Oral Vitamin D supplementation as a safe, affordable treatment for profound vitamin D deficiency in pregnancy

Background: Vitamin D deficiency in pregnancy is profound across distinct geographical areas of the Indian subcontinent, where levels of deficiency between 70-100% are reported and is detrimentally associated with multiple adverse outcomes including co-morbidities of pregnancy in the mother (e.g. preeclampsia, pre-term birth and gestational diabetes); increased infections in mother and baby; rickets, low birth weight and baby length and increased respiratory symptoms in the child at 3-5 years. Clinical trials of vitamin D in pregnancy in the USA provide evidence that (i) supplementation with ~10 fold higher levels of vitamin D than those currently within the recommended daily allowance in India are safe and achieve vitamin D sufficiency in the majority (>80%) of pregnant women; and (ii) daily supplementation from early in pregnancy has the greatest effect in improving adverse clinical outcomes in both mother and her child. Earlier studies in India focused largely on bolus administration in late pregnancy. We propose that daily supplementation with higher levels of vitamin D in India will have a major impact on health outcomes for both the mother and her child. However concerns exist in India about these higher levels of supplementation and this proposal aims to address these concerns directly.

Hypothesis: Ensuring vitamin D sufficiency in pregnant women in India from early pregnancy till term improves maternal health outcomes in pregnancy and in her baby during the first year of life.

Aim 1. To perform a pilot feasibility study to determine whether the highest acceptable level of vitamin D supplementation (2000 IU/daily from 10-14 weeks of gestation), which is slightly less than half of that studied in USA trials, leads to vitamin D repletion in pregnant women at St. John's Medical College Hospital (SJHMC), Bangalore. We have obtained Institutional Ethics Committee and Government of India approvals for such a study.

Aim 2. Form a cross India network comprising scientists, clinicians, health care workers, policy makers to participate in a 3-day workshop. We will invite international experts in the field who have participated in global trials of high dose vitamin D supplementation in pregnancy. Our goal is to discuss the heterogeneity in global studies and concerns within India of vitamin D dose and supplementation regimens in pregnancy to potentially overcome the perceived roadblock to higher levels of supplementation in India. Our workshop is designed to provide a meta-analysis of vitamin D clinical studies in India in the context of global vitamin D trial outcomes and a projected high impact review with the potential to influence national strategy is planned. Our workshop program will include a training component on laboratory-based methods that underpin the science of how vitamin D supplementation benefits clinical parameters in both mother and baby and biological pathways likely to underpin this, to enhance knowledge transfer and capacity building.

Together these aims will empower testing of our hypothesis in a future application to the GCRF. Our goal will be to perform a large-scale clinical study to determine the potential of a safe and inexpensive public health intervention targeted to a vulnerable maternal and neonatal populations across India.

We aim to address to the extent supplementation with 2000 IU/day vitamin D3 corrects deficiency in pregnant women in India, which has not previously been tested. We propose this is linked to lack of awareness amongst stakeholders of the benefits of offering higher vitamin D doses than current Indian RDA (<500 IU/day).

Aim 1: In a pilot study determine whether the highest acceptable level of vitamin D supplementation approved by the Govt. of India leads to repletion of pregnant women at St. John's Medical College Hospital, Bangalore.
Study design: Pregnant women (n=186-200) will receive 2000 IU vitamin D/day from end of the 1st trimester to term. Vitamin D status will be monitored in pregnancy [T1, T2, T3] in serum (5ml), and in the baby by sensitive LC-MS.
Samples: Cord blood from a subset of babies will be sued to study the impact of maternal intervention on innate secreted cytokine responses as a measure of newborn immunity, powered on our immune data from the USA VDAART trial.
Aim 2: Form a cross India network comprising scientists, clinicians, health care workers, policy makers to discuss realizing the known benefits of vitamin D supplementation in pregnancy. We will invite international experts to a workshop to discuss heterogeneity globally and within India on vitamin D dose and supplementation regimens; a meta-analysis of vitamin D studies in India in the context of global vitamin D trial outcomes and a projected review with the potential to influence national strategy are planned.
Days 1-2: A closed 2-day workshop discussing whether vitamin D dose and timing regimen is the same across different clinical (e.g. skeletal vs non-skeletal), biochemical and immune outcomes. We anticipate strong representation of vitamin D interests across India.
Day 3: This session will be open to all interested parties across India to ensure knowledge dissemination and transfer, and to help understand the depth of interest in vitamin D and existing concerns in India

The United Nations Millennium Development Goals initiative reduced global under-five mortality by more than 50% between 1990 to 2015, nevertheless, annual deaths remain unacceptably high, estimated at 5.9 million in 2015. Approximately 50% of these deaths occurred within the first month of life and were greatest in low- and middle-income countries. Infections in mother and baby contributed significantly to morbidity and mortality. Given the size of the problem, and the huge number of individuals at risk, even incremental advances in our knowledge and improvement in treatment options have the potential to have massive public health impact.
There is increasing evidence that vitamin D sufficiency in pregnancy is beneficial for both mother and baby, however despite profound levels of deficiency in India, concerns exist across India regarding levels of supplementation that exceed current guidelines. Our broad goals are to provide evidence through a pilot study for whether an increased level of vitamin D supplementation in pregnant women in India achieves repletion and to open dialogue across interested parties in India of the safety, efficacy, optimal treatment regimens, potential clinical benefits and underlying biological mechanisms of higher levels of vitamin D currently being investigated globally.
The ACOG concludes that higher levels of vitamin D supplementation of 1000-2000 IU/day in pregnancy are safe. Emerging data from the USA and Europe increasingly suggest that these and higher levels of vitamin D supplementation have a beneficial impact for the pregnant women, the newborn and the infant. These include evidence for improvements in the incidence of pre-eclampsia, gestational diabetes mellitus, pre-term birth in the mother, of infections in mother and baby, low birth weight, length and rickets in the offspring and a reduction in respiratory symptoms and allergic sensitizations in the child at 3-years of age. Whether comparable effects occur in India, which faces different challenges, including greatly increased infectious risk and which has some of the highest levels of vitamin D deficiency in pregnancy globally, is unknown. Appropriately powered RCTs are needed, but enthusiasm is tempered by expense and logistic challenges, as well as caution in India of levels of supplementation above current RDA. Our pilot study seeks evidence to support acceptance and use of 2000 IU/d in pregnant women in India, which as far as we are aware has not been previously addressed.
Our proposed study will test if the higher vitamin D supplementation dose of 2000IU/d during pregnancy in India effectively repletes the mother and if this in turn influences immune mechanisms in the newborn, which are central to the control of infection, and we propose effective vaccination. Through the proposed workshop we plan to host, this information has the potential to inform the design and monitoring of future large-scale RCT. Vitamin D supplementation is a comparatively cheap, publically acceptable, and non-invasive strategy that has the potential to benefit many aspects of human health. Therefore, there is a real need to improve all aspects of our knowledge related to the rationale and justification for early implementation of vitamin D supplementation. Our ambition is that this pilot study will provide new scientific knowledge that will inform and expedite a future definitive multicentre clinical trial across India.