Thiamine dose response in human milk with supplementation among lactating women in Cambodia: study protocol for a double-blind, four-parallel arm randomised controlled trial

Abstract

IntroductionThiamine (vitamin B1) deficiency remains a concern in Cambodia where women with low thiamine intake produce thiamine-poor milk, putting their breastfed infants at risk of impaired cognitive development and potentially fatal infantile beriberi. Thiamine fortification of salt is a potentially low-cost, passive means of combating thiamine deficiency; however, both the dose of thiamine required to optimise milk thiamine concentrations as well as usual salt intake of lactating women are unknown.Methods and analysisIn this community-based randomised controlled trial, 320 lactating women from Kampong Thom, Cambodia will be randomised to one of four groups to consume one capsule daily containing 0, 1.2, 2.4 or 10 mg thiamine as thiamine hydrochloride, between 2 and 24 weeks postnatal. The primary objective is to estimate the dose where additional maternal intake of thiamine no longer meaningfully increases infant thiamine diphosphate concentrations 24 weeks postnatally. At 2, 12 and 24 weeks, we will collect sociodemographic, nutrition and health information, a battery of cognitive assessments, maternal (2 and 24 weeks) and infant (24 weeks only) venous blood samples (biomarkers: ThDP and transketolase activity) and human milk samples (also at 4 weeks; biomarker: milk thiamine concentrations). All participants and their families will consume study-provided saltad libitumthroughout the trial, and we will measure salt disappearance each fortnight. Repeat weighed salt intakes and urinary sodium concentrations will be measured among a subset of 100 participants. Parameters of Emaxdose–response curves will be estimated using non-linear least squares models with both ‘intention to treat’ and a secondary ‘per-protocol’ (capsule compliance ≥80%) analyses.Ethics and disseminationEthical approval was obtained in Cambodia (National Ethics Committee for Health Research 112/250NECHR), Canada (Mount Saint Vincent University Research Ethics Board 2017–141) and the USA (University of Oregon Institutional Review Board 07052018.008). Results will be shared with participants’ communities, as well as relevant government and scientific stakeholders via presentations, academic manuscripts and consultations.Trial registration numberNCT03616288.

Thiamine supplementation holds neurocognitive benefits for breastfed infants during the first year of life

“…The full study protocol is published elsewhere 8 . This community‐based, double‐blind, four‐parallel‐arm randomized controlled trial took place between September 2018 and December 2019 in Kampong Thom province, Cambodia.…”

“…Data analysts were necessarily unblinded during the analysis due to the primary analysis. 8 Procedures Participant demographic, socioeconomic, and health information were collected by healthcare workers at delivery, and by field workers at baseline (2 weeks postnatal), midline (12 weeks postnatal), endline (24 weeks postnatal), and at 1 year (52 weeks postnatal). Using calibrated instruments and standard protocols, 15 infant anthropometric measurements (weight, length, and head circumference) were collected.…”

Infantile thiamine deficiency in South and Southeast Asia: An age‐old problem needing new solutions

“…The discovery that otherwise well‐nourished children with subclinical thiamine deficiency in early life exhibit long‐lasting neurodevelopmental deficits is concerning for populations with unrecognised subclinical thiamine deficiency. This highlights the urgent need for further research to understand the long‐term effects of thiamine deficiency and the impacts of preventive interventions, such as maternal supplementation, and functional outcomes in infants, with efforts currently ongoing to fill these knowledge gaps (Whitfield et al 2019…”

“…), although, at present, there is no data on efficacy, coverage of or adherence to these programmes. Ongoing studies aim to better understand the optimal timing, dose and duration of maternal thiamine supplementation (Whitfield et al 2019…”

Establishing a case definition of thiamine responsive disorders among infants and young children in Lao PDR: protocol for a prospective cohort study

“…The knowledge and information gained from the present study will be promptly and broadly disseminated through peer-reviewed scientific open access articles, and through communications and presentations at conferences. Moreover, the present study is part of a larger multi-country effort to address critical questions related to thiamine deficiency and public health in Asia and Africa 45 46. An important aspect of the overall project is to exchange research results among the collaborators.…”