Desideratum: a developmentalist view of Zika virus infection
Authors: Christa Einspieler, Peter B Marschik
Journal: The Lancet Infectious Diseases (2020)

Zika virus was first isolated from the blood of a rhesus macaque during a study on yellow fever transmission in the Zika forest in Uganda in the late 1940s.1Dick GW Kitchen SF Haddow AJ Zika virus. I. Isolations and serological specificity.Trans R Soc Trop Med Hyg. 1952; 46: 509-520Summary Full Text PDF PubMed Scopus (1681) Google Scholar In the following years, the virus, transmitted through Aedes mosquitos, remained, besides reports on local case series, almost unrecognised until the 2007 outbreak in the Federated States of Micronesia. It was another 8 years later that the 2015–16 epidemic in Brazil suddenly brought Zika virus into the spotlight because of unexpected severe neurological complications.2Koppolu V Shantha Raju T Zika virus outbreak: a review of neurological complications, diagnosis, and treatment options.J Neurovirol. 2018; 24: 255-272Crossref PubMed Scopus (22) Google Scholar Most alarming was a dramatic increase of newborn babies with brain anomalies such as calcifications, ventriculomegaly, and particularly microcephaly3Nithiyanantham SF Badawi A Maternal infection with Zika virus and prevalence of congenital disorders in infants: systematic review and meta-analysis.Can J Public Health. 2019; 110: 638-648Crossref PubMed Scopus (18) Google Scholar (congenital Zika syndrome4Moore CA Staples JE Dobyns WB et al.Characterizing the pattern of anomalies in congenital zika syndrome for pediatric clinicians.JAMA Pediatr. 2017; 171: 288-295Crossref PubMed Scopus (488) Google Scholar) indicating vertical transmission from the pregnant woman to her fetus. Since then, a large body of research has shown that Zika virus can cross the placental barrier by inducing vascular damage, apoptosis of trophoblasts, and hyperplasia of placental macrophages,5Chiu CF Chu LW Liao IC et al.The mechanism of the Zika virus crossing the placental barrier and the blood-brain barrier.Front Microbiol. 2020; 11: 214Crossref PubMed Scopus (28) Google Scholar which conveys the virus to the fetal compartment, particularly to the fetal brain. Targeting of neural progenitor and microglial cells by the virus leads to downregulation of neurogenesis and upregulation of apoptosis, which in turn result in stunted growth or even death of developing neurons.6Wen Z Song H Ming GL How does Zika virus cause microcephaly?.Genes Dev. 2017; 31: 849-861Crossref PubMed Scopus (69) Google Scholar The consequence is a marked reduction in brain size. But how often is this the case? In their Article in The Lancet Infectious Diseases, A E Ades and colleagues7Ades AE Soriano-Arandes A Alarcon A et al.Vertical transmission of Zika virus and its outcomes: a Bayesian synthesis of prospective studies.Lancet Infect Dis. 2020; (published online Oct 14.)https://doi.org/10.1016/S1473-3099(20)30432-1Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar provided rates of vertical transmission and adverse outcomes, based on Bayesian latent class analysis of data from seven prospective studies done in different settings in the Americas, as well as in travellers and immigrants to Spain from the Americas. Although the diagnostic sensitivity of markers of congenital Zika virus infection is estimated to be lowest in the first trimester of pregnancy,7Ades AE Soriano-Arandes A Alarcon A et al.Vertical transmission of Zika virus and its outcomes: a Bayesian synthesis of prospective studies.Lancet Infect Dis. 2020; (published online Oct 14.)https://doi.org/10.1016/S1473-3099(20)30432-1Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar the susceptibility of the developing nervous system seems to be the highest in the first trimester. With an estimated average vertical transmission rate of 47% (95% credible interval 26–76), around 130 per 1000 pregnancies have an adverse outcome when maternal infection happens during the first trimester compared with 30 per 1000 when maternal infection occurs during the second trimester, and only three per 1000 in the third trimester.7Ades AE Soriano-Arandes A Alarcon A et al.Vertical transmission of Zika virus and its outcomes: a Bayesian synthesis of prospective studies.Lancet Infect Dis. 2020; (published online Oct 14.)https://doi.org/10.1016/S1473-3099(20)30432-1Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar Adverse outcome comprised fetal loss and stillbirth, congenital Zika syndrome, and any other neonatal neurological, auditory, or ophthalmological abnormalities potentially related to prenatal Zika virus exposure. Although it is important to have the vertical transmission rate available—particularly in light of pending results of several multicentre studies on prenatal Zika virus exposure7Ades AE Soriano-Arandes A Alarcon A et al.Vertical transmission of Zika virus and its outcomes: a Bayesian synthesis of prospective studies.Lancet Infect Dis. 2020; (published online Oct 14.)https://doi.org/10.1016/S1473-3099(20)30432-1Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar—fetal and neonatal outcomes are not the only outcomes to consider when it comes to recognising the full spectrum of consequences of Zika virus infection during pregnancy. Through our involvement in follow-up studies of children prenatally exposed to Zika virus in the Rio de Janeiro Zika cohort,8Brasil P Pereira Jr, JP Moreira ME et al.Zika virus infection in pregnant women in Rio de Janeiro.N Engl J Med. 2016; 375: 2321-2334Crossref PubMed Scopus (1155) Google Scholar we learnt that neonatal brain imaging results were less predictive for neurodevelopmental outcomes in toddlers than had been assumed; for example, this type of imaging has been shown to be quite insensitive for predicting neurodevelopmental assessments up to 12 months of age (50%; 95% CI 19–81).9Einspieler C Utsch F Brasil P et al.Association of infants exposed to prenatal Zika virus infection with their clinical, neurologic, and developmental status evaluated via the general movement assessment tool.JAMA Netw Open. 2019; 2e187235Crossref PubMed Scopus (49) Google Scholar Sensitivities for predicting scores below average in the Bayley Scales of Infant and Toddler Development (third edition) in the first half of the second year of life have been shown to be 60% (95% CI 39–79) for language development and 86% (95% CI 42–100) for cognitive development.10Lopes Moreira ME Nielsen-Saines K Brasil P et al.Neurodevelopment in infants exposed to Zika virus in utero.N Engl J Med. 2018; 379: 2377-2379Crossref PubMed Scopus (41) Google Scholar Specificity values between 67% (95% CI 56–76) for cognition10Lopes Moreira ME Nielsen-Saines K Brasil P et al.Neurodevelopment in infants exposed to Zika virus in utero.N Engl J Med. 2018; 379: 2377-2379Crossref PubMed Scopus (41) Google Scholar and 76% (60–88) for neurodevelopmental assessment9Einspieler C Utsch F Brasil P et al.Association of infants exposed to prenatal Zika virus infection with their clinical, neurologic, and developmental status evaluated via the general movement assessment tool.JAMA Netw Open. 2019; 2e187235Crossref PubMed Scopus (49) Google Scholar also indicate substantial false positive rates. Even for congenital Zika syndrome, two of the eight children who had microcephaly recognised at birth had their symptoms resolve over time.11Nielsen-Saines K Brasil P Kerin T 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: 1213-1217Crossref PubMed Scopus (101) Google Scholar On the other hand, two children of the 208 in the follow-up cohort who were reported to be healthy at birth developed secondary microcephaly and scored below average in developmental assessments later on.11Nielsen-Saines K Brasil P Kerin T 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: 1213-1217Crossref PubMed Scopus (101) Google Scholar Outcomes at one single timepoint in early development need to be interpreted with caution. Milder forms of dysfunctions might improve spontaneously or through targeted intervention, whereas neuropsychiatric disorders can only be recognised later in childhood. Usually, group comparisons are provided when reporting follow-up observations, without acknowledging the limited help available for individual families who need tailored support rather than risk calculations and predictive values. Development is characterised by fluctuations and inconsistencies, which allow for adaptability to continuously changing conditions. That maternal Zika virus infection during pregnancy results in high vertical transmission rates—depending on the time of maternal infection7Ades AE Soriano-Arandes A Alarcon A et al.Vertical transmission of Zika virus and its outcomes: a Bayesian synthesis of prospective studies.Lancet Infect Dis. 2020; (published online Oct 14.)https://doi.org/10.1016/S1473-3099(20)30432-1Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar—does not take away from the fact that birth and the neonatal period are not the only outcomes of a prenatal condition. They are short periods in an individual trajectory undergoing continuous ontogenetic adaptation, an interaction of endogenous and exogenous factors influencing variability within and across developmental domains. We declare no competing interests. Vertical transmission of Zika virus and its outcomes: a Bayesian synthesis of prospective studiesThis preliminary analysis recovers the causal effects of Zika virus from disparate study designs. Higher transmission in the first trimester is unusual with congenital infections but accords with laboratory evidence of decreasing susceptibility of placental cells to infection during pregnancy. Full-Text PDF Open Access