{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:56:18Z","timestamp":1790841378611,"version":"4.1.0"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.22430.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T00:00:00Z","timestamp":1729123200000}}],"reference-count":49,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T00:00:00Z","timestamp":1729123200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["225925"],"award-info":[{"award-number":["225925"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns3:p>Background In utero exposure to infections might set the stage for a chain of events leading to a wide spectrum of long-term health outcomes observed in children and adolescents. This proposal aims to investigate whether syphilis, zika, dengue and chikungunya during pregnancy can increase the risk of the offspring developing a non-infectious chronic condition during childhood and adolescence. Objectives 1) Estimate the risk of non-infectious chronic conditions associated to syphilis, zika, dengue and chikungunya during pregnancy and when appropriate, explore if the risk varies by timing during pregnancy when the infection is acquired (first, second or third trimester) and severity (such as severe or mild dengue); 2) Investigate whether in uterus exposure to maternal infection affects the growth pattern of children and adolescents; 3) Examine the extent to which the relationship between maternal infection and non-infectious chronic outcomes are mediated by intrauterine growth restriction and preterm birth. Methods We will compare health outcomes and growth trajectories of children and adolescents born to mothers with and without specific infections during pregnancy using conventional multivariable regression in the whole study population, in a within sibship design, using the subgroup of offspring with at least one sibling who is not exposed to the infection, and negative control outcome. Then we will decompose the direct and mediated effects (by preterm birth and small for gestational age) of maternal infection on chronic disorders. Results and Conclusions The results from this study will advance our understanding of the relationship between infections during pregnancy and chronic disorders, with widespread implications enabling targeting of critical points along the path from in utero exposure to outcomes to avoid or mitigate illness and disability over the life course.<\/ns3:p>","DOI":"10.12688\/wellcomeopenres.22430.2","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T11:30:14Z","timestamp":1729164614000},"page":"320","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["A nationwide longitudinal investigation on the role of prenatal exposure to infectious diseases on the onset of chronic conditions in children and adolescents in Brazil"],"prefix":"10.12688","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4797-908X","authenticated-orcid":false,"given":"Enny 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Choi","year":"2016","journal-title":"Science."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"e817-25","DOI":"10.1542\/peds.2008-3582","article-title":"Can association between preterm birth and autism be explained by maternal or neonatal morbidity?","volume":"124","author":"S Buchmayer","year":"2009","journal-title":"Pediatrics."},{"key":"ref-6","doi-asserted-by":"publisher","first-page":"1150-1158","DOI":"10.1001\/jamaoncol.2019.1215","article-title":"Association between birth defects and cancer risk among children and adolescents in a population-based assessment of 10 million live births.","volume":"5","author":"P Lupo","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"98-109","DOI":"10.1016\/j.jpeds.2019.10.046","article-title":"Maternal infection in pregnancy and childhood leukemia: a systematic review and meta-analysis.","volume":"217","author":"J He","year":"2020","journal-title":"J Pediatr."},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"406-415","DOI":"10.1038\/bjc.1997.399","article-title":"Leukaemia and non-Hodgkin\u2019s lymphoma in children and young adults: are prenatal and neonatal factors important determinants of disease?","volume":"76","author":"E Roman","year":"1997","journal-title":"Br J Cancer."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"509-11","DOI":"10.1136\/bmj.290.6467.509","article-title":"Long term effects of exposure to viral infections in utero.","volume":"290","author":"P Fine","year":"1985","journal-title":"Br Med J (Clin Res Ed)."},{"key":"ref-10","doi-asserted-by":"publisher","first-page":"2885-90","DOI":"10.1002\/ijc.23847","article-title":"Prenatal and perinatal risk factors for neuroblastoma.","volume":"123","author":"E Bluhm","year":"2008","journal-title":"Int J Cancer."},{"key":"ref-11","doi-asserted-by":"publisher","first-page":"100-5","DOI":"10.1016\/j.bbi.2014.09.001","article-title":"Maternal 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(Lond)."},{"key":"ref-33","doi-asserted-by":"publisher","first-page":"37-38","DOI":"10.1093\/ije\/dyaa255","article-title":"Cohort profile: Centro de Integra\u00e7\u00e3o de Dados e Conhecimentos para Sa\u00fade (CIDACS) birth cohort.","volume":"50","author":"E Paixao","year":"2021","journal-title":"Int J Epidemiol."},{"key":"ref-34","doi-asserted-by":"publisher","first-page":"183-8","DOI":"10.1590\/0103-0582201432306","article-title":"Evaluation of data on live birth certificates from the information system on live births (SINASC) in campinas, s\u00e3o paulo, 2009.","volume":"32","author":"G Gabriel","year":"2014","journal-title":"Rev Paul Pediatr."},{"key":"ref-35","doi-asserted-by":"publisher","DOI":"10.1590\/0102-311X00214918","article-title":"Evaluation of data from the brazilian information system on live births (SINASC).","volume":"35","author":"C Szwarcwald","year":"2019","journal-title":"Cadernos de Saude Publica."},{"key":"ref-36","doi-asserted-by":"publisher","first-page":"1721-30","DOI":"10.1590\/0102-311x00131113","article-title":"Evolution of the deaths registry system in Brazil: associations with changes in the mortality profile, under-registration of death counts, and ill-defined causes of death.","volume":"30","author":"E De Lima","year":"2014","journal-title":"Cad Saude Publica."},{"key":"ref-37","article-title":"Portaria no 264, de 17 de Fevereiro de 2020.","year":"2020"},{"key":"ref-38","article-title":"SIM. Sistema de Informa\u00e7\u00f5es sobre Mortalidade.","year":"2017","journal-title":"Datasus."},{"key":"ref-39","doi-asserted-by":"publisher","DOI":"10.1590\/1980-549720190028","article-title":"Cobertura da avalia\u00e7\u00e3o do consumo alimentar no sistema de vigil\u00e2ncia alimentar e nutricional Brasileiro: 2008 a 2013.","volume":"22","author":"F do Nascimento","year":"2019","journal-title":"Rev Bras Epidemiol."},{"key":"ref-40","doi-asserted-by":"publisher","DOI":"10.1186\/s12911-020-01285-w","article-title":"CIDACS-RL: a novel indexing search and scoring-based record linkage system for huge datasets with high accuracy and scalability.","volume":"20","author":"G Barbosa","year":"2020","journal-title":"BMC Med Inform Decis Mak."},{"key":"ref-41","doi-asserted-by":"publisher","first-page":"62","DOI":"10.11606\/s1518-8787.2023057004655","article-title":"Quality of child anthropometric data from SISVAN, Brazil, 2008\u20132017.","volume":"57","author":"N Silva","year":"2023","journal-title":"Rev Saude Publica."},{"key":"ref-42","doi-asserted-by":"publisher","first-page":"1558-66","DOI":"10.1093\/ije\/dyq115","article-title":"SITAR\u2014a useful instrument for growth curve analysis.","volume":"39","author":"T Cole","year":"2010","journal-title":"Int J Epidemiol."},{"key":"ref-43","doi-asserted-by":"publisher","first-page":"3555-3570","DOI":"10.1002\/sim.7693","article-title":"Comparing predictive abilities of longitudinal child growth models.","volume":"38","author":"C Anderson","year":"2019"},{"key":"ref-44","doi-asserted-by":"publisher","first-page":"1-51","DOI":"10.18637\/jss.v106.i07","article-title":"Broken stick model for irregular longitudinal data.","volume":"106","author":"S van Buuren","year":"2023","journal-title":"J Stat Softw."},{"key":"ref-45","doi-asserted-by":"crossref","first-page":"37-48","DOI":"10.1097\/00001648-199901000-00008","article-title":"Causal diagrams for epidemiologic research.","volume":"10","author":"S Greenland","year":"1999","journal-title":"Epidemiology."},{"key":"ref-46","doi-asserted-by":"publisher","first-page":"1895-1903","DOI":"10.1093\/ije\/dyw328","article-title":"Causal inference-so much more than statistics.","volume":"45","author":"N Pearce","year":"2016","journal-title":"Int J Epidemiol."},{"key":"ref-47","doi-asserted-by":"publisher","first-page":"1866-1886","DOI":"10.1093\/ije\/dyw314","article-title":"Triangulation in aetiological epidemiology.","volume":"45","author":"D Lawlor","year":"2016","journal-title":"Int J Epidemiol."},{"key":"ref-48","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-019-1716-1","article-title":"A practical guide to methods controlling false discoveries in computational biology.","volume":"20","author":"K Korthauer","year":"2019","journal-title":"Genome Biol."},{"key":"ref-49","doi-asserted-by":"publisher","first-page":"1511-9","DOI":"10.1093\/ije\/dyt127","article-title":"Mediation analysis in epidemiology: methods, interpretation and 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.24711.r87456, Aja Louise Murray, The University of Edinburgh, Edinburgh, Scotland, 05 Aug 2024, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-320\/v1#referee-response-87456","order":0,"name":"referee-response-87456","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.25534.r105818, Anna Suleri, Erasmus University Medical Center, Rotterdam, 18 Oct 2024, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-320\/v2#referee-response-105818","order":1,"name":"referee-response-105818","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.25534.r112835, Marisa M Mussi-Pinhata, Department of Pediatrics, University of S\u00e3o Paulo, S\u00e3o Paulo, 25 Nov 2024, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-320\/v2#referee-response-112835","order":2,"name":"referee-response-112835","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Enny Paixao Cruz<\/b>; \n<i>Posted: 11 Mar 2025<\/i>; Thank you very much for your comments and for taking the time to review the protocol. We agree with both challenges you raised regarding asymptomatic infections and the characteristics of individuals in the Cad&Uacute;nico dataset. We have addressed these points in the&nbsp;material. In Table 2, we\u2019ve outlined the criteria used to diagnose infection in Brazil and clarified that infections such as dengue will present with symptoms. Additionally, we\u2019ve noted that the CIDACS Birth Cohort includes Brazilian live births whose families applied for social government benefits, representing the poorest half of the Brazilian population. I agree that we will only be able to answer the question of whether symptomatic infection increases the risk of the studied outcomes for diseases without universal screening, such as dengue, Zika, and chikungunya. However, regarding the study population, although it includes the poorest segment of the population, I believe that most of the findings will still be generalizable to the broader Brazilian population and even to other populations, as we are studying underlying biological mechanisms. I\u2019m happy to discuss this further if needed.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-320\/v2#referee-comment-6071","order":3,"name":"referee-comment-6071","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.25534.r107346, Suan-Sin Foo, Lerner Research Institute, Cleveland Clinic, Cleveland, 02 Dec 2024, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-320\/v2#referee-response-107346","order":4,"name":"referee-response-107346","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by Wellcome [225925]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":5,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}