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Maternal vitamin B12, folic acid and homocysteine as determinants of gestational diabetes, fetal growth and inter-generational programming of diabesity (Pune Intervention Study)


Funded By:  Medical Research Council, UK (MRC) - Indian Medical Research Council, India (ICMR)
Month and Year of Commencement:  June 2012
Current Status:  Ongoing

Principal Investigator (India Site):  Dr.C.S.Yajnik, Director, Diabetes Unit, KEM Hospital & Research Center, Pune, India
Co-Investigators: Dr Giriraj Chandak, Mr Charu Joglekar, Mr Dattatray Bhat, Ms Himangi Lubree, Dr Urmila Deshmukh

Principal Investigator (UK Site):
 Prof Caroline Fall, Professor of International Paediatric Epidemiology, Southampton General Hospital, UK
Co-Investigators: Dr Ponnusamy Saravanan, Prof Nigel Stallard, Prof Helga Refsum, Prof Cyrus Cooper, Prof Keith Godfrey, Prof Hazel Inskip, Dr Sian Robinson




PMNS1        PMNS2
» Background
» Objectives
» Methodology and Design
» Current status


Background

Our research programme over the years has highlighted high rates of vitamin B12 deficiency in our population. Our flagship study, the Pune Maternal Nutrition Study (PMNS) showed that vitamin B12 deficiency in the mother is associated with poor fetal growth and insulin resistance in the offspring, while the Parthenon Study in Mysore showed an increased risk of gestational diabetes in vitamin B12 deficient mothers. The effects of vitamin B12 deficiency may act through ‘epigenetic' (environmental influence on gene expression) mechanism, especially in the growing fetus. Improving the B12 status of young men and women before they become parents could be a novel, affordable and practical strategy to prevent diabetes in future generations.

Our proposed research programme has two arms: 1) a randomised controlled trial of B12 supplementation in rural Indian adolescents (girls and boys) who will marry and conceive within the next few years, with the aim of improving vitamin B12 status of their offspring, and reduction in adiposity and risk of diabetes in later life (Pune Intervention Study {PIS}), 2) two related observational studies in the UK: to replicate the earlier Indian findings and study their relevance to S Asian and white Caucasian populations. A) At Southampton Life-course Epidemiology Unit (Southampton Woman Study), we will measure vitamin B12, folate and homocysteine in pregnant mothers' blood samples and relate these to pregnancy outcomes, and childhood growth and adiposity of their children, in the ongoing study. B) In Warwick University (PRIDE study) we will study the predictive value of mother's vitamin B12 concentrations in early pregnancy for development of gestational diabetes (GDM). There is a high proportion of south Asian Indian women in this population (Coventry, Nuneaton and Leicester), and therefore a unique opportunity to compare the results with European population.

Future research will include genetic and epigenetic investigations in these studies. We expect this research to provide useful information for novel strategies to prevent adiposity and type 2 diabetes.


Objectives

To study impact of maternal nutrition before and during pregnancy on fetal growth



Methodology and Design

Pune Intervention Study
The Pune Intervention Study {PIS} is a randomised controlled trial of vitamin B12 supplementation in adolescent boys and girls who will marry and conceive in the next few years. These adolescents were born in the Pune Maternal Nutrition Study, and belong to 6 villages near the Vadu Health Centre of the KEM Hospital. There are approximately 700 adolescents in this study.

The intervention: The participants will be allocated to one of three groups:: 1. Vitamin B12, 2. Multivitamin tablets including Vitamin B1, and 3. No vitamins. The second group will also receive milk protein. All three groups will receive iron and folic acid tablets as per the Indian Government policy. The study will be blinded so that neither the participants nor the investigators are aware of the contents of the tablets. The girls will receive the medication until their first delivery, the boys will receive it for 3 years or till their wives become pregnant. The children born to these young men and women will be studied at birth and followed up for measurements of diabetes risk markers. All adverse events will be monitored and investigated by medical professionals, though we do not expect to see any significant adverse effects with this intervention.

The study has started in the second half of 2012 and it will run for at least four years. The study is approved by the Ethics Committee of the KEM Hospital Research Centre, and the Indian Government’s Health Ministry Screening Committee.




Current Status

The pre-intervention screening was completed between February and July 2012. Of the 690 who underwent screening, 557 were eligible for our study and were randomised into three groups. Those who were anaemic (n=2), severely B 12 deficient (< 100 pmol/L; n=117) or had chronic medical illness (n=14) were excluded and managed appropriately. There were no significant differences in the baseline characteristics of the three groups. Over 50% were B 12 deficient according to international standards (<150 pmol/L) while folate deficiency was rare (~2%). These adolescents had higher levels of B 12 deficiency compared to their mothers (34%).

The distribution of the micronutrient supplements commenced in September 2012. Compliance after 6 months of supplementation is over 80% in ~80% of the participants in all three groups; there were no significant differences in compliance between the three groups. There have been seven hospitalizations so far none of which were intervention related.




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