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Zinc status in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis of observational studies.
Ghoreishy, SM, Ebrahimi Mousavi, S, Asoudeh, F, Mohammadi, H
Scientific reports. 2021;(1):14612
Abstract
Previous studies regarding the zinc status in attention-deficit/hyperactivity disorder (ADHD) yielded inconsistent results. Thus, the present meta-analysis was aimed to estimate the association between hair and serum/plasma zinc levels and ADHD. Online databases of Medline, EMBASE, and Scopus were searched up to October 2020 with no limitation in time and language. Weighted mean differences (WMDs) of hair and serum/plasma zinc levels were calculated using a random-effects model. Overall, 22 articles with 1280 subjects with ADHD and 1200 controls were included. The pooled effect size indicated that serum/plasma zinc levels in subjects with ADHD were not statistically different than their controls (WMD = - 1.26 µmol/L; 95% CI - 3.72, 1.20). Interestingly, the exclusion of one study from the analysis showed that people with ADHD significantly have lower circulating levels of zinc compared to their controls (WMD: - 2.49 µmol/L; 95% CI - 4.29, - 0.69). Also, the pooled effect size indicated that hair zinc levels in cases with ADHD were not statistically different than their controls (WMD = - 24.19 μg/g; 95% CI - 61.80, 13.42). Present meta-analysis raises the possibility that subjects with ADHD are prone to have declined levels of zinc levels. Based on current findings, screening the zinc levels in subjects with ADHD could be reasonable. Further well-designed studies are needed to clarify the role of zinc in the etiology of ADHD.
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Environmental risk factors, protective factors, and peripheral biomarkers for ADHD: an umbrella review.
Kim, JH, Kim, JY, Lee, J, Jeong, GH, Lee, E, Lee, S, Lee, KH, Kronbichler, A, Stubbs, B, Solmi, M, et al
The lancet. Psychiatry. 2020;(11):955-970
Abstract
BACKGROUND Many potential environmental risk factors, environmental protective factors, and peripheral biomarkers for ADHD have been investigated, but the consistency and magnitude of their effects are unclear. We aimed to systematically appraise the published evidence of association between potential risk factors, protective factors, or peripheral biomarkers, and ADHD. METHODS In this umbrella review of meta-analyses, we searched PubMed including MEDLINE, Embase, and the Cochrane Database of Systematic Reviews, from database inception to Oct 31, 2019, and screened the references of relevant articles. We included systematic reviews that provided meta-analyses of observational studies that examined associations of potential environmental risk factors, environmental protective factors, or peripheral biomarkers with diagnosis of ADHD. We included meta-analyses that used categorical ADHD diagnosis criteria according to DSM, hyperkinetic disorder according to ICD, or criteria that were less rigorous than DSM or ICD, such as self-report. We excluded articles that did not examine environmental risk factors, environmental protective factors, or peripheral biomarkers of ADHD; articles that did not include a meta-analysis; and articles that did not present enough data for re-analysis. We excluded non-human studies, primary studies, genetic studies, and conference abstracts. We calculated summary effect estimates (odds ratio [OR], relative risk [RR], weighted mean difference [WMD], Cohen's d, and Hedges' g), 95% CI, heterogeneity I2 statistic, 95% prediction interval, small study effects, and excess significance biases. We did analyses under credibility ceilings, and assessed the quality of the meta-analyses with AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). This study is registered with PROSPERO, number CRD42019145032. FINDINGS We identified 1839 articles, of which 35 were eligible for inclusion. These 35 articles yielded 63 meta-analyses encompassing 40 environmental risk factors and environmental protective factors (median cases 16 850, median population 91 954) and 23 peripheral biomarkers (median cases 175, median controls 187). Evidence of association was convincing (class I) for maternal pre-pregnancy obesity (OR 1·63, 95% CI 1·49 to 1·77), childhood eczema (1·31, 1·20 to 1·44), hypertensive disorders during pregnancy (1·29, 1·22 to 1·36), pre-eclampsia (1·28, 1·21 to 1·35), and maternal acetaminophen exposure during pregnancy (RR 1·25, 95% CI 1·17 to 1·34). Evidence of association was highly suggestive (class II) for maternal smoking during pregnancy (OR 1·6, 95% CI 1·45 to 1·76), childhood asthma (1·51, 1·4 to 1·63), maternal pre-pregnancy overweight (1·28, 1·21 to 1·35), and serum vitamin D (WMD -6·93, 95% CI -9·34 to -4·51). INTERPRETATION Maternal pre-pregnancy obesity and overweight; pre-eclampsia, hypertension, acetaminophen exposure, and smoking during pregnancy; and childhood atopic diseases were strongly associated with ADHD. Previous familial studies suggest that maternal pre-pregnancy obesity, overweight, and smoking during pregnancy are confounded by familial or genetic factors, and further high-quality studies are therefore required to establish causality. FUNDING None.
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Sugar consumption, sugar sweetened beverages and Attention Deficit Hyperactivity Disorder: A systematic review and meta-analysis.
Farsad-Naeimi, A, Asjodi, F, Omidian, M, Askari, M, Nouri, M, Pizarro, AB, Daneshzad, E
Complementary therapies in medicine. 2020;:102512
Abstract
BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is a significant neurobehavioral disorder in children and adolescence which may be affected by diet. OBJECTIVE To evaluate the possible relationship between sugar consumption and the development of symptoms of ADHD. METHODS In March 2020, an exhaustive systematic literature search was conducted using Google Scholar, PubMed, and Scopus. In this meta-analysis of observational studies, odds ratios, relative risks, hazard ratios, and their 95% confidence intervals, which was reported for ADHD regarding SSBS, soft drink consumption, and dietary sugars, were used to calculate ORs and standard errors. At first, a fixed-effects model was used to drive the overall effect sizes using log ORs and SEs. If there was any significant between-studies heterogeneity, the random-effects model was conducted. Cochran's Q test and I2 were used to measure potential sources of heterogeneity across studies. The Newcastle-Ottawa scale was used to assess the quality of the included articles. RESULTS Seven studies, two cross-sectional, two case-control, and three prospective with a total of 25,945 individuals were eligible to include in the current meta-analysis. The association between sugar and soft drink consumption and the risk of ADHD symptoms were provided based on the random-effects model (pooled effect size: 1.22, 95%CI: 1.04-1.42, P = 0.01) (I² = 81.9%, P heterogeneity< 0.0001). CONCLUSION This meta-analysis indicated a positive relationship between overall sugar and sugar-sweetened beverages consumption and symptoms of ADHD; however, there was heterogeneity among included studies. Future well-designed studies that can account for confounds are necessary to confirm the effect of sugar on ADHD.
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Early Life Exposure to Perfluoroalkyl Substances (PFAS) and ADHD: A Meta-Analysis of Nine European Population-Based Studies.
Forns, J, Verner, MA, Iszatt, N, Nowack, N, Bach, CC, Vrijheid, M, Costa, O, Andiarena, A, Sovcikova, E, Høyer, BB, et al
Environmental health perspectives. 2020;(5):57002
Abstract
INTRODUCTION To date, the evidence for an association between perfluoroalkyl substances (PFAS) exposure and attention deficit and hyperactivity disorder (ADHD) is inconclusive. OBJECTIVE We investigated the association between early life exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), and ADHD in a collaborative study including nine European population-based studies, encompassing 4,826 mother-child pairs. METHODS Concentrations of PFOS and PFOA were measured in maternal serum/plasma during pregnancy, or in breast milk, with different timing of sample collection in each cohort. We used a validated pharmacokinetic model of pregnancy and lactation to estimate concentrations of PFOS and PFOA in children at birth and at 3, 6, 12, and 24 months of age. We classified ADHD using recommended cutoff points for each instrument used to derive symptoms scores. We used multiple imputation for missing covariates, logistic regression to model the association between PFAS exposure and ADHD in each study, and combined all adjusted study-specific effect estimates using random-effects meta-analysis. RESULTS A total of 399 children were classified as having ADHD, with a prevalence ranging from 2.3% to 7.3% in the studies. Early life exposure to PFOS or PFOA was not associated with ADHD during childhood [odds ratios (ORs) ranging from 0.96 (95% CI: 0.87, 1.06) to 1.02 (95% CI: 0.93, 1.11)]. Results from stratified models suggest potential differential effects of PFAS related to child sex and maternal education. CONCLUSION We did not identify an increased prevalence of ADHD in association with early life exposure to PFOS and PFOA. However, stratified analyses suggest that there may be an increased prevalence of ADHD in association with PFAS exposure in girls, in children from nulliparous women, and in children from low-educated mothers, all of which warrant further exploration. https://doi.org/10.1289/EHP5444.
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Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.
Demontis, D, Walters, RK, Martin, J, Mattheisen, M, Als, TD, Agerbo, E, Baldursson, G, Belliveau, R, Bybjerg-Grauholm, J, Bækvad-Hansen, M, et al
Nature genetics. 2019;(1):63-75
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Abstract
Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
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Maternal Thyroid Function in Early Pregnancy and Child Attention-Deficit Hyperactivity Disorder: An Individual-Participant Meta-Analysis.
Levie, D, Korevaar, TIM, Mulder, TA, Bath, SC, Dineva, M, Lopez-Espinosa, MJ, Basterrechea, M, Santa-Marina, L, Rebagliato, M, Sunyer, J, et al
Thyroid : official journal of the American Thyroid Association. 2019;(9):1316-1326
Abstract
Background: Thyroid hormone is essential for optimal fetal brain development. Evidence suggests that both low and high maternal thyroid hormone availability may have adverse effects on child neurodevelopmental outcomes, but the effect on behavioral problems remains unclear. We studied the association of maternal thyrotropin (TSH) and free thyroxine (fT4) concentrations during the first 18 weeks of pregnancy with child attention-deficit hyperactivity disorder (ADHD). Methods: A total of 7669 mother-child pairs with data on maternal thyroid function and child ADHD were selected from three prospective population-based birth cohorts: INfancia y Medio Ambiente (INMA; N = 1073, Spain), Generation R (N = 3812, The Netherlands), and Avon Longitudinal Study of Parents and Children (ALSPAC; N = 2784, United Kingdom). Exclusion criteria were multiple pregnancy, fertility treatment, usage of medication affecting the thyroid, and pre-existing thyroid disease. We used logistic regression models to study the association of maternal thyroid function with the primary outcome, ADHD, assessed via the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria by parents and/or teachers at a median child age of 4.5 to 7.6 years, and with the secondary outcome, an ADHD symptom score above the 90th percentile. Effect modification by gestational age and sex was tested with interaction terms and stratified analyses. Results: Overall, 233 (3%) children met the criteria for ADHD. When analyzed continuously, neither fT4 nor TSH was associated with a higher risk of ADHD (odds ratio [OR] 1.1, 95% confidence interval [CI 1.0-1.3], p = 0.060 and OR 0.9 [CI 0.9-1.1], p = 0.385, respectively) or with high symptom scores. When investigating effect modification by gestational age, a higher fT4 was associated with symptoms above the 90th percentile but only in the first trimester (for fT4 per 1 SD: OR 1.2 [CI 1.0-1.4], p = 0.027). However, these differential effects by gestational age were not consistent. No significant effect modification by sex was observed. Conclusions: We found no clear evidence of an association between maternal thyroid function and child ADHD.
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The Effect of Vitamin D Supplementation on Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Gan, J, Galer, P, Ma, D, Chen, C, Xiong, T
Journal of child and adolescent psychopharmacology. 2019;(9):670-687
Abstract
Objective: A systematic review and meta-analysis of randomized controlled trials (RCTs) were conducted to assess the benefits and harms of vitamin D supplementation for attention-deficit/hyperactivity disorder (ADHD) patients. Methods: We followed the standard methodological procedures of the Cochrane Handbook for Systematic Reviews of Intervention. PubMed, Embase, the Cochrane Central Register of Controlled Trials, Science and Conference Proceedings Citation Index-Social Science and Humanities (Web of Science), ClincalTrials.gov, and World Health Organization's International Clinical Trials Registry Platform were searched for RCTs in January 2019. Independently, two authors (J.G., T.X.) extracted data, assessed the risk of bias, combined the data, and graded evidence quality using the Grading of Recommendations Assessment, Development, and Evaluation approach. Our primary outcomes were assessed through rating scales of ADHD severity. Secondary outcomes measured were the possible adverse effects of vitamin D supplementation and vitamin D status after supplementation for ADHD. Results: We included four RCTs with 256 children addressing vitamin D supplementation as adjunctive therapy to methylphenidate on ADHD symptoms. Vitamin D supplementation demonstrated a small but statistically significant improvement in ADHD total scores, inattention scores, hyperactivity scores, and behavior scores. The improvement was likely limited due to the low to very low quality of evidence in the literature. There was no statistically significant improvement in oppositional scores. Reported adverse events in the vitamin D group were mild and not significantly different from the control group. Vitamin D supplementation increased serum vitamin D levels and the ratio of patients with sufficient vitamin D levels. Conclusions: Vitamin D supplementation as adjunctive therapy to methylphenidate appeared to reduce ADHD symptoms without serious adverse events, associated with improved vitamin D status. However, considering the generally low strength of evidence, well-designed RCTs are needed to determine the efficacy and safety of vitamin D supplementation for both children and adults with ADHD, especially in the setting of a combination of vitamin D and other ADHD treatments.
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Significantly lower serum and hair magnesium levels in children with attention deficit hyperactivity disorder than controls: A systematic review and meta-analysis.
Huang, YH, Zeng, BY, Li, DJ, Cheng, YS, Chen, TY, Liang, HY, Yang, WC, Lin, PY, Chen, YW, Tseng, PT, et al
Progress in neuro-psychopharmacology & biological psychiatry. 2019;:134-141
Abstract
The pathophysiology of attention deficient hyperactivity disorder (ADHD) is still obscure. Some studies have discussed that magnesium levels are lower in the serum and erythrocytes of children with ADHD. However, these findings are controversial. The aim of our study is to identify whether magnesium levels are in fact lower in children with ADHD. We conducted a thorough search of the literature and examined the connection between magnesium insufficiency and ADHD. A total of twelve studies were included into the current meta-analysis. The results of our meta-analysis found that peripheral blood magnesium levels, either in plasma, serum, or whole blood, of children diagnosed with ADHD were significantly lower than those in controls (k = 8, Hedges' g = -0.547, 95% CI = -0.818 to -0.276, p < .001). The subgroup meta-analysis with serum sample sources also suggested that peripheral serum magnesium levels of children diagnosed with ADHD were significantly lower than those in controls (k = 6, Hedges' g = -0.733, 95% CI = -0.911 to -0.555, p < .001). The subgroup meta-analysis focusing on subjects with ADHD diagnosed by definite diagnostic criteria also suggested significantly lower peripheral serum magnesium levels in ADHD children than those in controls (k = 4, Hedges' g = -0.780, 95% CI = -0.985 to -0.574, p < .001). We also noted that magnesium levels in the hair of children diagnosed with ADHD were significantly lower than those in controls (k = 4, Hedges' g = -0.713, 95% CI = -1.359 to -0.067, p = .031). In this meta-analysis, we found that children diagnosed with ADHD have lower serum and hair magnesium levels than children without ADHD. Further study may be needed to investigate the behavioral influence on ADHD due to lower magnesium levels, the association between brain and serum magnesium levels, and the effects brought about by larger longitudinal cohort studies.
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Vitamin D Status and Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Observational Studies.
Khoshbakht, Y, Bidaki, R, Salehi-Abargouei, A
Advances in nutrition (Bethesda, Md.). 2018;(1):9-20
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Abstract
An association between vitamin D and attention deficit hyperactivity disorder (ADHD) has been proposed by several researchers in recent years; however, the investigations have led to inconsistent results. The present study was conducted to summarize the published observational data on the relation between vitamin D status and the likelihood of ADHD. Online databases, including PubMed, the ISI Web of Science, Google Scholar, and Scopus, were checked up to June 2017 for relevant observational studies. A random-effects model was incorporated to summarize the study results. Out of 2770 retrieved articles, 13 observational studies (9 case-control or cross-sectional studies and 4 prospective studies) were eligible for inclusion in the systematic review and meta-analysis. Analysis of the 10,334 children and adolescents who attended the 9 case-control or cross-sectional studies revealed that children with ADHD have lower serum concentrations of 25-hydroxyvitamin D than do healthy children (weighted mean difference: -6.75 ng/mL; 95% CI: -9.73, -3.77 ng/mL; I2 = 94.9%]. Five case-control studies reported the OR for developing ADHD based on vitamin D status; the meta-analysis of their data revealed that lower vitamin D status is significantly associated with the likelihood of ADHD (OR: 2.57; 95% CI: 1.09, 6.04; I2 = 84.3%). Furthermore, the meta-analysis of prospective studies conducted in 4137 participants indicated that perinatal suboptimal vitamin D concentrations are significantly associated with a higher risk of ADHD in later life (RR: 1.40; 95% CI: 1.09, 1.81; I2 = 0.0%). It should be noted that the association found in prospective studies was sensitive to one of the included investigations. The present review provides evidence supporting the relation between vitamin D deficiency and ADHD. However, the overall effect sizes are small, and therefore the association should be considered equivocal at this time. Further prospective cohort studies and community-based intervention trials are highly recommended to better elucidate the causal association.
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Iron Status in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis.
Wang, Y, Huang, L, Zhang, L, Qu, Y, Mu, D
PloS one. 2017;(1):e0169145
Abstract
BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in children. However, the pathogenesis of ADHD remains unclear. Iron, an important trace element, is implicated in brain function and dopaminergic activity. Recent studies have investigated the association between iron deficiency and ADHD, but the results are inconsistent. METHODS A systemic search of MEDLINE, EMBASE, Web of Science and Cochrane Library databases was supplemented by manual searches of references of key retrieved articles. Study quality was evaluated using the Newcastle-Ottawa Scale. The standardised mean difference (SMD) and 95% confidence intervals (CIs) were calculated using a random-effects model. H2 and I2 were used to evaluate the heterogeneity, and sensitivity, subgroup and meta-regression analyses were conducted to explore the reason of heterogeneity. RESULTS The search yielded 11 studies published before July 25, 2016. Of these, 10 studies, comprising 2191 participants and 1196 ADHD cases, reported serum ferritin levels, and six studies, comprising 617 participants and 369 ADHD cases, reported serum iron levels. Serum ferritin levels were lower in ADHD cases (SMD = -0.40, 95% CI = -0.66 to -0.14). However, we found no correlation between serum iron levels and ADHD (SMD = -0.026, 95% CI = -0.29 to 0.24). Meta-regression analysis indicated that publication year, age, gender, sample size, and Hb levels did not significantly influence the pooled estimates of serum ferritin. CONCLUSION Lower serum ferritin rather than serum iron is associated with ADHD in children.