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. 2019 Aug 14:8:1433.
doi: 10.12688/f1000research.19918.1. eCollection 2019.

Zika virus infection as a cause of congenital brain abnormalities and Guillain-Barré syndrome: A living systematic review

Michel Jacques Counotte  1 , Kaspar Walter Meili  1 , Katayoun Taghavi  1 , Guilherme Calvet  2 , James Sejvar  3 , Nicola Low  1
Affiliations

Zika virus infection as a cause of congenital brain abnormalities and Guillain-Barré syndrome: A living systematic review

Michel Jacques Counotte et al. F1000Res. .

Abstract

Background: The Zika virus (ZIKV) caused a large outbreak in the Americas leading to the declaration of a Public Health Emergency of International Concern in February 2016. A causal relation between infection and adverse congenital outcomes such as microcephaly was declared by the World Health Organization (WHO) informed by a systematic review structured according to a framework of ten dimensions of causality, based on the work of Bradford Hill. Subsequently, the evidence has continued to accumulate, which we incorporate in regular updates of the original work, rendering it a living systematic review. Methods: We present an update of our living systematic review on the causal relation between ZIKV infection and adverse congenital outcomes and between ZIKV and GBS for four dimensions of causality: strength of association, dose-response, specificity, and consistency. We assess the evidence published between January 18, 2017 and July 1, 2019. Results: We found that the strength of association between ZIKV infection and adverse outcomes from case-control studies differs according to whether exposure to ZIKV is assessed in the mother (OR 3.8, 95% CI: 1.7-8.7, I 2=19.8%) or the foetus/infant (OR 37.4, 95% CI: 11.0-127.1, I 2=0%). In cohort studies, the risk of congenital abnormalities was 3.5 times higher after ZIKV infection (95% CI: 0.9-13.5, I 2=0%). The strength of association between ZIKV infection and GBS was higher in studies that enrolled controls from hospital (OR: 55.8, 95% CI: 17.2-181.7, I 2=0%) than in studies that enrolled controls at random from the same community or household (OR: 2.0, 95% CI: 0.8-5.4, I 2=74.6%). In case-control studies, selection of controls from hospitals could have biased results. Conclusions: The conclusions that ZIKV infection causes adverse congenital outcomes and GBS are reinforced with the evidence published between January 18, 2017 and July 1, 2019.

Keywords: Disease outbreaks; Guillain-Barré syndrome; Zika; arboviruses; causality; congenital abnormalities.

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Conflict of interest statement

No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. For congenital abnormalities due to ZIKV, exposure assessment in mother-infant pairs can be performed in the mother or the foetus or infant.
The latest and previous versions of this figure are available as extended data .
Figure 2.
Figure 2.. Map of the epidemiological studies that report on adverse congenital outcomes (blue) or Guillain-Barré syndrome (red) associated with Zika virus exposure.
The size of the points correspond with the number of exposed individuals with the adverse outcome, according to the definitions used in the publications. The latest and previous versions of this figure are available as extended data .
Figure 3.
Figure 3.. PRISMA flow-chart of publications retrieved, screened and included between January 18, 2017 and July 1, 2019.
Adapted from: Moher et al. (2009) . The latest and previous versions of this figure are available as extended data .
Figure 4.
Figure 4.
Forest plot and meta-analysis of case-control studies reporting on ZIKV infection assessed in mothers ( A) and in infants ( B) and adverse congenital outcomes (microcephaly, congenital malformations, central nervous system abnormalities). The odds ratio from the five case-control studies that assess exposure in mothers combined is 3.8 (95% CI: 1.7-8.7, tau 2=2.37, I 2=19.8%); the odds ratio for the studies that assess exposure in infants is 37.4 (95% CI: 11.0-127.1, tau 2=0, I 2=0%). The odds ratios are plotted on the log scale. Abbreviations: CSF, cerebrospinal fluid, PRNT, plaque reduction neutralisation test; RE, random effects; RT-PCR, reverse transcription polymerase chain reaction. The latest and previous versions of this figure are available as extended data .
Figure 5.
Figure 5.. Forest plot and meta-analysis of cohort studies reporting on ZIKV infection and adverse congenital outcomes.
The risk ratio from the random effects model is 3.5 (95% CI: 0.9-13.5, tau2=0,I 2=0%). The risk ratios are provided on the log scale. Abbreviations: ZIKV, Zika virus; PRNT, plaque reduction neutralisation test; RE, random effects; RT-PCR, Reverse transcription polymerase chain reaction. The latest and previous versions of this figure are available as extended data.
Figure 6.
Figure 6.. Forest plot of six included case-control studies and their exposure assessment.
Odds ratios (ORs) are shown on the log-scale. The meta-analysis is stratified by the selection of controls: Hospital controls, or community/household controls. Most similar exposure assessment measures are compared (IgM , , , , recent flavivirus infection , or IgM and/or RT-PCR ). OR: 7.0 [95% CI: 1.7-28.8, tau2=2.78, I 2=78.3%]. ORs from studies marked with an asterisk (*) are matched ORs, unmarked studies provided crude ORs. The latest and previous versions of this figure are available as extended data .
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Grants and funding

This work was supported by the Swiss National Science Foundation [320030_170069], end date: 31/10/2021