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Research Article| Volume 265, P162-168, October 2021

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Zika virus infection in pregnant women and their children: A review

  • Elena Marbán-Castro
    Affiliations
    ISGlobal, Hospital Clínic-Universitat de Barcelona, Barcelona, Spain
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  • Anna Goncé
    Affiliations
    Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Institut Clínic de Ginecología, Obstetricia i Neonatologia, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain

    Centre for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain
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  • Victoria Fumadó
    Affiliations
    Infectious and Imported Diseases Unit, Department of Pediatrics, Hospital Sant Joan de Déu, Barcelona, Spain
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  • Lucía Romero-Acevedo
    Affiliations
    Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain
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  • Azucena Bardají
    Correspondence
    Corresponding author at: ISGlobal, Hospital Clínic-Universitat de Barcelona, Rosselló 132, 5-1, 08036 Barcelona, Spain.
    Affiliations
    ISGlobal, Hospital Clínic-Universitat de Barcelona, Barcelona, Spain

    Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain

    Centro de Investigação em Saúde de Manhiça (CISM), Manhiça, Maputo, Mozambique
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Open AccessPublished:July 08, 2021DOI:https://doi.org/10.1016/j.ejogrb.2021.07.012
Zika virus infection in pregnant women and their children: A review
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      Highlights

      • •
        Zika virus (ZIKV) infection in pregnancy is a cause of pregnancy loss and child neurodevelopmental impairment.
      • •
        Congenital Zika syndrome includes microcephaly, brain disruption, ocular anomalies, contractures, and seizures among other birth defects.
      • •
        Infants exposed to ZIKV in utero with no defects at birth may develop postnatal microcephaly and/or present with later neurodevelopmental impairment.
      • •
        Screening for ZIKV infection in exposed pregnant women is essential, as most infections are asymptomatic and clinical manifestations non-specific.
      • •
        The follow-up of children with prenatal exposure to ZIKV is crucial for a prompt detection of any potential neurological impairment.

      Abstract

      Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) transmitted primarily by Aedes mosquitoes. ZIKV can be transmitted to humans by non-vector borne mechanisms such as sexual intercourse, maternal-foetal transmission or blood transfusion. In 2015, ZIKV emerged in the Americas, and spread to 87 countries and territories with autochthonous transmission, distributed across four of the six WHO regions. Most ZIKV infections in pregnancy are asymptomatic, but mother to child transmission of the virus can occur in 20 to 30% of cases and cause severe foetal and child defects. Children exposed to ZIKV while in utero might develop a pattern of structural anomalies and functional disabilities secondary to central nervous system damage, known as congenital Zika syndrome, and whose most common clinical feature is microcephaly. Normocephalic children born to mothers with ZIKV infection in pregnancy, and with no observable Zika-associated birth defects, may also present with later neurodevelopmental delay or post-natal microcephaly. Screening and detection of ZIKV infection in pregnancy is essential, because most women with ZIKV infection are asymptomatic and clinical manifestations are non-specific. However, the diagnosis of ZIKV infection poses multiple challenges due to limited resources and scarce laboratory capabilities in most affected areas, the narrow window of time that the virus persists in the bloodstream, the large proportion of asymptomatic infections, and the cross-reactivity with other flaviviruses such as Dengue virus (DENV). Molecular methods (RT-PCR) are the most reliable tool to confirm ZIKV infection, as serodiagnosis requires confirmation with neutralization tests in case of inconclusive or positive serology results. Prenatal ultrasound assessment is essential for monitoring foetal development and early detection of possible severe anomalies. A mid- and long-term follow-up of children exposed to ZIKV while in utero is necessary to promptly detect clinical manifestations of possible neurological impairment.
      Tweetable abstract: Zika virus infection during pregnancy is a cause of pregnancy loss and disability in children. Protection against mosquito bites, access to sexual and reproductive health services, prompt screening and detection of ZIKV infection in pregnancy, and prenatal ultrasound monitoring are key control strategies whilst a vaccine is not available.

      Keywords

      What is Zika virus?

      Zika virus (ZIKV) is an RNA arthropod-borne virus (arbovirus) from the Flavivirus genus and the Flaviviridae family [
      • Musso D.
      • Gubler D.J.
      Zika Virus.
      Clin Microbiol Rev. 2016; 29: 487-524https://doi.org/10.1128/CMR.00072-15
      ,
      • Plourde A.R.
      • Bloch E.M.
      A literature review of Zika virus.
      Emerg Infect Dis. 2016; 22: 1185-1192https://doi.org/10.3201/eid2207.151990
      ]. Other viruses of clinical importance in the family are Dengue virus (DENV), West Nile virus (WNV) and Yellow Fever virus (YFV) [
      • Plourde A.R.
      • Bloch E.M.
      A literature review of Zika virus.
      Emerg Infect Dis. 2016; 22: 1185-1192https://doi.org/10.3201/eid2207.151990
      ]. In 1947, scientists conducting routine surveillance for YFV in the Zika forest in Uganda isolated the ZIKV in samples taken from a captive, sentinel rhesus monkey [
      • Musso D.
      • Gubler D.J.
      Zika Virus.
      Clin Microbiol Rev. 2016; 29: 487-524https://doi.org/10.1128/CMR.00072-15
      ]. Antibodies anti-ZIKV were detected in serosurvey studies in different animals which could act as their hosts, that included monkey species in Africa and Asia, bats, goats, rodents, and sheep [
      • Musso D.
      • Gubler D.J.
      Zika Virus.
      Clin Microbiol Rev. 2016; 29: 487-524https://doi.org/10.1128/CMR.00072-15
      ]. This sylvatic cycle involving nonhuman primates and mosquitoes is likely maintained in Africa, while in other countries ZIKV has adapted to humans as their own reservoir, following a human-mosquito-human cycle [
      • Musso D.
      • Gubler D.J.
      Zika Virus.
      Clin Microbiol Rev. 2016; 29: 487-524https://doi.org/10.1128/CMR.00072-15
      ].

      Epidemiology

      In 1952, the first human cases of ZIKV infection were detected in Uganda and the United Republic of Tanzania in a study demonstrating the presence of neutralizing antibodies against ZIKV in sera, but cases remained sporadic for half century [
      • Musso D.
      • Gubler D.J.
      Zika Virus.
      Clin Microbiol Rev. 2016; 29: 487-524https://doi.org/10.1128/CMR.00072-15
      ]. The complete genome of ZIKV strain was sequenced in 2006 from an infected patient in Thailand [
      • Nitatpattana N.
      • Chaiyo K.
      • Rajakam S.
      • Poolam K.
      • Chansiprasert K.
      • Pesirikan N.
      • et al.
      Complete genome sequence of a Zika virus strain isolated from the serum of an infected patient in Thailand in 2006.
      Genome Announc. 2018; 6https://doi.org/10.1128/genomeA.00121-18
      ]. The first human outbreak was reported in 2007 on the Western Pacific island of Yap (Federated States of Micronesia), and it was the first time ZIKV was reported outside Africa or Asia [
      • Hayes E.B.
      Zika virus outside Africa.
      Emerg Infect Dis. 2009; 15: 1347-1350https://doi.org/10.3201/eid1509.090442
      ]. The outbreak was characterized by presence of rash, arthralgia, and conjunctivitis [
      • Hayes E.B.
      Zika virus outside Africa.
      Emerg Infect Dis. 2009; 15: 1347-1350https://doi.org/10.3201/eid1509.090442
      ]. A larger epidemic in the South Pacific French Polynesia followed in 2013–14, where 30,000 symptomatic infections were estimated to have occurred [
      • Hayes E.B.
      Zika virus outside Africa.
      Emerg Infect Dis. 2009; 15: 1347-1350https://doi.org/10.3201/eid1509.090442
      ], and where the first severe complications and non-vector-borne transmission were reported [
      • Baud D.
      • Gubler D.J.
      • Schaub B.
      • Lanteri M.C.
      • Musso D.
      An update on Zika virus infection.
      Lancet (London, England). 2017; 390: 2099-2109https://doi.org/10.1016/S0140-6736(17)31450-2
      ]. Smaller outbreaks followed in 2014 in New Caledonia, the Cook Islands and Easter Island; and in 2015 in Vanuatu, the Solomon Islands, Samoa and Fiji [
      • Musso D.
      • Gubler D.J.
      Zika Virus.
      Clin Microbiol Rev. 2016; 29: 487-524https://doi.org/10.1128/CMR.00072-15
      ]. In February 2015, ZIKV emerged in the Americas spreading to twelve countries and territories by the end of the year [
      • Musso D.
      • Gubler D.J.
      Zika Virus.
      Clin Microbiol Rev. 2016; 29: 487-524https://doi.org/10.1128/CMR.00072-15
      ]. The potential link between maternal ZIKV infection and a congenital syndrome was suggested in September 2015 after an unusual and rapid increase in the number of cases of microcephaly, a twenty-fold increase in microcephaly rates compared with previous years, among newborns in Pernambuco state, North-eastern Brazil [
      • Baud D.
      • Gubler D.J.
      • Schaub B.
      • Lanteri M.C.
      • Musso D.
      An update on Zika virus infection.
      Lancet (London, England). 2017; 390: 2099-2109https://doi.org/10.1016/S0140-6736(17)31450-2
      ,

      Albuquerque MdeFPM. de; Souza WV de, Araujo TVB, Braga MC, Miranda Filho D deB, Ximenes RA de A, de Melo Filho DA, Brito CAAde, Valongueiro S, Melo APL de, et al. The microcephaly epidemic and Zika virus: building knowledge in epidemiology. Cad. Saude Publica 2018, 34, e00069018, https://dx.doi.org/10.1590/0102-311X00069018.

      ]. Similar clusters of microcephaly were also observed retrospectively in French Polynesia during the 2013–14 outbreak [
      • Baud D.
      • Gubler D.J.
      • Schaub B.
      • Lanteri M.C.
      • Musso D.
      An update on Zika virus infection.
      Lancet (London, England). 2017; 390: 2099-2109https://doi.org/10.1016/S0140-6736(17)31450-2
      ]. These studies also suggested an increase in severe neurological complications in adults with ZIKV infection, presenting with Guillain-Barré syndrome (GBS) [
      • Ikejezie Juniorcaius
      • Shapiro Craig N.
      • Kim Jisoo
      • Chiu Monica
      • Almiron Maria
      • Ugarte Ciro
      • et al.
      Zika virus transmission - Region of the Americas, May 15, 2015-December 15, 2016.
      MMWR Morb Mortal Wkly Rep. 2017; 66: 329-334https://doi.org/10.15585/mmwr.mm6612a4
      ]. Massive autochthonous circulation of the virus was reported in the Americas, and in February 2016 the World Health Organization (WHO) declared the ZIKV-related microcephaly clusters and other neurologic disorders as a Public Health Emergency of International Concern (PHEIC) [
      • Ikejezie Juniorcaius
      • Shapiro Craig N.
      • Kim Jisoo
      • Chiu Monica
      • Almiron Maria
      • Ugarte Ciro
      • et al.
      Zika virus transmission - Region of the Americas, May 15, 2015-December 15, 2016.
      MMWR Morb Mortal Wkly Rep. 2017; 66: 329-334https://doi.org/10.15585/mmwr.mm6612a4
      ]. ZIKV joined a group of tropical diseases that disproportionally affected maternal, foetal and reproductive health. The last WHO epidemiological update on ZIKV, dating of July 2019, reported that there were still 87 countries and territories with autochthonous ZIKV transmission, distributed across four of the six WHO regions (African, Americas, South-East Asia, and Western Pacific Regions) [

      WHO. Zika epidemiology update July 2019. July 2019. Accessible at: https://www.who.int/emergencies/diseases/zika/zika-epidemiology-update-july-2019.pdf?ua=1.

      ]. The re-emergence of ZIKV across the Americas was linked to changes in land use due to urbanization, changing of agricultural practices and deforestation [
      • Weinstein Joshua S.
      • Leslie Timothy F.
      • von Fricken Michael E.
      Spatial Associations between land use and infectious disease: Zika virus in Colombia.
      Int J Environ Res Public Health. 2020; 17: 1127https://doi.org/10.3390/ijerph17041127
      ]. Currently, ZIKV is endemic in all tropical areas of the world, similarly to DENV; and nearly half of the global population lives in areas at risk of ZIKV infection [
      • Castanha Priscila M S
      • Marques Ernesto T A
      Vaccine development during global epidemics: the Zika experience.
      Lancet Infect Dis. 2020; 20: 998-999https://doi.org/10.1016/S1473-3099(20)30360-1
      ].

      ZIKV mechanisms of transmission

      The primary mode of transmission is vectorial, through the injection of infectious saliva via the bite of Aedes mosquitoes, specially Aedes aegypti [
      • Musso D.
      • Gubler D.J.
      Zika Virus.
      Clin Microbiol Rev. 2016; 29: 487-524https://doi.org/10.1128/CMR.00072-15
      ]. ZIKV can also be transmitted by several Aedes mosquitoes, such as Aedes hensilii, Aedes polynesiensis, and Aedes albopictus [
      • Musso D.
      • Gubler D.J.
      Zika Virus.
      Clin Microbiol Rev. 2016; 29: 487-524https://doi.org/10.1128/CMR.00072-15
      ]. Non vector transmission of ZIKV infection can occur vertically (mother-to-child transmission), sexually (both from symptomatic and asymptomatic individuals), by transfusion, via bone marrow or organ transplantation [
      • Musso D.
      • Gubler D.J.
      Zika Virus.
      Clin Microbiol Rev. 2016; 29: 487-524https://doi.org/10.1128/CMR.00072-15
      ]. While infective ZIKV particles have been detected in breast milk samples, lactation has not been confirmed as a mode of transmission [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ,

      Sampieri CL, Montero H, Breastfeeding in the time of Zika: a systematic literature review. PeerJ 2019, 7, e6452, https://dx.doi.org/10.7717/peerj.6452.

      ]. The WHO still recommends breastfeeding, as benefits outweigh the potential risks of the milk borne transmission of ZIKV [

      Sampieri CL, Montero H, Breastfeeding in the time of Zika: a systematic literature review. PeerJ 2019, 7, e6452, https://dx.doi.org/10.7717/peerj.6452.

      ].

      Clinical features of ZIKV infection on pregnant women

      In the general population, most ZIKV infections are asymptomatic (75–80%), and symptomatic infections are generally mild [

      Masmejan S, Musso D, Vouga M, Pomar L, Dashraath P, Stojanov M, Panchaud A, Baud, D. Zika Virus. Pathog. (Basel, Switzerland) 2020, 9, https://dx.doi.org/10.3390/pathogens9110898.

      ,
      • Rasmussen S.A.
      • Jamieson D.J.
      Teratogen update: Zika virus and pregnancy.
      Birth defects Res. 2020; 112: 1139-1149
      ]. After an incubation period of three to fourteen days, the most frequent symptoms include an itchy macular or papular rash (90%), mild fever (65%), arthralgia (65%), non-purulent conjunctivitis (55%), myalgia (48%), headache (45%), oedema (19%), and vomiting (10%) [
      • Rasmussen S.A.
      • Jamieson D.J.
      Teratogen update: Zika virus and pregnancy.
      Birth defects Res. 2020; 112: 1139-1149
      ]. If symptomatic, infection is clinically self-limited in most occasions, however, it may eventually result in serious neurological complications such as meningoencephalitis, myelitis, and GBS. GBS is a post-infection autoimmune polyneuropathy characterized by an acute onset flaccid paralysis presumed to be triggered by an exaggerated immune response after infection [

      Barbi L, Coelho AVC, Alencar LCA de, Crovella S. Prevalence of Guillain-Barré syndrome among Zika virus infected cases: a systematic review and meta-analysis. Brazilian J Infect Dis Off Publ Brazilian Soc Infect Dis 2018, 22, 137–141, https://dx.doi.org/10.1016/j.bjid.2018.02.005.

      ]. It is estimated to occur in 1.23% of infections in the general population [

      Barbi L, Coelho AVC, Alencar LCA de, Crovella S. Prevalence of Guillain-Barré syndrome among Zika virus infected cases: a systematic review and meta-analysis. Brazilian J Infect Dis Off Publ Brazilian Soc Infect Dis 2018, 22, 137–141, https://dx.doi.org/10.1016/j.bjid.2018.02.005.

      ]. GBS has a mortality rate of 5%, and 20% of the affected patients usually remain with significant disability [
      • Blázquez A.-B.
      • Saiz J.-C.
      Neurological manifestations of Zika virus infection.
      World J Virol. 2016; 5: 135-143https://doi.org/10.5501/wjv.v5.i4.135
      ]. GBS mortality increases to 10–35% if the affected individual is a pregnant woman [
      • Pacheco L.D.
      • Saad A.F.
      • Hankins G.D.V.
      • Chiosi G.
      • Saade G.
      Guillain-Barré syndrome in pregnancy.
      Obstet Gynecol. 2016; 128: 1105-1110https://doi.org/10.1097/AOG.0000000000001716
      ]. The clinical features of ZIKV infection are similar in pregnant compared to non-pregnant women [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ], though symptomatic infections seem to be more frequent during pregnancy. In a cohort study in the USA (n = 599), 36% of pregnant women with confirmed or probable ZIKV infection presented with symptoms [

      Reynolds MR, Jones AM, Petersen EE, Lee EH, Rice ME, Bingham A, Ellington SR, Evert N, Reagan-Steiner S, Oduyebo T, et al. 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 2017, 66, 366–373, https://dx.doi.org/10.15585/mmwr.mm6613e1.

      ], and in a prospective study in Spain, 75% of women with confirmed infection, and 48% of women with probable infection, compared to 18% of negative cases, reported Zika-like symptoms [
      • Marbán-Castro Elena
      • Goncé Anna
      • Fumadó Victoria
      • Martínez Miguel J.
      • López Marta
      • García-Otero Laura
      • et al.
      Zika virus infection in pregnant travellers and impact on childhood neurodevelopment in the first two years of life: a prospective observational study.
      Travel Med Infect Dis. 2021; 40: 101985https://doi.org/10.1016/j.tmaid.2021.101985
      ]. Of note, data from Brazil and Colombia showed higher rates of symptomatic ZIKV infections among women of reproductive age compared to men of same age, suggesting an increased susceptibility to ZIKV infection among women [
      • Coelho Flavio Codeço
      • Durovni Betina
      • Saraceni Valeria
      • Lemos Cristina
      • Codeco Claudia Torres
      • Camargo Sabrina
      • et al.
      Higher incidence of Zika in adult women than adult men in Rio de Janeiro suggests a significant contribution of sexual transmission from men to women.
      Int J Infect Dis IJID Off Publ Int Soc Infect Dis. 2016; 51: 128-132https://doi.org/10.1016/j.ijid.2016.08.023
      ,
      • Pacheco Oscar
      • Beltrán Mauricio
      • Nelson Christina A.
      • Valencia Diana
      • Tolosa Natalia
      • Farr Sherry L.
      • et al.
      Zika virus disease in Colombia - Preliminary report.
      N Engl J Med. 2020; 383: e44https://doi.org/10.1056/NEJMoa1604037
      ]. However, it is unknown whether behavioural factors or sexual transmission mechanisms may explain this difference in the risk of ZIKV infection [
      • Coelho Flavio Codeço
      • Durovni Betina
      • Saraceni Valeria
      • Lemos Cristina
      • Codeco Claudia Torres
      • Camargo Sabrina
      • et al.
      Higher incidence of Zika in adult women than adult men in Rio de Janeiro suggests a significant contribution of sexual transmission from men to women.
      Int J Infect Dis IJID Off Publ Int Soc Infect Dis. 2016; 51: 128-132https://doi.org/10.1016/j.ijid.2016.08.023
      ,
      • Pacheco Oscar
      • Beltrán Mauricio
      • Nelson Christina A.
      • Valencia Diana
      • Tolosa Natalia
      • Farr Sherry L.
      • et al.
      Zika virus disease in Colombia - Preliminary report.
      N Engl J Med. 2020; 383: e44https://doi.org/10.1056/NEJMoa1604037
      ].

      ZIKV infection and the placenta

      The pathogenesis of the mother-to-child transmission of ZIKV infection is driven by the inflammation of the placenta (placentitis), including multiplication of placental macrophages (Hofbauer cells) that facilitate viral transfer from the placenta to the foetal brain [
      • Evans-Gilbert Tracy
      Vertically transmitted chikungunya, Zika and dengue virus infections: The pathogenesis from mother to fetus and the implications of co-infections and vaccine development.
      Int J Pediatr Adolesc Med. 2020; 7: 107-111https://doi.org/10.1016/j.ijpam.2019.05.004
      ,
      • Rosenberg A.Z.
      • Yu W.
      • Hill D.A.
      • Reyes C.A.
      • Schwartz D.A.
      Placental Pathology of Zika Virus: Viral infection of the placenta Induces Villous Stromal Macrophage (Hofbauer Cell) proliferation and hyperplasia.
      Arch Pathol Lab Med. 2017; 141: 43-48https://doi.org/10.5858/arpa.2016-0401-OA
      ,
      • Coyne Carolyn B.
      • Lazear Helen M.
      Zika virus — Reigniting the TORCH.
      Nat Rev Microbiol. 2016; 14: 707-715https://doi.org/10.1038/nrmicro.2016.125
      ]. Similar to DENV, the infection of the placenta with ZIKV may lead to hypoperfusion, foetal loss, and neonatal infection [
      • Evans-Gilbert Tracy
      Vertically transmitted chikungunya, Zika and dengue virus infections: The pathogenesis from mother to fetus and the implications of co-infections and vaccine development.
      Int J Pediatr Adolesc Med. 2020; 7: 107-111https://doi.org/10.1016/j.ijpam.2019.05.004
      ]. ZIKV infects and replicates in primary human placental macrophages and cytotrophoblasts [
      • Quicke Kendra M.
      • Bowen James R.
      • Johnson Erica L.
      • McDonald Circe E.
      • Ma Huailiang
      • O’Neal Justin T.
      • et al.
      Zika virus infects human placental macrophages.
      Cell Host Microbe. 2016; 20: 83-90https://doi.org/10.1016/j.chom.2016.05.015
      ,

      Martines RB, Bhatnagar J, de Oliveira Ramos AM, Davi HPF, Iglezias SD, Kanamura CT, Keating MK, Hale G, Silva-Flannery L, Muehlenbachs A, et al. Pathology of congenital Zika syndrome in Brazil: a case series. Lancet (London, England) 2016, 388, 898–904, https://dx.doi.org/10.1016/S0140-6736(16)30883-2.

      ]. Active replication of the ZIKV in the placenta has been demonstrated to occur in mice models, and infective viruses have been found in human pregnancy losses, and in brain tissues of human foetuses with microcephaly [
      • Evans-Gilbert Tracy
      Vertically transmitted chikungunya, Zika and dengue virus infections: The pathogenesis from mother to fetus and the implications of co-infections and vaccine development.
      Int J Pediatr Adolesc Med. 2020; 7: 107-111https://doi.org/10.1016/j.ijpam.2019.05.004
      ,
      • Coyne Carolyn B.
      • Lazear Helen M.
      Zika virus — Reigniting the TORCH.
      Nat Rev Microbiol. 2016; 14: 707-715https://doi.org/10.1038/nrmicro.2016.125
      ,
      • Goncé A.
      • Martínez M.J.
      • Marbán-Castro E.
      • Saco A.
      • Soler A.
      • Alvarez-Mora M.I.
      • et al.
      Spontaneous abortion associated with Zika virus infection and persistent viremia.
      Emerg Infect Dis. 2018; 24: 933-935
      ]. Different routes for ZIKV to cross the placental barrier have been suggested, as ZIKV infects numerous primary cell types [
      • Coyne Carolyn B.
      • Lazear Helen M.
      Zika virus — Reigniting the TORCH.
      Nat Rev Microbiol. 2016; 14: 707-715https://doi.org/10.1038/nrmicro.2016.125
      ,
      • Quicke Kendra M.
      • Bowen James R.
      • Johnson Erica L.
      • McDonald Circe E.
      • Ma Huailiang
      • O’Neal Justin T.
      • et al.
      Zika virus infects human placental macrophages.
      Cell Host Microbe. 2016; 20: 83-90https://doi.org/10.1016/j.chom.2016.05.015
      ,

      Martines RB, Bhatnagar J, de Oliveira Ramos AM, Davi HPF, Iglezias SD, Kanamura CT, Keating MK, Hale G, Silva-Flannery L, Muehlenbachs A, et al. Pathology of congenital Zika syndrome in Brazil: a case series. Lancet (London, England) 2016, 388, 898–904, https://dx.doi.org/10.1016/S0140-6736(16)30883-2.

      ]. ZIKV is the only vertically transmitted flavivirus with the potential to infect brain cortical progenitor cells interfering with cell migration [
      • Evans-Gilbert Tracy
      Vertically transmitted chikungunya, Zika and dengue virus infections: The pathogenesis from mother to fetus and the implications of co-infections and vaccine development.
      Int J Pediatr Adolesc Med. 2020; 7: 107-111https://doi.org/10.1016/j.ijpam.2019.05.004
      ]. A systematic review aiming to characterize changes in placentas infected with ZIKV found histopathological features which were non-specific and similar to those described in other placental infections [
      • Venceslau Emanuella Meneses
      • Guida José Paulo
      • Amaral Eliana
      • Modena José Luis Proença
      • Costa Maria Laura
      Characterization of placental infection by Zika virus in humans: A review of the literature.
      Rev Bras Ginecol e Obstet Rev da Fed Bras das Soc Ginecol e Obstet. 2020; 42: 577-585https://doi.org/10.1055/s-0040-1712126
      ]. These features included chronic placentitis, villitis, increased number of Hofbauer cells, irregular fibrin deposits, increased mononuclear cells in villous stroma, villous immaturity, oedema, hypervascularization, stromal fibrosis, calcifications, and focal necrosis of syncytiotrophoblasts [
      • Venceslau Emanuella Meneses
      • Guida José Paulo
      • Amaral Eliana
      • Modena José Luis Proença
      • Costa Maria Laura
      Characterization of placental infection by Zika virus in humans: A review of the literature.
      Rev Bras Ginecol e Obstet Rev da Fed Bras das Soc Ginecol e Obstet. 2020; 42: 577-585https://doi.org/10.1055/s-0040-1712126
      ].
      ZIKV vertical transmission can occur and cause severe foetal defects involving particularly the brain and the eye [

      Rice ME, Galang RR, Roth NM, Ellington SR, Moore CA, Valencia-Prado M, Ellis EM, Tufa AJ, Taulung LA, Alfred JM, et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR. Morb. Mortal. Wkly. Rep. 2018, 67, 858–867, https://dx.doi.org/10.15585/mmwr.mm6731e1.

      ]. Recent estimates, based on prospective studies and case reports, have calculated a vertical transmission rate of 20–30%, irrespective of the trimester when maternal infection occurred [

      Masmejan S, Musso D, Vouga M, Pomar L, Dashraath P, Stojanov M, Panchaud A, Baud, D. Zika Virus. Pathog. (Basel, Switzerland) 2020, 9, https://dx.doi.org/10.3390/pathogens9110898.

      ,
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ]. The risk of maternal-foetal transmission, foetal loss or foetal abnormalities is not related either to the presence or the severity of maternal symptoms [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ]. In clinical practice, determining the risk of maternal-foetal transmission remains challenging because of the transience of ZIKV-RNA in amniotic and newborn fluids, and the low sensitivity of techniques to detect newborn’s specific IgMs [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ]. Though testing of amniotic fluid provides additional evidence for maternal diagnosis of ZIKV infection, frequency of Zika-associated birth defects are similar among women with ZIKV-RNA detected in amniotic fluid or other non-amniotic fluid specimens [
      • Mercado Marcela
      • Ailes Elizabeth C.
      • Daza Marcela
      • Tong Van T.
      • Osorio Johana
      • Valencia Diana
      • et al.
      Zika virus detection in amniotic fluid and Zika-associated birth defects.
      Am J Obstet Gynecol. 2020; 222: 610.e1-610.e13https://doi.org/10.1016/j.ajog.2020.01.009
      ].

      Impact of ZIKV infection on maternal and infant health

      Microcephaly and congenital Zika syndrome

      Microcephaly was the first birth anomaly reported in infants born to mothers with ZIKV infection [

      Reynolds MR, Jones AM, Petersen EE, Lee EH, Rice ME, Bingham A, Ellington SR, Evert N, Reagan-Steiner S, Oduyebo T, et al. 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 2017, 66, 366–373, https://dx.doi.org/10.15585/mmwr.mm6613e1.

      ]. It is defined as a head circumference (HC) of two standard deviations (SD) below the mean or below the third percentile according to sex and gestational age; and severe microcephaly is a HC of less than 3 SD below the mean on reference charts (Intergrowth 21st standards) [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ,
      • DeSilva M.
      • Munoz F.M.
      • Sell E.
      • Marshall H.
      • Tse Kawai A.
      • Kachikis A.
      • et al.
      Congenital microcephaly: Case definition & guidelines for data collection, analysis, and presentation of safety data after maternal immunisation.
      Vaccine. 2017; 35: 6472-6482https://doi.org/10.1016/j.vaccine.2017.01.044
      ]. Brain abnormalities associated to ZIKV can, however, occur in the absence of microcephaly, which makes neuroimaging key in foetal diagnosis [

      Reynolds MR, Jones AM, Petersen EE, Lee EH, Rice ME, Bingham A, Ellington SR, Evert N, Reagan-Steiner S, Oduyebo T, et al. 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 2017, 66, 366–373, https://dx.doi.org/10.15585/mmwr.mm6613e1.

      ]. The most common neuroimaging anomalies detected in a study with 71 infants with prenatal ZIKV infection in Rio de Janeiro included structural abnormalities such as calcifications (especially in the cortico-subcortical white-matter junction), cortex malformations, ventriculomegaly and reduced brain volumes followed by brainstem hypoplasia, cerebellar hypoplasia and dysgenesis of the corpus callosum [
      • Pool Kara-Lee
      • Adachi Kristina
      • Karnezis Stellios
      • Salamon Noriko
      • Romero Tahmineh
      • Nielsen-Saines Karin
      • et al.
      Association between neonatal neuroimaging and clinical outcomes in Zika-Exposed infants From Rio de Janeiro, Brazil.
      JAMA Netw Open. 2019; 2: e198124https://doi.org/10.1001/jamanetworkopen.2019.8124
      ]. Other foetal and birth severe brain abnormalities described in ZIKV affected children are cerebellar hypoplasia, lissencephaly with hydrocephalus, and foetal akinesia deformation sequence (arthrogryposis) [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ]. ZIKV-associated brain anomalies are caused by disruption in brain development during gestation with subsequent skull collapse and neuronal and glial migration disorder [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ].
      The spectrum of ZIKV infection in foetuses and infants extends beyond microcephaly, which is observed at birth in 80% of children with congenital Zika syndrome (CZS) [
      • Baud D.
      • Gubler D.J.
      • Schaub B.
      • Lanteri M.C.
      • Musso D.
      An update on Zika virus infection.
      Lancet (London, England). 2017; 390: 2099-2109https://doi.org/10.1016/S0140-6736(17)31450-2
      ,

      Rice ME, Galang RR, Roth NM, Ellington SR, Moore CA, Valencia-Prado M, Ellis EM, Tufa AJ, Taulung LA, Alfred JM, et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR. Morb. Mortal. Wkly. Rep. 2018, 67, 858–867, https://dx.doi.org/10.15585/mmwr.mm6731e1.

      ], to a pattern of structural anomalies and functional disabilities secondary to CNS damage [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ,
      • Moore Cynthia A.
      • Staples J. Erin
      • Dobyns William B.
      • Pessoa André
      • Ventura Camila V.
      • Fonseca Eduardo Borges da
      • et al.
      Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians.
      JAMA Pediatr. 2017; 171: 288https://doi.org/10.1001/jamapediatrics.2016.3982
      ]. CZS is defined as a spectrum of birth defects including foetal brain disruption sequence, brain anomalies, ocular anomalies, congenital contractures, intrauterine growth restriction, seizures, pyramidal or extrapyramidal abnormalities and neurodevelopmental delay [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ]. Foetuses of women infected with ZIKV during pregnancy have a 5 to 14% risk of developing CZS, and a 4 to 6% risk of presenting with ZIKV-associated microcephaly [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ,

      Reynolds MR, Jones AM, Petersen EE, Lee EH, Rice ME, Bingham A, Ellington SR, Evert N, Reagan-Steiner S, Oduyebo T, et al. 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 2017, 66, 366–373, https://dx.doi.org/10.15585/mmwr.mm6613e1.

      ,

      Rice ME, Galang RR, Roth NM, Ellington SR, Moore CA, Valencia-Prado M, Ellis EM, Tufa AJ, Taulung LA, Alfred JM, et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR. Morb. Mortal. Wkly. Rep. 2018, 67, 858–867, https://dx.doi.org/10.15585/mmwr.mm6731e1.

      ,
      • Brasil Patrícia
      • Pereira José P.
      • Moreira M. Elisabeth
      • Ribeiro Nogueira Rita M.
      • Damasceno Luana
      • Wakimoto Mayumi
      • et al.
      Zika Virus infection in pregnant women in Rio de Janeiro.
      N Engl J Med. 2016; 375: 2321-2334https://doi.org/10.1056/NEJMoa1602412
      ,

      Pomar L, Vouga M, Lambert V, Pomar C, Hcini N, Jolivet A, et al. Maternal-fetal transmission and adverse perinatal outcomes in pregnant women infected with Zika virus: Prospective cohort study in French Guiana. Bmj, 2018. 363: p. k4431.

      ,
      • Honein Margaret A.
      • Dawson April L.
      • Petersen Emily E.
      • Jones Abbey M.
      • Lee Ellen H.
      • Yazdy Mahsa M.
      • et al.
      Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy.
      JAMA. 2017; 317: 59https://doi.org/10.1001/jama.2016.19006
      ,
      • Hoen Bruno
      • Schaub Bruno
      • Funk Anna L.
      • Ardillon Vanessa
      • Boullard Manon
      • Cabié André
      • et al.
      Pregnancy outcomes after ZIKV infection in french territories in the Americas.
      N Engl J Med. 2018; 378: 985-994https://doi.org/10.1056/NEJMoa1709481
      ]. The risk of developing CZS is the highest in the first trimester of pregnancy (8–15%), compared to second and third trimesters (4–5%) [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ,
      • Rasmussen S.A.
      • Jamieson D.J.
      Teratogen update: Zika virus and pregnancy.
      Birth defects Res. 2020; 112: 1139-1149
      ,

      Reynolds MR, Jones AM, Petersen EE, Lee EH, Rice ME, Bingham A, Ellington SR, Evert N, Reagan-Steiner S, Oduyebo T, et al. 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 2017, 66, 366–373, https://dx.doi.org/10.15585/mmwr.mm6613e1.

      ,
      • Mulkey Sarah B.
      • Arroyave-Wessel Margarita
      • Peyton Colleen
      • Bulas Dorothy I.
      • Fourzali Yamil
      • Jiang JiJi
      • et al.
      Neurodevelopmental abnormalities in children with in utero Zika virus exposure without congenital Zika syndrome.
      JAMA Pediatr. 2020; 174: 269https://doi.org/10.1001/jamapediatrics.2019.5204
      ]. Both symptomatic and asymptomatic ZIKV infections in pregnancy have been reported to cause ZIKV-related birth anomalies. The national birth defects surveillance system in Costa Rica reported that 64% of all infants with Zika-associated anomalies were born to women who reported Zika-like symptoms, thus, 36% of these children were born to asymptomatic women [
      • Benavides-Lara Adriana
      • la Paz Barboza-Arguello María de
      • González-Elizondo Mauricio
      • Hernández-deMezerville Marcela
      • Brenes-Chacón Helena
      • Ramírez-Rojas Melissa
      • et al.
      Zika Virus-associated birth defects, Costa Rica, 2016–2018.
      Emerg Infect Dis. 2021; 27https://doi.org/10.3201/eid2702.202047
      ].
      Absence of clinical and radiologic anomalies at birth indicative of ZIKV does not exclude the eventual occurrence of later neurodevelopmental impairment including body tone anomalies, seizures, hearing loss, visual impairment, dysphagia or neurodevelopmental delay [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ,

      Rice ME, Galang RR, Roth NM, Ellington SR, Moore CA, Valencia-Prado M, Ellis EM, Tufa AJ, Taulung LA, Alfred JM, et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR. Morb. Mortal. Wkly. Rep. 2018, 67, 858–867, https://dx.doi.org/10.15585/mmwr.mm6731e1.

      ]. CZS shares common characteristics with most TORCH pathogens, such as presenting with a mild illness in the infected mother, potential vertical transmission, development of several foetal anomalies, and that maternal therapy may not ameliorate consequences on the foetus [

      Mehrjardi MZ, Is Zika Virus an Emerging TORCH Agent? An Invited Commentary. Virology (Auckl). 2017, 8, 1178122X17708993, https://dx.doi.org/10.1177/1178122X17708993.

      ]. While many characteristics of the CZS, such as cognitive, sensory and motor disabilities are similar to those of other congenital infections, there are distinct manifestations of the syndrome [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ,
      • Moore Cynthia A.
      • Staples J. Erin
      • Dobyns William B.
      • Pessoa André
      • Ventura Camila V.
      • Fonseca Eduardo Borges da
      • et al.
      Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians.
      JAMA Pediatr. 2017; 171: 288https://doi.org/10.1001/jamapediatrics.2016.3982
      ]. Unique features include severe microcephaly with partially collapsed skull, subcortical calcifications, specific ocular lesions, congenital contractures, and hypertonia [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ,
      • Moore Cynthia A.
      • Staples J. Erin
      • Dobyns William B.
      • Pessoa André
      • Ventura Camila V.
      • Fonseca Eduardo Borges da
      • et al.
      Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians.
      JAMA Pediatr. 2017; 171: 288https://doi.org/10.1001/jamapediatrics.2016.3982
      ]. Ocular lesions found in CZS comprise microphthalmia, coloboma, cataract, posterior anomalies, chorioretinal atrophy, focal pigmentary mottling and optic nerve hypoplasia/atrophy [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ]. Though these anomalies might be observed in other congenital infections, their presence in CZS is particularly common. [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ,
      • Li Hongda
      • Saucedo-Cuevas Laura
      • Shresta Sujan
      • Gleeson Joseph G.
      The neurobiology of Zika virus.
      Neuron. 2016; 92: 949-958https://doi.org/10.1016/j.neuron.2016.11.031
      ]. As children with CZS get older, further neurodevelopmental problems have been recognized; still, the full spectrum and risks of CZS remain unknown [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ,

      Rice ME, Galang RR, Roth NM, Ellington SR, Moore CA, Valencia-Prado M, Ellis EM, Tufa AJ, Taulung LA, Alfred JM, et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR. Morb. Mortal. Wkly. Rep. 2018, 67, 858–867, https://dx.doi.org/10.15585/mmwr.mm6731e1.

      ] and the broad range of neurological impairment might be life-long [
      • Lowe Rachel
      • Barcellos Christovam
      • Brasil Patrícia
      • Cruz Oswaldo
      • Honório Nildimar
      • Kuper Hannah
      • et al.
      The Zika virus epidemic in Brazil: From discovery to future implications.
      Int J Environ Res Public Health. 2018; 15: 96https://doi.org/10.3390/ijerph15010096
      ].

      Pregnancy loss and perinatal outcomes

      ZIKV in pregnancy is also associated with poor pregnancy outcomes such as miscarriage, intrauterine growth restriction, stillbirths and perinatal death [
      • Evans-Gilbert Tracy
      Vertically transmitted chikungunya, Zika and dengue virus infections: The pathogenesis from mother to fetus and the implications of co-infections and vaccine development.
      Int J Pediatr Adolesc Med. 2020; 7: 107-111https://doi.org/10.1016/j.ijpam.2019.05.004
      ,
      • Brasil Patrícia
      • Pereira José P.
      • Moreira M. Elisabeth
      • Ribeiro Nogueira Rita M.
      • Damasceno Luana
      • Wakimoto Mayumi
      • et al.
      Zika Virus infection in pregnant women in Rio de Janeiro.
      N Engl J Med. 2016; 375: 2321-2334https://doi.org/10.1056/NEJMoa1602412
      ,
      • van der Eijk A.A.
      • van Genderen P.J.
      • Verdijk R.M.
      • Reusken C.B.
      • Mögling R.
      • van Kampen J.J.A.
      • et al.
      Miscarriage associated with Zika virus infection.
      N Engl J Med. 2016; 375: 1002-1004
      ,

      Kleber de Oliveira W, Cortez-Escalante J, De Oliveira WTGH, do Carmo GMI, Henriques CMP, Coelho GE, Araujo de Franca GV. 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, https://dx.doi.org/10.15585/mmwr.mm6509e2.

      ]. While the first and second trimesters of pregnancy represent the highest foetal risk [
      • Honein Margaret A.
      • Dawson April L.
      • Petersen Emily E.
      • Jones Abbey M.
      • Lee Ellen H.
      • Yazdy Mahsa M.
      • et al.
      Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy.
      JAMA. 2017; 317: 59https://doi.org/10.1001/jama.2016.19006
      ,
      • Pomar L.
      • Malinger G.
      • Benoist G.
      • Carles G.
      • Ville Y.
      • Rousset D.
      • et al.
      Association between Zika virus and fetopathy: A prospective cohort study in French Guiana.
      Ultrasound Obstet Gynecol. 2017; 49: 729-736https://doi.org/10.1002/uog.17404
      ], ZIKV infections occurring later in pregnancy have also been linked with adverse outcomes including intrauterine growth restriction and foetal loss [
      • Brasil Patrícia
      • Pereira José P.
      • Moreira M. Elisabeth
      • Ribeiro Nogueira Rita M.
      • Damasceno Luana
      • Wakimoto Mayumi
      • et al.
      Zika Virus infection in pregnant women in Rio de Janeiro.
      N Engl J Med. 2016; 375: 2321-2334https://doi.org/10.1056/NEJMoa1602412
      ,
      • Alvarado-Socarras Jorge L.
      • Idrovo Álvaro J.
      • Contreras-García Gustavo A.
      • Rodriguez-Morales Alfonso J.
      • Audcent Tobey A.
      • Mogollon-Mendoza Adriana C.
      • et al.
      Congenital microcephaly: A diagnostic challenge during Zika epidemics.
      Travel Med Infect Dis. 2018; 23: 14-20https://doi.org/10.1016/j.tmaid.2018.02.002
      ]. Data from several studies showed an overall rate of foetal loss of 1–4% among pregnant women with confirmed ZIKV infection [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ,
      • Hoen Bruno
      • Schaub Bruno
      • Funk Anna L.
      • Ardillon Vanessa
      • Boullard Manon
      • Cabié André
      • et al.
      Pregnancy outcomes after ZIKV infection in french territories in the Americas.
      N Engl J Med. 2018; 378: 985-994https://doi.org/10.1056/NEJMoa1709481
      ], and 3 to 22% risk of perinatal death in Zika-affected pregnancies [
      • Leisher Susannah Hopkins
      • Balalian Arin A.
      • Reinebrant Hanna
      • Shiau Stephanie
      • Flenady Vicki
      • Kuhn Louise
      • et al.
      Systematic review: fetal death reporting and risk in Zika-affected pregnancies.
      Trop Med Int Health. 2021; 26: 133-145https://doi.org/10.1111/tmi.v26.210.1111/tmi.13522
      ]. A study in Brazil reported a four-fold excess neonatal mortality in infants born to ZIKV positive mothers compared to negative cases [
      • França Giovanny V A
      • Schuler-Faccini Lavinia
      • Oliveira Wanderson K
      • Henriques Claudio M P
      • Carmo Eduardo H
      • Pedi Vaneide D
      • et al.
      Congenital Zika virus syndrome in Brazil: A case series of the first 1501 livebirths with complete investigation.
      Lancet (London, England). 2016; 388: 891-897https://doi.org/10.1016/S0140-6736(16)30902-3
      ].

      Impact of ZIKV in pregnancy beyond early infancy

      Children exposed to ZIKV in utero, normocephalic with no observable defects at birth, may present with later cognitive and language neurodevelopmental delay [
      • Marbán-Castro Elena
      • Goncé Anna
      • Fumadó Victoria
      • Martínez Miguel J.
      • López Marta
      • García-Otero Laura
      • et al.
      Zika virus infection in pregnant travellers and impact on childhood neurodevelopment in the first two years of life: a prospective observational study.
      Travel Med Infect Dis. 2021; 40: 101985https://doi.org/10.1016/j.tmaid.2021.101985
      ,
      • Mulkey Sarah B.
      • Arroyave-Wessel Margarita
      • Peyton Colleen
      • Bulas Dorothy I.
      • Fourzali Yamil
      • Jiang JiJi
      • et al.
      Neurodevelopmental abnormalities in children with in utero Zika virus exposure without congenital Zika syndrome.
      JAMA Pediatr. 2020; 174: 269https://doi.org/10.1001/jamapediatrics.2019.5204
      ,
      • Faiçal Adriana Virginia
      • de Oliveira Juliana Cabral
      • Oliveira João Vitor Vieira
      • de Almeida Breno Lima
      • Agra Iluska Andrade
      • Alcantara Luiz Carlos Junior
      • et al.
      Neurodevelopmental delay in normocephalic children with in utero exposure to Zika virus.
      BMJ Paediatr Open. 2019; 3: e000486https://doi.org/10.1136/bmjpo-2019-000486
      ,
      • Nielsen-Saines Karin
      • Brasil Patrícia
      • Kerin Tara
      • Vasconcelos Zilton
      • Gabaglia Claudia Raja
      • Damasceno Luana
      • et al.
      Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children.
      Nat Med. 2019; 25: 1213-1217https://doi.org/10.1038/s41591-019-0496-1
      ,

      Lopes Moreira ME, Nielsen-Saines K, Brasil P, Kerin T, Damasceno L, Pone M, Carvalho LMA, Pone SM, Vasconcelos Z, Ribeiro IP, et al. Neurodevelopment in Infants Exposed to Zika Virus In Utero. N. Engl. J. Med. 2018, 379, 2377–2379.

      ]. It has been estimated that up to 40% of children with prenatal ZIKV exposure may develop any type of neurodevelopmental delay [

      Lopes Moreira ME, Nielsen-Saines K, Brasil P, Kerin T, Damasceno L, Pone M, Carvalho LMA, Pone SM, Vasconcelos Z, Ribeiro IP, et al. Neurodevelopment in Infants Exposed to Zika Virus In Utero. N. Engl. J. Med. 2018, 379, 2377–2379.

      ,
      • Valdes Viviane
      • Zorrilla Carmen D.
      • Gabard-Durnam Laurel
      • Muler-Mendez Natalia
      • Rahman Zarin Ibnat
      • Rivera Diego
      • et al.
      Cognitive development of infants exposed to the Zika virus in Puerto Rico.
      JAMA Netw Open. 2019; 2: e1914061https://doi.org/10.1001/jamanetworkopen.2019.14061
      ]. A study by Massaroni et al. showed a neurodevelopmental delay of 15% in the first year of age among in-utero exposed children, while by the second year, this percentage increased up to 50% of children [
      • Peçanha Pedro Massaroni
      • Gomes Junior Saint Clair
      • Pone Sheila Moura
      • Pone Marcos Vinicius da Silva
      • Vasconcelos Zilton
      • Zin Andrea
      • et al.
      Neurodevelopment of children exposed intra-uterus by Zika virus: A case series.
      PLoS ONE. 2020; 15: e0229434https://doi.org/10.1371/journal.pone.0229434
      ]. The language function seems to be the most affected domain in ZIKV exposed children [
      • Marbán-Castro Elena
      • Goncé Anna
      • Fumadó Victoria
      • Martínez Miguel J.
      • López Marta
      • García-Otero Laura
      • et al.
      Zika virus infection in pregnant travellers and impact on childhood neurodevelopment in the first two years of life: a prospective observational study.
      Travel Med Infect Dis. 2021; 40: 101985https://doi.org/10.1016/j.tmaid.2021.101985
      ,
      • Mulkey Sarah B.
      • Arroyave-Wessel Margarita
      • Peyton Colleen
      • Bulas Dorothy I.
      • Fourzali Yamil
      • Jiang JiJi
      • et al.
      Neurodevelopmental abnormalities in children with in utero Zika virus exposure without congenital Zika syndrome.
      JAMA Pediatr. 2020; 174: 269https://doi.org/10.1001/jamapediatrics.2019.5204
      ,
      • Faiçal Adriana Virginia
      • de Oliveira Juliana Cabral
      • Oliveira João Vitor Vieira
      • de Almeida Breno Lima
      • Agra Iluska Andrade
      • Alcantara Luiz Carlos Junior
      • et al.
      Neurodevelopmental delay in normocephalic children with in utero exposure to Zika virus.
      BMJ Paediatr Open. 2019; 3: e000486https://doi.org/10.1136/bmjpo-2019-000486
      ,
      • Nielsen-Saines Karin
      • Brasil Patrícia
      • Kerin Tara
      • Vasconcelos Zilton
      • Gabaglia Claudia Raja
      • Damasceno Luana
      • et al.
      Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children.
      Nat Med. 2019; 25: 1213-1217https://doi.org/10.1038/s41591-019-0496-1
      ,

      Lopes Moreira ME, Nielsen-Saines K, Brasil P, Kerin T, Damasceno L, Pone M, Carvalho LMA, Pone SM, Vasconcelos Z, Ribeiro IP, et al. Neurodevelopment in Infants Exposed to Zika Virus In Utero. N. Engl. J. Med. 2018, 379, 2377–2379.

      ]. In the USA, among one-year-old children born to mothers with confirmed or possible ZIKV infection in pregnancy, 6% had a Zika-associated birth defect, 9% had more than one neurodevelopmental anomaly, and 1% presented both [

      Rice ME, Galang RR, Roth NM, Ellington SR, Moore CA, Valencia-Prado M, Ellis EM, Tufa AJ, Taulung LA, Alfred JM, et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR. Morb. Mortal. Wkly. Rep. 2018, 67, 858–867, https://dx.doi.org/10.15585/mmwr.mm6731e1.

      ]. Given that most children, apparently healthy at birth, might not have had full developmental evaluations during infancy and childhood, these percentages might be higher [

      Rice ME, Galang RR, Roth NM, Ellington SR, Moore CA, Valencia-Prado M, Ellis EM, Tufa AJ, Taulung LA, Alfred JM, et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR. Morb. Mortal. Wkly. Rep. 2018, 67, 858–867, https://dx.doi.org/10.15585/mmwr.mm6731e1.

      ]. HC growth deceleration (postnatal microcephaly) has been reported in exposed infants born with a normal HC at birth [
      • Baud D.
      • Gubler D.J.
      • Schaub B.
      • Lanteri M.C.
      • Musso D.
      An update on Zika virus infection.
      Lancet (London, England). 2017; 390: 2099-2109https://doi.org/10.1016/S0140-6736(17)31450-2
      ,

      Rice ME, Galang RR, Roth NM, Ellington SR, Moore CA, Valencia-Prado M, Ellis EM, Tufa AJ, Taulung LA, Alfred JM, et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR. Morb. Mortal. Wkly. Rep. 2018, 67, 858–867, https://dx.doi.org/10.15585/mmwr.mm6731e1.

      ]. Postnatal-onset microcephaly is estimated to occur in 1% of children born to mothers with ZIKV infection in pregnancy [

      Rice ME, Galang RR, Roth NM, Ellington SR, Moore CA, Valencia-Prado M, Ellis EM, Tufa AJ, Taulung LA, Alfred JM, et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR. Morb. Mortal. Wkly. Rep. 2018, 67, 858–867, https://dx.doi.org/10.15585/mmwr.mm6731e1.

      ].

      ZIKV control

      Screening and diagnosis

      ZIKV screening is based on two main approaches: the detection of viral RNA by nucleic acid amplification testing (NAAT), which main method is Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR); and the detection of antibodies (IgMs and IgGs) against ZIKV by serological assays (enzyme-linked immunosorbent assay -ELISA- tests) with confirmation by microneutralization assays or plaque reduction neutralization test (PRNT) [
      • Jääskeläinen A.J.
      • Korhonen E.M.
      • Huhtamo E.
      • Lappalainen M.
      • Vapalahti O.
      • Kallio-Kokko H.
      Validation of serological and molecular methods for diagnosis of Zika virus infections.
      J Virol Methods. 2019; 263: 68-74https://doi.org/10.1016/j.jviromet.2018.10.011
      ]. qRT-PCR is the most reliable method to confirm ZIKV infection, though the narrow window of detection in blood samples of 3–14 days after symptom onset represents a limitation in the diagnosis [
      • Voermans Jolanda J.C.
      • Pas, Suzan D.
      • van der Linden Anne
      • GeurtsvanKessel Corine
      • Koopmans Marion
      • van der Eijk Annemiek
      • et al.
      Whole-blood testing for diagnosis of acute Zika virus infections in routine diagnostic setting.
      Emerg Infect Dis. 2019; 25: 1394-1396https://doi.org/10.3201/eid2507.182000
      ]; also it requires extensive sample preparation, expensive equipment, and technical expertise [
      • Silva Severino Jefferson Ribeiro da
      • Pardee Keith
      • Pena Lindomar
      Loop-mediated isothermal amplification (LAMP) for the diagnosis of Zika virus. A Review.
      Viruses. 2019; 12: 19https://doi.org/10.3390/v12010019
      ]. The window of detection by molecular methods can be considerable extended with the use of urine samples, for more than 10 days after symptom onset [
      • Voermans Jolanda J.C.
      • Pas, Suzan D.
      • van der Linden Anne
      • GeurtsvanKessel Corine
      • Koopmans Marion
      • van der Eijk Annemiek
      • et al.
      Whole-blood testing for diagnosis of acute Zika virus infections in routine diagnostic setting.
      Emerg Infect Dis. 2019; 25: 1394-1396https://doi.org/10.3201/eid2507.182000
      ,
      • Gourinat Ann-Claire
      • O’Connor Olivia
      • Calvez Elodie
      • Goarant Cyrille
      • Dupont-Rouzeyrol Myrielle
      Detection of Zika virus in urine.
      Emerg Infect Dis. 2015; 21: 84-86https://doi.org/10.3201/eid2101.140894
      ]. Additionally, prolonged viremias of up to 70 days of duration have been described in serum and plasma samples during pregnancy [
      • Voermans Jolanda J.C.
      • Pas, Suzan D.
      • van der Linden Anne
      • GeurtsvanKessel Corine
      • Koopmans Marion
      • van der Eijk Annemiek
      • et al.
      Whole-blood testing for diagnosis of acute Zika virus infections in routine diagnostic setting.
      Emerg Infect Dis. 2019; 25: 1394-1396https://doi.org/10.3201/eid2507.182000
      ]. Testing multiple specimen types, such as urine, plasma, and whole blood is recommended to improve RNA detection [
      • Rossini Giada
      • Gaibani Paolo
      • Vocale Caterina
      • Cagarelli Roberto
      • Landini Maria Paola
      Comparison of Zika virus (ZIKV) RNA detection in plasma, whole blood and urine - Case series of travel-associated ZIKV infection imported to Italy, 2016.
      J Infect. 2017; 75: 242-245https://doi.org/10.1016/j.jinf.2017.05.021
      ]. A positive qRT-PCR confirms the infection, but a negative result does not exclude it, due to the time that ZIKV-RNA can be detected in blood or urine samples by molecular methods [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ]. The combined sensitivity of serum and urine qRT-PCR testing within the first 14 days of onset of illness allows capturing of nearly 75% of serologically confirmed infections [
      • Munoz-Jordan J.L.
      Diagnosis of Zika virus infections: Challenges and opportunities.
      J Infect Dis. 2017; 216: S951-S956https://doi.org/10.1093/infdis/jix502
      ]. Currently, ZIKV laboratory diagnosis is mostly based on molecular detection, because of the high cross-reactivity to several flaviviruses [
      • Munoz-Jordan J.L.
      Diagnosis of Zika virus infections: Challenges and opportunities.
      J Infect Dis. 2017; 216: S951-S956https://doi.org/10.1093/infdis/jix502
      ], and high false positive rates of serological assays [
      • Silva Severino Jefferson Ribeiro da
      • Pardee Keith
      • Pena Lindomar
      Loop-mediated isothermal amplification (LAMP) for the diagnosis of Zika virus. A Review.
      Viruses. 2019; 12: 19https://doi.org/10.3390/v12010019
      ]. Of note, loop-mediated isothermal amplification (LAMP) techniques are considered a point-of-care alternative for their rapidity, low cost, high sensitivity, and high specificity [
      • Silva Severino Jefferson Ribeiro da
      • Pardee Keith
      • Pena Lindomar
      Loop-mediated isothermal amplification (LAMP) for the diagnosis of Zika virus. A Review.
      Viruses. 2019; 12: 19https://doi.org/10.3390/v12010019
      ], particularly for low-resource settings with lesser laboratory capacities in place.
      Main serological tests for the diagnosis of ZIKV infection include ELISA for the detection of antibodies IgM and IgG against ZIKV [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ]. Additionally, other serological methods such as immunofluorescence assays (IFA), immunoblots and (chemiluminescent) microsphere immunoassays (CMIA) are also being used [
      • Sharma Vikrant
      • Sharma Manisha
      • Dhull Divya
      • Sharma Yashika
      • Kaushik Sulochana
      • Kaushik Samander
      Zika virus: An emerging challenge to public health worldwide.
      Can J Microbiol. 2020; 66: 87-98https://doi.org/10.1139/cjm-2019-0331
      ,
      • Van den Bossche Dorien
      • Michiels Johan
      • Cnops Lieselotte
      • Foque Nikki
      • Meersman Kathleen
      • Huits Ralph
      • et al.
      Challenges in diagnosing Zika-experiences from a reference laboratory in a non-endemic setting.
      Eur J Clin Microbiol Infect Dis. 2019; 38: 771-778https://doi.org/10.1007/s10096-019-03472-8
      ]. Generally, a positive IgM indicates a recent infection, while a positive IgG result indicates a past flavivirus infection (presumptive positive infection of ZIKV or other flaviviruses) [
      • Sharp Tyler M.
      • Fischer Marc
      • Muñoz-Jordán Jorge L.
      • Paz-Bailey Gabriela
      • Staples J. Erin
      • Gregory Christopher J.
      • et al.
      Dengue and Zika virus diagnostic testing for patients with a clinically compatible illness and risk for infection with both viruses.
      MMWR Recomm Reports Morb Mortal Wkly Report Recomm Rep. 2019; 68: 1-10https://doi.org/10.15585/mmwr.rr6801a1
      ]. Confirmation by pathogen-specific microneutralization or PRNT is recommended [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ,
      • Munoz-Jordan J.L.
      Diagnosis of Zika virus infections: Challenges and opportunities.
      J Infect Dis. 2017; 216: S951-S956https://doi.org/10.1093/infdis/jix502
      ], though it is not generally used for clinical management, because it is usually only available in highly specialized laboratories, or for research purposes [

      Masmejan S, Musso D, Vouga M, Pomar L, Dashraath P, Stojanov M, Panchaud A, Baud, D. Zika Virus. Pathog. (Basel, Switzerland) 2020, 9, https://dx.doi.org/10.3390/pathogens9110898.

      ].
      ZIKV testing represents a challenge, particularly in an epidemic context due to limited resources and scarce laboratory capabilities in many affected areas [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ], the narrow window of time that the virus persists in the bloodstream, the large proportion of asymptomatic infections, and the cross-reactivity with other flaviviruses, especially with DENV serotypes [
      • Lowe Rachel
      • Barcellos Christovam
      • Brasil Patrícia
      • Cruz Oswaldo
      • Honório Nildimar
      • Kuper Hannah
      • et al.
      The Zika virus epidemic in Brazil: From discovery to future implications.
      Int J Environ Res Public Health. 2018; 15: 96https://doi.org/10.3390/ijerph15010096
      ]. However, laboratory confirmation of ZIKV infection in pregnancy is essential, because most women with ZIKV infection are asymptomatic and even among those presenting symptoms these are non-specific [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ]. According to the CDC, ZIKV testing is recommended for symptomatic pregnant women with possible ZIKV exposure (residence in, or history of travel to, an area with mosquito-borne ZIKV transmission; or reporting unprotected sex with a partner who has travelled to, or resides, in an area with ZIKV transmission), asymptomatic pregnant women with possible exposure, and any pregnant women presenting with foetal anomalies detected by ultrasound scan (USS) and possible previous exposure to ZIKV [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ]. Testing of pregnant women with possible exposure to ZIKV is recommended as early as possible during pregnancy, and up to 12 weeks after travel to affected areas or symptoms’ onset [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ,
      • Munoz-Jordan J.L.
      Diagnosis of Zika virus infections: Challenges and opportunities.
      J Infect Dis. 2017; 216: S951-S956https://doi.org/10.1093/infdis/jix502
      ]. The CDC recommends molecular ZIKV diagnosis three times during pregnancy, however, due to resource constrains in most affected areas, effective implementation of this recommendation differs by countries and regions [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ,
      • Sharp Tyler M.
      • Fischer Marc
      • Muñoz-Jordán Jorge L.
      • Paz-Bailey Gabriela
      • Staples J. Erin
      • Gregory Christopher J.
      • et al.
      Dengue and Zika virus diagnostic testing for patients with a clinically compatible illness and risk for infection with both viruses.
      MMWR Recomm Reports Morb Mortal Wkly Report Recomm Rep. 2019; 68: 1-10https://doi.org/10.15585/mmwr.rr6801a1
      ,
      • Adebanjo Tolulope
      • Godfred-Cato Shana
      • Viens Laura
      • Fischer Marc
      • Staples J. Erin
      • Kuhnert-Tallman Wendi
      • et al.
      Update: Interim guidance for the diagnosis, evaluation, and management of infants with possible congenital Zika virus infection - United States, October 2017.
      MMWR Morb Mortal Wkly Rep. 2017; 66: 1089-1099https://doi.org/10.15585/mmwr.mm6641a1
      ]. Exclusive serologic testing is not recommended due to inherent limitations of the test and potential false negative results [
      • Sharp Tyler M.
      • Fischer Marc
      • Muñoz-Jordán Jorge L.
      • Paz-Bailey Gabriela
      • Staples J. Erin
      • Gregory Christopher J.
      • et al.
      Dengue and Zika virus diagnostic testing for patients with a clinically compatible illness and risk for infection with both viruses.
      MMWR Recomm Reports Morb Mortal Wkly Report Recomm Rep. 2019; 68: 1-10https://doi.org/10.15585/mmwr.rr6801a1
      ,
      • Adebanjo Tolulope
      • Godfred-Cato Shana
      • Viens Laura
      • Fischer Marc
      • Staples J. Erin
      • Kuhnert-Tallman Wendi
      • et al.
      Update: Interim guidance for the diagnosis, evaluation, and management of infants with possible congenital Zika virus infection - United States, October 2017.
      MMWR Morb Mortal Wkly Rep. 2017; 66: 1089-1099https://doi.org/10.15585/mmwr.mm6641a1
      ]. For symptomatic pregnant women, the CDC recommends concurrent diagnosis for ZIKV along with DENV and CHIKV, by NAAT and IgM testing on serum samples [
      • Plourde A.R.
      • Bloch E.M.
      A literature review of Zika virus.
      Emerg Infect Dis. 2016; 22: 1185-1192https://doi.org/10.3201/eid2207.151990
      ,
      • Sharp Tyler M.
      • Fischer Marc
      • Muñoz-Jordán Jorge L.
      • Paz-Bailey Gabriela
      • Staples J. Erin
      • Gregory Christopher J.
      • et al.
      Dengue and Zika virus diagnostic testing for patients with a clinically compatible illness and risk for infection with both viruses.
      MMWR Recomm Reports Morb Mortal Wkly Report Recomm Rep. 2019; 68: 1-10https://doi.org/10.15585/mmwr.rr6801a1
      ].

      Clinical management and treatment

      ZIKV infection is generally a mild illness and the most important part of antenatal management is prenatal detection of foetal abnormalities. In cases where a pregnant woman is confirmed or suspected to have been exposed to ZIKV, serial prenatal USS examinations are recommended to assess the anatomy of the foetus, particularly the CNS, foetal growth, and amniotic fluid volume. The International Society of Ultrasound Obstetrics and Gynaecology (ISUOG) recommends detailed monthly USS including a specialized neurosonography in cases with suspected foetal brain abnormalities. If not available, in endemic areas, women should receive at least routine USS examinations as part of standard prenatal care [
      • Papageorghiou A.T.
      • Thilaganathan B.
      • Bilardo C.M.
      • Ngu A.
      • Malinger G.
      • Herrera M.
      • et al.
      ISUOG Interim Guidance on ultrasound for Zika virus infection in pregnancy: information for healthcare professionals.
      Ultrasound Obstet Gynecol Off J Int Soc Ultrasound Obstet Gynecol. 2016; 47: 530-532https://doi.org/10.1002/uog.15896
      ]. Foetal USS findings associated with maternal ZIKV infection include microcephaly, intracranial calcifications, ventriculomegaly, abnormalities of cortical development and of the corpus callosum, hypoplasia of the cerebellum and limb abnormalities [

      Viens LJ, Fleck-Derderian S, Baez-Santiago MA, Oduyebo T, Broussard CS, Khan S, Jones AM, Meaney-Delman D. Role of Prenatal Ultrasonography and Amniocentesis in the Diagnosis of Congenital Zika Syndrome: A Systematic Review. Obstet Gynecol 2020, 135, 1185–1197, https://dx.doi.org/10.1097/AOG.0000000000003829.

      ]. A recent systematic review showed a prenatal detection rate of CZS by USS of 83% in infected women, though the interval between maternal infection and the appearance of USS abnormalities ranged between 7 and 23 weeks [

      Viens LJ, Fleck-Derderian S, Baez-Santiago MA, Oduyebo T, Broussard CS, Khan S, Jones AM, Meaney-Delman D. Role of Prenatal Ultrasonography and Amniocentesis in the Diagnosis of Congenital Zika Syndrome: A Systematic Review. Obstet Gynecol 2020, 135, 1185–1197, https://dx.doi.org/10.1097/AOG.0000000000003829.

      ]. This means that, in most countries, diagnosis may extend beyond the time limit for legal termination of pregnancy [

      Viens LJ, Fleck-Derderian S, Baez-Santiago MA, Oduyebo T, Broussard CS, Khan S, Jones AM, Meaney-Delman D. Role of Prenatal Ultrasonography and Amniocentesis in the Diagnosis of Congenital Zika Syndrome: A Systematic Review. Obstet Gynecol 2020, 135, 1185–1197, https://dx.doi.org/10.1097/AOG.0000000000003829.

      ]. CNS magnetic resonance imaging (MRI) after 30 weeks allows for a better evaluation of the cortical gyration and development, and should be considered [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ]. Routine amniocentesis is not recommended, because ZIKV-RNA virus may be present only transiently, and a negative result cannot rule out congenital ZIKV infection [

      Management of Patients in the Context of Zika Virus: ACOG COMMITTEE OPINION SUMMARY, Number 784. Obstet. Gynecol. 2019, 134, 655–657, https://dx.doi.org/10.1097/AOG.0000000000003400.

      ]. Moreover, the predictive value of a positive result for ZIKV infection in amniotic fluid in the absence of USS abnormalities has not been well defined [

      Viens LJ, Fleck-Derderian S, Baez-Santiago MA, Oduyebo T, Broussard CS, Khan S, Jones AM, Meaney-Delman D. Role of Prenatal Ultrasonography and Amniocentesis in the Diagnosis of Congenital Zika Syndrome: A Systematic Review. Obstet Gynecol 2020, 135, 1185–1197, https://dx.doi.org/10.1097/AOG.0000000000003829.

      ]. In cases of foetal defects after maternal exposure to ZIKV, the decision to perform an amniocentesis to detect ZIKV infection, and to rule out other genetic or infectious pathologies should be discussed with the patient [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ]. There is no specific antiviral treatment for ZIKV infection [
      • Musso D.
      • Gubler D.J.
      Zika Virus.
      Clin Microbiol Rev. 2016; 29: 487-524https://doi.org/10.1128/CMR.00072-15
      ]. Therapeutic options are palliative, based on treatment of specific symptoms, paracetamol for fever, headache, and myalgia, antihistamines for pruritic rash, hydration, and rest [

      da Silva S, Oliveira Silva Martins D, Jardim ACG, A Review of the Ongoing Research on Zika Virus Treatment. Viruses 2018, 10, https://dx.doi.org/10.3390/v10050255.

      ]. Non-steroidal anti-inflammatory drugs should be avoided because of the risks of haemorrhagic complications [

      da Silva S, Oliveira Silva Martins D, Jardim ACG, A Review of the Ongoing Research on Zika Virus Treatment. Viruses 2018, 10, https://dx.doi.org/10.3390/v10050255.

      ]. The search for efficient antivirals remains a challenge [

      da Silva S, Oliveira Silva Martins D, Jardim ACG, A Review of the Ongoing Research on Zika Virus Treatment. Viruses 2018, 10, https://dx.doi.org/10.3390/v10050255.

      ].

      Preventive measures

      Strategies to prevent ZIKV infection include prevention of mosquito bites and vector-control strategies, considering that Aedes mosquitoes are more active in the daytime [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ]. Measures to prevent mosquito bites comprise using bed-nets, screens on doors and windows [
      • Rather I.A.
      • Kumar S.
      • Bajpai V.K.
      • Lim J.
      • Park Y.-H.
      Prevention and control strategies to counter ZIKA epidemic.
      Front Microbiol. 2017; 8: 305https://doi.org/10.3389/fmicb.2017.00305
      ], using insect repellents (DEET -N,N-diethyl-meta-toluamide- applied to exposed skin, and permethrin-treated clothing) [
      • Rather I.A.
      • Kumar S.
      • Bajpai V.K.
      • Lim J.
      • Park Y.-H.
      Prevention and control strategies to counter ZIKA epidemic.
      Front Microbiol. 2017; 8: 305https://doi.org/10.3389/fmicb.2017.00305
      ,

      Centers for Disease Control and Prevention. Yellow Book, 2020. Chapter 3. Environmental Hazards & Other Noninfectious Health Risks. Mosquitoes, Ticks & Other Arthropods. https://wwwnc.cdc.gov/travel/yellowbook/2020/noninfectious-health-risks/mosquitoes-ti.

      ], staying indoors in early morning and before sunset, emptying and cleaning containers that can hold standing water, remaining in air-conditioned locations [

      Management of Patients in the Context of Zika Virus: ACOG COMMITTEE OPINION SUMMARY, Number 784. Obstet. Gynecol. 2019, 134, 655–657, https://dx.doi.org/10.1097/AOG.0000000000003400.

      ], and wearing long-sleeved shirts and long pants [
      • Rabaan Ali A.
      • Bazzi Ali M.
      • Al-Ahmed Shamsah H.
      • Al-Ghaith Mohamed H.
      • Al-Tawfiq Jaffar A.
      Overview of Zika infection, epidemiology, transmission and control measures.
      J Infect Public Health. 2017; 10: 141-149https://doi.org/10.1016/j.jiph.2016.05.007
      ]. Insect repellents containing DEET have been recommended by the CDC for its use in pregnancy to prevent WNV, Lyme disease, and ZIKV in pregnancy, due to its proved safety [
      • Wylie B.J.
      • Hauptman M.
      • Woolf A.D.
      • Goldman R.H.
      Insect Repellants during pregnancy in the era of the Zika virus.
      Obstet Gynecol. 2016; 128: 1111-1115https://doi.org/10.1097/AOG.0000000000001685
      ,

      Mytton OT, McGready R, Lee SJ, Roberts CH, Ashley EA, Carrara VI, Thwai KL, Jay MP, Wiangambun T, Singhasivanon P, et al. Safety of benzyl benzoate lotion and permethrin in pregnancy: A retrospective matched cohort study. BJOG 2007, 114, 582–587, https://dx.doi.org/10.1111/j.1471-0528.2007.01290.x.

      ]. The WHO guidelines for the prevention of sexual transmission of ZIKV in areas with ongoing transmission include a full range of contraceptives and counselling to make an informed choice about whether and when to get pregnant, and to avoid possible adverse outcomes of ZIKV during gestation [

      WHO guidelines for the prevention of sexual transmission of Zika virus. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO.

      ]. Recommendations for pregnant women not residing in areas with ZIKV transmission are to avoid travelling to risk areas [
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ,

      WHO guidelines for the prevention of sexual transmission of Zika virus. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO.

      ]. Yet, when there is a need to travel, ZIKV preventive measures are similar to those recommended for pregnant women residing in ZIKV transmission areas [
      • Longo Dan L.
      • Musso Didier
      • Ko Albert I.
      • Baud David
      Zika virus infection - After the pandemic.
      N Engl J Med. 2019; 381: 1444-1457https://doi.org/10.1056/NEJMra1808246
      ,
      • Pomar Léo
      • Musso Didier
      • Malinger Gustavo
      • Vouga Manon
      • Panchaud Alice
      • Baud David
      Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome.
      Prenat Diagn. 2019; 39: 420-430https://doi.org/10.1002/pd.v39.610.1002/pd.5446
      ,
      • Rather I.A.
      • Kumar S.
      • Bajpai V.K.
      • Lim J.
      • Park Y.-H.
      Prevention and control strategies to counter ZIKA epidemic.
      Front Microbiol. 2017; 8: 305https://doi.org/10.3389/fmicb.2017.00305
      ,

      Hills SL, Russell K, Hennessey M, Williams C, Oster AM, Fischer M, Mead P. Transmission of Zika Virus Through Sexual Contact with Travelers to Areas of Ongoing Transmission - Continental United States, 2016. MMWR. Morb. Mortal. Wkly. Rep. 2016, 65, 215–216, https://dx.doi.org/10.15585/mmwr.mm6508e2.

      ,

      Vouga M, Chiu Y-C, Pomar L, de Meyer SV, Masmejan S, Genton B, Musso D, Baud D, Stojanov M. Dengue, Zika and chikungunya during pregnancy: pre- and post-travel advice and clinical management. J. Travel Med. 2019, 26, https://dx.doi.org/10.1093/jtm/taz077.

      ].

      Pregnant women’s views about ZIKV

      Gender inequality in roles and responsibilities lead to women to have a greater risk for acquiring ZIKV infection and suffering the consequences of the disease [
      • Forero‐Martínez Luz J.
      • Murad Rocío
      • Calderón‐Jaramillo Mariana
      • Rivillas‐García Juan C.
      Zika and women’s sexual and reproductive health: Critical first steps to understand the role of gender in the Colombian epidemic.
      Int J Gynaecol Obstet. 2020; 148: 15-19https://doi.org/10.1002/ijgo.v148.s210.1002/ijgo.13043
      ]. The additional implications for maternal, sexual and reproductive health make the understanding of women’s experiences, knowledge, perceptions, and attitudes towards ZIKV certainly crucial [
      • Forero‐Martínez Luz J.
      • Murad Rocío
      • Calderón‐Jaramillo Mariana
      • Rivillas‐García Juan C.
      Zika and women’s sexual and reproductive health: Critical first steps to understand the role of gender in the Colombian epidemic.
      Int J Gynaecol Obstet. 2020; 148: 15-19https://doi.org/10.1002/ijgo.v148.s210.1002/ijgo.13043
      ]. A multidimensional approach that considers healthcare services, gender issues, and environmental factors, is key to comprehend the repercussions of ZIKV infection on affected populations [
      • Forero‐Martínez Luz J.
      • Murad Rocío
      • Calderón‐Jaramillo Mariana
      • Rivillas‐García Juan C.
      Zika and women’s sexual and reproductive health: Critical first steps to understand the role of gender in the Colombian epidemic.
      Int J Gynaecol Obstet. 2020; 148: 15-19https://doi.org/10.1002/ijgo.v148.s210.1002/ijgo.13043
      ]. During the ZIKV epidemic in 2015–16, the international media coverage and circulation of misinformation shaped communities' perceptions and behaviours regarding ZIKV disease [

      Albuquerque MdeFPM. de; Souza WV de, Araujo TVB, Braga MC, Miranda Filho D deB, Ximenes RA de A, de Melo Filho DA, Brito CAAde, Valongueiro S, Melo APL de, et al. The microcephaly epidemic and Zika virus: building knowledge in epidemiology. Cad. Saude Publica 2018, 34, e00069018, https://dx.doi.org/10.1590/0102-311X00069018.

      ]. Images of infants with congenital malformations touched the global community, leading to perceptions of fear and concerns about the development of the foetus and the eventual quality of life among mothers both affected or potentially exposed to ZIKV [

      Albuquerque MdeFPM. de; Souza WV de, Araujo TVB, Braga MC, Miranda Filho D deB, Ximenes RA de A, de Melo Filho DA, Brito CAAde, Valongueiro S, Melo APL de, et al. The microcephaly epidemic and Zika virus: building knowledge in epidemiology. Cad. Saude Publica 2018, 34, e00069018, https://dx.doi.org/10.1590/0102-311X00069018.

      ]. Mental health of women diagnosed with ZIKV during pregnancy, and of mothers of children with CZS was a matter of concern reported in several studies where increased levels of stress, anxiety and poor emotional health were reported [

      Horan H, Cheyney M, Nako E. Bovbjerg, M. Maternal stress and the ZIKV epidemic in Puerto Rico. Crit Public Health 2020, 1–11, https://dx.doi.org/10.1080/09581596.2020.1808189.

      ,

      Freitas, P.S.S.; Soares, G.B.; Mocelin, H.J.S.; Lamonato, L.C.X.L.; Sales, C.M.M.; Linde-Arias, A.R.; Bussinger, E.C.A.; Maciel, E.L.N. How do mothers feel? Life with children with congenital Zika syndrome. Int. J. Gynaecol. Obstet. 2020, 148 Suppl, 20–28, https://dx.doi.org/10.1002/ijgo.13044.

      ,

      Romero-Acosta, K.; Marbán-Castro, E.; Arroyo, K.; Arrieta, G.; Mattar, S. Perceptions and Emotional State of Mothers of Children with and without Microcephaly after the Zika Virus Epidemic in Rural Caribbean Colombia. Behav. Sci. (Basel, Switzerland) 2020, 10 https://dx.doi.org/10.3390/bs10100147.

      ].
      In 2017, in Brazil, knowledge about ZIKV among pregnant women infected with ZIKV was restricted to the little information they received through the TV and the Internet; healthcare services were rarely the primary source of information [

      Sousa CA de, Mendes D do CO, Mufato LF, Queirós P de S. Zikavírus: knowledge, perceptions, and care practices of infected pregnant women. Rev Gauch Enferm 2018, 39, e20180025, https://dx.doi.org/10.1590/1983-1447.2018.20180025.

      ]. In Peru, a study showed that pregnant women with ZIKV infection lacked information about ZIKV-associated neurological disorders, sexual transmission of the virus or ways to prevent the infection [
      • Weldon Caroline T.
      • Riley-Powell Amy R.
      • Aguerre Ines M.
      • Celis Nacimento Rosa A.
      • Morrison Amy C.
      • Oberhelman Richard A.
      • et al.
      “Zika is everywhere”: A qualitative exploration of knowledge, attitudes and practices towards Zika virus among women of reproductive age in Iquitos, Peru.
      PLoS Negl. Trop. Dis. 2018; 12: e0006708https://doi.org/10.1371/journal.pntd.000670810.1371/journal.pntd.0006708.s001
      ]. Similarly, other studies also reported knowledge gaps on ZIKV being a sexually transmitted infection, both among pregnant women living in areas with ZIKV transmission [

      Sousa CA de, Mendes D do CO, Mufato LF, Queirós P de S. Zikavírus: knowledge, perceptions, and care practices of infected pregnant women. Rev Gauch Enferm 2018, 39, e20180025, https://dx.doi.org/10.1590/1983-1447.2018.20180025.

      ,
      • Weldon Caroline T.
      • Riley-Powell Amy R.
      • Aguerre Ines M.
      • Celis Nacimento Rosa A.
      • Morrison Amy C.
      • Oberhelman Richard A.
      • et al.
      “Zika is everywhere”: A qualitative exploration of knowledge, attitudes and practices towards Zika virus among women of reproductive age in Iquitos, Peru.
      PLoS Negl. Trop. Dis. 2018; 12: e0006708https://doi.org/10.1371/journal.pntd.000670810.1371/journal.pntd.0006708.s001
      ,

      Johns Hopkins University. Monitoring Outcomes for Zika Prevention Knowledge and Behaviors in Dominican Republic, El Salvador, Guatemala and Honduras SMS MONITORING SURVEY: FINAL REPORT. 2017. Accessible at: https://www.zikacommunicationnetwork.org/sites/d.

      ,
      • Gurman Tilly
      • Ballard Sara Anne
      • Villanueva Lorenzo Florentina
      • Luis Desirée
      • Hunter Gabrielle
      • Maloney Sean
      • et al.
      The role of gender in Zika prevention behaviors in the Dominican Republic: Findings and programmatic implications from a qualitative study.
      PLoS Negl Trop Dis. 2020; 14: e0007994https://doi.org/10.1371/journal.pntd.0007994
      ,
      • Nelson E.J.
      • Luetke M.C.
      • Kianersi S.
      • Willis E.
      • Rosenberg M.
      Knowledge and perceptions of Zika virus transmission in the community of Puerto Plata Dominican Republic.
      BMC Infect Dis. 2019; 19: 339https://doi.org/10.1186/s12879-019-3952-0
      ,

      Abu-Rish EY, Elayeh ER, Browning MJ. Travelers to U.S.: Zika Virus Knowledge, Attitudes, and Determinants of Practices in the Middle East-Insights for Future Awareness Campaigns. Int. J. Environ. Res. Public Health 2019, 16, https://dx.doi.org/10.3390/ijerph16142517.

      ,
      • Mendoza Carolina
      • Jaramillo Gloria-Isabel
      • Ant Thomas H.
      • Power Grace M.
      • Jones Robert T.
      • Quintero Juliana
      • et al.
      An investigation into the knowledge, perceptions and role of personal protective technologies in Zika prevention in Colombia.
      PLoS Negl Trop Dis. 2020; 14: e0007970https://doi.org/10.1371/journal.pntd.0007970
      ,

      PASMO, Population Services International, U.S. Agency for International Development. PSI Zika Omnibus study results, LAC region. 2017. Accessible at https://www.zikacommunicationnetwork.org/resources/psi-zika-omnibus-study-results-lac-region-january-2017

      ,
      • Chandrasekaran N.
      • Marotta M.
      • Taldone S.
      • Curry C.
      Perceptions of community risk and travel during pregnancy in an Area of Zika transmission.
      Cureus. 2017; 9e1516https://doi.org/10.7759/cureus.1516
      ], and pregnant travellers [
      • Rodriguez Miguel
      • Lord Ayla
      • Sanabia Carolina C
      • Silverio Abigail
      • Chuang Meleen
      • Dolan Siobhan M
      Understanding Zika virus as an STI: Findings from a qualitative study of pregnant women in the Bronx.
      Sex Transm Infect. 2020; 96: 80-84https://doi.org/10.1136/sextrans-2019-054093
      ,
      • Marbán-Castro Elena
      • Villén-Gonzalvo Ana
      • Enguita-Fernàndez Cristina
      • Marín-Cos Anna
      • Menéndez Clara
      • Maixenchs Maria
      • et al.
      Fear and stigma: Perceptions of Zika virus among pregnant women in Spain.
      Int J Environ Res Public Health. 2020; 17: 6643https://doi.org/10.3390/ijerph17186643
      ,
      • Castanha Priscila M.S.
      • Marques Ernesto T.A.
      A glimmer of hope: recent updates and future challenges in Zika vaccine development.
      Viruses. 2020; 12: 1371https://doi.org/10.3390/v12121371
      ]. Psychosocial support has been pointed out necessary when ZIKV results are given to pregnant women and likewise throughout antenatal care and infant follow-up. Also in non-endemic areas, pregnant migrants and travellers to ZIKV areas have been reported to face the collateral effects of the epidemic and having suffered from stigma and discrimination when they returned from their home-countries [
      • Garg Himanshu
      • Mehmetoglu-Gurbuz Tugba
      • Joshi Anjali
      Recent advances in Zika virus vaccines.
      Viruses. 2018; 10: 631https://doi.org/10.3390/v10110631
      ].

      Vaccines against ZIKV

      As of September 2020, there were at least 20 vaccine candidates for ZIKV under clinical evaluation in phase I clinical trials, one trial in phase II, and more than 75 candidates in preclinical stages [
      • Poland Gregory A
      • Kennedy Richard B
      • Ovsyannikova Inna G
      • Palacios Ricardo
      • Ho Paulo Lee
      • Kalil Jorge
      Development of vaccines against Zika virus.
      Lancet Infect Dis. 2018; 18: e211-e219https://doi.org/10.1016/S1473-3099(18)30063-X
      ]. Most of the trials are being conducted in non-endemic countries, mainly in the USA and in Europe [
      • Poland Gregory A
      • Kennedy Richard B
      • Ovsyannikova Inna G
      • Palacios Ricardo
      • Ho Paulo Lee
      • Kalil Jorge
      Development of vaccines against Zika virus.
      Lancet Infect Dis. 2018; 18: e211-e219https://doi.org/10.1016/S1473-3099(18)30063-X
      ]. The only study in phase II (VRC5283) was performed in flavivirus endemic and non-endemic areas, including several sites in Central and South America [
      • Poland Gregory A
      • Kennedy Richard B
      • Ovsyannikova Inna G
      • Palacios Ricardo
      • Ho Paulo Lee
      • Kalil Jorge
      Development of vaccines against Zika virus.
      Lancet Infect Dis. 2018; 18: e211-e219https://doi.org/10.1016/S1473-3099(18)30063-X
      ], and assessed the efficacy of a three-dose regimen (0,4,8 weeks) in non-pregnant adults and adolescents [
      • Poland Gregory A
      • Kennedy Richard B
      • Ovsyannikova Inna G
      • Palacios Ricardo
      • Ho Paulo Lee
      • Kalil Jorge
      Development of vaccines against Zika virus.
      Lancet Infect Dis. 2018; 18: e211-e219https://doi.org/10.1016/S1473-3099(18)30063-X
      ]. Vaccine candidates under clinical development include purified inactivated virus, live attenuated virus, DNA, mRNA, subunit, and viral vectors vaccines [
      • Vannice Kirsten S.
      • Cassetti M. Cristina
      • Eisinger Robert W.
      • Hombach Joachim
      • Knezevic Ivana
      • Marston Hilary D.
      • et al.
      Demonstrating vaccine effectiveness during a waning epidemic: A WHO/NIH meeting report on approaches to development and licensure of Zika vaccine candidates.
      Vaccine. 2019; 37: 863-868https://doi.org/10.1016/j.vaccine.2018.12.040
      ]. Based on modelling analyses, a large ZIKV epidemic would be expected to occur in the next 10–15 years, a reason why it is critical to advance towards phase III trials that would make possible an approved vaccine for prevention of ZIKV in the upcoming years [
      • Poland Gregory A
      • Kennedy Richard B
      • Ovsyannikova Inna G
      • Palacios Ricardo
      • Ho Paulo Lee
      • Kalil Jorge
      Development of vaccines against Zika virus.
      Lancet Infect Dis. 2018; 18: e211-e219https://doi.org/10.1016/S1473-3099(18)30063-X
      ].
      Research priorities on ZIKV vaccines should include the establishment of correlates of protection, determination of ZIKV vaccine-induced immune responses, evaluation of vaccine immunogenicity and efficacy in several populations (pregnant women, children, elderly people, populations of different ethnicities, genders, and socio-economic statuses) [
      • Wilder-Smith Annelies
      • Vannice Kirsten
      • Durbin Anna
      • Hombach Joachim
      • Thomas Stephen J.
      • Thevarjan Irani
      • et al.
      Zika vaccines and therapeutics: landscape analysis and challenges ahead.
      BMC Med. 2018; 16https://doi.org/10.1186/s12916-018-1067-x
      ]. However, a major barrier for evaluation of ZIKV vaccines is the current context of reduced incidence after the ZIKV epidemic, which limits the plans for clinical development through phase II and III clinical trials [
      • Vannice Kirsten S.
      • Cassetti M. Cristina
      • Eisinger Robert W.
      • Hombach Joachim
      • Knezevic Ivana
      • Marston Hilary D.
      • et al.
      Demonstrating vaccine effectiveness during a waning epidemic: A WHO/NIH meeting report on approaches to development and licensure of Zika vaccine candidates.
      Vaccine. 2019; 37: 863-868https://doi.org/10.1016/j.vaccine.2018.12.040
      ,
      • Wilder-Smith Annelies
      • Vannice Kirsten
      • Durbin Anna
      • Hombach Joachim
      • Thomas Stephen J.
      • Thevarjan Irani
      • et al.
      Zika vaccines and therapeutics: landscape analysis and challenges ahead.
      BMC Med. 2018; 16https://doi.org/10.1186/s12916-018-1067-x
      ]. Some issues would also need to be considered such the ethical implications of study design of vaccine trials in pregnant women living in areas with ZIKV transmission within an epidemic context [
      • Garg Himanshu
      • Mehmetoglu-Gurbuz Tugba
      • Joshi Anjali
      Recent advances in Zika virus vaccines.
      Viruses. 2018; 10: 631https://doi.org/10.3390/v10110631
      ], and strategies to effectively enrol pregnant women in ZIKV vaccine trials, as willingness to participate in previous hypothetical ZIKV vaccine trials has been reported to be low [
      • Marbán-Castro Elena
      • Villén-Gonzalvo Ana
      • Enguita-Fernàndez Cristina
      • Romero-Acosta Kelly Carolina
      • Marín-Cos Anna
      • Arrieta Germán J.
      • et al.
      Acceptability of a hypothetical zika vaccine among women from Colombia and Spain exposed to zikv: A qualitative study.
      Vaccines. 2020; 8: 580https://doi.org/10.3390/vaccines8040580
      ].

      Summary

      ZIKV infection entails severe consequences on maternal, child and reproductive health. Maternal-foetal transmission occurs in a high percentage of infected women , and is associated with high risk of foetal loss, structural and functional anomalies including microcephaly, and long-term neurodevelopmental sequelae. Screening for ZIKV in exposed pregnant women is essential as most infections are asymptomatic and clinical manifestations are non-specific. Prenatal ultrasound assessment is recommended for monitoring and early detection of possible ZIKV-associated foetal anomalies. A mid- and long-term follow-up of children exposed to ZIKV while in utero is crucial to promptly detect any clinical manifestations of possible neurological impairment.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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      Article info

      Publication history

      Published online: July 08, 2021
      Accepted: July 6, 2021
      Received in revised form: July 5, 2021
      Received: April 1, 2021

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      DOI: https://doi.org/10.1016/j.ejogrb.2021.07.012

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