Preliminary studies highlight both the urgent requirement for further investigation of neurodevelopmental outcomes in children with different level of prenatally ZIKV exposure, as well as the challenge to identify appropriate instruments to evaluate children across the spectrum of CZS, especially for those with severe microcephaly.17–19
We applied the SWYC screening test to assess neurodevelopment and behavior of prenatal ZIKV exposed children with and without microcephaly, born around the ZIKV microcephaly outbreak (2015–2017) in Recife, Northeast of Brazil.20
Almost all participants with severe microcephaly (Group 1) were considered “at risk of development delay”, according to SWYC, followed by 65% for moderate microcephaly (Group 2). In comparison, ZIKV-exposed normocephalic children (Group 3) and control group (Group 4) lower deceased risk, varying from 13,8%-21,7%.
The high frequency of “risk of development delay” observed in children with microcephaly could be attributed to the severity of the cerebral damage. Cerebral malformations generally imply a poor prognosis in terms of neurodevelopmental functions.21 The risk of intellectual disability in a child with microcephaly caused by other etiologies is approximately 10.5% when HC is between the 2nd and 3rd percentile; increasing to 51,2% for HC between − 3 and − 4 SD, and 100% for HC bellow − 4SD.22
In fact, the majority of cases in Group 1 had marked chronic encephalopathy and extensive intraparenchymal cortical calcifications, among other neuroimaging abnormalities. For Group 1 the frequency of central nervous system malformations, pyramidal syndrome, epilepsy, inadequate response to visual and auditory stimuli were higher than other groups evaluated. These clinical and neuroimaging 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 applying Bayley Scale of Infant and Toddler Development III (Bayley-III) to children with cerebral palsy and probable CZS, of whom 97.5% had microcephaly, reported scores below 70, suggesting severe developmental delays for almost all participants across all three scales (i.e., cognitive, 95.1%; language, 97.6%; motor, 97.6%).23
A case series study with 24 children with ZIKV-related microcephaly in northeastern Brazil applying Denver Developmental Screening Test II also found high degree of impairment for neuropsychomotor development. It 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
In our sample, although the moderate cases with microcephaly scored lower than the severe ones, the scores were higher than the normocephalic children, including ZIKV-exposed and control group. Both normocephalic groups had similar findings in the SWYC, and less than 22% of them showed risk of development delay corresponding to an expected percentage for the general population with screening tests.27
Until now, there are not enough studies with comparable methodology to answer the development issue of ZIKV prenatal exposed children without microcephaly. A cohort assembled in the Southeast Brazil using Bayley-III, found that 28% of exposed children presented at least one score of cognitive, language, and motor functions between − 1 and − 2 SD (scores < 85 − 70), below average.28 Using a screening test, we would expect an even higher percentage of children at risk of developmental delay when compared to more comprehensive scales of developmental assessment, such as Bayley-III, but our results suggest a lower frequency of risk of developmental delay in these children compared to the Rio de Janeiro sample. However, a normal SWYC test cannot exclude late neurodevelopment repercussions, and a longitudinal and more accurate evaluation, using other tests, such as the Bayley-III, is recommended.29
The SWYC Adapted Form made it possible to observe that children with severe microcephaly only performed developmental milestones corresponding to much lower chronological ages than theirs. Even though, over 74% of them belonged to the age group > 24 months at assessment, over 80% were unable to perform tasks corresponding to the expected 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), there were no differences related to developmental milestones (except the item “Laughs”). When comparing the performance of older and younger, the findings suggest a significant limitation in gaining abilities as they get older, which may be explained by the severity of their neurological impairment.
The Adapted Form not only enabled the detection of the delay, but also the description of the deficit profile, allowing earlier and more targeted multidisciplinary intervention. Although it was not specifically designed for this purpose, it is an additional application of the SWYC, since there is no specific instrument for evaluating development in this population. Further follow-up studies or repeated measures should be necessary to confirm this result.
The risk for behavioral and emotional symptoms was similar among the groups. However, the SWYC questions related to behavior and emotional symptoms probably have generated inconsistent responses for severe microcephaly, due to the 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", seem out of context. It does not mean that Group 1 has lower risk for behavior problems, but such children did not possess cognitive, emotional and motor skills that allow the demonstration of a risk behavior. Therefore, this result should be interpreted with caution.
Initial description of CZS mention irritability as a frequent clinical finding.30 This characteristic was often reported and observed in newborns and young infants with a typical phenotype of CZS, although this became less evident as the children grew (personal observation). For Group 1, irritability was not a predominant complaint, which may be related to the fact that most of these children were assessed above the second year of life, when that symptom was no longer present. 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
On the other side, children without microcephaly (Groups 3 and 4) demonstrated a high frequency of risk signs on behavioral and emotional symptoms (42,5% and 63.7%). Studies worldwide have shown a progressive increase of behavioral changes in childhood.32–34 In our study, it is possible to assume that the low quality of parents’ educational practices limits the infant development of social and emotional skills, thereby generating “at risk” behavior. Another hypothesis is that caregivers’ factors such as poor schooling and low socioeconomic level may have influenced the comprehension of the test, leading to a possible overestimation on behavioral and emotional disturbances.