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 (). 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.

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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, and heavy alcohol use, which was identified as a teratogen after the recognition of a characteristic pattern of malformations that became known as the fetal alcohol syndrome.

In contrast, some teratogens have been identified on the basis of epidemiologic studies (e.g., valproic acid was identified as a teratogen after a case–control study showed an odds ratio of 20 for the association of spina bifida with use of this drug during the first trimester of pregnancy). Shepard’s Criteria In 1994, Thomas Shepard, a pioneer in the field of teratology, proposed a set of seven criteria for “proof” of human teratogenicity ( Table 1 Shepard’s Criteria for Proof of Teratogenicity in Humans as Applied to the Relationship between Zika Virus Infection and Microcephaly and Other Brain Anomalies. ) that incorporated both approaches. These criteria were an amalgamation of criteria developed by other teratologists and guided by methods that were used to identify previous teratogens.

These criteria have been used to guide discussions about causation in teratology-related litigation and to assess other potential teratogens. We used Shepard’s criteria as a framework to evaluate whether the currently available evidence supports the hypothesis that prenatal Zika virus infection is a cause of microcephaly and other brain anomalies ( ). According to these criteria, causality is established when either criteria 1, 3, and 4 (rare exposure–rare defect approach) or criteria 1, 2, and 3 (epidemiologic approach) are fulfilled. The first criterion states that a proven exposure to an agent must occur at a critical time during prenatal development. The severe microcephaly and other brain anomalies that have been observed in many infants are consistent with an infection occurring in the first or early second trimester of pregnancy.

Several case reports and studies have shown that women who had fetuses or infants with congenital brain anomalies that were believed, on the basis of the mother’s symptoms or laboratory confirmation, to be due to Zika virus infection were infected in the first or early second trimester of pregnancy, as determined either according to the timing of the symptoms or according to the timing of travel to an area where Zika virus is endemic. An analysis of the timing of laboratory-confirmed Zika virus transmission in certain states in Brazil and of the increase in the cases of microcephaly identified the first trimester as the critical time period for infection. Zika virus infections that occur later in pregnancy have been associated with poor intrauterine growth, fetal death, or in some pregnancies, defects on prenatal imaging that have not yet been confirmed postnatally because the pregnancies are ongoing. We conclude that Shepard’s first criterion has been met. Shepard’s second criterion requires that two epidemiologic studies of high quality support the association. Although ecologic data do not necessarily qualify as an epidemiologic study, data from Brazil regarding the temporal and geographic association between Zika virus infection and the later appearance of infants with congenital microcephaly are compelling. Two epidemiologic studies also provide support.

In a study conducted during the outbreak in Brazil, 88 pregnant women who had had an onset of rash in the previous 5 days were tested for Zika virus RNA. Among the 72 women who had positive tests, 42 underwent prenatal ultrasonography, and fetal abnormalities were observed in 12 (29%); none of the 16 women with negative tests had fetal abnormalities. The abnormalities that were observed on ultrasonography varied widely, and some findings lacked postnatal confirmation because the pregnancies were ongoing. A retrospective analysis after the 2013–2014 outbreak of Zika virus disease in French Polynesia identified eight cases of microcephaly; the authors used serologic and statistical data and mathematical modeling to estimate that 1% of the fetuses and neonates who were born to mothers who had been infected with Zika virus in the first trimester had microcephaly — a prevalence that was approximately 50 times as high as the estimated baseline prevalence. However, this estimate was based on small numbers, confidence intervals were wide, and the risk of other adverse outcomes (e.g., other brain anomalies) was not assessed.

Although these studies provide important evidence in support of a causal relationship between Zika virus and microcephaly and other brain anomalies, both have limitations as noted by their authors, such as a lack of control for confounding factors and relatively small numbers of cases, and therefore they do not meet the stringent criteria set by Shepard. Thus, we conclude that Shepard’s second criterion has not yet been satisfied. The third criterion, careful delineation of clinical cases with the finding of a specific defect or syndrome, appears to be met.

Previous teratogens have caused specific birth defects or syndromes rather than a broad range of birth defects. Other Criteria Other criteria can also be used to assess this relationship. Koch’s postulates, developed in the late 19th century, are often cited as necessary to show causation in infectious disease; however, many authors have noted the need for Koch’s postulates to be updated to accommodate modern technologies. The Bradford Hill criteria provide another framework to assess causation; Frank et al. Recently used these criteria to assess the relationship between prenatal Zika virus infection and microcephaly and concluded that additional information was needed to assume that the relationship was causal. However, several key pieces of evidence have become available since they performed their analysis, including two epidemiologic studies, a study of the effects of Zika virus on neural progenitor cells, and a case report of a fetus with brain anomalies and decreasing head size from whose brain live Zika virus was isolated. On the basis of our update of their analysis, which incorporates newly available evidence ( Table 2 Bradford Hill Criteria for Evidence of Causation as Applied to the Relationship between Zika Virus Infection and Microcephaly and Other Brain Anomalies ), nearly all the relevant criteria have been met, with the exception of the presence of experimental evidence.

However, Hill emphasizes that meeting all nine criteria is not necessary; instead, the criteria should serve as a framework to assess when the most likely interpretation of a relationship is causation. Assessment of Criteria Thus, on the basis of a review of the available evidence, using both criteria that are specific for the evaluation of potential teratogens and the Bradford Hill criteria as frameworks, we suggest that sufficient evidence has accumulated to infer a causal relationship between prenatal Zika virus infection and microcephaly and other severe brain anomalies. Also supportive of a causal relationship is the absence of an alternative explanation; despite the extensive consideration of possible causes, researchers have been unable to identify alternative hypotheses that could explain the increase in cases of microcephaly that were observed first in Brazil and then retrospectively in French Polynesia, and now in preliminary reports that are being investigated in Colombia. Moving from a hypothesis that Zika virus is linked to certain adverse outcomes to a statement that Zika virus is a cause of certain adverse outcomes allows for direct communications regarding risk, both in clinical care settings and in public health guidance, and an intensified focus on prevention efforts, such as the implementation of vector control, the identification of improved diagnostic methods, and the development of a Zika virus vaccine. In addition, after recognizing a causal relationship between Zika virus infection and adverse pregnancy and birth outcomes, we can focus research efforts on other critical issues: First, understanding the full spectrum of defects caused by congenital Zika virus infection; if Zika virus is similar to other teratogens, an expansion of the phenotype would be expected (e.g., with the congenital rubella syndrome, the phenotype was expanded from cataracts to include other findings such as hearing loss, congenital heart defects, and microcephaly). Second, quantifying the relative and absolute risks among infants who are born to women who were infected at different times during pregnancy. Third, identifying factors that modify the risk of an adverse pregnancy or birth outcome (e.g., coinfection with another virus, preexisting immune response to another flavivirus, genetic background of the mother or fetus, and severity of infection).

Addressing these issues will improve our efforts to minimize the burden of the effects of Zika virus infection during pregnancy. Nicecast License Key Free on this page. Polaris Office Viewer 5 Apk Download.

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