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      Health outcomes associated with Zika virus infection in humans: a systematic review of systematic reviews

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          Abstract

          Objective

          With the emergence of Zika virus (ZIKV) disease in Central and South America in the mid-2010s and recognition of the teratogenic effects of congenital exposure to ZIKV, there has been a substantial increase in new research published on ZIKV. Our objective is to synthesise the literature on health outcomes associated with ZIKV infection in humans.

          Methods

          We conducted a systematic review (SR) of SRs following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched MEDLINE, Embase, Cochrane and LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde) databases from inception to 22 July 2019, and included SRs that reported ZIKV-associated health outcomes. Three independent reviewers selected eligible studies, extracted data and assessed the quality of included SRs using the AMSTAR 2 (A MeaSurement Tool to Assess Systematic Reviews 2) tool. Conflicts were resolved by consensus or consultation with a third reviewer.

          Results

          The search yielded 1382 unique articles, of which 21 SRs met our inclusion criteria. The 21 SRs ranged from descriptive to quantitative data synthesis, including four meta-analyses. The most commonly reported ZIKV-associated manifestations and health outcomes were microcephaly, congenital abnormalities, brain abnormalities, neonatal death and Guillain-Barré syndrome. The included reviews were highly heterogeneous. The overall quality of the SRs was critically low with all studies having more than one critical weakness.

          Conclusion

          The evolving nature of the literature on ZIKV-associated health outcomes, together with the critically low quality of existing SRs, demonstrates the need for high-quality SRs to guide patient care and inform policy decision making.

          PROSPERO registration number

          CRD42018091087.

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          Most cited references30

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          Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation.

          In November, 2015, an epidemic of microcephaly was reported in Brazil, which was later attributed to congenital Zika virus infection. 7830 suspected cases had been reported to the Brazilian Ministry of Health by June 4, 2016, but little is known about their characteristics. We aimed to describe these newborn babies in terms of clinical findings, anthropometry, and survival.
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            Zika Virus Infection as a Cause of Congenital Brain Abnormalities and Guillain–Barré Syndrome: Systematic Review

            Background The World Health Organization (WHO) stated in March 2016 that there was scientific consensus that the mosquito-borne Zika virus was a cause of the neurological disorder Guillain–Barré syndrome (GBS) and of microcephaly and other congenital brain abnormalities based on rapid evidence assessments. Decisions about causality require systematic assessment to guide public health actions. The objectives of this study were to update and reassess the evidence for causality through a rapid and systematic review about links between Zika virus infection and (a) congenital brain abnormalities, including microcephaly, in the foetuses and offspring of pregnant women and (b) GBS in any population, and to describe the process and outcomes of an expert assessment of the evidence about causality. Methods and Findings The study had three linked components. First, in February 2016, we developed a causality framework that defined questions about the relationship between Zika virus infection and each of the two clinical outcomes in ten dimensions: temporality, biological plausibility, strength of association, alternative explanations, cessation, dose–response relationship, animal experiments, analogy, specificity, and consistency. Second, we did a systematic review (protocol number CRD42016036693). We searched multiple online sources up to May 30, 2016 to find studies that directly addressed either outcome and any causality dimension, used methods to expedite study selection, data extraction, and quality assessment, and summarised evidence descriptively. Third, WHO convened a multidisciplinary panel of experts who assessed the review findings and reached consensus statements to update the WHO position on causality. We found 1,091 unique items up to May 30, 2016. For congenital brain abnormalities, including microcephaly, we included 72 items; for eight of ten causality dimensions (all except dose–response relationship and specificity), we found that more than half the relevant studies supported a causal association with Zika virus infection. For GBS, we included 36 items, of which more than half the relevant studies supported a causal association in seven of ten dimensions (all except dose–response relationship, specificity, and animal experimental evidence). Articles identified nonsystematically from May 30 to July 29, 2016 strengthened the review findings. The expert panel concluded that (a) the most likely explanation of available evidence from outbreaks of Zika virus infection and clusters of microcephaly is that Zika virus infection during pregnancy is a cause of congenital brain abnormalities including microcephaly, and (b) the most likely explanation of available evidence from outbreaks of Zika virus infection and GBS is that Zika virus infection is a trigger of GBS. The expert panel recognised that Zika virus alone may not be sufficient to cause either congenital brain abnormalities or GBS but agreed that the evidence was sufficient to recommend increased public health measures. Weaknesses are the limited assessment of the role of dengue virus and other possible cofactors, the small number of comparative epidemiological studies, and the difficulty in keeping the review up to date with the pace of publication of new research. Conclusions Rapid and systematic reviews with frequent updating and open dissemination are now needed both for appraisal of the evidence about Zika virus infection and for the next public health threats that will emerge. This systematic review found sufficient evidence to say that Zika virus is a cause of congenital abnormalities and is a trigger of GBS.
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              Zika virus infection complicated by Guillain-Barré syndrome – case report, French Polynesia, December 2013

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                Author and article information

                Journal
                BMJ Open
                BMJ Open
                bmjopen
                bmjopen
                BMJ Open
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2044-6055
                2019
                3 November 2019
                : 9
                : 11
                : e032275
                Affiliations
                [1 ] departmentToronto Health Economics and Technology Assessment (THETA) Collaborative , University Health Network , Toronto, Ontario, Canada
                [2 ] departmentInstitute of Health Policy, Management and Evaluation , University of Toronto , Toronto, Ontario, Canada
                [3 ] departmentDivision of Infectious Diseases and Centre for Global Child Health , Hospital for Sick Children , Toronto, Ontario, Canada
                [4 ] departmentDepartment of Pediatrics , Faculty of Medicine, University of Toronto , Toronto, Ontario, Canada
                [5 ] departmentDepartment of Obstetrics and Gynecology , Mount Sinai Hospital , Toronto, Ontario, Canada
                [6 ] Public Health Ontario , Toronto, Ontario, Canada
                [7 ] ICES , Toronto, Ontario, Canada
                Author notes
                [Correspondence to ] Dr Raphael Ximenes; raphael.ximenes@ 123456theta.utoronto.ca
                Author information
                http://orcid.org/0000-0003-2536-951X
                Article
                bmjopen-2019-032275
                10.1136/bmjopen-2019-032275
                6858219
                31685512
                1e336ba4-530b-4548-8ac7-6953bea1e626
                © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

                History
                : 12 June 2019
                : 25 September 2019
                : 27 September 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000193, International Development Research Centre;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Award ID: FRN149784
                Categories
                Infectious Diseases
                Original Research
                1506
                1706
                Custom metadata
                unlocked

                Medicine
                zika virus infection,epidemiology,congenital zika syndrome,neurology,guillain-barré syndrome,microcephaly

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