Brief Report: Children with a history of both maternal immune activation and prematurity are not at increased risk of ADHD

Brief Report: Children with a history of both maternal immune activation and prematurity are not at increased risk of ADHD | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Brief Report: Children with a history of both maternal immune activation and prematurity are not at increased risk of ADHD Pierre Ellul, Solène Wallez, Eric Acquaviva, Michelle Rosenzwajg, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2776943/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Aug, 2023 Read the published version in European Child & Adolescent Psychiatry → Version 1 posted 8 You are reading this latest preprint version Abstract Maternal autoimmune diseases (AID) are risk factors for Attention Deficit Hyperactivity Disorder (ADHD). Animal studies suggest that maternal immune activation (MIA) is a disease primer for ADHD, with second environmental factor precipitating the onset of the disease. Prematurity is also a major risk factor for ADHD. In this study, w e sought to explore the interaction between parental AID and prematurity on ADHD risk in a community sample. Children of AID parents born prematurely appeared at increased odds of ADHD but but these two risk facto rs do not appear to be additive (OR: 1.39 [95 CI 0.75; 2.46]). Longitudinal studies with larger numbers of participants are needed. Neurodevelopment neuroimmunology two-hit model epidemiology 1. Introduction Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by persistent difficulties with attention and/or hyperactivity-impulsivity, affecting 5.3% of children worldwide [ 1 ]. There is strong genetic involvement in the emergence of ADHD, with some candidate genes also being involved in the regulation of the immune system [ 2 ]. Environmental risk factors, such as prenatal immune-mediated events (infection or maternal AID during pregnancy), prematurity or maternal tobacco use increase the risk of ADHD. Confirming the immune hypothesis, epidemiological evidences underlie a link between maternal immune disease (AID) during pregnancy and increased risk of ADHD in children [ 3 ]. Although the exact mechanisms behind this association are not understood, it is assumed that there is a direct action of the maternal immune activation (MIA) on the fetal brain [ 4 ]. Fortunately, in the majority of pregnancies, the fetus is resilient to the effects of MIA and recent animal studies suggest that MIA is a disease primer, with perinatal or postnatal environmental factors acting as second hits, resulting in the emergence of a neurodevelopmental disorder such as ADHD [ 4 ]. Among environmental injuries, prematurity is an additional risk factor for ADHD, suspected to affect brain development, in part through inflammation [ 5 , 6 ]. The aim of this study was thus to explore the interaction between parental AID and preterm birth on the risk of ADHD. The literature exploring this so-called two-hit model in humans is limited. We hypothesized that they will act as additive factors on the risk for ADHD. To answer this question we used naturalistic data from a French national study cohort. 2. Methods 2.1 Study design and population The GAZEL cohort started in 1989 and included 20,625 participants aged 35–50 (15,011 men and 5,614 women) from employees of the French national energy and distribution company: “ Électricité de France-Gaz de France ” (EDF-GDF) [ 7 ]. At inclusion, all participants competed a detailed self-administered questionnaire encompassing demographic information and medical history. Participants have been completing yearly follow-up questionnaires. The GAZEL protocol was approved by the French authority for data confidentiality (« Commission Nationale Informatique et Liberté ») and by the Ethics Evaluation Committee of the « Institut National de la Santé et de la Recherche Médicale » (INSERM) (IRB0000388, FWA00005831). The TEMPO study is a nested cohort started in 2009 among adult children of participants of the GAZEL cohort, who had been evaluated for mental health conditions in 1991 and 1999 [ 8 ]. The aims of the TEMPO cohort was designed to test the associations between environmental risk factors and mental health conditions. Participants were followed-up in 2009, 2011, 2015 and 2018. 3,401 participated in at least one, 2,176 in at least two and 1,230 in at least 3 cohort study waves. The TEMPO study received approval of France’s national committees for data protection (CCTIRS: « Comité Consultatif sur le Traitement des Informations pour la Recherche en Santé »: CNIL: « Commission Nationale Informatique et Liberté »). 2.2 Outcomes ADHD was measured using standardized scales based on the Child Behavior Checklist (CBCL: 1½-18 years of age) and the Adult Self-Report -Achenbach system (ASR: 18–59 years of age). To ascertain life course symptoms of emotional difficulties and hyperactivity/inattention/impulsivity, longitudinal trajectories of ADHD were estimated using the Group-Based Trajectory Modeling (GBTM) method [ 9 ]. 2.3 Exposure assessment Parental autoimmune diseases were self-reported in GAZEL (1989–2018). The presence of the most common AID (mainly psoriasis, Type 1 Diabetes, dysthyroidism (hyper or hypo), Gougerot-Sjögren's syndrome) was defined as parental report on at least two occasions during the course of the follow-up period. TEMPO participants’ preterm birth (i.e., before 37 weeks of gestation) was reported by parents in 1999. To observe the effect of being exposed to both exposures, these were combined as follows: ‘Neither’, ‘Only prematurity’, ‘Only auto immune disease’, ‘Both’. 2.4 Covariates Covariates included: parental gender (“Male”, “Female”), parental age at the time of the child’s birth (“38 years old or less”, “After 38 years old”), parental occupational category (“Executive, craftsmen, shopkeepers and company managers”, “Farmers and intermediate professions”, “Employees and manual workers”), parental tobacco status (“Non-smoker”, “Former-smoker”, “Smoker”) and parental alcohol abuse (“No”, “Yes”). 2.5 Statistical analysis Participants’ characteristics according to their ADHD trajectory were tested using Pearson's Chi-square tests. All the variables with a p-value lower than 0.2, were included in the multivariate regression model. A multivariate logistic regression model was used to test associations between parental AID, child prematurity and symptom severity of ADHD. 3. Results We included 1,082 TEMPO participants (Supplementary Table 1). Two longitudinal trajectories of ADHD were identified (Supplementary Table 2), 211 (19.5%) had persistently high levels of ADHD symptoms (ADHD + ), 341 (31.5%) had a parent with AID, 313 (28.9%), had a history of preterm birth and 89 (8.2%) had both a parent with AID and a preterm birth. Among ADHD + , we observed a high occurrence of parental history of AID (p-value = 0.004), but not prematurity ( p-value = 0.5). Multivariate logistic regression analyses (Table 1 ) revealed that parental AID only, was associated with increased odds of ADHD in the offspring ( n = 252, OR: 2.04 [95 CI 1.40; 2.97] p-value < 0.001). Interestingly, both maternal ( n = 113, OR: 1.95 [95 CI 1.12; 3.44], p-value = 0.019) and paternal ( n = 139, OR: 2.03 [95 CI 1.21; 3.39], p-value = 0.007) AID were associated with ADHD. Prematurity only, also increased the odds of ADHD symptoms ( n = 224, OR: 1.66 [95 CI 1.10; 2.49], p-value = 0.01). Children born prematurely to an AID parent showed increased odds of ADHD but this association did not appear to be cumulative ( n = 89 OR: 1.39 [95 CI 0.75; 2.46] p-value = 0.3). Table 1 Association between parental autoimmune disease, child premature birth and offspring persistent symptoms of ADHD (TEMPO cohort study, France, 1991–2021, multivariate logistic regression models, OR, 95% CI) Overall (n = 1,082) Mothers (n = 372) Fathers (n = 710) Variable N OR 1 95% CI 1 p-value N OR 1 95% CI 1 p-value N OR 1 95% CI 1 p-value Parental auto immune disease and premature birth Neither 517 — — 167 — — 350 — — Only premature birth 224 1.66 1.10, 2.49 0.014 63 1.22 0.59, 2.46 0.6 161 1.95 1.18, 3.22 0.009 Only auto immune disease 252 2.04 1.40, 2.97 < 0.001 113 1.95 1.12, 3.44 0.019 139 2.03 1.21, 3.39 0.007 Both 89 1.39 0.75, 2.46 0.3 29 1.61 0.62, 3.88 0.3 60 1.28 0.55, 2.72 0.5 Child’s gender Male 536 — — 180 — — 356 — — Female 546 0.77 0.57, 1.05 0.11 192 1.01 0.62, 1.65 > 0.9 354 0.65 0.43, 0.97 0.036 Parental gender Male 710 — — Female 372 1.69 1.20, 2.38 0.003 Parental age at birth 38 years old or less 900 — — 360 — — 540 — — After 38 years old 182 2.23 1.49, 3.33 0.9 170 2.47 1.60, 3.78 0.9 Smoker 341 1.29 0.91, 1.84 0.2 124 1.20 0.70, 2.03 0.5 217 1.39 0.86, 2.24 0.2 1 OR = Odds Ratio, CI = Confidence Interval 4. Discussion To our knowledge, our study is the first to examine perinatal environmental risk factors in ADHD from a multiple hit perspective. Our results confirmed that maternal and paternal AID were associated with a similar increase in the odds of ADHD [ 10 ].. It further suggests that this association could be mediated by common genetic factors. However we were unable to detect a cumulative effect in the odds of ADHD in children born prematurely to parents with AID. Beyond the deficit of power of our analysis, our results may suggest that MIA and prematurity may increase the risk of ADHD via the same biological pathway, hence the absence of a cumulative effect. Further larger prospective studies exploring MIA with a non-immune mediated risk factor are needed to confirm our results. Declarations The GAZEL protocol was approved by the French authority for data confidentiality («Commission Nationale Informatique et Liberté») and by the Ethics Evaluation Committee of the «Institut National de la Santé et de la Recherche Médicale» (INSERM) (IRB0000388, FWA00005831). The TEMPO study received approval from France’s national committees for data protection (CCTIRS: «Comité Consultatif sur le Traitement des Informations pour la Recherche en Santé»: CNIL: «Commission Nationale Informatique et Liberté»). Author contributions: PE proposed the idea for the study and conceptualized the design in collaboration with other authors. SW analyzed the data. PE, SW and MM interpreted the data. PE wrote the first version of the article and revised it after its revisions by co-authors. All the co-authors participated in the revision of the first version of the article and approved the final version, and all agree to be accountable for all aspects of the work. Competing Interests The authors declare that they have no competing interests. References Posner J, Polanczyk GV, Sonuga-Barke E (2020) Attention-deficit hyperactivity disorder. Lancet 395:450–462. https://doi.org/10.1016/S0140-6736(19)33004-1 Cabana-Domínguez J, Soler Artigas M, Arribas L, et al (2022) Comprehensive analysis of omics data identifies relevant gene networks for Attention-Deficit/Hyperactivity Disorder (ADHD). Transl Psychiatry 12:409. https://doi.org/10.1038/s41398-022-02182-8 Nielsen TC, Nassar N, Shand AW, et al (2021) Association of Maternal Autoimmune Disease With Attention-Deficit/Hyperactivity Disorder in Children. JAMA Pediatr 175:e205487. https://doi.org/10.1001/jamapediatrics.2020.5487 Han VX, Patel S, Jones HF, Dale RC (2021) Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nat Rev Neurol 17:564–579. https://doi.org/10.1038/s41582-021-00530-8 Pierrat V, Marchand-Martin L, Marret S, et al (2021) Neurodevelopmental outcomes at age 5 among children born preterm: EPIPAGE-2 cohort study. BMJ 373:n741. https://doi.org/10.1136/bmj.n741 Tso WW-Y, Ho FKW, Coghill D, et al (2022) Preterm postnatal complications and risk of attention-deficit/hyperactivity disorder. Dev Med Child Neurol. https://doi.org/10.1111/dmcn.15401 Goldberg M, Leclerc A, Zins M (2015) Cohort Profile Update: The GAZEL Cohort Study. Int J Epidemiol 44:77–77g. https://doi.org/10.1093/ije/dyu224 Mary-Krause M, Herranz Bustamante JJ, Bolze C, et al (2021) Cohort Profile: The TEMPO Cohort Study. Int J Epidemiol 50:1067–1068k. https://doi.org/10.1093/ije/dyab026 Nagin DS, Odgers CL (2010) Group-based trajectory modeling in clinical research. Annu Rev Clin Psychol 6:109–138. https://doi.org/10.1146/annurev.clinpsy.121208.131413 Hegvik T-A, Chen Q, Kuja-Halkola R, et al (2021) Familial co-aggregation of attention-deficit/hyperactivity disorder and autoimmune diseases: a cohort study based on Swedish population-wide registers. Int J Epidemiol dyab151. https://doi.org/10.1093/ije/dyab151 Additional Declarations No competing interests reported. Supplementary Files Supplementary.docx Cite Share Download PDF Status: Published Journal Publication published 03 Aug, 2023 Read the published version in European Child & Adolescent Psychiatry → Version 1 posted Editorial decision: Major revision 23 May, 2023 Reviews received at journal 03 May, 2023 Reviewers agreed at journal 02 May, 2023 Reviewers agreed at journal 02 May, 2023 Reviewers invited by journal 02 May, 2023 Submission checks completed at journal 05 Apr, 2023 Editor assigned by journal 05 Apr, 2023 First submitted to journal 04 Apr, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2776943","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":189477797,"identity":"6796d371-80d3-47d4-9dd9-98a17b47bc81","order_by":0,"name":"Pierre Ellul","email":"","orcid":"","institution":"University of Paris Cité","correspondingAuthor":false,"prefix":"","firstName":"Pierre","middleName":"","lastName":"Ellul","suffix":""},{"id":189477798,"identity":"5640958b-e1cd-4f12-8fd7-33c75e9eb389","order_by":1,"name":"Solène Wallez","email":"","orcid":"","institution":"Sorbonne Université, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique, IPLESP, Equipe de Recherche en Epidémiologie Sociale, ERES","correspondingAuthor":false,"prefix":"","firstName":"Solène","middleName":"","lastName":"Wallez","suffix":""},{"id":189477799,"identity":"f42a6b0d-f16d-4845-8ba8-fdf48f416f1a","order_by":2,"name":"Eric Acquaviva","email":"","orcid":"","institution":"University of Paris Cité","correspondingAuthor":false,"prefix":"","firstName":"Eric","middleName":"","lastName":"Acquaviva","suffix":""},{"id":189477800,"identity":"74c0d903-1eb3-4a5f-adc0-903c112e0dc1","order_by":3,"name":"Michelle Rosenzwajg","email":"","orcid":"","institution":"INSERM U959, Sorbonne University","correspondingAuthor":false,"prefix":"","firstName":"Michelle","middleName":"","lastName":"Rosenzwajg","suffix":""},{"id":189477801,"identity":"0d03e024-7914-4cc9-b3ff-c94919e8607e","order_by":4,"name":"David Klatzmann","email":"","orcid":"","institution":"INSERM U959, Sorbonne University","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Klatzmann","suffix":""},{"id":189477802,"identity":"9bdf8f83-413b-42ea-bf51-8414c6590c83","order_by":5,"name":"Richard Delorme","email":"","orcid":"","institution":"University of Paris Cité","correspondingAuthor":false,"prefix":"","firstName":"Richard","middleName":"","lastName":"Delorme","suffix":""},{"id":189477803,"identity":"aae33309-ebce-4f0e-ab57-7f902d9ea284","order_by":6,"name":"Maria Melchior","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIie3OvWoCQRDA8YGDsxm0tRB9gsDIgUEQfRVFWJslae2SSps8wIHvkSrFLAtW6rYHW0ngKgs1TQqL7HFahfVai/0Xy37wYxYgFHrQuFjqgMVmgNfLdjWJSyJuJKkeVRCXvp395Gm53fMvfLbj2lbx6cu0nht6fc6AXn2kt5mR+gCbxPgyVmlusZ+K6UoC9d99hAUwgp0smkga2SJlmEQSLuSdYnJQF7BvV7JDMubHEfKTTIB2U8ZxSRiJZVRBctAtst0FSlIpT93HhPsY3SFGRKfD3HYatU1yPPJwREZ/R3LuJ2X/nytAKBQKhe73B4CwVEn+2hH4AAAAAElFTkSuQmCC","orcid":"","institution":"Sorbonne Université, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique, IPLESP, Equipe de Recherche en Epidémiologie Sociale, ERES","correspondingAuthor":true,"prefix":"","firstName":"Maria","middleName":"","lastName":"Melchior","suffix":""}],"badges":[],"createdAt":"2023-04-04 14:00:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2776943/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2776943/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00787-023-02276-8","type":"published","date":"2023-08-03T21:49:54+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":44736194,"identity":"3b816f73-dccc-40c8-b71d-e327152fe50f","added_by":"auto","created_at":"2023-10-16 22:29:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":281722,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2776943/v1/82e41eb7-fa56-4d0d-897a-4078f61aa80b.pdf"},{"id":35430002,"identity":"21461aa4-d5ba-470b-8a4d-2c39276c6fea","added_by":"auto","created_at":"2023-04-07 06:00:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21455,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-2776943/v1/414bedf6d9bf5c161e719c81.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Brief Report: Children with a history of both maternal immune activation and prematurity are not at increased risk of ADHD","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAttention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by persistent difficulties with attention and/or hyperactivity-impulsivity, affecting 5.3% of children worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. There is strong genetic involvement in the emergence of ADHD, with some candidate genes also being involved in the regulation of the immune system [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Environmental risk factors, such as prenatal immune-mediated events (infection or maternal AID during pregnancy), prematurity or maternal tobacco use increase the risk of ADHD. Confirming the immune hypothesis, epidemiological evidences underlie a link between maternal immune disease (AID) during pregnancy and increased risk of ADHD in children [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although the exact mechanisms behind this association are not understood, it is assumed that there is a direct action of the maternal immune activation (MIA) on the fetal brain [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Fortunately, in the majority of pregnancies, the fetus is resilient to the effects of MIA and recent animal studies suggest that MIA is a disease primer, with perinatal or postnatal environmental factors acting as second hits, resulting in the emergence of a neurodevelopmental disorder such as ADHD [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Among environmental injuries, prematurity is an additional risk factor for ADHD, suspected to affect brain development, in part through inflammation [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe aim of this study was thus to explore the interaction between parental AID and preterm birth on the risk of ADHD. The literature exploring this so-called two-hit model in humans is limited. We hypothesized that they will act as additive factors on the risk for ADHD. To answer this question we used naturalistic data from a French national study cohort.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design and population\u003c/h2\u003e \u003cp\u003eThe GAZEL cohort started in 1989 and included 20,625 participants aged 35\u0026ndash;50 (15,011 men and 5,614 women) from employees of the French national energy and distribution company: \u0026ldquo;\u003cem\u003e\u0026Eacute;lectricit\u0026eacute; de France-Gaz de France\u003c/em\u003e\u0026rdquo; (EDF-GDF) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. At inclusion, all participants competed a detailed self-administered questionnaire encompassing demographic information and medical history. Participants have been completing yearly follow-up questionnaires. The GAZEL protocol was approved by the French authority for data confidentiality (\u0026laquo;\u003cem\u003eCommission Nationale Informatique et Libert\u0026eacute;\u003c/em\u003e\u0026raquo;) and by the Ethics Evaluation Committee of the \u0026laquo;\u003cem\u003eInstitut National de la Sant\u0026eacute; et de la Recherche M\u0026eacute;dicale\u003c/em\u003e\u0026raquo; (INSERM) (IRB0000388, FWA00005831).\u003c/p\u003e \u003cp\u003eThe TEMPO study is a nested cohort started in 2009 among adult children of participants of the GAZEL cohort, who had been evaluated for mental health conditions in 1991 and 1999 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The aims of the TEMPO cohort was designed to test the associations between environmental risk factors and mental health conditions. Participants were followed-up in 2009, 2011, 2015 and 2018. 3,401 participated in at least one, 2,176 in at least two and 1,230 in at least 3 cohort study waves. The TEMPO study received approval of France\u0026rsquo;s national committees for data protection (CCTIRS: \u0026laquo; \u003cem\u003eComit\u0026eacute; Consultatif sur le Traitement des Informations pour la Recherche en Sant\u0026eacute;\u003c/em\u003e \u0026raquo;: CNIL: \u0026laquo; \u003cem\u003eCommission Nationale Informatique et Libert\u0026eacute;\u003c/em\u003e \u0026raquo;).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Outcomes\u003c/h2\u003e \u003cp\u003eADHD was measured using standardized scales based on the Child Behavior Checklist (CBCL: 1\u0026frac12;-18 years of age) and the Adult Self-Report -Achenbach system (ASR: 18\u0026ndash;59 years of age). To ascertain life course symptoms of emotional difficulties and hyperactivity/inattention/impulsivity, longitudinal trajectories of ADHD were estimated using the Group-Based Trajectory Modeling (GBTM) method [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Exposure assessment\u003c/h2\u003e \u003cp\u003eParental autoimmune diseases were self-reported in GAZEL (1989\u0026ndash;2018). The presence of the most common AID (mainly psoriasis, Type 1 Diabetes, dysthyroidism (hyper or hypo), Gougerot-Sj\u0026ouml;gren's syndrome) was defined as parental report on at least two occasions during the course of the follow-up period. TEMPO participants\u0026rsquo; preterm birth (i.e., before 37 weeks of gestation) was reported by parents in 1999. To observe the effect of being exposed to both exposures, these were combined as follows: \u0026lsquo;Neither\u0026rsquo;, \u0026lsquo;Only prematurity\u0026rsquo;, \u0026lsquo;Only auto immune disease\u0026rsquo;, \u0026lsquo;Both\u0026rsquo;.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Covariates\u003c/h2\u003e \u003cp\u003eCovariates included: parental gender (\u0026ldquo;Male\u0026rdquo;, \u0026ldquo;Female\u0026rdquo;), parental age at the time of the child\u0026rsquo;s birth (\u0026ldquo;38 years old or less\u0026rdquo;, \u0026ldquo;After 38 years old\u0026rdquo;), parental occupational category (\u0026ldquo;Executive, craftsmen, shopkeepers and company managers\u0026rdquo;, \u0026ldquo;Farmers and intermediate professions\u0026rdquo;, \u0026ldquo;Employees and manual workers\u0026rdquo;), parental tobacco status (\u0026ldquo;Non-smoker\u0026rdquo;, \u0026ldquo;Former-smoker\u0026rdquo;, \u0026ldquo;Smoker\u0026rdquo;) and parental alcohol abuse (\u0026ldquo;No\u0026rdquo;, \u0026ldquo;Yes\u0026rdquo;).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical analysis\u003c/h2\u003e \u003cp\u003eParticipants\u0026rsquo; characteristics according to their ADHD trajectory were tested using Pearson's Chi-square tests. All the variables with a p-value lower than 0.2, were included in the multivariate regression model. A multivariate logistic regression model was used to test associations between parental AID, child prematurity and symptom severity of ADHD.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eWe included 1,082 TEMPO participants (Supplementary Table\u0026nbsp;1). Two longitudinal trajectories of ADHD were identified (Supplementary Table\u0026nbsp;2), 211 (19.5%) had persistently high levels of ADHD symptoms (ADHD\u003csup\u003e+\u003c/sup\u003e), 341 (31.5%) had a parent with AID, 313 (28.9%), had a history of preterm birth and 89 (8.2%) had both a parent with AID and a preterm birth. Among ADHD\u003csup\u003e+\u003c/sup\u003e, we observed a high occurrence of parental history of AID (p-value\u0026thinsp;=\u0026thinsp;0.004), but not prematurity (\u003cem\u003ep-value\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.5).\u003c/p\u003e \u003cp\u003eMultivariate logistic regression analyses (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) revealed that parental AID only, was associated with increased odds of ADHD in the offspring (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;252, OR: 2.04 [95 CI 1.40; 2.97] \u003cem\u003ep-value\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Interestingly, both maternal (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;113, OR: 1.95 [95 CI 1.12; 3.44], \u003cem\u003ep-value\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019) and paternal (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;139, OR: 2.03 [95 CI 1.21; 3.39], \u003cem\u003ep-value\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007) AID were associated with ADHD. Prematurity only, also increased the odds of ADHD symptoms (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;224, OR: 1.66 [95 CI 1.10; 2.49], \u003cem\u003ep-value\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01). Children born prematurely to an AID parent showed increased odds of ADHD but this association did not appear to be cumulative (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;89 OR: 1.39 [95 CI 0.75; 2.46] \u003cem\u003ep-value\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAssociation between parental autoimmune disease, child premature birth and offspring persistent symptoms of ADHD (TEMPO cohort study, France, 1991\u0026ndash;2021, multivariate logistic regression models, OR, 95% CI)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"13\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1,082)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eMothers\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;372)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c13\" namest=\"c10\"\u003e \u003cp\u003eFathers\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;710)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOR\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95% CI\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e95% CI\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOR\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e95% CI\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParental auto immune disease and premature birth\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeither\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e517\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e350\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOnly premature birth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e224\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.10, 2.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.59, 2.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1.18, 3.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOnly auto immune disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e252\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.40, 2.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.12, 3.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.019\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e139\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1.21, 3.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e0.007\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBoth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75, 2.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.62, 3.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.55, 2.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChild\u0026rsquo;s gender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e536\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e356\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e546\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.57, 1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e192\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.62, 1.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e354\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.43, 0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e0.036\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParental gender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e710\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e372\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.20, 2.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParental age at birth\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e38 years old or less\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e900\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e360\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e540\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAfter 38 years old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.49, 3.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.23, 3.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1.60, 3.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParental tobacco status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e454\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e189\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e265\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer-smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e287\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.59, 1.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.35, 1.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e228\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.59, 1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e341\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.91, 1.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.70, 2.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e217\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.86, 2.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"13\" nameend=\"c13\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e1\u003c/sup\u003eOR = Odds Ratio, CI\u0026thinsp;=\u0026thinsp;Confidence Interval\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e\u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eTo our knowledge, our study is the first to examine perinatal environmental risk factors in ADHD from a multiple hit perspective. Our results confirmed that maternal and paternal AID were associated with a similar increase in the odds of ADHD [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].. It further suggests that this association could be mediated by common genetic factors. However we were unable to detect a cumulative effect in the odds of ADHD in children born prematurely to parents with AID. Beyond the deficit of power of our analysis, our results may suggest that MIA and prematurity may increase the risk of ADHD via the same biological pathway, hence the absence of a cumulative effect. Further larger prospective studies exploring MIA with a non-immune mediated risk factor are needed to confirm our results.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe GAZEL protocol was approved by the French authority for data confidentiality (\u0026laquo;Commission Nationale Informatique et Libert\u0026eacute;\u0026raquo;) and by the Ethics Evaluation Committee of the \u0026laquo;Institut National de la Sant\u0026eacute; et de la Recherche M\u0026eacute;dicale\u0026raquo; (INSERM) (IRB0000388, FWA00005831).\u003c/p\u003e\n\u003cp\u003eThe TEMPO study received approval from France\u0026rsquo;s national committees for data protection (CCTIRS: \u0026laquo;Comit\u0026eacute; Consultatif sur le Traitement des Informations pour la Recherche en Sant\u0026eacute;\u0026raquo;: CNIL: \u0026laquo;Commission Nationale Informatique et Libert\u0026eacute;\u0026raquo;).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePE proposed the idea for the study and conceptualized the design in collaboration with other authors. SW analyzed the data. PE, SW and MM interpreted the data. PE wrote the first version of the article and revised it after its revisions by co-authors. All the co-authors participated in the revision of the first version of the article and approved the final version, and all agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePosner J, Polanczyk GV, Sonuga-Barke E (2020) Attention-deficit hyperactivity disorder. Lancet 395:450\u0026ndash;462. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0140-6736(19)33004-1\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(19)33004-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCabana-Dom\u0026iacute;nguez J, Soler Artigas M, Arribas L, et al (2022) Comprehensive analysis of omics data identifies relevant gene networks for Attention-Deficit/Hyperactivity Disorder (ADHD). 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Int J Epidemiol dyab151. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/ije/dyab151\u003c/span\u003e\u003cspan address=\"10.1093/ije/dyab151\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-child-and-adolescent-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ecap","sideBox":"Learn more about [European Child \u0026 Adolescent Psychiatry](http://link.springer.com/journal/787)","snPcode":"787","submissionUrl":"https://submission.nature.com/new-submission/787/3","title":"European Child \u0026 Adolescent Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Neurodevelopment, neuroimmunology, two-hit model, epidemiology","lastPublishedDoi":"10.21203/rs.3.rs-2776943/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2776943/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMaternal autoimmune diseases (AID) are risk factors for Attention Deficit Hyperactivity Disorder (ADHD). Animal studies suggest that maternal immune activation (MIA) is a disease primer for ADHD, with second environmental factor precipitating the onset of the disease. Prematurity is also a major risk factor for ADHD. \u003cb\u003eIn this study, w\u003c/b\u003ee sought to explore the interaction between parental AID and prematurity on ADHD risk in a community sample. Children of AID parents born prematurely appeared at increased odds of ADHD but but these two risk facto\u003cb\u003ers do not appear to be additive\u003c/b\u003e (OR: 1.39 [95 CI 0.75; 2.46]). Longitudinal studies with larger numbers of participants are needed.\u003c/p\u003e","manuscriptTitle":"Brief Report: Children with a history of both maternal immune activation and prematurity are not at increased risk of ADHD","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-04-07 06:00:10","doi":"10.21203/rs.3.rs-2776943/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-05-23T18:23:23+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-05-03T05:15:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"b94ab51f-a8e6-49d8-8144-57a0bb75c00a","date":"2023-05-02T14:29:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"04cd7b77-b802-4b94-ae40-1c13871638b6","date":"2023-05-02T14:27:52+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-05-02T14:22:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-04-05T16:35:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-04-05T16:35:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Child \u0026 Adolescent Psychiatry","date":"2023-04-04T14:00:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-child-and-adolescent-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ecap","sideBox":"Learn more about [European Child \u0026 Adolescent Psychiatry](http://link.springer.com/journal/787)","snPcode":"787","submissionUrl":"https://submission.nature.com/new-submission/787/3","title":"European Child \u0026 Adolescent Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7b0a3d6c-14dd-43af-bcd1-2ffc46d88f95","owner":[],"postedDate":"April 7th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T22:18:55+00:00","versionOfRecord":{"articleIdentity":"rs-2776943","link":"https://doi.org/10.1007/s00787-023-02276-8","journal":{"identity":"european-child-and-adolescent-psychiatry","isVorOnly":false,"title":"European Child \u0026 Adolescent Psychiatry"},"publishedOn":"2023-08-03 21:49:54","publishedOnDateReadable":"August 3rd, 2023"},"versionCreatedAt":"2023-04-07 06:00:10","video":"","vorDoi":"10.1007/s00787-023-02276-8","vorDoiUrl":"https://doi.org/10.1007/s00787-023-02276-8","workflowStages":[]},"version":"v1","identity":"rs-2776943","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2776943","identity":"rs-2776943","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}