Carlo Agostoni
Silvia Bettocchi


Different aspects may contribute to neurodevelopment. Specific nutrients, energy requirements, gut microbiota composition mandatorily adjusted for environmental factors, may exert a strong influence on brain development and cognitive function throughout life. Pregnancy, infancy, and childhood represent the sensitive periods, and many studies have been performed to understand the specific mechanisms that take place during these phases and how diet may affect them in association with other variables. In this chapter, original articles on nutrition and cognition comprising randomized controlled trials (RCT), observational studies, and reviews published from July 1, 2019 to June 30, 2020 have been collected into 3 categories:
1 Maternal dietary intake during pregnancy
2 Children’s diet
3 Diet considered together with other factors possibly influencing cognition (holistic approach).
All comments are included following each section.

Pregnancy/Intrauterine Exposure

Association between maternal fluoride exposure during pregnancy and IQ scores in offspring in Canada

Comments: In this observational study, the authors investigated the possible adverse effects of maternal fluoride exposure during gestation on child’s neurodevelopment in a large birth cohort (512 Canadian mother-child pairs) receiving optimally fluoridated water. Fluoride levels in mothers have been evaluated in 512 Canadian mother-child pairs through maternal urinary fluoride averaged across 3 trimesters, as well as self-reported maternal daily fluoride intake from water and beverage consumption in 400 pregnant women, and children’s IQ has been assessed at ages 3–4 years. The estimate of maternal fluoride intake during pregnancy in this study showed that an increase of 1 mg of fluoride was associated with a decrease of 3.7 IQ points in boys and girls. The finding observed for fluoride intake in both boys and girls may reflect postnatal exposure to fluoride, and reconsideration of maternal fluoride intakes and/or supplementations during pregnancy is suggested to ensure cognitive outcomes in the offspring.

Modification of the effects of prenatal manganese exposure on child neurodevelopment by maternal anemia and iron deficiency

Comments: It is widely agreed that iron may contribute to early-life neurodevelopment. The first study took into account data from the INMA Cohort population-based study to assess the connections between either iron status and intakes in women during gestation and neuropsychological outcomes in children at 7 years of age, respectively. According to the results, after controlling for potential confounders, normal maternal serum ferritin levels (from 12 to 60 mg/L) and iron intake (from 14.5 to 30.0 mg/day), respectively, were related to better scores in working memory and executive functioning in
the offspring.

The second study shows interesting data on possible interactions of iron with manganese (Mn). Mn is a crucial component of human metabolism and, while taking part in neurodevelopment, high concentrations have been associated with neurotoxicity. Indeed, Mn may interact with other metals, including iron, and it accumulates during conditions of iron deficiency, possibly increasing its neurotoxic effects. Positive effects of Mn on child cognition, verbal, memory, motor, and quantitative scores have been found, provided that maternal iron status in the 2nd and 3rd trimesters of gestation is optimal. In contrast, associations between Mn status and brain development were negative in children whose mothers were either anemic in the 3rd trimester or iron deficient in the 2nd trimester. These results suggest that iron and Mn status may act in a synergistic way when iron stores are replenished but that iron deficiency can highlight negative effects of Mn. Further studies are needed to define a maternal optimal status for a synergistic, positive effects of iron and Mn.


Effect of continued folic acid supplementation beyond the first trimester of pregnancy on cognitive performance in the child: A follow-up study from a randomized controlled trial (FASSTT Offspring Trial)

Comments: Optimal maternal folate status started before conception followed through the first 10–12 week of gestation is essential to prevent offspring neural tube defects at a recommended dose of at least 400 μg/day. While some reports underline negative effects of quite higher dosages to later neurodevelopmental achievement, the effects of continuing folic acid at recommended dosages after the first trimester on cognitive function are not well studied. The authors have conducted a follow-up study of children whose mothers had participated in an RCT of folic acid supplementation in the second and third trimesters [1] and have found a positive effect of prolonged folic acid supply on cognitive performance of children at 3 years and up to 7 years of age.


Vegetarian diet during pregnancy is not associated with poorer cognitive performance in children at age 6–7 years

Comments: Vegetarianism may lead to a deficiency of selected nutrients that are essential for brain growth and function, and for many years, its practice has been even discouraged in pregnant mothers. The authors have performed a prospective observational study to investigate the effect of maternal vegetarian diet during pregnancy on cognition in children at 6–7 years of age. Although consuming a vegetarian diet during pregnancy was associated with lower maternal levels of specific nutrients relevant to brain anatomic and functional development (namely, cobalamin, and arachidonic and docosahexaenoic acids), no negative effects on cognitive function of children at 6–7 years have been shown, even after adjusting for maternal IQ, maternal education, and maternal age. Of note, vegetarianism in pregnancy was linked also to other markers of a positive lifestyle (for instance, a longer breastfeeding duration and lower incidence of smoking), suggesting that either different nutritional, or non-nutritional, factors in vegetarians exert a positive impact on neurodevelopment.


Nutrients in Childhood

Maternal health and nutrition status, human milk composition, and growth and development of infants and children: A prospective Japanese human milk study protocol

Comments: Concerning the role of early nutrition on later neurodevelopmental steps (and health outcomes in general), a worldwide growing interest is devoted to human milk composition and the relationships with maternal dietary habits, adjusted for local variables. We have chosen a recently published protocol to highlight the complexity of the issue, where the methodological approach is critical to prevent bias in results and interpretations. An adequate sample, including explanation, of 1,122 Japanese lactating women (out of 1,200 calculated) and their offspring has been enrolled, and a protocol for a longitudinal prospective cohort study has been planned in order to examine the influence of maternal health and nutrition status, socioeconomic factors, and lifestyles on human milk composition. The relationships of these parameters with growth and development in infancy and childhood will be evaluated too.


Effects of vitamin D deficiency on neurobehavioural outcomes in children: A systematic review

Comments: Nutrients are modifiable variables possibly contributing to proper neurodevelopment during early life. We have selected 4 studies evaluating specific micronutrient status and/or supplementation in children and youths and their cognitive outcomes at short, medium, and longer term. Omega-3 PUFA: This meta-analysis aimed to add data on the impact of omega-3 supplementation on cognition in youths. Results obtained were rather small and inconclusive, and heterogeneity of design studies does not help to disentangle any relevant association. Further studies should be performed to assess the separate effects of EPA and DHA omega-3 PUFA supplementation on domain-specific cognitive test performance in youths.

Vitamin D: The authors selected a few studies, including 1 RCT, 19 mother-child observational studies, and 11 child observational studies, about the role of vitamin D in neurobehavioral outcomes in children. Overall, in less than 50% of the recruited subjects, an association between low maternal or child 25-hydroxyvitamin D levels and impaired neurobehavioral outcomes in children has been reported. Accordingly, findings are limited and uncertain. Newer studies are needed to determine if vitamin D is beneficial for brain growth in children and optimal dosage and timing of supplementation.


The relationship between dietary micronutrients intake and cognition test performance among school aged children in government owned primary schools in Kumasi metropolis, Ghana

Comments: Comments on this article are incorporated in the comments on the article by Koshy et al.


Body iron and lead status in early childhood and its effects on development and cognition: A longitudinal study from urban Vellore

Comments: Inadequate micronutrient intakes in childhood remain a public health issue in developing and transition countries, well separated from the Western setting where many environmental factors may further contribute. We have selected two examples from the recent literature. In the first study, vitamin A, iron, vitamin B12, vitamin B6, zinc, and folate intakes have been examined cross-sectionally in a cohort of Ghanaian children aged 9–13 years, with cognition measured through a 36-question test. Weak positive associations were observed between cognition scores and zinc and folate intakes, while other dietary micronutrient intakes, in spite being inadequate in most children, did not show significant associations with the cognitive performance.

In a prospective birth cohort follow-up from the urban slum of Vellore, India, the relationships of Hb, Fe, and Pb levels with cognition in around 250 children at 5 years of age have been investigated. Based on the results, an optimization of body Fe status and the reduction of Pb exposure in children may ameliorate their cognition, particularly in low-middle income states. Once more, the peculiar settings of the last two studies should be taken into account for a balanced interpretation of the reported data.


Holistic Approach

An overview on the associations between health behaviors and brain health in children and adolescents with special reference to diet quality

Comments: Comments on this article as well as the following one (Jirout et al.) are incorporated in the comments on the article by Dubuc et al.


Lifestyle habits predict academic performance in high school students: The adolescent student academic performance longitudinal study (ASAP)

Comments: We have collected three studies suggesting the opportunity of a holistic approach to support child and adolescent neurodevelopment in developed countries.
According to the first overview, while we take for granted that diet may have direct, indirect, and synergistic effects on brain and cognition with physical activity, sedentary behaviors, cardiometabolic health, and sleep, associations remain modest since most of the existing literature is represented by cross-sectional studies. Therefore, longitudinal interventions integrating all these mechanisms, and adequately powered, are needed to evaluate the effects of integrated interventions.

The second thematic review further underlines the necessity to integrate lifestyle factors (including diet) and cognition with learning. While a vast literature is available, including basic research and animal studies, associations and causal relationships in real life and different settings between these factors are greatly understudied. More holistic approaches, adequately powered, to support child development are required to improve current knowledge on predictors of optimal cognition and learning. The third longitudinal real-life survey investigates whether lifestyle habits could predict changes in cognitive control and academic performance in a cohort of 187 highschool students after completing 3-year follow-up in Quebec, Canada. The results suggest that lifestyle habits may be able to predict the changes in cognitive control and academic performance of high-school students during a 3-year period, with some gender-related differences. Accordingly, education programs based on healthy lifestyle promotion (i.e., increasing the consumption of fruits/vegetables, early bedtime, and lessening screen time) in high school could be planned to improve also academic performances. Based on these last observations, we may conclude that the complexity of the interaction of the different factors that influence child cognitive outcomes requires further long-term surveys.


Sociodemographic, nutritional, and environmental factors are associated with cognitive performance among Orang Asli children in Malaysia

Comments: Comments on this article are incorporated in the comments on the article by Atukunda et al.


Nutrition, hygiene and stimulation education for impoverished mothers in rural Uganda: Effect on maternal depression symptoms and their associations to child development outcomes

Comments: Besides life-threatening nutritional deficiencies among children living in developing countries, repeatedly associated with lower neurodevelopmental achievements, increased childhood morbidity is also connected with low sociocultural and socioeconomic backgrounds. Poor level of parental education and related maternal depression may be associated with lower child development domains. We have collected two studies further supporting the validity of the holistic approach, even more in low-income rural settings. The first study evaluated the connection between sociodemographic, nutritional (body composition and hemoglobin) and environmental factors and cognition in a sample of underprivileged indigenous children living in poverty, known as Orang Asli children in Malaysia. According to the results, parental (father’s) education level, availability of learning material and responsiveness were highly related factors, suggesting the need of a holistic approach involving parents, communities, and government agencies. The second study consisted of a follow-up of an open cluster-randomized education trial on mothers with depression symptoms in rural Uganda and cognitive performance in their children.

The education trial focusing on complementary feeding, hygiene, and stimulation education among mothers of 6- to 8-month-old children resulted in a significant reduction of maternal depression symptoms and positive effects on child cognitive and language development outcomes at child ages of 20–24 and 36 months. Early interventions aimed at improving family’s education and responsiveness to nutrition, hygiene, and sanitation might effectively ensure better cognitive outcomes in underprivileged children. Even if well-controlled trials are welcome, we may firmly affirm that – even out of a strictly scientific setting – also a shared common sense may well agree on these points.


Microbiota and the social brain

Comments: The last paper of this section, conclusive of the chapter on cognition, is a fascinating review on the mechanisms possibly linking the gastrointestinal microbial community on one side and the neurodevelopment and programming of social behaviors on the other across the animal kingdom. In a wider sense, it may also represent a holistic approach, even if it may generate more hypotheses than suggest solutions. Some points deserve attention, since that may be connected with social life in unexpected ways. Indeed, although the microbiota may affect behavior endogenously through the regulation of the gut-brain axis, some animal species may have evolved to use symbiotic bacteria exogenously to mediate communication between members of the same species. Sociability is a possible means to ensure the transmission of microbial symbionts from one animal to another. Newer studies will provide insights into the evolution of social behavior and will also expand our understanding of disorders of the social brain, and the type of mediation exerted by this unique entity represented by the microbiota.