Congenital toxoplasmosis and auditory disorders: a literature review

Background Congenital toxoplasmosis (CT) occurs mainly by primary maternal infection during pregnancy. It is estimated that the incidence of vertical transmission to the fetus is 20% and that infected women are more likely to have a premature birth or low birth weight neonate since there is an association between CT and the rate of premature birth and low birth weight. In addition to severe neurological and ophthalmic consequences, hearing disorders such as hearing loss are also among the clinical manifestations seen in children with CT. Given the above, the objective of this study is to verify what are the auditory disorders seen in children with CT. Methods This literature review was structured according to the PRISMA statement and based on the terms of Study Target Population, Intervention, Comparison, Outcomes, and Study Types (PICOS). To obtain the studies, the following electronic databases were consulted: PubMed, Web of Science, Scopus, and Lilacs. The combined terms used for the search were: (“auditory evoked potentials” OR “hearing” OR “hearing loss”) AND (“congenital toxoplasmosis”). The selection of articles was carried out independently, blindly, by two of the authors, to minimize risk of bias. Results The search in the databases identified 172 articles, after excluding duplicate articles, 105 studies were identified. From the selection made by reading the titles and abstracts, 11 studies were selected for full-text reading. A total of 94 studies were excluded. An article was selected from the list of references. Therefore, 12 studies were included in the final analysis. It was observed that a significant percentage of studies sought to study the peripheral auditory pathway, verifying the occurrence or association between hearing loss and the presence of congenital infection. Only two studies evaluated the central auditory pathway, using the Brainstem Auditory Evoked Potential (BAEP) and the Frequency Following Response (FFR). Conclusion Toxoplasmosis affects not only the peripheral areas but central areas as well. Most studies suggest this pathology as a risk factor for both peripheral and central impairment. Research has found a greater association between CT and mild to moderate hearing loss, in addition to alterations in exams such as BAEP and FFR. These data recommend that CT be reported as a global public health problem and can help assess complications and impacts of hearing disorders as a result of CT. There is a gap about studies that retract the co-occurrence between CT and other Risk Indicators for Hearing Loss (RIHL), such as prematurity, permanence in the intensive care unit, and use of ototoxic medications, lack of longitudinal studies, that accompany the development of hearing and language of children with CT, since the consequences of this infection may be late.


Introduction
Congenital toxoplasmosis (CT) occurs mainly by primary maternal infection during pregnancy and brings an economic and health burden for affecting many pregnant women, especially those with low and middle income in underdeveloped countries.It is estimated that the incidence of vertical transmission to the fetus is 20% (Li et al., 2014) and that infected women are more likely to have a premature birth or the low birth weight neonate, since there is an association between CT and the rate of premature birth and low birth weight (Hurt et al., 2022).In addition, congenital and perinatal infections affect 0.5 to 2.5% of neonates and are the main causes of infant morbidity and mortality, complications of premature birth are the main cause of death in children under 5 years old (Liu et al., 2016).
The clinical diagnosis in this period is a challenge for professionals in the area since most cases are asymptomatic.However, the consequences are significant for the health of the child population and may occur in the neonatal period or late sequelae (Mirambo et al., 2019).
The clinical manifestations observed by this pathology depend on factors such as the mode of transmission, time of infection in relation to gestational age, maturity of the fetal immune system, and presence or absence of maternal immunity at the time of infection (Menson and Lyall, 2005).
In addition to severe neurological and ophthalmic consequences, hearing disorders are also among the clinical manifestations observed in children with CT (Al-Amari and Kameswaran, 1996;Andrade et al., 2008;de Resende et al., 2010;Vos et al., 2015;Besen et al., 2022).When analyzing the histopathology of the temporal bone in children with CT, researchers described that hearing loss in this infection may be a consequence of post-natal inflammation, since they found an inflammatory process, triggered by the parasite, in the inner ear (Salviz et al., 2013).
Although recommendations for children's hearing health (Lewis et al., 2010;Joint Committee on Infant Hearing, 2019) cite CT and prematurity as Risk Indicators for Hearing Loss (RIHL), the results found in studies are variable.Thus, there is no consensus in the literature between the presence of hearing loss and this infection.While some authors report that such infection is a RIHL in children (Al-Amari and Kameswaran, 1996;Andrade et al., 2008;de Resende et al., 2010;Vos et al., 2015;Besen et al., 2022), other studies do not find this association (Lipka et al., 2002;Austeng et al., 2010).
Given the above, the objective of this study is to verify what are the auditory disorders observed in children with CT.

Materials and method
This literature review was structured according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and based on the terms of PICOS (Participants, Interventions, Comparators, Outcomes, and Study Design).

Eligibility criteria
Studies based on PICOS terms that evaluated the association between congenital toxoplasmosis and the presence of auditory disorders were included.PICOS stands for Study Target Population, Intervention, Comparison, Outcomes, and Study Types.Target population (P) corresponds to children; intervention (I) relates to congenital infections; comparison (C) was considered as children without congenital infections and typical audiological development; outcome (O) refers to the existence or not of auditory disorders; and the types of studies admitted (S) were observational, cohort, cross-sectional and randomized clinical trials.No restrictions were applied regarding language and year of publication.The studies should also obtain a score greater than 80% in the Study Quality Assessment Tools, showing that this is a high-quality study.
Studies that did not address the subject of this review, which were not carried out with the target population, reviews, letters, books, conference abstracts, case reports, case series, systematic and literature reviews, and opinion articles were excluded.

Search strategy
To obtain the studies, the following electronic databases were consulted: PubMed, Web of Science, Scopus and Lilacs.The  To investigate the association between maternal T. gondii infection during pregnancy and subsequent risk of AP in the offspring.
22 of the 27,727 children (0.08%) had HL.Forty women had T. gondii in pregnancy and none of their offspring had PA.
There was also no association between T. gondii infection before pregnancy and AP in the offspring.To describe the audiological and language evolution in children with diagnosed CT and treated early.
106 children were diagnosed with CT, of which 60 had normal hearing (56.6%) and 46 had altered hearing, 13 (12.3%)with conductive alteration, 4 (3.8%) with SNHL and 29 (27, 4%) with retrocochlear involvement.There was an association between the presence of hearing alteration and language deficit.Even with early diagnosis and treatment, a high prevalence of audiological impairment was observed in children with CT.There seems to be strong circumstantial evidence to consider CT as one of the important factors in the etiology of congenital deafness in our population.

McGee et al., 1992
A total of 30 congenitally infected infants and children; BAEP.
To verify the occurrence of hearing loss in children with treated CT.
The preliminary results we describe suggest that HL may be less frequent than previously reported in children with treated CT.This could be because of the prolonged antimicrobial therapy these children received.research was carried out between May 2023 and June 2023, with individual search strategies by two researchers.Manual searches were also performed in bibliographic references in order to include relevant studies.
The combined terms used for the search were: ("auditory evoked potentials" OR "hearing" OR "hearing loss") AND ("congenital toxoplasmosis").Filters referring to the year of publication and language were not applied, however, filters related to the age of the sample were applied.

Selection of studies
The selection of articles was carried out independently, blindly, by two of the authors, avoiding any risk of bias.In this way, the names of authors and journals were masked to avoid any potential bias and conflict of interest.The articles were, at first, selected by title and abstract and were excluded for not respecting at least one of the inclusion criteria.The remaining articles were read in full and evaluated for eligibility.Any disagreement was resolved by discussion.

Risk of bias in individual studies
The risk of bias analysis was also performed independently, blindly, by two of the authors and subsequently agreed between them and a third author.For the analysis, the questionnaires of the Systematic reviews of etiology and risk instruments were used, specifically the Critical appraisal checklist for analytical crosssectional studies and the Critical appraisal checklist for cohort studies.The final quality of each article was categorized by the following scores of answers "Yes, " "No" and "Little applicable, " being >70%, low risk of bias; between 50 and 69%, moderate risk of bias; <50%, high risk of bias.

Data extraction, synthesis and analysis
The information extracted from the studies were: authors, year of publication, age group studied, sample size, objective, results, and conclusion (Table 1) to then evaluate the association between congenital infections and hearing disorders.The extracted data were analyzed descriptively and comparatively.When any of this information was not available, the corresponding author was contacted by email.

Selected studies
In the blind selection of articles, the researchers identified 172 articles.After removing duplicates, 105 studies were selected for eligibility according to the criteria previously established.Finally, 11 studies were selected for full-text reading after careful title and abstract screening.A total of 94 studies were excluded (16 for being a systematic review, eight for being case studies, one for not finding the full text and 70 for not addressing the proposed topic).An article was selected from the list of references.Therefore, 12 studies were included for the final analysis.Supplementary Figure 1 demonstrates the study selection process in detail.

Characteristics of the studies
The selected studies were published between 1977 and 2021, with a greater number of publications between 2000 and 2010.All studies were published in English, four of which are also available in Portuguese.As for the design of the studies, 13 cross-sectional studies and one cohort study were selected.The vast majority of studies evaluated children from 1 day of life to 2 years of age.
It was observed that a significant percentage of studies sought to study the peripheral auditory pathway, verifying the occurrence or association between hearing loss and the presence of congenital infection.Only two studies evaluated the central auditory pathway, using the Brainstem Auditory Evoked Potential (BAEP) and the Frequency Following Response (FFR).
The authors verified the existence of both hearing loss (Al-Amari and Kameswaran, 1996;de Azevedo et al., 2000;Andrade et al., 2008;de Resende et al., 2010) and increased latency values in the BAEP and FFR responses (de Resende et al., 2010;Fontes et al., 2019;Ferreira et al., 2020).Therefore, the auditory pathway of children with CT can be affected both at the peripheral and central hearing levels.
To illustrate the analyzed studies, a table was prepared with the description of each one of them, with the identification of authorship, year of publication, title, objective, results and conclusion (Table 1).

Quality assessment
The quality assessment of the studies indicated that most of the studies were considered at low risk of bias, two studies were 10.3389/fpsyg.2023.1286211categorized with moderate risk of bias and one with a high risk of bias.Table 2 shows the details of this analysis.

Discussion
Together, the data found in this review show that children with congenital toxoplasmosis may have both hearing loss (Al-Amari and Kameswaran, 1996;de Azevedo et al., 2000;Andrade et al., 2008;de Resende et al., 2010) and alterations in central auditory pathways (de Resende et al., 2010;Fontes et al., 2019;Ferreira et al., 2020).Thus, this infection should be pointed out as a risk for disturbances in the peripheral and central auditory pathway.This finding suggests children with CT should undergo, besides typical audiological assessments, other more specific procedures for differential diagnosis.
Regarding the presence of hearing loss in children with CT, the literature does not demonstrate a consensus, as previously mentioned.While some authors found an association with hearing loss (Al-Amari and Kameswaran, 1996;de Azevedo et al., 2000;Andrade et al., 2008;de Resende et al., 2010) and language disorders (de Resende et al., 2010), another study did not find any association (Austeng et al., 2010).
Still regarding the degree of sensory auditory deficit, there is no significant relationship that children with congenital toxoplasmosis have profound hearing loss (Noorbakhsh et al., 2019).There is a greater correlation between children with CT and cases of mild to moderate hearing loss (Noorbakhsh et al., 2019).
Similar data were found in two studies that sought to understand the relationship between CT, hearing loss and possible changes in the Central Auditory Processing (CAP) (de Azevedo et al., 2000;de Resende et al., 2010).The results of these studies indicated that 54.2% to 56.6% of children with CT do not have auditory alterations, 12.3% to 12.5% have transient and conductive alterations, 3.8% have peripheral sensorineural alterations, 27.4% have retrocochlear changes and 33.3% have CAP changes (de Azevedo et al., 2000;de Resende et al., 2010).
In view of this, it is inferred that children with CT may demonstrate alterations in the basic diagnosis of hearing, evidenced by both conductive and sensorineural hearing loss.When performing differential assessments, children may also manifest changes in CAP.
The presence of clinical neurological manifestations in children with CT makes it essential to carry out the differential diagnosis of hearing.Through the evaluation of the central auditory nervous system, research has shown that children with CT may present alterations both at the brainstem level and at the subcortical and cortical levels (de Resende et al., 2010;Fontes et al., 2019;Ferreira et al., 2020).
At the brainstem level, the literature highlights that a child with CT, aged between 1 and 3 months, has a five times greater risk of manifesting an alteration in BAEP when compared to a child without the disease (Fontes et al., 2019).Furthermore, alterations at the subcortical and cortical level were verified through the FFR evaluation.The authors report that the group of children with CT showed a statistically significant increase in the latency of V, A, E, F, and O and a decrease in the amplitude of the A and F waves (Ferreira et al., 2020).Another interesting fact, when evaluating a group of children only exposed to toxoplasmosis during pregnancy, the authors observed that these children did not differ from the non-exposed group in terms of cochlear and conductive hearing loss, although they presented a higher occurrence of possible retrocochlear alteration (Leite Filho et al., 2017).Researchers, who report neurophysiological delays in the central auditory pathway of children with CT when compared to neurotypical children, do not detail whether the group with the infection is behavior for term-born children.Considering that prematurity can cause immaturity in the auditory pathway and consequently delay in the latency of the waves of such potentials, this discussion would be interesting.
Given these data, the relevance of evaluations classified as differential diagnosis in this population is highlighted.It can be concluded that toxoplasmosis does not affect only the peripheral portion of the auditory pathway and that other evaluations deserve attention.However, more research is needed to establish in more detail the links and reflexes of congenital toxoplasmosis in the central auditory nervous system.
A limitation observed among the studies in this literature review is the restriction in relation to birth and health data and the demographic profile of the participants, which made it difficult to detail the characteristics of the population.There is a lack of research that portrays the co-occurrence between CT and other RIHLs, such as prematurity, permanence in the intensive care unit and use of ototoxic medications, in addition to reporting whether the existence of another RIHL increases or not the chances of hearing disorders.
In addition, another gap is the lack of longitudinal studies that follow the development of hearing and language of children with CT, since the consequences of this infection may be late.Therefore, it is recommended that studies be conducted to provide information regarding central auditory nervous system evaluations and to correlate the auditory disorders present in this population with their impact on the language of these children.
However, understanding the importance of an integral peripheral and central auditory system for the child to have an adequate acquisition and appropriation of language, such findings lead to a concern regarding child development.For this reason, the importance of audiological and language monitoring within newborn hearing screening programs is highlighted, as already mentioned in the literature (Lewis et al., 2010;Joint Committee on Infant Hearing, 2019).

Conclusion
Given these data, the relevance of evaluations classified as differential diagnosis in this population is highlighted.It can be concluded that toxoplasmosis does not affect only the peripheral and most studies suggest that this pathology is a risk factor for peripheral and central impairment.Research has found a greater association between CT and mild to moderate hearing loss, in addition to alterations in exams such as BAEP and FFR.These data recommend that CT be reported as a global public health problem and can help assess complications and impacts of hearing disorders as a result of CT.In addition to serving as support for the development of guidelines for child health services.

TABLE 1
Description of the included studies, presented in descending order of publication.IgM positive was found within 8/45 (17.7%) and also one of these cases (2.2%) had T. gondii-IgG Test.T. gondii was observed to have a relative role within younger cases with profound SNHL, but a greater role within mild to moderate SNHL.
Of the 168 patients, 102 had TORCH laboratory results.Although, no patient tested positive for toxoplasma or syphilis.Austeng et al., 2010A total of 27,727 children born in Norway between the years 1992-1994; Pre-and post-natal serological examination.
in ten of 59 patients with CMV infection and in 5 of 12 patients with CT.These data establish congenital infections as an important public health problem and confirm the fact that CT may be associated with late-appearing deficits.BAEP, Brainstem Auditory Evoked Potential; CT, Congenital toxoplasmosis; SNHL, sensorineural hearing loss; RIHL, Risk indicator for hearing loss; CAP, Central Auditory Processing; HL, Hearing loss; T. gondii, Toxoplasma gondii; CMV, cytomegalovirus.

TABLE 2
Risk of bias analysis based on the instrument's questionnaires.