Effects of iron and n-3 fatty acid supplementation, alone and in combination, on cognition in school children: a randomized, double-blind, placebo-controlled intervention in South Africa.

Randomized, double-blind, placebo-controlled intervention in schoolchildren aged 6-11 years from four primary schools in rural KwaZulu-Natal, South Africa. The enrolled population had iron deficiency and poor n-3 fatty acid status; 321 children were randomized and 294 completed follow-up.

This was a 2-by-2 factorial oral supplementation trial testing iron, DHA/EPA, both together, or matching placebos for 8.5 months. The active iron regimen was 50 mg iron as iron sulfate 4 days/week, and the active n-3 regimen was 2 gelatin-coated fish-oil capsules providing 420 mg DHA and 80 mg EPA 4 days/week; iron doses were given with a vitamin C beverage and supplementation was supervised.

Iron supplementation improved cognition, especially learning and memory, whereas DHA/EPA did not improve cognition and showed adverse effects in some subgroups. Iron increased HVLT recall 2 by 0.90 words (95% CI: 0.18, 1.62); in anemic children, iron improved Atlantis Delayed scores by 1.51 (95% CI: 0.03, 2.99) and HVLT recall 2 by 2.02 (95% CI: 0.55, 3.49). DHA/EPA had no overall cognitive benefit and reduced Atlantis test scores in children who were anemic at baseline (22.48; 95% CI: 23.99, 20.96) and Atlantis Delayed scores in girls with iron deficiency (20.9; 95% CI: 21.45, 20.36). The iron plus DHA/EPA combination showed no overall cognitive advantage.

The trial had a relatively modest sample size after attrition, and several findings came from subgroup analyses, increasing the risk of chance findings. Some endpoint assessments were unavailable, arm-specific demographic details were limited, and the results apply mainly to low-income rural South African children with iron deficiency and poor n-3 status. Multiple cognitive outcomes and interactions were tested, which raises concern for multiplicity.