{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:27:08Z","timestamp":1760236028730,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T00:00:00Z","timestamp":1634428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Iron deficiency anemia (IDA) accounts for most of the anemia in pregnancy, and iron is essential for neurodevelopment. Tics and Tourette\u2019s syndrome (TS) are neurodevelopmental disorders that manifest in childhood. A few studies reported an inconclusive association between iron deficiency and tics in children. No study has investigated the relationship between prenatal maternal anemia and tics in children. We aimed to assess the relationship between prenatal anemia exposure and the incidence of tics or TS in offspring. We linked the Taiwan National Health Insurance Research Database to the Maternal and Child Health Database for the analysis and identified 153,854 children with prenatal anemia exposure and 2,014,619 children without prenatal anemia exposure from 2004 to 2016 and followed them through 2017. Cox regression models were applied to compare the risk of tics or TS between the exposed and nonexposed groups. Among the exposed group, 37,832 were exposed at \u226412 weeks of gestational age (GA) and 116,022 at &gt;12 weeks of GA. We observed an increased risk of tics and TS in those exposed at \u226412 weeks compared with the nonexposed group (adjusted hazard ratio (aHR) = 1.23, 95% confidence interval (CI): 1.12\u20131.34). The result remained consistent after adjusting for birth year, sex, birth order, maternal age, low-income levels, gestational age, birth weight, and alcohol use and smoking during pregnancy (aHR = 1.16, CI: 1.04\u20131.28). Fetuses exposed to maternal anemia at \u226412 weeks of GA are at high risk of tics or TS. However, this effect was attenuated to insignificance in the sibling comparison. Our study highlights the importance of detection of anemia during pregnancy and proper timing of iron supplementation.<\/jats:p>","DOI":"10.3390\/jpm11101038","type":"journal-article","created":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T23:05:47Z","timestamp":1634511947000},"page":"1038","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Association of Prenatal Maternal Anemia with Tics and Tourette\u2019s Syndrome in Offspring"],"prefix":"10.3390","volume":"11","author":[{"given":"Yi-Chun","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Changhua Christian Children\u2019s Hospital, Changhua 500, Taiwan"},{"name":"Department of Psychiatry, Changhua Christian Hospital, Changhua 500, Taiwan"},{"name":"Department of Healthcare Administration, Asia University, Taichung 413, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent Chin-Hung","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, Chang Gung University, Taoyuan 333, Taiwan"},{"name":"Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3143-3672","authenticated-orcid":false,"given":"Yin-To","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2934-5814","authenticated-orcid":false,"given":"Yi-Lung","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Healthcare Administration, Asia University, Taichung 413, Taiwan"},{"name":"Department of Psychology, Asia University, Taichung 413, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"f3443","DOI":"10.1136\/bmj.f3443","article-title":"Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: Systematic review and meta-analysis","volume":"346","author":"Haider","year":"2013","journal-title":"BMJ"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"108608","DOI":"10.1016\/j.diabres.2020.108608","article-title":"Prepregnancy hemoglobin levels and gestational diabetes mellitus in pregnancy","volume":"171","author":"Kim","year":"2020","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_3","first-page":"1189","article-title":"Anemia in pregnancy","volume":"51","author":"Lops","year":"1995","journal-title":"Am. Fam. Physician"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1903S","DOI":"10.3945\/ajcn.110.000885","article-title":"Fetal regulation of iron transport during pregnancy","volume":"94","author":"Gambling","year":"2011","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"McDonald, E.A., Gundogan, F., Olveda, R.M., Bartnikas, T.B., Kurtis, J.D., and Friedman, J.F. (2020). Iron transport across the human placenta is regulated by hepcidin. Pediatr. Res., 1\u20138.","DOI":"10.1038\/s41390-020-01201-y"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/BF03033574","article-title":"Brain iron deficiency and excess; cognitive impairment and neurodegeneration with involvement of striatum and hippocampus","volume":"14","author":"Youdim","year":"2008","journal-title":"Neurotox. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1093\/jn\/137.4.1043","article-title":"Gestational and Lactational Iron Deficiency Alters the Developing Striatal Metabolome and Associated Behaviors in Young Rats","volume":"137","author":"Ward","year":"2007","journal-title":"J. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"585","DOI":"10.3389\/fnhum.2013.00585","article-title":"Perinatal iron deficiency and neurocognitive development","volume":"7","author":"Radlowski","year":"2013","journal-title":"Front. Hum. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1203\/00006450-200008000-00009","article-title":"Perinatal Iron Deficiency Decreases Cytochrome c Oxidase (CytOx) Activity in Selected Regions of Neonatal Rat Brain","volume":"48","author":"Rao","year":"2000","journal-title":"Pediatr. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Pino, J.M.V., Nishiduka, E.S., Da Luz, M.H.M., Silva, V.F., Antunes, H.K.M., Tashima, A.K., Guedes, P.L.R., De Souza, A.A.L., and Lee, K.S. (2020). Iron-deficient diet induces distinct protein profile related to energy metabolism in the striatum and hippocampus of adult rats. Nutr. Neurosci., 1\u201312.","DOI":"10.1080\/1028415X.2020.1740862"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.bbr.2006.04.001","article-title":"Persistent neurochemical and behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deficiency anemia in rats","volume":"171","author":"Felt","year":"2006","journal-title":"Behav. Brain Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nespoli, E., Rizzo, F., Boeckers, T., Schulze, U., and Hengerer, B. (2018). Altered dopaminergic regulation of the dorsal striatum is able to induce tic-like movements in juvenile rats. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0196515"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.expneurol.2015.01.001","article-title":"Corticostriatal interactions in the generation of tic-like behaviors after local striatal disinhibition","volume":"265","author":"Pogorelov","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"152","DOI":"10.12688\/f1000research.7424.1","article-title":"Recent Advances in Understanding and Managing Tourette Syndrome","volume":"5","author":"Thenganatt","year":"2016","journal-title":"F1000Research"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1017\/S0033291716002981","article-title":"Heritability of tic disorders: A twin-family study","volume":"47","author":"Zilhao","year":"2016","journal-title":"Psychol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1001\/jamapsychiatry.2015.0627","article-title":"Familial Risks of Tourette Syndrome and Chronic Tic Disorders","volume":"72","author":"Isomura","year":"2015","journal-title":"JAMA Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.biopsych.2018.09.011","article-title":"Polygenic Risk Scores Derived From a Tourette Syndrome Genome-wide Association Study Predict Presence of Tics in the Avon Longitudinal Study of Parents and Children Cohort","volume":"85","author":"Abdulkadir","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/B978-0-444-63233-3.00023-3","article-title":"Tourette disorder and other tic disorders","volume":"147","author":"Fernandez","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41398-018-0202-y","article-title":"Striatal dopaminergic alterations in Tourette\u2019s syndrome: A meta-analysis based on 16 PET and SPECT neuroimaging studies","volume":"8","author":"Hienert","year":"2018","journal-title":"Transl. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1212\/01.wnl.0000180957.98702.69","article-title":"Caudate volumes in childhood predict symptom severity in adults with Tourette syndrome","volume":"65","author":"Bloch","year":"2005","journal-title":"Neurology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"31069","DOI":"10.1074\/jbc.M115.688275","article-title":"Dual Action of Zn2+ on the Transport Cycle of the Dopamine Transporter","volume":"290","author":"Li","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jinorgbio.2014.03.018","article-title":"Cu(II)-catalyzed oxidation of dopamine in aqueous solutions: Mechanism and kinetics","volume":"137","author":"Pham","year":"2014","journal-title":"J. Inorg. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.expneurol.2014.06.023","article-title":"Low brain iron effects and reversibility on striatal dopamine dynamics","volume":"261","author":"Unger","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.3389\/fneur.2019.01324","article-title":"The Blood Levels of Trace Elements Are Lower in Children With Tic Disorder: Results from a Retrospective Study","volume":"10","author":"Qian","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.psychres.2018.05.066","article-title":"Serum 25-hyroxyvitamin D levels and tic severity in Chinese children with tic disorders","volume":"267","author":"Li","year":"2018","journal-title":"Psychiatry Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.2147\/NDT.S212322","article-title":"Clinical improvement following vitamin D3 supplementation in children with chronic tic disorders","volume":"15","author":"Li","year":"2019","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.ijdevneu.2011.04.004","article-title":"The biological basis of injury and neuroprotection in the fetal and neonatal brain","volume":"29","author":"Rees","year":"2011","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11366","DOI":"10.1073\/pnas.1203350109","article-title":"Prenatal growth in humans and postnatal brain maturation into late adolescence","volume":"109","author":"Raznahan","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s11065-010-9148-4","article-title":"The Basics of Brain Development","volume":"20","author":"Stiles","year":"2010","journal-title":"Neuropsychol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e198714","DOI":"10.1001\/jamanetworkopen.2019.8714","article-title":"Attention-Deficit\/Hyperactivity Disorder and Mortality Risk in Taiwan","volume":"2","author":"Chen","year":"2019","journal-title":"JAMA Netw. Open"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1053\/j.semperi.2008.02.009","article-title":"Growth Abnormalities and Multiple Gestations","volume":"32","year":"2008","journal-title":"Semin. Perinatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"54.E1","DOI":"10.1016\/j.ajog.2010.02.032","article-title":"Clinical outcome in neonates with twin anemia-polycythemia sequence","volume":"203","author":"Lopriore","year":"2010","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_33","first-page":"209","article-title":"Set-up and future applications of the Taiwan Maternal and Child Health Database (TMCHD)","volume":"35","author":"Li","year":"2016","journal-title":"Taiwan Gong Gong Wei Sheng Za Zhi"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e2018062","DOI":"10.4178\/epih.e2018062","article-title":"Data resource profile: The National Health Insurance Research Database (NHIRD)","volume":"40","author":"Lin","year":"2018","journal-title":"Epidemiol. Health"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1176\/ajp.2006.163.7.1264","article-title":"Ferritin Levels and Their Association With Regional Brain Volumes in Tourette\u2019s Syndrome","volume":"163","author":"Gorman","year":"2006","journal-title":"Am. J. Psychiatry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1001\/jamapsychiatry.2019.2309","article-title":"Association of Prenatal Maternal Anemia With Neurodevelopmental Disorders","volume":"76","author":"Wiegersma","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1038\/mp.2017.31","article-title":"Perinatal risk factors in Tourette\u2019s and chronic tic disorders: A total population sibling comparison study","volume":"23","author":"Brander","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/0925-4927(94)90015-9","article-title":"Abnormal magnetic resonance imaging T2 relaxation time asymmetries in Tourette\u2019s syndrome","volume":"55","author":"Peterson","year":"1994","journal-title":"Psychiatry Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1007\/s00381-017-3424-z","article-title":"Relationship of serum ferritin level and tic severity in children with Tourette syndrome","volume":"33","author":"Ghosh","year":"2017","journal-title":"Child\u2019s Nerv. Syst."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Chen, M.-H., Su, T.-P., Chen, Y.-S., Hsu, J.-W., Huang, K.-L., Chang, W.-H., Chen, T.-J., and Bai, Y.-M. (2013). Association between psychiatric disorders and iron deficiency anemia among children and adolescents: A nationwide population-based study. BMC Psychiatry, 13.","DOI":"10.1186\/1471-244X-13-161"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1192\/bjp.bp.112.125468","article-title":"Association between pre- and perinatal exposures and Tourette syndrome or chronic tic disorder in the ALSPAC cohort","volume":"204","author":"Mathews","year":"2014","journal-title":"Br. J. Psychiatry"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1097\/EDE.0b013e31825fa230","article-title":"Sibling comparison designs: Bias from non-shared confounders and measurement error","volume":"23","author":"Frisell","year":"2012","journal-title":"Epidemiology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.3945\/jn.112.162362","article-title":"Maternal Serum Ferritin Concentration Is Positively Associated with Newborn Iron Stores in Women with Low Ferritin Status in Late Pregnancy","volume":"142","author":"Shao","year":"2012","journal-title":"J. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"118","DOI":"10.4103\/jfcm.JFCM_115_18","article-title":"Effect of maternal anemia on the status of iron stores in infants: A cohort study","volume":"26","author":"Shukla","year":"2019","journal-title":"J. Fam. Community Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1093\/ajcn\/76.1.198","article-title":"Iron absorption in breast-fed infants: Effects of age, iron status, iron supplements, and complementary foods","volume":"76","author":"Abrams","year":"2002","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Mihaila, C., Schramm, J., Strathmann, F.G., Lee, D.L., Gelein, R.M., Luebke, A.E., and Mayer-Pr\u00f6schel, M. (2011). Identifying a Window of Vulnerability during Fetal Development in a Maternal Iron Restriction Model. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017483"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.pedneo.2013.05.005","article-title":"Parental Smoking During Pregnancy and Its Association with Low Birth Weight, Small for Gestational Age, and Preterm Birth Offspring: A Birth Cohort Study","volume":"55","author":"Ko","year":"2014","journal-title":"Pediatr. Neonatol."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/10\/1038\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:16:25Z","timestamp":1760166985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/10\/1038"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,17]]},"references-count":47,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["jpm11101038"],"URL":"https:\/\/doi.org\/10.3390\/jpm11101038","relation":{},"ISSN":["2075-4426"],"issn-type":[{"type":"electronic","value":"2075-4426"}],"subject":[],"published":{"date-parts":[[2021,10,17]]}}}