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. Author manuscript; available in PMC: 2026 Sep 4.
Published before final editing as: Ear Hear. 2026 Jun 19:10.1097/AUD.0000000000001854. doi: 10.1097/AUD.0000000000001854

Cortical Auditory Neural Responses to Speech and Communicative Functioning in Normocephalic Children with Prenatal Exposure to the Zika Virus

Alexandra P Key 1,2, Craig Mason 3, Sarah L Powell 2, Juliana Cavalcante 4, Ana Frizzo 5, Patricia P Mandra 4, Adriana Tavares 4, Pedro Menezes 6, Linda J Hood 2
PMCID: PMC13539425  NIHMSID: NIHMS2204378  PMID: 42312689

Abstract

Objectives.

Prenatal exposure to the Zika virus may have an adverse effect on communicative functioning in children even in the absence of microcephaly associated with the Congenital Zika Syndrome. This study characterized cortical auditory neural function and communication abilities in normocephalic children with and without prenatal Zika virus exposure.

Design.

Cortical auditory evoked potentials (CAEP) were recorded in response to naturally spoken consonant-vowel syllables in 117 Brazilian children with prenatal exposure to the Zika virus (M age: 6.29±0.42 years) and a comparison group of 90 non-exposed children (M age: 5.54±0.95 years). Language and communication abilities in daily life were evaluated using a battery of standardized behavioral measures and caregiver reports.

Results.

Caregivers of exposed children reported significantly lower than typical adaptive functioning in the communication and socialization domains. CAEP analyses identified earlier speech sound differentiation in the non-exposed controls than the exposed group (P1 vs. N2 response). Exploratory analyses controlling for multiple postnatal factors indicated that greater cortical N2 speech sound differentiation was associated with more adaptive communication abilities.

Conclusions.

Normocephalic children with prenatal exposure to the Zika virus may exhibit subtle differences in auditory processing of speech that are associated with less adaptive communicative functioning in daily life. These results highlight the value of longitudinal follow-up of children with prenatal virus exposures and the utility of auditory evoked potentials in assessing populations at risk for altered neurodevelopment.

Keywords: communication, cortical auditory evoked response, speech, prenatal, Zika virus

Introduction

Prenatal virus exposures are a known risk factor for atypical neurodevelopment in children (Gérardin et al., 2014; Zimmer et al., 2021). Clinical, epidemiologic, and laboratory evidence following the 2015–2016 Zika virus outbreak in Brazil linked maternal infection during pregnancy with nearly a 20-fold increase in the incidence of infants born with microcephaly (de Araújo et al., 2018), referred to as Congenital Zika Virus Syndrome (CZS) and associated with significant developmental delays affecting communication, cognition, visual, and motor functions (Gordon-Lipkin & Peacock, 2019; Marques et al., 2024; Rosa et al., 2020; Wheeler et al., 2020). However, over 90% of the infants with prenatal exposure to the Zika virus appeared asymptomatic at birth (i.e., no microcephaly; Blackmon et al., 2022; Sobral da Silva et al., 2021). This population has received much less research attention compared to the CZS group but is critical for understanding the broader impacts of Zika exposure. Indeed, at least 30–35% of the normocephalic children with prenatal Zika virus exposure exhibited some form of a neurodevelopmental concern by 18 months (Mulkey et al., 2020, Pecanha et al., 2020). The language and communication domain was the most often reported area of vulnerability (Marban-Castro et al., 2022; Antoniou et al., 2021; Hcini et al., 2021), with lower receptive than expressive skills (Andrade et al., 2021, Familiar et al., 2021, Stringer et al., 2021). At the same time, cognitive function remained in the typical range (Faiçal et al., 2019; Gerzson et al., 2019; Nielsen-Sains et al., 2019). A longitudinal analysis of 194 exposed infants between 3 and 24 months of age (Key et al., 2021) noted a significantly slower rate of growth for receptive and expressive language compared to cognitive function. In another sample of 111 exposed children, prevalence of communication difficulties was negligible at 6 months (1.6%) but increased to 45% by 24 months and remained present at 36 months (37%) (Alvarado-Domenech et al., 2022).

More long-term follow-up studies (i.e., past 18 months of age) and those including a non-exposed comparison group resulted in more mixed findings. For example, Mulkey et al. (2020) reported a decline in language scores in normocephalic infants with prenatal Zika exposure over the first 18 months of life but then found no differences from the controls when the children reached 4–5 years of age (Mulkey et al., 2024). When evaluated between 12–36 months of age, a higher proportion of exposed than non-exposed toddlers had Bayley Scales of Infant Development scores fall in the “at risk” or “delay” category for language and cognitive domains, but this group difference was not statistically significant (Alger et al., 2024). A similar lack of differences between exposed and non-exposed children was reported in a large sample of 24-month-olds on a Bayley Screening Test-3 (Godoi et al., 2023). Others observed no exposure-related effects in 3–4-years-olds on NEPSY-2 language scores (Fernandes et al., 2023) or Mullen Early Learning Composite (Max et al., 2024). Other studies reporting no evidence of atypical neurodevelopment in the exposed children relied on as few as 5–13 children per group, limited data from brief caregiver reports of general functioning (Blackmon et al., 2022, da Hora et al., 2021), retrospective medical record review (García-Boyano et al., 2021), or scored objective assessments only categorically (i.e., above/below the typical cut-off) even when clinical reports noted language delays (Sobral et al., 2021). In combination, the findings to date highlight the apparent high heterogeneity in developmental outcomes of the normocephalic children prenatally exposed to the Zika virus and support the need for continued developmental follow-up into school age when the demands on language and communication skills greatly increase (Schuler-Faccini et al., 2022; Mulkey et al., 2024; Marban-Castro et al., 2022).

One area that is highly relevant to language and communicative development but has been understudied in the context of prenatal Zika virus exposure is auditory processing. The ability to effectively detect and differentiate speech sounds is directly associated with the optimal development of receptive and expressive language (Bailey & Snowling, 2002; Tallal et al., 1993) and is important for learning, adaptive communication, and social functioning (Vouloumanos & Curtin, 2014). The current audiological evidence suggests that the incidence of peripheral hearing loss in the exposed children is low (Anastasio et al., 2018; Fandiño-Cárdenas et al., 2018; Prestes et al., 2023) and therefore unlikely to account for the reported communicative difficulties (Almeida et al., 2022). Thus, altered central auditory neural processes could be a promising area of inquiry.

Cortical auditory evoked potentials (CAEPs) offer a noninvasive means to probe auditory processing without the extensive behavioral demands. CAEPs are sensitive to sound encoding and stimulus differentiation (Ponton et al., 2000; Molfese et al., 2002; Yoder et al., 2006). CAEP amplitude variation in response to contrasting speech sounds has been used previously to characterize auditory development and predict communicative outcomes in infants and children with typical development (Choudhury & Benasich, 2011; Guttorm et al., 2001; Molfese, 2000) and in a variety of neurodevelopmental disorders (Key et al., 2016; Maitre et al., 2013, 2014; Sandbank et al., 2017). In school-age children, reduced speech sound differentiation at the cortical level was related to increased incidence of language disorders (Key et al., 2016). Speed of cortical responses to speech (i.e., CAEP latency differences) reflects efficiency of linguistic information processing and contributes to language understanding and use (Gilley et al., 2006; Lahey et al., 2001; Makhdoum et al., 1998; Molfese & Molfese, 1985).

Recently, speech-evoked P1 and N2 CAEP responses were examined in 4–7-year-old children with microcephaly due to CZS compared to age- and sex-matched non-exposed controls; this research identified reduced N2 amplitudes as well as limited evidence of speech sound differentiation, reflected mainly by the N2 response latency (Key et al., 2024). Caregiver reports of more adaptive communication skills in children with CZS were associated with greater speech sound differences in the P1 and N2 amplitudes. Examining speech-evoked CAEPs in normocephalic children with prenatal Zika virus exposure could provide new insights into their language and communicative functioning.

The main objective of the current study was to evaluate language abilities and cortical auditory processing of speech sounds in a relatively understudied group of normocephalic children prenatally exposed to the Zika virus. Based on limited available data, we hypothesized that compared to the non-exposed healthy controls recruited from the same communities, the exposed group may exhibit lower language abilities and communicative functioning, measured by standardized behavioral tests and caregiver reports, as well as altered P1 and N2 characteristics (e.g., latency and/or amplitude). Furthermore, receptive and expressive language skills will be positively associated with the magnitude and efficiency of cortical speech sound processing and differentiation.

With assessments performed at an older age, it is also important to take into consideration the possible postnatal environmental contributors to the observed language and communicative outcomes following prenatal Zika exposure. Emerging findings have suggested socioeconomic factors, maternal characteristics, and stimulating postnatal environment as possible protective factors reducing the negative impact of prenatal virus exposure (Rodrigues-Rabassa et al., 2024; Acosta-Mass et al., 2024). Therefore, we included measures of SES and maternal education as covariates in the analyses and documented participation in early educational and enrichment activities as well as receipt of any speech and language treatments. To account for the theoretical possibility that the effects of prenatal Zika virus exposure may extend beyond language and communication to affect cognitive functioning more broadly, measures of nonverbal abilities were also included in the test battery.

Material and Methods

Participants

The study sample included 117 normocephalic children prenatally exposed to the Zika virus (M age: 6.29±0.42 years, 49 females) and a comparison group of 90 non-exposed children (M age: 5.54±0.95 years, 47 females). Exclusion criteria for both groups included genetic syndromes, head injury, prenatal dengue or chikungunya exposure, and family history of congenital or genetic sensorineural hearing loss or language disorders. All children passed newborn hearing screening. The summary of demographic characteristics for each group is presented in Table 1. The study procedures received approval from the local institutional Ethics Committees, and the parents/guardians provided written informed consent. Children provided verbal assent.

Table 1.

Demographic characteristics of the study participants.

Domain Measure Exposed Controls p-value ω2
M SD Min Max M SD Min Max
Demographics N (m/f) 117 (68/49) 90 (47/43)
Age (years) 6.29 0.42 5.59 7.38 5.54 0.95 4.51 7.68 <.001 0.216
Head circumference (cm) 51.86 2.00 47 59.2 51.87 1.65 48.5 56.3 .973 −0.005
Trimester of exposure First: 22
Second: 55
Third: 40
Race White: 54
Black: 11
Brown: 47
Yellow: 1
Not reported: 4		 White: 51
Black: 5
Brown: 31
Yellow: 1
Not reported: 2		 .467
SES (BECC) Total 25.66 9.09 7 53 28.88 8.60 11 53 .010 0.027
Maternal Education < Elementary 1
Elementary: 16
Middle: 28
High School: 50
College 20
Not reported: 2		 < Elementary 2
Elementary: 3
Middle: 9
High School: 51
College 25
Not reported: 0		 .002
Maternal Education (years) 11.66 3.10 5 18 13.82 3.71 3 23 .001 0.084
Language & Communication Child Language Test (ABFW; Phonology) Mean 92.53 12.84 7.95 100 89.29 14.77 37.5 100 .098 0.009
LAVE (Expressive) Total 290.18 28.62 124 313 287.20 34.71 58 308 .506 −0.003
Picture Naming Test SS 106.46 18.56 46 196 118.65 20.49 84 195 <.001 0.084
PPVT Raw 49.24 17.33 12 95 44.26 16.14 11 93 .038 0.016
VABS-3 Communication SS 80.51 13.70 42 140 89.94 14.61 55 134 <.001 0.095
Receptive V-Score 12.23 3.32 1 20 13.43 2.72 7 21 .007 0.031
Expressive V-Score 13.02 2.86 1 20 14.55 2.64 5 20 <.001 0.066
VABS-3 Socialization SS 89.12 15.66 36 125 99.73 14.52 66 135 <.001 0.104
Interpersonal V-Score 13.46 3.48 1 21 15.06 3.02 8 22 <.001 0.051
VABS-3 Adaptive Behavior Composite 82.36 12.21 52 122 92.98 13.99 64 128 <.001 0.137
Nonverbal Cognition Columbia Mental Maturity Scale SS 104.02 12.78 50 130 106.55 15.29 59 150 .209 0.003
Wechsler Nonverbal Scale of Ability Total 90.37 16.68 44 128 101.38 14.83 64 140 <.001 0.102
Matrix Reasoning T Score 46.45 9.95 10 70 52.78 9.25 26 72 <.001 0.092
Coding T Score 45.49 11.36 18 76 47.53 9.46 31 72 .179 0.004
Set Objects T Score 43.07 9.46 21 69 49.15 10.69 26 85 <.001 0.079
Recognition T Score 47.06 10.74 18 79 53.78 10.17 30 84 <.001 0.088
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SES – Socioeconomic status; BECC – Brazilian Economic Classification Criteria; LAVE – List of Evaluation of the Expressive Vocabulary; PPVT – Peabody Picture Vocabulary Test (Brazilian adaptation); VABS-3 – Vineland Adaptive Behavior Scales-3rd Edition; SS – standard score.

*

Race definitions in Brazil are different from those in the United States. The labels listed represent the terms used in official Brazilian government communications (e.g., by the Brazilian Institute of Geography and Statistics [IBGE]).

All children were tested at two sites: Clinical University Hospital at Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil, and State University of Health Sciences of Alagoas – UNCISAL, Maceió, Brazil. At the Ribeirão Preto site, laboratory evidence of maternal Zika virus infection during pregnancy included Zika 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 (Coutinho et al., 2020). 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. In Maceió, a region with fewer resources, when RT-PCR testing was not available, the history of maternal Zika virus infection was determined based on established epidemiologic criteria: presence of symptoms during pregnancy (e.g., rash, fever, headache, myalgia, edema, skin pruritus, red eyes), residing in an area linked to the Zika virus, negative test results for other infections (STORCH, dengue, chikungunya). These criteria have been successfully used in other clinical studies (Fandiño-Cárdenas et al., 2018; Gomes et al., 2023) to identify children with prenatal Zika virus exposure.

Procedure

The children completed a battery of measures that lasted approximately 3 hours and included objective auditory evaluation as well as caregiver interviews and direct assessments. Breaks and snacks were provided as needed to accommodate developmental level and comfort needs of the children and their families.

Language and Communicative Skills Assessments

All language tests were administered by speech-language pathologists.

Child Language Test (ABFW; Silva et al., 2017; Wertzner, 2002; Wertzner et al., 2004), developed and standardized for native speakers of Brazilian Portuguese aged from 2–12 years old, was used to assess the phonetic inventory and phonological processes. This test includes a picture naming task (34 pictures of objects, 90 consonants) and a word imitation task (39 words, 107 consonants). In the naming task, the child is asked to name the presented objects. If the child does not know the target word, the evaluator names the picture and presents it again after 5 other images. If, on the second attempt, the child does not name the figure correctly, the trial is recorded as incorrect. In the imitation task, the children repeat the words spoken by the evaluator, and trials with unintelligible responses are repeated again at the end of the test. All verbal responses were audio recorded and phonetically transcribed. The percentage of correct consonants was used in the analyses (Wertzner et al., 2017).

List of Evaluation of the Expressive Vocabulary (LAVE) is a parent report of expressive vocabulary for children 2–6 years old adapted to Brazilian Portuguese from the Language Development Survey (LDS; Rescorla, 1997) and commonly used in research with typical children in Brazil (Pedromônico et al., 2002; Silva et al., 2017). The LAVE includes 307 high-frequency words from multiple semantic categories (e.g., food, toys, environment, animals, body parts, places, household objects, people, clothes, vehicles, etc.). The parent/caregiver is asked to identify the words produced by the child. The LAVE was included for use with children with significant language delays, for whom it would be developmentally appropriate despite the chronological age being out of range. The raw scores (total number of words) were used to compare the groups.

Picture Naming Test (PNT) for Children (Seabra et al., 2012) was developed from the Boston Naming Test (Kaplan et al., 1983) and standardized in children 3–14 years old from municipal public schools with a low and medium socioeconomic status in São Paulo state. This test evaluates expressive language and access to long-term verbal memory, as these abilities are related to the subsequent fluid reading ability (Cardoso-Martins & Pennington, 2001). The evaluator asks the child to name 60 individual images. For analysis, the raw scores were converted to a standard score based on age (M=100, SD=15).

Peabody Picture Vocabulary Test – Brazilian Adaptation (PPVT; Capovilla & Capovilla, 1997) was used to assess receptive vocabulary. The Brazilian version is suitable for ages 2–14 years and consists of 125 words from multiple categories (e.g., people, actions, body parts, objects). The child is asked to point to one of four pictures that corresponds to the word spoken by the examiner. The number of correct responses can be converted to standard scores based on age. However, the preliminary Brazilian validation did not account for the socioeconomic level of the normative group and, given the published evidence that the standard scores for children with lower socioeconomic level may be significantly lower than would be expected for their age (Qi et al., 2006), the raw scores were used in analyses with age and SES as covariates.

Vineland Adaptive Behavior Scales, Third Edition (VABS-3, Sparrow et al., 2016), a standardized caregiver report appropriate for use in populations with and without developmental disabilities was used to evaluate adaptive functioning in daily life. The VABS-3 data were collected by a licensed psychologist using the caregiver interview format. The Communication and Socialization domain standard scores (M=100, SD=15) as well as receptive and expressive communication and interpersonal subscale v-scores (M =15, SD=3) were included in the analyses.

Peripheral Hearing Evaluation

Peripheral hearing was evaluated with otoscopic inspection, middle-ear testing, otoacoustic emissions, and pure-tone audiometry. Each ear was tested individually. An otoscopic exam ruled out the presence of occluding cerumen and/or visible pathology. Tympanometry was completed using a 226 Hz probe tone and considered normal if an identifiable tympanometric peak was observed between −100 and +100 daPa and static compliance ranging from 0.2 to 0.9 cc. Distortion product otoacoustic emissions (DPOAE) were evaluated from 0.5–8 kHz in half-octave steps at stimulus intensities of L1=65 dB SPL, L2=55 dB SPL, and f1-f2 ratio=1.22. Absolute amplitude >0 dB SPL and a SNR ≥6 dB were the criteria for present responses. Hearing threshold testing was completed using conditioned play audiometry with earphones. Normal hearing was defined as 4-frequency pure-tone averages (PTA; 0.5, 1, 2, 4 kHz) ≤ 25 dB HL in each ear. Children who showed abnormalities on otoscopic inspection or did not pass the hearing evaluation based on a conductive type of disorder (e.g., otitis media, etc.) were referred for medical examination and were given an option to continue in the study after resolution of the problem and meeting inclusion hearing evaluation criteria.

Cortical Auditory Evoked Potentials (CAEP)

Cortical speech sound processing was evaluated using CAEP responses recorded in sound field with a speaker positioned 1 meter in front of the participant. Data were acquired using a Bio-logic Navigator Pro Auditory Evoked Potential System (v. 7.2.1) with a two-channel recording montage (a non-inverting electrode placed at the vertex (Cz), inverting electrodes at the ipsilateral and contralateral ears (mastoid; A1, A2) and a forehead ground (Fpz) in a sound-attenuating booth. Electrode impedance was maintained at <5 kOhm and <2 kOhm difference between electrodes. Test parameters included differential amplification with a gain of 100,000, filters set at 0.1–30 Hz, 512 Hz sampling rate, and online artifact rejection. During the CAEP test, children were awake, sitting quietly while watching muted videos. Digitally recorded consonant-vowel syllables varying in the place of articulation (/ba/, /da/, /ga/; 290–305 ms; Supplementary Figure 1) produced by a female native speaker of Brazilian Portuguese were presented at 75 dB SPL with equal probability in random order at a rate of 0.7/s for a total of 300 trials. The choice of the specific stimuli was motivated by the established evidence of CAEP sensitivity to place of articulation differences, and previously reported associations with performance on behavioral language measures in children with typical and atypical development (Molfese et al., 2002; Key et al., 2014; Yoder et al., 2006). The use of naturally spoken stimuli further increased ecological validity of the CAEP protocol (Whitten et al., 2020; Theunissen & Elie, 2014; Hamilton & Huth, 2018).

Averaged CAEPs based on at least 30 artifact-free sweeps per stimulus were exported as text files for data scoring and manually baseline-corrected. The actual number of retained sweeps was more than double the minimum requirement and was not significantly different between the participant groups or the stimulus types (M controls = 70.18+/−2.42, range: 57–88; M exposed = 69.82+/−2.31, range: 56–84). Visual inspection of the grand-averaged responses confirmed that the waveform morphology was consistent with the P1-N2 response (Figure 1), a developmental precursor of the adult P1-N1-P2 complex. Baseline-to-peak amplitudes and peak latency of the P1 (100–250 ms) and N2 (250–400 ms) responses were scored for the individual syllables in each participant using automated procedures. Those procedures included combining the individual text file exports into a single document and using the max, min, and index functions in Microsoft Excel to obtain peak amplitude and latency measures.

Figure 1.

Figure 1.

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Average cortical auditory evoked potentials for each stimulus syllable (/ba/, /da/, /ga/) and participant group (exposed and non-exposed control children). The shaded areas for each stimulus waveform reflect the standard error of the mean.

Postnatal Environment and Experiences

Family socioeconomic status was determined using the Brazilian Economic Classification Criteria (BECC) based on a questionnaire by the Brazilian Association of Research Companies (2018) that assesses household resources. BECC scores range from 0 to 100, with greater values indicating higher socioeconomic status.

Data on participation in early education and enrichment activities (e.g., sports, music lessons), history of speech/language, physical, or occupational therapy, and prior testing for developmental concerns (e.g., cognitive, language, hearing), were collected via caregiver reports. The questions focused on the history of such activities (yes/no), and if present, age when started and total duration of involvement.

Nonverbal Cognitive Ability Assessments

Prenatal virus exposures may impact general neurodevelopment and not just the language and communication domains (Gordon-Lipkin et al., 2021). Therefore, the testing battery included measures of nonverbal cognition.

Columbia Mental Maturity Scale - Third Edition (CMMS; Burgemeister et al., 1972) was administered by a psychologist to assess children’s general reasoning ability. The test is commonly used in Brazil and is designed for children between 3;6 and 9;11 years. On each trial, the child is presented with 3 to 5 figures and is asked to indicate which one is different from or not related to the others. Test items do not require a verbal response and have minimal motor demands. The 92 items are arranged in a series of eight overlapping sets (A to H) based on the child’s chronological age. Raw scores are converted to age deviation scores, percentile ranks, stanines, and Maturity Index (MI): Lower (percentile ≤ 04), Lower Medium (percentile between 04 and 22), Medium (percentile between 23 and 76), Upper Medium (percentile between 77 and 95), and Upper (percentile ≥ 96).

Wechsler Nonverbal Scale of Ability (WNV; Wechsler & Naglieri, 2006) is a nonverbal measure designed to test general cognitive ability for ages 4;0 to 21;11 years, and is optimal for individuals from diverse linguistic, cultural, educational, and socioeconomic backgrounds, as well as for those with language disabilities or hearing loss. This measure is not confounded by language ability and it is widely used in Brazil, including the psychologists on our teams. Raw scores are converted to standard subscale and full-scale scores (M=100, SD=15). Inclusion of the WNV measure allowed us to assess whether prenatal Zika virus exposure affects nonverbal abilities in addition to language and communication, reflecting a broader impact on neurodevelopmental outcomes.

Statistical analyses

Demographic and Behavioral Measures.

Group differences in demographic characteristics and postnatal experiences were evaluated using independent group t-tests assuming unequal variances and chi-square tests. Group differences in behavioral performance on the measures of verbal and nonverbal functioning were evaluated using one-way ANCOVAs. Preliminary data review noted that the exposed and control groups in the final sample were not balanced on age, SES, and maternal education. Thus, between-group comparisons for the language/communication and cognitive measures were performed while controlling for these demographic characteristics. There were no group differences in the biological sex distribution, and in the absence of specific predictions about the sex differences, we did not control for sex.

CAEPs.

The presence of the CAEP P1 and N2 responses was first objectively confirmed within the exposed and control groups separately using one-sample t-tests against zero. Next, preliminary analyses examined the effect of age at test, biological sex, SES, and maternal education on CAEP amplitudes and latencies and observed no significant influences. Therefore, these demographic variables were not included in the CAEP analyses. The amplitude and latency measures for the P1 and N2 were submitted to separate repeated measures ANOVAs with Stimulus (3: /ba/, /da/, /ga/) as the within-subject factor and Group (2: exposed, control) as the between-subject factor to evaluate differences in speech sound differentiation. Greenhouse-Geisser correction was used for sphericity violations. The hypothesis that the CAEPs of the exposed group may show reduced speech sound differentiation compared to the non-exposed children was evaluated by within-group planned comparisons using paired t-tests to examine differences in amplitude or latency between the three contrasting speech syllables.

Brain-Behavior Associations.

Exploratory analyses (not corrected for multiple comparisons) used correlations to examine the potential associations between performance on the behavioral measures of language skills, adaptive communication and CAEP responses. To reduce the total number of analyses, the CAEP variables were limited to the difference scores between the contrasting consonant-vowel syllables, reflecting individual differences in speech sound differentiation. Only the speech sound pairs showing significant amplitude or latency differences were included in the correlational analyses. In the absence of a priori predictions for the directional relationship among the amplitudes and latencies associated with each of the stimulus speech sounds, the absolute values indexing the overall magnitude of CAEP differences were analyzed. The two participant groups were not fully matched on age, SES, and maternal education; therefore, these demographic variables were controlled for using partial correlations.

Results

Postnatal Experiences

The summary data for the postnatal experiences of the exposed and non-exposed children are presented in the Supplementary Table 1. Despite the efforts to keep the two groups socioeconomically balanced by recruiting from the same communities, the non-exposed group had a slightly higher mean BECC score (28.8±8.60 vs. 25.66±9.09, p=.010), indicating access to more household resources in the non-exposed group. Nevertheless, the mean scores for both groups fell within the same socioeconomic stratum, generally corresponding to the middle class. The two groups were not significantly different in the age of starting early educations activities (e.g., attending a preschool), or the time spent participating in sports, dance, or music lessons (p’s>.466). However, more children in the exposed than non-exposed group received speech and language (p=.012) or physical (p=.004) therapy. Only the exposed children reported obtaining occupational therapy (13%). In addition, significantly more caregivers of children in the exposed than non-exposed group reported seeking out professional evaluation for language, cognitive, or other developmental concerns prior to the current study (p<.001). The time spent in various therapy activities by the individual children did not differ between the groups (p’s ≥ .154).

Nonverbal Cognition

After adjusting for age, SES, and maternal education, the two participant groups were not significantly different in performance on Columbia Mental Maturity Scale (p=.686). However, the children in the exposed group scored lower on Wechsler Nonverbal Ability total score (p=.016). Nevertheless, both groups had scores in the average range: exposed M=90.37 +/− 16.68, controls M=101.38 +/− 14.83. Further review indicated that 5% of the exposed children and 2% of the non-exposed group scored in the potential disability range (2 standard deviations below the mean). For the Columbia Mental Maturity Scales, the corresponding rates were 1% and 2%, respectively.

Language and Communicative function

After adjusting for age, SES, and maternal education, the non-exposed control group had significantly higher caregiver-reported scores on VABS-3 Adaptive Behavior Composite (p<.001), Socialization and Socialization standard scores (p’s<.001), as well as Receptive (p=.021), Expressive (p<.001), and Interpersonal (p=.003) subscale v-scores. However, the two groups were not significantly different on the behavioral measures of phonological processing (ABFW), expressive vocabulary (LAVE) and language (Picture Naming) as well as receptive language (PPVT) (p’s>.373).

The summary of performance on tests of nonverbal cognition, speech and communicative function is presented in Table 1.

Speech-evoked CAEPs

Usable CAEP data exceeding the minimum number of artifact-free sweeps were available for 108 of 117 exposed children and for 80 of 90 controls. The lowest number of sweeps contributing to analyses was 56. Grand-average CAEP waveforms in response to each speech sound for the exposed and non-exposed groups are presented in Figure 1. The amplitudes of P1 and N2 responses were significantly different from zero for all speech sounds in both participant groups (p<.001), confirming CAEP presence. A summary of the amplitude and latency measures for the P1 and N2 CAEP responses to the speech sound stimuli is presented in Table 2.

Table 2.

Cortical auditory evoked potentials P1 and N2 peak amplitudes and latencies in response to the individual speech stimuli in children with prenatal exposure to the Zika virus and non-exposed controls.

Exposed Controls
Amplitude Latency Amplitude Latency
M SD M SD M SD M SD
P1 /ba/ 4.45 3.38 171.70 40.64 5.13 2.86 167.77 34.12
/da/ 3.94 3.09 135.04 33.14 3.99 2.74 126.79 25.62
/ga/ 3.78 2.56 138.34 31.36 3.89 2.26 132.29 25.06
N2 /ba/ −7.83 4.46 338.49 26.31 −6.75 3.43 341.72 28.18
/da/ −6.56 4.28 317.66 55.46 −6.91 3.57 314.31 55.83
/ga/ −7.12 3.93 315.61 30.45 −7.33 3.29 317.65 35.13
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P1 Amplitude and Latency

For the P1 amplitude, the rmANOVA identified the main effect of Stimulus, F(1.891, 351.670)=8.236, p<.001, η2p =.042. Follow-up testing indicated that /ba/ elicited larger P1 amplitudes than /da/ and /ga/, t(187)=2.783, p=.006, d=.203, and t(187)=3.810, p<.001, d=.278, respectively. There were no significant differences between the CAEP amplitudes for /da/ and /ga/ (p=.589). Planned comparisons examining speech sound differentiation within each group revealed that this main effect was driven mainly by the non-exposed group: /ba/ - /da/ t(79)=3.314, p=.001, d=.370, and /ba/ - /ga/ t(79)=3.934, p<.001, d=.440. The same contrasts did not yield robust evidence of speech sound differentiation in the exposed group (p’s≥.055). The overall Stimulus x Group interaction was not significant (p=.390).

A main effect of Stimulus, F(1.805, 335.775)=97.251, p<.001, η2p =.343, was observed for P1 latency. Follow-up testing indicated that P1 latency was longer in response to /ba/ than /da/ and /ga/, t(187)=11.285, p<.001, d=.823, and t(187)=11.342, p<.001, d=.827, respectively. There were no significant differences between the P1 latencies for /da/ and /ga/ (p=.099). Planned comparisons identified the same pattern of findings within each group: exposed group: /ba/ - /da/ t(107)=7.503, p<.001, d=.722, and /ba/ - /ga/ t(107)=7.684, p<.001, d=.739; non- exposed group: /ba/ - /da/ t(79)=8.917, p<.001, d=.997, and /ba/ - /ga/ t(79)=8.745, p<.001, d=.978.

N2 Amplitude and Latency

For N2 amplitude, the rmANOVA identified a Stimulus x Group interaction, F(1.846, 343.299)=3.290, p=.042, η2p =.017. Follow-up testing indicated no between-group differences in response to any individual speech sound (p’s>.071). Within-group analyses noted that in the exposed group, /ba/ elicited larger (more negative) N2 amplitudes than /da/ and /ga/, t(107)=−2.686, p=.008, d=.258, and /ba/ - /ga/, t(107)=−1.999, p=.048, d=.192, respectively. The amplitude differences between /da/ and /ga/ were not significant (p=.181). No between-sound differences reached significance in the non-exposed group (p’s>.170).

A main effect of Stimulus, F(1.572, 292.326)=27.075, p<.001, η2p =.127, was observed for N2 latency. Follow-up testing indicated that N2 latency was longer in response to /ba/ than /da/ and /ga/, t(187)=5.639, p<.001, d=.411, and t(187)=9.207, p<.001, d=.671, respectively. There were no significant latency differences between /da/ and /ga/ (p=.975). Planned comparisons identified the same pattern of findings within each group: exposed group: /ba/ - /da/ t(107)=3.981, p<.001, d=.374, and /ba/ - /ga/ t(107)=7.338, p<.001, d=.706; non-exposed group: /ba/ - /da/ t(79)=4.091, p<.001, d=.457, and /ba/ - /ga/ t(79)=5.650, p<.001, d=.632.

Overall, speech sound differentiation was observed for P1 amplitude in the non-exposed children and N2 amplitude in the exposed group, while the patterns of P1 and N2 latencies were similar across all participants.

Brain-Behavior Associations

Based on the above findings, only the /ba/-/da/ and /ba/-/ga/ difference scores were included in the exploratory correlational analyses. The partial correlations controlled for group membership, age at test, SES, and maternal education. The results indicated significant positive associations between larger N2 amplitude differences for the /ba/-/ga/ contrast and caregiver reports of more adaptive receptive and expressive communication, r=.335, p=.001 and r=.306, p=.003, respectively, as well as better interpersonal relationships, r=.223, p=.034, on VABS-3. In addition, a larger /ba/-/da/ N2 amplitude difference was associated with higher scores on VABS-3 adaptive behavior composite, r=.206, p=.05, and Wechsler Nonverbal Scale of Ability total, r=.223, p=.033. Visual representations of these associations are presented in Figure 2.

Figure 2.

Figure 2.

Open in a new tab

Partial correlations between the behavioral measures of verbal and nonverbal functioning and the absolute N2 amplitude differences for the /ba/-/ga/ and /ba/-da/ contrasts. The unstandardized residuals are plotted for each variable after controlling for group membership, age, SES, and maternal education.

Discussion

The goal of this study was to characterize language and communication skills as well as the auditory neural function in normocephalic children prenatally exposed to the Zika virus and a non-exposed control group. Our results noted lower than typical expressive and receptive communicative functioning in daily life as reported by the caregivers, and some differences in cortical auditory neural function in the exposed children compared to controls.

Our battery of standardized behavioral assessments evaluated nonverbal cognition phonological processing, receptive and expressive vocabulary, and adaptive communication skills. Previous studies in Zika-exposed infants and toddlers identified language and communication domains as the possible areas of vulnerability (e.g., Andrade et al., 2021; Lindsay et al., 2021; Familiar et al., 2021), while cognitive function remained unaffected (Faiçal et al., 2019; Nielsen-Sains et al., 2019; Peçanha et al., 2020). Continued longitudinal follow-up into the preschool age using general measures of development (e.g., Bayley Scales of Infant Development; Ages & Stages, etc.) noted high heterogeneity in outcomes (see Marban-Castro et al., 2022 for review) with the possibility of more typical performance as the exposed children continued to grow and develop (Godoi et al., 2023). Our behavioral results in older, 4–7-year-old, participants provided partial support for the hypothesis that prenatal Zika virus exposure in otherwise healthy children would be associated with lower language abilities and communicative functioning. The exposed children were not significantly different from the controls on the direct assessments targeting discrete language skills. However, the caregivers of the exposed children consistently described their receptive and expressive communication skills as falling below average on a standardized survey of adaptive behavior (VABS-3). A recent study in normocephalic children with prenatal exposure to the Zika virus (Rodríguez-Rabassa et al., 2024) also reported a discrepancy between the performance in the average range on a direct assessment (Bayley Scales of Infant Development) and parental reports of difficulties in the personal-social domain. Importantly, prior studies have repeatedly demonstrated that parents/caregivers are accurate reporters of their children’s abilities observable in daily life (Peyton et al., 2021; Coplan, 1982; Bennetts et al., 2016; Sachse & von Suchodoletz, 2008). Therefore, the caregiver-reported difficulties in daily communication skills in the exposed group should not be disregarded despite the largely typical performance on the other behavioral measures. It is possible that the latter could be explained by the postnatal experiences of the exposed group that provided opportunities to compensate for the developmental risks associated with the prenatal Zika virus exposure. Indeed, our findings based on caregiver reports noted a higher incidence of professional evaluations for developmental concerns and a greater number of exposed children receiving speech and language therapy compared to the controls. In combination, our behavioral findings support the need for the continued developmental follow-up of the exposed children as they get older (see also Fernandes et al., 2023; Martelli et al., 2024).

Examination of the CAEPs indicated that both groups encoded and differentiated the contrasting consonant-vowel syllables varying in the place of articulation. This ability is a known predictor of language outcomes in infants (Molfese & Molfese, 1997; Maitre et al., 2013) and is often disrupted in communication disorders (Key et al., 2016; Yoder et al., 2006). Previous work demonstrated that greater cortical speech sound differentiation is associated with higher adaptive communication skills in children with the Congenital Zika Syndrome and microcephaly, the most severe cases of prenatal Zika virus exposure (Key et al., 2024). In that group, cortical speech sound encoding was present while differentiation was reduced and delayed compared to healthy controls. In the current sample of normocephalic children with prenatal Zika exposure, the CAEPs elicited by the individual natural speech sounds were not significantly different from those in the non-exposed controls. However, while the control group demonstrated evidence of speech sound differentiation at the earliest stage of cortical auditory processing indexed by the P1 amplitude, the exposed group appeared to do so later, at the N2 stage, in line with the hypothesized detrimental impact of Zika virus exposure on cortical speech processing. Previously, P1 has been associated with the stimulus feature encoding, while N2 was thought to reflect sound content processing (Čeponienė et al., 2005). Prior studies observed prolonged and reduced speech sound differentiation in children with language and communication difficulties due to other neurodevelopmental conditions (e.g., dyslexia, specific language impairment; Leppanen & Lyytinen, 1997; Yoder et al., 2013). In the current sample, after controlling for group membership, chronological age, SES, and maternal education, the larger N2 amplitude differences for the /ba/-/ga/ and /ba/-/da/ contrasts were associated with the caregiver reports of more adaptive receptive and expressive communication abilities (VABS-3) and higher scores on the measure of nonverbal cognition (WNV). These findings support the hypothesized positive association between better cortical speech sound differentiation and more optimal developmental outcomes and are consistent with the previously reported brain-behavior associations for speech-evoked CAEPs (Maitre et al., 2013; Key et al., 2024; Key et al., 2023; Matsuzaki et al., 2019). Our results highlight the informational utility of physiological responses in assessing central auditory speech processing in populations at risk for neurodevelopmental difficulties (see also Liu et al., 2021).

Of note, we observed no associations between the trimester of Zika virus exposure and any demographic, behavioral, or neural characteristics in the exposed group. It could be due to the majority of the sample being exposed in the 2nd and 3rd trimester, while the published evidence associates the more severe developmental consequences with the virus exposure earlier in gestation as seen in Congenital Zika Syndrome (Nielsen-Saines et al., 2019; Reynolds et al., 2017).

In combination, our behavioral and neural findings suggest that prenatal Zika exposure in children without microcephaly may not affect discrete, context-free phonological, receptive or expressive language task performance or cortical encoding of the individual speech sounds. At the same time, it may be associated with specific weaknesses in rapid and flexible stimulus processing, reflected by the delayed speech sound differentiation and difficulties with adaptive language and communication use in daily life. This interpretation is in line with the current understanding of the neurobiological effects of prenatal Zika exposure on brain development and function. The available neuroimaging evidence noted that even children without microcephaly may experience disruption of neuronal migration, myelination, and synapse formation, which in turn could impact neural signaling and coordination across brain regions resulting in less efficient information processing (Sanami et al., 2025; Martins et al., 2025). Notably, neuroimaging and behavioral follow-up of Zika-exposed children without microcephaly remains limited. Our current findings provide further support for the importance of longitudinal studies that delineate the effects of prenatal exposure on the development of neural function even in the absence of significant structural deficits.

While providing novel findings regarding the effects of prenatal exposure to the Zika virus, this study has some limitations. First, the two participant groups were intended to be matched on age, sex, ethnicity, and socioeconomic status, but the final sample with usable data turned out to be unbalanced on these measures. We controlled for these variables using statistical means; however, such adjustments do not fully eliminate the confounding risk. Future studies need to strive for closer matching given the known influence of these factors on behavioral and neural development and language skills (Merz et al., 2019; Pace et al., 2017; Rodrigues-Rabassa et al., 2024). Second, the auditory evoked potential test system (Bio-Logic Navigator Pro), the only option available at both study sites, allowed for limited CAEP data collection at a single scalp location. As a result, this study was unable to evaluate hemisphere or other topographic differences in speech sound processing, Previously, increased or absent hemisphere differences in neural responses to speech have been associated with more versus less adaptive language and communicative functioning, respectively, in children with or at risk for neurodevelopmental disabilities (Maitre et al., 2014; Kuhl et al., 2013). Future CAEP studies using higher channel counts could provide additional insights into differences and similarities in central auditory function between the exposed children and controls.

In conclusion, the current findings suggest that despite the absence of pronounced developmental delays on the standardized measures of discrete cognitive and language skills in 4–7-year-old normocephalic children relative to the non-exposed controls, prenatal Zika virus exposure may be associated with difficulties in adaptive communication in daily life and delays in cortical speech sound differentiation. These findings extend the previous reports of increased vulnerability to challenges in the communication domain observed in the infants and toddlers with prenatal exposure to Zika virus and support the need for their continued follow-up in the school-age years, when the demands on effective auditory and language processing increase.

Supplementary Material

Supplementary Table 1
Supplementary Figure 1

Acknowledgements

This research received primary support from the National Institutes of Health: National Institute on Deafness and Other Communication Disorders (NIDCD) R56DC019113, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) P50 HD103537, and National Center for Advancing Translational Sciences (NCATS) UL1TR000445. The funding organizations had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the decision to submit the article for publication; or in the preparation, review, or approval of the article.

Children in the control group at Ribeirão Preto site previously participated in the Zika in Infants and Pregnancy (ZIP) study (NCT02856984).

We are grateful to Janice Creel and Kylie Hilsen for assistance with data entry and management.

Footnotes

Conflict of Interest Statement

The authors report no conflict of interest.

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).

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Table 1
NIHMS2204378-supplement-Supplementary_Table_1.docx (15.5KB, docx)
Supplementary Figure 1
NIHMS2204378-supplement-Supplementary_Figure_1.pptx (113.6KB, pptx)

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).

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