Abstract
Zika virus (ZIKV) infection during pregnancy has been linked to birth defects,1 yet the magnitude of risk remains uncertain. A study of the Zika outbreak in French Polynesia estimated that the risk of microcephaly due to ZIKV infection in the first trimester of pregnancy was 0.95% (95% confidence interval: 0.34-1.91%), based on eight microcephaly cases identified retrospectively in a population of approximately 270,000 people with an estimated 66% ZIKV infection rate.2
In the current outbreak, thousands of suspected cases of infants with microcephaly or other central nervous system developmental anomalies possibly associated with ZIKV infection have been reported in Brazil. To estimate the magnitude of microcephaly risk in Brazil, we analyzed data from Bahia (Fig. A).3 Serosurvey data from Yap4 and French Polynesia2 indicate that reported Zika cases only represent a small fraction of the number of ZIKV infections that actually occur. The infection rate in Bahia cannot be reliably inferred from currently available data, so we assumed that it could range from 10% to 80% based on estimates from Yap and French Polynesia (66-73%)2,4 and reports from non-outbreak ZIKV serosurveys (6-40%, Supplementary Materials). We apportioned this risk across 2015 according to the temporal distribution of reported cases (Fig. B) and assessed the association of infection risk with microcephaly cases reported in the Brazilian Live Births Information System5 between July 2015 and February 2016 (as of March 21, 2016, accounting for a reporting delay, Fig. C).
Considering different infection rate scenarios (from 10% to 80%), possible over-reporting (0% or 100%), and an uncertain baseline microcephaly rate (2-12 cases per 10,000 births), microcephaly risk was strongly associated with infection risk in the first trimester, with a negligible association in the second and third trimesters, consistent with the association found in population-level estimates for French Polynesia2 (Supplementary Material). Estimated baseline microcephaly risk was low, approximately 2 per 10,000 births (Tables S1–2, Fig. D–F), but estimated risk due to infection in the first trimester ranged from 0.88% (95% Credible Interval (CI): 0.80-0.97%) with an 80% overall ZIKV infection rate and 100% over-reporting of microcephaly cases to 13.2% (95% CI: 12.0-14.4) with a 10% ZIKV infection rate and no over-reporting. The lower end of this range is similar to the approximately 1% risk estimated for French Polynesia, especially if infection rates in Bahia were high (40% or more with over-reporting, 70% or more without over-reporting). It is also possible that the French Polynesia estimate is an underestimate; it is from a single outbreak relying on retrospective microcephaly case detection. Furthermore, higher microcephaly risks have been documented for some other viruses.2 Both estimates are consistent with the lack of reported microcephaly cases in Yap; if microcephaly risk due to first trimester ZIKV infection was 0.88-13.2%, 0-4 microcephaly cases would have been expected.
There are uncertainties and limitations to all current estimates of microcephaly risk associated with ZIKV infection. First, available data are very limited, especially in recently affected areas like Bahia where infection rates are unknown and microcephaly cases are still being reported and evaluated. The limited information on ZIKV infection rates is compounded by difficulty in clinical confirmation of microcephaly, as evidenced by low confirmation rates in the independent, temporary microcephaly reporting system established by Brazil in late 2015.6 Carefully designed serosurveys and data from other locations can help refine these estimates.
Recent studies show associations between symptomatic ZIKV infection during all trimesters and adverse pregnancy outcomes7 and potential peak risk during gestational weeks 14-17.8 How these outcomes relate to the clear association between first trimester risk and microcephaly at the population level in French Polynesia and Bahia is unclear. On the population level, the temporal relationship is confounded by varying infection risk, gestational ages, and fetal outcome assessment. Meanwhile in clinically described cases, infections in early pregnancy may be more difficult to document as pregnancy status may not be known and outcomes associated with mild or asymptomatic ZIKV infection during pregnancy have yet to be described. Risk of adverse events may be higher in symptomatic infections7, but mild infections are likely more common and thus may also contribute substantially to the overall burden. Furthermore, microcephaly is only one possible adverse outcome among a spectrum of conditions that may be part of congenital Zika syndrome. A population-level increase in central nervous system anomalies has been observed in both French Polynesia9 and Brazil.6 More data are needed to refine gestational age-specific risk estimates for microcephaly and these other outcomes related to ZIKV infection.
While much remains unknown about the effects of ZIKV infection during pregnancy, there is a clear association between first trimester ZIKV infection and microcephaly risk from population-level data in French Polynesia and Bahia. If the risk of infection and adverse outcomes is similar in the other areas where ZIKV has spread, many more cases of microcephaly and other adverse outcomes are likely to occur. In light of the growing evidence, it is prudent to take precautions to avoid ZIKV infection during pregnancy10 and for health care systems to prepare for an increased burden of adverse pregnancy outcomes in the coming years.
Acknowledgements:
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. All data are publicly available and code is available from MAJ upon request. MAJ, LMTR, JR, SMG, and SLH conceived of the research, wrote, and approved of the manuscript. MAJ and LMTR performed the analyses. MAJ received partial support from the Models of Infectious Disease Agent Study program (Cooperative Agreement 1U54GM088558).