Pilot interventions in pregnant women in Bangladesh and India
WP 3 leader: Ranjan Yajnik
A pilot complex intervention was developed in Bangladesh 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.
The trial is now registered here: http://www.controlled-trials.com/ISRCTN83599025/
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.