Zika virus infection as a cause of congenital brain abnormalities and Guillain-Barré syndrome: systematic review
Authors: Krauer Fabienne , Riesen Maurane , Reveiz Ludovic , Oladapo Olufemi T , Martínez-Vega Ruth , Porgo Teegwendé V. , Haefliger Anina , Broutet Nathalie J , Low Nicola ,   for the WHO Zika Causality Working Group
Published: September 2016

Background

The World Health Organization 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 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 re-assess 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) Guillain-Barré syndrome 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 10 dimensions; temporality, biological plausibility, strength of association, alternative explanations, cessation, dose-response, 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, a multidisciplinary panel of experts assessed the review findings and reached consensus on causality. We found 1091 unique items up to May 30, 2016. For congenital brain abnormalities, including microcephaly, we included 72 items; for eight of 10 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 Guillain-Barré syndrome, 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 non-systematically from May 30-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 61 microcephaly; and b) the most likely explanation of available evidence from outbreaks of Zika virus infection and Guillain-Barré syndrome is that Zika virus infection is a trigger of Guillain-Barré syndrome. The expert panel recognised that Zika virus alone may not be sufficient to cause either congenital brain abnormalities or Guillain-Barré syndrome 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 co-factors, 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 rapid systematic review found sufficient evidence to say that Zika virus is a cause of congenital abnormalities and is a trigger of Guillain-Barré situation.