Carlo Agostoni, Silvia Bettocchi

This chapter includes articles published in the area of nutrition and cognition from July
1, 2018, up to June 30, 2019. Pregnancy, infancy, and early childhood are crucial periods
for neurodevelopment and are influenced by several factors. During these critical
phases, nutrients and energy requirements of mothers and their offspring should be
ensured to permit optimal brain growth as well as cognitive outcomes throughout life.
Accordingly, all the articles that have been selected fall into four categories connected
with later neurocognitive performance in the offspring: (1) Breastfeeding, with 2 observational studies, (2) Fatty Acids, including 2 RCT and 1 observational study, (3) a
new paragraph, Holistic Approach, with 2 observational studies and 2 reviews, respectively,
focusing on the role of socioeconomics conditions, environmental factors, and
maternal stress up to the ingestion of amniotic fluid, and (4) Nutrients in pregnancy,
with a selection of 10 studies, mostly observational, with a few systematic reviews and
1 RCT design from a major developing country. Comments following the abstracts are
included for each of the 4 sections.


Is breast feeding associated with offspring IQ at age 5? Findings from prospective cohort: lifestyle during pregnancy study

Breast feeding is associated with health benefits for both mother and child, but many studies focusing on neurodevelopment have lacked information on important confounders and few randomised trials exist. Our objective was to examine the influence of breast feeding on child IQ at 5 years of age while taking maternal IQ and other relevant factors into account.
Design: Prospective observational study.
Setting: Population-based birth cohort in Denmark.
Participants: We used data from The Lifestyle During Pregnancy Study 1,782 mother-child pairs sampled from the Danish National Birth Cohort (n = 101,042). Outcome Measures: Child IQ was assessed at age 5 years by the Wechsler Primary and Preschool Scales of Intelligence-Revised. On the same occasion maternal intelligence was assessed by Wechsler Adult Intelligence Scale and Raven’s Standard Progressive Matrices. Exposure data on duration of breast feeding ( n = 1,385) were extracted from telephone interviews conducted when the child was 6 and 18 months, and analyses were weighted by relevant sampling fractions.
Results: In multivariable linear regression analyses adjusted for potential confounders breast feeding was associated with child IQ at 5 years (categorical χ 2 test for overall association p = 0.03). Compared with children who were breast fed ≤ 1 month, children breast fed for 2–3, 4–6, 7–9 and 10 or more months had 3.06 (95% CI 0.39 to 5.72), 2.03 (95% CI –0.38 to 4.44), 3.53 (95% CI 1.18 to 5.87) and 3.28 (95% CI 0.88 to 5.67) points higher IQ after adjustment for core confounders, respectively. There was no dose-response relation and further analyses indicated that the main difference in IQ was between breast feeding ≤ 1 month versus > 1 month.
Conclusions: Breastfeeding duration of 1 month or shorter compared with longer periods was associated with approximately three points lower IQ, but there was no evidence of a dose-response relation in this prospective birth cohort, where we were able to adjust for some of the most critical confounders, including maternal intelligence.

Nutrients or nursing? Understanding how breast milk feeding affects child cognition

To explore the associations between type of milk feeding (the “nutrients”) and mode of breast milk feeding (the “nursing”) with child cognition.
Methods: Healthy children from the GUSTO (Growing Up in Singapore Toward healthy Outcomes) cohort participated in repeated neurodevelopmental assessments between 6 and 54 months. For “nutrients”, we compared children exclusively bottle-fed according to type of milk received: formula only (n = 296) vs some/all breast milk (n = 73). For “nursing,” we included only children who were fully fed breast milk, comparing those fed directly at the breast ( n = 59) versus those fed partially/completely by bottle (n = 63).
Results: Compared to infants fed formula only, those who were bottle-fed breast milk demonstrated significantly better cognitive performance on both the Bayley Scales of Infant and Toddler Development (Third Edition) at 2 years [adjusted mean difference (95% CI) 1.36 (0.32, 2.40)], and on the Kaufman Brief Intelligence Test (Second Edition) at 4.5 years [7.59 (1.20, 13.99)]. Children bottle-fed breast milk also demonstrated better gross motor skills at 2 years than those fed formula [1.60 (0.09, 3.10)]. Among infants fully fed breast milk, those fed directly at the breast scored higher on several memory tasks compared to children bottle-fed breast milk, including the deferred imitation task at 6 months [0.67 (0.02, 1.32)] and relational binding tasks at 6 [0.41 (0.07, 0.74)], 41
[0.67 (0.04, 1.29)] and 54 [0.12 (0.01, 0.22)] months.
Conclusions: Our findings suggest that nutrients in breast milk may improve general child cognition, while nursing infants directly at the breast may influence memory.
Comments: In these two studies, from different geographic settings (Denmark and Singapore, respectively), the authors try to disentangle from population cross-over designs the role of possible confounders on the proverbial association between breastfeeding and/or human milk and optimal neurofunctional development. The first study, while accounting for several confounders (maternal intelligence quotient, IQ, at first), does not show any dose–response relationship as continuous variable in terms of progressively longer breastfeeding duration and higher IQ scores. The only recorded difference has been found for breastfeeding ≤ 1 month (lower IQ) and > 1 month (higher IQ), raising questions on the potential role of post-natal factors not considered within the
survey. The Singapore study had the opportunity to focus on three categories, formula-
fed infants, infants fed only human milk at the breast, and infants fed only human milk but at least partially as expressed and given through a bottle as assessed at the age of 3 months. The 2 human milk-fed groups showed higher developmental scores when visited between 6 and 54 months. Those fed at the breast showed a further advantage in memory items, so allowing for the conclusive remarks at the question “Nutrients or nursing?” in terms of “nutrients in breast milk may improve general child cognition, while nursing infants directly at the breast may influence memory.” The reasons of the relatively high rate of mothers giving their expressed milk by bottle (the 2 samples were comparable) are not detailed by the authors, just referring to a generic “preferred mean of administration in some cultures.”

Fatty Acids

The effect of Atlantic salmon consumption on the cognitive performance of preschool children. A randomized controlled trial

Background and Aims: 
Long chain polyunsaturated n-3 fatty acids (LC-PUFA) are of functional and structural importance for brain development. Observational studies have shown positive relations between fatty fish consumption and cognitive performance in children, but Results from intervention studies using supplementary n-3 LC-PUFA are conflicting. Salmon is a good source of n-3 LC-PUFA, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We tested the hypothesis that an increased dietary salmon intake results in better cognitive outcomes than a meat based diet.
Methods: Children ( n = 205, age 4–6 years) in this trial were individually randomized to eating meals containing farmed Atlantic salmon or meat three times weekly for 16 weeks. Pre- and postintervention a cognitive test (Wechsler Preschool and Primary Scale of Intelligence, 3rd edition, WPPSI-III) and a fine-motor coordination test (Nine Hole Peg Test, 9-HPT) were performed. Biochemical analyses included glycerophospholipid fatty acid profiles in plasma and cheek cells, serum 25 hydroxyvitamin D, and urinary iodine concentration. Dietary intake before and during the
study were determined using food frequency questionnaires.
Results: Intakes of EPA, DHA, vitamin D and iodine were higher in the salmon than the meat group, but on biomarker level only EPA and DHA increased significantly in the salmon group compared to the meat group ( p < 0.001). In general linear models no significant differences between the intervention groups were found in the scale scores of the WPPSI-III tests and the 9-HPT. In analyses of the raw scores, the salmon group showed significantly better improvement in two of the eight raw scores compared to the meat group (symbol search p = 0.038, picture concepts p = 0.047).
Conclusions: Intake of farmed Atlantic salmon led to a greater increase of the raw scores of the picture concept and symbol search subtests, while in the six other subtests raw scores were not different between the groups. This might indicate a modest positive association of salmon intake with the performance of preschool children in some subtests evaluating fluid intelligence but does not suggest an influence on global IQ development.

Fatty fish intake and the effect on mental health and sleep in preschool children in FINS-KIDS, a randomized controlled trial

Mental health and sleep problems are prevalent in children during preschool years. The aim of the current study was to investigate if increased intake of fatty fish compared with meat improves mental health and sleep in four- to six-year-old children. The children ( n = 232) in the twoarmed randomized controlled trial, Fish Intervention Studies-KIDS (FINS-KIDS), were randomly assigned to lunch meals with fatty fish (herring/mackerel) or meat (chicken/lamb/beef) three times a week for 16 weeks. The fish and meat were weighed before and after the meals to record the exact consumption in grams (dietary compliance). Mental health problems were assessed by the strengths
and difficulties questionnaire (SDQ) and sleep by parent report pre- and post-intervention. There was no significant statistical difference between changes in mental health and sleep for the fish eating group compared with the meat eating group, neither in the crude analysis nor after adjusting for intake of fish or meat (dietary compliance).
Comments: Two nice randomized trials explored the effects on neurodevelopment (the first) and mental health and sleep problems (the second) of fatty fish (salmon and blue fish, respectively) 3 times per week, through 16 weeks each, in preschool children aged 4–6 years, in well-developed settings. The results are modest in the first case and negligible in the second, suggesting that in well-developed countries, the positive effects of n-3 LC-PUFA from natural sources in preschool years may be overcome by other factors or, alternatively, quite higher intakes should be needed for a meaningful effect.

Whole blood n-3 fatty acids are associated with executive function in 2–6-year old Northern Ghanaian children

Several studies demonstrate the importance of essential fatty acids (EFAs), and the long chain polyunsaturated FA docosahexaenoic acid (DHA), on cognition and brain development. The objective of this study was to investigate the relationship between whole-blood FAs and executive function in children from Northern Ghana. A total of 307, 2-to-6-year-old children attempted the dimensional change card sort (DCCS) task to assess executive function, and dried blood spot samples were collected and analyzed for FA content. Significant differences in mean % total whole-blood fatty acids were observed between children who could not follow directions on the DCCS test (49.8% of the sample) and those who could (50.2% of the sample). Positive associations with DCCS performance were observed for DHA (β = 0.25, p = 0.06), total n -3 (β = 0.17, p = 0.06) and dihomo-gamma-linolenic acid (DGLA; β = 0.60, p = 0.06). Children with the highest levels of total n -3 and DHA were three and four times, respectively, more likely to pass at least one condition of the DCCS test of executive function than those with the lowest DHA levels. The results of this study indicate an association between n-3
FAs and high-level cognitive processes in children two to six years of age, providing impetus for further studies into possible interventions to improve EFA status of children in developing countries.
Comments: Preliminary observational studies showing associations between blood circulating levels of major LCPUFA (DHA/total n-3 and n-6 DHGLA, respectively) in 2–6 years growing children within a developing country and executive functions, suggesting major potential effects of dietary supplemental LCPUFA in poorer settings.

Holistic Approach

Low socioeconomic status and severe obesity are linked to poor cognitive performance in Malaysian children

Socioeconomic factors and nutritional status have been associated with childhood cognitive development. However, previous Malaysian studies had been conducted with small populations and had inconsistent results. Thus, this present study aims to determine the association between socioeconomic and nutritional status with cognitive performance in a nationally representative sample of Malaysian children.
Methods: A total of 2406 Malaysian children aged 5 to 12 years, who had participated in the South East Asian Nutrition Surveys (SEANUTS), were included in this study. Cognitive performance [non-verbal intelligence quotient (IQ)] was measured using Raven’s Progressive Matrices, while socioeconomic characteristics were determined using parent-report questionnaires. Body mass index (BMI) was calculated using measured weight and height, while BMI-for-age Z-score (BAZ) and height-for-age Z-score (HAZ) were determined using WHO 2007 growth reference.
Results: Overall, about a third (35.0%) of the children had above average non-verbal IQ (high average: 110–119; superior: ≥ 120 and above), while only 12.2% were categorized as having low/borderline IQ (< 80). Children with severe obesity (BAZ > 3 SD), children from very low household income families and children whose parents had only up to primary level education had the highest prevalence of low/borderline non-verbal IQ, compared to their non-obese and higher socioeconomic counterparts. Parental lack of education was associated with low/borderline/below average IQ [paternal, OR = 2.38 (95%CI 1.22, 4.62); maternal, OR = 2.64 (95% CI 1.32, 5.30)]. Children from the lowest income group were twice as likely to have low/borderline/below average IQ [OR = 2.01 (95% CI 1.16, 3.49)]. Children with severe obesity were twice as likely to have poor non-verbal IQ than children with normal BMI [OR = 2.28 (95% CI 1.23, 4.24)].
Conclusions: Children from disadvantaged backgrounds (that is those from very low-income families and those whose parents had primary education or lower) and children with severe obesity are more likely to have poor non-verbal IQ. Further studies to investigate the social and environmental factors linked to cognitive performance will provide deeper insights into the measures that can be taken to improve the cognitive performance of Malaysian children.

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

Children aged 2 to 6 years are in a crucial period of growth development, during which it is important for them to attain specific cognition related to concentration and attention so that they can perform well in school later in life. Various factors influence children’s cognition during this crucial period. However, to date, only a limited number of studies have examined the cognitive performance of underprivileged children living in poverty, particularly indigenous children (also known as Orang Asli children in Malaysia). Therefore, this cross-sectional study aimed to determine the associations
between sociodemographic factors, nutritional factors (body composition and hemoglobin), and environmental factors (home environment and parasitic infections) with cognitive performance among Orang Asli children in Negeri Sembilan, Malaysia. The participants were 269 children (51% boys, 49% girls) aged 2 to 6 years (M = 4.0, SD = 1.2 years) and their mothers, from 14 Orang Asli villages. Face-to-face interviews were conducted with the mothers, and the children’s cognitive performance, operationalized
as working memory index (WMI), processing speed index (PSI), and cognitive proficiency index (CPI), was assessed using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV). The children’s weight and height were measured, and their blood and stool samples were collected to assess hemoglobin level and parasitic infections, respectively. Multiple linear regression analysis showed that the father’s years of education (β = 0.262–0.342, p < 0.05), availability of learning materials at home (β = 0.263–0.425, p < 0.05), and responsiveness of the parent to the child (β = 0.192–0.331, p < 0.05) were consistently associated with all three cognitive indices
(WMI, PSI, and CPI). A holistic approach involving parents, communities, and government agencies should be established to improve the cognitive performance of these underprivileged children.
Comments: These 2 observational studies from the same developing country (Malaysia) show that associations between disadvantaged social backgrounds and nutritional conditions (from anemia to obesity) are closely linked to neurodevelopmental indices in children of either preschool and school years. On a practical standpoint, all the aspects need attention when exploring children’s conditions and planning public health interventions in these settings. Furthermore, the study offers a model of holistic approach to be applied also in well-developed and rich countries, from poorer ethnic communities to the prevention of chronic degenerative disorders in the local, economically more advantaged population, as shown in other recent studies [1].

The interplay between nutrition and stress in pregnancy: implications for fetal programming of brain development

 Growing evidence supports an important role for the intrauterine environment in shaping fetal development and subsequent child health and disease risk. The fetal brain is particularly plastic, whereby even subtle changes in structure and function produced by in utero conditions can have longterm implications. Based on the consideration that conditions related to energy substrate and likelihood of survival to reproductive age are particularly salient drivers of fetal programming, maternal nutrition and stress represent the most commonly, but independently, studied factors in this context. However, the effects of maternal nutrition and stress are context dependent and may be moderated by one another. Studies examining the effects of the bidirectional nutrition-stress interplay in pregnancy on fetal programming of brain development are beginning to emerge in the literature. This review incorporates all currently available animal and human studies of this interplay and provides a synthesis and critical discussion of findings. Nine of the 10 studies included here assessed nutrition-stress interactions and offspring neurodevelopmental or brain development outcomes. Despite significant heterogeneity in study design and methodology, two broad patterns of results emerge to suggest that the effects of prenatal stress on various aspects of brain development may be mitigated by 1) higher fat diets or increased intake and/or status of specific dietary fats and 2) higher dietary intake or supplementation of targeted nutrients. The limitations of these studies are discussed, and recommendations are provided
for future research to expand on this important area of fetal programming of brain development.

You are what you (first) eat

As far back as we can remember, we eat. In fact, we eat before we can remember. Our first meal is amniotic fluid. We swallow it during the first trimester of gestation, and with that, we expose our gut to a universe of molecules. These early molecules have a profound influence on gut and brain function. For example, the taste of the amniotic fluid changes based on the mother’s diet. Indeed, recent findings suggest that food preferences begin in utero . Likewise, a baby’s first exposure to bacteria, previously thought to be during birth, appears to be in utero as well. And just as postnatal food and microbiota are implicated in brain function and dysfunction, prenatal nutrients and microbes may have a long-lasting impact on the development of the gut-brain neural circuits processing food, especially considering their plasticity during this vulnerable period. Here, we use current literature to put forward concepts needed to understand how the gut first meets the brain, and how this encounter may help us remember food.
These 2 papers have been separated from the following section on Nutrients in Pregnancy since they deal with unusual aspects, within a more holistic and comprehensive approach to nutrition. The first paper explores the possible combined effects of maternal stress and nutritional factors on fetal programming of brain function. The second paper describes the potential role of nutrients dispersed in the amniotic fluid and eaten by the fetus on an early taste imprinting or influencing the gut-brain neural circuits in the offspring by means .of the in utero exposure to bacteria affecting the development of the gut microbioma.

Nutrients IN Pregnancy

The importance of maternal folate status for brain development and function
of offspring

The importance of an adequate periconceptional maternal folate status to prevent fetal neural tube defects has been well demonstrated and resulted in the recommendation for women to use folic acid supplements during the periconception period. The importance of maternal folate status for offspring neurodevelopment and brain health is less well described. We reviewed the current evidence linking maternal folate status before conception and during pregnancy with neurodevelopment and cognition of the offspring. We discuss both animal and human studies. Preclinical research revealed the importance of maternal folate status for several key processes required for normal neurodevelopment and brain functioning in the offspring, including DNA synthesis, regulation of gene expression, synthesis of phospholipids and neurotransmitters, and maintenance of healthy plasma homocysteine concentrations. Human observational studies are inconclusive; about half have shown a positive association between maternal folate status and cognitive performance of offspring. Whereas some studies suggest a positive association between maternal folate intake and cognition of offspring during childhood, data from interventional studies are too limited to conclude that there is a direct effect. Future preclinical studies are needed to help us characterize the behavioral effects, understand the underlying mechanisms, and to establish an optimal dosage and time window of folate supplementation. Moreover, more conclusive data from well-designed human observational studies and randomized
controlled trials are needed to determine whether current recommendations for folic acid supplementation during pregnancy cover the needs for normal cognitive development in the offspring.

Prenatal air pollution and childhood IQ: Preliminary evidence of effect modification by folate

 Animal studies suggest that air pollution is neurotoxic to a developing fetus, but evidence in humans is limited. We tested the hypothesis that higher air pollution is associated with lower child IQ and that effects vary by maternal and child characteristics, including prenatal nutrition.
Methods: We used prospective data collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study. Outdoor pollutant exposure during pregnancy was predicted at geocoded home addresses using a validated national universal kriging model that combines ground-based monitoring data with an extensive database of land-use covariates. Distance to nearest major roadway was also used as a proxy for traffic-related pollution. Our primary outcome was full-scale IQ measured at age 4–6. In regression models, we adjusted for multiple determinants
of child neurodevelopment and assessed interactions between air pollutants and child
sex, race, socioeconomic status, reported nutrition, and maternal plasma folate in second trimester.
Results: In our analytic sample ( n = 1,005) full-scale IQ averaged 2.5 points (95% CI: 0.1, 4.8) lower per 5 μg/m 3 higher prenatal PM 10 , while no associations with nitrogen dioxide or road proximity were observed. Associations between PM 10 and IQ were modified by maternal plasma folate (p interaction = 0.07). In the lowest folate quartile, IQ decreased 6.8 points (95% CI: 1.4, 12.3) per 5-unit increase in PM 10 ; no associations were observed in higher quartiles.
Conclusions: Our findings strengthen evidence that air pollution impairs fetal neurodevelopment and suggest a potentially important role of maternal folate in modifying these effects.

Maternal iodine status is associated with offspring language skills in infancy and toddlerhood

Inadequate iodine status affects the synthesis of the thyroid hormones and may impair brain development in fetal life. The aim of this study was to explore the association between maternal iodine status in pregnancy measured by urinary iodine concentration (UIC) and child neurodevelopment at age 6, 12 and 18 months in a population-based cohort. In total, 1036 families from nine locations in Norway were enrolled in the little in Norway cohort. The present study includes n = 851 mother-child
pairs with singleton pregnancies, no use of thyroid medication in pregnancy, no severe genetic disorder, data on exposure (UIC) in pregnancy and developmental outcomes (Bayley Scales of Infant and Toddler Development, third edition). Data collection also included general information from questionnaires. We examined associations between UIC (and use of iodine-containing supplements) and repeated measures of developmental outcomes using multivariable mixed models. The median UIC
in pregnancy was 78 μg/L (IQR 46–130), classified as insufficient iodine intake according to the WHO. Eighteen percent reported use of iodine-containing multisupplements. A UIC below ∼ 100 was associated with reduced receptive ( p = 0.025) and expressive language skills (p = 0.002), but not with reduced cognitive or fine- and gross motor skills. Maternal use of iodine-containing supplements was associated with lower gross motor skills (b = − 0.18, 95% CI = − 0.33, − 0.03, p = 0.02), but not with the other outcome measures. In conclusion, an insufficient iodine intake in pregnancy, reflected in a UIC below ∼ 100 μg/L, was associated with lower infant language skills up to 18 months. The use of iodine-containing supplements was not associated with beneficial effects.

Association of maternal iodine status with child IQ: a meta-analysis of individual-participant data

 While the consequences of severe iodine deficiency are beyond doubt, the effects of mildto-moderate iodine deficiency in pregnancy on child neurodevelopment are less well established.
Objective: To study the association between maternal iodine status during pregnancy and child IQ
and to identify vulnerable time-windows of exposure to suboptimal iodine availability.
Design: Meta-analysis of individual-participant data from three prospective population-based birth cohorts: Generation R (The Netherlands), INMA (Spain), and ALSPAC (United Kingdom); pregnant women were enrolled between 2002–2006, 2003–2008, and 1990–1992, respectively. Setting: General community.
Participants: 6,180 mother-child pairs with measures of urinary iodine and creatinine concentrations in pregnancy and child IQ. Exclusion criteria were multiple pregnancy, fertility treatment, medication affecting the thyroid, and pre-existing thyroid disease.
Intervention(s): none. Main Outcome Measure: Child non-verbal and verbal IQ assessed at 1.5–8 years of age.
Results: There was a positive curvilinear association of the urinary iodine-to-creatinine ratio (UI/Creat) with mean verbal IQ only. UI/Creat < 150 μg/g was not associated with lower non-verbal IQ [–0.6 points, 95% CI –1.7 to 0.4, p = 0.246] or lower verbal IQ [–0.6, 95% CI –1.3 to 0.1, p = 0.082]. Stratified analyses showed that the association of UI/Creat with verbal IQ was only present up to 14 weeks of gestation.
Conclusions: Fetal brain development is vulnerable to mild-to-moderate iodine deficiency, particularly in the first trimester. Our results show that any potential randomized, controlled trial investigating the effect of iodine supplementation in mild-to-moderate iodine deficient women on child neurodevelopment, should start with supplementation not later than the first trimester.

Maternal dietary intake of polyunsaturated fatty acids modifies association between prenatal DDT exposure and child neurodevelopment: A cohort study

Objectives: To assess whether maternal dietary intake of ω-3 and ω-6 during pregnancy modifies the association between exposure to DDE and child neurodevelopment from age 42–60 months.
Methods: Prospective cohort study with 142 mother–child pairs performed in Mexico. DDE serum levels were determined by electron capture gas chromatography. Dietary ω-3 and ω-6 intake was estimated by questionnaire. Child neurodevelopment was assessed by McCarthy Scales.
Results: Docosahexaenoic (DHA) fatty acid intake significantly modified the association between DDE and motor component: increased maternal DDE was associated with lower motor development in children whose mothers had lower DHA intake (β log2DDE = –1.25; 95% CI: –2.62, 0.12), in contrast to the non-significant increase among children whose mothers had higher DHA intake (β log2DDE-motor = 0.50; 95% CI: 0.55, 1.56). Likewise, arachidonic fatty acid (ARA) intake modified the association between DDE and memory component: increased maternal DDE was associated with a significantly larger reduction in the memory component in children whose mothers had lower ARA intake (β log2DDE = –1.31; 95% CI: –2.29, –0.32) than children whose mothers had higher
ARA intake (β log2DDE-memory = 0.17; 95% CI: − 0.78, 1.11).
Conclusions: Dietary intake of DHA and ARA during pregnancy may protect against child neurodevelopment damage associated with prenatal maternal DDE levels.

The impact of docosahexaenoic acid supplementation during pregnancy and lactation on neurodevelopment of the offspring in India (DHANI): trial protocol

 Evidence suggests a strong association between nutrition during the first 1,000 days (conception to 2 years of life) and cognitive development. Maternal docosahexaenoic acid (DHA) supplementation has been suggested to be linked with cognitive development of their offspring. DHA is a structural component of human brain and retina, and can be derived from marine algae, fatty fish and marine oils. Since Indian diets are largely devoid of such products, plasma DHA levels are low. We are testing the effect of pre- and post-natal DHA maternal supplementation in India on infant motor and mental development, anthropometry and morbidity patterns.
Methods: DHANI is a double-blinded, parallel group, randomized, placebo controlled trial supplementing 957 pregnant women aged 18–35 years from ≤ 20 weeks gestation through 6 months postpartum with 400 mg/d algal-derived DHA or placebo. Data on the participant’s socio-demographic profile, anthropometric measurements and dietary intake are being recorded at baseline. The motherinfant dyads are followed through age 12 months. The primary outcome variable is infant motor and mental development quotient at 12 months of age evaluated by Development Assessment Scale in Indian Infants (DASII). Secondary outcomes are gestational age, APGAR scores, and infant anthropometry. Biochemical indices (blood and breast-milk) from mother-child dyads are being collected to estimate changes in DHA levels in response to supplementation. All analyses will follow the intent-totreat principle. Two-sample t test will be used to test unadjusted difference in mean DASII score between placebo and DHA group. Adjusted analyses will be performed using multiple linear regression.
Discussion: Implications for maternal and child health and nutrition in India: DHANI is the first large pre- and post-natal maternal dietary supplementation trial in India. If the trial finds substantial benefit, it can serve as a learning to scale up the DHA intervention in the country.

Associations between vitamin D status in pregnancy and offspring neurodevelopment: a systematic literature review

Vitamin D plays an important role in the development of the brain, which is one of the earliest fetal organs to develop. Results from epidemiological studies investigating associations between maternal levels of vitamin D during pregnancy and offspring neurodevelopment are mixed and inconclusive.
Objective: This systematic review of studies that examined vitamin D levels in pregnancy and offspring neurodevelopment used 3 specific domains-timing of exposure during pregnancy trimesters, neurodevelopmental outcomes, and offspring age at assessment of outcomes-to determine whether vitamin D status in pregnancy is associated with offspring neurodevelopment.
Data Source: A search of the Embase, PsychInfo, Scopus, and The Cochrane Library databases in September 2017 and February 2018 identified 844 articles, of which 46 were retrieved for full-text assessment.
Study Selection: Eligibility criteria were used to select studies. All authors examined the studies, and consensus was reached through discussion. Results were divided according to the 3 domains
Data Extraction: Authors examined the studies independently, and data from eligible studies were extracted using a modified version of the Cochrane data collection form. Using the modified Downs and Black checklist, 2 authors assessed the quality of the studies independently and were blinded to each other’s assessment. Consensus was reached upon discussion and with the involvement of the third author.
Results: Fifteen observational studies were included. Vitamin D in pregnancy was associated with offspring language and motor skills in young children. Associations persisted into adolescence, and results were not dependent on the timing of vitamin D exposure during pregnancy. No supplementation studies were identified.
Conclusions: There is some evidence that low vitamin D status in pregnancy is associated with offspring language and motor development, particularly in young children.

Maternal selenium status and neuropsychological development in Spanish preschool children

The relationship between maternal selenium (Se) status and child neurodevelopment has been scarcely assessed. In a previous study we observed an inverse U-shaped association between maternal Se concentrations and infant neurodevelopment at 12 months of age. In this study, this non-linear association was explored at preschool age. The effect modification by breastfeeding, child’s sex and cord blood mercury was also evaluated.
Methods: Study subjects were 490 mother-child pairs from the Spanish Childhood and Environment Project (INMA, 2003–2012). Child neuropsychological development was assessed at around 5 years of age by the McCarthy Scales of Children’s Abilities (MSCA). Sociodemographic and dietary characteristics were collected by questionnaire at the first and third trimester of gestation and at 5 years of age. Se was measured in serum samples by ICP-MS at the end of the first trimester of pregnancy (mean ± standard deviation (SD) = 12.4 ± 0.6 weeks of gestation).
Results: The mean ± SD of maternal serum Se concentrations was 79.9 ± 8.1 μg/L. In multivariate analysis, no linear association was found between Se concentrations and the nine MSCA scales. Generalized additive models indicated inverted U-shaped relationships between Se concentrations and the verbal and global memory scales. When assessing the influence of effect modifiers, breastfeeding played a role: the association between Se and neuropsychological development was inverted U-shaped for the quantitative, general cognitive, working memory, fine motor, global motor and
executive function scales only for non-breastfed children.
Conclusion: Low and high maternal Se concentrations seem to be harmful for child neuropsychological development, however further studies should explore this non-linear relationship.

Prenatal selenium status, neonatal cerebellum measures and child neurodevelopment at the age of 18 months

The aim of this study was to evaluate the association of maternal blood selenium (Se) levels and cord blood Se levels with neonatal cerebellum measures and child neurodevelopment at the age of 18 months. Moreover, to investigate whether the neonatal cerebellum measures could be used as a potential biomarker for selenium homeostasis during pregnancy. Study Group and Methods: The study population consisted of 205 mother-child pairs from Croatian Mother and Child Cohort. Maternal blood and cord blood were obtained at delivery and selenium level was analyzed by Inductively Coupled Plasma Mass Spectrometry. Cranial ultrasonography examination was performed on 49 newborns – cerebellum length and width have been measured. Neurodevelopmental assessment of cognitive, language and motor skills were conducted on 154 children, using The Bayley Scales of Infant and Toddler Development, Third Edition (BSIDIII), at the age of 18 months.
Results: The mean levels of selenium in maternal blood and cord blood were 92.6 ng/g and 97.0 ng/g, respectively. Maternal blood selenium levels were moderately and negatively correlated ( r = –0.372; p = 0.008) with cerebellum length, while cord blood selenium levels were positively correlated with cerebellum width ( r = 0.613; p = 0.007) among female children group. Maternal blood selenium levels were weakly and positively correlated ( r = 0.176; p = 0.029) with child’s cognitive abilities.
Conclusions: To the best of our knowledge, our study is the first one investigating the association between neonatal brain measures and selenium levels in mother-child pairs. Our results indicate that prenatal selenium intake correlated with cerebellum length and width measured by cranial ultrasonography. Hence, cerebellum may be used as a potential biomarker and a target “organ” for early detection of possible adverse effects of prenatal status to various micronutrients.

Maternal copper status and neuropsychological development in infants and
preschool children

Introduction: Copper (Cu) is an essential element involved in biological processes; however, excessive Cu could be harmful because of its reactive nature. Very few studies have evaluated its potential neurotoxic effects. We aimed to evaluate the association between maternal Cu levels and children’s neuropsychological development.
Methods: Study subjects were mother-child pairs from the Spanish INMA (i.e. Childhood and Environment) Project. Cu was measured by inductively coupled plasma mass spectrometry in serum samples taken at the first trimester of pregnancy (2003–2005). Neuropsychological development was assessed using the Bayley Scales of Infant Development (BSID) at 12 months ( n = 651) and the McCarthy Scales of Children’s Abilities (MSCA) at 5 years of age ( n = 490). Covariates were obtained by questionnaires during pregnancy and childhood. Multivariate linear and non-linear models were built in order to study the association between maternal Cu and child neuropsychological development.
Results: The mean ± standard deviation of maternal Cu concentrations was 1,606 ± 272 μg/L. In the multivariate analysis, a negative linear association was found between maternal Cu concentrations and both the BSID mental scale (beta = –0.051; 95% confidence intervals [CI]: –0.102, –0.001) and the MSCA verbal scale (beta = –0.044; 95% CI: –0.094, 0.006). Boys obtained poorer scores than girls, with increasing Cu at 12 months (interaction p value = 0.040 for the mental scale and 0.074 for the psychomotor scale). This effect modification disappeared at 5 years of age. The association
between Cu and the MSCA scores (verbal, perceptive performance, global memory and motor, general cognitive, and executive function scales) was negative for those children with lowest maternal iron concentrations (< 938 μg/L).
Conclusion: The Cu concentrations observed in our study were within the reference range established for healthy pregnant women in previous studies. The results of this study contribute to the body of scientific knowledge with important information on the possible neurotoxic capability of Cu during pregnancy.
We have selected 10 studies on hundreds of mother–child pairs focusing on the levels of specific micronutrients in pregnancy (from the first trimester onward) and neurodevelopmental outcomes at short, medium, and longer term. Most studies are observational, with a few systematic reviews, and just one RCT as protocol. The nutrients involved are mostly expected, that is, folate, iodine, LC-PUFA (inclusive of the RCT protocol from a developing country, India), selenium (2 studies per each element, respectively), and 2 reports concerning vitamin D and copper, respectively. We hereby describe the main findings per micronutrient. 
Folate: Data suggest a positive link between sufficient maternal folate status and offspring cognitive function, but there is still insufficient support from human interventional studies to draw harsh conclusions. The effects of folate intakes higher than recommended remain to be clarified. The neuroprotective role of folate is furthermore
suggested by the observation that maternal folate may modify the negative effects of
air pollution at 4–6 years of age.
Iodine: Fetal brain development is vulnerable to mild-to-moderate iodine deficiency,
particularly in the first trimester, and an insufficient iodine intake in pregnancy is associated with lower infant language skills up to 18 months. Any RCT with iodine supplementation should start not later than the first trimester.
LC-PUFA: a neuroprotective effect, similar to that described for folate, has been shown
at 42–60 months for dietary intake of DHA and ARA during pregnancy and child neurodevelopment impairment associated with prenatal maternal DDE levels. An interesting RCT study protocol of DHA supplementation from ≤ 20 weeks gestation through 6 months postpartum with 400 mg/day algal-derived DHA or placebo comes from India, and the results will be very valuable to look at any effect in a transition country.
Vitamin D: A systematic review shows that low vitamin D levels, as early as the second
trimester of pregnancy, may be related to adverse effects on language skills and motor
development between 1 and 5 years of age. Associations may persist up to adolescence. We lack data from large, well-conducted RCT trials on the effects of vitamin D in pregnancy on offspring neurodevelopment and (even from observational studies) on associations with above-normal vitamin D levels in pregnancy.
Selenium: Lowest and highest maternal serum levels at the end of the first trimester
of pregnancy have been associated with a less favorable neuropsychological development at 5 years but only in non-breastfed children. An association has been described between selenium in maternal blood and cord and neonatal cerebellum length and width at 1–3 days (cranial ultrasonography).
Copper: Higher maternal levels at 3 months pregnancy have been associated with
lower scores at developmental scales at 1 and 5 years, thus suggesting a potential
neurotoxicity of copper, possibly connected with its chemically reactive nature.
On the whole, this huge set of data shows an increasing interest in the field of the effects
of micronutrients intake and/or status in pregnancy and neurodevelopmental aspects in the offspring, waiting for more results from large randomized trials, particularly
from developing and transition countries.