Date Published: January 3, 2017
Publisher: Public Library of Science
Author(s): Fabienne Krauer, Maurane Riesen, Ludovic Reveiz, Olufemi T. Oladapo, Ruth Martínez-Vega, Teegwendé V. Porgo, Anina Haefliger, Nathalie J. Broutet, Nicola Low, Lorenz von Seidlein
Abstract: BackgroundThe 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 FindingsThe 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.ConclusionsRapid 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.
Partial Text: An “explosive pandemic of Zika virus infection”  in 2015 caught the world by surprise. The Pan American Health Organization (PAHO) and World Health Organization (WHO) published an alert about a possible association with increases in reports of congenital abnormalities and Guillain–Barré syndrome (GBS) on December 1, 2015 . On February 1, 2016, WHO declared a Public Health Emergency of International Concern . Microcephaly at birth is a clinical finding that can include a range of brain malformations resulting from a failure of neurogenesis . Infections acquired in pregnancy, including cytomegalovirus and rubella, are established causes . GBS is an immune-mediated ascending flaccid paralysis, which typically occurs within a month of an infection, such as Campylobacter jejuni or cytomegalovirus . As of October 20, 2016, 67 countries have reported autochthonous transmission of the mosquito-borne flavivirus Zika since 2015, and 27 of these countries have reported cases of congenital brain abnormalities, GBS, or both . The emergency committee recommended increased research  to provide more rigorous scientific evidence of a causal relationship as a basis for the global health response.
We describe three linked components: the causality framework, the systematic reviews, and the expert panel assessment of the review findings. The WHO Zika Causality Working Group convened the expert panel of 18 members with specialist knowledge in the fields of epidemiology and public health, virology, infectious diseases, obstetrics, neonatology, and neurology (membership of the expert panel is provided in the Acknowledgments).
We found 1,091 unique items published from 1952 to May 30, 2016 (S1 Fig, S3 Table). Most excluded items were reviews or editorials and commentaries (44%, n = 479). We included 106 items from 87 groups (Table 1), of which 83% were published in 2016. For both outcomes, the majority of items were clinical, individual-level case reports, case series, or population-level surveillance data.
Up to May 30, 2016, we found evidence that supported a causal association between Zika virus infection and congenital brain abnormalities, including microcephaly, with at least one study addressing one or more specific questions for eight of ten causality dimensions and between Zika virus infection and GBS, with at least one study about one or more specific questions in seven of ten dimensions. There are methodological weaknesses, inconsistencies, and gaps in the body of evidence for both sets of conditions. Studies found after the cut-off for our first searches did not change our conclusions but strengthened the evidence about biological plausibility, strength of association, and exclusion of alternative explanations.