Implications of Zika virus and congenital Zika syndrome for the number of live births in Brazil

Discussion

This study provides a comprehensive analysis of the impact of ZIKV on live births in Brazil. Our analysis was based on monthly data from January 2010 to December 2016 for Brazil and for each of the 26 states and the Federal District. Forecasts of the GFR for the period from September 2015 to December 2016 demonstrated that fewer births than expected were observed after the emergence of ZIKV in Brazil. Despite the decline in births, no significant increases in fetal death rates were observed, and hospitalizations due to abortion complications were fewer than expected. However, our results show that hospitalizations happened at later gestational ages after the ZIKV and microcephaly outbreaks.

Guided by our proposed framework (SI Appendix, Fig. S1), our results demonstrate that postponement of pregnancy may have contributed to the decline in births after April 2016. These findings are supported by a survey conducted in all capital cities of the Northeast region between March 30 and June 3, 2016, which showed that about 18% of the women using contraception did so because of the ZIKV epidemic (34). Fetal deaths did not seem to have played a major role, corroborating findings of a cohort study of women in Rio de Janeiro (21). Also, the fact that hospitalizations due to abortion complications were fewer than expected cannot rule out a possible increase in abortions. All pregnancy terminations that were conducted safely would not result in a hospitalization, and thus would not be captured by routine administrative data collection. Indeed, a large increase in online requests for abortion medications in Brazil was reported between November 2015 and March 2016—after PAHO issued an epidemiological alert (36)—and drug-induced abortions carry a very small risk of complications (37). As for the spatial extent of the birth declines, our results indicate that after April 2016 they were not as concentrated in the ZIKV hardest-hit areas as we initially hypothesized.

We urge caution in the interpretation of these results, as well as on any attempt to assess declines in births due to ZIKV. By no means should one claim that all declines in births were a result of the ZIKV outbreak, and we offer four reasons why. First, economic crises can affect the decision to have a child (38⇓–40), and since January 2015 unemployment rates in Brazil have been increasing; the annual average unemployment rates were 8.5, 11.5, and 12.7 in 2015, 2016, and 2017, respectively, reaching a peak of 13.7 in March 2017 (41). Second, current legislation states that births should be reported up to 60 d after birth. However, longer lag periods may occur, in which case the use of incomplete data would bias the analysis (more specifically, overestimate the difference between forecasted and observed births). We limited our analysis to births reported until December 2016, since later data were still incomplete. Thus, although a few events in the studied period may be missing, we expect this number to be small and thus not to change our results. Third, the quality (completeness and accuracy) of administrative data varies (Materials and Methods). However, given the increased attention to track pregnancies and births for CZS, particularly during the peak of the ZIKV epidemic, it is expected that, at that time, underreporting was lower than usual. Last, part of the decline may result from lower desired fertility (irrespective of ZIKV). However, based on the Brazilian experience (42), it is unlikely that this factor alone may account for the observed deficit in births during the forecasted period.

Our results raise five important questions. First, will the decline persist over time and affect the total fertility rate (TFR)? Fertility in Brazil has rapidly declined since the 1960s, across all socioeconomic strata, and in 2010 the TFR was 1.9, below replacement level (43). Approximately 3 million births are observed annually, 39% in the Southeast region (home to megacities such as São Paulo and Rio de Janeiro) and 28% in the Northeast. We argue that since ZIKV transmission has declined, and the attention has waned, it is unlikely that reductions in births will persist over time. Instead, we expect that the decline in births will characterize a tempo distortion in period fertility (44). While this could be an issue for women in the older age range of the reproductive period, only 13% of the fertility rate in Brazil is concentrated above age 35.

Second, was there an increase in seeking behavior for a safe abortion? There are no systematic data to answer this question. Safe procedures, either medical or surgical, can only be estimated through self-reported surveys. In addition, unsafe procedures that result in hospitalizations could be underreported to protect the woman or the doctor from legal complications. However, our results revealed significant declines in hospitalizations due to abortion complications in several states, which could suggest that safer procedures were sought. Data showing a spike on requests for abortion medications suggest an increase in safe procedures following the ZIKV epidemic (36). This question needs to be reassessed and quantified based on indirect estimates (45) and special surveys.

Third, was there a selection in who decided to perform an abortion? About 83% of women who had a child with CZS in Brazil were nonwhites (24), whereas 49.7% of the female Brazilian population is nonwhite (in Brazil, the standard racial categories are white, black, brown, yellow, and indigenous). In the absence of selective abortion and contraception, this would only be possible if nonwhites were under a higher risk of a ZIKV infection. Although poor housing conditions, precarious infrastructure, and low socioeconomic status are factors often associated with higher transmission of Aedes aegypti-related diseases (46), health care provided by the private sector is largely underreported in the Brazilian National Notifiable Diseases Information System, despite the fact that notification is mandatory (47). This subnotification, however, cannot explain the racial difference in mothers who had babies with CZS since the birth registration system captures vital events irrespective of delivery location. Also, the use of contraception in Brazil is high (around 80%), irrespective of region and race (48). Therefore, we argue that the higher percentage of babies with CZS born to nonwhite mothers reflects a lower number of safe abortions among nonwhites. As a result, the ZIKV epidemic resulted in a generation of CZS babies that reflect and exacerbate well-documented regional and social inequalities in Brazil (49).

Fourth, are there specific factors prevalent in the Northeast region or among certain populations that increased the severity of ZIKV during pregnancy? It is possible that the observed burden of CZS in the Northeast and among the nonwhite population is not solely a result of differentiated use of abortion and contraception, but of other conditions that could alter the risk of a ZIKV infection. While this issue is being investigated by different research groups, currently there is no evidence that such factors exist. Also, although some cases of CZS complications only manifest later in infancy (20, 50), it is unlikely that those babies are predominately outside the Northeast.

Fifth, in the absence of a vaccine, are there ideal temporal windows of conception to minimize the risk of CZS? Birth seasonality is observed in most human populations (51). In Brazil, the peak of births consistently occurs between March and May, corresponding to conceptions during the winter months of June to August, and a secondary peak is observed in September (conceptions in December); the valley happens from October to December, associated with conceptions during the summer months of January to March (52). Similarly, ZIKV transmission follows a seasonal pattern common to arboviruses, with peaks usually observed during warmer and wetter months (53), which in Brazil ranges from December to April. Thus, the peak of conception coincides with the low transmission season of ZIKV, but part of the second and all third trimester would overlap the favorable months for Ae. aegypti. In contrast, conceptions during the summer months expose the pregnant woman to an infection in the first trimester, part of the second, and the later part of the third. That pattern is reflected on the curves of CZS per 10,000 births, where peaks were observed in November for Brazil, and in December for the Northeast region (24). As a result, the months when fewer births are often observed were those with higher risk of delivering a baby with CZS, given a higher exposure to ZIKV during conception. Although ZIKV transmission in Brazil has been drastically reduced, a new wave of transmission is possible. Therefore, a comprehensive modeling of CZS risk by gestation month of infection to devise potential temporal windows for conception that minimize the burden of fetal complications is needed.

Although we cannot disentangle the causes of the decline in live births reported in our analysis, we argue that both abortions and pregnancy postponement were important, with crucial differences by state and some population groups that reflect social inequalities in Brazil. The possibility that pregnancies were intentionally terminated (and some performed later in the gestational period), particularly when the link between ZIKV and microcephaly got attention in the media, raise concerns about reproductive women’s health and rights. The most recent evaluation of abortion safety estimated that 45.1% of worldwide abortions performed in the period of 2010–2014 were unsafe; in South America, this number was 75.1% (54). This issue has been heavily debated in Brazil, and in September 2016, the National Prosecutor publicly expressed his support for abortion for pregnant women infected with ZIKV, since the continuation of pregnancy could not only result in CZS but also compromise the mental health status of the mother (agenciabrasil.ebc.com.br/geral/noticia/2016-09/em-parecer-janot-defende-aborto-para-gravidas-com-virus-zika). However, no legislation change has happened yet.

Although the incidence of ZIKV cases has declined, the threat is not gone. Ae. aegypti reigns in Brazilian cities and currently transmits dengue, Zika, chikungunya, and Mayaro virus, and is competent to transmit the strains of the yellow fever virus circulating in the country (55); indeed, in 2018 urban yellow fever was recorded in Brazil, 76 y after urban transmission had been successfully eliminated. A new epidemic of ZIKV is possible, and could be exacerbated by climatic conditions (56, 57). On the one hand, vector control efforts do need to be strengthened, involving the collaboration of different sectors of the government in an effort to address challenges of the urban landscape that favor the proliferation of mosquito breeding habitats (e.g., regular access to water and waste collection). On the other hand, the health and social consequences of the 2015–2016 ZIKV epidemic in Brazil should motivate strategies that properly address women’s reproductive health and rights, ranging from communication to access to contraception and safe abortion. Failure to do either will result in further generations of CZS babies, disproportionately affecting the poor. Time will tell.