Abnormal Development - Zika Virus

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Zika virus world map (CDC 2016)
Zika Virus Pregnancy USA (2015-2016)
Zika Virus Pregnancy USA (2015-2016)[1]

Zika virus (ZIKV) is a mosquito-borne flavivirus related to dengue virus first isolated from a rhesus monkey in Zika forest, Uganda (1947). Transmitted by mosquitoes (Aedes aegypti) it was then identified in humans in Nigeria in 1954 and subsequently in South America, Asia and Pacific regions. More recently in Australia from returning travellers.[2]

Mosquito lifecycle

Mosquito bites lead to an initial infection of skin cells.[3] The virus may also be transmitted transplacentally or during delivery.[4]

Now good evidence, from Brazil and other South American countries, for association with neural abnormalities (microcephaly, vision development, Guillian Barre Syndrome). This possible association in other developmental systems requires more clinical and scientific evidence before being confirmed.

Microlissencephaly MRI-01.jpg


Viral Links: viral infection | TORCH | cytomegalovirus | hepatitis | HIV | parvovirus | polio | rubella virus | chickenpox | Lymphocytic Choriomeningitis Virus | Zika virus | human papillomavirus | rotavirus | West Nile virus | varicella virus | vaccination | zoonotic infection | environment
Historic Embryology - Viral 
1941 Rubella Cataracts | 1944 Rubella Defects

Some Recent Findings

USA Zika Pregnancy Registry (2016)[5]
  • Experience in diagnosing congenital Zika syndrome in Brazilian children born to asymptomatic mothers[6] "Typical symptoms of primary Zika virus infection are not specific and share similarities with other arbovirus infections such as dengue fever and chikungunya. As acute infection can be asymptomatic in up to 73% of cases, infants with microcephaly represent a diagnostic challenge for pediatricians. We describe the frequency of congenital Zika syndrome (CZS) in Brazilian children born to asymptomatic pregnant mothers and its differential diagnosis. This longitudinal, observational study was conducted on children with suspected CZS whose mothers did not report rash during pregnancy, referred to the reference hospital in a metropolitan area of ​ Rio de Janeiro, Brazil. The diagnosis of suspected CZS was based on Brazilian Ministry of Health protocol. Forty-three (17%) of 246 referred children were born to mothers without rash history during pregnancy. Thirteen (30%) of 43 children met the Brazilian Ministry of Health criteria for CZS, all with microcephaly (two post-natal). The other children included 11 cases with post-natal microcephaly due to hypoxic-ischemic encephalopathy (6), non-progressive encephalopathy of unknown etiology (2), microcephaly under investigation (2) and congenital toxoplasmosis (1); 17 children were misdiagnosed with microcephaly and progressed with normal head circumference during the follow-up period; one child was included because of epidemiological link and one was loss to follow-up. All children who underwent laboratory investigation for ZIKV infection during neonatal period had negative RT-qPCR tests. We emphasize the increasing importance of CZS in differential diagnosis of microcephaly at birth or post-natal period. Detailed clinical investigation assisted by neuroimaging tests may clarify the diagnosis of CZS when laboratory tests are not available during the acute phase of the disease."
  • Zika Virus Detection in Amniotic Fluid and Zika-Associated Birth Defects[7] "Zika virus (ZIKV) infection during pregnancy can cause serious birth defects, including brain and eye abnormalities. The clinical importance of detection of ZIKV ribonucleic acid (RNA) in amniotic fluid is unknown. We conducted a retrospective cohort analysis of women with amniotic fluid specimens submitted to Colombia's National Institute of Health as part of national ZIKV surveillance from January 2016 to January 2017. ...Testing of amniotic fluid provided additional evidence for maternal diagnosis of ZIKV infection. Zika-associated birth defects were more common among women with ZIKV RNA detected in prenatal amniotic fluid specimens than women with no laboratory evidence of ZIKV infection, but similar to women with ZIKV RNA detected in other, non-amniotic fluid specimen types."

Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology[8] "Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS). Here we infect pregnant rhesus macaques and investigate the impact of persistent ZIKV infection on uteroplacental pathology, blood flow, and fetal growth and development. Despite seemingly normal fetal growth and persistent fetal-placenta-maternal infection, advanced non-invasive in vivo imaging studies reveal dramatic effects on placental oxygen reserve accompanied by significantly decreased oxygen permeability of the placental villi. The observation of abnormal oxygen transport within the placenta appears to be a consequence of uterine vasculitis and placental villous damage in ZIKV cases. In addition, we demonstrate a robust maternal-placental-fetal inflammatory response following ZIKV infection." monkey

  • Exhaustive TORCH Pathogen Diagnostics Corroborate Zika virus Etiology of Congenital Malformations in Northeastern Brazil[9] "Our data support a link between maternal ZIKV infection and congenital malformations and suggest the occurrence of predominantly vector-borne ZIKV transmission in these cases. In addition, some highly prevalent TORCH pathogens may be misinterpreted as representative of ongoing ZIKV activity in the absence of exhaustive diagnostics in northeastern Brazil."
More recent papers  
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Search term: Abnormal Development Zika Virus | Zika Virus

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Zika virus infection in a pregnant Canadian traveler with congenital fetal malformations noted by ultrasonography at 14-weeks gestation[10] "Following emergence of Zika virus in the Americas, a devastating new congenital syndrome has been documented, leading to significant morbidity among Zika-infected fetuses and neonates.

A 29-year-old pregnant woman infected with Zika virus at 9-weeks gestation in Trinidad presented with one-month of fever, headache, and myalgia with persistent viremia. Significant fetal abnormalities were identified at 14-week ultrasound, which is the earliest ultrasound to describe a severely affected fetus following Zika virus infection to our knowledge."

  • A single mutation in the prM protein of Zika virus contributes to fetal microcephaly [11] "Here, we show that a single serine to asparagine substitution (S139N) in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs), led to more significant microcephaly in the mouse fetus, and higher mortality in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. "
  • Update on Zika Virus-Associated Birth Defects and Evaluation of All U.S. Infants with Congenital Zika Virus Exposure - U.S. Zika Pregnancy Registry, 2016[5] "During the analysis period, 1,297 pregnant women in 44 states were reported to the USZPR. Zika virus-associated birth defects were reported for 51 (5%) of the 972 fetuses/infants from completed pregnancies with laboratory evidence of possible recent Zika virus infection (95% confidence interval [CI] = 4%-7%); the proportion was higher when restricted to pregnancies with laboratory-confirmed Zika virus infection (24/250 completed pregnancies [10%, 95% CI = 7%-14%]). Birth defects were reported in 15% (95% CI = 8%-26%) of fetuses/infants of completed pregnancies with confirmed Zika virus infection in the first trimester. Among 895 liveborn infants from pregnancies with possible recent Zika virus infection, postnatal neuroimaging was reported for 221 (25%), and Zika virus testing of at least one infant specimen was reported for 585 (65%). CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: These findings highlight why pregnant women should avoid Zika virus exposure. Because the full clinical spectrum of congenital Zika virus infection is not yet known, all infants born to women with laboratory evidence of possible recent Zika virus infection during pregnancy should receive postnatal neuroimaging and Zika virus testing in addition to a comprehensive newborn physical exam and hearing screen. Identification and follow-up care of infants born to women with laboratory evidence of possible recent Zika virus infection during pregnancy and infants with possible congenital Zika virus infection can ensure that appropriate clinical services are available."
  • Congenital Zika Virus Infection: Beyond Neonatal Microcephaly[12] "Recent studies have reported an increase in the number of fetuses and neonates with microcephaly whose mothers were infected with the Zika virus (ZIKV) during pregnancy. To our knowledge, most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects. To describe the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurological damage associated with ZIKV infection in Brazil....Three of 11 neonates died, giving a perinatal mortality rate of 27.3%. The median (SD) cephalic perimeter at birth was 31 (3) cm, a value lower than the limit to consider a microcephaly case. In all patients, neurological impairments were identified, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence (ie, arthrogryposis). Results of limited testing for other causes of microcephaly, such as genetic disorders and viral and bacterial infections, were negative, and the ZIKV genome was found in both maternal and neonatal tissues (eg, amniotic fluid, cord blood, placenta, and brain)."
  • Modeling Zika Virus Infection in Pregnancy[13] "Collectively, the findings from the stud- ies in mice support the hypothesis that infection during pregnancy with contemporary ZIKV strains causes placental infection and injury and that ZIKV spreads to the fetal brain and kills neuronal progenitor cells, which probably con- tributes to the microcephaly and other congeni- tal malformations that have been observed in human neonates."
  • Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study[14] "23 children with a diagnosis of congenital infection presumably associated with the Zika virus during the Brazilian microcephaly epidemic. Types of abnormalities and the radiological pattern of lesions identified on CT and MRI brain scans. Six of the 23 children tested positive for IgM antibodies to Zika virus in cerebrospinal fluid. The other 17 children met the protocol criteria for congenital infection presumably associated with the Zika virus, even without being tested for IgM antibodies to the virus-the test was not yet available on a routine basis. Of the 23 children, 15 underwent CT, seven underwent both CT and MRI, and one underwent MRI. ...Severe cerebral damage was found on imaging in most of the children in this case series with congenital infection presumably associated with the Zika virus. The features most commonly found were brain calcifications in the junction between cortical and subcortical white matter associated with malformations of cortical development, often with a simplified gyral pattern and predominance of pachygyria or polymicrogyria in the frontal lobes. Additional findings were enlarged cisterna magna, abnormalities of corpus callosum (hypoplasia or hypogenesis), ventriculomegaly, delayed myelination, and hypoplasia of the cerebellum and the brainstem."
  • Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities[15] "The current outbreak of Zika virus (ZIKV) infection has been associated with an apparent increased risk of congenital microcephaly. We describe a case of a pregnant woman and her fetus infected with ZIKV during the 11th gestational week. The fetal head circumference decreased from the 47th percentile to the 24th percentile between 16 and 20 weeks of gestation. ZIKV RNA was identified in maternal serum at 16 and 21 weeks of gestation. At 19 and 20 weeks of gestation, substantial brain abnormalities were detected on ultrasonography and magnetic resonance imaging (MRI) without the presence of microcephaly or intracranial calcifications. On postmortem analysis of the fetal brain, diffuse cerebral cortical thinning, high ZIKV RNA loads, and viral particles were detected, and ZIKV was subsequently isolated."
  • Zika virus outbreaks prompt warnings to pregnant women[16] "The rapid spread of Zika virus in the Americas, where there is little population immunity, is a major concern, especially given the possible link between infection during pregnancy and the congenital abnormality microcephaly, the World Health Organization has warned. Margaret Chan, WHO’s director general, said, “Although a causal link between Zika infection in pregnancy and microcephaly has not been established, the circumstantial evidence is suggestive and extremely worrisome. An increased occurrence of neurological syndromes, noted in some countries coincident with arrival of the virus, adds to the concern."
  • Ocular Findings in Infants With Microcephaly Associated With Presumed Zika Virus Congenital Infection in Salvador, Brazil[17] "Twenty-three of 29 mothers (79.3%) reported suspected ZIKV infection signs and symptoms during pregnancy, 18 in the first trimester, 4 in the second trimester, and 1 in the third trimester. Of the 29 infants (58 eyes) examined (18 [62.1%] female), ocular abnormalities were present in 17 eyes (29.3%) of 10 children (34.5%). Bilateral findings were found in 7 of 10 patients presenting with ocular lesions, the most common of which were focal pigment mottling of the retina and chorioretinal atrophy in 11 of the 17 eyes with abnormalities (64.7%), followed by optic nerve abnormalities in 8 eyes (47.1%), bilateral iris coloboma in 1 patient (2 eyes [11.8%]), and lens subluxation in 1 eye (5.9%)."

Virus Structure

Virus particles are 40 nm in diameter, with an outer envelope, and an inner dense core. ZIKV is an RNA virus containing 10,794 nucleotides encoding 3,419 amino acids.[18]

Zika virus Zika virions (red circles)
Zika virus TEM01.jpg Zika virus TEM02.jpg

Lineage: Viruses; ssRNA viruses; ssRNA positive-strand viruses, no DNA stage; Flaviviridae; Flavivirus; Spondweni virus group

Zika virus conserved domains.jpg

Zika Virus Translation - 3,419 amino acids  

Zika History

Zika virus (ZIKV) is a mosquito-borne flavivirus related to dengue virus first isolated from a rhesus monkey in Zika forest, Uganda (1947), Africa. Transmitted by mosquitoes (Aedes aegypti) it was then identified in humans in Nigeria in 1954 and subsequently in South America, Asia and Pacific regions. More recently in Australia from returning travellers.[2]

Documented Outbreaks

  • 2007 - Micronesia island of Yap (Pacific)
  • 2013 - Micronesia island of Yap (Pacific)
  • May 2015 - Brazil (South America)
  • October 2015 - Republic of Cabo Verde (Africa)
  • November 2015 - Suriname, El Salvador, Mexico, Guatemala, Paraguay, and Bolivarian Republic of Venezuela


Pyriproxyfen structure
Pyriproxyfen structure

(C20H19NO3) A chemical larvicide used to control mosquito populations, and therefore mosquito-bourns infections. A juvenile hormone analog to insect growth regulator (IGR), inhibiting metamorphosis and embryogenesis in several insects. Suggested that the chemical exposure can act at two levels; firstly the blood-fed females may carry the chemical to the larval habitats, thereby inhibiting adult emergence;secondly that tarsal contact with the chemical may inhibit egg maturation in adult mosquitoes.[19]

Links: Malaria


Skull microcephaly
Skull - microcephaly

Microcephaly describes an abnormality of development resulting in a small skull cranium marked by premature fusion of the skull sutures and also under-developed brain.

International Classification of Diseases XVII Congenital Malformations

Congenital malformations of the nervous system (Q00-Q07)

  • Q02 Microcephaly Incl.: Hydromicrocephaly Micrencephalon Excl.: Meckel-Gruber syndrome (Q61.9)

Links: Skull Development | Neural System - Abnormalities | International Classification of Diseases XVII Congenital Malformations

Vision Abnormalities

Some viral infections (herpes and rubella) are known to cause developmental vision abnormalities. A clinical study[17] of infants from Zika infected mothers in Brazil have described vision abnormalities including:

  • bilateral ocular lesions
  • focal pigment mottling of the retina
  • chorioretinal atrophy
  • optic nerve abnormalities
iris coloboma
  • lens subluxation

Links: Vision Abnormalities


  1. Simeone RM, Shapiro-Mendoza CK, Meaney-Delman D, Petersen EE, Galang RR, Oduyebo T, Rivera-Garcia B, Valencia-Prado M, Newsome KB, Pérez-Padilla J, Williams TR, Biggerstaff M, Jamieson DJ & Honein MA. (2016). Possible Zika Virus Infection Among Pregnant Women - United States and Territories, May 2016. MMWR Morb. Mortal. Wkly. Rep. , 65, 514-9. PMID: 27248295 DOI.
  2. 2.0 2.1 Pyke AT, Daly MT, Cameron JN, Moore PR, Taylor CT, Hewitson GR, Humphreys JL & Gair R. (2014). Imported zika virus infection from the cook islands into australia, 2014. PLoS Curr , 6, . PMID: 24944843 DOI.
  3. Hamel R, Dejarnac O, Wichit S, Ekchariyawat P, Neyret A, Luplertlop N, Perera-Lecoin M, Surasombatpattana P, Talignani L, Thomas F, Cao-Lormeau VM, Choumet V, Briant L, Desprès P, Amara A, Yssel H & Missé D. (2015). Biology of Zika Virus Infection in Human Skin Cells. J. Virol. , 89, 8880-96. PMID: 26085147 DOI.
  4. Besnard M, Lastere S, Teissier A, Cao-Lormeau V & Musso D. (2014). Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill. , 19, . PMID: 24721538
  5. 5.0 5.1 Reynolds MR, Jones AM, Petersen EE, Lee EH, Rice ME, Bingham A, Ellington SR, Evert N, Reagan-Steiner S, Oduyebo T, Brown CM, Martin S, Ahmad N, Bhatnagar J, Macdonald J, Gould C, Fine AD, Polen KD, Lake-Burger H, Hillard CL, Hall N, Yazdy MM, Slaughter K, Sommer JN, Adamski A, Raycraft M, Fleck-Derderian S, Gupta J, Newsome K, Baez-Santiago M, Slavinski S, White JL, Moore CA, Shapiro-Mendoza CK, Petersen L, Boyle C, Jamieson DJ, Meaney-Delman D & Honein MA. (2017). Vital Signs: Update on Zika Virus-Associated Birth Defects and Evaluation of All U.S. Infants with Congenital Zika Virus Exposure - U.S. Zika Pregnancy Registry, 2016. MMWR Morb. Mortal. Wkly. Rep. , 66, 366-373. PMID: 28384133 DOI.
  6. Vianna RAO, Rua EC, Fernandes AR, Dos Santos TCS, Dalcastel LAB, Dos Santos MLB, de Paula PDS, de Carvalho FR, Pache de Faria AO, Almeida PL, Sales LF, Riley LW, de Oliveira SA & Cardoso CAA. (2020). Experience in diagnosing congenital Zika syndrome in Brazilian children born to asymptomatic mothers. Acta Trop. , 206, 105438. PMID: 32165128 DOI.
  7. Reyes MM, Ailes EC, Daza M, Tong VT, Osorio J, Valencia D, Turca AR, Galang RR, González Duarte M, Ricaldi JN, Anderson KN, Kamal N, Thomas JD, Villanueva J, Burkel VK, Meaney-Delman D, Gilboa SM, Honein MA, Jamieson DJ & Martinez MO. (2020). Zika Virus Detection in Amniotic Fluid and Zika-Associated Birth Defects. Am. J. Obstet. Gynecol. , , . PMID: 31954155 DOI.
  8. Hirsch AJ, Roberts VHJ, Grigsby PL, Haese N, Schabel MC, Wang X, Lo JO, Liu Z, Kroenke CD, Smith JL, Kelleher M, Broeckel R, Kreklywich CN, Parkins CJ, Denton M, Smith P, DeFilippis V, Messer W, Nelson JA, Hennebold JD, Grafe M, Colgin L, Lewis A, Ducore R, Swanson T, Legasse AW, Axthelm MK, MacAllister R, Moses AV, Morgan TK, Frias AE & Streblow DN. (2018). Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology. Nat Commun , 9, 263. PMID: 29343712 DOI.
  9. Moreira-Soto A, Cabral R, Pedroso C, Eschbach-Bludau M, Rockstroh A, Vargas LA, Postigo-Hidalgo I, Luz E, Sampaio GS, Drosten C, Netto EM, Jaenisch T, Ulbert S, Sarno M, Brites C & Drexler JF. (2018). Exhaustive TORCH Pathogen Diagnostics Corroborate Zika Virus Etiology of Congenital Malformations in Northeastern Brazil. mSphere , 3, . PMID: 30089647 DOI.
  10. Schwartz KL, Chan T, Rai N, Murphy KE, Whittle W, Drebot MA, Gubbay J & Boggild AK. (2018). Zika virus infection in a pregnant Canadian traveler with congenital fetal malformations noted by ultrasonography at 14-weeks gestation. Trop Dis Travel Med Vaccines , 4, 2. PMID: 29632700 DOI.
  11. A single mutation in the prM protein of Zika virus contributes to fetal microcephaly Science 28 Sep 2017: eaam7120 DOI: 10.1126/science.aam7120
  12. Melo AS, Aguiar RS, Amorim MM, Arruda MB, Melo FO, Ribeiro ST, Batista AG, Ferreira T, Dos Santos MP, Sampaio VV, Moura SR, Rabello LP, Gonzaga CE, Malinger G, Ximenes R, de Oliveira-Szejnfeld PS, Tovar-Moll F, Chimelli L, Silveira PP, Delvechio R, Higa L, Campanati L, Nogueira RM, Filippis AM, Szejnfeld J, Voloch CM, Ferreira OC, Brindeiro RM & Tanuri A. (2016). Congenital Zika Virus Infection: Beyond Neonatal Microcephaly. JAMA Neurol , 73, 1407-1416. PMID: 27695855 DOI.
  13. Mysorekar IU & Diamond MS. (2016). Modeling Zika Virus Infection in Pregnancy. N. Engl. J. Med. , 375, 481-4. PMID: 27433842 DOI.
  14. de Fatima Vasco Aragao M, van der Linden V, Brainer-Lima AM, Coeli RR, Rocha MA, Sobral da Silva P, Durce Costa Gomes de Carvalho M, van der Linden A, Cesario de Holanda A & Valenca MM. (2016). Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study. BMJ , 353, i1901. PMID: 27075009
  15. Driggers RW, Ho CY, Korhonen EM, Kuivanen S, Jääskeläinen AJ, Smura T, Rosenberg A, Hill DA, DeBiasi RL, Vezina G, Timofeev J, Rodriguez FJ, Levanov L, Razak J, Iyengar P, Hennenfent A, Kennedy R, Lanciotti R, du Plessis A & Vapalahti O. (2016). Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities. N. Engl. J. Med. , 374, 2142-51. PMID: 27028667 DOI.
  16. Torjesen I. (2016). Zika virus outbreaks prompt warnings to pregnant women. BMJ , 352, i500. PMID: 26813766
  17. 17.0 17.1 de Paula Freitas B, de Oliveira Dias JR, Prazeres J, Sacramento GA, Ko AI, Maia M & Belfort R. (2016). Ocular Findings in Infants With Microcephaly Associated With Presumed Zika Virus Congenital Infection in Salvador, Brazil. JAMA Ophthalmol , , . PMID: 26865554 DOI.
  18. Kuno G & Chang GJ. (2005). Biological transmission of arboviruses: reexamination of and new insights into components, mechanisms, and unique traits as well as their evolutionary trends. Clin. Microbiol. Rev. , 18, 608-37. PMID: 16223950 DOI.
  19. Ohba SY, Ohashi K, Pujiyati E, Higa Y, Kawada H, Mito N & Takagi M. (2013). The effect of pyriproxyfen as a "population growth regulator" against Aedes albopictus under semi-field conditions. PLoS ONE , 8, e67045. PMID: 23843982 DOI.



Marano G, Pupella S, Vaglio S, Liumbruno GM & Grazzini G. (2016). Zika virus and the never-ending story of emerging pathogens and transfusion medicine. Blood Transfus , 14, 95-100. PMID: 26674815 DOI.


Marcondes CB & Ximenes Mde F. (2016). Zika virus in Brazil and the danger of infestation by Aedes (Stegomyia) mosquitoes. Rev. Soc. Bras. Med. Trop. , 49, 4-10. PMID: 26689277 DOI.

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Cite this page: Hill, M.A. (2024, May 25) Embryology Abnormal Development - Zika Virus. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Zika_Virus

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