Supplemental choline to prevent and treat learning and memory deficits of early-life iron deficiency (The SupCHO Study): study protocol for a randomized, placebo-controlled trial in Ugandan infants with iron deficiency anemia

Background: Iron deficiency (ID) limits the neurodevelopmental potential of more than 200 million children each year. Iron therapy started when IDA is first diagnosed—typically by screening for anemia at or detection of clinical symptoms of IDA at 12 months of age—does not fully correct earlier ID-mediated brain dysfunction, underscoring the need for low-cost, easily implementable adjunct therapies to iron to treat or prevent this dysfunction in high-risk populations. Supplementation with the essential nutrient choline lessens damage done to the developing hippocampus when given with iron in pre-clinical rodent models, and choline supplementation improves hippocampus-mediated memory and learning in 2-3-year-old children with Fetal Alcohol Spectrum Disorders, a condition associated with hippocampal damage and one for which ID is a component of the neuropathology. Choline has not been tested in children with IDA. Our overall aim is to conduct a randomized, placebo-controlled clinical trial to test whether nine months of daily choline supplementation along with standard iron therapy improves hippocampus-dependent neurobehavioral outcomes in Ugandan infants with IDA. Methods: Three hundred 6-month-old infants with IDA who present to immunization clinics at Mulago and Kawempe National Referral Hospitals in Kampala, Uganda, will be randomized to iron plus choline or iron plus placebo. Iron (oral ferrous sulfate 2 mg/kg/day) will be given for the first three months of follow-up, and a dispersible tablet of choline (200 mg as choline bitartrate) or identical placebo will be given daily for all nine months of follow-up. We will conduct neurobehavioral tests assessing hippocampus-specific memory and attention and global cognition at enrollment (when each infant is 6 months of age) and after nine months of follow-up (when each infant is 15 months of age). Discussion: If we find a neurobehavioral benefit when choline is given along with iron, choline could be added immediately to standard of care treatment for IDA. This low-cost intervention could safely mitigate the brain dysfunction of early-life ID that is often not diagnosed until the hippocampal critical window is closing, providing life-long benefit for both the individual and the economic and social prosperity of entire regions. Trial registration: Clinical trials.gov# NCT06527391; Registered 24 July 2024