{"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":1790841378646,"version":"4.1.0"},"reference-count":33,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T00:00:00Z","timestamp":1677196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"Ministry of Health of Brazil"},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["213589\/Z\/18\/Z"],"award-info":[{"award-number":["213589\/Z\/18\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["205377\/Z\/16\/Z"],"award-info":[{"award-number":["205377\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union Horizon 2020","award":["ZikaPLAN; 734584"],"award-info":[{"award-number":["ZikaPLAN; 734584"]}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Children with congenital Zika syndrome (CZS) have severe damage to the peripheral and central nervous system (CNS), greatly increasing the risk of death. However, there is no information on the sequence of the underlying, intermediate, immediate, and contributing causes of deaths among these children. The aims of this study are describe the sequence of events leading to death of children with CZS up to 36 months of age and their probability of dying from a given cause, 2015 to 2018.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and findings<\/jats:title>\n<jats:p>In a population-based study, we linked administrative data on live births, deaths, and cases of children with CZS from the SINASC (Live Birth Information System), the SIM (Mortality Information System), and the RESP (Public Health Event Records), respectively. Confirmed and probable cases of CZS were those that met the criteria established by the Brazilian Ministry of Health. The information on causes of death was collected from death certificates (DCs) using the World Health Organization (WHO) DC template. We estimated proportional mortality (PM%) among children with CZS and among children with non-Zika CNS congenital anomalies (CA) by 36 months of age and proportional mortality ratio by cause (PMRc). A total of 403 children with confirmed and probable CZS who died up to 36 months of age were included in the study; 81.9% were younger than 12 months of age. Multiple congenital malformations not classified elsewhere, and septicemia unspecified, with 18 (PM = 4.5%) and 17 (PM = 4.2%) deaths, respectively, were the most attested underlying causes of death. Unspecified septicemia (29 deaths and PM = 11.2%) and newborn respiratory failure (40 deaths and PM = 12.1%) were, respectively, the predominant intermediate and immediate causes of death. Fetuses and newborns affected by the mother\u2019s infectious and parasitic diseases, unspecified cerebral palsy, and unspecified severe protein-caloric malnutrition were the underlying causes with the greatest probability of death in children with CZS (PMRc from 10.0 to 17.0) when compared to the group born with non-Zika CNS anomalies. Among the intermediate and immediate causes of death, pneumonitis due to food or vomiting and unspecified seizures (PMRc = 9.5, each) and unspecified bronchopneumonia (PMRc = 5.0) were notable. As contributing causes, fetus and newborn affected by the mother\u2019s infectious and parasitic diseases (PMRc = 7.3), unspecified cerebral palsy, and newborn seizures (PMRc = 4.5, each) were more likely to lead to death in children with CZS than in the comparison group. The main limitations of this study were the use of a secondary database without additional clinical information and potential misclassification of cases and controls.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>The sequence of causes and circumstances involved in the deaths of the children with CZS highlights the greater vulnerability of these children to infectious and respiratory conditions compared to children with abnormalities of the CNS not related to Zika.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pmed.1004181","type":"journal-article","created":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T18:27:10Z","timestamp":1677263230000},"page":"e1004181","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Causes of death in children with congenital Zika syndrome in Brazil, 2015 to 2018: A nationwide record linkage study"],"prefix":"10.1371","volume":"20","author":[{"given":"Maria da Concei\u00e7\u00e3o N.","family":"Costa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2262-2439","authenticated-orcid":true,"given":"Luciana Lobato","family":"Cardim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia A.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6825-2867","authenticated-orcid":true,"given":"Eliene dos Santos","family":"de Jesus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Carvalho-Sauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0215-4930","authenticated-orcid":true,"given":"Mauricio L.","family":"Barreto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura C.","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Smeeth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2428-0460","authenticated-orcid":true,"given":"Lav\u00ednia","family":"Schuler-Faccini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth B.","family":"Brickley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9662-1930","authenticated-orcid":true,"given":"Wanderson K.","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo Hage","family":"Carmo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia Moreira","family":"Pescarini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9323-1400","authenticated-orcid":true,"given":"Roberto F. S.","family":"Andrade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1594-2311","authenticated-orcid":true,"given":"Moreno M. S.","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4413-193X","authenticated-orcid":true,"given":"Rafael V.","family":"Veiga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2463-445X","authenticated-orcid":true,"given":"Larissa C.","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanny V. A.","family":"Fran\u00e7a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3318-3408","authenticated-orcid":true,"given":"Maria Gloria","family":"Teixeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4797-908X","authenticated-orcid":true,"given":"Enny S.","family":"Paix\u00e3o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,2,24]]},"reference":[{"key":"pmed.1004181.ref001","doi-asserted-by":"crossref","first-page":"e0242367","DOI":"10.1371\/journal.pone.0242367","article-title":"Congenital Zika syndrome: A systematic review","volume":"15","author":"DA Freitas","year":"2020","journal-title":"PLoS ONE"},{"key":"pmed.1004181.ref002","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1056\/NEJMoa2101195","article-title":"Mortality from Congenital Zika Syndrome\u2014Nationwide Cohort Study in Brazil","volume":"386","author":"ES Paixao","year":"2022","journal-title":"N Engl J Med"},{"key":"pmed.1004181.ref003","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/S2352-4642(20)30041-9","article-title":"Neurological outcomes of congenital Zika syndrome in toddlers and preschoolers: a case series","volume":"4","author":"HVFS Pereira","year":"2020","journal-title":"Lancet Child Adolesc Health"},{"key":"pmed.1004181.ref004","article-title":"Case Fatality Rate Related to Microcephaly Congenital Zika Syndrome and Associated Factors: A Nationwide Retrospective Study in Brazil","volume":"12","author":"MCN Costa","year":"2020","journal-title":"Viruses"},{"key":"pmed.1004181.ref005","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1001\/jamapediatrics.2016.3982","article-title":"Congenital Zika syndrome: Characterizing the pattern of anomalies for pediatric healthcare providers","volume":"171","author":"CA Moore","year":"2017","journal-title":"JAMA Pediatr"},{"key":"pmed.1004181.ref006","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0125620","article-title":"The REporting of Studies Conducted Using Observational Routinely-Collected Health Data (RECORD) Statement: Methods for Arriving at Consensus and Developing Reporting Guidelines","volume":"10","author":"SG Nicholls","year":"2015","journal-title":"PLoS ONE"},{"key":"pmed.1004181.ref007","unstructured":"Brasil. 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Bahia, 2015\u20132017","volume":"82","author":"R Carvalho-Sauer","year":"2019","journal-title":"Int J Infect Dis"},{"key":"pmed.1004181.ref019","doi-asserted-by":"crossref","first-page":"e105017","DOI":"10.1371\/journal.pone.0105017","article-title":"The Immune System in Children with Malnutrition\u2014A Systematic Review","volume":"9","author":"MJH Rytter","year":"2014","journal-title":"PLoS ONE"},{"key":"pmed.1004181.ref020","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.3201\/eid2308.170354","article-title":"Characteristics of dysphagia in infants with microcephaly caused by congenital zika virus infection, Brazil, 2015","volume":"23","author":"MC Leal","year":"2017","journal-title":"Emerg Infect Dis"},{"key":"pmed.1004181.ref021","doi-asserted-by":"crossref","first-page":"876","DOI":"10.3390\/v14050876","article-title":"Anthropometric Parameters of Children with Congenital Zika Virus Exposure in the First Three Years of Life","volume":"14","author":"EB de 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children with cerebral palsy: Implications for practice","volume":"29","author":"KM Gilson","year":"2014","journal-title":"J Child Neurol"},{"key":"pmed.1004181.ref032","first-page":"49","article-title":"S\u00edndrome Cong\u00eanita do v\u00edrus Zika e a pobreza multidimensional: uma aplica\u00e7\u00e3o do m\u00e9todo Alkire-Foster com as m\u00e3es paraibanas","volume":"33","author":"E Porto da Silva","year":"2018","journal-title":"Pensam Real"},{"key":"pmed.1004181.ref033","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1002\/bdr2.1546","article-title":"Updated baseline prevalence of birth defects potentially related to Zika virus infection","volume":"111","author":"SM Olson","year":"2019","journal-title":"Birth Defects Res"}],"container-title":["PLOS 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