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Abstract

Objective:

Congenital toxoplasmosis is a condition caused by Toxoplasma gondii infection during pregnancy that can lead to serious consequences, including sensorineural hearing loss. This systematic review aimed to evaluate the efficacy of pharmacological treatment of congenital toxoplasmosis in mitigating hearing loss sequelae in children.

Methods:

The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered in Prospero under the number CRD42024581716. Defined according to the PICO strategy (P: population/patients; I: intervention/exposure; C: comparison/control; O: outcome), a search was conducted on 29 August 2024, in the following databases: Embase, Lilacs, PubMed, SciELO, Scopus, and Web of Science.

Results:

Of the 396 studies initially identified, 10 met the inclusion criteria, and 2 additional studies were included through manual search, totaling 12 articles for the review. The selected articles lacked standardization regarding therapeutic protocols, with most studies being from Brazil, where the regimen of sulfadiazine, pyrimethamine, and folinic acid for 1 year is recommended. Moreover, despite region-specific therapeutic schemes, a considerable portion of cases still exhibited auditory sequelae, suggesting a potential inefficacy of the implemented protocols.

Conclusions:

There are a small number of studies on the treatment of toxoplasmosis, and its effects on avoiding hearing outcomes are understudied. Locally, there is a need to establish good outcomes and targets to intervene. Strategies to improve adherence to long-term treatment, adjusts to the therapeutic protocol, alongside the promotion of research on the efficacy of treatments for specific outcomes of toxoplasmosis are necessary, especially in places where more virulent strains can be responsible for more aggressive infections and worse prognosis.

Keywords

Congenital toxoplasmosis hearing loss treatment auditory sequelae

Introduction

Toxoplasmosis is an infectious disease with significant prevalence in the world, being especially high in tropical regions and developing countries.^1–3 Regarding IgG seroprevalence, the Americas show the highest estimated prevalence at 45.2%, followed by the Eastern Mediterranean (39.7%), Africa (36.5%), Europe (30%), Southeast Asia (25%), and finally, the Western Pacific region (11.2%). As for IgM seroprevalence, which predominantly reflects active infections, the highest prevalence is found in Europe at 39%, followed by the Americas at 37%, the Western Mediterranean at 36%, Africa at 22%, the Western Pacific at 22%, and Southeast Asia at 17%.⁴ Toxoplasmosis is caused by systemic infection with Toxoplasma gondii, an intracellular protozoan parasite. Since, in most adult cases, the infection is asymptomatic, the importance of toxoplasmosis in humans remained unclear until the first reports of its congenital form.⁵ The T. gondii life cycle was understood in the late 1960s with the discovery of the role of felines, as its final host, harboring the parasitic sexual cycle and spreading its oocysts through its feces.⁶ The ingestion of oocysts excreted in cat's feces, or the ingestion of raw, undercooked meat containing its bradyzoite cyst form is the common way of acquiring Toxoplasma infection in humans.⁷

Congenital toxoplasmosis (CT) occurs when a pregnant woman acquires an active, acute infection during pregnancy and, in the parasitemia phase, parasites cross the placental barrier reaching the fetal circulation. The risk of congenital transmission varies with gestational age at the time of infection, increasing from about 10–15% in infections acquired in the first trimester to 70–90% in the ones acquired in the third trimester.⁸ Inversely, the severity of sequelae tends to be more significant in babies infected early in pregnancy.⁹ Common sequelae include mental retardation, seizures, microcephaly, hydrocephalus, ocular lesions, hearing disorders, and psychomotor impairment.¹⁰ Even babies that show no clinical symptoms at birth can present sequelae later in life.¹¹ Congenital infections are a group of perinatal infections that may have similar clinical presentations.¹² Toxoplasmosis is included in the TORCH complex, which refers to congenital infections of toxoplasmosis, others (syphilis, hepatitis B), rubella, cytomegalovirus (CMV), and herpes simplex.¹³ Although congenital CMV infection is the most common and most studied as the main cause of sensorineural hearing loss,¹⁴ CT is one of the main statistically significant risk factors for hearing loss.¹⁵

Many different strains were associated with severity of disease, and the ones occurring in South America are usually more virulent and show greater genetic variability.¹⁶ For instance, Brazil has a high prevalence of virulent strains of the parasite.¹⁰ Atypical strains are common, and they are associated with a higher prevalence of ocular disease compared to other regions of the world.^17,18 Congenitally infected in Brazil may have a 5-fold higher risk than European children of developing ocular lesions and vision impairment.^18,19 Although CT is a known risk factor for sensorineural hearing impairment,²⁰ studies that focus on hearing loss in the context of CT and especially on the effects of toxoplasmosis treatment on mitigating those sequelae are sparse. The rate of hearing loss related to CT is poorly known, and available studies indicate that it varies greatly, ranging from 3.8% to 30%.²¹ Auditory disorders caused by toxoplasmosis are mostly associated with inflammatory response and calcifications in the inner ear and vestibulocochlear nerve.^22,23 It has been established that T. gondii, in its cystic form, can be found in the stria vascularis, spiral ligament, saccular macula, or internal auditory canal, and its tachyzoite form was found associated with immune response in the internal auditory canal,^22,23 making sensorineural hearing loss the most relevant type of hearing loss related to CT.²⁴

T. gondii crosses the blood–brain barrier and establishes persistent infections in the bradyzoite stage, which is resistant to drugs.²⁵ Treatment is based on the biological similarity among parasites of the phylum Apicomplexa.²⁶ The first-line therapy consists of a combination of pyrimethamine and sulfadiazine with leucovorin, added to prevent hematological toxicity. This combination is effective because it acts on different stages of T. gondii's folate metabolism, which is essential for its survival and reproduction.²⁵ Pyrimethamine and sulfadiazine act synergistically against T. gondii, showing a combined activity eight times greater than when used individually.²⁷ Treatment of gestational toxoplasmosis should begin as early as possible. In the first trimester, spiramycin is indicated, as it does not cross the placental barrier, thereby avoiding teratogenic risks. From the 18th week of pregnancy, the triple therapy regimen (sulfadiazine, pyrimethamine, and folinic acid) is recommended, but it is avoided in the first trimester due to the teratogenic potential of pyrimethamine.²⁷ In confirmed cases of CT, the same medications are administered to the newborn, and the treatment should be extended up to 1 year of age.²⁸

Previous reviews on the effects of CT treatment on avoiding neurosensory sequelae are scarce, especially concerning auditory outcomes.^21,24,29 Some previous reviews focused on determining the importance of screening and treatment protocols for toxoplasmosis without associating the impact of treatment with mitigating sequelae/specific outcome.^9,30,31 Up to this moment, important reviews have investigated some of the aspects related to hearing loss in congenital infections.^{24,30,32–34} A robust review that evaluated toxic effects of first-choice drugs for toxoplasmosis found toxicity in 62% of patients and serious side effects. However, the study looked at Toxoplasma encephalitis in adults with acquired immune deficiency, and there was no focus on hearing loss.³⁵ More recent reviews on hearing loss in children have shown greater interest in studying the sequelae caused by CMV.^33,34 We found two recent reviews on the subject, one of which verified the hearing disorders observed in children with CT, but did not consider its association with the type of medication used to treat toxoplasmosis.²⁴ Another one mapped the effects of ototoxic medications on newborn hearing but did not focus on CT medication.³⁶ Considering the available literature at this time, we did not find a systematic survey of studies that associate the presence and type of treatment for toxoplasmosis and hearing loss in babies and children, that could be comparable to what we conducted in this review.

Given the crucial role of auditory input in the development of auditory input for the development of language, speech, and higher cognitive functions that are associated with language,³⁷ and knowing that timely and appropriate identification of hearing impairment is of utmost importance to ensure optimal rehabilitation, we conducted a systematic review aiming to synthesize data on the efficacy of CT treatment in mitigating auditory sequelae.

Method

Search strategies, data sources, and selection process

The search strategy for this systematic review was developed by a series of searches and discussions on the results of the initial screening. This review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020.³⁸

The descriptors were defined according to PICO strategy, where (P) corresponds to the population of interest, that is, children with CT; intervention (I) refers to the pharmacological treatment implemented; comparison (C) refers to the comparison group, noting that the control group may still be absent; outcome (O) refers to the presence or absence of auditory disorders. The research question was formulated to address the following: “What is the effect of pharmacological treatment on auditory outcomes in children diagnosed with CT?”.

Based on this, the validated search strategy was executed on 29 August 2024 and is described in detail in Supplemental Table S1. The results were cross-referenced among the Embase, Lilacs, PubMed, SciELO, Scopus, and Web of Science databases, searching within titles, abstracts, and keywords of the articles.

Eligibility criteria

Were included observational studies that (a) evaluated the associations between the implementation of pharmacological treatments for CT and the outcome, regarding the sequelae, (b) patients have undergone at least one auditory evaluation and (c) were original peer-reviewed articles, with full-text available, focusing on the auditory system assessment of children diagnosed with CT. There were no restrictions on publication date or language.

Exclusion criteria

Articles were excluded if they (a) evaluated children diagnosed after two years of age, (b) reported coinfection or CT in deceased individuals, and (c) were case reports, reviews, editorials, letters, book summaries, congresses, seminars, or opinion articles.

Screening procedure

The screening process began with the removal of duplicate records using the Rayyan AI platform.³⁹ After exclusion, the remaining studies were screened in pairs through a title and abstract review, following the previously established exclusion criteria. The resulting articles were then eligible for full-text reading along with other studies included by manual search. After that, the authors discussed their findings, reaching a consensus and approving the articles for the development of this review. Any disagreements during the selection process were resolved by consensus with a third author.

Quality assessment

The tool used to assess the methodological quality and risk of bias of the studies was the “Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies” created by the National Heart, Lung, and Blood Institute (NHLBI) in 2013.⁴⁰ This tool was not designed to include criteria for classification through a numerical assessment but presents concepts that assist the author in making a judgment and categorizing the study as good, fair, or poor in quality due to flaws in the design or implementation of each study in question.

Data extraction

The data were extracted from the articles using a predesigned form containing the reference, country, and study design. Sample data and study objectives, toxoplasmosis assessment measures, and description of medications were included. Auditory outcomes evaluated and main associations found.

Registration

Registered at PROSPERO, under number CRD42024581716.

Results

Study selection

The initial search presented a total of 396 studies. After eliminating duplicate articles, 197 studies remained for the initial title and abstract screening. Following this analysis, 34 studies were deemed eligible for full-text reading, with four additional studies included from manual search of other articles’ references. A total of 26 studies were excluded, ending 12 studies included (Supplemental Figure S1).

Characteristics of the included studies

The 12 articles involved a total of 831 participants. The included studies are distributed into 10 longitudinal studies and 2 cross-sectional studies, published from 1980 to 2024. Table 1 shows the distribution of this sample by country. Participants’ ages ranged from birth^41,42 to 10 years.⁴³ Data extracted from the included studies are summarized in Table 2. In relation to the gender of participants evaluated in the studies, in five of them, there was no information about the comparison between the two sex categories. In the other seven studies, a lower prevalence of female participants was observed in six of them, with proportions varying from 41.9%⁴⁴ to 45.5%.⁴⁵ In the study with the highest prevalence of female participants, a proportion of 53.94% was observed.⁴⁶

Table 1.

Sample by country.

Country	Number of studies	Total participants
Brazil	4	292
Italy	2	201
USA	3	174
Iran	1	75
Portugal	1	71
Turkey	1	18
Total	12	831

Table 2.

Descriptive characteristics of the included studies.

Reference/country/type of study	N/age/gender/purposes	Toxoplasmosis congenital diagnosis	Treatment	Auditory assessment	Main associations	Quality
Andrade et al., 2008 Brazil Longitudinal	N = 19 Age: No information Gender: No information To analyze hearing loss in CT	Presence of IgM and/or IgA in the first 6 months of life or IgG at 12 months in the blood of babies.	Antimicrobial treatment: sulfadiazine, pyrimethamine and folinic acid during the first year of life.	Otoacoustic emission tests (EOAE) and brainstem evoked auditory potential - BEAP	Four children (21.1%) had neurosensory impairment and two children who were adequately treated still had hearing loss. Additionally, one of these children had other risk factors for hearing loss in addition to toxoplasmosis.	***
Auriti et al., 2022 Italy Longitudinal	N = 18 Age: No information Gender: No information To analyze the association between Toxoplasmosis symptoms and the occurrence of long-term sequelae	Children presenting clinical signs at birth, such as: chorioretinitis, intracranial calcifications, and hydrocephalus and or microcephaly, intracranial calcifications, chorioretinitis, cataracts, convulsions, nystagmus, jaundice, petechiae, anemia, prematurity and severe intrauterine growth restriction, and positive IgG and/or IgM antibodies against T. gondii. Additionally, if they did not have clinical symptoms, they were diagnosed with positive IgG and IgM antibodies against T. gondii, or with an increasing IgG serum level.	Antimicrobial treatment: pyrimethamine and sulfadiazine	Automatic auditory brainstem response (AABR) and brainstem auditory evoked potentials (BAEPs)	In the 1-year follow-up, 1 child presented mild sensorineural hearing loss	**
Filho et al., 2017 Brazil Longitudinal	N = 91 Age: Birth up to 24 months Gender: No information To assess the occurrence of hearing impairment of toxoplasmosis during pregnancy	Patients referred from the institution's Pediatric Infectology Department due to exposure to toxoplasmosis during pregnancy without other risk indicators for hearing loss	Treatment for 1 year with sulfadiazine, pyrimethamine and folinic acid	Acoustic immittance measurements, audiometry with visual and playful reinforcement, brainstem auditory evoked potential by click and tone burst stimuli, suppression of otoacoustic emissions and transient evoked otoacoustic emissions	About children exposed to toxoplasma: 10 (20.8%) had conductive hearing loss, 21 (2.1%) cochlear loss and 10 (20.8%) retrocochlear loss	**
Fontes et al., 2019 Brazil Cross-sectional	N = 76 Age: Between 1 and 3 months Gender: 53.94% females To analyze and compare the results of audiological tests in patients with and without a diagnosis of CT	Infants between 1 and 3 months of age were assessed for toxoplasmosis using IgM serology. If the results were positive, confirmation was achieved through the detection of IgM and/or IgA in the serum, in addition to specific IgG, or by the presence of IgG alongside clinical manifestations of the infection.	Antimicrobial treatment: Sulfadiazine, pyrimethamine and folinic acid during the first year of life.	Transient evoked otoacoustic emissions, brainstem auditory evoked potential, and automatic brainstem auditory evoked potential	A total of 69 ears of patients diagnosed with toxoplasmosis, 10 had altered results while 59 had normal results.	***
Gundeslioglu et al., 2024 Turkey Longitudinal	N = 18 Age: 1 months median Gender: 45.5% females To evaluate the demographic, clinical and treatment characteristics and complications of patients with CT	The maternal infection and prenatal diagnosis by detection of seroconversion during pregnancy or assessment of IgG avidity and antibody kinetics. The postnatal diagnoses include (a) Increase in Toxo IgG titers during the first year of life or compared to the mother; (b) positive Toxo IgG and IgM; (c) positive PCR for T. gondii in cerebrospinal fluid, blood, or urine; (d) positive Toxo IgG beyond 12 months of age; (e) characteristic clinical findings with positive Toxo IgG and negative Toxo IgM.	Antimicrobial treatment: sulfadiazine, pyrimethamine and folinic acid during the first year of life.	Auditory brainstem response (ABR)	Hearing loss was observed in 2 (11.1%) patients in the study	**
Losa et al., 2024 Portugal Longitudinal	N = 71 Age: No information Gender: 45.1% females To analyze suspected cases and incidence of CT in a tertiary hospital.	Maternal serology for T. gondii with proven seroconversion during pregnancy, presence of IgM and IgG, or positive IgM with negative IgG, positive PCR for toxoplasmosis in the amniotic fluid, and characteristic symptoms of CT.	Antimicrobial treatment: spiramycin or pyrimethamine, sulfadiazine, and folinic acid or spiramycin, pyrimethamine, sulfadiazine, and folinic acid	No information	1 case out of 71 suspects presented alterations in the audiological examination	***
McGee et al., 1992 USA Longitudinal	N = 30 Age: Birth up to 17 months Gender: No information To evaluate the feasibility and safety of treatment for CT.	Presence of Toxoplasma IgM detected in neonatal serum or in cerebrospinal fluid and/or Toxoplasma IgM or Sabin Feldman dye test >300 IU in maternal serum with clinical symptoms of toxoplasmosis.	Antimicrobial treatment: pyrimethamine, sulfadiazine, or spiramycin.	Auditory brainstem response (ABR)	No children had sensorineural hearing loss, and the results suggest that hearing loss in children with CT treated for 1 year may be less frequent than in children treated for shorter periods, possibly because of prolonged antimicrobial therapy.	***
McLeod et al., 2006 USA Longitudinal	N = 120 Age: 10 years (4.2) Gender: 45% females To analyze results after monitored treatment throughout the first year of life in CT	The diagnosis was based on infants under 2.5 months of age with clinical symptoms and tests conducted in the Toxoplasmosis Serology Laboratory.	Treatments: daily doses of pyrimethamine (1 mg/kg) were given for 2 months or 6 months. After that, this dose was given only 3 times a week for the remainder of 1 year. Sulfadiazine (100 mg/kg/day, divided into 2 doses) and leucovorin were given for 12 months.	No information	There were no patients with hearing loss	***
Noorbakhsh et al., 2019 Iran Cross-sectional	N = 75 Age: No information Gender: 41.9% females To assess the immunity to T. gondii and Cytomegalovirus in children who have undergone cochlear implant surgery and present with profound idiopathic	Enzyme-linked immunosorbent assay and the antibodies were calculated qualitatively by cut-off controls according to the manufacturer's instructions	Iranian population has previous immunity to T. gondii ranging from 24% to 57.7%	Diagnosis of profound Sensorineural Hearing Loss (SNHL) if acuity < 95 dB is present	Children diagnosed with deep SNHL had T. gondii IgM positivity in 17% (8/45) and IgG positivity was detected in 2.2% (1/45). Additionally, the control group had IgG positivity in 60% (18/30) cases and no cases of IgM positivity.	*
Resende et al., 2010 Brazil Longitudinal	N = 106 Age: 50 days (15.4) Gender: 45.3% females To analyze hearing and language in CT treated early	Presence of IgA and/or IgM in the first 60 days of life, or by the persistence of IgG at the end of 12 months of age	Antimicrobial treatment: Sulfadiazine, pyrimethamine and folinic acid during the first year of life.	Measurements of acoustic immittance, transient and distortion product evoked otoacoustic emissions, brainstem auditory evoked potential and observation of auditory behavior.	46 children had hearing impairment. Additionally, 13 children (12.3%) had conductive impairment, 4 (3.8%) had sensorineural hearing loss and 29 (27.4%) had central dysfunction.	***
Salomé et al., 2024 Italy Longitudinal	N = 183 Age: Gender: To define guidelines for audiological monitoring in CT	Detection of Toxoplasmosis DNA in amniotic fluid, positive Toxoplasmosis IgM and/or IgA at birth and positive immunoblotting OR an increase in IgG in the First months of life with symptoms clinics, radiological and laboratory evaluation	Variants doses of pyrimethamine, sulfadiazine and leucovorin	Transient evoked otoacoustic emissions, visual reinforcement audiometry, conditioned play audiometry, acoustic immittance, and brainstem auditory evoked potential by click stimuli.	No patient had late hearing loss, regardless of whether they received treatment or not.	***
Wilsom et al., 1980 USA Longitudinal	N = 24 Age: No information Gender: 45.83% females To analyze children diagnosed with toxoplasmosis and define the frequency and severity of late sequelae	Screening of cord serum on infants for IgM antibodies and IgG and IgM Toxoplasma antibodies.	Antimicrobial treatment: pyrimethamine and sulfadiazine or pyrimethamine and trisulfapyrimidines.	Hearing thresholds obtained by pure tone audiometry and speech audiometry	A total of 5 patients with toxoplasmosis presented hearing loss, 2 of whom had mild bilateral loss. It is not known which received treatment or not.	***

***

Good quality.

Fair quality.

Poor quality.

Regarding the objective of the studies, four of them contained aspects related to the treatment itself of CT, whether involving the feasibility and safety of the treatment,⁴² or the mitigation of sequelae associated with the implementation of the treatment.^43,47 In five of the remaining studies, the objective was to analyze the symptoms and sequelae of CT, always with a greater focus on the auditory aspect of the disease.^{41,46,48,49,50}

CT diagnosis assessment

Among the included studies, only one did not specify the diagnostic method for CT, with the sample consisting of patients referred from a tertiary hospital.⁴¹ The other studies presented an analysis based on immunoassay tests for specific immunoglobulins for toxoplasmosis, specifically: in one study, IgM alone was used as a diagnostic criterion;⁴² IgM and IgG were used together in four studies;^45,49–51 IgA, IgM, and IgG were used in four studies;^46–48,50 and two other studies^43,44 did not specify which immunoglobulins were analyzed in diagnostic method.

Regarding the material used for immunoglobulin analysis, there was great variation in the methods employed, with many studies not clarifying the source of the material analyzed.^{41,43,44,46–48} Additionally, other studies mentioned the analysis of maternal serum, patient serum, cerebrospinal fluid, urine, and amniotic fluid among their methodologies.^{42,45,49–52}

Patients’ clinical signs and symptoms were also used as complementary diagnostic criteria in seven studies.^{42,43,45,46,49,51,52} For the remaining studies,^{41,44,47,48,50} there was no information on whether this data was used as a complementary diagnostic method.

Finally, regarding the timing, the diagnosis was made both during pregnancy, with the serological conversion of the mother,^45,51 and after birth, with infants being diagnosed within the first 12 months of life.^47,48 In the other studies,^{41–44,46,49,50,52} there is no precise information on when the material was collected for diagnosis.

Analysis of therapeutic strategies

The treatment used in five studies^41,45–48 consisted of sulfadiazine, pyrimethamine, and folinic acid administered for 12 months after birth. Four of these studies^41,46–48 included samples from Brazil, while one study⁴⁵ involved a sample from Turkey. Additionally, one study with a sample from Portugal⁵¹ used the same therapy, with the inclusion of spiramycin, resulting in combinations of spiramycin, pyrimethamine, sulfadiazine, and folinic acid.

Two other studies^43,52 reported treatment with various regimens of pyrimethamine, sulfadiazine, and leucovorin, with samples from the USA and Italy, respectively. Furthermore, two additional studies with samples from the USA reported different treatment regimens, specifically, pyrimethamine and sulfadiazine, or pyrimethamine and trisulfapyrimidines,⁵⁰ and pyrimethamine, sulfadiazine, or spiramycin.⁴² Another study from Italy reported a treatment regimen of pyrimethamine and sulfadiazine.⁴⁹

An exception was found in our results, in which no treatment was specified. In the Iranian population, there is a high population immunity to T. gondii, and screening for intrauterine infections either during pregnancy or in neonates is not available, so that the study aimed at determining immunity to T. gondii among children with cochlear implant surgery due to idiopathic sensorineural hearing loss.⁴⁴

Regarding the treatment dosage, only one study⁴³ provided the medication dosages: pyrimethamine (1 mg/kg) daily for up to 6 months and then three times a week for 1 year and sulfadiazine (100 mg/kg/day) divided into two doses. Additionally, the studies that used sulfadiazine, pyrimethamine, and folinic acid^41,45–48 did not report dosages but indicated the treatment duration, which was 1 year.

Auditory assessment

For the evaluation of hearing acuity, eight studies^{41,42,45–49,52} used auditory brainstem response (ABR) tests either as part of their auditory assessment methodology or as the sole method. ABR is an electrophysiological test that can tell us about the integrity of auditory pathways and bioelectrical responses to frequencies that includes the human speech range of frequencies.^53,54 Even if it does not test the entire range of audible frequencies, as a screening test, it is safe and fast and can signal the presence of important hearing losses in patients that can then be referred for diagnosis, where other approaches and methods can be used according to each case to close the diagnosis.⁵⁵ Six of those studies also used otoacoustic emissions (OAEs). Both tests are considered adequate methods for universal hearing screening.⁵⁵

Three other studies^44,50,51 employed different methodologies; the first did not specify the method for assessing hearing loss, having informed only that patients were candidates for cochlear implant surgery due to idiopathic profound sensorineural hearing loss; the second informed that the assessment was made by auditory screening, not specifying the methods employed for that end (if either ABR and/or OAE); and the last one used pure tone and speech audiometry.

One of the included studies⁴³ did not provide information as to how the audiological evaluation was conducted, informing only that tests were carried out by audiology specialists.

Main associations assessment

Nine of the included studies^41,44–51 reported patients with some degree of hearing loss. Three other studies found no association between hearing loss and CT.^42,43,52

Regarding the association between treatment and the incidence of hearing loss, two of the studies that showed no hearing loss association^43,52 applied the same treatment protocol for toxoplasmosis: pyrimethamine, sulfadiazine, and leucovorin. In another study that also showed no association,⁴² the infected individuals were treated with pyrimethamine, sulfadiazine, or spiramycin.

Among the studies that reported some degree of hearing loss, five^41,45–48 used the treatment regimen of sulfadiazine, pyrimethamine, and folinic acid. One study⁵¹ applied the same therapy with the inclusion of spiramycin, with different combinations of spiramycin, pyrimethamine, sulfadiazine, and folinic acid.

Another study⁴⁹ used only pyrimethamine and sulfadiazine, while one study⁵⁰ treated patients similarly, with an additional drug to the combination, resulting in pyrimethamine and sulfadiazine or pyrimethamine and trisulfapyrimidines. In one study,⁴⁴ the patients were not identified nor treated in pre or postnatal periods due to the assumed pre-existing populational immunity to toxoplasmosis, which led to a late diagnosis of CT cases, made when hearing loss was already established.

In terms of the countries of origin, all studies with samples from Brazil reported hearing alterations.^41,46,47,48 Among the studies from the USA, two showed no hearing loss,^42,43 while one reported hearing impairment, but did not specify whether or not the sample with higher incidence of hearing loss received treatment.⁵⁰ Among studies from Italy, one reported no hearing loss,⁵² and the other observed only one patient with mild sensorineural hearing loss.⁴⁹ The remaining studies with samples from Iran, Portugal, and Turkey^44,45,51 all showed findings of hearing impairment.

Quality assessment

The summaries of the quality assessment for cross-sectional and longitudinal studies are presented in Table 2 and Supplemental Table S2, according to the items of the ‘Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies’ from the NHLBI. Of the 12 observational studies assessed, 8 (66.67%) were of good quality, 3 (25%) were of fair quality, and 1 (8.33%) was of poor quality.

Discussions

This systematic review is an attempt to gather and provide compiled evidence about the effectiveness of CT treatment in minimizing hearing loss sequelae. CT faces challenges related to the lack of funding, low prioritization as a public health issue, and difficulties in carrying out studies, especially due to ethical–legal restrictions. The scarcity of funding and the lack of prioritization are interconnected, since in a limited resources scenario, it is not strategic for the state to invest in research and treatments aimed at low prevalence conditions, given the need to allocate resources to more prevalent and urgent health issues.

Brazil, which concentrates most of the studies on CT, had around 12,120 confirmed cases of CT in the year 2022.⁵⁶ Meanwhile, other conditions have significantly higher prevalence, such as congenital syphilis, also part of TORCH infections, with more than 27 thousand confirmed cases in the same year, presenting greater population impact.⁵⁷ This context, as said, reinforces the need to prioritize more common illnesses, which ends up resulting in a smaller amount of research dedicated to CT. Furthermore, there are significant ethical–legal limitations for carrying out studies on pregnant women, a central group for understanding the disease. Although these restrictions are fundamental to ensuring humanization and safety in scientific research, they make it difficult to conduct clinical trials on pregnant women, which, in turn, slows down the advances in the discovery of new drugs and more effective treatments.⁵⁸

Most studies included in this analysis have reported the occurrence of hearing loss in CT patients, especially in samples originating from Brazil,^41,46–48 supporting the suggestion of a possible association between more virulent strains and the severity of sequelae. High prevalence of atypical strains and greater genetic variability of T. gondii in Brazil can also be a determinant factor to more severe manifestations and not necessarily associated with inefficacy of drug treatment strategies.¹⁶

Studies that did not report hearing loss assessed samples from USA and Italy^42,43,52 and can indicate the influence of regional differences in strains virulence, either regarding its epidemiological profiles or its response to treatment. Those observations can suggest that response to treatment and severity of clinical manifestations can be intrinsically linked to the parasitic local characteristics, thus demanding for differential therapeutic and preventive approaches in regions of higher observed virulence such as Brazil.¹¹

Due to the limited number of research dedicated to auditory outcomes in CT, included studies presented a heterogeneity of methods and treatment schemes, making it difficult to synthesize our findings and conclusions. Diagnostic and treatment data were not always complete or clear. This is partly due to the fact that auditory outcomes are not the focus of most of the rigorous and robust research in this field. Well-designed, current research with clear methods that evaluate diagnosis and treatment are available but are not focused on the auditory sequelae of CT.^59,60

Many studies in this review evaluated toxoplasmosis through serological tests, probably due to the time in which they were conducted, since in our methodology, there were no restrictions on publication date, or due to the guidelines of the health service in which it occurred. We know that IgG antibodies against T. gondii persist for years and can be a reliable serological biomarker for diagnosing previous exposure to the parasite.⁶¹ Current evidence, however, suggests that serological methods should be confirmed by molecular tests for CT diagnosis.⁶² Comparison of immunological and molecular methods and different types of biological samples for lab diagnosis of toxoplasmosis are more explored in studies focused on ocular outcomes, even in regions where toxoplasmosis may be more virulent and CT is more prevalent.⁶³ Nowadays, the gold standard for the detection of CT is PCR, due to its high sensitivity and ability to identify the DNA of T. gondii. However, in developing countries, the analysis of IgA, IgM, and IgG immunoglobulins represents an effective and more cost-efficient alternative. When analyzed together, these immunoglobulins offer high sensitivity and specificity, particularly in contexts where maternal serological history is available. This approach enables reliable large-scale diagnoses, reducing the need for more expensive and complex methods.⁶⁴

In addition to toxoplasmosis, the use of aminoglycosides was seen as a risk factor for postnatal hearing loss, in a previous review.³² However, the authors found inconclusive results, largely due to studies with small samples and conducted in only one location. Ototoxicity, an adverse reaction that can affect the inner ear or auditory nerve, is a known risk with the use of some medications commonly prescribed in neonatal intensive care unit.^36,65 Monitoring ototoxicity, however, can be a challenge.³⁶ The studies included in this review are unclear regarding the monitoring of hearing loss caused by ototoxicity, so the results must be interpreted with caution given the frequent use of those medications in hospitalized neonates.³⁴

Another important issue is the monitoring of CT-directed treatment. Toxoplasmosis treatment failures during clinical trials have been difficult to characterize. Those are most often due to nonadherence to long-term treatment and to a variable tolerance or absorption of medication itself.²⁶ Those factors were present in some studies included in this review, also making it difficult to generalize our results. Considering the child's general health picture, a recent study corroborates our findings on the importance of maternal screening for toxoplasmosis, since the treatment of pregnant women led to a much smaller number of affected babies.⁵⁹ In practice, studies like this could equip health professionals in the implementation of greater rigor regarding the drug treatment of CT patients.

Regarding the efficacy of treatment, some of the studies showed that a considerable proportion of children treated for CT still presented some auditory impairment,^41,44–51 suggesting that drug therapy may not be completely effective in mitigating auditory sequelae in all cases, especially in regions where the T. gondii strains are more virulent. Thus, although the drug treatment is widely used and recommended, the results suggest that it might need adjustments or complementation in areas with more aggressive strains.

Magnetic resonance imaging (MRI) findings also play a crucial role in the neurological prognosis of patients with CT. Alterations such as ventriculomegaly, cyst formation, and abnormal myelination patterns are frequently identified and associated with neurosensory deficits, including hearing loss.^66,67 These structural markers, in addition to indicating the severity of brain impairment, allow for a more precise assessment of the risk of neurological and auditory sequelae.⁶⁶ Changes in the cochlear nerve, enlarged vestibular aqueduct, and other structural abnormalities, often detected by MRI, have a direct impact on auditory prognosis and language development.^66,67 In children with congenital sensorineural hearing loss, early identification of these abnormalities could guide interventions such as the use of hearing aids or cochlear implants. When performed early, these interventions are essential to mitigate the effects of hearing loss on cognitive and social development.⁶⁷ Although Auriti et al.⁴⁹ did use MRI as part of the CT diagnostic process for some of the samples, unfortunately none of the studies in our survey included MRI data specifically focused on hearing outcomes. Those tests can be expensive and thus not suitable for screening but could be an important part of the diagnostic process when available.

Another important aspect to mention is the potential confounding variables that were not addressed in the selected articles for this review. Factors such as prematurity, length of stay in neonatal units, and family history were not considered. Prematurity may bias auditory tests due to the underdevelopment of neonates’ auditory systems, potentially resulting in false-negative outcomes.⁶⁸ The issue of neonatal units relates to the noise levels produced by the machines, which, despite being standardized at 45 dB, can exceed this limit in some cases.⁶⁹ In the long term, this could lead to sensorineural hearing sequelae in children, independent of toxoplasmosis or its treatment. Lastly, family history may predispose individuals to genetic alterations that reduce auditory,⁷⁰ potentially serving as a concomitant cause alongside the diagnosis of CT.

Limitations and future directions

The limitations of this review stem from the small number of articles found. Although it was possible to identify some relevant studies, the reduced number of publications limits the robustness of the conclusions and the generalization of the results. This scarcity of literature may be related to the lack of focus on toxoplasmosis, as it is not a prevalent disease in first-world countries.

Additionally, there is a diversity of methodological and contextual information, resulting in highly heterogeneous findings. This heterogeneity complicates a more precise analysis of the results presented and hinders the possibility of conducting a meta-analysis. Finally, not limiting the publication date was a strategy to capture a larger number of studies. However, the inclusion of older studies presents challenges to the robustness of the findings. Older studies, mostly conducted in global south countries, often lacked methodological rigor, which is understandable given the urgency of the health measures needed in the absence of precise diagnostics. The lack of strict control over medication use, treatment standardization, and participant retention until the end of the studies adds a degree of fragility to the results.

For future research, it is necessary to carry out population-based studies on already existing programs for detecting hearing loss after birth that could improve current practices and contribute to the creation of evidence-based guidelines for hearing monitoring. Furthermore, the inflammatory process present in acute toxoplasmosis recruits macrophages as the first line of defense;^71,72 therefore, increasing drug absorption by macrophages may be an important target during the development of new, more effective drugs.⁷³

Conclusion

This systematic review highlights the scarcity of scientific literature on the treatment of CT regarding its effects on mitigating auditory outcomes. It was often not possible to identify whether the long-term treatment was fully monitored, and the nonadherence is a confounding factor. The lack of complete data, the methodological heterogeneity of included studies, and known differences among T. gondii strains from different parts of the globe also makes it difficult to establish a causal relationship between treatment effectiveness and the presence or absence of hearing loss. Confounding factors must be addressed to avoid biases in future analyses and to more precisely determine the causality of auditory sequelae. Finally, there is a need to encourage further research on CT and its auditory outcomes and to consider implementing specific therapeutic protocols to prevent auditory sequelae in infected children.

Supplemental Material

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Supplemental material, sj-docx-1-sci-10.1177_00368504251320834 for The effectiveness of congenital toxoplasmosis treatment in minimizing hearing loss: A systematic review by Renata Maria Silva Santos, Raquel Liboredo, André Soares da Silva, Athos Paixão Silva Santos, Luciana Macedo, Marco Aurélio Romano-Silva and Débora Marques de Miranda in Science Progress

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Supplemental material, sj-docx-4-sci-10.1177_00368504251320834 for The effectiveness of congenital toxoplasmosis treatment in minimizing hearing loss: A systematic review by Renata Maria Silva Santos, Raquel Liboredo, André Soares da Silva, Athos Paixão Silva Santos, Luciana Macedo, Marco Aurélio Romano-Silva and Débora Marques de Miranda in Science Progress

Footnotes

Acknowledgements

FAPEMIG.

Author contributions

R.M.S.S., R.L.P., and A.S.S.: conceptualization, methodology, investigation, data curation, formal analysis, and writing – original draft. A.P.S.S.: data curation, formal analysis, and writing – original draft. M.A.R-S.: supervision and funding acquisition. D.M.M.: conceptualization, validation, writing – review & editing, and supervision.

Data availability

All data will be available with the published article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project is funded by the government agencies Fundação de Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Instituto Nacional de Ciência e Tecnologia Neurotech-R.

ORCID iDs

Raquel Liboredo

André Soares da Silva

Débora Marques de Miranda

Supplemental material

Supplemental material for this article is available online.

References

Prado-Rangel

Moreira-Souza

ACA

da Silva

SRB

, et al. Inflammatory response and parasite regulation in acute toxoplasmosis: the role of P2X7 receptor in controlling virulent atypical genotype strain of Toxoplasma gondii. Front Immunol 2024; 15: 1452828. Published 2024 Aug 29.

Barbosa

Holanda

CMCX

de Andrade-Neto

. Toxoplasmosis screening and risk factors amongst pregnant females in Natal, northeastern Brazil. Trans R Soc Trop Med Hyg 2009; 103: 377–382.

Mitsuka-Breganó

Lopes-Mori

FMR

Navarro

. orgs. Toxoplasmose adquirida na gestação e congênita: vigilância em saúde, diagnóstico, tratamento e condutas [online]. Londrina: EDUEL, 2003, 2010. p.62. ISBN 978-85-7216-676-8. Available from SciELO Books.

Bigna

Tochie

Tounouga

, et al. Global, regional, and country seroprevalence of Toxoplasma gondii in pregnant women: a systematic review, modelling and meta-analysis. Sci Rep 2020; 10: 12102. Published 2020 Jul 21. doi:10.1038/s41598-020-69078-9.

Schwartzman

Maffia

. Congenital toxoplasmosis. J Pediatr 1948; 33: 66–73.

Hutchison

Dunachie

Siim

, et al. Life cycle of Toxoplasma gondii. Br Med J 1969; 4: 06.

Montoya

Liesenfeld

. Toxoplasmosis. Lancet (London, England) 2004; 363: 1965–1976.

Dunn

Wallon

Peyron

, et al. Mother-to-child transmission of toxoplasmosis: risk estimates for clinical counselling. Lancet 1999; 353: 1829–1833.

Peyron

Wallon

Liou

, et al. Treatments for toxoplasmosis in pregnancy. Cochrane Database Syst Rev 2000; 1999: CD001684.

10.

Robert-Gangneux

Dardé

. Epidemiology of and diagnostic strategies for toxoplasmosis [published correction appears in Clin Microbiol Rev. 2012 Jul;25(3):583]. Clin Microbiol Rev 2012; 25: 264–296.

11.

Denis

Lemoine

J-P

L'ollivier

, et al. Contribution of serology in congenital toxoplasmosis diagnosis: results from a 10-year French retrospective study. J Clin Microbiol 2023; 61: e0035423.

12.

Leung

KKY

Hon

Yeung

, et al. Congenital infections in Hong Kong: an overview of TORCH. Hong Kong Med J 2020; 26: 127–138.

13.

Jaan

Rajnik

. TORCH Complex. In: StatPearls. Treasure Island, FL: StatPearls Publishing, July 17, 2023.

14.

Schleiss

Blázquez-Gamero

. Universal newborn screening for congenital cytomegalovirus infection. Lancet Child Adolesc Health 2025; 9: 57–70.

15.

Alhazmi

. Risk factors associated with hearing impairment in infants and children: a systematic review. Cureus 2023; 15: e40464. Published 2023 Jun 15.

16.

Shwab

Zhu

X-Q

Majumdar

, et al. Geographical patterns of Toxoplasma gondii genetic diversity revealed by multilocus PCR-RFLP genotyping. Parasitology 2014; 141: 453–461.

17.

Furtado

Smith

Belfort

Jr , et al. Toxoplasmosis: a global threat. J Glob Infect Dis 2011; 3: 281–284.

18.

Gilbert

Freeman

Lago

, et al. Ocular sequelae of congenital toxoplasmosis in Brazil compared with Europe. PLoS Negl Trop Dis 2008; 2: e277. Published 2008 Aug 13.

19.

Vasconcelos-Santos

Machado Azevedo

Campos

, et al. Congenital toxoplasmosis in southeastern Brazil: results of early ophthalmologic examination of a large cohort of neonates. Ophthalmology 2009; 116: 2199–205.e1.

20.

Joint Committee on Infant Hearing; American Academy of Audiology; American Academy of Pediatrics; American Speech-Language-Hearing Association; Directors of Speech and Hearing Programs in State Health and Welfare Agencies. Year 2000 position statement: principles and guidelines for early hearing detection and intervention programs. Joint Committee on Infant Hearing, American Academy of Audiology, American Academy of Pediatrics, American Speech-Language-Hearing Association, and Directors of Speech and Hearing Programs in State Health and Welfare Agencies. Pediatrics 2000; 106: 798–817.

21.

Corrêa

Maximino

Weber

SAT

. Hearing disorders in congenital toxoplasmosis: a literature review. Int Arch Otorhinolaryngol 2018; 22: 330–333.

22.

Kelemen

. Toxoplasmosis and congenital deafness. A M A Arch Otolaryngol 1958; 68: 547–561.

23.

Salviz

Montoya

Nadol

, et al. Otopathology in congenital toxoplasmosis. Otol Neurotol. August 2013; 34: 1165–1169.

24.

Ferreira

Sanfins

Pinto

, et al. Congenital toxoplasmosis and auditory disorders: a literature review. Front Psychol 2024; 14: 1286211. Published 2024 Jan 4.

25.

Norouzi

Niyyati

Ghorbani-Bidkorpeh

, et al. Evaluation of the efficacy of chitosan nanoparticles based on rosuvastatin in the treatment of acute toxoplasmosis: an in vitro and in vivo study. Microb Pathog 2024; 195: 106897.

26.

Alday

Doggett

. Drugs in development for toxoplasmosis: advances, challenges, and current status. Drug Des Devel Ther 2017; 11: 273–293. Published 2017 Jan 25.

27.

Diniz

EMA

Vaz

. What is the current recommendation for the treatment of congenital toxoplasmosis? À beira do leito. Rev Assoc Med Bras 2003 Jan; 49: 16.

28.

Remington

, et al. Toxoplasmosis. In: Remington J,S, et al. (eds) Infectious diseases of the fetus and newborn infant. 6 ed. Philadelphia: Elsevier Saunders, 2006, pp.947–1091.

29.

Cabra-Bautista

Paz-Córdoba

Henao-Pabón

, et al. Quality of clinical practice guidelines for gestational and congenital toxoplasmosis: a systematic review of the literature. J Eval Clin Pract 2022; 28: 218–224.

30.

Brown

Chau

Atashband

, et al. A systematic review of neonatal toxoplasmosis exposure and sensorineural hearing loss. Int J Pediatr Otorhinolaryngol 2009; 73: 707–711.

31.

Wallon

Liou

Garner

, et al. Congenital toxoplasmosis: systematic review of evidence of efficacy of treatment in pregnancy. Br Med J 1999; 318: 1511–1514.

32.

Beswick

Driscoll

Kei

. Monitoring for postnatal hearing loss using risk factors: a systematic literature review. Ear Hear 2012; 33: 745–756.

33.

Singh

Gaidhane

. A review of sensorineural hearing loss in congenital cytomegalovirus infection. Cureus 2022; 14: e30703. Published 2022 Oct 26.

34.

Al-Ani

. Various aspects of hearing loss in newborns: a narrative review. World J Clin Pediatr 2023; 12: 86–96. Published 2023 Jun 9.

35.

Porter

Sande

. Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med 1992; 327: 1643–1648.

36.

Rameshsankar

Seethapathy

Balakrishnan

. Ototoxic drug exposure and hearing loss in neonates: a scoping review. Am J Audiol 2024; 33: 1356–1377.

37.

Shojaei

Jafari

Gholami

. Effect of early intervention on language development in hearing-impaired children. Iran J Otorhinolaryngol 2016; 28: 13–21.

38.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ (Clinical Research ed.) 2021; 372: 71.

39.

Johnson

Phillips

. Rayyan for systematic reviews. J. Electr. Resour. Librarianship 2018; 30: 46–48.

40.

Study Quality Assessment Tools. NHLBI, NIH. https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools (accessed on 26 september 2024).

41.

Leite

Lagreca

LCC

Jesus

, et al. Alterações auditivas em crianças expostas à toxoplasmose durante a gestação. Rev CEFAC 2017; 19: 330–339.

42.

McGee

Wolters

Stein

, et al. Absence of sensorineural hearing loss in treated infants and children with congenital toxoplasmosis. Otolaryngol Head Neck Surg 1992; 106: 75–80.

43.

McLeod

Boyer

Karrison

, et al. Outcome of treatment for congenital toxoplasmosis, 1981-2004: the National Collaborative Chicago-Based, Congenital Toxoplasmosis Study. Clin Infect Dis 2006; 42: 1383–1394.

44.

Noorbakhsh

Farhadi

Shokrollahi

, et al. Cytomegalovirus and Toxoplasma gondii: common causes of profound sensori neural hearing loss in children with cochlear implant surgery in a highly immune population: Tehran; Iran. Open Neurol J 2019; 13: 45–49.

45.

Gundeslioglu

Haytoglu

Esen

, et al. Congenital toxoplasmosis and long-term outcomes. Konjenital Toksoplazmozis ve Uzun Dönem Sonuçları. Turkiye Parazitol Derg 2024; 48: 8–14.

46.

Fontes

Carvalho

SADS

Andrade

GMQ

, et al. Study of brainstem auditory evoked potentials in early diagnosis of congenital toxoplasmosis. Braz J Otorhinolaryngol 2019; 85: 447–455.

47.

de Resende

Andrade

GQM

de Azevedo

, et al. Toxoplasmose congênita: evolução da função auditiva e da linguagem em crianças diagnosticadas e tratadas precocemente. Sci Med (Porto Alegre) 2010; 20: 13–19.

48.

Andrade

Resende

Goulart

, et al. Hearing loss in congenital toxoplasmosis detected by newborn screening. Braz J Otorhinolaryngol 2008; 74: 21–28.

49.

Auriti

Bucci

De Rose

, et al. Maternal-fetal infections (cytomegalovirus, Toxoplasma, syphilis): short-term and long-term neurodevelopmental outcomes in children infected and uninfected at birth. Pathogens 2022; 11: 1278. Published 2022 Oct 31.

50.

Wilson

Remington

Stagno

, et al. Development of adverse sequelae in children born with subclinical congenital Toxoplasma infection. Pediatrics 1980; 66: 767–774.

51.

Losa

Carvalho

Sousa

, et al. Diagnosis of congenital toxoplasmosis: challenges and management outcomes. Cureus 2024; 16: e52971. Published 2024 Jan 26.

52.

Salomè

Malesci

Delle Cave

, et al. Congenital toxoplasmosis and audiological outcome: from a case series to a suggestion of patient-based schedule. Front Pediatr 2024; 11: 1297208. Published 2024 Jan 4.

53.

Sleifer

da Costa

Cóser

, et al. Auditory brainstem response in premature and full-term children. Int J Pediatr Otorhinolaryngol 2007; 71: 1449–1456.

54.

Guilhoto

Quintal

da Costa

. Brainstem auditory evoked response in normal term neonates. Arq Neuropsiquiatr 2003; 61: 906–908.

55.

Benito-Orejas

Ramírez

Morais

, et al. Comparison of two-step transient evoked otoacoustic emissions (TEOAE) and automated auditory brainstem response (AABR) for universal newborn hearing screening programs. Int J Pediatr Otorhinolaryngol 2008; 72: 1193–1201.

56.

de Jesus Prata

Prado

Nascimento

, et al. Análise da incidência epidemiológica de toxoplasmose congênita nas regiões brasileiras durante os anos de 2019 a 2022. Braz J Infect Dis 2023; 27: 103498.

57.

Syphilis: between January and June 2022, Brazil registered more than 122 thousand new cases of the disease. Ministry of Health of Brazil. https://www.gov.br/saude/pt-br/assuntos/noticias/2023/fevereiro/sifilis-entre-janeiro-e-junho-de-2022-brasil-registrou-mais-de-122-mil-novos-casos-da-doenca (accessed 28 December 2024).

58.

Walsh

Oddie

McGuire

. Ethical issues in perinatal clinical research. Neonatology 2019; 116: 52–57.

59.

Guarch-Ibáñez

Carreras-Abad

Frick

, et al. REIV-TOXO project: results from a Spanish cohort of congenital toxoplasmosis (2015-2022). The beneficial effects of prenatal treatment on clinical outcomes of infected newborns. PLoS Negl Trop Dis 2024; 18: e0012619. Published 2024 Oct 22.

60.

Khanaliha

Bokharaei-Salim

Hedayatfar

, et al. Comparison of real-time PCR and nested PCR for toxoplasmosis diagnosis in toxoplasmic retinochoroiditis patients. BMC Infect Dis 2021; 21: 1180. Published 2021 Nov 23.

61.

Mardani-Kataki

Beiromvand

Teimoori

, et al.

Is immuno-PCR better than ELISA test for detection of Toxoplasma gondii IgG antibody?

Acta Parasitol 2022; 67: 904–911.

62.

Abedian

Esboei

Kordi

, et al. Efficacy of amniotic fluid, blood and urine samples for the diagnosis of toxoplasmosis in pregnant women candidates for amniocentesis using serological and molecular techniques. BMC Pregnancy Childbirth 2024; 24: 71. Published 2024 Nov 22.

63.

Ramos

RCF

Barbosa

ADS

Aleixo

ALQDC

, et al. Comparison of immunological and molecular methods for laboratory diagnosis of ocular toxoplasmosis in blood, serum and tears in Brazil. PLoS One 2024; 19: e0298393. Published 2024 Feb 6.

64.

Pomares

Montoya

. Laboratory diagnosis of congenital toxoplasmosis. J Clin Microbiol 2016; 54: 2448–2454.

65.

Ganesan

Schmiedge

Manchaiah

, et al. Ototoxicity: a challenge in diagnosis and treatment. J Audiol Otol 2018; 22: 59–68.

66.

Kachniarz

Chen

Gilani

, et al. Diagnostic yield of MRI for pediatric hearing loss: a systematic review. Otolaryngol Head Neck Surg 2015; 152: 5–22.

67.

Liao

Fung

, et al. Predictors of successful natural sleep MRI for sensorineural hearing loss in infants. Int J Pediatr Otorhinolaryngol 2023; 165: 111430.

68.

Moosan

Hoare

Jayasinghe

, et al. Neonatal markers of prematurity as predictors of permanent childhood hearing loss and neurodevelopmental impairment in children admitted to the neonatal intensive care unit. Brain Sci 2024; 14: 26.

69.

Parra

de Suremain

Berne Audeoud

, et al. Sound levels in a neonatal intensive care unit significantly exceeded recommendations, especially inside incubators. Acta Paediatr 2017; 106: 1909–1914.

70.

Ray

Sarkar

Sable

. Comprehensive functional network analysis and screening of deleterious pathogenic variants in non-syndromic hearing loss causative genes. Biosci Rep 2021; 41: BSR20211865.

71.

Kato

. How does Toxoplama gondii invade host cells? J Vet Med Sci 2018; 80: 1702–1706.

72.

Lima

Lodoen

. Mechanisms of human innate immune evasion by Toxoplasma gondii. Front Cell Infect Microbiol 2019; 9: 03. Published 2019 Apr 16.

73.

Khosravi

Mohammad Rahimi

Doroud

, et al. In vitro evaluation of mannosylated paromomycin-loaded solid lipid nanoparticles on acute toxoplasmosis. Front Cell Infect Microbiol 2020; 10: 33.Published 2020 Feb 13.

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