Effects of food supplementation on cognitive function, cerebral blood flow, and nutritional status in young children at risk of undernutrition: randomized controlled trial

Abstract

Objective: To assess the effects of food supplementation on improving working memory and additional measures including cerebral blood flow in children at risk of undernutrition.

Design: Randomized controlled trial.

Setting: 10 villages in Guinea-Bissau.

Participants: 1059 children aged 15 months to 7 years; children younger than 4 were the primary population.

Interventions: Supervised isocaloric servings (≈1300 kJ, five mornings each week, 23 weeks) of a new food supplement (NEWSUP, high in plant polyphenols and omega 3 fatty acids, within a wide variety and high fortification of micronutrients, and a high protein content), or a fortified blended food (FBF) used in nutrition programs, or a control meal (traditional rice breakfast).

Main outcome measurements: The primary outcome was working memory, a core executive function predicting long term academic achievement. Additional outcomes were hemoglobin concentration, growth, body composition, and index of cerebral blood flow (CBFi). In addition to an intention-to-treat analysis, a predefined per protocol analysis was conducted in children who consumed at least 75% of the supplement (820/925, 89%). The primary outcome was assessed by a multivariable Poisson model; other outcomes were assessed by multivariable linear mixed models.

Results: Among children younger than 4, randomization to NEWSUP increased working memory compared with the control meal (rate ratio 1.20, 95% confidence interval 1.02 to 1.41, P=0.03), with a larger effect in the per protocol population (1.25, 1.06 to 1.47, P=0.009). NEWSUP also increased hemoglobin concentration among children with anemia (adjusted mean difference 0.65 g/dL, 95% confidence interval 0.23 to 1.07, P=0.003) compared with the control meal, decreased body mass index z score gain (-0.23, -0.43 to -0.02, P=0.03), and increased lean tissue accretion (2.98 cm2, 0.04 to 5.92, P=0.046) with less fat (-5.82 cm2, -11.28 to -0.36, P=0.04) compared with FBF. Additionally, NEWSUP increased CBFi compared with the control meal and FBF in both age groups combined (1.14 mm2/s×10-8, 0.10 to 2.23, P=0.04 for both comparisons). Among children aged 4 and older, NEWSUP had no significant effect on working memory or anemia, but increased lean tissue compared with FBF (4.31 cm2, 0.34 to 8.28, P=0.03).

Conclusions: Childhood undernutrition is associated with long term impairment in cognition. Contrary to current understanding, supplementary feeding for 23 weeks could improve executive function, brain health, and nutritional status in vulnerable young children living in low income countries. Further research is needed to optimize nutritional prescriptions for regenerative improvements in cognitive function, and to test effectiveness in other vulnerable groups.

Trial registration: ClinicalTrials.gov NCT03017209.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from philanthropic donations from Bill Schawbel and Judy Samelson, Schawbel Group, LLC, Judy and Peter Hourihan, Karen, Ivan and Janet Brown, Charles Clough, Ronald Diamond, Scott Epstein, Linda and Michael Frieze, Arthur Gallagher, Judith and Stephen Hoffman, Eos Foundation, Susan Penta, Ellen and Michael Sandler, Rosalyn and Richard Slifka, Michael Tooke, and Ellen and Peter Zane to Tufts University and by the Boston Foundation; Massachusetts General Hospital Research Sundry; and USAID; Tufts University has filed a patent application claiming subject matter covered by this paper, and coauthors of the patent (SBR, ES, AK) had no role in outcome assessments, no access to study data, and were not responsible for statistical analyses; MAF has a financial interest in 149 Medical, a company developing DCS technology for assessing and monitoring cerebral blood flow in newborn infants; MAF’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies, and she was blinded to subject randomization during oversight of outcomes testing. No other relevant potential conflicts are reported for this article.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Fig 1

Consort diagram showing primary trial populations for intention-to-treat and per protocol analyses (≥75% adherence to supplement consumption) for three randomized groups (new supplement (NEWSUP), fortified blended food (FBF), control meal). Age groups were children younger than 4 and children aged 4 and older

Fig 2

Changes in cerebral blood flow index (CBFi) in four prefrontal cranial sites with consumption of new supplement (NEWSUP), fortified blended food (FBF), or control meal. The four cranial sites correspond approximately to Brodmann areas BA 10 and 46 (ventrolateral prefrontal cortex), and upper left and upper right over BA 9 (dorsolateral prefrontal cortex). Cluster adjusted means adjusted for age, sex, baseline head circumference, and baseline CBFi are given with standard errors, and models are summarized in supplementary appendix. Means are adjusted for age, sex, baseline head circumference, and baseline CBFi. Significant differences between groups are indicated by same superscript. Dark purple bars indicate results for intention-to-treat cohort and light purple bars represent per protocol cohort

Fig 3

Changes in cerebral oxygen metabolism index (CMRO2i) in four prefrontal cranial sites with consumption of new supplement (NEWSUP), fortified blended food (FBF), or control meal. The four cranial sites correspond approximately to Brodmann areas BA 10 and 46 (ventrolateral prefrontal cortex), and upper left and upper right over BA 9 (dorsolateral prefrontal cortex). Cluster adjusted means adjusted for age, sex, baseline head circumference, and baseline CMRO2i are given with standard errors, and models are summarized in supplementary appendix. Means are adjusted for age, sex, baseline head circumference, and baseline CMRO2i. Significant differences between groups are indicated by same symbols. Dark purple bars indicate results for intention-to-treat cohort and light purple bars represent per protocol cohort

Fig 4

Changes in lean and fat tissue with consumption of new supplement (NEWSUP), fortified blended food (FBF), or control meal. Cluster adjusted means and standard errors are given for tissue areas at the mid-upper arm circumference site. Means are adjusted for age, sex, study cohort, and baseline measurement. Significant differences between groups are indicated by same symbol. Dark purple bars indicate results for intention-to-treat cohort and light purple bars represent per protocol cohort