SUMMARY
Developmental trends between 3 and 24 months were assessed in 194 normocephalic infants with prenatal Zika virus exposure. Bayley Scales of Infant and Toddler Development Screening Test–3rd Edition cognitive scores remained in the typical range. Communication skills developed at a slower rate suggesting that neurodevelopmental delays may emerge at older ages.
Keywords: Cognition, Communication, Delay, Neurodevelopment, Prenatal, Zika virus
1. Introduction
Prenatal exposure to the mosquito-borne Zika virus (ZIKV; a flavivirus from the Flaviviridae family that includes West Nile and Dengue viruses) had a devastating effect on infants born during the epidemic in Brazil that peaked in 2015–2016. Between 2015 and 2018 there were 239,742 reported cases of ZIKV infection in the general population of Brazil, and the northeastern areas were hardest hit [1]. Clinical, epidemiologic, and laboratory evidence linked prenatal ZIKV infection with nearly a 20-fold increase in the incidence of microcephaly compared to prior years [2].
Initial studies on the effects of prenatal ZIKV exposure focused on infants with microcephaly, referred to as Congenital Zika Virus Syndrome (CZS), who exhibited significant neuropathology and developmental delays [3,4]. However, emerging data suggest that the impact of ZIKV infection extends beyond symptomatic CZS [5]. Studies of infants with prenatal exposure to ZIKV but without microcephaly, who initially appeared asymptomatic, reported that clinically significant reductions in head size compared to unexposed controls could emerge during the first year of life [5,6]. Neurodevelopmental delays have been identified in at least 30–35% of normocephalic ZIKV-exposed infants by 18 months, and most commonly involve the language/communication domain [7,8], even when cognitive function remains in the typical range [9]. The main objective of this study was to evaluate developmental trajectories for cognitive and communication domains during the first two years of life in infants with prenatal ZIKV-exposure born without microcephaly in order to determine whether these infants may be at risk for poor developmental outcomes.
2. Material and methods
2.1. Participants
A total of 280 infants with confirmed prenatal ZIKV exposure but without microcephaly or other brain imaging abnormalities born at or referred shortly after birth (<3 months) to the Clinical University Hospital at Ribeirão Preto Medical School, University of São Paulo (HCFMRP-USP), Brazil in 2016 were evaluated repeatedly from 3 to 24 months of age as a part of the Natural History of Zika Virus Infection in Gestation (NATZIG) cohort described in [10]. Subjects were not pre-selected based on sex, socioeconomic status, or other characteristics. Eighty-six infants completed only one study visit and therefore were excluded from the current longitudinal analysis. The final sample included 194 infants who had at least two evaluations during the study period (see Table 1 for demographic characteristics). The demographic characteristics of the included and excluded infants were not appreciably different (see Supplementary Table). All study procedures received ethical approval (Processes #7404/2016, #5914/2017), and the mothers provided written informed consent.
Table 1.
Categorization of the Bayley Scales of Infant and Toddler Development Screening Test – 3rd Edition scores in cognitive and communication domains according to age of evaluation among 194 infants.
| Scores categorization |
Age at evaluation |
|||||
|---|---|---|---|---|---|---|
| Cognitive domain, n (%) | 3mo (n = 92) |
6mo (n = 157) |
9mo (n = 66) |
12mo (n = 12) |
18mo (n = 124) |
24mo (n = 153) |
| Competent | 92 (100%) | 144 (91.7%) | 62 (93.9%) | 9 (75%) | 109 (87.9%) | 145 (94.8%) |
| Emerging | 0 | 9 (5.7%) | 4 (6.1%) | 3 (25%) | 12 (9.7%) | 8 (5.2%) |
| At risk | 0 | 4 (2.6%) | 0 | 0 | 3 (2.4%) | 0 |
| Receptive communication domain, n (%) | ||||||
| Competent | 91 (98.9%) | 138 (87.9%) | 57 (86.4%) | 9 (75%) | 108 (87.1%) | 135 (88.2%) |
| Emerging | 1 (11.1%) | 13 (8.3%) | 8 (12.1%) | 3 (25%) | 10 (8.1%) | 16 (10.5%) |
| At Risk | 0 | 6 (3.8%) | 1 (1.5%) | 0 | 6 (4.8%) | 2 (1.3%) |
| Expressive communication domain, n (%) | ||||||
| Competent | 91 (98.9%) | 148 (94.3%) | 61 (92.4%) | 10 (83.4%) | 96 (77.4%) | 112 (73.2%) |
| Emerging | 1 (11.1%) | 8 (5.1%) | 5 (7.6%) | 2 (16.6%) | 24 (19.4%) | 36 (23.5%) |
| At risk | 0 | 1 (0.6%) | 0 | 0 | 4 (3.2%) | 5 (3.3%) |
Laboratory evidence of maternal ZIKV infection during pregnancy included ZIKV-RNA detected in blood (within five days of symptoms), urine (within eight days of symptoms), amniotic fluid, or feto-placental tissue by RT-PCR testing by Adolfo Lutz Institute [11]. Mothers testing positive for syphilis and HIV were excluded. Infants with findings suggestive of congenital infections were tested for syphilis (treponemal and reaginic tests) and toxoplasmosis (IgM and IgG ELISA). Blood, saliva, urine, and/or cerebrospinal fluid were tested for enterovirus, parvovirus, HHV-6, HSV-I, HSV-II, and CMV via PCR assays in these infants. All infants were tested for ZIKV-RNA using the previously mentioned test, within one week of birth and none had positive results. Normocephalic status at birth was confirmed by the review of medical records. The head circumference measured before hospital discharge was classified according to the INTERGROWTH-21st criterion [12], as recommended by Pan American Health Organization.
2.2. Procedure
The Bayley Scales of Infant and Toddler Development Screening Test – 3rd Edition [13] was administered by a certified examiner in a quiet room in the outpatient clinic every three to six months between the ages of 3 and 24 months. The study participants had a median of three (range: 2–5) evaluations during the study period, contributing data for two (n = 63), three (n = 70), four (n = 38) or five (n = 23) time points. At each visit, the infants were tested according to the standard procedures in five domains: cognitive, communication (receptive and expressive) and motor (fine and gross). Assessment duration varied according to the age and abilities of each child, ranging from 10 to 15 min at 3 months to 45–60 min at 24 months. All participants cooperated with completing all five domains of the screener. Raw scores in each domain were compared with the reference scale and classified as reflecting “competent” or “emerging”/“at risk” functioning. The development of cognitive and communication domains was the main focus of this study; therefore, the motor scores were not included in the analyses and are not reported.
2.3. Statistical analysis
While the scaled scores reflect whether each infant’s performance is age-appropriate, they are designed to be stable across time even when the absolute level of performance increases [14]. Therefore, raw scores were used in the statistical analysis to evaluate developmental trends across the assessment time points. Differences in slopes for scores in cognitive and communicative domains were tested using t-tests. The missing data for the 12-month assessment are due to the majority of the infants completing the full Bayley Scales of Infant Development evaluation at that time point. The data missing at the other time points are due to scheduling difficulties and families moving out of the area.
3. Results
All infants had preserved hearing function (passed newborn hearing screening). None of the children developed postnatal microcephaly. Behavioral performance classification at each assessment point between 3 and 24 months of age is presented in Table 1. The majority (>70%) of 194 normocephalic infants with prenatal exposure to ZIKV were classified as competent at each study visit. Fig. 1 depicts the developmental trends from 3 to 24 months and reveals the expected increase in the raw scores for each domain. However, the developmental trajectories for cognitive and communication domains differed: the slope for cognitive development was steeper than for receptive (t(8) = 3.27, p = .011) and expressive communication (t(8) = 3.04, p = .016). Slower rate of development for the latter suggests that difficulties in these domains may emerge with increasing age. The slopes for the receptive and expressive communication domains were not significantly different (p = .74).
Fig. 1.
Bayley Scales of Infant and Toddler Development Screening Test – 3rd Edition average raw scores in 194 normocephalic infants with prenatal ZIKV exposure by domain (cognitive, receptive and expressive communication) and age at test. Error bars reflect standard deviations.
These longitudinal results indicate that prenatal ZIKV exposure may have a detrimental effect on infant neurodevelopment, particularly in the communicative domains, including in those who appeared asymptomatic for CZS at birth. The risk for suboptimal outcomes is more apparent when considering the developmental trends rather than scores at a single assessment point. Previously, developmental trajectory monitoring for a simple standardized assessment (the Developmental Assessment of Young Children) during the first 12 months has been reported as an effective predictor of cerebral palsy before more complex neurodevelopmental testing could be performed [15]. In the current study, communicative development between 3 and 24 months was identified as an emerging area of weakness despite typical cognitive and motor performance. By design, the Bayley Screening test provides a less detailed evaluation than the full Bayley Scales of Infant and Toddler Development because it is intended to be a time- and cost-effective way to identify infants in need of further, more comprehensive testing. Therefore, future studies with more specialized measures of language and communicative function will need to characterize the specific developmental difficulties associated with prenatal ZIKV-exposure in normocephalic infants. Regular developmental follow-up of such infants should continue during early childhood to facilitate identification and treatment of emerging concerns such as language delays and learning disabilities.
Supplementary Material
Acknowledgements
We acknowledge the support of Stephani F. Rodrigues, Nádia L. M. Siqueira, Danusa Menegat, Thamires M. N. Felice, Mariana B. D. Costa Silva who were in charge of the neurodevelopmental screening testing, and the staff members of the Study Center on Maternal, Perinatal, and Infant Infection from Ribeirão Preto Medical School (NEIMPI).
Funding
This study was supported by Fundação de Apoio ao Ensino Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FAEPA), Brazil, and received partial support from the CVE - Centro de Vigilância Epidemiológica “Prof. Alexandre Vranjac” da Secretaria da Saúde do Estado de São Paulo. This work was also supported in part by Eunice Kennedy Shriver National Institute of Child Health and Human Development (EKS NICHD) grant P50HD103537 (Vanderbilt Kennedy Center). The opinions expressed herein are those of the authors and do not necessarily represent the official position of the funding agencies.
Footnotes
Declaration of competing interest
The authors declare that they have no conflict of interest.
NATZIG (NATural history of Zika Virus Infection in Gestation) Cohort Study membersObstetrics: Geraldo Duarte, Conrado Milani Coutinho, Patrícia Pereira dos Santos Melli, Marília Carolina Razera Moro, Ligia Conceição Marçal Assef, Greici Schroeder, Silvana Maria Quintana. Pediatrics: Marisa Márcia Mussi-Pinhata, Adriana Aparecida Tiraboschi Bárbaro, Juliana Dias Crivelenti Pereira Fernandes, Márcia Soares Freitas da Motta, Fabiana Rezende Amaral, Paulo Henrique Manso, Bento Vidal de Moura Negrini, Daniela Anderson, Juannicelle Tenório Albuquerque Madruga Godoi, Marina de Mattos Louren. Pathology: Fernando da Silva Ramalho. Neuropediatrics: Ana Paula Andrade Hamad, Carla Andréa Cardoso Tanuri Caldas, Marili André Coelho, Rafaela Pichini de Oliveira. Neurodevelopment: Silvia Fabiana Biason de Moura Negrini, Stephani Ferreira Rodrigues, Nádia Lombardi Maximino Siqueira, Danusa Menegat, Thamires Máximo Neves Felice. Ophthalmology: João Marcello Fortes Furtado, Milena Simões Freitas e Silva, Rafael Estevão De Angelis. Audiology: Adriana Ribeiro Tavares Anastasio, Evelin Fernanda Teixeira, Cristiane Silveira Guidi, Priscila Morales Andreazzi. Neuroimaging: Sara Reis Teixeira, Jorge Elias Junior, Antônio Carlos dos Santos. Social Service: Adriana Veneziani Morales Morimoto, Joseane Cristina Bonfim Augusto. Research Nurses: Maria Natalina Ferreira da Silva, Eunice Gonçalves da Silva, Maria Beatriz Cruz de Souza. Laboratory support: Aparecida Yulie Yamamoto, Cleonice de Souza Barbosa Sandoval, Mirian Borges de Oliveira, Alessandra Santos Zampolo.
Supplementary data to this article can be found online at https://doi.org/10.1016/j.earlhumdev.2021.105470.
Data accessibility statement
De-identified data can be made available to qualified scientists upon reasonable request and in accordance with the Brazilian National Ethics Committee (CONEP) and University of São Paulo rules.
References
- [1].Venancio FA, Bernal ME, Ramos MD, Chaves NR, Hendges MV, Souza MM, Medeiros MJ, Pinto CD, Falcão de Oliveira E, Congenital Zika syndrome in a Brazil-Paraguay-Bolivia border region: clinical features of cases diagnosed between 2015 and 2018, PLoS One 14 (10) (2019. October 4), e0223408. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].de Araújo TVB, de Alencar Ximenes RA, de Barros Miranda-Filho D, Souza WV, Montarroyos UR, et al. Association between microcephaly, Zika virus infection, and other risk factors in Brazil: final report of a case-control study. Lancet Infect. Dis 2018; 18:328–336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika virus and birth defects – reviewing the evidence for causality. N. Engl. J. Med 2016; 374:1981–1987. [DOI] [PubMed] [Google Scholar]
- [4].Barton MA, Salvadori MI, Zika virus and microcephaly, CMAJ 188 (2016) E118–E119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [5].Moore CA, Staples JE, Dobyns WB, Pessoa A, Ventura CV, et al. Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr. 2017; 171:288–295. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [6].Van der Linden V, Pessoa A, Dobyns W, Barkovich AJ, van der Linden H Jr, et al. Description of 13 infants born during October 2015–January 2016 with congenital Zika virus infection without microcephaly at birth—Brazil. Morb. Mortal. Wkly Rep, 2016; 65:1343–1348. [DOI] [PubMed] [Google Scholar]
- [7].Vianna RAO, Lovero KL, Oliveira SA, Fernandes AR, Santos TCS, et al. Children born to mothers with rash during Zika virus epidemic in Brazil: first 18 months of life. J. Trop. Pediatr 2019; 65(6):592–602. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [8].Mulkey SB, Arroyave-Wessel M, Peyton C, Bulas DI, Fourzali Y, et al. Neurodevelopmental abnormalities in children with in utero Zika virus exposure without congenital Zika syndrome. JAMA Pediatr. 2020; 174:269–276. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Faiçal AV, de Oliveira JC, Oliveira JVV, de Almeida BL, Agra IA, et al. Neurodevelopmental delay in normocephalic children with in utero exposure to Zika virus. BMJ Paediatrics Open 2019; 3:e000486, 1–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [10].Gerzson LR, de Almeida CS, da Silva JH, Feitosa MMA, de Oliveira LN, Schuler-Faccini L. Neurodevelopment of nonmicrocephalic children, after 18 months of life, exposed prenatally to Zika virus. J. Child Neurol 2019; 35:278–282. [DOI] [PubMed] [Google Scholar]
- [11].Coutinho CM, Negrini S, Araujo D, Teixeira SR, Amaral FR, et al. Early maternal Zika infection predicts severe neonatal neurological damage: results from the prospective Natural history of Zika virus infection in gestation cohort study. Br. J. Obstet. Gynaecol 2020. September 13. [DOI] [PubMed] [Google Scholar]
- [12].Lanciotti RS, Kosoy OL, Laven JJ, Velez JO, Lambert AJ, et al. Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerging Infectious Diseases. 2008;14(8):1232–1239. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Bayley N Bayley Scales of Infant and Toddler Development. 3th ed. Screening test manual. Oxford: PsychCorp; 2006. [Google Scholar]
- [14].Westerhausen R, Friesen C-M, Rohani DA, Krogsrud SK, Tamnes CK, et al. The corpus callosum as anatomical marker of intelligence? A critical examination in a large-scale developmental study. Brain Struct. Funct. 2017; 223 (1):285–296. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Maitre NL, Slaughter JC, & Aschner JL Early prediction of cerebral palsy after neonatal intensive care using motor development trajectories in infancy. Early Hum. Dev 2013; 89(10):781–786. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Data Availability Statement
De-identified data can be made available to qualified scientists upon reasonable request and in accordance with the Brazilian National Ethics Committee (CONEP) and University of São Paulo rules.