A randomised controlled trial to compare two different doses of maternal B12 supplementation in improving infant B12 deficiency and neurodevelopment

Vitamin B12, also called cobalamin, is a water-soluble vitamin that has a key role in the normal functioning of the brain and nervous system. Up to 74% women are reported deficient during antenatal period in some populations. Deficiency of B12 in newborns is problematic given the role Vitamin B12 plays in neuronal health (brain and nerve cells health) and in the development of foetal and infant brain. We propose this research to compare two different doses (a treatment dose in comparison with a dose known to just prevent further deficiency) of maternal Vitamin B12 supplementation in terms of their effectiveness in removing infant B12 deficiency and neurodevelopment.
We propose to undertake a multi-centric trial in India and Nepal as these are countries where high incidence of deficiency is reported. We will recruit 720 pregnant women from the antenatal clinics of the department of Gynaecology and Obstetrics at Sitaram Bhartia institute of Science and Research, New Delhi and Paropakar Indrarajayalaxmi Maternity Hospital, Kathmandu, Nepal. The subjects will be recruited at their first presentation to the antenatal clinic and should be vegetarian as they are at high-risk of B12 deficiency. Mothers who are >35 years of age, are already on B12 supplementation, have multiple gestation, chronic medical conditions, known psychological illnesses or those who anticipate moving out of the city before/after delivery will be excluded from the study. Recruited mothers will be randomly allocated to 2 equal groups (360 each). Group 1 (Intervention) will receive daily 250 micrograms Vitamin B12 supplementation to the mother through pregnancy and up to 6 months post-partum. Group 2 (Control) will receive 50 micrograms Vitamin B12 supplementation to the mother through pregnancy and up to 6 months post-partum. The profile information of the mother including age, height, weight, ethnicity, education, socioeconomic status, maternal dietary assessment (by Food Frequency Questionnaire), intake of any supplements (iron, folate, Vitamin-D) etc. will be recorded. Vitamin B12 dosage will be provided at enrolment and then monthly to mothers. Mother's blood levels for Vitamin B12 status and other deficiencies will be drawn. Sampling for these biochemical tests will be combined with other routine tests at these stages to avoid any additional discomfort for the mother.
At childbirth, the delivery and post-delivery course of the new-born will be monitored and documented for any problems potentially influencing neurodevelopment. After discharge, all neonates will be routinely followed with preventive and vaccination care as per standard protocols. During routine visits, anthropometric measurements including weight, length and head circumference will be recorded and signs of micronutrient deficiency (especially anaemia and rickets) will be noted. Any illnesses suffered by the child in the intervening period will be recorded. Supplementation of the mother in both groups will be stopped at 6 months after childbirth followed by evaluation at 9 months. The neurodevelopmental assessment and home environment assessment will be done by a developmental therapist and complementary feeding assessment by a nutritionist. Along with routine sampling for Hb screening at 9 months, infant B12 levels status will be determined. The assessment of the infant neurodevelopment scores, the biochemical measures of B12 status of the infant and those of the mother will then be compared between the two groups to see if the neurodevelopment and/or B12 status in the group receiving the higher dose (250 mcg) is better and safe. A positive or a negative result will generate scientific evidence on whether B12 should be supplemented in vegetarian pregnant women with a view to preventing B12 deficiency and its neurodevelopmental consequences in the infant. This will also allow the development of policies and frameworks for routine/wider usage of this supplement in high-risk populations

Supplementation with Iron and folate have been part of a worldwide strategy targeting anaemia and neural tube defects for many years. However, vitamin B12 deficiency has received much less attention. High prevalence of B12 deficiency in mothers in the antenatal period and in their infants has been documented. Multiple case series document the neurological consequences of severe deficiency and their reversal with B12. Trials on the subject are limited and those available have either used an ineffective dose or for a short duration. We propose this randomised controlled trial to compare the efficacy of two different doses of maternal Vitamin B12 supplementation in preventing infant B12 deficiency and adverse neurodevelopment. We propose to undertake a multi-centric trial in India and Nepal at a pay-for-service hospital catering to middle income populace from India and a public hospital catering to lower income groups from Nepal. We will recruit 720 vegetarian, pregnant women from the antenatal clinics of the Indian and Nepalese centres at their first antenatal visit. In Stage 1, recruited mothers will be randomized into 2 equal groups (Intervention and Control). Intervention group will be given daily 250 microgram vitamin B12 supplementation. Control group would receive a daily dose of 50 micrograms vitamin B12 supplementation from 1st trimester and continued up to 6 months post-partum. In Stage 2, the birth and post-delivery course of the new-born will be monitored and documented for any morbidity. At 9 months, the neurodevelopmental, complementary feeding and home environment will be assessed and infant B12 status will be determined. The 2 groups will be compared for the primary (neurodevelopment) and secondary outcomes (biochemical parameters in mother and infant). The results of this study will be used to generate scientific evidence on whether B12 should be supplemented in pregnant women to prevent it's deficiency and adverse neurodevelopment consequences

The potential impact of this study is considerable, particularly in terms of its relevance to current and future policy initiatives in India and Nepal. We have a multi-disciplinary team consisting of clinical trial experts, epidemiologists, public health experts, obstetricians and paediatricians with a global health research and field experience especially in South Asia. The PI and Co-PIs have significant experience in carrying out the specified impact activities. A key impact of the grant will be the training and capacity building of human resource involved. We will develop the skills of the developmental therapists in Nepal and India by providing first-hand training on developmental assessment, counselling and therapy in a clinical setting. Opportunities will be created for visits between study sites and the UK to encourage cross-cultural learning and help researchers develop a global health perspective. As one of the few large-scale trials of B12 supplementation in pregnancy, a key aim of the project is to reset significant elements of the research agenda in maternal and child health. We also aim to contribute to the evidence base on improving neurodevelopmental outcomes in vulnerable infants (i.e. born to vegetarian mothers who are at high risk of vitamin B12 deficiency). While a positive result for the trial would help develop an intervention program to reduce developmental delay using vitamin B12 as a supplementation in pregnant women, a negative result would also add to existing knowledge and lay the groundwork for future work on the subject. The impact of the study not only will be achieved through dissemination of our findings to wider audiences in India, Nepal and the UK but will also be relevant to pregnant mothers globally. The team will engage with researchers globally from the outset of the study (presentations and publications in high impact journals of the protocol and study findings) to optimize the time between the study starting and influencing the international research agenda. We will ensure that the findings are widely disseminated by utilising our links with the National Governments of India and Nepal, Federation of Obstetric and Gynaecological Societies of India, Indian Academy of Pediatrics, National South Asian Health Foundation Children's Working Group, Indian Public Health Association. The findings of the study will help underpin micronutrient supplementation policy in India as envisaged in the recently released 'National Health Policy', and the micronutrient initiative in Nepal. The project will provide key insights to strengthen the existing national nutrition programmes like 'National Iron plus Initiative', 'Janini Suraksha Yojna' and 'Janini Shishu Suraksha Karyakram' initiated by the Government of India and similar initiatives by the Government of Nepal. Because of the high worldwide prevalence of maternal B12 deficiency, the study findings will be highly relevant for maternal/neonatal health in nutritionally vulnerable and high-risk populations (e.g. vegetarians) globally. The clinical implications of our findings are multiple, and of great importance, as the work will provide evidence on the utility, dose, duration and time of initiation of vitamin B12 supplementation in pregnant women/infants and its impact on infant neurodevelopment in diverse sociodemographic settings. Our team, especially Dr. Mathur and Dr. Pant have considerable links with policy makers in India and Nepal. The lead investigators have memberships of various high level global panels on nutrition to influence global policy and research priorities. We will also aim for a significant online presence. Periodic blog posts, Twitter messages, Facebook messages and online articles will be prepared to reach a significant section of young and middle aged internet users for whom the information will be of great interest.