Early Life Thiamine Study

Please see attached study protocol for full details.Background:Thiamine (vitamin B1) is an essential micronutrient crucial for normal physiologicalfunctioning and healthy child development. Thiamine requirements increase withcarbohydrate‐rich diets (e.g. white rice) and during periods of high metabolism (e.g.perinatal women, infancy). The limited data available show that the prevalence ofthiamine deficiency is high in women of childbearing age and their infants in severallow‐ and middle‐income settings, notably in South and Southeast Asia, where white rice isthe dietary staple, but also in several African countries. Thiamine‐deficient pregnantand lactating women produce breastmilk low in thiamine, putting their breastfed infantsat risk of deficiency, and potentially fatal beriberi. In addition, recent evidencesuggests that sub‐clinical thiamine deficiency may be conferred prenatally, placingmillions of infants at risk of neurocognitive deficits, undercutting life‐long well‐beingand productivity.Preliminary Data:In coordination with the Cambodian Ministry of Health, study investigators undertook afour‐parallel‐arm, randomized, controlled trial (NCT03616288) in rural Cambodia toestimate the dose of maternal thiamine required postpartum to optimize breastmilkthiamine concentrations; secondary exploratory outcomes included neurocognitiveassessments. Mothers were randomized to consume 0, 1.2, 2.4, or 10 mg daily thiamine from2 weeks through 6 months postnatal. While milk thiamine concentrations were significantlyhigher in all thiamine groups compared to placebo, critically, at 6 months postnatal,only infants in the 10 mg/d group showed robust neurocognitive benefits. Additionally,infants whose mothers had higher milk thiamine concentrations at our pre‐supplementationbaseline (2 weeks postpartum) showed significantly improved neurocognitive outcomes at 6months postnatal, suggesting that infants' prenatal access to adequate thiamine may havecritical benefits for neurocognitive development.Research Gap:The prior trial indicated that 10 mg/d maternal thiamine supplementation, higher thancurrent recommendations, was needed to support infant neurocognitive development inseveral domains. However, supplementation started at 2 weeks postpartum. Given how muchfoundational neurodevelopment occurs from conception through infancy, earlier and longerthiamine supplementation ‐‐ starting in pregnancy and maintained through 18 monthspostnatal ‐‐ is likely to further support neurocognitive development.Design:This will be a two parallel‐arm, double‐blind randomized controlled trial to compare thestandard dose of thiamine in multiple micronutrient supplements throughout the perinataland early childhood periods to a higher thiamine dose. Our primary outcome is infantneurocognitive development (Mullen Scales of Early Learning Early Learning Composite,MSEL‐ELC) at 18 months postnatal. Secondary neurocognitive outcomes include the MSELsub‐scales, Global Scales of Early Development (GSED), and Visual Paired‐Comparison Task(VPC), at 18 months postnatal.Sample Size:To detect a mean difference in 3 points in MSEL scores with 90% power (d=0.16, two‐tailedα=0.05), and accounting for 20% losses, this study will require N=1,972 participants, 986per group, to detect the main effect on the primary outcome, MSEL‐ELC, at 18 monthspostnatal.Statistical Analysis for Primary Outcome:Scores on MSEL‐ELC at 18 months will be compared between groups using a linear‐regressionmodel, with adjustment for health center, gestational age at enrolment, and birthanthropometry, and using generalized estimating equations with an independenceworking‐correlation structure to account for multiple births. The effect of treatmentwill be described as a mean difference with a 95% CI. In all analyses, missing outcomedata will be addressed using multiple imputation, performed separately by randomizedgroup using chained equations. Outcomes will be analyzed on an intention‐to‐treat basis.