Zika Virus and Birth Defects - Reviewing the Evidence for Causality NEJM

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Zika Virus and Birth Defects — Reviewing the Evidence for Causality

Sonja A. Rasmussen, M.D., Denise J. Jamieson, M.D., M.P.H., Margaret A. Honein, Ph.D., M.P.H., and Lyle R. Petersen, M.D., M.P.H.

April 13, 2016DOI: 10.1056/NEJMsr1604338

http://www.nejm.org/doi/full/10.1056/NEJMsr1604338?query=featured_home

 

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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.

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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 year1; this was followed by the recognition of a similar increase in French Polynesia after an outbreak there in 2013 and 2014.2 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.3 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,4 and no reports of adverse pregnancy or birth outcomes were noted during previous outbreaks of Zika virus disease in the Pacific Islands.5,6

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.7 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.8 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)9: first, the identification of a combination of a rare exposure and a rare defect (sometimes referred to as the astute clinician approach),10 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,11 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.12 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).13

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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 1TABLE 1Shepard’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.9These 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 litigation30 and to assess other potential teratogens.10 We used Shepard’s criteria9 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 (Table 1).

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.14-20 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.1 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.14 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.1,31,32 Two epidemiologic studies also provide support.2,14 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.14

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 microcephaly2 — 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.2 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.33 Many fetuses and infants with presumed congenital Zika virus infection have had a typical pattern, including severe microcephaly, intracranial calcifications, and other brain anomalies, sometimes accompanied by eye findings, redundant scalp skin, arthrogryposis, and clubfoot15,20-23; such findings have led authors to use the term “congenital Zika syndrome.”22,34,35 On the basis of clinical details from a limited number of cases, some infants with presumed congenital Zika virus infection have had features that were consistent with fetal brain disruption sequence,24 a phenotype involving the brain that is characterized by severe microcephaly, overlapping cranial sutures, prominent occipital bone, redundant scalp skin, and considerable neurologic impairment.20,22 For example, 11 of 35 infants (31%) with microcephaly whose cases were reported to a Brazil Ministry of Health registry had excessive and redundant scalp skin,20 a finding that is not typically seen in other forms of microcephaly.36 These findings suggest an interruption of cerebral growth, but not in that of the scalp skin, after an injury (e.g., viral infection, hyperthermia, or vascular disruption) that occurred after the initial formation of brain structures, followed by partial collapse of the skull. The fetal brain disruption sequence is rare; only 20 cases were identified in a literature review in 2001.24

Shepard’s fourth criterion refers to the association between a rare exposure and a rare defect; we conclude that this criterion also has been met. The concept behind this criterion is that a rare defect occurring after a rare exposure during pregnancy implies causation because of the unlikelihood of the two rare events occurring together.10 Microcephaly is a rare defect that is estimated to occur in 6 infants per 10,000 liveborn infants in the United States.25 Zika virus would not be a rare exposure among women living in Brazil during the Zika virus outbreak. However, reports of adverse birth outcomes among travelers who spent only a limited time period in an area where there is active Zika virus transmission are consistent with Zika virus being a rare exposure.16,18,19

A recent report is illustrative: a pregnant woman traveled for 7 days to Mexico, Guatemala, and Belize during her 11th week of gestation and had a positive test for Zika virus immunoglobulin M (IgM) antibodies 4 weeks later. On fetal ultrasonography and magnetic resonance imaging performed at 19 to 20 weeks of gestation, severe brain anomalies were diagnosed in the fetus, and the pregnancy was terminated at 21 weeks of gestation. Microcephaly was not present at the time of pregnancy termination, but the head circumference had decreased from the 47th percentile at 16 weeks of gestation to the 24th percentile at 20 weeks of gestation (a finding that is consistent with the timing of diminishing head sizes in previous cases),14 which suggests that microcephaly would have developed in the fetus had the pregnancy continued.16 In this woman, Zika virus would be considered a rare exposure, and her fetus had a rare outcome.

The last three criteria are helpful if they are present, but they are not considered to be essential. The fifth criterion, the need for an animal model that shows teratogenicity, has not been met. Although animal models have shown that Zika virus is neurotropic,27,28 no studies that tested for teratogenicity in an animal model have been published, although studies are under way. The sixth criterion, that the association should make biologic sense, is clearly met here. Other viral infections have had similar effects (microcephaly and eye problems).24,26 In addition, pathologic evidence supports this association: Zika virus RNA has been seen in damaged mononuclear cells (presumably glial cells and neurons) in the brains of newborns with microcephaly,17 and the virus appears to be neurotropic.17,19 Live Zika virus has been cultured from the brain of a fetus with severe brain anomalies after maternal infection at 11 weeks of gestation.16 Furthermore, Zika virus efficiently infects neural progenitor cells and produces cell death and abnormal growth, thus providing a possible mechanism for microcephaly.29 The seventh criterion, proof in an experimental system that the agent acts in an unaltered state, is aimed at medications or chemical exposures and does not apply to infectious agents. Thus, given Shepard’s criteria as a framework, criteria 1, 3, and 4 have been satisfied — evidence that is considered sufficient to identify an agent as a teratogen.

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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.37-39 The Bradford Hill criteria40 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.41 However, several key pieces of evidence have become available since they performed their analysis, including two epidemiologic studies,2,14 a study of the effects of Zika virus on neural progenitor cells,29 and a case report of a fetus with brain anomalies and decreasing head size from whose brain live Zika virus was isolated.16 On the basis of our update of their analysis, which incorporates newly available evidence (Table 2TABLE 2Bradford 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 necessary40; instead, the criteria should serve as a framework to assess when the most likely interpretation of a relationship is causation.

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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 teratogens9 and the Bradford Hill criteria40 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.1,2,42

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.44 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).11 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.

 

 

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on April 13, 2016, at NEJM.org.

SOURCE INFORMATION

From the Division of Public Health Information Dissemination, Center for Surveillance, Epidemiology, and Laboratory Services (S.A.R.), Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion (D.J.J.), and Division of Congenital and Developmental Disorders, National Center on Birth Defects and Developmental Disabilities (M.A.H.), Centers for Disease Control and Prevention, Atlanta; and the Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, CO (L.R.P.).

Address reprint requests to Dr. Rasmussen at the Centers for Disease Control and Prevention, 1600 Clifton Rd., MS E-33, Atlanta, GA 30329, or at [email protected].

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REFERENCES

1. 1

   Kleber de Oliveira W, Cortez-Escalante J, De Oliveira WT, et al. Increase in reported prevalence of microcephaly in infants born to women living in areas with confirmed Zika virus transmission during the first trimester of pregnancy — Brazil, 2015. MMWR Morb Mortal Wkly Rep 2016;65:242-247
   CrossRef | Medline

2. 2

   Cauchemez S, Besnard M, Bompard P, et al. Association between Zika virus and microcephaly in French Polynesia, 2013-15: a retrospective study. Lancet2016 March 15 (Epub ahead of print)
   Medline

3. 3

   Petersen LR, Jamieson DJ, Powers AM, Honein MA. Zika virus. N Engl J Med2016;374:1552-1563

4. 4

   O’Leary DR, Kuhn S, Kniss KL, et al. Birth outcomes following West Nile Virus infection of pregnant women in the United States: 2003-2004. Pediatrics 2006;117:e537-45
   CrossRef | Web of Science | Medline

5. 5

   Duffy MR, Chen T-H, Hancock WT, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med 2009;360:2536-2543
   Free Full Text | Web of Science | Medline

6. 6

   Ioos S, Mallet HP, Leparc Goffart I, Gauthier V, Cardoso T, Herida M. Current Zika virus epidemiology and recent epidemics. Med Mal Infect 2014;44:302-307
   CrossRef | Web of Science | Medline

7. 7

   Chang C, Ortiz K, Ansari A, Gershwin ME. The Zika outbreak of the 21st century. J Autoimmun 2016;68:1-13
   CrossRef | Medline

8. 8

   Associated Press-NORC Center for Public Affairs Research. The Zika virus: Americans’ awareness and opinions of the U.S. response. April 2016 (http://www.apnorc.org/PDFs/Zika/2016-04%20Zika%20Virus%20Issue%20Brief%20DTPB_v1r5.pdf).

9. 9

   Shepard TH. “Proof” of human teratogenicity. Teratology 1994;50:97-98
   CrossRef | Medline

10. 10

    Carey JC, Martinez L, Balken E, Leen-Mitchell M, Robertson J. Determination of human teratogenicity by the astute clinician method: review of illustrative agents and a proposal of guidelines. Birth Defects Res A Clin Mol Teratol 2009;85:63-68
    CrossRef | Web of Science | Medline

11. 11

    Webster WS. Teratogen update: congenital rubella. Teratology 1998;58:13-23
    CrossRef | Medline

12. 12

    Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet1973;302:999-1001
    CrossRef | Medline

13. 13

    Lammer EJ, Sever LE, Oakley GP Jr.. Teratogen update: valproic acid. Teratology1987;35:465-473
    CrossRef | Medline

14. 14

    Brasil P, Pereira JP Jr, Raja Gabaglia C, et al. Zika virus infection in pregnant women in Rio de Janeiro — preliminary report. N Engl J Med. DOI: 10.1056/NEJMoa1602412
    Free Full Text | Medline

15. 15

    Calvet G, Aguiar RS, Melo AS, et al. Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. Lancet Infect Dis2016 February 17 (Epub ahead of print)
    Medline

16. 16

    Driggers RW, Ho CY, Korhonen EM, et al. Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. N Engl J Med. DOI: 10.1056/NEJMoa1601824
    Free Full Text | Medline

17. 17

    Martines RB, Bhatnagar J, Keating MK, et al. Notes from the field: evidence of Zika virus infection in brain and placental tissues from two congenitally infected newborns and two fetal losses — Brazil, 2015. MMWR Morb Mortal Wkly Rep 2016;65:159-160
    CrossRef | Web of Science | Medline

18. 18

    Meaney-Delman D, Hills SL, Williams C, et al. Zika virus infection among U.S. pregnant travelers — August 2015–February 2016. MMWR Morb Mortal Wkly Rep 2016;65:211-214
    CrossRef | Web of Science | Medline

19. 19

    Mlakar J, Korva M, Tul N, et al. Zika virus associated with microcephaly. N Engl J Med2016;374:951-958
    Free Full Text | Web of Science | Medline

20. 20

    Schuler-Faccini L, Ribeiro EM, Feitosa IM, et al. Possible association between Zika virus infection and microcephaly — Brazil, 2015. MMWR Morb Mortal Wkly Rep 2016;65:59-62
    CrossRef | Web of Science | Medline

21. 21

    Ventura CV, Maia M, Bravo-Filho V, Góis AL, Belfort R Jr.. Zika virus in Brazil and macular atrophy in a child with microcephaly. Lancet 2016;387:228-228
    CrossRef | Web of Science | Medline

22. 22

    Miranda-Filho Dde B, Martelli CM, Ximenes RA, et al. Initial description of the presumed congenital Zika syndrome. Am J Public Health 2016;106:598-600
    CrossRef | Medline

23. 23

    Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves Sampaio S, Bispo de Filippis AM. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg? Ultrasound Obstet Gynecol 2016;47:6-7
    CrossRef | Web of Science | Medline

24. 24

    Corona-Rivera JR, Corona-Rivera E, Romero-Velarde E, Hernández-Rocha J, Bobadilla-Morales L, Corona-Rivera A. Report and review of the fetal brain disruption sequence. Eur J Pediatr 2001;160:664-667
    CrossRef | Web of Science | Medline

25. 25

    National Birth Defects Prevention Network. Major birth defects data from population-based birth defects surveillance programs in the United States, 2006-2010. August 2013 (http://www.nbdpn.org/docs/DataDirectory2013_NBDPN_AR.pdf).

26. 26

    Bale JF Jr.. Fetal infections and brain development. Clin Perinatol 2009;36:639-653
    CrossRef | Web of Science | Medline

27. 27

    Dick GW. Zika virus. II. Pathogenicity and physical properties. Trans R Soc Trop Med Hyg1952;46:521-534
    CrossRef | Web of Science | Medline

28. 28

    Bell TM, Field EJ, Narang HK. Zika virus infection of the central nervous system of mice.Arch Gesamte Virusforsch 1971;35:183-193
    CrossRef | Medline

29. 29

    Tang H, Hammack C, Ogden SC, et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell2016 March 4 (Epub ahead of print)

30. 30

    Public Affairs Committee of the Teratology Society. Causation in teratology-related litigation. Birth Defects Res A Clin Mol Teratol 2005;73:421-423
    CrossRef | Web of Science | Medline

31. 31

    Teixeira MG, da Conceição N Costa M, de Oliveira WK, Nunes ML, Rodrigues LC. The epidemic of Zika virus-related microcephaly in Brazil: detection, control, etiology, and future scenarios. Am J Public Health 2016;106:601-605
    CrossRef | Medline

32. 32

    Reefhuis J, Gilboa SM, Johansson MA, et al. Projecting month of birth for at-risk infants after Zika virus disease outbreaks. Emerg Infect Dis (in press).

33. 33

    Mitchell AA. Proton-pump inhibitors and birth defects — some reassurance, but more needed. N Engl J Med 2010;363:2161-2163
    Full Text | Web of Science | Medline

34. 34

    Costa F, Sarno M, Khouri R, et al. Emergence of congenital Zika syndrome: viewpoint from the front lines. Ann Intern Med2016 February 24 (Epub ahead of print)
    Medline

35. 35

    Chan JF, Choi GK, Yip CC, Cheng VC, Yuen KY. Zika fever and congenital Zika syndrome: an unexpected emerging arboviral disease. J Infect2016 March 3 (Epub ahead of print)

36. 36

    Abuelo D. Microcephaly syndromes. Semin Pediatr Neurol 2007;14:118-127
    CrossRef | Medline

37. 37

    Byrd AL, Segre JA. Infectious disease: adapting Koch’s postulates. Science 2016;351:224-226
    CrossRef | Web of Science | Medline

38. 38

    Fredricks DN, Relman DA. Sequence-based identification of microbial pathogens: a reconsideration of Koch’s postulates. Clin Microbiol Rev 1996;9:18-33
    Web of Science | Medline

39. 39

    Williams JV. Déjà vu all over again: Koch’s postulates and virology in the 21st century. J Infect Dis 2010;201:1611-1614
    CrossRef | Web of Science | Medline

40. 40

    Hill AB. The environment and disease: association or causation? Proc R Soc Med1965;58:295-300
    Medline

41. 41

    Frank C, Faber M, Stark K. Causal or not: applying the Bradford Hill aspects of evidence to the association between Zika virus and microcephaly. EMBO Mol Med2016 March 14 (Epub ahead of print)

42. 42

    Instituto Nacional de Salud. Boletin Epidemiologico Semanal. April 2016 (http://www.ins.gov.co/boletin-epidemiologico/Boletn%20Epidemiolgico/2016%20Boletín%20epidemiológico%20semana%2012.pdf).

43. 43

    Hubálek Z, Rudolf I, Nowotny N. Arborviruses pathogenic for domestic and wild animals.Adv Virus Res 2014;89:201-275
    CrossRef | Web of Science | Medline

44. 44

    Palacios R, Poland GA, Kalil J. Another emerging arbovirus, another emerging vaccine: targeting Zika virus. Vaccine2016 March 23 (Epub ahead of print)
    Medline

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CDC Confirms Link Between Zika Virus and Birth Defects

Agency finds enough evidence to conclude it can cause abnormalities in infants of women infected during pregnancy

 

ENLARGE

CDC Director Tom Frieden said, ‘There is no longer any doubt that Zika causes microcephaly’—in which the head is small for gestational age and sex. PHOTO: ESTEFAN RADOVICZ/XINHUA/ZUMA PRESS

By 

BETSY MCKAY

April 13, 2016 5:01 p.m. ET

2 COMMENTS

The U.S. Centers for Disease Control and Prevention said Wednesday that enough evidence has accumulated for it to conclude that the Zika virus can cause birth defects in the infants of women who are infected during pregnancy.

In a paper published in the New England Journal of Medicine, the public health agency said several established criteria to determine a causal relationship have been met, including Zika infection in mothers whose babies developed microcephaly—in which the head is small for gestational age and sex—and other severe brain abnormalities.

“There is no longer any doubt that Zika causes microcephaly,” CDC Director Tom Frieden said in a telephone briefing.

Most public health officials and scientists have been operating on the assumption that Zika is the cause of a sharp rise in the number of babies born in Brazil over the past six months with these birth defects, as well as an increase in abnormalities in fetuses of pregnant women who have been exposed in other countries where Zika is circulating. Many also assume the virus is behind at least two types of neurological complications in adults, including Guillain-Barre syndrome. The CDC said it is still studying whether Zika causes Guillain-Barre.

Zika has been found circulating in 40 countries and territories, according to the CDC. 

 

The U.S. Centers for Disease Control and Prevention believes the zika virus has reached 30 states, and urges travelers and expectant mothers to be vigilant. Photo: CDC

READ MORE

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• Couples Should Delay Pregnancy Plans in Event of Zika Symptoms, CDC Says (March 25)
• Evidence Grows Linking Zika Virus to Birth Defect, Paralysis (March 4)
• New Study Links Zika Virus to Microcephaly (Feb. 10)
• Five Things to Know About Zika Virus(Feb. 1)

The World Health Organization said in its most recent weekly situation report that “there is scientific consensus that Zika virus is a cause of microcephaly and Guillain-Barre syndrome.”

The CDC said its declaration won’t change its current warnings for pregnant women regarding travel to countries where Zika is circulating, or its guidance for preventing the spread of Zika through sexual transmission. But the agency said it hopes that declaring Zika a cause of birth defects in children will help to intensify efforts to raise public awareness of the risks of Zika infection, control the mosquitoes that spread the virus and develop a vaccine against it. A number of vaccine candidates are in development, as are new methods to control or eliminate the Aedes aegypti and Aedes albopictus mosquitoes that spread Zika and other dangerous viruses such as dengue and chikungunya.

Many critical questions remain and could take years to answer, Dr. Frieden said. They include what types of and how many birth defects are caused by Zika cause and how common are the defects. One recent study estimated that a woman infected with Zika during her first trimester of pregnancy faces a 1% risk that her baby will develop microcephaly. Another study found abnormalities in 29% of the fetuses of a group of pregnant women who had had the virus. The CDC said it has other studies under way to answer some of these questions.

The agency said it based its conclusion on several pieces of evidence. First, in cases the CDC reviewed, exposure to Zika occurred during a critical time in pregnancy: babies with birth defects were born to mothers who were infected with Zika in the first or early second trimester.

Second, there was a specific pattern of birth defects, including severe microcephaly and brain lesions, the CDC said. Third, the link between Zika and birth defects involves a rare exposure and a rare birth defect, the CDC said. Infants of pregnant women who have traveled to areas where Zika is circulating have developed microcephaly, a rare condition that normally affects only 6 in 10,000 newborns.

Write to Betsy McKay at [email protected]

http://www.wsj.com/articles/cdc-confirms-link-between-zika-virus-and-babies-birth-defects-1460581319

 

[niman]

It’s confirmed. Zika virus causes microcephaly and other birth defects, CDC says

 

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BY NSIKAN AKPAN  April 13, 2016 at 5:00 PM EDT  | Updated: Apr 13, 2016 at 5:53 PM

CDC director: This study marks a turning point in the Zika outbreak. Photo by Paulo Whitaker/REUTERS

Today, the Centers for Disease Control and Prevention definitively confirmed what may have seemed a forgone conclusion: Zika virus causes microcephaly and other neurological birth defects.

“This study marks a turning point in the Zika outbreak. It is now clear that the virus causes microcephaly,” CDC director Tom Frieden said in a statement. “We’ve now confirmed what mounting evidence has suggested, affirming our early guidance to pregnant women and their partners to take steps to avoid Zika infection and to health care professionals who are talking to patients every day.”

The health agency’s assessment is not based on a single piece of evidence, but rather months of careful evaluation and the growing number of reports of showing a biological connection between the brain disorders. A synopsis of those findings has been published in the New England Journal of Medicine.

The researchers reached this conclusion by using Shepard’s criteria — an accepted set of seven rules used to identify causes of birth defects. One sticking point was the abundance of microcephaly observed in fetuses and newborns that had been exposed to the virus in the womb.

Shepard’s criteria for proof of Zika-related birth defects in humans as applied to the relationship between Zika virus infection and microcephaly and other brain anomalies. Photo by Rasmussen SA et al., New England Journal of Medicine, (2016)

Research into Zika virus has satisfied five of the seven criteria. The missing elements involve tests in animal models, which have not been developed, and the seventh criteria that only apply to chemical agents.

For now, the CDC’s guidance for pregnant women remains the same. They recommend that pregnant women avoid travel to Zika-hit regions. Infected men, with or without symptoms, can pass Zika virus to sexual partners. So, the CDC recommends abstinence or condom usage for couples if a male partner has traveled to a Zika-impacted region.

The Zika outbreak has afflicted 33 countries and territories in the Americas, according to the World Health Organization.

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  Nsikan Akpan

  Nsikan Akpan is the digital science producer for PBS NewsHour.

  http://www.pbs.org/newshour/rundown/its-confirmed-zika-virus-causes-microcephaly-and-other-birth-defects-cdc-says/

   

[niman]

CDC confirms Zika causes severe birth defects

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MARIO TAMA/GETTY IMAGES

Nadja Cristina Gomes Bezerra, of Recife, Brazil, displays a photograph of her daughter, who was born with microcephaly.

By HELEN BRANSWELL @HelenBranswell

APRIL 13, 2016

 

 

 

The Centers for Disease Control and Prevention said Wednesday the time has come to drop the squishy language previously used to describe the Zika virus. It isn’t just suspected of causing birth defects; it does cause birth defects.

Senior scientists involved in the agency’s Zika response argue in an articlerushed to print by the New England Journal of Medicine that the virus has met a test used to determine whether an exposure — to a disease agent like a virus or a chemical, for instance — causes birth defects in a developing fetus.

The test is called the Shepard criteria, and it lays out seven factors that can be used to determine if an exposure causes birth defects. Zika currently meets four of the seven — and only three are needed to prove causality, the scientists said.

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Scientists at the CDC and the World Health Organization have been clear for weeks that they believed infection during pregnancy was leading in some instances to babies with severe microcephaly — smaller than normal heads — and signs of profound brain damage.

But officially, they have avoided saying Zika infection “causes” brain-related birth defects, because in scientific terms there simply wasn’t enough evidence yet to say that definitively.

READ MORE

5 things the world has learned about Zika so far

At the end of March, however, the WHO took the plunge, saying in a weekly Zika update that “based on observational, cohort and case-control studies there is strong scientific consensus that Zika virus is a cause” of microcephaly and other neurological disorders.

Wednesday’s article, however, is the first time scientists have laid out the argument for why Zika can be said to cause birth defects.

The lead author of the paper, Dr. Sonja Rasmussen, said it was important to go through that process, both to record the claim in the scientific literature, but also to persuade the public to take the threat seriously.

Rasmussen told STAT there continue to be those who doubt the link. CDC wants the public — especially pregnant women — to take the risk seriously, she said, and take the preventive steps it has recommended.

“We do these things because we want to be sure that people take action on the recommendations that we make,” said Rasmussen, editor in chief of CDC’s Morbidity and Mortality Weekly Report and an expert in birth defects research.

“We really want to do our very best to make sure that pregnant women hear the message that we’re giving them — that if you are thinking about traveling to one of these places where there is Zika virus transmission, please don’t. And if your partner has traveled to one of those places, to take precautions … to prevent sexual transmission.”

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The Obama administration has been pressing Congress to approve an emergency request for additional funding to research Zika and support a public health response to the virus. Republicans have refused to date to approve the White House’s request for $1.9 million in funding, insisting that money committed but not yet used in the Ebola response be used first.

On Wednesday, there was a hint that Republicans may be getting ready to work toward providing additional money. The chairman of the House Appropriations Committee, Representative Hal Rogers of Kentucky, said during a committee hearing that his staff was working on an emergency funding bill that would provide more money in the current fiscal year, which ends in September. But he said his committee needs more information from the administration before it can produce a bill.

The administration has already announced, in the meantime, it would divert $500 million from the Ebola fund to the Zika response.

Dylan Scott in Washington contributed reporting.

 

Helen Branswell can be reached at [email protected] 
Follow Helen on Twitter @HelenBranswell 

https://www.statnews.com/2016/04/13/zika-birth-defects-causes/

 

[niman]

Zika Virus Does Cause Birth Defects

Scientists confirm what many suspected, but questions remain.

 

John Tozzi jtozz

April 13, 2016 — 5:00 PM EDT

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After months of mounting evidence, scientists are ready to say definitively that the mosquito-borne Zika virus spreading across the Americas is causing birth defects, a link that the head of the Centers for Disease Control called “unprecedented.”

“There is no longer any doubt that Zika causes microcephaly,” CDC Director Tom Frieden declared Wednesday. A spike in microcephaly, when babies are born with abnormally small heads, raised the level of alarm about the disease in Brazil last year. “Never before in history has there been a situation where a bite from a mosquito could result in a devastating malformation.”

QUICKTAKEZika Virus
Zika transmission has been reported in 33 countries and territories in the Americas since it was first detected in Brazil in 2015, according to the World Health Organization. Microcephaly and other birth defects have been linked to the virus in French Polynesia, Brazil, Colombia, Panama, and elsewhere.

 

 

Zika Virus: What You Need to Know in Two Minutes

Frieden said that “no single piece of evidence” proved that the virus causes birth defects. An accumulation of research conducted as the epidemic moved across the continent pointed to the CDC's conclusion, published in the New England Journal of Medicine. That still leaves a long list of urgent questions unanswered, and some may not be answered for years.

Among them are what other birth defects might Zika cause? Does it cause developmental problems that aren’t evident at birth but may manifest years later? Are women at risk if they get the Zika virus but don't develop symptoms? Does Zika cause other neurological problems, such as the Guillain-Barré syndrome it’s been linked to?

There’s a global public health effort under way to answer these and other questions. But the evidence may be conflicting and slow to point to concrete answers.

For example, one analysis of a Zika outbreak in French Polynesia indicated that about 1 percent of women infected with Zika during pregnancy would give birth to children with microcephaly. Another study in Brazil indicated that 30 percent had some kind of abnormality detected in ultrasounds, said Sonja Rasmussen, director of the CDC’s division of public health information and dissemination.

 

The cases of microcephaly caused by Zika appear to be unusually severe, Rasmussen said. And further evidence may indicate a link to other defects or disorders. “We do expect that that’s likely to be the tip of the iceberg,” Rasumussen said.

The conclusion affirms the CDC’s earlier advice that pregnant women avoid traveling to areas where Zika is circulating. After evidence was discovered that men infected with the virus can spread it to sex partners, the agency also advised pregnant women to use condoms or abstain from sex.

http://www.bloomberg.com/news/articles/2016-04-13/zika-virus-does-cause-birth-defects