title: Zika Virus Infection as a Cause of Congenital Brain Abnormalities and Guillain-Barré Syndrome: Systematic Review.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Institute of Social and Preventive Medicine, University of Bern, Switzerland.
authors.forename: Fabienne
authors.identifier: http://orcid.org/0000-0001-8341-4011
authors.initials: F
authors.lastname: Krauer
authors.affiliation: Institute of Social and Preventive Medicine, University of Bern, Switzerland.
authors.forename: Maurane
authors.identifier: http://orcid.org/0000-0002-3460-1758
authors.initials: M
authors.lastname: Riesen
authors.affiliation: Pan American Health Organization, Washington DC, United States of America.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Reveiz
authors.affiliation: UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland.
authors.forename: Olufemi T
authors.initials: OT
authors.lastname: Oladapo
authors.affiliation: Escuela de Microbiologia, Universidad Industrial de Santander, Santander, Colombia.
authors.forename: Ruth
authors.initials: R
authors.lastname: Martínez-Vega
authors.affiliation: UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland.|Department of Social and Preventative Medicine, Laval University, Québec, Canada.
authors.forename: Teegwendé V
authors.identifier: http://orcid.org/0000-0003-0298-0711
authors.initials: TV
authors.lastname: Porgo
authors.affiliation: Institute of Social and Preventive Medicine, University of Bern, Switzerland.
authors.forename: Anina
authors.initials: A
authors.lastname: Haefliger
authors.affiliation: UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland.
authors.forename: Nathalie J
authors.identifier: http://orcid.org/0000-0002-3665-4861
authors.initials: NJ
authors.lastname: Broutet
authors.affiliation: Institute of Social and Preventive Medicine, University of Bern, Switzerland.
authors.forename: Nicola
authors.identifier: http://orcid.org/0000-0003-4817-8986
authors.initials: N
authors.lastname: Low
mesh_terms: D001921:Brain / Q000002:abnormalities* / Q000821:virology; D005333:Fetus / Q000002:abnormalities* / Q000821:virology; D020275:Guillain-Barre Syndrome / Q000151:congenital / Q000453:epidemiology* / Q000821:virology; D006801:Humans; D008831:Microcephaly / Q000453:epidemiology* / Q000821:virology; D011634:Public Health; D000071244:Zika Virus / Q000502:physiology*; D000071243:Zika Virus Infection / Q000150:complications / Q000453:epidemiology*