SUMMARY
The Zika virus has spread rapidly in the Americas since its first identification in Brazil in early 2015. Prenatal Zika virus infection has been linked to adverse pregnancy and birth outcomes, most notably microcephaly and other serious brain anomalies. To determine whether Zika virus infection during pregnancy causes these adverse outcomes, we evaluated available data using criteria that have been proposed for the assessment of potential teratogens. On the basis of this review, we conclude that a causal relationship exists between prenatal Zika virus infection and microcephaly and other serious brain anomalies. Evidence that was used to support this causal relationship included Zika virus infection at times during prenatal development that were consistent with the defects observed; a specific, rare phenotype involving microcephaly and associated brain anomalies in fetuses or infants with presumed or confirmed congenital Zika virus infection; and data that strongly support biologic plausibility, including the identification of Zika virus in the brain tissue of affected fetuses and infants. Given the recognition of this causal relationship, we need to intensify our efforts toward the prevention of adverse outcomes caused by congenital Zika virus infection. However, many questions that are critical to our prevention efforts remain, including the spectrum of defects caused by prenatal Zika virus infection, the degree of relative and absolute risks of adverse outcomes among fetuses whose mothers were infected at different times during pregnancy, and factors that might affect a woman’s risk of adverse pregnancy or birth outcomes. Addressing these questions will improve our ability to reduce the burden of the effects of Zika virus infection during pregnancy.
POTENTIAL RELATIONSHIP BETWEEN ZIKA VIRUS INFECTION AND BIRTH DEFECTS
Since the identification of the Zika virus in Brazil in early 2015, the virus has spread rapidly throughout the Americas (www.cdc.gov/zika/geo/active-countries.html). An increase in the number of infants with microcephaly in Brazil was first noted in September 2015, after the recognition of Zika virus transmission in the country earlier in the year; this was followed by the recognition of a similar increase in French Polynesia after an outbreak there in 2013 and 2014. Despite accumulating evidence that supports the link between Zika virus infection and microcephaly, most experts have taken care not to state that Zika virus infection is causally related to these adverse outcomes. This cautious approach toward ascribing Zika virus as a cause of birth defects is not surprising, given that the last time an infectious pathogen (rubella virus) caused an epidemic of congenital defects was more than 50 years ago, no flavivirus has ever been shown definitively to cause birth defects in humans, and no reports of adverse pregnancy or birth outcomes were noted during previous outbreaks of Zika virus disease in the Pacific Islands.
On the basis of the available evidence, the public health response to the outbreak of Zika virus disease has moved forward, with the distribution of health messages about the importance of mosquito-bite prevention, recommendations by public health authorities in some of the most severely affected countries to delay pregnancy, and advisories that pregnant women avoid travel to areas with active Zika virus transmission. However, communications regarding Zika virus have been challenging: a recent survey showed low levels of knowledge and concern about Zika virus in the United States. The recognition of Zika virus as a cause of microcephaly and other serious brain anomalies would allow for more direct communication, which might lead to improved understanding of and adherence to public health recommendations. Therefore, a review of the evidence linking Zika virus infection and adverse pregnancy and birth outcomes is needed.
As is typically the case in epidemiology and medicine, no “smoking gun” (a single definitive piece of evidence that confirms Zika virus as a cause of congenital defects) should have been anticipated. Instead, the determination of a causal relationship would be expected to emerge from various lines of evidence, each of which suggests, but does not on its own prove, that prenatal Zika virus infection can cause adverse outcomes. Two approaches have been used to identify potential teratogens (exposures to a mother during pregnancy that have a harmful effect on her embryo or fetus): first, the identification of a combination of a rare exposure and a rare defect (sometimes referred to as the astute clinician approach), and second, the use of epidemiologic data to confirm an association. Many teratogens were first identified by means of the rare exposure–rare defect approach, including rubella virus, which was identified after an ophthalmologist noted a characteristic form of cataracts in infants whose mothers had rubella during pregnancy.