Association between microcephaly and hearing disorders in children exposed or suspected of exposure to the Zika virus during the intrauterine period

doi:10.21203/rs.3.rs-4991369/v1

Download PDF

Research Article

Association between microcephaly and hearing disorders in children exposed or suspected of exposure to the Zika virus during the intrauterine period

https://doi.org/10.21203/rs.3.rs-4991369/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Purpose

This study aimed to evaluate the association between microcephaly and hearing disorders in children with exposed or suspected of exposure to Zika virus (ZIKV) during the intrauterine period.

Methods

This cross-sectional study, we enrolled children exposed or suspected of being exposed to ZIKV and born to mothers with confirmed or suspected ZIKV infection during pregnancy, admitted to the hospital between April 2016 and July 2018, and followed up until September 2021. All children underwent at least one automated auditory brainstem response (AABR) test. For analysis, the patients were divided into four groups: those with microcephaly, without microcephaly, suspected ZIKV infection, and controls. Other causes of microcephaly were excluded. Hearing impairment was assessed using the AABR to determine associations with microcephaly or central nervous system (CNS) abnormalities.

Results

Of the 134 children included, 34 (25.4%) were diagnosed with congenital Zika syndrome (CZS), of whom 28 (82.4%) had microcephaly, and the remaining six (17.6%) without microcephaly. Among the 28 children with microcephaly, 3 (10.7%) had abnormal AABR. Among children without microcephaly (n = 106), 3 (2.8%) had abnormal AABR (p = 0.09).

Conclusion

In our study population, children with and without microcephaly had abnormal AABR.

In 2016, the World Health Organization (WHO) declared microcephaly related to the Zika virus (ZIKV) as a public health emergency of international concern [1]. In Brazil, 20,874 suspected cases of congenital ZIKV infection were reported by the Ministry of Health between 2015 and 2022, including 1,852 (49.9%) confirmed cases of congenital Zika syndrome (CZS) [2]. CZS has been defined as ZIKV infection in children during intrauterine period, being primarily characterized by the presence of microcephaly, cerebral cortex thinning with subcortical calcifications, spasticity, early hypertonia with extrapyramidal symptoms, and ophthalmologic and orthopedic disorders [3].

Microcephaly results from the direct action of the virus on cells of the fetal central nervous system (CNS), causing neural progenitor cell death, altering cell proliferation, migration, and differentiation, and impairing the growth of the head circumference [3–5]. Although microcephaly is the most frequently observed clinical profile, intrauterine ZIKV infection causes other severe congenital anomalies, mainly in the CNS, including ocular abnormalities and sensorineural hearing loss [6–8].

The association between congenital ZIKV infection and hearing loss has been studied, especially after the 2015 epidemic in Latin America, with reports of sensorineural hearing loss in infants with microcephaly caused by ZIKV [9–13]. The hearing impairment presumably results from damage to the inner ear or auditory nerve caused by the direct action of the virus or is mediated by an autoimmune process [11]. This virus behaves similarly to syphilis, toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus (congenital infections). As demonstrated in other congenital infections, the association between ZIKV infection and hearing loss has been hypothesized to be based on the occurrence of neurological and ocular alterations and multiple malformations [14].

In 2019, the Joint Committee of Infant Hearing established that intrauterine exposure to ZIKV was a risk factor for hearing loss [15]. However, the relationship between microcephaly caused by ZIKV and hearing disorders remains limited. Therefore, this study aimed to assess the association between microcephaly and hearing disorders in children exposed to or suspected of being exposed to ZIKV during the intrauterine period.

2.1. Study design

In this cross-sectional study, we enrolled participants from a cohort of 253 children exposed or suspected of exposure to ZIKV and born to mothers with confirmed or suspected ZIKV infection during pregnancy (16,17). This cohort of children was admitted between April 2016 and July 2018 and followed-up until September 2021 at the Department of Otorhinolaryngology, Pediatric Infectious Diseases Outpatient Clinic, Antônio Pedro University Hospital/Universidade Federal Fluminense (Hospital Universitário Antônio Pedro [HUAP/UFF]). HUAP/UFF is a quaternary hospital located in Niterói, Rio de Janeiro, Brazil, with a population of approximately 500,000 and a coverage area spanning seven adjacent cities, totaling approximately 2,000,000 inhabitants. This hospital is located in the second largest metropolitan area in Rio de Janeiro, Brazil. Children were referred from other departments and cities or self-referred for clinical follow-up at the Pediatric Infectious Diseases Outpatient Clinic at HUAP/UFF.

To participate in the study, the children had to undergo at least one automated auditory brainstem response (AABR) test during clinical follow-up. Before the test, all infants underwent otorhinolaryngological examination with otoscopy to rule out middle ear disease, so as not to interfere with hearing assessment results. For the analysis, the participants were divided into four groups. Group 1 (exposed to ZIKV with microcephaly) included children with microcephaly at birth or postnatally, defined as a positive maternal reverse transcription-quantitative polymerase chain reaction [RT-qPCR] test for ZIKV and/or clinical diagnosis of microcephaly caused by ZIKV according to the criteria of the Ministry of Health. Briefly, CZS was defined as the presence of at least two of the following developmental abnormalities associated with maternal exanthema during pregnancy: neuroanatomical, neurosensory, visual, or auditory abnormalities [1]. Group 2 (exposed to ZIKV without microcephaly) involved children without microcephaly born to mothers diagnosed with ZIKV (positive maternal RT-qPCR test). Group 3 (suspected ZIKV infection without microcephaly) included children without microcephaly born to mothers who had exanthema during pregnancy, coinciding with the National Public Health Emergency Period for ZIKV (November 2015 to May 2017) (Brazil, 2015), but did not undergo RT-qPCR test. Group 4 (control) included children without microcephaly born to mothers who had exanthema during pregnancy and had a negative RT-qPCR test result.

Children with perinatal hypoxia, infections with other arboviruses such as dengue and chikungunya, other congenital infections (syphilis, toxoplasmosis, rubella, cytomegalovirus, or human immunodeficiency virus), microcephaly due to other etiologies, and/or did not undergo AABR test were excluded from the study.

2.2. Procedures

The head circumference (HC) of the children was measured within 24–48 hours of birth. Microcephaly at birth was defined as HC with more than two standard deviations below the mean for sex and gestational age. Severe microcephaly was defined as HC with more than three standard deviations below the mean, in accordance with the 2016 WHO definitions [18]. HC growth was analyzed based on the INTERGROWTH-21st Fetal Growth Standards and WHO Child Growth Standards for Infants.

The hearing disorders were investigated using the AABR test, an electrophysiological examination that evaluates neural tissue integrity from the cochlea to the brainstem (reflects the activity of the cochlea, auditory nerve and brainstem). The test is considered suitable for investigating auditory synchrony, as healthy auditory nerve fibers indicate auditory synchrony [19, 20]. Detects, in addition to neural changes, sensorial changes (Joint Committee on Infant Hearing, 2007).

Hearing was assessed according to the protocol described by Faria et al. [13]. The AABR test was conducted in both ears and in random order using Titan software (ABRIS 440 Interacoustics, Middelfart, Denmark) in PC mode. The test was performed with the children naturally asleep or in a quiet, “non agitated” state, placed on the lap of the mother or legal guardian. The CE-chirp stimulus was applied at a repetition rate of 90 Hz with alternating polarity and intensity of 30 dB hearing level. The ABRIS 440 TITAN software enables automatic response detection based on sample statistics and Bayesian weighting. In the AABR test, the response to the auditory stimulus was deemed present or absent, and recorded as Pass or Fail, respectively.

The laboratory evidence of ZIKV infection during pregnancy was based on positive maternal RT-qPCR results. The test was performed using serum and/or urine samples during the period recommended by the Ministry of Health of Brazil (until the 5th day of exanthema for serum samples, and up to the 14th day of exanthema for urine samples) [21].

Transfontanelar ultrasound (TFU) was performed in children with a permeable fontanela or in those up to 6 months of age. Cranial computed tomography (CT) was performed in children who could not be evaluated by TFU. Cranial magnetic resonance imaging (MRI) was performed to clarify the TFU and CT images when necessary, according to the evaluation of the attending physician.

2.3. Statistical analysis

All results are expressed as mean ± standard deviation (SD) for continuous variables with normal distribution, and as medians and interquartile ranges for the other continuous variables. The study variables included microcephaly at birth and in the postnatal period, maternal exanthema, and hearing disorders. The small sample size of each subgroup (1, 2, 3, and 4) precluded all statistical analysis even though some results are presented when possible.

This study was conducted according to the Helsinki declaration, and was approved by the Research Ethics Committee of the School of Medicine, UFF (approval number: 1.908.635). All legal guardians signed an Informed Consent Form before any procedure was performed.

Figure 1 shows the study population flowchart. From April 2016, 253 children were followed up by a multidisciplinary team in our outpatient clinic. Of these, 134 were included in the study and stratified into 4 groups. Twenty-eight (20.9%) children were included in the Group 1 (exposed to ZIKV with microcephaly); 32 (23.9%) in the Group 2 (exposed to ZIKV without microcephaly); 43 (32.1%) in the Group 3 (suspected ZIKV exposed without microcephaly) and 31 (23.1%) in the Group 4 (control, not exposed to ZIKV), (Fig. 1).

Of the 28 children in Group 1, 22 (78.6%) had microcephaly at birth, six (21.4%) had post-natal microcephaly and eighteen (64.2%) were male, and all children showed abnormalities upon neurological examination. Regarding maternal exanthema, 13 (46.4%) children were born to mothers who had exanthema in the first trimester, and 12 (42.9%) whose mothers did not have exanthema during pregnancy. The children’s median age at admission was 40 days (IQR = 16.75–371 days), and the median HC was 29.5 cm (IQR = 29 − 30.75) (Table 1).

Table 1

General characteristics of the study population (children exposed or suspected of exposure to ZIKV during the intrauterine period)
Characteristics	Group 1 With microcephaly N = 28 (%)	Group 2 Without microcephaly N = 32 (%)	Group 3 (suspected CZS) N = 43 (%)	Group 4 Control N = 31 (%)
Female	10 (35.7)	17 (53.1)	22 (51.1)	14 (45.1)
Age (days) at admission, median (IQR)	40 (16.8–371)	155 (20.8-153.5)	30 (15.5–61.5)	45 (22-141.5)
Exanthema
Before pregnancy	0	1 (3.1)	7 (16.3)	0
1st Trimester	13 (46.4)	4 (12.5)	8 (18.6)	4 (13)
2nd Trimester	2 (7.1)	17 (53.1)	17 (39.5)	16 (51.6)
3rd Trimester	1 (3.5)	10 (31.3)	11 (25.6)	11 (35.4)
No exanthema	12	0	0	0
Head circumference in cm, median (IQR)	29.5 (29-30.8)	34.5 (33–35)	33 (33–35)	34.5 (33–35)
Microcephaly	28	0	0	0
CZS	28 (100)	5 (15.6)	1 (2.3)	0
IQR: interquartile range; CZS: congenital Zika syndrome; cm: centimeter.

Three (10.7%) children of Group 1 showed AABR abnormalities, two with unilateral neurosensorial hearing loss and one with bilateral hearing loss. These patients had neurological and imaging abnormalities related to CZS (dolichocephaly, ventriculomegaly, coarse periventricular and basal ganglia calcifications, cerebellar hypoplasia, polymicrogyria, corpus callosum dysgenesis, dysplasia cortical). Two of three AABR affected infants had microcephaly at birth and were born to mothers without exanthema. The third infant developed postnatal microcephaly, and the maternal exanthema occurred during the second trimester.

In Group 2, 17 of 32 (53.1%) children were female, and 4 (12.5%) of the 32 mothers had exanthema in the first trimester. Six (18.8%) of 32 children had neuroimaging abnormalities and neurological involvement, five of them were related to CZS. Two children (6.3%) showed AABR abnormalities, one with bilateral conductive hearing loss, and the other with bilateral neurosensorial loss (Table 1). One of them had neurological and neuroimaging abnormalities related to CZS (corpus callosum with thinning between the body and splenium, hypertense foci in the frontal periventricular white matter, with the parieto-occipital region showing a choline peak on spectroscopy). The other child had normal MRI and neurological examination abnormalities without features of CZS. Both mothers had a positive RT-qPCR test and exanthema, one in the third trimester and the other couple of weeks before pregnancy.

Of the 43 children in Group 3, 22 (51,1%) were female and 8 (18.6%) were born to mothers who had exanthema in the first trimester (Table 1). One Group 3 infant (2.3%), whose maternal rash occurred in the second trimester, had AABR with unilateral conductive loss, but normal MRI and neurological evaluation. Five children (11.6%) showed neuroimaging abnormalities, one (2.3%) of whom also had neurological abnormalities related to CZS.

Of the 31 children in Group 4 (control, not exposed to Zikv), 17 (54.8%) were male and 4 (12.9%) were born to mothers who had exanthema during the first trimester (Table 1). All children had normal AABR tests, neuroimaging, and neurological evaluations.

Overall, no significant differences were observed when the groups were compared, concerning the relationship between microcephaly and hearing disorders (Fisher's exact test p > 0.05).

In our study, AABR abnormalities were found in children with CZS both with and without microcephaly. Furthermore, AABR abnormalities were also found in infants without CZS, but born to mothers with confirmed or suspected ZIKV infection during pregnancy. When comparing all groups, we did not find a difference in the relationship between microcephaly and hearing disorders.

Our results showed that 11.8% of CZS children (with or without microcephaly) and 2.9% of ZIKV exposed children without CZS showed AABR abnormalities. In a retrospective study of 70 infants with microcephaly and presumed ZIKV infection, an auditory analysis revealed that 5.8% children had neurosensorial hearing loss [9]. Similarly, a 9% hearing loss rate due to otoacoustic emission was reported in another study of 104 newborns with microcephaly and ZIKV infection [22]. Unlike our study, these authors included only infants with microcephaly, and with other methods, which may have contributed to the slight differences in frequency of auditory abnormalities.

Several studies have shown that ZIKV compromises neural tissues and may cause devastating brain damage [3, 23] and hearing impairment [9, 13, 24]. CZS children with abnormal neuroimaging findings and microcephaly had auditory abnormalities, while those with minor CNS alterations and without microcephaly also had hearing impairment. Of the six children with AABR abnormalities, three had microcephaly and abnormal neuroimaging findings, one had neuroimaging abnormalities without microcephaly, and two had neurological examination abnormalities without features related to CZS. These findings showed that not all infants with hearing impairment, born to mothers with confirmed or suspected ZIKV infection during pregnancy, exhibit CNS alterations. However, we could not rule out changes in the central auditory pathway at the cortical level because the AABR evaluates the auditory system up to the brainstem. Therefore, other assessment methods, such as the P300, are needed to ensure a more accurate diagnosis, or even a set of tests for a complete analysis of the auditory pathway to confirm the nature of the abnormality. Mittal et al. [11] previously showed that many CZS infants with microcephaly and neurosensorial hearing loss, without clear damage to the inner ear structures, possibly had brainstem or cortical hearing impairments due to brain malformations. Considering the tropism of ZIKV for nervous tissues, the neural conduction of the acoustic stimulus in infants exposed to the virus and with microcephaly may differ from other infants, including those exposed to other congenital infections [10].

Barbosa et al. [24] demonstrated that not all infants exposed to ZIKV during the intrauterine period had hearing impairments, which is in line with our findings. In our study, of the 28 children with microcephaly exposed to ZIKV (Group 1), 3 (10.7%) had hearing impairment, and of the 75 children without microcephaly (32 in Group 2, 43 in Group 3) exposed or suspected of being exposed to ZIKV, 3 (4%) had hearing impairment (AABR abnormalities). Barbosa et al. [24] also observed that the risk of hearing impairment was strongly associated with the severity of CNS alterations, possibly because many studies have only been conducted in infants with microcephaly. Accordingly, hearing loss may be related to a wider spectrum of clinical involvement or with CNS alterations.

In contrast, because we evaluated children with and without microcephaly, our results showed that even infants without microcephaly, CZS, or imaging abnormalities had AABR abnormalities. In our study, two children with no features related to CZS, but with mild abnormalities on neurological examination were also found to have hearing impairment. This finding suggests that infants born to women with evidence of ZIKV infection during pregnancy, including infants without microcephaly and neuroimaging abnormalities or not, should also be screened for hearing impairment.

Of the 34 children with CZS included in our study who underwent AABR testing, 4 (11.8%) had abnormal AABR results, in agreement with Muniz et al. [25], who reported hearing loss in 10 (9.3%) of 107 infants in their study. The three children with CZS and microcephaly at birth or postnatally who showed AABR abnormalities also showed major imaging abnormalities as well as severe neurological impairment, in line with Borja et al. [10]. These authors observed infants with CZS, most of whom exhibited neuroimaging abnormalities, including decreased brain volume, ventriculomegaly, subcortical calcifications, and cortical malformations. Therefore, imaging abnormalities should be considered during the investigation of hearing loss.

Teixeira et al. [26] considered microcephaly to be a sign of CZS that may or may not manifest; therefore, the absence of microcephaly at birth does not exclude infection or brain, neuropsychomotor, auditory, or visual abnormalities related to ZIKV infection. In our study, among the 72 children without microcephaly and with normal AABR, five (6.9%) were diagnosed with CZS, all of whom had CNS changes on CT/MRI and neurological abnormalities. Gouvea et al. [27] also reported that although microcephaly was the most common finding, ZIKV infection had a wide range of impacts, as confirmed by patients with ophthalmological and audiological abnormalities possibly related to ZIKV, with normal neurological exams or mild neurocognitive dysfunction.

This study has some limitations. The sample size was relatively small, precluded a more detailed statistical analysis. Nevertheless, the study highlights the importance of conducting a long-term evaluation and follow-up of infants with and without microcephaly exposed to prenatal infection with ZIKV as little is known about the impact of this infection on the development of the auditory system and the late onset of abnormalities. Therefore, an early approach and long-term follow-up must be prioritized to reduce the risk of loss and delay in global growth and development. To implement better preventive measures, further studies are required to clarify the pathophysiology of hearing disorders in infants with ZIKV infection.

Overall, the results of this study suggested that hearing impairment assessed using the AABR was not associated with microcephaly or severe CNS alterations in our cohort. Therefore, just like other congenital infections, such as: rubella, cytomegaloviruses, toxoplasmosis, herpes virus infection and syphilis, CZS can evolve with auditive changes, and should be considered a risk factor to hearing loss. Hearing tests should be a routine approach in infants born to women with evidence of ZIKV infection during pregnancy, including infants without microcephaly at birth, as hearing changes may subsequently occur. More follow-up studies may clarify the mechanisms involved in the commitment of the hearing system by Zika virus and allow the early diagnosis of the hearing impairment.

AABR: Automated Auditory Brainstem Response

CNS: Central Nervous System

CT: Computed Tomography

CZS: Congenital Zika Syndrome

HC: Head Circumference

MRI: Magnetic Resonance Imaging

RTq-PCR: Reverse Transcription-Quantitative Polymerase Chain Reaction

TFU: Transfontanelar Ultrasound

WHO: World Health Organization

ZIKV: Zika Virus

Author Contribution

AOCA, AOP, LABD, SSAA, ARF, SAO, CAAC, MEVCRM, and RAOV made substantial contributions to the conception or design of the study.FRC and LGCV made important contributions to the analysis and interpretation of the data. AOCA, SAO, CAAC, and RAOV revised it critically for important intellectual content. All authors reviewed and approved the version to be published.

Acknowledgements

The authors thank the children and their families who participated in the study, the Multiuser Laboratory for Research Support in Nephrology and Medical Sciences (Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas – LAMAP), the Clinical Research Unit (Unidade de Pesquisa Clínica – UPC), and the colleagues from the ZIKA Group / Fluminense Federal University (Universidade Federal Fluminense – UFF), who collaborated in this study.

Conflicts of Interest and Source of Funding

Nothing to declare.

Ministry of Health, Department of Health Surveillance, Department of Health Care (2016) Integrated guidelines for surveillance and health care within the scope of the Public Health Emergency of National Concern: procedures for monitoring changes in growth and development from pregnancy to early childhood, related to Zika virus infection and other infectious etiologies within the operational capacity of SUS. Ministry Of Health, Brasília. http://portalarquivos.saude.gov.br/images/pdf/2016/dezembro/12/orientacoes-integradas-vigilancia-atencao.pdf Available From
Brasil (2022) Ministério da Saúde [Ministryof Health]. Bol Epidemiológico/ Secretaria de vigilância em saúde 53:95Situação epidemiológica da Síndrome congênita associada à infecção pelo vírus Zika: Brasil, 2015 a 2022 [Epidemiological Situation Of The Congenital Zika Syndrome: Brazil, 2015 to 2022]
Moore CA, Staples JE, Dobyns WB et al (2017) Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr 171:288–295
Li H, Saucedo-Cuevas L, Shresta S et al (2016) The Neurobiology of Zika virus. Neuron 92:949–950
Walter LT, Higa GSV, Ikebara JM et al (2018) Evaluation of possible consequences of Zika virus infection in the developing nervous system. Mol Neurobiol 55:1620–1629
Mehrjardi MZ (2017) Is Zika virus an emerging TORCH agent? An invited commentary. Virol (Auckl) 8:1178122X17708993
Honein MA, Dawson AL, Petersen EE et al (2017) Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA 317(1):59–68
Abramov DM, Saad T, Gomes-Junior SC et al (2018) Auditory brainstem function in microcephaly related to Zika virus infection. Neurology 90:el–9
Leal MC, Muniz LF, Ferreira TSA et al (2016) Hearing loss in infants with microcephaly and evidence of congenital Zika virus infection-Brazil, November 2015-May 2016. MMWR Morb Mortal Wkly Rep 65:917–919
Borja A, Araújo RPC (2017) Hearing screening in children exposed to Zika virus during pregnancy. RevCiêncMédicas Biol 16:271–276
Mittal R, Fifer RC, Liu XZ (2018) A Possible Association Between Hearing Loss and Zika Virus Infections. JAMA Otolaryngol Head NeckSurg 144:3–4
Fandiño-Cárdenas M, Idrovo AJ, Velandia R et al (2019) Zika virus infection during pregnancy and sensorineural hearing loss among children at 3 and 24 months postpartum. J Trop Pediatr 65:328–335
Faria AOP, Miterhof MEVCR, Vianna RAO et al (2020) Audiological findings in children suspected to have been exposed to the Zika virus in the intrauterine period. Otol Neurotol 41(7):848–853
Cohen BE, Durstenfeld A, Roehm PC (2014) Viral causes of hearing loss: A review for hearing health professionals. Trends Hear 18:1–17
Joint Committee on Infant Hearing (2019) Year 2019 position statement: Principles and guidelines for early hearing detection and intervention programs. J Early Hear Detect Interv 4(2):1–44
Vianna RAO, Rua EC, Fernandes AR et al (2020) Experience in diagnosing congenital Zika syndrome in Brazilian children born to asymptomatic mothers. Acta Trop 206:105438
Vianna RAO, Lovero KL, Oliveira SA et al (2019) Children Born to Mothers with Rash During Zika Virus Epidemic in Brazil: First 18 Months of Life. J Trop Pediatr 65(6):592–602
WHO Multicentre Growth Reference Study Group (2006) WHO Child Growth standards based on length/height, weight, and age. ActaPaediatrSuppl 95:76–85
Hood LJ (1998) Clinical Application on the ABR in estimating hearing sensitivity. Clinical applications of the Auditory Brainstem Response. Singular publishing group, San Diego, pp 95–123
Hall JW (2006) New Handbook for Auditory Evoked Responses. Pearson Education, Boston
Brasil (2023) March. Ministério da Saúde [Ministry of Health]. Orientações Integradas de Vigilância e Atenção à Saúde no Âmbito da Emergência de Saúde Pública de Importância Nacional [Integrated guidelines for surveillance and health care in the context of the Public Health Emergency of National Concern (PHEIC)]. http://portalarquivos.saude.gov.br/images/pdf/2016/dezembro/ Follow-Up of Children Born to Mothers with Rash 601 Downloaded from https://academic.oup.com/tropej/article/65/6/592/5475884 by guest on 10 October 2021 12/orientações-integradas-vigilancia-atencao.pdf Accessed in
Microcephaly Epidemic Group. Microcephaly in infants, Pernambuco State, Brazil (2015) EmergInfectDis2016; 22: 1090–3.http://wwwnc.cdc.gov/eid/article/22/6/16-0062_article
Mlakar J, Korva M, Tul N et al (2016) Zika virus associated with microcephaly. N Engl J Med 374(10):951–958
Barbosa MHM, Garcia CFD, Barbosa MCM et al (2020) Normal hearing function in children prenatally exposed to zika virus. Int Arch Otorhinolaryngol 24:299–307
Muniz LF, Maciel RJF, Ramos DS et al Audiological follow up of children with congenital Zika syndrome. Heliyon 2022(8): e08720
Teixeira GA, Dantas DNA, Carvalho GAFL et al (2020) Analysis of the concept of the zika virus congenital syndrome. Ciência e Saúde coletiva 25(2):567
Gouvea LA, Martins M, Vivacqua D et al (2021) Complications and Sequelae in patients with congenital microcephaly associated with zika virus infection: two years follow up. J Child Neurol 36:537–534

No competing interests reported.

Download PDF

Reviews received at journal
24 Oct, 2024
Reviewers agreed at journal
19 Oct, 2024
Reviewers agreed at journal
19 Oct, 2024
Reviewers agreed at journal
10 Sep, 2024
Reviewers invited by journal
02 Sep, 2024
Editor assigned by journal
02 Sep, 2024
Submission checks completed at journal
02 Sep, 2024
First submitted to journal
28 Aug, 2024

You are reading this latest preprint version

Association between microcephaly and hearing disorders in children exposed or suspected of exposure to the Zika virus during the intrauterine period

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Material and Methods

Results

Discussion

Abbreviations

Declarations

Author Contribution

Acknowledgements

References

Additional Declarations

Status:

Version 1