Prior studies have highlighted both the urgent need for further investigation of neurodevelopmental outcomes in children with prenatal ZIKV exposure and the challenge of identifying instruments appropriate for evaluating children across the spectrum of CZS, especially those with severe microcephaly.17-19
In this investigation, we applied the SWYC screening test to assess the neurodevelopment and behavior of prenatally ZIKV-exposed children with and without microcephaly who were born during the ZIKV microcephaly epidemic (2015-2017) in Pernambuco in the Northeast of Brazil.20
According to the SWYC screening, virtually all participants with severe microcephaly (Group 1) and approximately two-thirds of participants with moderate microcephaly (Group 2) were considered “at risk of development delay.” In comparison, 21.7% of ZIKV-exposed normocephalic children (Group 3) and 13.8% of control group children (Group 4) were identified by SWYC assessment as being “at risk.”
The high frequency of “risk of development delay” observed in children with microcephaly is likely attributable to the severity of the cerebral damage. Cerebral malformations generally indicate a poor prognosis in terms of neurodevelopmental function.21 In a child with microcephaly caused by etiologies other than ZIKV, the risk of intellectual disability has been estimated to be 10.5% for HC between -2 and -3 SD, 51.2% for HC between -3 and -4 SD, and 100% for HC below -4SD. 22
In this cohort of children with ZIKV-related microcephaly, the majority of cases in Group 1 had marked chronic encephalopathy and extensive intraparenchymal cortical calcifications, among other neuroimaging abnormalities. Furthermore, the frequency of central nervous system malformations, pyramidal syndrome, epilepsy, inadequate response to visual and auditory stimuli were higher in Group 1 than in the other groups evaluated. These neuroimaging and clinical findings are predictors of severe neuropsychomotor impairment and are among the phenotypic characteristics of CZS.1, 2, 23-25
Consistent with our findings, a 2019 Brazilian investigation assessing children with cerebral palsy and probable CZS, of whom 97.5% had microcephaly, using the Bayley Scale of Infant and Toddler Development III (Bayley-III) reported scores below 70 (i.e., suggesting severe developmental delays) for almost all participants across all three scales: cognitive, 95.1%; language, 97.6%; motor, 97.6%.23
A case series study assessing 24 children with ZIKV-related microcephaly in Northeast Brazil using the Denver Developmental Screening Test II also found a high degree of impairment for neuropsychomotor development. The study reported that children with a mean age of 19.9 months scored, on average, development milestones equivalent of ages 2.1 to 3.4 months, across the domains of language, motor, and personal/social skills.26
Microcephaly, of any severity, is considered a useful indicator for developmental delays. However, in our study we compared neurodevelopment in children with severe and moderate microcephaly and observed, that among children with moderate microcephaly, 35% "Appear to Meet Age Expectations" using the SWYC assessment. Therefore, this strategy of classifying the microcephaly into moderate or severe allowed us to observe that the predictive value of SWYC varies according to the severity of microcephaly.
Although the frequency of cases with moderate microcephaly in our sample “at risk of developmental delay” was lower than the frequency in cases with severe microcephaly, the percentage of “at risk” children was higher than that found in the normocephalic groups, which included the ZIKV-exposed and control children. Indeed, both normocephalic groups had similar frequencies of “at risk” children to each other and to the percentage of “at risk” children expected to be found with screening tests in the general population.27
Prior to this study, few studies with comparable methods have investigated the development of children without microcephaly who were exposed to ZIKV prenatally. In a cohort in the Southeast Brazil that was assessed using Bayley-III, 28% of ZIKV-exposed children presented with at least one below average score (i.e., scores <85-70) for cognitive, language, and motor function.28 In using a screening test instead of a more comprehensive developmental assessment, such as Bayley-III, we would expect an even higher percentage of children identified as being at risk of developmental delay; however, our results from the SWYC screening suggest a lower frequency of children at risk of developmental delay in this cohort than compared to the Rio de Janeiro sample. Nevertheless, we note that a normal SWYC test cannot exclude subsequent later-onset neurodevelopment repercussions. Therefore, we recommend that children with prenatal ZIKV exposure should undergo a longitudinal evaluation, using additional and more accurate and comprehensive tests, such as the Bayley-III.29
The adapted SWYC form made it possible to observe that children with severe microcephaly were severely limited in their ability to achieve developmental milestones that were appropriate for their chronological age. Even though over 74% of the children assessed were >24 months of age, over 80% were unable to perform tasks corresponding to the expected skill acquisition for 5-8 month of age, such as item 14 of the adapted form ("passes a toy from one hand to another"). When children were divided into two groups (14-24 months vs. 25-32 months), we observed no differences in the achievement of developmental milestones, with the exception of the item indicating “Laughs”. When comparing the performance of the older and younger groups, these findings suggest a significant limitation in the ability of the children with severe microcephaly to achieve new milestones as they get older, which may be explained by the severity of their neurological impairment.
The adapted form not only enabled the detection of this delay, but also allowed us to describe of the deficit profile, which has the potential to inform earlier and more targeted multidisciplinary intervention to address the identified needs. Although the SWYC tool was not specifically designed for this purpose, this study demonstrates an additional application of the SWYC, which addresses the current lack of specific instruments for evaluating development in children with severe neurological impairment. Further follow-up studies and repeated measures will be valuable for confirming the observation that children with severe ZIKV-related microcephaly achieve developmental milestones corresponding to lower chronological ages than their own.
Using the SWYC checklists, the risk for behavioral and emotional symptoms was observed to be similar among the groups. It is plausible that the SWYC questions related to behavior and emotional symptoms may have generated inconsistent responses for children with severe microcephaly, due to the children’s serious motor and intellectual limitations. Questions such as "Is your child interested in playing with other children", "Does your child break things on purpose", or "Is your child fidgety or unable to sit still" are likely out of context for most children with severe microcephaly. Therefore, we suggest that these results do not mean that Group 1 has lower risk for behavioral problems, but rather that children with severe microcephaly do not possess the cognitive, emotional and motor skills required to demonstrate the “at risk” behaviors. Therefore, this result should be interpreted with caution.
Initial descriptions of CZS mentioned irritability as a frequent clinical finding.30 Although this characteristic was often reported and observed in newborns and young infants with a phenotype typical for CZS, irritability became less evident as the children grew (personal observation of the authors). In this investigation, irritability was not a predominant complaint in Group 1, which may be related to the fact that most of these children were assessed after the second year of life, at which time irritability may have been less likely to be presented. It is not possible to determine whether the condition was resolved or if this behavior was modified by the frequent use of anticonvulsants in this population.31
Also unexpectedly, children without microcephaly (Groups 3 and 4) demonstrated high frequencies of risk signs of behavioral and emotional symptoms (42.5% and 63.7%, respectively). Studies worldwide have shown a progressive increase of in the prevalence of behavioral abnormalities in childhood.32-34 In our study, it is possible that the low level of parents’ educational attainment may have limited the infants’ development of social and emotional skills, thereby generating a high frequency of “at risk” behavior.