The association between Zika virus infection and microcephaly in Brazil 2015–2017: An observational analysis of over 4 million births

Abstract

Background In 2015, high rates of microcephaly were reported in Northeast Brazil following the first South American Zika virus (ZIKV) outbreak. Reported microcephaly rates in other Zika-affected areas were significantly lower, suggesting alternate causes or the involvement of arboviral cofactors in exacerbating microcephaly rates. Methods and findings We merged data from multiple national reporting databases in Brazil to estimate exposure to 9 known or hypothesized causes of microcephaly for every pregnancy nationwide since the beginning of the ZIKV outbreak; this generated between 3.6 and 5.4 million cases (depending on analysis) over the time period 1 January 2015–23 May 2017. The association between ZIKV and microcephaly was statistically tested against models with alternative causes or with effect modifiers. We found no evidence for alternative non-ZIKV causes of the 2015–2017 microcephaly outbreak, nor that concurrent exposure to arbovirus infection or vaccination modified risk. We estimate an absolute risk of microcephaly of 40.8 (95% CI 34.2–49.3) per 10,000 births and a relative risk of 16.8 (95% CI 3.2–369.1) given ZIKV infection in the first or second trimester of pregnancy; however, because ZIKV infection rates were highly variable, most pregnant women in Brazil during the ZIKV outbreak will have been subject to lower risk levels. Statistically significant associations of ZIKV with other birth defects were also detected, but at lower relative risks than that of microcephaly (relative risk < 1.5). Our analysis was limited by missing data prior to the establishment of nationwide ZIKV surveillance, and its findings may be affected by unmeasured confounding causes of microcephaly not available in routinely collected surveillance data. Conclusions This study strengthens the evidence that congenital ZIKV infection, particularly in the first 2 trimesters of pregnancy, is associated with microcephaly and less frequently with other birth defects. The finding of no alternative causes for geographic differences in microcephaly rate leads us to hypothesize that the Northeast region was disproportionately affected by this Zika outbreak, with 94% of an estimated 8.5 million total cases occurring in this region, suggesting a need for seroprevalence surveys to determine the underlying reason.

Association of past dengue fever epidemics with the risk of Zika microcephaly at the population level in Brazil

“…Therefore, we could not control for Zika incidence in the models. It is possible that the differences in microcephaly rates were a consequence of different ZIKV attack rates across the regions, as suggested in a recent paper 37 . In this study, after testing for other concurrent factors, ZIKV was assumed to be the only cause of the microcephaly epidemic, with no unmeasured confounders or effect modifiers.…”

“…In this study, after testing for other concurrent factors, ZIKV was assumed to be the only cause of the microcephaly epidemic, with no unmeasured confounders or effect modifiers. However, if Zika incidence alone explains the excess microcephaly rates, then microcephaly would simply be a proxy for Zika, and it remains unclear as to why the NE region would have presented with a Zika incidence more than ten times larger than anywhere else in Brazil 37 .…”

Envelope Protein Glycosylation Mediates Zika Virus Pathogenesis

“…subsequent detection of ZIKV in Brazil in 2015 and the rapid spread of ZIKV to many countries in the Americas (5)(6)(7)(8) has revealed that ZIKV infection during pregnancy can cause a broad range of congenital malformations termed congenital Zika syndrome (2,9,10).…”

Explaining Pathogenicity of Congenital Zika and Guillain–Barré Syndromes: Does Dysregulation of RNA Editing Play a Role?

“…Referred to as antibody‐dependent enhancement, this results in increased infection of cultured human placental macrophages, as well as increased viremia in human placental explants . Recent large‐scale observational analysis showed no evidence of changes in microcephaly risk due to concurrent exposure to DENV or CHIKV …”