Zinc intake-status-health relationships and the impact of multiple micronutrient supplementation on cognitive function in Peruvian pre-school children.

Background: Dietary zinc recommendations vary widely across Europe. The EURRECA (European Micronutrient Recommendations Aligned) Network of Excellence was brought together to harmonise the approach to setting micronutrient recommendations. The overall aim was to produce a set of guidelines and an extensive database that may be of use to expert panels in underpinning future micronutrient recommendations, based on a series of systematic reviews and meta-analysis of published data. A secondary aim was to identify gaps in knowledge regarding micronutrient status, intake and health outcomes for future research. A third aim, coming from the result of the secondary aim, was to investigate the long term effect of supplementation on cognition. Objectives: The objectives of this thesis were: (1) To adapt the methodology for undertaking a systematic review and meta-analysis developed by EURRECA for zinc in all population groups (infants, children, adolescents, pregnant and lactating women and adults and elderly). (2) To identify knowledge gaps in the research through the assessment of the interrelationships between zinc intake, status and health outcomes. (3) To design and implement a study to explore the intake-status-health relationships between micronutrient supplementation and cognitive function in Peruvian children. Methods: Phase 1: The EURRECA systematic review. Database searches were conducted in MEDLINE, Embase and the Cochrane library, from inception to March 2014. For the assessment of the intake-status relationship, an intake-status regression coefficient (^) was estimated for each individual study and the overall pooled ^ and SE ^ was calculated using random effect meta-analysis on a double log scale. The systematic review included randomized controlled trials, cohort studies, cross sectional studies and nested case-control studies in healthy children and adult populations that measured zinc intake (diet and supplements) and zinc status (serum/plasma zinc) in association health outcomes that included cognitive function and psychomotor development. Phase 2: Empirical study. This included the assessment of multiple micronutrients (MMN) supplementation and cognitive development in Peruvian children when compared with giving iron supplements alone. These tests were considered to reflect theoretical dimensions of working memory (Nine boxes), and inhibitory control (Day/Night stroop task). Intelligence Quotient (IQ) was measured using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI); social-emotional behaviour was assessed via the Brief Infant–Toddler Social and Emotional Assessment (BITSEA) and reasoning through the theory of mind test. Results: Meta-analysis of data reporting zinc intake and status revealed that doubling intake increased plasma zinc concentration by 9% in children, by 3% during pregnancy, by 1% during lactation and by 6% in adults and elderly. The systematic review of zinc and health outcomes highlighted the need for further research on the relationship between micronutrients and cognitive function. The empirical study was therefore designed and undertaken. The results revealed that there were no significant differences between the iron and the MMN supplemented groups for all cognitive tests, with the exception of the vocabulary WPPSI subtest in girls (mean±SD), (MMN, 6.83±2.05; iron 5.78±1.59, p = 0.028) and no significant differences were found for plasma zinc and haemoglobin concentrations between the two groups. Conclusions: The systematic reviews provided novel dose-response estimates between zinc intake-status that could be used either qualitatively or quantitatively with balance studies when setting future zinc recommendations. Following an assessment of the impact of micronutrient supplementation on cognitive and social-emotional development in Peruvian preschool children, it can be concluded that MMN supplements had no long term additional effects on cognitive function compared with iron alone, however the timing of the supplement for maximal potential benefit needs to be explored further

The Long Term Impact of Micronutrient Supplementation during Infancy on Cognition and Executive Function Performance in Pre-School Children

Brain growth and development are critically dependent on several micronutrients. During early development cellular activity may be sensitive to micronutrient deficiencies, however the evidence from human studies is equivocal. The objective of this study was to examine the long-term cognitive and social-emotional effects of multiple micronutrient supplementation compared with iron supplementation alone, administered during infancy. This study was a follow-up to an initial randomized, double-blind controlled trial (RCT) in 2010 in which 902 infants, aged 6-17 months, from Lima, Peru, were given daily supplements of either iron (Fe) or multiple micronutrients (MMN) including zinc (451 in each group). The supplementation period for both groups was six months. In 2012, a subsample of 184 children from the original cohort (now aged 36-48 months) was randomly selected to participate in a follow-up trial and was assessed for intelligence, working memory, inhibition, and executive function. The tests showed no significant differences between the supplementation groups though there were some gender differences, with girls displaying higher scores than boys across both groups on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) Verbal IQ sentences subtest, the Day-Night cognitive test and on the Brief Infant-Toddler Social Emotional Assessment (BITSEA) social competency, and boys scoring higher than girls in problem behaviour. The results indicate that MMN supplementation had no long term additional effects on cognitive function compared with iron supplementation alone. The timing of supplement administration for maximum impact on a child's cognitive development requires further investigation

The relationship between zinc intake and serum/plasma zinc concentration in adults: a systematic review and dose–response meta-analysis by the EURRECA Network

Dietary zinc recommendations vary widely across Europe due to the heterogeneity of pproaches used by expert panels. Under the EURRECA consortium a protocol was designed to systematically review and undertake meta-analyses of research data to create a database that includes “best practice” guidelines which can be used as a resource by future panels when setting micronutrient recommendations. As part of this process, the objective of the present study was to undertake a systematic review and meta-analysis of previously published data describing the relationship between zinc intake and status in adults. Searches were performed of literature published up to February 2010 using MEDLINE, Embase, and Cochrane Library. Data extracted included population characteristics, dose of zinc, duration of study, dietary intake of zinc, and mean concentration of zinc in plasma or serum at the end of the intervention period. An intake-status regression coefficient was estimated for each individual study, and pooled meta-analysis undertaken. The overall pooled for zinc supplementation on serum/plasma zinc concentrations from RCTs and observational studies was 0.08 (95% CI 0.05, 0.11; p<0.0001; I2 84.5%). An overall of 0.08 means that for every doubling in zinc intake, the difference in zinc serum or plasma concentration is (20.08 = 1.06), which is 6%. Whether the dose-response relationship, as provided in this paper, could be used as either qualitative or quantitative evidence to substantiate the daily zinc intake dose necessary to achieve normal or optimal levels of biomarkers for zinc status, remains a matter of discussion

The relationship between zinc intake and growth in children aged 1-8 years: a systematic review and meta-analysis

BACKGROUND/OBJECTIVES: It is estimated that zinc deficiency affects 17% of the world's population, and because of periods of rapid growth children are at an increased risk of deficiency, which may lead to stunting. This paper presents a systematic review and meta-analysis of the randomised controlled trials (RCTs) that assess zinc intake and growth in children aged 1–8 years. This review is part of a larger systematic review by the European Micronutrient Recommendations Aligned Network of Excellence that aims to harmonise the approach to setting micronutrient requirements for optimal health in European populations (www.eurreca.org). SUBJECT/METHODS: Searches were performed of literature published up to and including December 2013 using MEDLINE, Embase and the Cochrane Library databases. Included studies were RCTs in apparently healthy child populations aged from 1 to 8 years that supplied zinc supplements either as capsules or as part of a fortified meal. Pooled meta-analyses were performed when appropriate. RESULTS: Nine studies met the inclusion criteria. We found no significant effect of zinc supplementation of between 2 weeks and 12 months duration on weight gain, height for age, weight for age, length for age, weight for height (WHZ) or WHZ scores in children aged 1–8 years. CONCLUSIONS: Many of the children in the included studies were already stunted and may have been suffering from multiple micronutrient deficiencies, and therefore zinc supplementation alone may have only a limited effect on growth

Effect of zinc intake on growth in infants: A meta-analysis

A systematic review and meta-analysis of available randomized controlled trials (RCTs) was conducted to evaluate the effect of zinc (Zn) intake on growth in infants. Out of 5500 studies identified through electronic searches and reference lists, 19 RCTs were selected after applying the exclusion/inclusion criteria. The influence of Zn intake on growth was considered in the overall meta-analysis. Other variables were also taken into account as possible effect modifiers: doses of Zn intake, intervention duration, nutritional status, and risk of bias. From each select growth study, final measures of weight, length, mid upper arm circumference (MUAC), head circumference, weight for age z-score (WAZ), length for age z-score (LAZ), and weight for length z-score (WLZ) were assessed. Pooled β and 95% confidence interval (CI) were calculated. Additionally, we carried out a sensitivity analysis. Zn intake was not associated with weight, length, MUAC, head circumference, and LAZ in the pooled analyses. However, Zn intake had a positive and statistically effect on WAZ (β = 0.06; 95%CI 0.02 to 0.10) and WLZ (β = 0.05; 95%CI 0.01 to 0.08). The dose–response relationship between Zn intake and these parameters indicated that a doubling of Zn intake increased WAZ and WLZ by approximately 4%. Substantial heterogeneity was present only in length analyses (I2 = 45%; p = 0.03). Zn intake was positively associated with length values at short time (four to 20 weeks) (β = 0.01; CI 95% 0 to 0.02) and at medium doses of Zn (4.1 to 8 mg/day) (β = 0.003; CI 95% 0 to 0.01). Nevertheless, the effect magnitude was small. Our results indicate that Zn intake increases growth parameters of infants. Nonetheless, interpretation of these results should be carefully considered

Dietary zinc intake and whole blood zinc concentration in subjects with type 2 diabetes versus healthy subjects: A systematic review, meta-analysis and meta-regression

The aim of this systematic review, meta-analysis and meta-regression was to examine the relationship between type 2 diabetes mellitus (T2DM) and concentration of zinc in whole blood, as well as dietary zinc intake. Searches were performed using Ovid MEDLINE, Embase (Ovid) and The Cochrane Library (CENTRAL). Observational studies conducted on diabetic and healthy adults, with data on dietary zinc intake and/or concentration of zinc in whole blood, were selected. The search strategy yielded 11,150 publications and the manual search 6, of which 11 were included in the meta-analyses. Mean difference (MD) and 95% confidence interval (CI), were calculated using the generic inverse-variance method with random-effects models. Heterogeneity was assessed by the Cochran Q-statistic and quantified by the I2 statistic. Meta-regressions and stratified analysis were used to examine whether any covariate had influence on the results. The pooled MD for the dietary zinc intake meta-analysis was −0.40 (95% CI: −1.59 to 0.79; I2 = 61.0%). Differences between diabetic and non-diabetic subjects became significant in the presence of complications associated with diabetes (MD = −2.26; 95% CI: −3.49 to −1.02; I2 = 11.9%). Meta-regression showed that for each year since the diagnosis of diabetes the concentration of zinc in whole blood decreased in diabetic patients regarding healthy controls [MD (concentration of zinc in blood) = 732.61 + (−77.88303) × (duration of diabetes in years)], which is not generally explained by a lower intake of zinc

Zinc Intake and Status and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

Zinc could have a protective role against type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis aimed to evaluate the association between dietary, supplementary, and total zinc intake, as well as serum/plasma and whole blood zinc concentration, and risk of T2DM. Observational studies, conducted on cases of incident diabetes or T2DM patients and healthy subjects that reported a measure of association between zinc exposure and T2DM, were selected. Random effects meta-analyses were applied to obtain combined results. Stratified meta-analyses and meta-regressions were executed to assess sources of heterogeneity, as well as the impact of covariates on the findings. From 12,136 publications, 16 studies were selected. The odds ratio (OR) for T2DM comparing the highest versus lowest zinc intake from diet was 0.87 (95% CI: 0.78–0.98). Nevertheless, no association between supplementary or total zinc intake from both diet and supplementation, and T2DM was observed. A direct relationship was found between serum/plasma zinc levels and T2DM (OR = 1.64, 95% CI: 1.25–2.14). A moderately high dietary zinc intake, in relation to the Dietary Reference Intake, could reduce by 13% the risk of T2DM, and up to 41% in rural areas. Conversely, elevated serum/plasma zinc concentration was associated with an increased risk of T2DM by 64%, suggesting disturbances in zinc homeostasis

The Relationship between Zinc Intake and Serum/Plasma Zinc Concentration in Children: A Systematic Review and Dose-Response Meta-Analysis

Recommendations for zinc intake during childhood vary widely across Europe. The EURRECA project attempts to consolidate the basis for the definition of micronutrient requirements, taking into account relationships among intake, status and health outcomes, in order to harmonise these recommendations. Data on zinc intake and biomarkers of zinc status reported in randomised controlled trials (RCTs) can provide estimates of dose-response relationships which may be used for underpinning zinc reference values. This systematic review included all RCTs of apparently healthy children aged 1–17 years published by February 2010 which provided data on zinc intake and biomarkers of zinc status. An intake-status regression coefficient was calculated for each individual study and calculated the overall pooled and SE using random effects meta-analysis on a double log scale. The pooled dose-response relationship between zinc intake and zinc status indicated that a doubling of the zinc intake increased the serum/plasma zinc status by 9%. This evidence can be utilised, together with currently used balance studies and repletion/depletion studies, when setting zinc recommendations as a basis for nutrition policies

Review Article Socio-economic determinants of micronutrient intake and status in Europe: a systematic review

Objective To provide the evidence base for targeted nutrition policies to reduce the risk of micronutrient/diet-related diseases among disadvantaged populations in Europe, by focusing on: folate, vitamin B-12, Fe, Zn and iodine for intake and status; and vitamin C, vitamin D, Ca, Se and Cu for intake. Design MEDLINE and Embase databases were searched to collect original studies that: (i) were published from 1990 to 2011; (ii) involved gt 100 subjects; (iii) had assessed dietary intake at the individual level; and/or (iv) included best practice biomarkers reflecting micronutrient status. We estimated relative differences in mean micronutrient intake and/or status between the lowest and highest socio-economic groups to: (i) evaluate variation in intake and status between socio-economic groups; and (ii) report on data availability. Setting Europe. Subjects Children, adults and elderly. Results Data from eighteen publications originating primarily from Western Europe showed that there is a positive association between indicators of socio-economic status and micronutrient intake and/or status. The largest differences were observed for intake of vitamin C in eleven out of twelve studies (5-47 %) and for vitamin D in total of four studies (4-31 %). Conclusions The positive association observed between micronutrient intake and socio-economic status should complement existing evidence on socio-economic inequalities in diet-related diseases among disadvantaged populations in Europe. These findings could provide clues for further research and have implications for public health policy aimed at improving the intake of micronutrients and diet-related diseases

Micronutrient intake and status in Central and Eastern Europe compared with other European countries, results from the EURRECA network

Objective: To compare micronutrient intakes and status in Central and Eastern Europe (CEE) with those in other European countries and with reference values. Design: Review of the micronutrient intake/status data from open access and grey literature sources from CEE. Setting: Micronutrients studied were folate, iodine, Fe, vitamin B-12 and Zn (for intake and status) and Ca, Cu, Se, vitamin C and vitamin D (for intake). Intake data were based on validated dietary assessment methods; mean intakes were compared with average nutrient requirements set by the Nordic countries or the US Institute of Medicine. Nutritional status was assessed using the status biomarkers and cut-off levels recommended primarily by the WHO. Subjects: For all population groups in CEE, the mean intake and mean/median status levels were compared between countries and regions: CEE, Scandinavia, Western Europe and Mediterranean. Results: Mean micronutrient intakes of adults in the CEE region were in the same range as those from other European regions, with exception of Ca (lower in CEE). CEE children and adolescents had poorer iodine status, and intakes of Ca, folate and vitamin D were below the reference values. Conclusions: CEE countries are lacking comparable studies on micronutrient intake/status across all age ranges, especially in children. Available evidence showed no differences in micronutrient intake/status in CEE populations in comparison with other European regions, except for Ca intake in adults and iodine and Fe status in children. The identified knowledge gaps urge further research on micronutrient intake/status of CEE populations to make a basis for evidence-based nutrition policy