Canadian Journal of Public Health

, Volume 110, Issue 5, pp 638–648 | Cite as

Maternal infection with Zika virus and prevalence of congenital disorders in infants: systematic review and meta-analysis

  • Saiee F. Nithiyanantham
  • Alaa BadawiEmail author
Systematic Review



Zika virus (ZIKV) infection is a vector-borne disease that can be transmitted sexually and vertically. The vertical transmission of the virus may lead to congenital Zika syndrome in infants. The aim of this study is to conduct a systematic review and meta-analysis of published reports documenting the prevalence of congenital Zika-related disorders in infants of mothers infected with ZIKV during pregnancy.


We conducted a comprehensive search in Ovid MEDLINE, Ovid MEDLINE (R) Epub ahead of print, Embase, Embase Classic and Web of Science databases to identify human studies reporting prevalence of congenital disorders in infants of ZIKV-infected mothers.


We identified 25 reports selected for inclusion in the current study (n = 4683 subjects). The majority of the studies were from South American high-risk countries. Only one third of the identified studies were conducted in the United States. Clinical maternal symptoms included maculopapular rash (76.9%), arthralgia (46.4%), fever (45.5%) and headache (31.8%) with myalgia and conjunctivitis only presented in 25% of the cases. The most prevalent congenital disorder in the newborns was brain calcifications (42.6; 95% CI, 30.8–54.4), followed by ventriculomegaly (21.8; 95% CI, 15.2–28.4), joint abnormalities (13.2; 95% CI, 9.4–18.2), ocular abnormalities (4.2; 95% CI, 1.0–7.5) and microcephaly (3.9; 95% CI, 2.4–5.4).


The current study highlights the high prevalence of a range of congenital disorders in newborns of mothers infected with ZIKV. It warrants developing studies to further clarify the mechanisms by which each of these disorders occurs in response to the viral infection during pregnancy and its vertical transmission to the infants.


Zika virus Microcephaly Congenital disease Brain calcification Systematic review 



L'infection par le virus Zika (ZIKV) est une maladie à vecteur pouvant être transmise sexuellement et verticalement. La transmission verticale du virus peut entraîner un syndrome congénital de Zika chez les nourrissons. Le but de cette étude est de réaliser une revue systématique et une méta-analyse de rapports publiés documentant la prévalence de troubles congénitaux liés au Zika chez les nourrissons de mères infectées par le ZIKV pendant la grossesse.


Nous avons effectué une recherche exhaustive dans les bases de données Ovid MEDLINE, Ovid MEDLINE (R) avant impression, Embase, Embase Classic et Web of Science afin d'identifier des études humaines rapportant la prévalence de troubles congénitaux chez les nourrissons de mères infectées par le ZIKV.


Nous avons identifié 25 rapports sélectionnés pour inclusion dans la présente étude (n = 4 683 sujets). La majorité des études ont été réalisées dans des pays d'Amérique du Sud présentant un risque élevé. Seulement un tiers des études identifiées ont été menées aux États-Unis. Les symptômes maternels cliniques incluaient une éruption maculo-papuleuse (76,9 %), une arthralgie (46,4 %), une fièvre (45,5 %) et des maux de tête (31,8 %) avec myalgie et conjonctivite ne se présentant que dans 25 % des cas. Les troubles congénitaux les plus fréquents chez les nouveau-nés étaient les calcifications cérébrales (42,6, IC à 95% : 30,8–54,4), suivies par la ventriculomégalie (21,8, IC à 95% : 15,2–28,4), les anomalies articulaires (13,2, IC à 95% : 9,4–18,2), des anomalies oculaires (4,2, IC à 95% : 1,0–7,5) et une microcéphalie (3,9, IC à 95% : 2,4–5,4).


La présente étude met en évidence la prévalence élevée d'une gamme de troubles congénitaux chez les nouveau-nés de mères infectées par le ZIKV. Cela justifie de développer des études pour préciser davantage les mécanismes par lesquels chacun de ces troubles se produit en réponse à l’infection virale pendant la grossesse et à sa transmission verticale aux nourrissons.


Virus Zika Microcéphalie Maladie congénitale Calcification du cerveau Revue systématique 



This work was supported by the Public Health Agency of Canada (AB). The authors thank Mr. S.G. Ryoo for assistance with abstract selection, full-text screening and data analysis.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

41997_2019_215_MOESM1_ESM.docx (27 kb)
ESM 1 (DOCX 22 kb)


  1. Adams, L., Bello-Pagan, M., Lozier, M., Ryff, K. R., Espinet, C., Torres, J., et al. (2016). Update: ongoing Zika virus transmission - Puerto Rico, November 1, 2015-July 7, 2016. Morbidity and Mortality Weekly Report, 65, 774–779. Scholar
  2. Adhikari, E. H., Nelson, D. B., Johnson, K. A., Jacobs, S., Rogers, V. L., Roberts, S. W., et al. (2017). Infant outcomes among women with Zika virus infection during pregnancy: results of a large prenatal Zika screening program. American Journal of Obstetrics and Gynecology, 216, 292.e1–292.e8. Scholar
  3. Alves, L. V., Cruz, D. D-C. S., van der Linden, A. M. C., Falbo, A. R., de Mello, M. J. G., Paredes, C. E., et al. (2016). Epileptic seizures in children with congenital Zika virus syndrome. Revista Brasileira de Saude Materno Infantil, 16(suppl 1).
  4. Aragao, M. F. V. V., Holanda, A. C., Brainer-Lima, A. M., Petribu, N. C. L., Castillo, M., van der Linden, V., et al. (2017). Nonmicrocephalic infants with congenital Zika syndrome suspected only after neuroimaging evaluation compared with those with microcephaly at birth and postnatally: how large is the Zika virus “iceberg”? American Journal of Neuroradiology, 38, 1427–1434. Scholar
  5. Badawi, A., Velummailum, R., Ryoo, S. G., Senthinathan, A., Yaghoubi, S., Vasileva, D., et al. (2018). Prevalence of chronic comorbidities in dengue fever and West Nile virus: a systematic review and meta-analysis. PLoS ONE, 13, e0200200. Scholar
  6. Besnard, M., Eyrolle-Guignot, D., Guillemette-Artur, P., Lastère, S., Bost-Bezeaud, F., Marcelis, L., et al. (2016). Congenital cerebral malformations and dysfunction in fetuses and newborns following the 2013 to 2014 Zika virus epidemic in French Polynesia. Euro Surveillance, 21.
  7. Bhatnagar, J., Rabeneck, D. B., Martines, R. B., Reagan-Steiner, S., Ermias, Y., Estetter, L. B. C., et al. (2017). Zika virus RNA replication and persistence in brain and placental tissue. Emerging Infectious Diseases, 23, 405–414. Scholar
  8. Brasil, P., Pereira, J. P., Moreira, M. E., Ribeiro Nogueira, R. M., Damasceno, L., Wakimoto, M., et al. (2016). Zika virus infection in pregnant women in Rio de Janeiro. The New England Journal of Medicine, 375, 2321–2334. Scholar
  9. DerSimonian, R., & Laird, N. (1986). Meta-analysis in clinical trials. Controlled Clinical Trials, 7, 177–188.CrossRefGoogle Scholar
  10. Faizan, M. I., Abdullah, M., Ali, S., Naqvi, I. H., Ahmed, A., & Parveen, S. (2016). Zika virus-induced microcephaly and its possible molecular mechanism. Intervirology, 59, 152–158. Scholar
  11. Gregianini, T. S., Ranieri, T., Favreto, C., Nunes, Z. M. A., Tumioto Giannini, G. L., Sanberg, N. D., et al. (2017). Emerging arboviruses in Rio Grande do Sul, Brazil: chikungunya and Zika outbreaks, 2014-2016. Reviews in Medical Virology, 27, e1943. Scholar
  12. Guillemette-Artur, P., Besnard, M., Eyrolle-Guignot, D., Jouannic, J.-M., & Garel, C. (2016). Prenatal brain MRI of fetuses with Zika virus infection. Pediatric Radiology, 46, 1032–1039. Scholar
  13. Gulland, A. (2016). Zika virus is a global public health emergency, declares WHO. BMJ, 352, i657. Scholar
  14. Hall, N. B., Broussard, K., Evert, N., & Canfield, M. (2017). Notes from the field: Zika virus-associated neonatal birth defects surveillance — Texas, January 2016–July 2017. Morbidity and Mortality Weekly Report, 66, 835–836. Scholar
  15. Hamer, D. H., Barbre, K. A., Chen, L. H., Grobusch, M. P., Schlagenhauf, P., Goorhuis, A., et al. (2017). Travel-associated Zika virus disease acquired in the Americas through February 2016: A geosentinel analysis. Annals of Internal Medicine, 166, 99–108. Scholar
  16. Higgins, J. P., & Thompson, S. G. (2002). Quantifying heterogeneity in a meta-analysis. Statistics in Medicine, 21, 1539–1558.CrossRefGoogle Scholar
  17. Honein, M. A., Dawson, A. L., Petersen, E. E., Jones, A. M., Lee, E. H., Yazdy, M. M., et al. (2017). Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA, 317, 59–68. Scholar
  18. Hu, B., Huo, Y., Yang, L., Chen, G., Luo, M., Yang, J., et al. (2017). ZIKV infection effects changes in gene splicing, isoform composition and lncRNA expression in human neural progenitor cells. Virology Journal, 14, 217. Scholar
  19. Isaacs, A. M., Riva-Cambrin, J., Yavin, D., Hockley, A., Pringsheim, T. M., Jette, N., et al. (2018). Age-specific global epidemiology of hydrocephalus: systematic review, metanalysis and global birth surveillance. PLoS ONE, 13(10), e0204926. Scholar
  20. Janssens, S., Schotsaert, M., Karnik, R., Balasubramaniam, V., Dejosez, M., Meissner, A., et al. (2018). Zika virus alters DNA methylation of neural genes in an organoid model of the developing human brain. mSystems, 3, e00219–e00217. Scholar
  21. Kam, Y. W., Leite, J. A., Lum, F. M., Tan, J. J. L., Lee, B., Judice, C. C., et al. (2017). Specific biomarkers associated with neurological complications and congenital central nervous system abnormalities from Zika virus–infected patients in Brazil. The Journal of Infectious Diseases, 216, 172–181. Scholar
  22. Kıroğlu, Y., Çalli, C., Karabulut, N., & Öncel, C. (2010). Intracranial calcifications on CT. Diagnostic and Interventional Radiology, 16, 263–269.PubMedGoogle Scholar
  23. Kleber de Oliveira, W., Cortez-Escalante, J., De Oliveira, W. T., Ikeda do Carmo, G. M., Henriques, C. M. P., Coelho, G. E., et al. (2016). 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. Morbidity and Mortality Weekly Report, 65, 242–247. Scholar
  24. Krause, K. K., Azouz, F., Shin, O. S., & Kumar, M. (2017). Understanding the pathogenesis of Zika virus infection using animal models. Immune Netw, 17, 287–297. Scholar
  25. Liberati, A., Altman, D. G., Tetzlaff, J., Murlow, C., Gotzsche, P. C., Ioannidis, J. P. A., et al. (2009). The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of Clinical Epidemiology, 62, e1–e34. Scholar
  26. Manyam, B. V. (2005). What is and what is not ‘Fahr’s disease. Parkinsonism & Related Disorders, 11, 73–80.CrossRefGoogle Scholar
  27. Marques, V. M., Santos, C. S., Santiago, I. G., Marques, S. M., Nunes Brasil, M. D. G., Lima, T. T., et al. (2019). Neurological complications of congenital Zika virus infection. Pediatric Neurology, 91, 3–10.CrossRefGoogle Scholar
  28. Meaney-Delman, D., Hills, S. L., Williams, C., Galang, R. R., Iyengar, P., Hennenfent, A. K., et al. (2016). Zika virus infection among U.S. pregnant travelers - August 2015-February 2016. Morbidity and Mortality Weekly Report, 65, 211–214. Scholar
  29. Meaney-Delman, D., Oduyebo, T., Polen, K. N. D., White, J. L., Bingham, A. M., Slavinski, S. A., et al. (2016). Prolonged detection of Zika virus RNA in pregnant women. Obstetrics and Gynecology, 128, 724–730. Scholar
  30. Millet, J.-P., Montalvo, T., Bueno-Marí, R., Romero-Tamarit, A., Prats-Uribe, A., Fernández, L., et al. (2017). Imported Zika virus in a European city: how to prevent local transmission? Frontiers in Microbiology, 8, 1319. Scholar
  31. Moore, C. A., Staples, J. E., Dobyns, W. B., Pessoa, A., Ventura, C. V., da Fonseca, E. B., et al. (2017). Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatrics, 171, 288–295. Scholar
  32. Morris, J. K., Rankin, J., Garne, E., Loane, M., Greenlees, R., Addor, M.-C., et al. (2016). Prevalence of microcephaly in Europe: population based study. BMJ, 354, i4721. Scholar
  33. Noronha Ld, Z. C., Azevedo, M. L., Luz, K. G., & Santos, C. N. (2016). Zika virus damages the human placental barrier and presents marked fetal neurotropism. Memórias do Instituto Oswaldo Cruz, 111, 287–293. Scholar
  34. Pacheco, O., Beltrán, M., Nelson, C. A., Valencia, D., Tolosa, N., Farr, S. L., et al. (2016). Zika virus disease in Colombia - preliminary report. The New England Journal of Medicine.
  35. Pomar, L., Malinger, G., Benoist, G., Carles, G., Ville, Y., Rousset, D., et al. (2017). Association between Zika virus and fetopathy: a prospective cohort study in French Guiana. Ultrasound in Obstetrics & Gynecology, 49, 729–736. Scholar
  36. Quicke, K. M., Bowen, J. R., Johnson, E. L., McDonald, C. E., Ma, H., O’Neal, J. T., et al. (2016). Zika virus infects human placental macrophages. Cell Host & Microbe, 20, 83–90. Scholar
  37. Rao, R., Gaw, S. L., Han, C. S., Platt, L. D., & Silverman, N. S. (2017). Zika risk and pregnancy in clinical practice: ongoing experience as the outbreak evolves. Obstetrics and Gynecology, 129, 1098–1103. Scholar
  38. Reagan-Steiner, S., Simeone, R., Simon, E., Bhatnagar, J., Oduyebo, T., Free, R., et al. (2017). Evaluation of placental and fetal tissue specimens for Zika virus infection - 50 states and District of Columbia, January-December, 2016. Morbidity and Mortality Weekly Report, 66, 636–643. Scholar
  39. Reynolds, M. R., Jones, A. M., Petersen, E. E., Lee, E. H., Rice, M. E., Bingham, A., et al. (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. Morbidity and Mortality Weekly Report, 66, 366–373. Scholar
  40. Sanz Cortes, M., Rivera, A. M., Yepez, M., Guimaraes, C. V., Diaz Yunes, I., Zarutskie, A., et al. (2018). Clinical assessment and brain findings in a cohort of mothers, fetuses and infants infected with ZIKA virus. American Journal of Obstetrics and Gynecology, 218, 440.e1–440.e36. Scholar
  41. Schaub, B., Vouga, M., Najioullah, F., Gueneret, M., Monthieux, A., Harte, C., et al. (2017). Analysis of blood from Zika virus-infected fetuses: a prospective case series. The Lancet Infectious Diseases, 17, 520–527. Scholar
  42. Soares de Oliveira-Szejnfeld, P., Levine, D., Melo, A. S., Amorim, M. M., Batista, A. G., Chimelli, L., et al. (2016). Congenital brain abnormalities and Zika virus: what the radiologist can expect to see prenatally and postnatally. Radiology, 281, 203–218. Scholar
  43. Sohan, K., & Cyrus, C. A. (2017). Ultrasonographic observations of the fetal brain in the first 100 pregnant women with Zika virus infection in Trinidad and Tobago. International Journal of Gynaecology and Obstetrics, 139, 278–283. Scholar
  44. Tabata, T., Petitt, M., Puerta-Guardo, H., Michlmayr, D., Wang, C., Fang-Hoover, J., et al. (2016). Zika virus targets different primary human placental cells, suggesting two routes for vertical transmission. Cell Host & Microbe, 20, 155–166. Scholar
  45. Ventura, C. V., Maia, M., Ventura, B. V., van der Linden, V., Araujo, E. B., Ramos, R. C., et al. (2016). Ophthalmological findings in infants with microcephaly and presumable intra-uterus Zika virus infection. Arquivos Brasileiros de Oftalmologia, 79.
  46. Wallace, B. C., Dahabreh, I. J., Trikalinos, T. A., Lau, J., Trow, P., & Schmid, C. H. (2012). Closing the gap between methodologists and end-users: R as a computational back-end. Journal of Statistical Software, 49, 1–15. Scholar
  47. Wikan, N., & Smith, D. R. (2016). Zika virus: history of a newly emerging arbovirus. The Lancet Infectious Diseases, 16, e119–e126. Scholar
  48. Zambrano, H., Waggoner, J., León, K., Pinsky, B., Vera, K., Schettino, M., et al. (2017). High incidence of Zika virus infection detected in plasma and cervical cytology specimens from pregnant women in Guayaquil, Ecuador. American Journal of Reproductive Immunology, 77, e12630. Scholar
  49. Zin, A. A., Tsui, I., Rossetto, J., Vasconcelos, Z., Adachi, K., Valderramos, S., et al. (2017). Screening criteria for ophthalmic manifestations of congenital Zika virus infection. JAMA Pediatrics, 171, 847–854. Scholar

Copyright information

© The Canadian Public Health Association 2019

Authors and Affiliations

  1. 1.Faculty of Arts and ScienceUniversity of TorontoTorontoCanada
  2. 2.Public Health Risk Sciences DivisionPublic Health Agency of CanadaTorontoCanada
  3. 3.Department of Nutritional Sciences, Faculty of MedicineUniversity of TorontoTorontoCanada

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