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Conteúdo (article):

DEVELOPMENT OF CHILDREN BORN DURING THE ZIKA VIRUS EPIDEMIC IN BRAZIL: A GENERATION AT RISK?

Britto JAA, Lopes MCB, Guida L, Freitas M R, Barros L, Junior Saint Clair, Moreira MEL

ABSTRACT

In Brazil, during the Zika virus epidemic, studies primarily focused on the developmental outcomes of children with intrauterine exposure to the virus, despite recommendations to monitor all children born during this period. However, children not exposed in utero may also face developmental challenges influenced by environmental, social, and individual stressors, as well as maternal mental health during such epidemics. This study aimed to assess the prevalence of delays in cognitive, motor, and language development, identify factors influencing developmental scores, and discuss potential epidemic impacts. This cross-sectional study evaluated 78 children aged 11 to 39 months who were not exposed to the Zika virus in utero using the Bayley III method. Overall, 27% of the children exhibited delays in at least one developmental domain, with language being the most affected (24.4%). There were no significant relationships found between delays and sociodemographic factors. Given the observed high prevalence of developmental delays and the limited research on the developmental outcomes of children born without intrauterine Zika exposure during this period, questions remain about potential long-term developmental risks for this generation. Therefore, continuous developmental monitoring until school age is recommended.

Keywords: Zika; Child development; Epidemic; Delay.

Introduction
From 2015-2016, Brazil experienced a major epidemic caused by the Zika virus (ZIKV). Initially considered a benign exanthematous disease, it did not attract much attention from the health sector. However, as the epidemic expanded, aggressive neurotropism of this virus became evident, which is unusual compared to other endemic flaviviruses in Brazil, such as dengue and chikungunya viruses 1.
The association of ZIKV with an increase in microcephaly cases in the country was surprising, as was the occurrence of severe changes in child development, the most common of which was congenital ZIKV infection (CZS) 2.
The ZIKV epidemic period has been marked by challenges and alarming revelations, which have transformed the medical and scientific community’s understanding of the impacts of this emerging virus in the country. The correlation between ZIKV and adverse outcomes in child development highlighted the importance of a holistic approach to address epidemics of emerging diseases, considering not only biological and epidemiological aspects.
In 2016, the World Health Organization (WHO) declared a state of International Health Emergency 3 in response to the ZIKV epidemic. This statement not only emphasized the immediate dangers but also acknowledged the uncertainties that could impact future opportunities, particularly concerning the development of children born during the epidemic 4.
At the beginning of the epidemic, the focus of research was on symptomatic pregnant women whose children were born with microcephaly, and in this context, it was imperative to describe the natural history of this new disease and propose actions to combat it, including women’s reproductive health and the follow-up of children from pregnancy to early childhood 5. However, to the extent that we conducted our review, we found no studies that addressed the impact of this epidemic on the mother–child relationship and child development, particularly for pregnant women who were not tested for ZIKV because they did not present clinical signs of infection, although it is known that up to 80% of people may have had an asymptomatic form of the disease 6. However, these women expressed concern about their children due to the risk of microcephaly and about the development of those who were born apparently normal.
It is important to recognize that in large epidemics of emerging diseases, such as ZIKV and, more recently, COVID-19, additional conditions of environmental, social and individual stress may arise that have the potential to affect child development 7; therefore, these conditions need to be monitored and studied.
During the epidemic, the media reported the risk of becoming pregnant, emphasizing the concern about microcephaly, the impact on the development of children, the lack of an effective and safe vaccine in the short term, and the fragility of health systems to address the increase in cases. This led to situations of social stress that, among other effects, influenced the decision of women to become pregnant, resulting in a reduction in the birth rate in the country in 2016 compared to 2015 8.
Regarding children, the Zika Sciences Social Network - Fiocruz, linked to the Ministry of Health, recommended that careful monitoring of the development of the entire generation of children born during this epidemic be performed, even if there was no history of maternal infection, since these children could face developmental risks 9. These recommendations highlighted the importance of a comprehensive approach that considers not only the clinical aspects but also the psychosocial, cultural and political impacts that jointly influence maternal health and child development.
Regarding the development of children, the protocol of the Child Health Handbook 10 recommends routine developmental screening during the first three years of life, and those with signs of risk should undergo a complete developmental assessment. However, over time, this document has not been properly used. Health professionals often perform informal clinical evaluations, which are able to identify less than 30% of developmental delays in children 11, and there is no evidence that there have been changes in behavior during the epidemic period.
In this context, the objective of this study was to evaluate the prevalence of delays in the main domains of child development—cognitive, language and motor—in children born without intrauterine exposure to ZIKV during the epidemic. In addition, we aimed to identify factors associated with variations in developmental scores and discuss the possible impacts of the epidemic on child development.

Methods
This cross-sectional study was conducted at a public institute in Rio de Janeiro that specializes in the care of pregnant patients at high risk. The use of this institute for the monitoring of children broadens the scope of the study because it provides data from one of the Brazilian states most affected by the ZIKV epidemic.
The study involved children born between 2015 and 2017 without intrauterine exposure to ZIKV, thus comprising a control group within a cohort of children born with exposure to the virus. A total of 187 children aged between 11 and 39 months were selected for the study.
The inclusion criteria were a minimum gestational age of 37 weeks, a 5-minute Apgar score greater than or equal to 7, a minimum birth weight of 2.500 g and a head Z score between -1.9 and +2. All mothers and children were tested for ZIKV infection using anti-ZIKV ELISA IgM and IgG assays (Euroimmun, Lübeck, Germany), specifically targeting the NS1 ZIKV antigen, including those with negative results. These laboratory criteria were established to ensure that there was a sample of children without intrauterine exposure to ZIKV.
The exclusion criteria were children who had microcephaly, a gestational history of disease in the TORCH group, congenital malformations, genetic syndromes, perinatal infectious or respiratory complications and any postnatal comorbidities that could negatively influence their development and those who were unable to complete the development evaluation test.
All children were assessed between March 2018 and March 2020 using the Infant and Preschooler Development Scale, third version (Bayley-III) 12. This scale was chosen because it is considered the gold standard among child assessment instruments and because it has been validated in Brazil 13. The assessments were performed in three main domains of development: cognitive, language and motor. They were conducted by a psychologist certified for the application of the test and had an average duration of 40 minutes.
With respect to domains evaluated, the values of the composite score (SE), with a standard deviation (SD) ranging from 40 to 160 points, a mean of 100 and a standard deviation (SD) ± 15 points, were adopted. An EC between 85 and 160 (-1 to >2 SD), in the assessed domain, classifies development as appropriate for age. A score of 84 to 70 (-1 to -2 SD) is below the mean and is the cutoff point for mild to moderate delay, and scores below 70 (< -2 SD) are much lower than the mean, indicating severe developmental delay.
For the evaluation of development, the children were divided into two groups: those aged 11 to 24 months and those aged older than 24 months.
The anthropometric evaluation of the children was performed using 4 developmental indicators: weight for age, height for age, weight for height and head circumference for age. The Z scores were calculated using the Intergrowth 21 14 and WHO 15 values as references.
The sociodemographic variables considered relevant to the evaluation of outcomes related to the development of children included maternal age, education level, family income in minimum wage per month, sex of the child and age at evaluation. During the data collection process, information on these variables was obtained from the consultations performed or through a search of the medical records.
To ensure the ethics of the study, the mothers or guardians of the participating children were asked to sign an informed consent form that explained the objectives of the study, the procedures involved and the rights of the participants. In addition, at the end of the test, they received the evaluation results with guidance and referrals for complementary evaluations when necessary.
This study was approved by the Research Ethics Committee of the institution under registration number CAAE 5267566116000005269.

Statistical analysis
The data were stored in Excel, and later analyses were performed with SPSS software, version 3.6.1, for statistical analysis. Frequencies and percentages were used to characterize categorical data, while numerical data were described as the means and standard deviations or medians and interquartile ranges (IQRs). To verify the association between the presence of developmental changes and sociodemographic characteristics, Pearson\'s chi-squared test and Fisher\'s exact test were used (in cases in which at least one expected frequency of less than five was observed) for categorical variables. The Mann‒Whitney test was used for numerical variables. To compare the Bayley III Composite Score (CE) across different characteristics, the Mann‒Whitney and Kruskal‒Wallis tests and the Dunnet test were used for multiple comparisons between groups. The significance level adopted in the statistical analyses was 5%.

Results
Of the 187 children selected, 78 were included in the study. Of the 109 excluded patients, 10 had a gestational age of less than 37 weeks, two weighed less than 2500 g, six had postnatal comorbidities, 11 did not complete the test evaluation, 3 had incomplete data, and 77 mothers and/or children tested positive for ZIKV (Figure 1).
The sociodemographic data of the 78 mothers and their children are detailed in Table 1 and indicate that most mothers were young (median 29 years, IQR: [25-36 years]) and had between 10 and 12 years of schooling (69.2 %). Regarding family income based on minimum wages/month, the distribution was balanced, with 48.7% receiving less than 2 minimum wages/month. The distribution of children by sex was also balanced, with 48.7% being female. Most children (87.2%) were between 11 and 24 months of age.
None of the children presented stunted growth, low weight, a change in the length-for-age ratio, or a low weight-for-length, and the head circumference Z-score was normal in all children.
In Table 2, the developmental results showed that the development of the children 57 (73%) was adequate for their ages. On the other hand, 21 children (27%) had delayed Bayley III on assessment, with scores between -1 SD and less than -2 SD in at least one of the three functional domains assessed. Language development was the most affected domain, with 24.4% of the children achieving Bayley III scores below -1 SD in this domain. The motor domain affected 10.3% of the children, and the cognitive domain affected 6.4%.
In the distribution of scores in the language domain, we observed negative asymmetry, with a curve extending further to the left. This suggests the presence of lower scores in this domain, as shown in Figure 2.
The mean composite score in the language domain was 87.9 points (median 89), that in the cognitive domain was 97.3 points (median 97.5), and that in the motor domain was 93.7 points (median 94).
Concerning the analysis of sociodemographic variables as predictors of developmental delays, no significant relationship was found. This may be due in part to the size of the population; however, we observed a higher frequency of language delays among the boys (Table 3).
Discussion
During the ZIKV epidemic in Brazil, because this disease has never been described before, researchers have focused their studies on proving the causal relationship between the virus and microcephaly, as well as on the developmental impairment of children born with these conditions and of those who experienced intrauterine exposure during pregnancy and were still born apparently normal.
During an epidemic, the attention of the media and public health agencies tends to focus mainly on biological and epidemiological issues, often leaving aside issues involving the relationship between the mental health of mothers and the development of children affected by serious emerging infectious diseases, as in the case of the ZIKV epidemic in Brazil.
The difficulty faced by public health authorities in effectively controlling the Aedes aegypti mosquito, the ZIKV vector, and the tendency to blame the population for the lack of control of the proliferation of this mosquito generated an environment of environmental and social stress. This situation contributed to increased psychosocial tensions in the community, which was already concerned about the spread of the disease.
In addition, the fear of becoming pregnant during the epidemic due to the potential risk of children being born with microcephaly and the uncertainty about the presence of asymptomatic ZIKV infection, associated with the lack of access to prenatal testing that could clarify these risks, may have resulted in significant stress in terms of the mothers\' mental health. Although these factors have not been studied during the ZIKV epidemic, they may impair the emotional balance necessary for mothers to play a healthy role in the development of their children.
Understanding these issues is crucial for a comprehensive and effective response to emerging disease epidemics. Considering not only the biological aspects but also the psychosocial dimensions is essential for providing holistic support to affected families, minimizing the negative impact on mothers and children during and after the epidemic.
Regarding the evaluation of the development of Brazilian children, studies usually adopt a cross-sectional approach, being conducted in various settings, including schools, day care centers, health institutions and primary health care clinics. The results of these studies show notable variability, with a significant range of values that can vary from 9% to 53% of globally 16,17,18. In contrast, countries in North America, Europe and Asia that conducted population-based studies reported considerably lower prevalence rates, ranging from 5% to 15% 19.20,21.
The prevalence of the most common delay among healthy children is in the language domain and tends to be more pronounced in countries with less favorable socioeconomic conditions. In the literature, there are few studies in which language in infants and preschoolers was assessed in the first thousand days of life. It is known that this is a period of high brain neuroplasticity where early interventions can have an impact on development that will be reflected throughout the child\'s future life. The inclusion of this population strengthens our study. In Brazil, similar to global developmental delays, there is notable variation in the prevalence of language delays in infants and preschoolers. Studies have reported results that vary between 2.3% and 77% 22,23.
In our study, the prevalence of language delay was 24.4%, which is considerably high and quite different from that reported in studies conducted by Asian researchers who, through longitudinal studies using the Bayley III scale, reported a prevalence of language delay between 9% and 17% in healthy Asian children aged approximately two years, an age group similar to that of the children in our study 24.
Brazilian studies that applied the Bayley III scale to infants and preschoolers, including control groups, to compare children with and without intrauterine exposure to ZIKV revealed a significant prevalence of language delay in healthy children in the control groups, ranging from 12.8% to 25% 25,26. This rate is similar to that observed in the children in our study who were not exposed to ZIKV during pregnancy. This suggests that language delays could occur in all healthy children born during the epidemic, regardless of intrauterine exposure to the virus.
In our study, we did not find a statistically significant relationship between language delays and the demographic and biological variables that are often considered in child development assessment studies. However, we observed a higher number of boys with language delay, and this finding was consistent with the number of boys with language delay who had intrauterine exposure to ZIKV but were born asymptomatic27.
One of the limitations of our study is that it is a cross-sectional study that evaluates the child at a specific point and cannot capture variations in child development over time since development is a dynamic and individual process subject to changes and progressions specific to each child.
Another constraint observed was the impossibility of assessing maternal mental health in this dramatic and acute context, resulting in a gap in understanding the impact of mothers’ mental health on the mother–child relationship and its implications for child development.
The absence of a differential laboratory diagnosis between Zika and dengue was a limiting factor, resulting in the exclusion of 41% of the children due to the detection of positive IgG serology for ZIKV. It is known that there is a cross reaction between these two viruses 28. In addition, at that time, the country was facing a triple epidemic of Zika, dengue and chikungunya 29.
In our literature review, we did not find articles addressing the development of healthy children during the epidemic. As there are no updated population-based studies on the prevalence of language delay in Brazil, our results do not allow comparison with the pre epidemic period but indicate a very high frequency of this delay among children born during the epidemic. We also did not find studies addressing the role of environmental, social and individual stressors, which could provide a valuable context for the interpretation of our results and allow a more complete understanding of the factors that shape child development in epidemic scenarios.
In our study, the children were considered healthy at evaluation, as the pre-, peri- and postnatal biological risk was controlled. However, the study included pregnant adolescent girls, pregnant women of advanced age, and women with twin pregnancies, which are high-risk conditions. Maternal risk conditions can impact postnatal development in the long term 30,31. These factors must be considered when interpreting the results.
The absence of systematic screening for ZIKV in the prenatal period during the epidemic is still a major concern today. Many women may have developed the asymptomatic form of the disease and exposed their fetus to the virus without suspicion or recognition of the infection. As a direct result of this lack of detection, these children did not receive the differentiated follow-up that would have been recommended in case of confirmed infection, and this group may comprise a population of children with developmental disorders in which intrauterine exposure to ZIKV is not included in the diagnostic hypothesis.
It is essential that children who may have been born and raised during the epidemic receive specific support in cases of developmental delays. This involves a multidisciplinary approach that may include therapeutic interventions, rehabilitation programs, specialized medical follow-up and psychosocial support for families. Thus, the importance of monitoring development, as recommended during the epidemic 9 and up to school age, is highlighted, as guided by studies that follow the development of children exposed to ZIKV.
Early detection and intervention are critical about delays in child development. The earlier these delays are identified and treated, the greater the chances that the child will be able to overcome challenges and achieve healthy development. Therefore, effective systems for the triage and evaluation of child development in areas affected by epidemics is essential.
In addition, it is important for health professionals to be well informed about the possible impacts of ZIKV and other conditions related to maternal and child health. This would allow for a proactive approach to identifying and supporting children who might be at risk. Investment in public health services and the training of health professionals play a large role in ensuring that affected children receive the support they need to reach their full developmental potential.
Conclusion
In our study of children born during the epidemic without intrauterine exposure to ZIKV, we found a high percentage of children with language delays. This raises concerns about the impact of this virus on child development and perpetuates uncertainties regarding its effect on the development of this generation of children.
Future studies should adopt a comprehensive approach, considering epidemiological, biological, environmental, social and psychological factors. A review of screening and diagnostic strategies during pregnancy is essential to fully understand the impacts of ZIKV on child development in the event of new epidemics.
Understanding and studying the influence of health conditions during the intrauterine period and environmental conditions as risk factors, especially in the first three years of life, during epidemics is essential for monitoring child development.
Considering that, during the Zika epidemic in Brazil, no specific attention was devoted to child development, it is plausible that these children constitute a population at risk of delays. This raises the question of whether this generation comprises children under threat, thus deserving a rescue in the monitoring of their development.

References
1. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde Vírus Zika no Brasil: a resposta do SUS [recurso eletrônico] / Ministério da Saúde, Secretaria de Vigilância em Saúde. – Brasília : Ministério da Saúde, 2017. 136 p. Acesso em 06 junho 2019.
2. Brasil P, Pereira JP Jr, Moreira ME, Ribeiro Nogueira RM, Damasceno L, Wakimoto M, et al. Zika Virus Infection in Pregnant Women in Rio de Janeiro. N Engl J Med. 2016 Dec 15;375(24):2321-2334. doi: 10.1056/NEJMoa1602412.
3. OMS – Organização Mundial de Saúde - Director WH. General Summarizes the Outcome of the Emergency Committee Regarding Clusters of Microcephaly and Guillain-Barré Syndrome.Disponível em. Acesso em: 23 junho 2022.
4. Weir L, Mykhalovsky E. Global public health vigilance: creating a world on alert. 2010. Doi:10.4324/9780203857724.
5. Garcia LP. Epidemia do vírus Zika e microcefalia no Brasil: emergência, evolução e enfrentamento. Texto para Discussão; 2018.
6. Haby MM, Pinart M, Elias V, Reveiz L. Prevalence of asymptomatic Zika virus infection: a systematic review. World Health Organ. 2018 Jun 1;96(6):402- 413D. doi: 10.2471/BLT.17.201541.
7. Tucci V, Moukaddam N, Meadows J, Shan S, Galwankar SC, Kapur B. The forgotten plague: Psychiatric manifestations of Ebola , Zika, and emerging diseases. J Glob Infec Dis. 2017;9 (4):151-6. doi: 10.4103/jgid.jgid_66_17.
8. Marteleto LJ, Guedes G, Coutinho RZ, Weitzman A. Live births and fertility amid Zika virus epidemic in Brazil. 2020;57(3):843-72. doi: 10.1007/s13524- 020-00871-x.
9. Sociais RZ. Epidemia de Zika no Brasil. Lições aprendidas e recomendações. Rio de Janeiro: Rede Zika Ciências Sociais. 2019.
10. Ministério da Saúde (BR). Manual para a utilização da caderneta de saúde da criança. Brasília: Ministério da Saúde, 2005. Disponível em: http:// bvsms.saude.gov.br/bvs/publicacoes/ manual%200902.pdf.> 16/02/2019
11. Zeppone SC,Volpon LC, Del Ciampo L. Monitoring of child development held in Brazil. Rev Paul Pediatr. 2012;30(4):594-9. doi:10.1590/S0103- 05822012000400019.
12. Bayley N. Bayley Scales of Infants and Toddler Development, 3rd ed; Harcourt Assessment: San Antonio, TX,USA,2006. doi:10.1037/t14978-000
13. Madaschi V, Mecca TP, Macedo EC, Silvestre PC. Bayley-III Scales of Child Development : transcultural adaptation and psychometric properties. Paidéia. 2016;26(64):187-97. doi:10.1590/1982-43272664201606
14. Villar J, Altman DG, Purwar M, Noble JA, Knight HE, Ruyan P, et al. International Fetal and Newborn Growth Consortium for the 21st Century. The objectives, design and implementation of the INTERGROWTH-21st Project. BJOG. 2013 Sep;120 Suppl 2:9-26, v. doi: 10.1111/1471-0528.12047.
15. WHO M. Growth, Reference, Study, Group. WHO Child Growth Standards: Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: Methods and development. Geneva: World Health Organization. 2006;312
16. Torquato JA, Paes JB, Bento MC, Saikai GMP, Souto JN ,Lima EAM , et al. Prevalence of neuropsychomotor development delay in preschool children. J Hum Growth Dev.2011;21(2):259-268.
17. Coelho R, Ferreira JP, Sukiennik R, Halpern. Child development in primary care: a surveillance propose. J Pediatr (Rio J). 2016;92(5):505-11. doi: 10.1016/j.jped.2015.12.006.
18. Silva AC, Engstrong EM, Miranda CT. Factors associated with neurodevelopment in children 6-18 months of age in public daycare centers in João Pessoa, Paraiba state, Brazil. Cad Saude Publ. 2015;31(9):1881-93. doi: 10.1590/0102-311X00104814.
19. Correia LL, Rocha HAL, Sudfeld CR, Rocha SGMO, Leite ÁJM, Campos JS, et al. Prevalence and socioeconomic determinants of development delay among children in Ceará, Brazil: A population-based study. PLoS One. 2019 Nov 5;14(11):e0215343. doi: 10.1371/journal.pone.0215343.
20. Valla L, Wentzel-Larsen T, Hofoss D, Slinning K. Prevalence of suspected developmental delay in early childhood: results from a regional populationbased longitudinal study. BMC Pediatrics. 2015;15(1):215. doi:10.1186/s12887-015-0528-z.
21. King TM, Rosenberg LA, Fuddy L, Macfarlane E, Sia C, Duggan AK. Prevalence and early identification of language delays among at-risk three years old. J Develop Behav Pediat. 2005;26(4):293-303. doi: 10.1097/00004703- 200508000-00006.
22. Silva GM, Couto MI, Molini-Avejona DR. Risk factors identification in children with speech disorders: a pilot study. CODAS.2013; 25(05):456-62. doi: 10.1590/S2317-17822013000500010.
23. Paula S, Rohr EB, Peixoto MC, Sica CA , Kunzlen IM. Analysis of neuropsychomotor development of children participating in a motherbaby program. Rev Bras Prom Saúde 2019;32:1-10. doi: 10.5020/18061230.2019.8603
24. Choi JY, Kim CA, Song IJ, Lee KW, Gang MJ, Jung MJ et al. Clinical review of children diagnosed as especific language impairment. J Korean Child Neurol Soc. 2011;19:8-17.
25. Einspieler C, Utsch F, Brasil P, Panvequio Aizawa CY, Peyton C, Hydee Hasue R, 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;2(1):e187235. Published 2019 Jan 4. doi:10.1001/jamanetworkopen.2018.7235
26. Gerson LR, Almeida CS, Silva JH, Feitosa MMA, Oliveira LN ,Schuler-Faccini. Neurodevelopment of nonmicrocephalic children after 18 months of life exposed prenatally to Zika virus. J Child Neurol. 2019;35(4)278-82. doi: 10.1177/0883073819892128.
27. Nielsen-Saines K, Brasil P, Kerin T, Vasconcelos Z, Gabaglia CR, Damasceno L, et al. Delayed childhood neurodevelopment and neurosensory alterations in the secondyear of life in a prospective cohort of ZIKV-exposed children. Nat Med. 2019 Aug;25(8):1213-7.
28. Ribeiro BG, Werner H, Lopes FPPL, Hygino da Cruz LC Jr, Fazecas TM, Daltro PAN, et al. Central Nervous System Effects of Intrauterine Zika Virus Infection: A Pictorial Review. Radiographics. 2017 Oct;37(6):1840-1850. doi: 10.1148/rg.2017170023.
29. Santos DN, Aquino EM, de Souza Menezes GM, Paim JS, da Silva LM, de SouzaLE, et al. Documento de posição sobre a tríplice epidemia de Zikadengue- chikungunya. observatório de análise política em saúde. 2016.
30. Barker DJ. The developmental origins of chronic adult disease. Acta Paediatr Suppl. 2004 Dec;93(446):26-33. doi: 10.1111/j.1651-2227.2004.tb00236.x.
31. Lins A C L, Pedraza DF. Origem fetal das doenças: uma revisão narrativa das teorias explicativas. Anais Conbracis III, 2018. Campina Grande: Realize Editora, 2018. Disponível em: https://editorarealize.com.br/artigo/visializar/41238 Acesso em 15/12/2023.