With 43% of children <5 years of age worldwide at risk for poor mental development,1  interventions aimed at sustained improvement of cognition are urgently needed. Nutrition has proven to be an important predictor of neurodevelopment, and interventions to address malnutrition in many low- and middle-income countries have improved children’s short-term development.2  The expectation is that the early life neurobehavioral benefits, when the brain is developing rapidly and is most sensitive to interventions, extend beyond childhood. Yet little is known about the consequences of improving cognition in early life on school-aged and adult outcomes, such as school achievement, economic productivity, and overall well-being. Only a handful of nutrition interventions in children <5 years old follow up with the same participants to examine long-term benefits. Consequently, the follow-up study by Kvestad et al3  titled “Vitamin B12, Folate, and Cognition in 6- to 9-Year-Olds: A Randomized Controlled Trial” makes an important contribution to our understanding of the sustainability of early benefits.

One of the longest nutrition intervention follow-up studies is the seminal Institute of Nutrition of Central America and Panama study, which demonstrated the consistent effects of nutrition in childhood.4  Guatemalan children <7 years of age who received a highly nutritious supplement scored higher on intelligence tests in adolescence, remained in school longer, and performed better on cognitive tests in adulthood compared with controls who received a placebo.5,6  Furthermore, boys who were exposed to the supplement before 3 years of age had higher hourly wages later in life.7  Another more recent study in Ghana supplemented mothers in pregnancy and their children until 18 months postpartum with lipid-based nutrient supplements and observed significant effects on socioemotional development at 4 to 6 years of age.8  Yet, other follow-up studies of nutrition interventions do not show these same sustained effects.9  A substantial evidence gap exists in terms of demonstrating what types of interventions and population characteristics achieve long-term neurodevelopmental benefits.

Follow-up studies, such as that conducted by Kvestad et al,3  are important for several reasons. As the authors correctly state, measurements of cognition in early childhood have poor predictive validity.10  Assessments used later in school-aged children are more strongly related to academic achievement and future performance.11  Therefore, limiting measurements to early childhood may convey a limited picture of the effects of nutrition interventions, particularly those that can have subtle yet meaningful contributions at a population level; these include most micronutrient interventions, such as provision of vitamin B12 and folate. Therefore, regardless of whether effects were observed immediately postintervention in young children, follow-up studies are essential to create the evidence base for long-term effects of early life interventions. This evidence is needed to inform programs and policy decisions in the field of public health nutrition.

Findings from the study published by Kvestad et al3  provide convincing evidence that supplementation with vitamin B12 and folate in childhood does not have long-term consequences on cognition in children 6 to 9 years old despite observed effects immediately postintervention at 1 to 3 years of age. Their study had a good participation rate (79%) despite the long follow-up. The measures used were the gold standard in the field and were locally validated for India. They covered a range of cognitive functions, such as perceptual reasoning, memory, verbal skills, and executive function. No significant effects were found on any of the cognitive outcomes after controlling for confounders. The authors suggest that in the future, a prenatal (rather than childhood) supplement should be tested. However, supplementation in pregnancy yields few effects beyond early childhood.8,1214  Other reasons for the lack of long-term effects may have been the wide range of ages recruited in the initial study (6–30 months) and also the nature of the population studied. We note that the study recruited low- and middle-income families only. Participants may have faced multiple forms of biological and environmental adversity in the form of other nutritional deficiencies or infections that could prevent long-term benefits from vitamin B12 and folate. In fact, in the original study, children who received vitamin B12 and folate had a higher risk of persistent diarrhea immediately postintervention.15  In this type of setting, integrated approaches to address simultaneously the other causes of poor development may see larger and long-term effects.

Findings from this trial by Kvestad et al3  add to an important body of evidence examining the long-term potential of early life nutrition supplementation. Regardless of whether significant effects on child development are found immediately postintervention, follow-up studies are needed to inform which interventions have sustained effects. More integrated solutions and interventions that intervene at multiple points in utero and in childhood may be necessary to produce longer-term improvements in cognitive performance and behavior and should be tested in future studies.

Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.

FUNDING: No external funding.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-2316.

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.