomised into two groups to receive either B12 alone, or B12 with multiple micronutrients and protein, similar to the main trial.
We have also used GIFTS funds to collect and bank cord blood and placenta samples to study the full range of OMICs in babies born to mothers in the trial; these measurements will require separate funding and we have recently been funded by the Department of Biotechnology, Government of India for proof of principle studies.

Methionine Challenge Tests (MCT)

Pilot study: We initially examined the integrated changes in 1-C metabolism in an otherwise healthy group of Indian women (n=10) and compared them with a group of American women (n=13). This pilot study served to standardize our methodology and obtain an understanding of 1-C metabolism in young Indian women. Our data suggested that multi-nutrient deficiencies in the Indian women resulted in substantial changes in homocysteine concentrations and essential amino acids in the plasma.
MCT in severely B12 deficient young women: The baseline characteristics of the 39 participants had: a low BMI on average, normal levels of folate, high homocysteine levels (mean ~41 µmol/L) and hyperhomocysteinemia (>15 µmol/L) was common. The full results will be available once published.
Collection and banking of samples
Of the young women in the Pune intervention study (PRIYA) who were randomised into three groups, 93 are currently married, 8 are pregnant and 54 have already delivered. We have successfully collected and stored cord blood and placenta samples in all but three deliveries. Newborn anthropometry has been performed within 72 hours on all except three newborns.
The collection and banking of samples will result in a unique repository, which will be available to test newer hypotheses and a range of OMICs parameters. The RCT design will help in understanding causal relationships.
WP3- Pilot intervention in Bangladesh
A pilot complex intervention was developed from the initial data produced by WP2 and aimed to optimise the health of mothers and their newborns, targeting a selection of key determinants of foetal programming such as nutritional deficiency, aberrant foetal and neonatal growth, maternal behavior, breastfeeding and timing of introduction of supplemental foods.
Overall Objective and endpoints
• To pilot a complex intervention during pregnancy involving personalized micronutrient supplementation and lifestyle advice tailored on the nutritional status of the participant.
• The primary endpoint was to observe whether micronutrient deficiencies, specifically vitamin D and B12, can be reversed and maintained through pregnancy.

Research design and methods
• Study design: Randomized open label
• Study duration: June 2014 to October 2015
• Number of participants: 915 pregnant women from middle and low socioeconomic background living in 5 different locations of Dhaka (Azimpur, Lalbag, Hazaribag, Kamrangir char and Keraniganj)
• Randomization: Pregnant women with micronutrient deficiencies of either vitamin D and/or vitamin B12 were randomized to 2 arms: control (control arm 1) or an intervention arm. A third group were also included that consisted of pregnant women without nutritional deficiencies who were allocated to usual care (control arm 2).
• Main inclusion criteria: Pregnant women in the 1st trimester of pregnancy. Aged: 18-28yr. No pre-pregnancy diagnosis of diabetes.

Statistical methodology and analysis
Participants were separated by subjects who had vitamin D and/or B12 deficiency and those who did not. Those who had no vitamin D or B-12 deficiency followed routine pregnancy controls and served as one control arm (control arm 2). Following randomization we therefore had two control arms. The intervention arm received vitamin D in the following manner: participants who had vitamin D levels between 30-75nmol/L were given 1 supervised dose every 90 days-1 ampoule = 200,000 IU which is equivalent to 2222 IU every day. Participants with vitamin D levels < 30nmol/L were given 1 supervised dose every 60 days equivalent to 3333IU of vitamin D daily. In those deficient in B12 (< 200pg/ml) a B126TM tablet was given every 14 days which is equivalent to 14mcg of B12 per day. Control arm 1 received programmed dietary advice to compensate for the micronutrient deficiency. Population characteristics (mother and infant), in the form of anthropometric measurements and blood tests, were analyzed at several points throughout the study.

Changes to protocol determined by local investigators
1. Replacement of parenteral vitamin B12 with an intermittent dosing of oral B12 given as part of the multivitamin supplement.
2. Creation of a 2nd control group that was not randomized and consisted of pregnant women that were not deficient in either vitamin D or vitamin B12.
3. Control group 1 given personalized advice on vitamin D or vitamin B12 foods as appropriate to the participant
4. Intermittent oral dosing of vitamin D rather than daily dosing leading to a daily mean dose of vitamin D of 2222 IU/day (compared to 2000 IU/day as per protocol) or 3333 IU/day (compared to 4000 IU/day as per protocol) dependent on degree of vitamin D deficiency.

Discussion and Conclusions
As obesity and type 2 diabetes are major public health issues in Bangladesh, it is necessary to develop primary prevention strategies by creating a proactive attitude towards a healthy lifestyle before and during pregnancy. Our data has produced some interesting results and will be presented in forthcoming publications. The outcomes from this trial could potentially be used to establish the feasibility of an RCT in pregnant women living in Bangladesh or similar set-ups including Bangladeshi migrants elsewhere.

Potential future publications
One or two papers describing the output of this trial.

WP8 – Health economic analysis
The aim of WP8 was to assess the feasibility of data collection to inform a full-scale cost-effectiveness study, and to provide preliminary estimates of the cost-effectiveness of a complex intervention (dietary supplementation plus lifestyle advice –WP3) compared to lifestyle advice alone for pregnant women with vitamin deficiencies in Bangladesh.
The objectives of the economic evaluation were:
1. To test the feasibility of collecting health economics data;
2. To estimate the cost of the intervention per participant;
3. To estimate the use of health care resources (and associated costs) by study participants in the intervention and control groups;
4. To provide preliminary estimates of cost-effectiveness of dietary supplementation plus lifestyle advice compared to lifestyle advice alone.
5. To identify factors that potentially predict health care costs in the trial sample.

Outcomes of the health economics analysis included:
1. Estimate of the cost of intervention;
2. Estimate of the cost of healthcare services per participant, including and excluding the cost of the intervention;
3. Estimate of the total cost per participant (cost of intervention plus cost of healthcare services use plus cost of travel);
4. Identification of potential predictors of costs;
5. Estimate of the incremental cost-effectiveness ratio, linking total cost and the effectiveness outcome (subject to further analysis).
The pilot study provided estimates of intervention costs and health care costs in the intervention and control groups. Since this pilot study was not powered to detect significant differences between the intervention and control groups, our results were not compared statistically. We identified several issues associated with data collection that it would be important to account for when designing future evaluations of the intervention in other settings. For example, lack of detailed records concerning the inputs and costs associated with delivering tailored nutritional advice as part of the intervention – collection of these records in future would require further specific data collection to enable reliable cost estimates to be made; lack of specific data collection to inform the distinction between research-related health care tests/investigations and those that would be part of routine care – again this requires the use of specific data collection tools or more details in a trial protocol to set out clearly what additional tests/investigations would take place and in what context; problems with coding of missing data – this would need to be addressed through appropriate database set-up and training of relevant research staff. Further analyses will be undertaken on receipt of additional data from our collaborators.

Acceptability and feasibility of the trial
Acceptability: Both the local investigators and the participants opted for oral compared to injectable dosing of micronutrients. The local investigator preference was also for intermittent supervised oral dosing of vitamin D to ensure 100% concordance with medication. It was also not thought best practice by the obstetric units and local investigators to randomise pregnant women who had normal levels of both vitamin D and B12 and therefore only those with vitamin deficiencies were randomised to oral replacement. Similarly, the dieticians felt it important that the pregnant women allocated to not taking oral supplementation (control group 1) should have personalised advice on supplementing their diet with foods containing the relevant vitamin.

Feasibility: It is clear that the original protocol cannot be used for a larger scale trial in the current setting (Dhaka), and seems unlikely that it can be exported to another setting. However, the modified protocol, could be considered for a future trial assuming the primary endpoint of replenishment of the individual vitamin has been achieved (results are known but cannot be divulged until publication). If the primary end-point is not achieved for vitamin D then daily dosing of vitamin D will need to be considered with a change in trial design.
WP4 – Childhood outcomes
The Perinatal Care Project (PCP) survey represents a part of WP-4 (childhood outcomes) of the GIFTS programme. A participatory women’s groups (PWG) community mobilization intervention, conducted by PCP in 18 rural unions in 3 districts of Bangladesh (Faridpur, Bogra and Moulavibazar) in 2009-2011, reduced neonatal mortality by 38% and improved hygienic delivery and essential newborn care practices. The intervention was based on a participatory learning and action (PLA) cycle of monthly meetings facilitated by lay, locally recruited women. In the PLA cycle, women themselves identified and prioritized local health challenges and then designed, implemented and evaluated their own solutions to these challenges. Subsequent to the intervention and evaluation focused on neonatal mortality, facilitated PWGs continued to meet, focusing on child (under-fives) health and women’s and reproductive health, with encouraging results in relation to breastfeeding practices and knowledge and awareness of hygienic and nutritional practices.
We followed-up all children (aged 24-48 months at time of survey) born to women who were exposed to the PWG intervention during their pregnancy and a random sample of contemporary mothers and their children (control) in the same age group to assess the impact of the intervention on child growth and body fat.
Survey and anthropometric data were obtained from 2587 children: 1264 children and their mothers in intervention clusters and 1323 children and their mothers in control areas, representing response rates of 94% and 89% respectively. Interactions between child anthropometric outcomes and maternal BMI were explored and a clear differential effect of the intervention depending on maternal BMI was recorded. These results will be presented in a publication that is currently under submission.

There is an equal weight of evidence to link both under-nutrition (overall diet and specific nutritional deficiencies) and over-nutrition (obesity and hyperglycaemia) with the future development of obesity, diabetes and cardio-metabolic disease. It is therefore, of great interest that the PWGs had a differential effect on child outcomes dependant of the BMI category of the mother.

Milestone 3
Developing nutritional and genomic biomarkers of foetal programming and its overall response to a complex intervention.

WP5 – Development of more cost effective nutritional and DNA assays
The collection of blood samples for monitoring and research is hampered in low-income settings by the invasive nature of the procedure, the high cost of storage and analysis, and the requirement of specialist facilities. There is therefore a need to develop affordable assays for nutritional biomarkers and DNA from samples that are relatively easy and non-invasive to collect, and have scope for scalability at population level.
The team at Public Health Foundation India (PHFI) in collaboration with the London School of Hygiene and Tropical Medicine (LSHTM), have successfully developed low-cost nutritional assays using dried blood spot samples on a number of target nutritional biomarkers. They have demonstrated that the analysis of homocysteine, vitamin D and fatty acids could be achieved at low-cost and with low respondent burden in large scale epidemiological studies through collection of dried blood spots (using finger prick) rather than intravenous samples.
Similarly, they have also demonstrated the possibility of carrying out low-cost DNA assays from dried blood spots, saliva samples and vacuum tubes; all collection methods that would be appropriate for large-scale collection in epidemiological studies in low-resource settings.
These exciting results indicate that further genetic and biomarker research is feasible even in low-resource and limited-budget settings.
Use of our novel techniques and future publications
This line of research has already facilitated incorporation of dry blood spots as a choice method for collecting blood samples in surveys by the National Nutrition Monitoring Bureau (NNMB, NIN) in India. More than 40,000 samples have been collected so far in the last 2-3 years.
Numerous publications are being prepared as a result of this work covering the following topics:
➢ Biomarker assay development
➢ DNA extraction methods comparison
➢ Homocysteine association within family triads
➢ Relationship between child cardio-metabolic risk factors levels and parent Vitamin D and folate (overall and comparing maternal and paternal levels)
We anticipate further publications to arise from this work as more blood assays and rounds of cohort data collection are completed.

WP6 – Genetic studies

The genomics component of the GIFTS project has been designed to understand the influence of maternal genetic variants on foetal phenotype and markers of early growth, as well as the effect of maternal variants on the long-term risk of obesity & adverse metabolic outcomes in children. The direct effect of foetal gene variants on body constitution and related phenotypes is also being explored. Finally the interaction between genetic variants and different interventions, and their influence on the risk of intermediate traits related to metabolic syndrome will be studied. DNA samples were collected from South Asian populations residing in India, Bangladesh and the U.K. All the data used in WP6 were generated by single nucleotide polymorphism (SNP) genotyping arrays (Illumina human exome beadchip), The chip includes 250,000 tag SNPs and rare variants and thus allows exploration of the role of both coding and non-coding markers.
Data generation and analysis was divided into two arms due to an embargo on the shipment of DNA samples outside India and the large number of samples: The samples from India were processed and analysed by Dr Giriraj Chandak and his team at the Centre for Cellular and Molecular Biology (CSIR-CCMB), a CSIR Institute in Hyderabad, India. The remaining samples were to be processed at QMUL (DNA preparation) and by Prof Tim Frayling at the University of Exeter, UK for genotyping. Following analysis at each centre according to a common protocol, meta-analysis was planned using the combined data.
Data generation and analysis – India
After quality control checks on the array data, 1325 samples (678 children and 647 mothers, including 627 mother child pairs) were available for further analysis. Unbiased association analysis of variants with various traits was performed to try and identify novel variants. We also carried out targeted association analysis of established variants with various traits to establish the role of identified variants.
Finally, we performed Mendelian Randomization (MR) analysis:
– Using individual variants (established and novel, if any).
– Using genetic risk scores based on the number of effect alleles.
– Using weighted risk scores based on the effect size and the number of effect alleles.
Using the above approaches we have identified several loci that may indicate causal influence of these variants on determining birth weight. Analyses on other traits using similar approaches are underway.
Data generation and analysis – UK
In this arm of the study DNA was extracted from blood samples collected from WP2 Bangladesh, WP3 Bangladesh (intervention trial), WP2 London and the FEATURE study. A total of 1800 samples including 38 replicates have been prepared for processing on the Illumina Human Core Exome Beadchip and for epigenetic studies.
Unfortunately, we have not been able to array the samples on the beadchip for genotyping due to a number of confounding factors. We plan to run these samples using a new Illumina GWAS chip in the near future that will enable the meta-analysis of data sets.
WP7 – Epigenetic studies
Epigenomic studies applied to complex disease and complex phenotypes are generating insights into the aetiology and pathogenesis of type 2 diabetes. Epigenetic modifications, such as DNA methylation, can be studied across the genome and may vary according to genetic architecture and the environment. In early development, the epigenetic state of a developing embryo and fetus undergoes widespread changes (such as demethylation and remethylation) and as such, changes in the periconceptual and pregnancy environment may have significant changes in the epigenomic profile of a fetus at birth. We hypothesised that the epigenome of South Asian offspring could be modified by delivery of the targeted intervention to mothers in WP3 and/or vary according to maternal and fetal outcomes. Furthermore, we considered that epigenomic differences in these offspring could underlie the molecular mechanisms by which fetal programming of future type 2 diabetes might occur.
382 cord blood samples from the WP3 intervention trial were selected for the epigenetic discovery experiment. Extracted DNA was bisulphite-converted and hybridized to the Illumina Infinium HumanMethylation 450 Beadchip which allows genome-wide interrogation of approximately 450,000 pre-defined CpG sites, using fluorescent beads to detect methylated vs. unmethylated CpG sites. The data was subsequently quality control checked and 351 samples were found suitable for ongoing analysis.
Genome-wide analysis of methylation differences in cord blood was performed according to maternal booking BMI (underweight vs. normal weight vs. overweight/obese). Maternal and neonatal phenotypic characteristics and assays were used in quantitative trait analyses with methylation in cord blood. Maternal phenotypes studied included vitamin D status and vitamin B12 status at each antenatal visit as well as delta change of each. Other maternal phenotypes analysed were maternal gestational diabetes status and maternal BMI. Neonatal quantitative traits included cord blood assays of serum vitamin D, vitamin B12, homocysteine, folate (serum and red blood cell), leptin, ferritin, triglycerides, total cholesterol, HDL, blood glucose, serum insulin. Other measures analysed as quantitative variables included neonatal measurements: birth weight, birth length, ponderal index, mid-upper arm circumference, gestational age at delivery and placental weight.
Current work is investigating the potential confounding influence of maternal age, parity and gestational age on these methylation differences. Robust methylation variants, unconfounded by other influences, will be taken forward into replication experiments.
We have identified methylation variation associated with specific birth phenotypes relating to fetal growth and nutrient transport. Methylation analysis was put through stringent quality control checking and control for false discovery in the context of multiple testing. We are reassured by the commonality of methylation variants across related phenotypes (e.g. fetal size) as well as the preliminary replication of methylation variants in specific genes already identified in published research on birth weight and DNA methylation (e.g. HIF3A). Additional work is being performed to understand whether there are confounding influences on these DNA methylation differences, e.g. the effect of gestational age at delivery, or whether reference-based cell count correction identifies methylation differences according to cellular composition of the cord blood samples.

Milestone 4
Determining equity and access to antenatal care in the varied settings covered by the GIFTS consortium

WP9 – Developing behavioural and nutritional interventions in Europe in South Asians: qualitative research
The aim of this study was to gain a greater understanding of the illness experiences of South Asian women with gestational diabetes (living in London), and to inform the theorization and design of behavioral and nutritional interventions. The study consisted of narrative interviews [1] and focus groups with 45 women of Bangladeshi, Indian, Sri Lankan, or Pakistani origin aged 21– 45 years with a history of diabetes in pregnancy, recruited from diabetes and antenatal services in two deprived London boroughs about their diabetes.
Analysis of the focus groups and narrative interviews revealed that there were three key storylines (over-arching narratives) that recurred across the accounts of all the women who took part in the study: short-term storylines, medium term storylines and long-term storylines (figure 1). The short-term story lines depicted the experience of diabetic pregnancy as stressful, difficult to control, and associated with negative symptoms, especially tiredness. Taking exercise and restricting diet often worsened these symptoms and conflicted with advice from relatives and peers. Many women believed that exercise in pregnancy would damage the fetus and drain the mother’ s strength, and that eating would be strength-giving for mother and fetus.
These short-term storylines were nested within medium-term storylines about family life, especially the cultural, practical, and material constraints of the traditional South Asian wife and mother role and past experiences of illness and healthcare, and within longer-term storylines about genetic, cultural, and material heritage – including migration, acculturation, and family memories of food insecurity. Moreover, when reflecting on what information and knowledge was used to inform understanding and action peer advice was often considered to be familiar, meaningful, and morally resonant. In contrast health education advice from clinicians was usually considered to be unfamiliar and devoid of cultural meaning.
As demonstrated by the narratives described above diabetes in this group (and arguably all groups) has substantial anthropological and public health dimensions: its onset and course are strongly patterned by cultural practices and social determinants of health, including the material, cognitive and socio-cultural effects of poverty, migration, education and social capital. These findings chime with social ecological approaches [2] that view health-related behaviours as the result of influences at multiple levels: intrapersonal, interpersonal, organizational, community, and public policy. Glass and McAttee [2], propose a ‘stream of causation’ flowing over time from upstream (in utero and early life exposures and windows of vulnerability) to downstream (later life manifestations). They further propose a nested hierarchy of systems from genes, to cells and organs, the psychology of behaviour choices, the influence of social networks and groups and the local and global environment and a series of feedback loops and cross-level influences between these.

By using a using a narrative approach this research illuminates how this nested hierarchy influences can inflect the health related behaviours of the women that in turn shape their health outcomes (figure 2.). That is, that narratives collected and analysed have helped surface explanations about the reciprocal relationship between the different levels in the nested hierarchy, including how human agency (behaviour ‘choice’) is dynamically influenced by both the distal structural contingencies (external ‘chances’) and embodied biological and psychological drivers (e.g. physiological status, genetic predispositions, bodily sensations and personality traits).
Based on these findings it is claimed that ‘Behaviour change’ interventions aimed at preventing and managing diabetes in South Asian women before and during pregnancy are likely to be ineffective if delivered in a socio-cultural vacuum. Individual education should be supplemented with community-level interventions to address the socio-material constraints and cultural frames within which behavioural ‘choices’ are made [2].
1. Wengraf T: Qualitative Research Interviewing: Biographic Narrative and Semi-structured Methods. . London: Sage; 2001.
2. Glass TA, McAtee MJ: Behavioral science at the crossroads in public health: Extending horizons, envisioning the future. Social Science & Medicine 2006, 62(7):1650-1671.
3. Greenhalgh T, Clinch M, Afsar N, Choudhury Y, Sudra R, Campbell-Richards D, Claydon A, Hitman GA, Hanson P, Finer S: Socio-cultural influences on the behaviour of South Asian women with diabetes in pregnancy: qualitative study using a multi-level theoretical approach. BMC Med. 2015 May 21;13:120. doi: 10.1186/s12916-015-0360-1

WP10 – Equity and access to antenatal care
In order for behavioural and nutrition interventions developed from the GIFTS programme to be effective in reducing the risk of future metabolic diseases it is crucial that women and their families are able to access and engage with them. These interventions are likely to be delivered before pregnancy, during pregnancy, or in the postnatal period and, ultimately, to be integrated with routine pregnancy related services such as a package of antenatal care. There is evidence that women from both developed and developing countries do not always find it easy to access such pregnancy-related services and that those women who bear the burden of the worst outcomes for themselves and their babies are more likely to access care late or inconsistently.1-3 Work package 10 of the GIFTS programme aimed to explore these issues amongst South Asian women living in Europe and South Asia with a view to making recommendations to ensure that interventions from GIFTS are accessible and engaging.

This work package had two strands. The first was designed to investigate influences on the uptake of antenatal care and other pregnancy-related services by South Asian women living in East London and Oslo. In particular, the perspectives and experiences of South Asian women in relation to barriers and facilitators to accessing and engaging in relevant services were explored. This was achieved through a large qualitative study conducted in London and a smaller scale complementary qualitative study conducted in Oslo. The second strand investigated the factors influencing access to pregnancy related services for women living in urban areas of Bangladesh, Pakistan and India through a review of existing systematic reviews. The findings from both strands were integrated to make recommendations for the promotion of equitable access to, and engagement with, pregnancy related interventions to improve birth outcomes relevant to metabolic diseases in urban areas of Europe and South Asia.

Methods and results

a) Qualitative studies
Thirty interviews and four focus groups were conducted in East London with pregnant or recently pregnant women of Bangladeshi, Indian and Pakistani heritage, and a further three focus groups were conducted in Oslo with recently pregnant women of Pakistani heritage.
The interviews and focus group discussions used semi-structured schedules in which questions were open-ended with prompts to facilitate discussions. This helped to draw out contextual, process-oriented information and allowed respondents to identify issues from their own perspectives, along with providing rich and detailed information about their perceptions and experiences. All the discussions were recorded on a voice recorder. Data were transcribed, coded, and then analysed thematically by researchers trained in social anthropological and qualitative research.
Common themes from women’s accounts of their journeys into and through antenatal and postnatal services across East London and Oslo included: the significance of language barriers and unfamiliarity with the health system; a belief that antenatal and postnatal appointments were compulsory; and the central role of family in a women’s pregnancy (‘a family is pregnant not an individual’) which could work against rather than with the health system. Whilst women in Oslo and East London valued the free and standardised service offered, they also recounted feeling powerless due to a lack of choice and a stretched and impersonal service (‘you can’t get up and leave and take your custom elsewhere’).
There were some findings unique to the East London study from the interview data. There were particular challenges to women seeking pregnancy care in the first trimester. Some women spoke about needing a bit of time before disclosing the pregnancy to others. Although other women told everyone straightaway, the urgency in seeking care very early was not always apparent. Antenatal care sits within a health service associated with the treatment of illness; feeling unwell was a trigger for women to seek care and feeling perfectly fine made seeking care a lower priority and less urgent. When women did begin to seek care, navigating the health system was not always easy and required women to be proactive which can be difficult particularly if there are language barriers. Once on their antenatal journey some women reported feeling not listened to or even judged by midwives and others reported a lack of attention to practical, social and emotional needs.

b) Review of systematic reviews
Systematic searches were designed to identify reviews of qualitative research as well as reviews of statistical data and programs designed to promote access. Our searches identified a total of 422 records from which we identified 21 relevant reviews. Of these, two reviews focused on qualitative research examining factors influencing women’s uptake of antenatal care. Each review was assessed for overall quality; relevance and depth of synthesis and findings were integrated to identify common themes regarding a) the effectiveness of interventions to promote uptake of pregnancy-related services and b) factors influencing women’s uptake of pregnancy-related services.
Common themes amongst factors influencing women’s uptake of pregnancy-related services included: knowledge and awareness of services; socio-demographic factors; cultural factors and beliefs; service delivery; access and availability; and financial and economic.
Common themes identified on the effectiveness of interventions to increase access to pregnancy-related services included: use of peer or lay health workers; additional training and education for health workers; community mobilization and participatory learning and action: and integration of new interventions with routine services.
Discussion and Conclusions
Standardised and free maternity services In European health systems cannot always accommodate, and sometimes conflict with, the socio-cultural factors within the Bangladeshi, Indian and Pakistani communities living in European cities. Care-seeking requires women to be very proactive and barriers such as navigating the complexities of the health system are exacerbated by not being familiar with the service, not speaking the same language and stretched and limited resources. A health system that has a primary focus on ill-health and ‘patients’ can be seen as antithetical to the public health goals of antenatal care. All of these factors can lead to women feeling powerless within services with subsequent consequences for access and engagement.
Implications and recommendations for behavioural and nutrition interventions to reduce the risk of future metabolic diseases include:
• Early pregnancy is not an easy time to identify and recruit women into interventions as many women will not be registered within the health service until they are near the end of their first trimester. Community outreach using peer or lay workers and community organisations will need to be employed as well as targeting efforts towards the pre-conception period.
• Interventions need to be empowering for women with women taking an active role in the development and implementation of the intervention. This can be achieved through activities that mobilise communities such as co-design and co-production and well facilitated group work.
• Interventions will need to involve families and promote positive roles for fathers, parents and in-laws.
• Interventions and their evaluations need to be inclusive by ensuring there is provision for women who speak different languages to be involved (e.g. use of interpreters, visual materials).

(1) Cresswell JA, Yu G, Hatherall B, Morris J, Jamal F, Harden A, Renton A. (2013) Predictors of the timing of initiation of antenatal care in an ethnically diverse urban cohort in the UK. BMC Pregnancy Childbirth. 2013 3;13(1):103. DOI: 10.1186/1471-2393-13-103
(2) Finlayson K, Downe S. Why do women not use antenatal services in low- and middle-income countries? A meta-synthesis of qualitative studies PLoS Med 2013;10:e1001373.
(3) Hatherall B, Morris J, Jamal F, Sweeney L, Wiggins M, Kaur I, Renton A, Harden (2016) Timing of the initiation of antenatal care: an exploratory qualitative study of women and service providers in East London. Midwifery, 26:1-7.

Milestone 5
The dissemination activities within the project and externally to the major stakeholders

WP11 – Dissemination of information, training and technology exchange and informing public health
The following objectives have been developed to disseminate the information and results of the GIFTS project:
1. Condensation of the knowledge into a format to communicate the essence of the GIFTS project.
2. Dissemination of the gained knowledge of the project in the professional community by using professional networks.
3. Implementation of the knowledge gained in the project into the training of healthcare professionals.
To achieve these objectives the SME INSTRUCT, in collaboration with Prof Peter Schwarz and Jaakko Tuomilehto, have produced standard communication material for the European Commission, developed the project website, disseminated newsletters and provided guideline development and an e-learning training portal for prevention managers.
Methods and Results
To identify obstacles and challenges regarding the information and communication technology (ICT) framework of the target countries, a review about the digital infrastructure of India, Bangladesh, and Pakistan including expert interviews was conducted. The main focus was to clarify which dissemination and e-learning activities would be feasible in the partner countries. Furthermore, a survey among all participants about the need and use of new media in the project was conducted.
The website provides information about the project aims and details on each work packages. The website also has an events calendar showing the most important events in diabetes prevention and offers an overview to other projects in the field of diabetes prevention. A search engine optimization (SEO) to improve the website’s visibility on search engines was conducted and was updated on a regular basis. The website includes social media to increase the dissemination range.
The standard communication material (leaflet) was provided to the European Commission. Four annual newsletters were also distributed featuring the latest results of the project and made accessible through GIFTS network partners, the “Who is active in diabetes prevention“ network and the GIFTS project website.
To communicate as well as implement the results of the GIFTS project an e-learning training platform was developed, as an addition to existing training curricula to prevention managers. The GIFTS e-learning portal can be found at: and is detailed below. At its heart is 24 state of the art lectures given by international leaders in the field including Professors Jaakko Tuomilehto and Ranjan Yajnik.

E-learning portal contents
Structure all web-linked
1. Written material
2. Webcasts with power point (see list of names below)
3. Case Histories
4. Interviews
5. Q&A
Portal introduced by Prof Graham A Hitman
Module 1: Basics of Diabetes (with an emphasis on South Asians)
a) Aetiology and Complications: Dr Tahseen Chowdhury (Diabetologist, Barts and The London)
b) Diabetes in the South Asian population living in the UK: Anne Claydon (Nurse consultant, Barts and The London)
c) Gestational diabetes: Dr Philippa Hanson (Consultant Diabetes and Endocrinology, Barts and The London)

Module 2. Diabetes Prevention
a) Landmark studies: Prof Jaakko Tuomilehto (GIFTS WP11)
b) Organisation, delivery of diabetes prevention education: Prof Peter Schwarz (GIFTS WP11)
c) Models of care in Bangladesh: Prof Azad Khan(President of DAB)
Module 3. Pregnancy and foetal programming
a) Basics of pregnancy physiology and normal model of care: Angeliki Bolou, Research Midwife QMUL
b) Predictors of GDM and risk of T2D in mothers : Dr Girish Rayanagoudar (Registrar Endocrinology and Diabetes (Barts and The London; GIFTS WP2)
c) Prevention of GDM and excess weight gain in pregnancy: Prof Shakila Thangaratinam (Professor of Maternal and Perinatal Health, Barts and the London))
d) Models of antenatal care in South Asians: Fareeha Shaikh and Prof Abdul Basit (GIFTS Pakistan)
e) Foetal outcome (programming and metabolic diseases): Prof Chittaranjan Yajnik (GIFTS Deputy Director)
Module 4. GIFTS baseline results (WP2) and attitudes to prevention (WP9) and antenatal care (WP10)
a) Maternal status in SAs plus 1C cycle: Dr Sarah Finer (Barts and The London)
b) Social attitudes to diabetes in SAs: Megan Clinch (Barts and The London)
c) Equity of access/barriers: Prof Angela Harden (Professor of Community and Family Health UEL)/Bethan Hatherall (University of East London, UK))
Module 5. Interventions to improve the health of mother and baby
a) Interventions in pregnancy in SAs (overview of non-GIFTS cohorts including Mumbai, Mysore, PUNE): Prof Caroline Fall (WP4)
b) PCP maternal empowerment model and results on antenatal mortality: Prof Kishwar Azad (PCP director, DAB, Bangladesh) WP4
c) PCP results of effect on 2-4 yr old children (GIFTS): Prof Kishwar Azad/ Naveed Ahmed/Ed Fottrell GIFTS WP4 (Bangladesh/UCL London) WP4
d) GIFTS pilot study in Bangladesh on improving maternal nutrition (MCH): Prof Akhtar Hussain /Dr Bishwajit Bhowmik WP3
e) Health economics around maternal deficiencies (GIFTS WP8) (Prof Anita Patel, Barts and The London)
Module 6. Genomics and cost effective nutritional and DNA assays
a) Development of more cost effective nutritional and DNA assays Sanjay Kinra (LSHTM London and Delhi, India) (WP5)
b) Genetics of diabetes relevant to foetal programming: Prof Tim Frayling (address of Exeter MOOCH)
c) Genetics of diabetes in SAs and preliminary results : Dr Giriraj Ratan Chandak (Hyderabad, India) GIFTS WP6
d) Epigenetics relevant to foetal programing and preliminary results WP7: Dr Sarah Finer (Barts and The London)
Module 7. Tools associated with GIFTS
a) SOPs
b) PCP materials
c) Anthropometry measurements for adults – web-link to original
d) Maternity flip chart used in Intervention study in Bangladesh (original and English)
e) Miniaturization of DNA extraction and nutritional assays
Summary and synopsis of results Prof Graham A Hitman
The e-learning portal will be free of charge and open to anyone. The main target groups are health educators working in the field of diabetes prevention and care (working with people from India, Pakistan and Bangladesh), the scientific community and physicians. There are seven modules (Basics in diabetes, Basics in diabetes prevention, Pregnancy and foetal programming, Interventions to improve the health of mother and baby, Genetics, Epigenetics and Tools associated with GIFTS), which cover all aspects of the GIFTS project. The e-learning portal is structured in a didactical way to improve the learning outcome using the most efficient evidence based learning strategies including learning goals, assessment, video learning. The e-learning portal includes videos, screencasts, interactive graphics, texts, images, a self-assessment quiz and a final test. 24 state of the art online lectures starring international diabetes prevention experts from London, Germany, India, Pakistan and Bangladesh have been developed and implemented. A structured evaluation template is implemented into the e-learning portal.
To disseminate the e-learning portal, several social media channels have been used (Facebook, LinkedIn, YouTube, ResearchGate). Furthermore a GIFTS movie was made to foster the dissemination of the project and the e-learning portal. The information drawn from the GIFTS project is relevant for the guideline for prevention of diabetes. This mainly includes the practice guideline (toolkit), which was initially developed throughout the EU funded IMAGE project. The normal procedure is to analyze the results from your projects, to condense them into a chapter for the guidelines and then to discuss this with the authors of the guideline for inclusion. As the results of the GIFTS project are currently preliminary, this project will take place after the GIFTS project has finished. The results coming from the studies within the GIFTS project will be condensed after they are published and then included into the prevention toolkit after agreement of the authors. This will take place in the second half of 2016.
Results from GIFTS will also contribute to other maternal child health EU projects developing guidelines by exchanging views in key opinion leader discussions and data as relevant. Examples include in 2015 attendance at the DALI ( meeting in Brussels and for 2016 will include 2 planned meetings with Early Nutrition Academy ( that will include a presentation on the GIFTS project.
The Virtual Prevention Centre has been established to communicate and disseminate practical tools for the prevention of diabetes. Within the projects in GIFTS, a number of additional tools were used. All partners in GIFTS are encouraged to submit these tools to the coordinator of the Virtual Prevention Centre (Prof. Peter Schwarz) or to upload them directly in the VPC. This dissemination activity is sustainably open to all GIFTS partners.
Discussion: The e-learning training portal offers an excellent opportunity to implement the results of the GIFTS project into the training of health prevention experts and should be used in the future as a integral part of the training of prevention managers. Using the latest evidence of didactics and technology the portal is also ready for future use, as long as the content is revised and updated in a structured way to ensure updated information about diabetes prevention.
E-learning training portals can be used as a dissemination activity to spread the results, and provides sustainability for the results of the project as well as offering benefits for the community. The development of an e-learning training portal should thus be an integral part of the all projects done in the field of health science education. The guidelines will be implemented into the curriculum of the e-learning portal and offer a state-of-the-art curriculum for health educators. Cooperation with IDF to implement the e-learning portal into the training curricula of the IDF is in discussion.
Conclusions: Due to the activities of the WP11 team most of the objectives have been achieved and some have been exceeded. The leaflet, the newsletters and the project website have been used to condense the information of the project and disseminate the gained knowledge of the project into the professional community. The e-learning training portal will be used to implement the knowledge gained from the project into the training of health care professionals.
Planned publications and presentations
Presentation: Results of the e-learning portal. Annual meeting of the Association of Medical Education (AMEE), Barcelona, August 2016.
Presentation: The GIFTS e-learning portal. Annual meeting of the German Association of Medical Education (GMA), Bern, 2016.
Paper: The GIFTS e-learning portal. eLearning Papers. OpenEducation Europa

Potential Impact:
Potential impact and the use of data to inform a future planned trial

Baseline data has clearly indicated within South Asian peoples from the Indian sub-continent that there is a high prevalence of micronutrient deficiencies (vitamin D and vitamin B12) no matter whether they are living in London, Karachi or Dhaka. Furthermore, whereas in Karachi and Dhaka there is the dual problem in pregnancy of women who are underweight and overweight, in the European setting the predominant problem is that of overweight.
If the primary endpoint in the MCH pragmatic trial of the use of vitamin D and/or vitamin B12 to correct deficiencies has not been achieved either by the use of tablets or by dietary advice with food supplementation it would cast doubt on the validity of mounting a similar study either in this setting or in Europe as a means to improve metabolic health in the offspring. If, the other hand, the primary endpoint is achieved then the translation of the findings will be determined by metabolic benefits to the mother or to the offspring – this is currently under analysis. It seems likely that seasons (amount of sunlight) have a dominant affect on vitamin D levels such that one of the control groups who were selected as replete at 12-14 weeks of pregnancy, by term had appreciable rates of vitamin D deficiency.
The maternal empowerment program (Perinatal Care Project -PCP), however, could potentially be adapted to a European setting. In this program, women that were pregnant or intending to conceive participated in community group mobilisation interventions in rural Bangladesh, to improve maternal and newborn health. The PCP GIFTS follow up study on the offspring born to mothers who participated in the PCP suggest that there is an improvement in child growth for both underweight and overweight mothers; it is very important that further follow-up studies are conducted to validate these findings. Additionally, this approach needs to be tested in an urban setting in Bangladesh and Europe, as it provides a potential holistic population approach to the prevention of diabetes.
The recommendations based on the current findings of the qualitative research suggest that any targeted intervention has to be culturally sensitive. Moreover, any intervention should be tailored to ethnic groups within South Asian communities and also in different settings. A population approach, based on maternal empowerment, needs to be explored in urban settings and adapted to the cultural setting.

Overall recommendations
1. Based on the results of the qualitative research performed in WP9, it is recommended that health services intended to prevent and manage diabetes in South Asian women before and during pregnancy need to be redesigned. Specifically, health advice needs to be more culturally meaningful and morally resonant.
2. A significant percentage of the South Asian population, whether residing in Europe or South Asia, are deficient in vitamin B12 and this should be recognised in the current guidelines.
3. The results of the intervention confirm that there are high levels of vitamin D deficiency in women living in resource poor settings and it is hard to achieve replenishment in pregnancy. There is also high levels of deficiency in South Asians living in European settings. Considerations should therefore be given to replenish severe vitamin D deficiency in pregnancy (vit D <30nmol/l) that will require universal screening in each trimester of pregnancy and careful monitoring.
4. In the Indian sub-continent, where society is rapidly changing, there is the dual problem of many women presenting as either overweight or underweight, whereas in Europe the main problem in pregnancy is the need for appropriate lifestyle advice for the overweight pregnant mother.
5. The quantitative and qualitative research performed in GIFTS have proved extremely informative, however, based on the overall recommendations it is too early to plan a multicentre trial of South Asians living in different settings of Europe or the South Indian sub-continent.
6. The maternal empowerment program (Perinatal Care Project -PCP) needs:
a. Further investigation to see if the anthropometric changes translate to harder metabolic outcomes in older children in the same study.
b. To be assessed in an urban setting and in Europe as a program to prevent cardiometabolic disease in the offspring.

Main dissemination activities and exploitation of results

Please see starting page 21:
WP11-Dissemination of information, training and technology exchange and informing public health
In which the dissemination activities and exploitation of results are fully discussed as part of this work package

List of Websites: