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      Maternal Ferritin Levels during Pregnancy and ADHD Symptoms in 4-Year-Old Children: Results from the INMA–INfancia y Medio Ambiente (Environment and Childhood) Prospective Birth Cohort Study

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          Abstract

          Ferritin status during prenatal brain development may influence the risk of attention deficit and hyperactivity disorder (ADHD) symptoms in childhood. We investigated the association of maternal ferritin in pregnancy and ADHD-like symptoms in offspring. A total of 1095 mother-child pairs from three birth cohorts of the INMA Project (Spain) were studied. Maternal plasma ferritin in pregnancy was measured at 11.57 weeks of gestation. Children′s ADHD-like symptoms at ages 4–5 years were assessed using the ADHD Rating Scale-IV. The count model of the zero-inflated Poisson regression model showed a significant inverse association between ferritin (continuous variable) and inattention, β = −0.19 (−0.32, −0.07), for boys. Comparing ferritin level by tertiles, significant differences were observed between the first tertile ([1.98, 20.92]) and the second ([20.92, 38.79]) and third tertiles ([38.79, 216.5]) (mg/L).The number of symptoms was lower for those in the third tertile, β = −0.3 (−0.55, −0.5), and for those in the second one, β = −0.37 (−0.6, −0.14). The model stratification by sex also showed this inverse association for boys only, β = −0.21 (−0.34, −0.08). No associations were found between ferritin level and hyperactivity or total ADHD symptoms. High ferritin levels during pregnancy show a protective association with child inattentive-type ADHD symptoms.

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          The worldwide prevalence of ADHD: a systematic review and metaregression analysis.

          The worldwide prevalence estimates of attention deficit hyperactivity disorder (ADHD)/hyperkinetic disorder (HD) are highly heterogeneous. Presently, the reasons for this discrepancy remain poorly understood. The purpose of this study was to determine the possible causes of the varied worldwide estimates of the disorder and to compute its worldwide-pooled prevalence. The authors searched MEDLINE and PsycINFO databases from January 1978 to December 2005 and reviewed textbooks and reference lists of the studies selected. Authors of relevant articles from North America, South America, Europe, Africa, Asia, Oceania, and the Middle East and ADHD/HD experts were contacted. Surveys were included if they reported point prevalence of ADHD/HD for subjects 18 years of age or younger from the general population or schools according to DSM or ICD criteria. The literature search generated 9,105 records, and 303 full-text articles were reviewed. One hundred and two studies comprising 171,756 subjects from all world regions were included. The ADHD/HD worldwide-pooled prevalence was 5.29%. This estimate was associated with significant variability. In the multivariate metaregression model, diagnostic criteria, source of information, requirement of impairment for diagnosis, and geographic origin of the studies were significantly associated with ADHD/HD prevalence rates. Geographic location was associated with significant variability only between estimates from North America and both Africa and the Middle East. No significant differences were found between Europe and North America. Our findings suggest that geographic location plays a limited role in the reasons for the large variability of ADHD/HD prevalence estimates worldwide. Instead, this variability seems to be explained primarily by the methodological characteristics of studies.
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            Molecular genetics of attention-deficit/hyperactivity disorder.

            Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.
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              The role of iron in brain ageing and neurodegenerative disorders.

              In the CNS, iron in several proteins is involved in many important processes such as oxygen transportation, oxidative phosphorylation, myelin production, and the synthesis and metabolism of neurotransmitters. Abnormal iron homoeostasis can induce cellular damage through hydroxyl radical production, which can cause the oxidation and modification of lipids, proteins, carbohydrates, and DNA. During ageing, different iron complexes accumulate in brain regions associated with motor and cognitive impairment. In various neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, changes in iron homoeostasis result in altered cellular iron distribution and accumulation. MRI can often identify these changes, thus providing a potential diagnostic biomarker of neurodegenerative diseases. An important avenue to reduce iron accumulation is the use of iron chelators that are able to cross the blood-brain barrier, penetrate cells, and reduce excessive iron accumulation, thereby affording neuroprotection.
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                Author and article information

                Journal
                Int J Environ Res Public Health
                Int J Environ Res Public Health
                ijerph
                International Journal of Environmental Research and Public Health
                MDPI
                1661-7827
                1660-4601
                22 October 2020
                November 2020
                : 17
                : 21
                : 7704
                Affiliations
                [1 ]Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, C/Monforte de Lemos 3–5, 28029 Madrid, Spain; ambien4ss-san@ 123456euskadi.eus (L.S.-M.); jordi.sunyer@ 123456isglobal.org (J.S.); au-molinuevo@ 123456euskadi.eus (A.M.); llop_sab@ 123456gva.es (S.L.); jordi.julvez@ 123456isglobal.org (J.J.); mambien3-san@ 123456euskadi.eus (J.I.)
                [2 ]Biodonostia, Epidemiology and Public Health Area, Environmental Epidemiology and Child Development Group, 20014 San Sebastian, Spain; nerea.lertxundi@ 123456ehu.eus (N.L.); ainara.andiarena@ 123456ehu.eus (A.A.)
                [3 ]Public Health Division of Gipuzkoa, Basque Government, 20013 San Sebastian, Spain; l-imazgoienetxea@ 123456euskadi.eus
                [4 ]Faculty of Psychology, University of the Basque Country (UPV/EHU), Avenida Tolosa 70, 20018 San Sebastian, Spain
                [5 ]Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Barrio Sarriena s/n, 48940 Leioa, Spain
                [6 ]Hospital del Mar Research Institute, 08003 Barcelona, Spain
                [7 ]ISGlobal—Instituto de Salud Global de Barcelona–Campus MAR, PRBB, 08003 Barcelona, Spain
                [8 ]Epidemiology and Environmental Health Joint Research Unit, FISABIO–Universitat Jaume I–Universitat de València, 08003 València, Spain; beneito_and@ 123456gva.es
                [9 ]Institut d′Investigació Sanitària Pere Virgili (IISPV), Hospital Universitari Sant Joan de Reus, 43204 Reus, Spain
                [10 ]Biodonostia, Epidemiology and Public Health Area, Epidemiology of Chronic and Communicable Diseases Group, 20014 San Sebastian, Spain
                [11 ]Haringey Child and Adolescent Mental Health Service, Barnet, Enfield and Haringey NHS Mental Health Trust, London N15 3TH, UK; maiteferrin@ 123456yahoo.es
                [12 ]Recognition Health, London W1G 9RU, UK
                Author notes
                [* ]Correspondence: amaia.irizar@ 123456ehu.eus
                Author information
                https://orcid.org/0000-0002-1681-5939
                https://orcid.org/0000-0003-0818-4003
                https://orcid.org/0000-0001-6560-601X
                https://orcid.org/0000-0002-6933-5373
                https://orcid.org/0000-0002-3777-4953
                Article
                ijerph-17-07704
                10.3390/ijerph17217704
                7659477
                33105572
                50010f9d-8f0a-4f77-a059-415c894f22d7
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 02 October 2020
                : 19 October 2020
                Categories
                Article

                Public health
                ferritin status,pregnancy,adhd symptoms,childhood
                Public health
                ferritin status, pregnancy, adhd symptoms, childhood

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