Scoping review of hearing loss attributed to congenital syphilis

Aleena Amjad Hafeeez; Karina Cavalcanti Bezerra; Zaharadeen Jimoh; Francesca B Seal; Joan L Robinson; Nahla A Gomaa

doi:10.1371/journal.pone.0302452

. 2024 Apr 26;19(4):e0302452. doi: 10.1371/journal.pone.0302452

Scoping review of hearing loss attributed to congenital syphilis

Aleena Amjad Hafeeez ¹, Karina Cavalcanti Bezerra ², Zaharadeen Jimoh ³, Francesca B Seal ⁴, Joan L Robinson ^5,^*, Nahla A Gomaa ⁶

Editor: Bolajoko O Olusanya⁷

PMCID: PMC11051613 PMID: 38669285

Abstract

Background

There are no narrative or systematic reviews of hearing loss in patients with congenital syphilis.

Objectives

The aim of this study was to perform a scoping review to determine what is known about the incidence, characteristics, prognosis, and therapy of hearing loss in children or adults with presumed congenital syphilis.

Eligibility criteria

PROSPERO, OVID Medline, OVID EMBASE, Cochrane Library (CDSR and Central), Proquest Dissertations and Theses Global, and SCOPUS were searched from inception to March 31, 2023. Articles were included if patients with hearing loss were screened for CS, ii) patients with CS were screened for hearing loss, iii) they were case reports or case series that describe the characteristics of hearing loss, or iv) an intervention for hearing loss attributed to CS was studied.

Sources of evidence

Thirty-six articles met the inclusion criteria.

Results

Five studies reported an incidence of CS in 0.3% to 8% of children with hearing loss, but all had a high risk of bias. Seven reported that 0 to 19% of children with CS had hearing loss, but the only one with a control group showed comparable rates in cases and controls. There were 18 case reports/ case series (one of which also reported screening children with hearing loss for CS), reporting that the onset of hearing loss was usually first recognized during adolescence or adulthood. The 7 intervention studies were all uncontrolled and published in 1983 or earlier and reported variable results following treatment with penicillin, prednisone, and/or ACTH.

Conclusions

The current literature is not informative with regard to the incidence, characteristics, prognosis, and therapy of hearing loss in children or adults with presumed congenital syphilis.

Introduction

Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum. If not recognized and treated early in pregnancy, fetal transmission commonly occurs [1]. According to the international Joint Committee on Infant Hearing, congenital syphilis (CS) is a risk indicator for hearing loss [2,3]. The Centers for Disease Control and Prevention state: “Otosyphilis is caused by an infection of the cochleovestibular system with T. pallidum and typically presents with sensorineural hearing loss, tinnitus, or vertigo. Hearing loss can be unilateral or bilateral, have a sudden onset, and progress rapidly.” (Neurosyphilis, Ocular Syphilis, and Otosyphilis (cdc.gov)). Almost all cases of CS are treated with penicillin which is not known to be ototoxic.

For decades, congenital syphilis had almost disappeared in Canada and the United States due to low rates of syphilis in the community and universal prenatal screening.. The number of cases of confirmed early congenital syphilis born to women aged 15–39 years in Canada rose from 17 cases in 2018 to 117 in 2022 [4]. Trends in the United States (US) mirror this with an increase from 1325 congenital syphilis cases in 2018 to 3755 in 2022 [5].

The recent resurgence has increased interest in the clinical manifestations and complications of congenital syphilis. There are no published data summarizing the incidence or characteristics of hearing loss due to congenital syphilis. Despite the larger number of cases now occurring in Canada and the US, there are no evidence-based guidelines on screening or management of hearing loss in children with congenital syphilis. We therefore performed a scoping review. Our specific questions were:

How often is hearing loss due to congenital syphilis?
What is the incidence of hearing loss in children with congenital syphilis?
When hearing loss occurs from congenital syphilis, what is the usual age of onset? Is it unilateral or bilateral? How severe is it? How rapidly does it progress?
Is there evidence for any interventions for treatment of hearing loss attributed to congenital syphilis?

This will inform the studies that need to be done to determine the incidence and age of onset of hearing loss from CS, the severity of hearing loss, and interventions that warrant further study.

Methods

The methodology was based on the Preferred Reporting Items for a Systematic Review and Meta-analysis Extension for Scoping Reviews: The PRISMA-ScR statement [6] (See attached S1 Checklist). A search was executed by a health librarian on the following databases: PROSPERO, OVID Medline, OVID EMBASE, Cochrane Library (CDSR and Central), Proquest Dissertations and Theses Global, and SCOPUS using controlled vocabulary (e.g.: MeSH, Emtree, etc.) and selecting key words representing the concepts “congenital syphilis" or "hearing loss” (S1 Appendix). Databases were searched from inception to October 17, 2021, with an updated search to March 31, 2023.

Articles were included if they described persons of any age with hearing loss that the authors of the article attributed to congenital syphilis. To delineate the burden and incidence of hearing loss from congenital syphilis, we included any studies that i) screened children with hearing loss for evidence of congenital syphilis or ii) screened children with congenital syphilis for hearing loss. We also included randomized controlled trials (RCTs), cross-sectional studies, case series, and case reports that described the characteristics of hearing loss, the long-term outcomes of hearing loss, or the results of any interventions for hearing loss. We excluded autopsy reports, animal studies, studies focusing solely on acquired syphilis and those published in a language other than English, French, or Portuguese.

Articles published in English were screened by two reviewers independently [AH, KC], and conflicts were resolved by a senior author [JR, NG]. Articles published in French had a single reviewer [FS]. There were no articles published in Portuguese. Because of the small number of recent articles, preprints were included. The protocol has not been published.

Studies were divided into four types: i) those that screened patients with hearing loss for congenital syphilis, ii) those that screened patients with congenital syphilis for hearing loss, iii) case reports or case series that describe the characteristics of hearing loss in patients with congenital syphilis, and iv) studies that describe an intervention for hearing loss attributed to congenital syphilis. Data were collected and managed using Research Electronic Data Capture (REDCap) tools [7] hosted at the University of Alberta with the extracted data determined by the study type. Data were entered by a single investigator. The JBI critical appraisal tool was used as appropriate to assess all included studies [8–11] (S2 Appendix). The critical appraisal and bias risk assessment was completed by a single reviewer [NG], and all studies were rated as high, unclear or low risk of bias.

Results

The search yielded 1983 records of which 832 were duplicates. Screening led to 159 records for full-text review of which 36 met inclusion criteria (Fig 1). The figure outlines the reasons for exclusion of other records.

Screening of patients with hearing loss for congenital syphilis

There were 5 studies where patients with hearing loss were screened for CS. They were published from 1900 to 1990 and all had a high risk of bias (Tables 1 and 2). The incidence of CS ranged from 0.3% to 8% in children attending schools for the hearing impaired and was 2% in children seen at a clinic for the hearing impaired.

Table 1. Critical appraisal of studies of hearing loss attributed to congenital syphilis.

Type of study	Author (Year) Country	Risk of bias	Comments
Children with HL screened for CS	Gururaj [12] (1900) India	High	• Quota Sampling • Descriptive statistics • Method of diagnosis of CS or HL not described
	Yearsley [13] (1910) UK	High	• Only the demographics and phenotypes of patients in case reports described • Method of diagnosis of CS or HL not described • Inclusion or exclusion criteria not clear • Longitudinal reporting and follow up not defined
	Wright [14] (1968) UK	High	• Quota Sampling • Descriptive statistics ‐ no correlation between CS and HL proven • Method of diagnosis of CS or HL not described
	Kameswaran [15] (1976) India	High	• Judgmental non-probability sample • Method of diagnosis of HL subjective [audiometry] • Descriptive statistics ‐ no correlation between CS and HL proven
	Ganga [16] (1990) India	High	• Judgmental sampling • Descriptive statistics ‐ no correlation between CS and HL proven • Main objective was to look at the psychological impact rather than the etiology of HL
Children with CS were screened for HL	Keidel [17] (1923) US	Moderate	• Adequate sample size • Setting described • Descriptive study with no data analysis
	Ittkin [18] (1953) US and Canada	Low	• Adequate sample size • Study subjects and setting described • Sufficient data with statistical analysis • Identification of the condition valid
	Gleich [19] (1994) US	Moderate	• A quota sample used • ABR used for auditory screening • Descriptive study • Correlation could not be proved
	Simms [20] (2016) UK	Moderate	• A quota sample was used • Definition of CS precise but no clear definition of HL
	Lim [21] (2021) South Korea	High	• A quota sample used • No clear diagnostic criteria or tools for HL • Though they applied statistics, not clear what they were trying to prove
	Besen [22] (2022) Brazil	Low	• Adequate sample size • Study subjects and setting described • Sufficient data and analysis • Fails to describe how CS diagnosed
	Aguiar [23] (2022) Brazil	Low	• Adequate sample size • Study subjects and setting described • ABR used for auditory screening. Note that equipment was changed during study but no statistical significance. • Sufficient data and statistical analysis • Identification of condition valid
Case series	Yearsley [13] (1910) UK	High	• Only the demographics and phenotypes of patients in case reports were described. • Method of diagnosis of CS or HL not described • Inclusion or exclusion criteria unclear • Longitudinal reporting and follow up not defined
	Fraser [24] (1916) UK	High	• Patients demographics and phenotypes were described. • No diagnostic tests used to confirm HL
	Perlman [25] (1952) US	Moderate	• Demographics, and audio-vestibular loss described.
	Morton [26] (1955) UK	Moderate	• Demographics, CS diagnosis were described. • Audio vestibular symptoms depicted more than diagnostics.
	Morton [27] (1957) UK	Moderate	• Brief demographics and symptomatology • Audio-vestibular diagnosis not reported • Method of CS diagnosis not described
	Baron [28] (1967) France	High	• No patient’s demographics, patient’s history, clinical condition, or invention described • only the diagnostic tests or assessment methods in addition to intervention and post intervention clinical conditions • Adverse effects and objectives not clear.
	Dawkins [29] (1968) UK	Low	• Demographics and diagnostics well described
	Patterson [30] (1968) US	Low	• Demographics and diagnostics well described
	Kerr [31] (1970) Ireland	Low	• Brief demographics • Methods of CS diagnosis described
	Indesteege [32] (1989) Belgium	Low	• Brief demographics • Audio vestibular diagnosis of Leutic Meniere’s disease explained • Method of CS diagnosis explained
Case reports	Hastings [33] (1915) US	Low	• Demographic described well • Audio-vestibular finding explained • Longitudinal results of treatment assessed
	Murphy [34] (1958) US	Low	• Demographic described well • Audio-vestibular finding explained • Longitudinal results of treatment assessed
	Karmody [35] (1966) US	Low	• Demographic described well • Audio-vestibular finding explained • Histopathology added when autopsy performed
	Hughes [36] (1981) Germany	Low	• Demographic described well • Audio-vestibular finding explained • Longitudinal results documented
	Khetarpal [37] (2011) US	High	• Demographic described • More emphasis on other manifestation than on HL
	Pessoa [38] (2011) Brazil	High	• Demographics described • Symptoms and signs of CS explained including HL • Not all hearing assessments included
	Singhal [39] (2011) India	Low	• Method of diagnosis of CS described • Also had a cleft palate that could have contributed to HL.
	Kivekas [40] (2014) US	Low	• Demographics described. This is a case report of radiological findings in the temporal bones because of congenital syphilis. • Symptoms and signs were explained as well as interventions in addition to radiologic findings.
Studies of an intervention	Hahn [41] (1961) US	Moderate	• Small number/ cohort • Confounding factors were not accounted for • It was mentioned that longitudinal results are difficult to obtain
	Kerr [42] (1973) Ireland	Moderate	• Patients lost to follow up not accounted for • Longitudinal follow up unclear
	Smyth [43] (1976) Ireland	Low	• Exclusion criteria mentioned.
	Zoller [44] (1979) US	Moderate	• Detailed description of demographics and clinical picture • Audiometric results before and after treatment provided • No group comparison
	Wilson [45] (1981) US	Moderate	• Confounding factors not accounted for • Longitudinal results unclear
	Dobbin [46] (1983) US	Moderate	• Stats purely descriptive • No mention of confounding factors
	Kerr [47] (1983) Ireland	Low	• Adverse effects mentioned • Conclusion articulated

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CS–congenital syphilis; HL–hearing loss; UK–United Kingdom; US–United States.

Table 2. Studies where multiple children with hearing loss were screened for congenital syphilis.

Author (Year) Country	Description of participants screened for CS	Number of children with CS
Gururaj [12] (1900) India	300 children with HL at a school for children with visual and hearing impairment	15 (5%)
Yearsley [13] (1910) UK	225 children with acquired HL in “deaf centres” in London with acquired HL (did not test 229 with congenital HL or 46 with unclear timing of onset of HL)	17 (8%)
Wright [14] (1968) UK	1157 patients with SNHL at the Royal National Throat, Nose, and Ear Hospital 1963 to 1966	20 (2%)
Kameswaran [15] (1976) India	367 children at schools for the hearing impaired	1 (0.3%)
Ganga [16] (1990) India	100 children at schools for the hearing impaired	1 (1%)

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CS–congenital syphilis; HL–hearing loss; SNHL–sensorineural hearing loss.

Screening of patients with CS for hearing loss

There were 7 studies of which 4 were published from 2016 to 2022 (Table 3). The risk of bias was high for 1, unclear for 3, and low for 3. Hearing loss was reported in 0 to 19% of children with probable or proven CS. One study from the modern era showed an incidence of 6% (22/342) (12). However, a small recent study reported no hearing loss for 7 infants treated in utero, a 5% incidence for 37 treated at birth, and a 6% incidence in 49 controls [23].

Table 3. Studies where children with congenital syphilis were screened for hearing loss.

Author (Year) Country	Population screened	Participants with HL	Hearing loss pattern
Keidel [17] (1923) US	230 with CS seen at Syphilis Clinic at John Hopkins Hospital 1917–1923.	23 (10%)	Late SNHL was found in 22 patients plus one had deafness due to gummatous condition in nasopharynx. Onset occurred from 7 to 27 years of age. Four had sudden HL (over the course of a week.). Seven had bilateral HL.
Ittkin [18] (1953) US and Canada	59 with late CS	11 (19%)	Two had sudden onset HL, 3 had gradual onset, with no comment on the other 6. Three had excessive high tone HL and 8 had subnormal HL (defined as narrowed range to voice, forks and audiometric tests with impaired bone conduction
Gleich [19] (1994) US	75 neonates with positive FTA-ABS or MHA-TP and Apgar > 9 at 5 minutes of life (provide no data on how many had CS versus passive antibodies– 41 had CSF obtained and none had evidence for CNS syphilis)	0	NR
Simms [20] (2016) UK	17 patients born 2010–2015 with possible or proven CS	1 (6%)	NR
Lim [21] (2021) South Korea	250 neonates treated for possible or proven CS	34 (14%) including 6 of 14 (43%) with neurosyphilis	NR 14% had hearing impairment according to The International Classification of Diseases-10 codes
Besen [22] (2022) Brazil	21,434 newborns evaluated in a Brazilian reference hearing health service of the UNHS Program.	22 (6%)	NR
Aguiar [23] (2022) Brazil	93 newborns divided into three groups. Group 1: Prenatal treatment for syphilis (n = 7) Group 2: Treatment for syphilis after birth (n = 37) Group 3: Control group with no syphilis (= 49)	Group 1: 0/7 Group 2: 2/37 (5%) Group 3: 3/49 (6%)	NR

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CSF–cerebrospinal fluid; CNS–central nervous system; CS–congenital syphilis; HL–hearing loss; NR–not reported.

SNHL–sensorineural hearing loss.

Case series and case reports of hearing loss attributed to CS

There were 10 case series (one of which was also included in Table 2) (Table 4A) and 8 case reports (Table 4B) of which all but 6 were published prior to 1980. The risk of bias was high for 5 articles, unclear for 3 and low for 10. In these reports, hearing loss was often first noted in adolescence or adulthood with the youngest being 5 years old at diagnosis. Many cases also had interstitial keratitis. Follow-up was too variable to allow determination of the expected rate of progression of hearing loss. A wide variety of therapies are reported with small numbers of patients and inconsistent results that were often subjective.

Table 4.

A ‐ Case series of hearing loss attributed to congenital syphilis. B ‐ Case reports of hearing loss attributed to congenital syphilis.

Author (Year) Country	Demographics	Hearing loss assessment	Interventions
Yearsley [13] (1910) UK	17 cases with onset at 6 to 14 years (unknown for 2 cases). All had interstitial keratitis (preceded deafness in at least 10 cases).	Bone conduction, otoscopy, traditional ear exam -used subjective unconfirmed behavioral measures.	NR
Fraser [24] (1916) UK	33 cases between the ages of 7 and 38 with HL recognition at 3,6,7 (n = 2), 8 (n = 4), 9 (n = 2), 10 (n = 2), 11 (n = 3),12,14, 15 (n = 2), 16, 17, 18, 19 (n = 2), 20, 24, 25, 27 (n = 2), 21(n = 2), 30, and 33 years. HL sudden (N = 8), gradual (N = 14) and unknown (N = 11). All but one had interstitial keratitis.	Bone conduction, otoscopy, vestibular irritation test.	One case received potassium iodide application and pilocarpine injection with no improvement
Perlman [25] (1952) US	11 cases with recognition of HL loss at 9, 11, 12, 17 (N = 2), 18, 19, 23, 33, and 35 (N = 2) years. All had interstitial keratitis.	All but one had bilateral HL. Cold caloric test abnormal in 10 of 11 and fistula test positive in 2 of 9 where results reported.	Bismuth, arsenic +/- penicillin given to 5 with no improvement–all 5 then given ACTH and 3 had improvement
Morton [26] (1955) UK	4 cases with onset at approximately ages 15, 34, 35 and 53 years	Traditional audiometry inconsistently mentioned	All received beta-pyridylcarbinol, and 2 of 4 received penicillin– 3 reported subjective improvement
Morton [27] (1957) UK	4 cases with onset at approximately 18, 24 and 35 years (unknown for one patient)	Unclear	-Penicillin treatment in 3 of 4 cases. Three received prednisone 10 mg three times daily for 3 days followed by 5 mg twice daily for 3 weeks. One reported subjective improvement.
Baron [28] (1967) France	3 children aged 10, 11 and 16 years with maternal diagnosis made after diagnosis in child	Traditional audiometry: moderate bilateral HL (N = 1), minimal bilateral hearing loss (N = 1), mild HL on right and minimal on left	Case 1: Penicillin 80 million U and mercury cyanide. Deterioration of hearing bilaterally. Case 2: Multiple course antibiotics. Improvement of hearing bilaterally. Case 3: Removal of vegetations, radiotherapy of skull, tubal massages, and antibiotics. Deterioration of hearing on the left and improvement on the right
Dawkins [29] (1968) UK	5 cases with onset of HL at age 13, 20, 42, 37 and 55 years	Traditional audiometry: Moderate HL in right ear and moderate-severe in left (N = 1), minimal HL in right ear and mild HL in left (N = 1), mild HL bilaterally (N = 1), profound HL in right and moderate HL in left (n = 1) and mild HL in right and severe in left (N = 1)	All treated with prednisone of which 3 responded: Case 1 right ear improved. Case 3 had a slight response but only to pure tone audiogram and case 5 had moderate improvement that was not maintained
Patterson [30] (1968) US	4 cases with onset of HL at age 26,32 29, and 39 years)	Limited results reported	All received prednisone and reported some improvement in symptoms with 2 having documented improved speech discrimination but 3 prescribed maintenance prednisone as improvement transient
Kerr [31] (1970) Ireland	3 cases aged 46 to 55 years with onset of HL at ages 26, 47 and 53 years	Pure tone threshold and speech discrimination: Left ear HL followed by right ear HL with vertigo (N = 1), fluctuating HL with rotational vertigo (N = 1) and bilateral HL (N = 1)	All cases: high dose penicillin for four weeks, prednisone for ten days with ten-day taper. All reported to have improved speech discrimination in at least one ear and vertigo improved in both cases
Indesteege [32] (1989) Belgium	5 cases aged 50 to 61 years at time of study (not clear when HL started)	Audiometry, tympanometry and stapedial reflex. Found to have symmetrical HL with Meniere’s disease and tinnitus (N = 3), mixed, bilateral perceptive, symmetric, and fluctuant HL with Meniere’s disease and tinnitus with vertigo (N = 1) and bilateral perceptive and fluctuant HL with Meniere’s disease, tinnitus and vertigo	2 cases treated with corticosteroids but discontinued due to side-effects

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CSF–cerebrospinal fluid; CNS -central nervous system; HL–hearing loss; NR–not reported; UK–United Kingdom: US–United States.

HL–hearing loss; NR–not reported.

Studies with interventions for hearing loss

The 7 studies included a range of 6 to 39 patients with the most recent one being from 1983 (Table 5). All were observational. Most commonly patients were prescribed penicillin with addition of prednisone followed by ACTH if response was poor or transient. Outcomes were often subjective and inconsistent. Risk of bias was unclear for 5 studies and low for 2 studies.

Table 5. Studies with an intervention for hearing loss that was attributed to congenital syphilis with minimal details on individual patients.

Author (Year) Country	Total participants	Intervention	HL characteristics prior to intervention	HL characteristics following intervention
Hahn [41] (1961) US	Group A: Patients with syphilitic neural deafness (N = 19) Group B: Patients with non-syphilitic neural deafness (N = 20)	Prednisone 30 mg daily in divided doses for one week, then 20 mg daily, then 2.5 mg taper per day each month if progressing well. Six patients received penicillin at the start of prednisone therapy.	Group A: On average, lower discrimination scores prior to treatment. Group B: Cases described often had sudden HL with decreases in discrimination scores noted.	Group A: Definite improvement in discrimination score occurred for eight patients. Two patients had slight increases in discrimination scores. The other 9 patients saw no significant improvements. Group B: Very slight improvements in 3/20 cases, but overall, no improvements noted
Kerr [42] (1973) Ireland	12	All got ampicillin, at least 3 also got prednisone, 4 of whom also got ACTH.	Case 1: Fluctuations in pure tone hearing and speech discrimination for 2–3 years prior to treatment. Case 2 and 3: Profound deafness for greater than 6 months with speech discrimination score of 0. Case 4: High speech discrimination score, but low pure tone hearing score with sudden drop in speech discrimination prior to treatment.	All had improved speech discrimination.
Smyth [43] (1976) Ireland	19	Group A (N = 9): Ampicillin for 4 weeks. Group B (N = 13 –includes 3 who failed from Group A): ampicillin plus prednisone 10 mg TID for 10 days (if no improvement additional 10 days of prednisone at same dose). Group C (N = 8, all of whom failed in Group B): ampicillin, prednisone and ACTH 40 to 120 units per week (duration of treatment not specified)	Group A: 6 ears initially had low speech discrimination scores; 9 ears had satisfactory hearing. Group B: 11 ears had profoundly HL and 12 had significant HL. Group C: 6 ears with profound and 8 ears with significant HL. Overall: 2 patients had severe tinnitus and 5 patients had vertigo.	Group A: 6 ears which initially had low speech discrimination scores improved by 20% in speech discrimination score–was only maintained in 2 ears. 9 ears had satisfactory hearing and maintained their hearing. Group B: All initially improved but 7 ears relapsed. Group C: All improved. All but one had serviceable hearing with follow-up of maximum 6.5 years.
Zoller [44] (1979) US	12	Penicillin G plus 80 mg prednisone every other day	Mean SRT in left ear was 54.5 dB and 51.0 dB on the right. Mean speech discrimination score was 47.2% on the left and 61.6% on the right	3 patients had sustained improvement in HL at 1 year, 1 had transient improvement, and 5 had no improvement in HL.
Wilson [45] (1981) US	7	3 months of weekly benzathine penicillin G and 80 mg of prednisone orally every other day up to one month.	All had vertigo	Vertigo improved in 4 and unchanged in 3.
Dobbin [46] (1983) US	13	Penicillin G IV daily for 2 weeks followed by benzathine penicillin every other week for 10 weeks. Prednisone was co-administered starting at 80 mg every other morning for 1 month and tapered based on patient response.	Unknown	9 of 26 ears showed a response to treatment. 2 ears showed improvements to pure tone threshold while 8 ears showed improvements (one ear demonstrated improvements in both). 5 ears demonstrated transitory improvements discrimination Only 4 ears had any lasting response in speech discrimination or pure tone threshold.
Kerr [47] (1983) Ireland	17	Group A (N = 1): Ampicillin for 4 weeks Group B (N = 7): Ampicillin and prednisone 10 mg for 10 days with 10-day taper. Group C (N = 6): Ampicillin, prednisone, and ACTH (40 units to 120 units) for prolonged course Group D (N = 3)–deceased Followed for mean 10.5 years	Group A: Fluctuating HL. Group B: Mean speech discrimination score 62%. 4 ears had profound, 6 had fluctuating HL and 4 were stable. Group C: Mean speech discrimination score 46%. 3 ears had profound and 8 had fluctuating HL.	Group A: Fluctuating HL, speech discrimination score remained normal. Group B: No response for those with profound HL. 4 of 6 ears with fluctuating HL remained fluctuating with no changes to speech discrimination score. 2 remained stable and 1 ear had an improvement in speech discrimination score from 28% to 56%. For the 4 stable ears prior to treatment, 2 remained stable, 1 developed profound and 1 developed fluctuating HL post-treatment. Group C: No response for those with profound HL. Out of those with fluctuating HL, 1 remained stable and 1 progressed to profound HL. The other 6 continue to have fluctuating hearing loss.

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ACTH ‐ Adrenocorticotropic hormone; HL–Hearing loss; PTA–pure tone average; SRT–speech recognition threshold.

Discussion

The scoping review shows that studies of hearing loss due to congenital syphilis are limited and low quality. All but one study reported as a pre-print [23] are observational studies and only 15 of 36 studies (42%) were at low risk of bias. One cannot determine the incidence or characteristics of hearing loss from congenital syphilis or the efficacy of interventions from this review. It seems unlikely that a systematic review would find further studies that could answer these questions.

As expected, there were major variations in the study methodologies employed to diagnose hearing loss. In the early 1900s, investigators used basic tuning fork tests and subjective behavioral responses [24]. Studies performed after the year 2000, used full diagnostic tests or Auditory Brainstem Responses (ABR) for neonates [21].

A small percentage of children attending schools for the hearing impaired had evidence of congenital syphilis. However, these data are of limited value without a control group from the same jurisdiction. The percentage of hearing loss that is due to congenital syphilis no doubt varies considerably by country and over time.

It is perhaps unexpected that almost all case reports and case series describe recognition of hearing loss only in adolescence or adulthood. It is possible that hearing loss started years prior but was not recognized, particularly, if the hearing loss was slowly progressive. The major problem with all these reports is that they do not exclude the possibility that the patient had acquired syphilis or had another etiology for their hearing loss.

Clearly, there is paucity of up-to-date literature regarding this important health problem. The majority of articles were published before 1980. The recent surge in congenital syphilis cases in Canada and the United States may lead to further studies. Recent results from neonatal hearing screening programs in low- or middle-income countries where the incidence of congenital syphilis never waned are informative. Besen reported screening 21,434 newborns in Brazil 2017 through 2019 and reported a prevalence of test failure in the Universal Neonatal Hearing Screening Program (UNHS) of 1.6% (95% CI: 1.4; 1.8). This study used Otoacoustic Emission and ABR to identify both cochlear and retrocochlear damage. They report that 1.7% (95% CI: 1.5; 1.8) had congenital syphilis but do not report how many with congenital syphilis had hearing loss [22]. In a follow-up report of 34,801 infants screened 2017 through 2021, they report that neonates with congenital syphilis were 2.38 times as likely to fail in the UNHS as those without congenital syphilis [48]. However, another small study from Brazil reported as a pre-print examined failed hearing screens at 2 months of life did not find an association between congenital syphilis and failed hearing screens [23].

It is not clear whether there is a treatment for hearing loss due to congenital syphilis. Antibiotics were presumably always given at the time of diagnosis of hearing loss if the patient had not previously been adequately treated. There are no convincing reports that this alone resulted in sustained improved hearing. Uncontrolled studies that included corticosteroids with or without ACTH reported variable response and improvement in hearing was often subjective.

The main limitation of this scoping review is the lack of high-quality studies.

Conclusion

Our scoping review outlines a general map of the trend of publications across the decades and shows that the incidence of hearing loss due to congenital syphilis is completely unknown. It is not clear whether the stage of maternal syphilis or the age at which infants are treated changes outcomes. The literature does not inform us as to whether treatment in-utero prevents development of hearing loss. Until there are high quality long-term observational studies, it is difficult to know what hearing screening to recommend for children with congenital syphilis. Hearing loss attributed to congenital syphilis is often first recognized in adolescence or adulthood. Therefore, there is a need to increase awareness that people of all ages with unexplained hearing loss of sudden or gradual onset should be screened for syphilis. Other than treatment of the congenital syphilis, no other treatments can be recommended until there are RCTs or cohort studies with valid control groups.

Supporting information

S1 Checklist. Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist.

(DOCX)

pone.0302452.s001.docx^{(83.8KB, docx)}

S1 Appendix. Systematic review search strategy.

(DOCX)

pone.0302452.s002.docx^{(22.5KB, docx)}

S2 Appendix. Joanna Briggs Institute (JBI) critical appraisal checklist.

(DOCX)

pone.0302452.s003.docx^{(27.9KB, docx)}

Data Availability

All data are in the manuscript and/or supporting information files.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0302452.r001

Decision Letter 0

Sangamanatha Ankmnal Veeranna

22 Nov 2023

PONE-D-23-32597

Scoping review of hearing loss attributed to congenital syphilis.

PLOS ONE

Dear Dr. Robinson,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we have decided that your manuscript does not meet our criteria for publication and must therefore be rejected.

I am sorry that we cannot be more positive on this occasion, but hope that you appreciate the reasons for this decision.

Kind regards,

Sangamanatha Ankmnal Veeranna, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments:

The authors have put a lot of effort into this article. But the manuscript is not conveying the important message of this scoping review. A lot of key information is missing in the introduction, results, and the discussion section.

What is the purpose of this scoping review?

What are the authors trying to convey from this scoping review? Do the authors think that there should be a systematic review conducted based on a scoping review?

How does congenital syphilis cause hearing loss? Hearing loss is the sequelae? or medicine given to treat syphilis causes hearing loss?

What is the current gap in the knowledge base on congenital syphilis?

What is the available evidence in individuals with congenital syphilis?

I did not see the overview or the map of evidence on congenital syphilis.

How was the hearing research conducted in the past and currently?

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Title of the Manuscript:

"Scoping Review of hearing loss attributed to congenital syphilis."

Overall Evaluation:

The paper offers valuable insights into hearing loss attributed to congenital syphilis. The authors put a lot of effort into finding the relevant literature and conducting the scoping review. Overall, I find the work satisfactory. However, I find changes are required to the text. There were a few spelling and grammar mistakes. I recommend improving the organization of the content in the paper.

Major Contributions:

Relevance of Topic: The topic is of high importance and is aptly chosen.

Comprehensiveness: The review covers a wide array of studies and provides a comprehensive overview.

Originality: The topic that the authors selected is a novel research area. There is adequate information; however, I suggest improvements to further identify gaps and mention potential areas for future research.

Areas for improvement:

A document with suggestions for improvements is attached. Please refer to the document. The document also contains the paper with corrections and questions marked in red. Please refer.

Summary and Recommendation:

Overall, this manuscript is a commendable effort in synthesizing the current knowledge on hearing loss attributed to congenital syphilis. It provides an insightful overview, though some areas require refinement for clarity and depth. With revisions, particularly in the introduction, methodology, and discussion sections, this manuscript will be a valuable addition to the literature. I recommend acceptance of the manuscript after revisions.

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

- - - - -

For journal use only: PONEDEC3

Attachment

Submitted filename: PONE-D-23-32597_reviewer.pdf

pone.0302452.s004.pdf^{(2MB, pdf)}

PLoS One. 2024 Apr 26;19(4):e0302452. doi: 10.1371/journal.pone.0302452.r002

Author response to Decision Letter 0

19 Dec 2023

Thank-you for agreeing to review a revision of our manuscript. We have addressed the comments of the reviewers as follows:

A. Editor’s Comments:

1. What is the purpose of this scoping review?

Response: The submitted version of the manuscript stated in the introduction: “There are no published data on the incidence or characteristics of hearing loss from CS. We therefore performed a scoping review to better characterize this entity. This will inform the studies that need to be done to determine the incidence and age of onset of hearing loss from CS, the severity of hearing loss, and interventions that warrant further study”.

To make our objectives clearer, we added the following to this paragraph:

Our specific questions were:

• How often is hearing loss due to congenital syphilis?

• What is the incidence of hearing loss in children with congenital syphilis?

• When hearing loss occurs from congenital syphilis, what is the usual age of onset? Is it unilateral or bilateral? How severe is it? How rapidly does it progress?

• Is there evidence for any interventions for treatment of hearing loss attributed to congenital syphilis?

We also added a sentence to make it clearer that there are no guidelines for ongoing management of hearing loss with CS.

2. What are the authors trying to convey from this scoping review? Do the authors think that there should be a systematic review conducted based on a scoping review?

Response: We agree that we should have made it clearer that the scoping review showed a great need for higher quality studies. We have added the following sentence to the first paragraph in the discussion: “One cannot determine the incidence or characteristics of hearing loss from CS or the efficacy of interventions from this review. It seems unlikely that a systematic review would yield answers to any of these questions.”

3. How does congenital syphilis cause hearing loss? Hearing loss is the sequelae? or medicine given to treat syphilis causes hearing loss?

Response: We agree that we could have explained this better and added to the first paragraph: “The Centers for Disease Control and Prevention state: “Otosyphilis is caused by an infection of the cochleovestibular system with T. pallidum and typically presents with sensorineural hearing loss, tinnitus, or vertigo. Hearing loss can be unilateral or bilateral, have a sudden onset, and progress rapidly.” Penicillin is the only treatment used and it is not known to be an ototoxic drug. We now state “Almost all cases of CS are treated with penicillin which is not known to be ototoxic.”

4. What is the current gap in the knowledge base on congenital syphilis?

Response: As noted above, the introduction of the submitted version of the manuscript stated: “There are no published data on the incidence or characteristics of hearing loss from CS.”

5. What is the available evidence in individuals with congenital syphilis?

Response: It is not clear what the editor is asking. Our scoping review summarizes the evidence on hearing loss. Did they want us to talk about all aspects of congenital syphilis?

6. I did not see the overview or the map of evidence on congenital syphilis.

Response: We used the Cochrane methods for our scoping review (See Scoping reviews: what they are and how you can do them | Cochrane Training ). I do not think that an overview or a map of evidence are a mandatory part of a scoping review. A review article on evidence mapping (Miake-Lye IM et al. What is an evidence map? A systematic review of published evidence maps and their definitions, methods, and products. Syst Rev. 2016 Feb 10:5:28. doi: 10.1186/s13643-016-0204-x) states: “… scoping reviews include “a descriptive narrative summary of the results” whereas evidence maps identify evidence gaps, and both use a tabular format to depict a summary of literature characteristics “. Given the lack of evidence we uncovered, it would be very difficult to make a useful evidence map.

7. How was the hearing research conducted in the past and currently?

Response: We are sorry but we could not determine what the editor is asking. We tell the reader that all but one study were observational studies so there is not a specific methodology.

B. Reviewer’s Comments:

Overall Evaluation:

Major Contributions:

Relevance of Topic: The topic is of high importance and is aptly chosen.

Comprehensiveness: The review covers a wide array of studies and provides a comprehensive overview.

Areas for improvement:

A document with suggestions for improvements is attached. Please refer to the document. The document also contains the paper with corrections and questions marked in red. Please refer.

Summary and Recommendation:

1. An explicit statement of research questions and objectives is not provided. I recommend rethinking and clearly rewriting the text. Please use bullet points and proper formatting. It helps the reader to understand clearly.

Response: Thanks for pointing out that our objectives were not as clear as we thought that they were. We added the following to the introduction:

Our specific questions were:

• How often is hearing loss due to congenital syphilis?

• What is the incidence of hearing loss in children with congenital syphilis?

• When hearing loss occurs from congenital syphilis, what is the usual age of onset? Is it unilateral or bilateral? How severe is it? How rapidly does it progress?

• Is there evidence for any interventions for treatment of hearing loss attributed to congenital syphilis?

2. State the process for selecting sources of evidence (i.e., screening and eligibility) included in the scoping review. Reviewer says: The selection process is clear. However, I recommend re-think and clearly describe in the text. Use bullet points and proper formatting. Formatting issues were identified.

Response: I am sorry but it was not clear what the reviewer wanted us to change. It is not common to use bullet points when describing the sources that were searched for a systematic or scoping review.

3. For each source of evidence, present characteristics for which data were charted and provide the citations. Reviewer states: Charts are included. I recommend moving the charts below to relevant sections in the text. Otherwise, it was challenging to scroll down and go back to the text to relate what the authors are trying to describe.

Response: I apologize for this error. I clearly did not read the author instructions carefully. The tables have been moved.

4. Discussion - Found complex sentence structures. Look into the text again and think of clear explanation.

Response: We tried to make the text clearer throughout the discussion.

5. The reviewer asked that we tell the reader the number of articles included in the “Design” section of the abstract.

Response: It is customary not to divulge results until the “Results” section of the abstract.

6. The reviewer suggests adding a reference to the sentence “Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum.”

Response: It seems unlikely that the reader would require a reference to believe that this statement is correct. We can add one if required.

7. We were asked to double-check whether the statistics that we quote in the introduction from previous studies are correct.

Response: We have no way of verifying this but have quoted the studies accurately.

8. Methods – We were asked where the keywords are.

Response: As far as we can tell, PLOS ONE does not request keywords. We can add some if required.

9. Articles published in English were screened by two reviewers independently [AH, KC], and conflicts were resolved by a senior author [JR, NG]. Articles published in French had a single reviewer [FS]. There were no Portuguese articles. Because of the small number of recent articles, preprints were included. The protocol has not been published.´The reviewer stated that perhaps we did not need to include this information and asked whether the protocol was in Prospero.

Response: We can omit this information if requested. The protocol is not in Prospero as unfortunately they only publish protocls for systematic reviews – not scoping reviews.

10. Figure 1 is far away from the text.

Response: Instructions to authors request that figures be submitted as a separate file.

11. “ One study from the modern era showed an incidence of 6% (22/342) (Besen et al., 2022).” Reviewer states: “not required or explain in words”, I think referring to 22/342.

Response; We think that it is helpful for the reader to not have to look at the table to determine the sample size for this statistic, but can omit that if requested.

12. Multiple minor changes were made in the text as requested.

Attachment

Submitted filename: Response to reviewers Dec 11.docx

pone.0302452.s005.docx^{(21.5KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0302452.r003

Decision Letter 1

Bolajoko O Olusanya

16 Feb 2024

PONE-D-23-32597R1Scoping review of hearing loss attributed to congenital syphilis.PLOS ONE

Dear Dr. Robinson,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Bolajoko O. Olusanya, MBBS, FMCPaed, FRCPCH, PhD

Academic Editor

PLOS ONE

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When submitting your revision, we need you to address these

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Additional Editor Comments (if provided):

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: N/A

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #2: The previous comments have been addressed. I have just a few additional comments:

1. The manuscript adheres to PRISMA-ScR reporting guidelines although on lines 79 and 80 of the revised manuscript, it states that ‘the methodology is based on Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA’.

2. Table 1 is more of a critical appraisal than a quality assessment and the title should reflect that.

3. The legend states that the purple shape is 'unclear or moderate' while the JBI checklist rates the risk of bias as low, high, unclear or not applicable.

4. Lines 150 and 151 in Results section, 'hearing loss is first noted in adolescence...' - is this a finding or part of the discussion as the statement is referenced.

5. The layout (orientation) of Table 5 needs to change to Landscape as with Tables 4A & B.

Reviewer #3: Thank you for this important article highlighting a knowledge deficit in the actual incidence, prognosis, response to therapy of/for congenital syphilis. The recent increase incidence of congenital syphilis in the USA and Canada with unknown incidence in LMICs make filling this knowledge gap even more important as we move forward. I feel the reviewers comments/concerns have been adequately addressed. I do wonder why the authors chose not to have a second reviewer for articles in French. It would be informative to identify which articles were in French but not critical to do so.

**********

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Reviewer #2: Yes: Zainab Imam

Reviewer #3: No

**********

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PLoS One. 2024 Apr 26;19(4):e0302452. doi: 10.1371/journal.pone.0302452.r004

Author response to Decision Letter 1

27 Feb 2024

Thanks for agreeing to review a revised version of our manuscript. We have addressed the suggestions as follows:

Please ensure that your manuscript meets PLOS ONE's style

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Response: Changes were made to meet these requirements.

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Response: The manuscript contains all raw data required to replicate the results of the study.

3. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response: Done

________________________________________

Reviewer #2: The previous comments have been addressed. I have just a few additional comments:

Response: Thanks for noticing this error. The manuscript and the accompanying reference have been corrected. We realized that our abstract was not compliant with this reporting guideline so minor changes were made to make in the abstract it compliant.

2. Table 1 is more of a critical appraisal than a quality assessment and the title should reflect that.

Response: The title was changed as suggested.

3. The legend states that the purple shape is 'unclear or moderate' while the JBI checklist rates the risk of bias as low, high, unclear or not applicable.

Response: We omitted ”or moderate” which was an error.

4. Lines 150 and 151 in Results section, 'hearing loss is first noted in adolescence...' - is this a finding or part of the discussion as the statement is referenced.

Response: This is a summary of the results in the table. The sentence is now started with “In these reports…”. The reference was removed as it makes it seem like we are talking about a study that is not in the table.

5. The layout (orientation) of Table 5 needs to change to Landscape as with Tables 4A & B.

Response: Done

Response: Only one of the authors is fluent in French. In the end, none of the studies in French met the inclusion criteria. Had there been many studies, we would have found another person who was fluent.

Response: Done

Attachment

Submitted filename: Response to reviewers - hearing loss.docx

pone.0302452.s006.docx^{(18KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0302452.r005

Decision Letter 2

Bolajoko O Olusanya

21 Mar 2024

PONE-D-23-32597R2Scoping review of hearing loss attributed to congenital syphilis.PLOS ONE

Dear Dr. Robinson,

Please submit your revised manuscript by May 05 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
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We look forward to receiving your revised manuscript.

Kind regards,

Bolajoko O. Olusanya, MBBS, FMCPaed, FRCPCH, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Additional Editor Comments (if provided):

This manuscript is much improved now. However, substantial essential edits are required before it can be accepted for publication.

INTRODUCTION:

Paragraph 2; Lines 3-5: “In 2021 in Canada, the incidence of infectious syphilis in females was 729% higher than in 2017.“

- This statement is incorrect. Authors should check and revise the percentage increase from 7 in 2017 to 96 in 2021.

RESULTS

Lines 1&2: Authors please clarify: “Screening led to 154 records for full-text review of which 36 met inclusion criteria (Figure 1).“

- This statement is unclear. Authors need to describe the process of study were selection after removing duplicates to arrive at 154.

Screening of patients with hearing loss for congenital syphilis

Line 1: “There were 5 studies where patients with hearing loss for were screened for CS.”

- Delete “for” after hearing loss.

Table 1: Delete “were” from the subtitles under Type of study column e.g. Children with HL were screened for CS

Studies with interventions for hearing loss

Line 2: “All were observational and typically included a penicillin with addition of…”

- Authors to revise sentence

DISCUSSION

Opening sentence: “The scoping review shows that the literature on hearing loss due to CS is immature.”

- The word “immature“ in the opening sentence is unclear. Authors should rewrite and clarify.

Para 1, Last sentence: ”It seems unlikely that a systematic review would answers these questions”

- change “answers” to ‘answer’

Para 4, Lines 2 & 3: “It is possible that hearing loss started years prior but was not recognized.”

- Authors may also add the following sentence: “Particularly, if the hearing loss is delayed or progressive.”

GENERAL

The manuscript requires extensive language edits.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

PLoS One. 2024 Apr 26;19(4):e0302452. doi: 10.1371/journal.pone.0302452.r006

Author response to Decision Letter 2

22 Mar 2024

Response to reviewers:

INTRODUCTION:

Paragraph 2; Lines 3-5: “In 2021 in Canada, the incidence of infectious syphilis in females was 729% higher than in 2017.“

- This statement is incorrect. Authors should check and revise the percentage increase from 7 in 2017 to 96 in 2021.

Response: We decided that it was simpler and clearer to remove percentages and remove maternal Canadian data and present actual data for congenital syphilis for the same years in Canada and the United States. We therefore changed this section to read: “The number of cases of confirmed early CS born to women aged 15-39 years in Canada rose from 17 in 2018 to 117 in 2022 [4]. Trends in the United States (US) mirror this with an increase from 1325 congenital syphilis cases in 2018 to 3755 in 2022 [5].”

RESULTS

Lines 1&2: Authors please clarify: “Screening led to 154 records for full-text review of which 36 met inclusion criteria (Figure 1).“

- This statement is unclear. Authors need to describe the process of study were selection after removing duplicates to arrive at 154.

Response: Thanks for pointing out this error. It should have been 159 rather than 154 full articles that were pulled. We now added to the text “The figure outlines the reasons for exclusion of other records. “ We can outline the reasons in the text as well if the reviewer thinks that this is necessary.”

Screening of patients with hearing loss for congenital syphilis

Line 1: “There were 5 studies where patients with hearing loss for were screened for CS.”

- Delete “for” after hearing loss.

Response: Thanks for pointing out this error. It was corrected.

Table 1: Delete “were” from the subtitles under Type of study column e.g. Children with HL were screened for CS

Response: Done

Studies with interventions for hearing loss

Line 2: “All were observational and typically included a penicillin with addition of…”

- Authors to revise sentence

Response: This was changed to “All were observational. Most commonly patients were prescribed penicillin with addition of prednisone followed by ACTH if response was poor or transient.”

DISCUSSION

Opening sentence: “The scoping review shows that the literature on hearing loss due to CS is immature.”

- The word “immature“ in the opening sentence is unclear. Authors should rewrite and clarify.

Response: We changed “immature” to “limited and low quality.”

Para 1, Last sentence: ”It seems unlikely that a systematic review would answers these questions”

- change “answers” to ‘answer’

Response: Done

Para 4, Lines 2 & 3: “It is possible that hearing loss started years prior but was not recognized.”

- Authors may also add the following sentence: “Particularly, if the hearing loss is delayed or progressive.”

Response: Thanks for the suggestion. We changed the sentence to read: “It is possible that hearing loss started years prior but was not recognized, particularly, if the hearing loss was slowly progressive.”

GENERAL

The manuscript requires extensive language edits.

Response: Many edits were made.

Attachment

Submitted filename: Response to reviewers.docx

pone.0302452.s007.docx^{(15.7KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0302452.r007

Decision Letter 3

Bolajoko O Olusanya

4 Apr 2024

Scoping review of hearing loss attributed to congenital syphilis.

PONE-D-23-32597R3

Dear Dr. Robinson,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Bolajoko O. Olusanya, MBBS, FMCPaed, FRCPCH, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Associated Data

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

Supplementary Materials

S1 Checklist. Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist.

(DOCX)

pone.0302452.s001.docx^{(83.8KB, docx)}

S1 Appendix. Systematic review search strategy.

(DOCX)

pone.0302452.s002.docx^{(22.5KB, docx)}

S2 Appendix. Joanna Briggs Institute (JBI) critical appraisal checklist.

(DOCX)

pone.0302452.s003.docx^{(27.9KB, docx)}

Attachment

Submitted filename: PONE-D-23-32597_reviewer.pdf

pone.0302452.s004.pdf^{(2MB, pdf)}

Attachment

Submitted filename: Response to reviewers Dec 11.docx

pone.0302452.s005.docx^{(21.5KB, docx)}

Attachment

Submitted filename: Response to reviewers - hearing loss.docx

pone.0302452.s006.docx^{(18KB, docx)}

Attachment

Submitted filename: Response to reviewers.docx

pone.0302452.s007.docx^{(15.7KB, docx)}

Data Availability Statement

All data are in the manuscript and/or supporting information files.

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PERMALINK

Scoping review of hearing loss attributed to congenital syphilis

Aleena Amjad Hafeeez

Karina Cavalcanti Bezerra

Zaharadeen Jimoh

Francesca B Seal

Joan L Robinson

Nahla A Gomaa

Roles

Abstract

Background

Objectives

Eligibility criteria

Sources of evidence

Results

Conclusions

Introduction

Methods

Results

Fig 1. PRISMA flow diagram.

Screening of patients with hearing loss for congenital syphilis

Table 1. Critical appraisal of studies of hearing loss attributed to congenital syphilis.

Table 2. Studies where multiple children with hearing loss were screened for congenital syphilis.

Screening of patients with CS for hearing loss

Table 3. Studies where children with congenital syphilis were screened for hearing loss.

Case series and case reports of hearing loss attributed to CS

Table 4.

Studies with interventions for hearing loss

Table 5. Studies with an intervention for hearing loss that was attributed to congenital syphilis with minimal details on individual patients.

Discussion

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Sangamanatha Ankmnal Veeranna

Roles

Author response to Decision Letter 0

Decision Letter 1

Bolajoko O Olusanya

Roles

Author response to Decision Letter 1

Decision Letter 2

Bolajoko O Olusanya

Roles

Author response to Decision Letter 2

Decision Letter 3

Bolajoko O Olusanya

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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