Preventing Zika Virus Infections in Pregnant Women: An Urgent Public Health Priority

Public health focus is now on Zika virus, a mosquito-borne flavivirus that emerged in the Americas in 2015 with new intensity and alarming potential sequelae, after circulating in Africa and Southeast Asia for decades with rare reports of outbreaks and no recognized serious adverse outcomes. Paralleling the rapid spread of chikungunya in the Americas in 2013,¹ Zika virus has affected many of the same areas since its arrival in Brazil in early 2015.² By February 26, 2016, local transmission had been reported from 31 countries and territories in the Americas, with concomitant outbreaks in Cape Verde and the Pacific Islands.³ In the United States, as of March 2, 2016, 153 cases, all travel associated, have been reported to ArboNet from 28 states and the District of Columbia; among the 108 cases reported to ArboNet from US territories, all but 1 have been locally acquired, with most cases reported from Puerto Rico (http://www.cdc.gov/zika/geo/united-states.html). Further spread throughout tropical areas in the Americas is likely. For most individuals, the Zika virus infection is associated with mild and self-limited clinical symptoms, but it is increasingly being linked to prenatal impacts, most notably congenital microcephaly.^4–6 Better understanding of this arboviral disease, including the epidemiology, clinical outcomes, nonmosquito modes of transmission, immune response, pathophysiology, and clinical course, is critically needed. The systematic review by Paixão et al.⁷ of 52 studies on Zika virus in this issue of AJPH yields valuable information in these areas that can help guide prevention and control efforts.

Preventing Zika virus infections in pregnant women is an urgent public health priority. Although maternal infection with other flaviviruses has not been shown to have pervasive adverse fetal effects, growing evidence suggests an association between maternal Zika virus infection and infant brain abnormalities. Microcephaly was not noted in the small population outbreak on Yap Island, but retrospective studies of the larger and later French Polynesian outbreak have identified potential linkages.⁸ In Brazil, the time frame and geographic birth locations of many of the newborns with microcephaly correspond well to a large outbreak of Zika virus infection that occurred in the area months earlier—aligning with early pregnancy in their mothers.⁵ Histopathologic evaluation of brain tissue from two newborns with congenital microcephaly who died shortly after birth also revealed the presence of Zika virus.⁹ Moreover, the severe pattern of congenital microcephaly described in many of the affected infants in Brazil appears consistent with clinical findings from other fetal infections having impact on a developing brain.¹⁰

Efforts to determine the exact number of cases of microcephaly in Brazil and the number of those cases potentially linked to Zika virus will be time-consuming and complex. The condition can be caused by numerous factors including other infections, genetic conditions, and drug or alcohol use during pregnancy; however, for most cases, the etiology is unknown. Increased attention to the condition may also have resulted in misidentification of cases. However, even with these limitations and no universally accepted definition, the numbers of cases of microcephaly in Brazil far exceed expectations. The articles in this issue of AJPH by Teixeira et al.¹¹ and Miranda-Filho et al.,¹² examining characteristics of congenital Zika virus syndrome and the epidemic of microcephaly in Brazil, will help clarify some of these uncertainties and the potential severity and scope of the problem.

Comparisons with other intrauterine infections known to cause birth defects may also provide useful information. Rubella is a relatively mild disease in clinical presentation in the general population, but has potentially severe manifestations when the embryo or fetus is infected in early pregnancy. Maternal infection with rubella virus has the greatest impact in the first 10 weeks of pregnancy: up to 85% of such pregnancies result in congenital rubella syndrome.¹³ The risk diminishes subsequently, with no known impact beyond 18 weeks of pregnancy. An early evaluation of potential congenital Zika virus infection in Brazil showed that nearly three fourths of the cases of microcephaly occurred in infants whose mothers reported a symptomatic rash during their first (60%) or second (14%) trimester of pregnancy.⁵ Rubella has a spectrum of fetal effects, with congenital heart defects, eye anomalies, and hearing impairment as the defining features and effects varying with gestational age at the time of infection. Interestingly, although microcephaly is one of the impacts, it is not a predominant feature. Among the many unknowns with congenital Zika virus infection is whether there is a spectrum of associated defects and, if so, how this spectrum might vary by timing of exposure in utero, severity of maternal infection, and other cofactors, such as maternal nutritional status.

Finding answers to many of the questions surrounding Zika virus infection is complicated by multiple factors. Large epidemiological studies are lacking, and research needs continue to evolve. The definition of microcephaly needs to be standardized and consistently applied. Diagnostic testing is also complex. With no commercially available diagnostic tests for the infection, laboratory testing capacity is currently limited primarily to public health and research institutions. While a highly specific reverse-transcriptase polymerase chain reaction assay is available, its usefulness is limited by the relatively short period during which the virus can be detected in serum. Available serologic and neutralizing antibody tests can detect recent infection, but results are often confounded by cross reactivity resulting from previous infection with or vaccination against related flaviviruses. Improved and commercially available diagnostic tests are urgently needed.

Effective mosquito control, a pivotal component of outbreak prevention and control, continues to be challenging, as evidenced by decades of dengue control efforts.¹⁴ Like dengue and chikungunya, the Zika virus is transmitted by Aedes mosquitoes, with Aedes aegypti as its most efficient vector. Characteristics of the A aegypti mosquito, including its easy adaptation to human environments, preference for biting humans, indoor and daytime feeding, and ability to breed in very small amounts of standing water, all add to the difficulties of substantially reducing its populations. Nonetheless, scale-up of vector control efforts is central to addressing the Zika outbreak, requiring aggressive, targeted measures aimed at reducing A aegypti populations. Ongoing research to optimize existing and develop new vector control methods, and to develop new vaccines and therapeutics, is critical. Finding innovative, cost-effective ways to help bring these strategies to market will help spur their development. In currently affected areas, however, and especially for pregnant women, immediate needs beyond vector control include widespread awareness of risks as well as increased availability and use of personal protection methods, including insect repellants, bed nets, and window screens.

With the many uncertainties surrounding Zika virus infection and its prenatal risks, information for pregnant women or women considering pregnancy must be provided as it unfolds, with public health guidance based on the best available evidence for reducing health risks. For public health and other leaders, communicating the most up-to-date information in the midst of uncertainty is challenging but essential. In addition to broad outreach, a direct route to potentially at-risk women is through their health care providers. Ensuring clinicians and other health care providers are aware of the latest findings on the risks from Zika virus infection and the need for appropriate clinical management can help protect women of childbearing age as well as the larger population.

Even with ongoing improvements in preparedness and response, outbreaks of newly emerging and reemerging infectious diseases will continue to yield surprises and require prompt mobilization of control efforts. Improving the global capacity to detect these emerging threats and ensuring rapid deployment of response capacity to affected areas—goals of the Global Health Security Agenda¹⁵—remain essential components of controlling Zika virus infections and require global commitments from affected countries and beyond.