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Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youths: A Placebo-Controlled Randomized Clinical Trial.
Johnstone, JM, Hatsu, I, Tost, G, Srikanth, P, Eiterman, LP, Bruton, AM, Ast, HK, Robinette, LM, Stern, MM, Millington, EG, et al
Journal of the American Academy of Child and Adolescent Psychiatry. 2022;61(5):647-661
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Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that affects about 5-7% of children. Characteristics of ADHD are age-inappropriate hyperactivity, impulsivity, and difficulties in focusing attention which arise from an impaired ability to regulate executive and emotional functions. The condition often persists into adulthood, where it presents an increased risk for poor educational achievements, substance abuse, incarceration, and mental health problems. In many cases, drug treatment can improve ADHD symptoms, yet concern remains about the side effects of these treatments. Some research has investigated the impact of nutrient supplementation on ADHD management, as many nutrients are essential for healthy brain function and are also involved in the production of neurotransmitters. In previous studies, supplementation with nutrients has shown some benefits but likewise also inconsistent results. This eight-week randomised placebo-controlled clinical trial evaluated the effects of a multi-nutrient supplement in 135 children with ADHD, aged 6-12 years. The study specifically focused on irritable mood symptoms. The multi-nutrient formula contained vitamins, minerals, amino acids, and antioxidants. Outcomes were measured by scores rated by clinicians (Clinical Global Impression-Improvement aka CGI-I) and scores rated by parents (Child and Adolescent Symptom Inventory-5 aka CASI-5). The multi-nutrient formula showed overall benefit in the blinded clinician rating but not by parental reports. According to the parents, overall improvement was reported, both in the placebo and intervention groups. The authors discussed how this absence of difference can be explained. Yet, on a subscale, the multi-nutrient group parents were more likely to report improvements. In addition, children with the additional micronutrients demonstrated greater height growth during the intervention. The supplement was well tolerated with good adherence and the monitored blood markers demonstrated safety of use.
Expert Review
Conflicts of interest:
None
Take Home Message:
This fully-blinded RCT of micronutrients addresses several concerns related to existing ADHD treatment, including the possibility of counteracting height suppression and treating associated irritable mood, emotional dysregulation, and aggression.
Although further research is needed, multinutrient supplementation should be considered for children with ADHD.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
Attention-deficit hyperactivity disorder (ADHD) is a common psychiatric condition that can result in low educational performance and achievement. Around 5-7% of children are believed to be affected. Alongside inattention and hyperactivity, emotional dysregulation is a common feature of ADHD. Psychiatric problems can continue into adulthood and an increased risk of incarceration and substance abuse have been reported.
Treatment with prescription medications may improve symptoms of ADHD, however, potential side effects include mild growth suppression, and mood and emotional dysregulation. Non-pharmacological treatments are therefore being investigated.
Previous research on single nutrients have shown mixed results for emotional dysregulation and mood issues in ADHD. The aim of this study was to test whether supplementation with a multi-nutrient could be beneficial to children aged 6-12 years with ADHD and irritability.
Methods
126 unmedicated children from North America with ADHD (mean age 9.8 years) completed this 8-week study. All participants had at least 1 symptom of anger, irritability, peer conflict or Disruptive Mood Dysregulation Disorder (DMDD).
Randomisation was into an intervention (n=71) or placebo (N=55) group with a 3:2 ratio to promote enrolment. Participants were required to take 6-12 capsules daily, depending on age and tolerance, of micronutrients or a placebo. Micronutrient dosages were above the recommended dietary allowance (RDA). Outcomes were measured using clinician and parent rated assessments and by a further adult who knew the child well.
The trial was blinded to all participants, parents and study staff.
Results
The clinician-rated results found 54% of the micronutrient group and 18% of the placebo group had improvements in irritability symptoms (Risk ratio =2.97, 97.5% CI: 1.5, 5.90, p<0.001). This was not replicated in the parent/adult rated results. Children in the micronutrient group grew on average 6mm more than the placebo group (p=0.002). No serious adverse treatment effects were reported. Adherence to protocol was met by >74% of participants (n=93).
Conclusions
In this study, clinicians reported that micronutrients showed greater benefits than placebo for treating irritability and supporting growth in children with ADHD.
The study and authors received funding from several research and association bodies. However, no funder was involved in the study design or reporting. No conflicts of interest were declared.
Clinical practice applications:
- Multinutrient supplementation including vitamins, minerals, amino acids, and antioxidants may support height growth in children who take pharmacologic treatment
- Multi nutrient supplementation may also help with irritable mood, emotional dysregulation, and aggression in ADHD children
- Micronutrients given at doses between the Recommended Dietary Allowance and Upper Tolerable Intake Level appear safe and may be developed into an alternative or complementary treatment for ADHD.
Considerations for future research:
- Further large scale research is needed into the potential benefits of micronutrients for children with ADHD and irritability
Abstract
OBJECTIVE To evaluate whether micronutrients (vitamins/minerals) benefit attention-deficit/hyperactivity disorder (ADHD) and irritability in a North American pediatric sample. METHOD A 3-site, 8-week, placebo-controlled, randomized clinical trial of micronutrients was conducted in nonmedicated children aged 6 to 12 years with ADHD and at least 1 impairing irritability symptom by parent report on the Child and Adolescent Symptom Inventory-5 (CASI-5). A priori-defined primary outcomes were Clinical Global Impression-Improvement (CGI-I) (CGI-I of 1 or 2 = treatment responder) and parent-rated CASI-5 composite score of ADHD, oppositional defiant, disruptive mood dysregulation, and peer conflict symptoms, including impairment scores. RESULTS Of 135 randomized (mean age 9.8 years), 126 youths (93%) comprised the modified intention-to-treat population. Blinding was maintained. For the CGI-I, 54% of the micronutrient and 18% of the placebo group were responders (risk ratio = 2.97, 97.5% CI = 1.50, 5.90, p < .001). CASI-5 composite scores improved significantly for both groups (p < .01), with a mean change of -0.31 (95% CI = -0.39, -0.23) in the micronutrient group and a mean change of -0.28 (95% CI = -0.38, -0.19) in the placebo group. However, the between-group difference was not significant (mean change = -0.02; 97.5% CI = -0.16, 0.12, effect size = 0.07, p = .70). The micronutrient group grew 6 mm more than the placebo group (p = .002). No serious adverse events or clinically significant changes from baseline in blood and urine tests occurred. CONCLUSION Micronutrients showed global benefit over placebo by blinded clinician rating, but not by parent-report CASI-5 composite rating in a population with ADHD and irritability. Micronutrients showed greater height growth. Micronutrients were well tolerated, and the majority of participants adhered to the number of capsules prescribed. This randomized controlled trial replicates safety and efficacy reported for ADHD in 2 smaller trials of a similar formula containing all vitamins and known essential minerals in amounts between the Recommended Dietary Allowance and Upper Tolerable Intake Level. CLINICAL TRIAL REGISTRATION INFORMATION Micronutrients for ADHD in Youth (MADDY) Study; https://clinicaltrials.gov; NCT03252522.
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Cross-sectional associations of schoolchildren's fruit and vegetable consumption, and meal choices, with their mental well-being: a cross-sectional study.
Hayhoe, R, Rechel, B, Clark, AB, Gummerson, C, Smith, SJL, Welch, AA
BMJ nutrition, prevention & health. 2021;4(2):447-462
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There has been an increase in mental health issues among school children in recent years. The importance of good nutrition for the physical and mental well-being of school children cannot be overstated. According to previous research, a diet high in processed foods, refined carbohydrates, and saturated fat are associated with mental health issues in children, while a diet high in fruits and vegetables may protect against mental health problems. The purpose of this cross-sectional study was to evaluate the relationship between dietary choices and mental well-being among primary and secondary school children. Among secondary school children, higher consumption of fruits and vegetables was associated with a greater sense of well-being, with those who consumed five or more fruits and vegetables reporting a higher sense of well-being. The well-being scores of secondary school children who consumed no breakfast and those who consumed high-energy drinks were lower than those of secondary school children who consumed conventional breakfast. Similarly, compared to children who had packed lunches, children who had no lunch had lower well-being. Among primary school children, higher intakes of fruits and vegetables were not significantly associated with well-being, whereas the type of lunch and breakfast were significantly associated with well-being. A comprehensive investigation is required to understand how dietary strategies and their components contribute to children's well-being and their modulating effects on various mechanisms. This research can be used by healthcare professionals to gain a better understanding of how a child's mental and physical health is impacted by their nutrition.
Abstract
BACKGROUND Poor mental well-being is a major issue for young people and is likely to have long-term negative consequences. The contribution of nutrition is underexplored. We, therefore, investigated the association between dietary choices and mental well-being among schoolchildren. METHODS Data from 7570 secondary school and 1253 primary school children in the Norfolk Children and Young People Health and Well-being Survey, open to all Norfolk schools during October 2017, were analysed. Multivariable linear regression was used to measure the association between nutritional factors and mental well-being assessed by the Warwick-Edinburgh Mental Well-being Scale for secondary school pupils, or the Stirling Children's Well-being Scale for primary school pupils. We adjusted all analyses for important covariates including demographic, health variables, living/home situation and adverse experience variables. RESULTS In secondary school analyses, a strong association between nutritional variables and well-being scores was apparent. Higher combined fruit and vegetable consumption was significantly associated with higher well-being: well-being scores were 3.73 (95% CI 2.94 to 4.53) units higher in those consuming five or more fruits and vegetables (p<0.001; n=1905) compared with none (n=739). The type of breakfast or lunch consumed was also associated with significant differences in well-being score. Compared with children consuming a conventional type of breakfast (n=5288), those not eating any breakfast had mean well-being scores 2.73 (95% CI 2.11 to 3.35) units lower (p<0.001; n=1129) and those consuming only an energy drink had well-being scores 3.14 (95% CI 1.20 to 5.09) units lower (p=0.002; n=91). Likewise, children not eating any lunch had well-being scores 2.95 (95% CI 2.22 to 3.68) units lower (p<0.001; 860) than those consuming a packed lunch (n=3744). In primary school analyses, the type of breakfast or lunch was associated with significant differences in well-being scores in a similar way to those seen in secondary school data, although no significant association with fruit and vegetable intake was evident. CONCLUSION These findings suggest that public health strategies to optimise the mental well-being of children should include promotion of good nutrition.
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The Role of Iron in Brain Development: A Systematic Review.
McCann, S, Perapoch Amadó, M, Moore, SE
Nutrients. 2020;12(7)
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Iron deficiency is the most common vitamin or mineral deficiency worldwide and is particularly common among pregnant women, infants and young children due to high iron demands during periods of rapid growth. Iron plays an important role in the development of the brain, and animal studies suggest that getting enough iron in pregnancy and early childhood is particularly important. The aims of this systematic review were to (i) investigate the relationship between iron status and brain development and (ii) assess whether this relationship differs according to age or type of development (‘domain’). The researchers looked for studies on iron deficiency or iron supplementation in pregnancy and up to 4 years of age. 26 observational studies and 28 intervention studies were included in the review. There was no clear relationship between iron status and developmental outcomes across any of the ages or domains included. Many of the studies were of low quality and there was a wide variation in study design, along with a lack of research on pregnancy and early infancy. The researchers concluded that evidence for the impact of iron deficiency or iron supplementation on early development is inconsistent. Further high-quality research is needed, particularly within pregnancy and early infancy, which has previously been neglected.
Abstract
One-third of children falter in cognitive development by pre-school age. Iron plays an important role in many neurodevelopmental processes, and animal studies suggest that iron sufficiency in pregnancy and infancy is particularly important for neurodevelopment. However, it is not clear whether iron deficiency directly impacts developmental outcomes, and, if so, whether impact differs by timing of exposure or developmental domain. We searched four databases for studies on iron deficiency or iron supplementation in pregnancy, or at 0-6 months, 6-24 months, or 2-4 years of age. All studies included neurodevelopmental assessments in infants or children up to 4 years old. We then qualitatively synthesized the literature. There was no clear relationship between iron status and developmental outcomes across any of the time windows or domains included. We identified a large quantity of low-quality studies, significant heterogeneity in study design and a lack of research focused on pregnancy and early infancy. In summary, despite good mechanistic evidence for the role of iron in brain development, evidence for the impact of iron deficiency or iron supplementation on early development is inconsistent. Further high-quality research is needed, particularly within pregnancy and early infancy, which has previously been neglected.
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Association Between Maternal Fluoride Exposure During Pregnancy and IQ Scores in Offspring in Canada.
Green, R, Lanphear, B, Hornung, R, Flora, D, Martinez-Mier, EA, Neufeld, R, Ayotte, P, Muckle, G, Till, C
JAMA pediatrics. 2019;173(10):940-948
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Fluoride is added to the water supply in some parts of the UK, US and Canada to help prevent tooth decay. However, some people think that fluoride could be harmful to health, and may affect brain development in foetuses. The aim of this Canadian study was to determine whether a mother’s exposure to fluoride during pregnancy was associated with her child’s IQ. Researchers recruited a total of 369 pregnant women from both fluoridated and non-fluoridated areas and measured the amount of fluoride in their urine. The children’s IQs were measured when they were aged 3 to 4 years. The researchers found that overall, maternal exposure to higher levels of fluoride during pregnancy was associated with lower IQ scores in children aged 3 to 4 years. The relationship was much stronger in boys than it was in girls. These findings indicate a possible need to reduce fluoride intake during pregnancy.
Abstract
IMPORTANCE The potential neurotoxicity associated with exposure to fluoride, which has generated controversy about community water fluoridation, remains unclear. OBJECTIVE To examine the association between fluoride exposure during pregnancy and IQ scores in a prospective birth cohort. DESIGN, SETTING, AND PARTICIPANTS This prospective, multicenter birth cohort study used information from the Maternal-Infant Research on Environmental Chemicals cohort. Children were born between 2008 and 2012; 41% lived in communities supplied with fluoridated municipal water. The study sample included 601 mother-child pairs recruited from 6 major cities in Canada; children were between ages 3 and 4 years at testing. Data were analyzed between March 2017 and January 2019. EXPOSURES Maternal urinary fluoride (MUFSG), adjusted for specific gravity and averaged across 3 trimesters available for 512 pregnant women, as well as self-reported maternal daily fluoride intake from water and beverage consumption available for 400 pregnant women. MAIN OUTCOMES AND MEASURES Children's IQ was assessed at ages 3 to 4 years using the Wechsler Primary and Preschool Scale of Intelligence-III. Multiple linear regression analyses were used to examine covariate-adjusted associations between each fluoride exposure measure and IQ score. RESULTS Of 512 mother-child pairs, the mean (SD) age for enrollment for mothers was 32.3 (5.1) years, 463 (90%) were white, and 264 children (52%) were female. Data on MUFSG concentrations, IQ scores, and complete covariates were available for 512 mother-child pairs; data on maternal fluoride intake and children's IQ were available for 400 of 601 mother-child pairs. Women living in areas with fluoridated tap water (n = 141) compared with nonfluoridated water (n = 228) had significantly higher mean (SD) MUFSG concentrations (0.69 [0.42] mg/L vs 0.40 [0.27] mg/L; P = .001; to convert to millimoles per liter, multiply by 0.05263) and fluoride intake levels (0.93 [0.43] vs 0.30 [0.26] mg of fluoride per day; P = .001). Children had mean (SD) Full Scale IQ scores of 107.16 (13.26), range 52-143, with girls showing significantly higher mean (SD) scores than boys: 109.56 (11.96) vs 104.61 (14.09); P = .001. There was a significant interaction (P = .02) between child sex and MUFSG (6.89; 95% CI, 0.96-12.82) indicating a differential association between boys and girls. A 1-mg/L increase in MUFSG was associated with a 4.49-point lower IQ score (95% CI, -8.38 to -0.60) in boys, but there was no statistically significant association with IQ scores in girls (B = 2.40; 95% CI, -2.53 to 7.33). A 1-mg higher daily intake of fluoride among pregnant women was associated with a 3.66 lower IQ score (95% CI, -7.16 to -0.14) in boys and girls. CONCLUSIONS AND RELEVANCE In this study, maternal exposure to higher levels of fluoride during pregnancy was associated with lower IQ scores in children aged 3 to 4 years. These findings indicate the possible need to reduce fluoride intake during pregnancy.
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A Biopsychosocial Model of Sex Differences in Children's Eating Behaviors.
Keller, KL, Kling, SMR, Fuchs, B, Pearce, AL, Reigh, NA, Masterson, T, Hickok, K
Nutrients. 2019;11(3)
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This paper discusses the role of sex on children’s appetite and responses to food cues. The review flips the question of whether the variations in obesity and eating disorders seen by biological sex are actually influenced by, and to what extent, by sex eg. is sex the determining factor for differing responses? It specifically reviews behaviours in children aged 11 years and younger, avoiding adolescence (the typical age when differences in eating patterns occur), to understand if these differences are correlated with sex, given the high incidence of female eating disorders. The researchers reviewed specific traits including food acceptance, food intake, picky eating, appetitive traits, eating compensation, eating in the absence of hunger, and meal-specific microstructural patterns (e.g., bite rate and eating speed). They found that girls typically like a wider variety of foods than boys and had a greater preference for plant foods whilst boys typically preferred meats and foods higher in fats and sugar. No sex differences were found for picky eating. Boys were found to have greater enjoyment for eating, with girls showing more food avoidance traits, however this may be from parental strategies reinforcing this behaviour in girls. Boys are more readily satiated and better able to regulate their food and drink intake than girls. Yet boys are also more likely to eat in the absence of hunger and have a faster eating rate and larger bite size. The paper concludes that the studies reviewed are suggestive of male–female differences in food liking and intake, appetitive traits, self-regulatory eating, and meal-related microstructure.
Abstract
The prevalence of obesity and eating disorders varies by sex, but the extent to which sex influences eating behaviors, especially in childhood, has received less attention. The purpose of this paper is to critically discuss the literature on sex differences in eating behavior in children and present new findings supporting the role of sex in child appetitive traits and neural responses to food cues. In children, the literature shows sex differences in food acceptance, food intake, appetitive traits, eating-related compensation, and eating speed. New analyses demonstrate that sex interacts with child weight status to differentially influence appetitive traits. Further, results from neuroimaging suggest that obesity in female children is positively related to neural reactivity to higher-energy-dense food cues in regions involved with contextual processing and object recognition, while the opposite was found in males. In addition to differences in how the brain processes information about food, other factors that may contribute to sex differences include parental feeding practices, societal emphasis on dieting, and peer influences. Future studies are needed to confirm these findings, as they may have implications for the development of effective intervention programs to improve dietary behaviors and prevent obesity.
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Swimming pool exposure is associated with autonomic changes and increased airway reactivity to a beta-2 agonist in school aged children: A cross-sectional survey.
Cavaleiro Rufo, J, Paciência, I, Silva, D, Martins, C, Madureira, J, Oliveira Fernandes, E, Padrão, P, Moreira, P, Delgado, L, Moreira, A
PloS one. 2018;13(3):e0193848
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Studies have shown an association between swimming in chemically-treated pools and a higher risk of asthma in children, although the mechanism is not fully understood. This study aimed to investigate how swimming pool attendance influences lung and nervous system function in school-aged children. Around 800 children were classified as current swimmers (CS), past swimmers (PS) or non-swimmers (NS). The children underwent several tests to determine their lung function and allergic response to common allergens. Parasympathetic nervous system function was tested by measuring the speed at which their pupils constricted in response to light. The current swimmers group had significantly lower pupil constriction speeds compared to PS and NS, suggesting a poorer functioning of the autonomic nervous system, possibly due to inflammation resulting from swimming pool chemical exposure. CS experienced greater constriction of the airways compared to NS. A non-significant trend for a higher risk of asthma, atopic eczema and rhinitis, was observed in swimmers. The authors concluded that swimming pool attendance appears to be associated with autonomic nervous system changes and increased baseline airway smooth muscle constriction even in children without asthma.
Abstract
BACKGROUND Endurance swimming exercises coupled to disinfection by-products exposure has been associated with increased airways dysfunction and neurogenic inflammation in elite swimmers. However, the impact of swimming pool exposure at a recreational level on autonomic activity has never been explored. Therefore, this study aimed to investigate how swimming pool attendance is influencing lung and autonomic function in school-aged children. METHODS A total of 858 children enrolled a cross sectional survey. Spirometry and airway reversibility to beta-2 agonist, skin-prick-tests and exhaled nitric oxide measurements were performed. Pupillometry was used to evaluate autonomic nervous function. Children were classified as current swimmers (CS), past swimmers (PS) and non-swimmers (NS), according to the amount of swimming practice. RESULTS Current swimmers group had significantly lower maximum and average pupil constriction velocities when compared to both PS and NS groups (3.8 and 5.1 vs 3.9 and 5.3 vs 4.0 and 5.4 mm/s, p = 0.03 and p = 0.01, respectively). Moreover, affinity to the beta-2 agonist and levels of exhaled nitric oxide were significantly higher in CS when compared to NS (70 vs 60 mL and 12 vs 10 ppb, p<0.01 and p = 0.03, respectively). A non-significant trend for a higher risk of asthma, atopic eczema and allergic rhinitis was found with more years of swimming practice, particularly in atopic individuals (β = 1.12, 1.40 and 1.31, respectively). After case-case analysis, it was possible to observe that results were not influenced by the inclusion of individuals with asthma. CONCLUSIONS Concluding, swimming pool attendance appears to be associated with autonomic changes and increased baseline airway smooth muscle constriction even in children without asthma.