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Observational Study
. 2019 Mar 5;16(3):e1002755.
doi: 10.1371/journal.pmed.1002755. eCollection 2019 Mar.

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

Affiliations
Observational Study

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

Oliver J Brady et al. PLoS Med. .

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Data sources, data processing, and analysis schema.
Numbers in bold indicate total number of births in each category; numbers in italics indicate number of cases of microcephaly with structural brain defects (MWSD) in each category. IBGE, Instituto Brasileiro de Geografia e Estatística; RESP, Registro de Eventos em Saúde Pública; SINAN/GAL, Sistema de Informação de Agravos de Notificação/Gerenciador de Ambiente Laboratorial; SINASC, Sistema de Informações sobre Nascidos Vivos; SISAGUA, Sistema de Informação de Vigilância da Qualidade da Água para Consumo Humano.
Fig 2
Fig 2. Association between candidate exposures and microcephaly with structural brain defects.
Relative risk compares areas with no exposure to those with median incidence of the exposure. Adjusted models included variables for region and sex of the baby (only bovine viral diarrhoea virus, Zika, and Zika [chikungunya coinfection] models; S2 Text, section 2.9). *The final column shows the Akaike Information Criterion (AIC) of a base model including a covariate for region minus the AIC of the adjusted exposure model (a larger reduction in AIC value equates to a more likely exposure model).
Fig 3
Fig 3. Relative risk of microcephaly with structural brain defects (MWSD) given Zika virus infection at different times in pregnancy.
Black dots and blue bars represent the mean and 95% confidence intervals, respectively, of the estimated microcephaly relative risk for women exposed to median Zika virus incidence levels at different times in pregnancy. The red line shows a relative risk of 1 (i.e., no risk).
Fig 4
Fig 4. Concentration of the Zika virus (ZIKV) outbreak in Northeast Brazil.
This figure shows (A) the ZIKV-attributable absolute rate of microcephaly with structural brain defects (MWSD) per 10,000 live births, (B) the relative risk of MWSD at birth given the ZIKV outbreak experienced in each municipality, (C) the model-predicted cumulative symptomatic Zika case incidence on a log 10 scale, and (D) the model-predicted total cumulative symptomatic Zika cases on a log 10 scale. All maps show municipality-level predictions averaged or summed over the time period January 2015–May 2017.
Fig 5
Fig 5. Relative risks of selected non-microcephaly birth defects with Zika virus.
Exposure areas were defined as municipalities that experienced at least 1 case of Zika. Adjusted relative risk (RR) predictions show predictions for the median Zika incidence observed in Brazilian municipalities over the time period. Mean and 95% confidence intervals of relative risk are shown. The chi-squared test statistic was used with Bonferroni correction of p-values for 12 hypothesis tests. Significant results at the p = 0.05 level are denoted by an asterisk (*). Full ICD-10 categories for grouped defects are provided in S2 Text, section 2.6. 1All brain defects category excludes microcephaly.

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