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. 2022 Oct 25;17(10):e0275253. doi: 10.1371/journal.pone.0275253

Gestational and congenital syphilis across the international border in Brazil

Leonor H Lannoy 1, Patrícia C Santos 2, Ronaldo Coelho 2, Adriano S Dias-Santos 2, Ricardo Valentim 3, Gerson M Pereira 2, Angelica E Miranda 1,*
Editor: Everton Falcão de Oliveira4
PMCID: PMC9595568  PMID: 36282795

Abstract

Background

Brazil lacks data from syphilis in its border areas. We aimed to describe the spatial and temporal distribution of acquired syphilis (AS), in pregnancy (SP) and congenital syphilis (CS) in Brazilian municipalities in the arches border contexts.

Methods

An ecological, cross-sectional study was conducted from 2010 to 2020. The study was based on the cases of syphilis available in the Notifiable Diseases Information System (SINAN), and on the Primary Health Care Information System. The detection rates of AS and SP, and the incidence of CS were estimated, and the time series was analyzed. Data between the border arches were compared.

Results

In 2020, data showed 7,603 cases of AS (detection rate 64.8/100,000 inhabitants), 3,960 cases of SP (detection rate of 21.6/1,000 live births) and 836 cases of CS (incidence of 4.6/1,000 live births) in the border region. Between 2010 and 2020, the mean annual increase of detection rate of SP was 53.4% in Brazil, 48.0% in the border region, 59.6% in the North Arch, 28.8% in the Central and 67.2% in the South. Annual variation on the incidence of CS for the same period was 31.0% in Brazil 38.4% at the border, in the North and South Arcs 18.3% and 65.7% respectively. The Central Arch showed an increase only between 2010 and 2018 (62.7%). A total of 427 (72.6%) municipalities has primary health care coverage ≥ 95% of the population. In 2019, 538 (91.8%) municipalities reported using rapid tests for syphilis, which decreased to 492 (84%) in 2020. In 2019, 441 (75.3%) municipalities reported administering penicillin, and 422 (72%) in 2020.

Conclusion

Our data show syphilis reman problem at the Brazilian border, rates in pregnant are high. It was observed a reduction in the detection rates, SP and the incidence of CS between 2018 and 2020. Syphilis should be included on the agenda of all management levels, aiming at expanding access and quality care.

Introduction

The Brazilian border region consists of 9 countries and the French Guiana, with 15,179 km of extension, 150 km of width and an area of 1.4 million km2 (equivalent to 16.6% of the Brazilian territory). The region comprises 11 states, 588 land municipalities, two aquifers and more than 10 million inhabitants (11,733,448) [1]. Its extension has spaces with different geopolitical characteristics that involve issues related to mobility, language barriers and situations of illegality, which lead to inaccessibility and affects physical, social and mental vulnerability [2].

Brazilian borders present different levels of integration and economic development depending on international political and economic dynamics that can hamper or facilitate local socioeconomic development [3]. Cultural diversity, the political structures of municipalities, the level of economic development, among others, influence the functioning and demand of local health systems [4]. Thus, global processes increasingly determine the health of a population. In general, these territories tend to show indicators of lower income, lower well-being, conditions of backwardness and socioeconomic and environmental vulnerability [5].

Syphilis is one of the most common sexually transmitted infections (STIs), with about 7.1 million new cases worldwide in 2020 [6]. Estimates show there were more than half a million (approximately 661,000) cases of congenital syphilis (CS) worldwide in 2016, which resulted in more than 200,000 stillborn and neonatal deaths [7]. Between 2010 and 2020, in Brazil, 853,256 cases of acquired syphilis (AS), 449,981 cases of syphilis in pregnancy (SP) and 197,700 cases of CS were reported in the Notifiable Diseases Information System (SINAN). In 2020, the AS detection rate was 54.5 cases/100,000 inhabitants (115,371 cases), the SP detection rate was 21.6 cases per 1,000 live births (LB) (61,441 cases) and the CS incidence was 7.7 cases per 1,000 live births (22,065 cases) [8]. These data emphasize the infection as a national public health problem.

Syphilis remains a global challenge in several countries and in Brazil it persists as a public health problem. In 2016, syphilis was considered a serious public health problem in Brazil due to constant increases in the detection rates of AS, SP and the incidence of CS. For this reason, the Ministry of Health prepared and launched the “Agenda of Strategic Actions for the Reduction of Congenital Syphilis 2017–2019” and the following year the “Rapid Response to Syphilis Project” to implement access to the diagnosis and treatment of syphilis throughout the country [9].

Primary health care diagnoses and treats AS and SP in Brazil, with 76.1% of population coverage in 2020 [10]. A strategy to diagnose the cases is first testing for syphilis with the point-of-care test (treponemal) and then confirming with non-treponemal tests, such as the Venereal Disease Research Laboratory Test (VDRL). Penicillin G Benzathine is recommended as the first choice for treatment [11].

The AS detection rates differ between the regions of Brazil and reflect in the prevalence of SP [12]. The differences between the regions may also suggest different levels of quality of services and accessibility, which affect the diagnosis and treatment. The incidence of congenital syphilis reflects this scenario [13].

Despite the importance of the border region in Brazil and the CS as a public health problem, few studies explored the epidemiology of this infection in the region. However, the knowledge on the dissemination of syphilis in the Brazilian border and the availability of primary health care services can help to understand the dynamics of the infection and allow control measures that meet the peculiarities of these environments. Based on it, this study was performed to describe the spatial and temporal distribution of syphilis in Brazilian municipalities in the arches border contexts.

Methods

This is an exploratory ecological study with multiple group designs. It is a descriptive study conducted with secondary data available in the information systems of the Brazilian Ministry of Health regarding land border municipalities in Brazil.

Information from the 586 municipalities of the land border were included and the two aquifer municipalities, Lagoa dos Patos and Lagoa Mirim, in the state of Rio Grande do Sul, were excluded since they did not have a population to be analyzed. Sociodemographic variables of health conditions, procedures/treatments performed (point-of-care tests and administration of penicillin G Benzathine), dates of diagnoses, outcome of pregnancy regarding congenital syphilis and coverage of primary health care were studied.

The definition used by the Border Development Program (PDFF) [14] of the Brazilian Government was considered for analysis, which establishes that the region is divided into three arches (North, Central and South). The North Arch includes the borders of the Federative Units, Amapá, Pará, Roraima, Amazonas and Acre with 69 municipalities; the Central Arch includes Rondônia, Mato Grosso and Mato Grosso do Sul with 101 municipalities and the South Arch includes the border of Paraná, Santa Catarina and Rio Grande do Sul, with 418 municipalities (two aquifers). The aspects of productive basis and cultural identity are considered for this division to emphasize the local potentials with the relationship and articulation with neighboring countries and implement actions according to the particularities of each region.

The detection rates of AS, SP and the incidence of CS were obtained from the data available in the panel of indicators of syphilis (http://indicadoressifilis.aids.gov.br/) [15] between 2010 and 2020. The coverage of diagnostic tests for syphilis and the analysis of administration of penicillin G Benzathine by primary health care were analyzed based on the information in the Health Information System for Primary Health Care [16].

The epidemiological data of the studied infection in the three population was obtained by nationally analyzing the notification data in the SINAN and the Primary Health Care Information System (E-SUS). A descriptive analysis with frequency distribution for qualitative variables and an estimate of mean for quantitative variables were performed, as well as appropriate graphs and maps.

The mean annual increase (annual variation) of detection rates of SP and incidence of CS between 2010 and 2020 and period from 2010 to 2018, were estimated for the evaluation of detection rates. The period from 2010 to 2018, was chosen because in October 2017 the congenital syphilis definition was changed in Brazil, it was adopted the case definition proposed by the WHO [17]. The detection rates underwent logarithmic transformation and then the autoregressive Prais-Winsten model was applied, according to Antunes and Cardoso’s methodology [18].

The coefficients of variation (β1) obtained after the model was applied, which correspond to each of the periods, were used in the following formula to obtain the annual variation rates:

Rate=1+eβ1×100

From the coefficient of variation (β1) and the standard error, the values of the confidence interval (CI) of the variation rates were obtained.

The significance level considered was 5%. The quantitative data were descriptively analyzed using the Statistical Package for the Social Sciences (SPSS) for Windows, version 20.0, Chicago, SPSS Inc. The time series analysis was performed using Stata for Windows, version 13.0. The program TabWin version 3.6, free software, was also used for the construction of thematic maps (http://siab.datasus.gov.br/DATASUS/).

The databases were analyzed without the identification of the subjects. It was an anonymous secondary database analysis performed after the authorization of the Brazilian Ministry of Health. The study was submitted to the Research Ethics Committee of the Center for Health Sciences of the Federal University of Espírito Santo, as recommended by resolution no. 466/2012 of the National Health Council and approved under the number 4,719,557/2021. Privacy and confidentiality were ensured at all stages of the project by codification.

Results

In 2020, the border region reported 7,603 cases of AS (detection rate 64.8/100,000 inhabitants), 3,960 cases of SP (detection rate of 21.6/1000 LB) and 836 cases of CS (incidence of 4.6/1,000 LB). Fig 1 shows that the detection and incidence rates of these infection cases differ in the three arches.

Fig 1. Detection rate of acquired syphilis per 100,000 inhabitants, syphilis in pregnancy and incidence of congenital syphilis per 1,000 live births, according to the border arches and in Brazil, 2020.

Fig 1

Source: http://siab.datasus.gov.br/DATASUS/.

The analysis of the sociodemographic characteristics of pregnant women with syphilis in 2020 shows a mean age of 24 years old, a mode of 20 years old, and median of 23 years old. This age categorization shows that 938 (23.7%) were between 15 and 19 years old, 2,194 (55.4%) between 20 and 29 years old and 701 (17.7%) were ≥ 30 years old. Information on schooling was reported as not informed by 871 (22%), 1,325 (34.2%) were illiterate or attended middle school, 1,567 (39.5%) had incomplete or complete high school and 169 (4.3%) had entered or completed higher education. Regarding race/color, 38.4% (1,520) declared themselves as white and 58.0% (2,295) as others (black, mixed race, Indigenous, Asian). We observed that the diagnosis of syphilis occurred in the first trimester of pregnancy in 1,760 (44.4%) of cases, with a greater proportion in the South Arch (52.2%), followed by the Central (40.9%) and North (32.9%) Arches. The clinical classification of syphilis was reported as not informed by 822 (20.8%) and 1,286 (32.5%) reported primary syphilis. Regarding the treatment of syphilis, 3,215 (81.1%) received adequate prescriptions based on the penicillin dose and clinical classification. In the Central Arch, however, only 762 (76.9%) pregnant women received adequate treatment. In 2020, 836 (26.8%) cases of syphilis in pregnancy resulted in congenital syphilis in the Brazilian border, with greater proportion, 30.7% (459), in the South Arch (Table 1).

Table 1. Sociodemographic characteristics, gestational age when diagnosed with syphilis, clinical classification, treatment of reported cases of pregnant women with syphilis and proportion of outcomes, according to the border arch of residence and year of delivery 2020.

North Arch Central Arch South Arch Total
Age group N % N % N % N %
 Under 15 years old 21 2.1 11 1.1 26 1.3 58 1.5
 15 to 19 years old 278 27.4 246 24.8 414 21.2 938 23.7
 20 to 29 years old 531 52.4 565 57.0 1,098 56.2 2,194 55.4
 ≥ 30 years old 184 18.1 169 17.1 417 21.3 770 17.7
Schooling
 Up to Middle school 385 38.0 358 36.1 609 31.2 1,353 34.2
 High School 431 42.5 326 32.9 810 41.5 1,567 39.5
 Higher education 40 3.9 37 3.7 92 4.7 169 4.3
 Not informed 158 15.6 270 27.2 443 22.7 871 22.0
Race/color
 White 57 5.6 254 25.6 1,209 61.8 1,520 38.4
 Other 924 91.1 712 71.8 659 33.7 2,295 57.9
 Not informed 33 3.3 25 2.5 87 4.5 145 3.7
Gestational age of diagnosis
 First trimester 334 32.9 405 40.9 1,021 52.2 1,760 44.4
 Second trimester 242 23.9 210 21.2 395 20.2 847 21.4
 Third trimester 315 31.1 346 34.9 456 23.3 1,117 28.2
 Gestational age not informed 123 12.1 30 3.0 83 4.2 236 6.0
Clinical classification
 Primary syphilis 344 33.9 264 26.6 678 34.7 1,286 32.5
 Secondary syphilis 52 5.1 47 4.7 80 4.1 179 4.5
 Tertiary syphilis 96 9.5 156 15.7 107 5.5 359 9.1
 Latent syphilis 331 32.6 384 38.7 599 30.6 1,314 33.2
 Not informed 191 18.8 140 14.1 491 25.1 822 20.7
Treatment
 Adequate 836 82.4 762 76.9 1,617 82.7 3,215 81.1
 Inadequate 138 13.6 97 9.8 163 8.3 398 10.1
 Not performed/ Not informed 40 3.9 132 13.3 175 9.0 347 8.8
Outcome of children exposed to syphilis
 CS—yes 188 18.5 189 19.1 459 30.7 836 26.8
 CS—no 826 81.5 802 80.9 1,496 69.3 3,124 73.2
Total 1,014 100% 991 100% 1,955 100% 3,960 100%

Fig 2 shows the mean annual increase in the detection rates of SP between 2010 and 2020. The number increased during this period in Brazil (53.4%). The mean annual increase of detection rate of syphilis in pregnancy was 59.6% in the North Arch, 28.8% in the Central and 67.2% in the South. In the analysis of the interrupted time series, the period (2010–2018) shows an increase in the three arches, North (72.8%), Central (34.7%) and South (102.0%) and in Brazil (66.3%). The increment rate was stationary between 2018 and 2020 in Brazil and decreased in the border (-9.0%).

Fig 2. Detection rate of syphilis in pregnancy per 1,000 live births, 2010–2020 and mean annual variation of the detection rate in the three border arches and in Brazil, during 2010 to 2020, 2010 to 2018, and increment rate 2018–2020.

Fig 2

The analysis of the annual variation of incidence of CS between 2010 and 2020 shows an increase in the incidence in Brazil (31.0%) and in the North (18.3%) and South (65.7%) Arches. The Central Arch showed an increase only between 2010 and 2018 (62.7%). The interrupted series also shows an increase in the South Arch (103.3%), Central (62,7%), North (23,4%) and in Brazil (45.8%) between 2010 and 2018. The increment of incidence of CS, between 2018 and 2020, is negative in the border region (-26%) and Brazil (-14%), being more accentuated in the central arch (-43%) (Fig 3).

Fig 3. Incidence rate of congenital syphilis per 1,000 live births, 2010–2020 and mean annual variation of incidence, in the three border arches and in Brazil, during 2010 to 2020, 2010 to 2018, and increment rate 2018–2020.

Fig 3

The reduction in the detection rates of AS (-29.4%), SP (-7.3%) and the incidence of CS (-16.4%) in the region, between 2019 and 2020, show a better control of syphilis in the country.

Data from the Primary Health Care Information System (SISAB) show 538 (91.8%) municipalities reported performing point-of-care test for SP health care units in 2019. This number decreased to 492 (84%) municipalities in 2020, with the North Arch showing a greater proportion of municipalities that reported this information (96%). In 2019, 441 (75.3%) border municipalities reported administering penicillin to treat syphilis in primary health care units, and 422 (72%) reported this information in 2020. Regarding the notification of AS in 2019, 80% (469) of municipalities reported at least one case of AS, and in 2020, 71.2% (417) of municipalities reported any case in the SINAN. The North Arch had the highest proportion of this information in the SISAB (rapid test 96% and administration of penicillin 81%) and reported AS in 2020 (83%) (Fig 4).

Fig 4. Proportion of municipalities in the border that reported point-of-care test for syphilis, notified acquired syphilis and administered penicillin to treat syphilis in primary health care units, 2020.

Fig 4

Source: http://siab.datasus.gov.br/DATASUS/.

The analysis on the primary health care coverage shows that 72.6% (427 municipalities) have a population coverage ≥ 95%. The Central Arch has the lowest proportion of municipalities with this coverage, 59% (58 municipalities), which is close to that of the North Arch, 61% (43 municipalities). Syphilis in pregnancy was reported in 61.4% (361) of border municipalities and 27.8% (164) have a detection rate ≥ national rate (21.6/1000 LB). Most municipalities, 67.5% (397), did not report cases of congenital syphilis in 2020 and 14.3% (84 municipalities) have an incidence of congenital syphilis ≥ 7.7/1000 LB (Fig 5).

Fig 5. Proportion of municipalities with a primary health care coverage ≥ 95%, detection rate of syphilis in pregnancy, incidence of congenital syphilis, according to the border arch, 2020.

Fig 5

Source: http://siab.datasus.gov.br/DATASUS/.

Discussion

The results of our study showed that the Brazilian border region in 2020, compared to the national data, had a higher detection rate of AS, an equal detection rate of SP and a lower incidence of CS [15]. The reduction in the detection rates of AS, SP and the incidence of CS in the region, between 2019 and 2020, show a better control of syphilis in the country. Other study showed the same tendency in the country [12]. However, we cannot measure how the COVID-19 pandemic affected these data. The pandemic required a greater mobilization of health care providers, which resulted in a change in the attention that used to be directed to other diseases [19].

Despite the number of plans and initiatives to develop the border region [14, 20, 21], it faces major challenges to advance on public policies [22]. Data from the Institute for Applied Economic Research (IPEA) (2016) confirm that the border municipalities of Brazil have the worst rates of income and schooling of their respective states, and suffer from illegal immigration, currency evasion, land conflicts, smuggling and many types of trafficking (weapons, drugs, people) [23, 24]. These characteristics can affect health care and disease control.

The cross-border flow of people and the seek for services increase the vulnerability of municipalities to the entry of infectious agents, which affect the financing of health actions and services [24]. In turn, the increase of transmission of STIs, including HIV also relates to the mobility of the population associated with multiple partnerships and sexual work in these territories [25]. We must emphasize that syphilis remains endemic in Latin American, Asian and African countries with limited resources, due to the difficulty of early diagnosis and treatment, which enable its dissemination [26].

Our data showed that pregnant women with syphilis in the border region were young, non-white and with low schooling. The distribution was different depending on the analyzed arc, as the data followed the distribution of the Brazilian population, and a greater number of women who self-reported white were from the southern arc. The northern arc had the lowest percentage, where there is a greater number of indigenous people. These data are in agreement with the sociodemographic characteristics described in other studies [13, 2729]. However, the expansion of primary health care in Brazil led to an increase in prenatal coverage and the coverage of prenatal screening exams, a measure that expanded access and service as well as improved the diagnosis and notification of syphilis cases in the country [3032].

The notification on the staging of the clinical phases of syphilis showed that more than 30% were reported as primary syphilis, 9% as tertiary syphilis and 21% as not informed. Since most cases in pregnant women are asymptomatic, diagnosed by serological tests in the latent form of infection [33], these data may be classification errors and provide evidence of the need to continuously train health care providers to improve the possibility of adequate treatment and the quality of surveillance data in the border region [30].

The time series shows that, between 2010 and 2020, the detection rates of SP and the incidence of CS tended to increase in the border arches and in Brazil, except for the incidence of CS in the Central Arch, which strongly increased until 2017 with subsequent strong reduction between 2018 and 2020. Both SP and CS rates show a reduction as of 2018, despite the SP rate being stationary in Brazil. It is important to note that the reduction in the incidence of CS may also be related to the change in the case definition for surveillance purposes, which as of September 2017, became more specific, and excluded the condition of treatment of the pregnant woman’s partner from the case definition [9].

The knowledge on the epidemiological situation of syphilis in countries bordering Brazil has been an issue in recent years due to the difference of surveillance and notification systems of the infection between the countries, as well as the priorities and available resources. This situation impairs the measuring and/or comparison between the rates of AS and SP, the vertical transmission of the infection, and the effect on local health systems related to the flows of people in the border region countries [3440].

CS is the result of the transmission of the spirochete of the Treponema pallidum from the infected pregnant woman’s bloodstream to the conceptus by transplacental route or, occasionally, by direct contact with the lesion at the time of delivery [33, 41]. Timely diagnosis and adequate treatment for the pregnant woman can prevent the infection, which is an essential indicator of the quality of prenatal care [13, 42]. The vertical transmission of syphilis is high and can reach almost 100% in recent forms of the infection without treatment [38]. The outcome rate of CS in the border region in 2020 was 26.7% and 35.9% in Brazil. A national hospital-based study found 34.3% (95% CI: 24.7–45.4) vertical transmission rate of syphilis [43], similar to the result of our study. This proportion of outcome is influenced by the increase in the capacity to diagnose and notify SP and the possibility to diagnose CS.

Regarding the availability of point-of-care tests for syphilis, we observed that 16% of municipalities in the border region did not report access to them in primary health care units and 28.8% did not report the administration of penicillin to treat syphilis. We must consider that border municipalities are mostly small, of low demographic density and remotely located [1]. In turn, a study with data from the National Program for Improvement of Access and Quality in Primary Health Care (PMAQ-AB) identified an improvement in the diagnoses of syphilis (treponemal and/or non-treponemal tests) in the municipalities evaluated, which enables the increase in the capacity to identify people with syphilis, and that about a third of the teams did not offer a rapid test, requiring an expansion for this measure [44].

SP is diagnosed and treated in primary health care in Brazil and since only 70% of border municipalities have primary health care coverage for 95% of the population, this care network must be strengthened to provide a better quality care [7, 29, 43]. Despite the improvements in the Brazilian Unified Health System (SUS), the control of CS, which is based on the treatment of SP, remains a challenge in Brazil and emphasizes the vulnerability in prenatal care, since it is essential to monitor access and quality of primary health care [27, 43, 44].

Our study also allowed essential analyses within each of the border arches, we emphasize below what we have found in each of them. In the North Arch, bordering the French Guiana, Suriname, Guyana, Venezuela, Colombia and Peru, despite the historical series of this territory always showing a detection rate of SP and incidence of CS, its rates were lower than in the other arches and the national mean rate. Compared to the Central and South Arches, it showed a higher proportion of pregnant women with syphilis under 19 years old (29.5%) and who studies up to middle school (38.0%), a lower proportion of detection of the infection diagnosed in the first trimester of pregnancy (32.9%) and a high proportion of primary syphilis among pregnant women (33.9%). However, it is the arch that shows the lowest proportion of congenital syphilis outcome among children exposed to syphilis (18.5%). The great territorial extension, the small population, the history of isolation from national centers and the rich cultural, ethnic and linguistic diversity [3] can influence access and adherence to health care services, as well as create care voids and hinder the identification of cases and early diagnosis.

The Central Arch borders Bolivia and Paraguay and has some of the twin cities with greater sociocultural integration and has consolidated urban centers. Local integration today is characterized by the dependence of foreign urban centers on Brazilian municipalities [1, 3, 5]. This arch shows high detection rates of SP since the beginning of the historical series and the proportion of CS outcomes is 19.1%. A total of 40.9% of the diagnoses of syphilis are made in the first trimester of pregnancy and it has the highest proportion of pregnant women with latent syphilis (38.7%). However, it is the region with the lowest proportion of pregnant women adequately treated (76.9%) and a high proportion of notifications without reporting the treatment used for syphilis and/or not performed (13.1%). The incidence of CS decreased of 43% between 2018 and 2020.

The South Arch, bordering Paraguay, Argentina and Uruguay, is the one with the highest level of development, higher urban density, with most twin cities and the highest level of regional integration based on health care due to initiatives, such as Mercosul and Unasul [3, 20]. This region shows a lower proportion of pregnant women with syphilis up to 19 years old (22.5%) and women who attended up to middle school (31.2%), a higher proportion of diagnosis in the first trimester of pregnancy (52.2%), but shows a higher proportion of pregnant women diagnosed with primary syphilis (34.7%) and no information regarding this issue (25.1%). The region has the highest proportion of CS as outcome (30.7%).

Our analysis corroborates studies that show a relationship between the prevalence of syphilis and municipalities with higher demographic densities, because they show social and health determinants that enable the dissemination of the infection and, despite offering a wider health care service, it maintains social disparities and the populations’ difficulties to access the services [5, 45].

Among the limitations of our study, we mention the use of secondary data without independent validation, which comes from health administration and can be biased and problems related to under-reported cases. Another limitation is due to the design of an ecological study, which does not allow direct interpretations of individual results. The descriptive approach is limited to univariate analyses, not adjusted by many risk factors and their interactions, nor by spatial data structure, which would be possible in a more complex analytical approach. However, syphilis is of compulsory notification and information systems are the biggest source of data to perform this evaluation. And once the data were analyzed by region, the distribution of the possible underreporting dissipates less heterogeneously. Besides, these cases of syphilis are in national agreements that involve accountability and financing for states and municipalities, which expects a good data coverage.

Our data show a reduction in the detection rates of AS, SP and the incidence of CS between 2018 and 2020. This reduction needs to be evaluated in another series in the coming years, due to the pandemic and the change in the case definition, it may not be attributed only to the improvement in care. It shows that strategies focused on syphilis should be included on the agenda of all management levels, aiming at expanding access and improving quality care. We expect with our analysis to contribute to advance in the implementation of public health policy for each arch region, based on the understanding of the political, symbolic and social power relationships in which each region was formed [46]. The results showed a good performance of pregnancy care and low CS index in the border region; however, the infection must be a priority on the agenda of all management levels, aiming at expanding access and quality care. Border regions represent unique spaces for regional development and integration and are characterized by the intense sociocultural and economic exchange. Few information available on the epidemiology of STIs in these areas limit the implementation of public policies. The solutions to address public health challenges depend on bilateral relationships. The understanding on the access to health services and the behavior of diseases in the region can contribute to the well-being of the community in the region and to specific policies for the citizens on both sides.

Supporting information

S1 Data. Study database tables frontiers.

(XLSX)

Data Availability

All relevant data are within the paper and its Supporting information files. A global view of all Brazilian data are available at http://indicadoressifilis.aids.gov.br/.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Everton Falcão de Oliveira

5 Jul 2022

PONE-D-22-16035Gestational and congenital syphilis across the international border in Brazil Syphilis in Brazilian land bordersPLOS ONE

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Reviewer #2: Partly

Reviewer #3: Partly

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Reviewer #2: Yes

Reviewer #3: Yes

**********

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5. Review Comments to the Author

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Reviewer #1: Dear Editor,

In this manuscript, the distribution of acquired syphilis, syphilis in pregnancy, and congenital syphilis was analyzed at the Brazilian border with other nine countries from 2010 to 2020. The results show that the number of cases for all three variables is increasing throughout the Brazilian border area. This is nothing new, as the number of syphilis cases has increased dramatically worldwide in recent years. However, given the lack of data on developing country borders, I believe that this manuscript should be considered for publication after some modifications as described below:

Abstract:

I suggest inserting a space between several words: pregnancy (SP), syphilis (CS), syphilis (AS), Brazil(38.4%), North(18.3%), South(65.7%), 427(72.6%), 441(75.3%), 422(72%).

Introduction:

- Why "Discussions about the border have intensified in recent decades due to the regionalization processes"?

- About "Despite the importance of the border region in Brazil and the congenital syphilis as a public health problem, few studies explored the epidemiology of this infection in the region." Are AS and SP a public health problem in Brazil? Or not?

Results:

- Note Figures 2 and 3. In the text below the figure, words are underlined. What does "2010 a 2020" mean?

- "Syphilis in pregnancy was reported in 61.4% (361) of border municipalities and 27.8% (164) have a detection rate ≥ national rate (21.6/1000 LB). Most municipalities, 67.5% (397), did not report cases of congenital syphilis in 2020 and 14.3% (84 municipalities ) have an incidence of congenital syphilis ≥ 7.7/1000 LB (Figure 5)." Define LB.

Discussion:

- Italianize Treponema pallidum: "CS is the result of the transmission of the spirochete of the Treponema pallidum from the infected pregnant woman's ..."

Reviewer #2: The manuscript is of relevance, it points out updated aspects with the syphilis theme. However, it presents internal and external biases. Title: adequate; Abstract: incomplete with the need for adaptation of items as presented throughout the text; Introduction: presents issues that belong to another topic such as the research scenario, the knowledge gap is fragile, without articulation with the uniqueness of the research. Methods: The research design is inadequate. According to Morgenstern (2011), ecological studies can be divided into: multiple group designs (exploratory and etiological), time trend designs (exploratory and etiological), mixed designs (between multiple groups and time trend, but also with sub-classifications between exploratory and etiological). By the detailing of the methods, the study is more articulated with an exploratory ecological study with multiple group designs. Results: are very well designed, but not validated with explanatory tests. The statistics are simple and make the text uncompetitive. Discussion: well elaborated with the inclusion of limitations. However, limited to the results, which in fact is not inconsistent, but does not address aspects related to the health model, the treatment of partners who are in another border country, the mobility of the standardization of treatment and availability of supplies among other aspects that interfere in the occurrence of the grievance in all its scopes, acquired syphilis, in pregnant women and congenital. I hope that the comments provided will help you with the publication elsewhere or to resubmit after adaptations.

MORGENSTERN, Hal. Ecologic Study. In: ROTHMAN, Kenneth L.; GREENLAND, Sander; LASH, Timothy L. Modern Epidemiology, 3rd Edition, 2008.

Reviewer #3: Syphilis represents a highly relevant issue globally. It remains a global challenge, the second most commonly reported STI. In Brazil, syphilis persists as a public health problem, particularly due to limited access to timely diagnosis and treatment, as well as limited monitoring of cases in the Unified Health System health care network, especially in Primary Health Care. The challenge is amplified when the critical political and institutional moment of the country is recognized. One of the great challenges has been to implement these health care actions integrated with surveillance and control, ensuring wide access to diagnosis, treatment, and monitoring in the Primary Health Care setting. These aspects are even more critical in border areas in the context of South America.

There is great variation in the operational performance of disease control in the country. This variation has been associated with operational factors such as access to testing via rapid tests, but also to the lower use of condoms, the reduced use of penicillin in routine PHC, and the period in which there was a shortage of the drug. These aspects should have been better described in the manuscript.

Moreover, both acquired syphilis, syphilis in pregnant women, and congenital syphilis are compulsorily notifiable diseases in the country but have registered systematic under-reporting, which compromises health planning actions, despite the improvement over time. This aspect should have been studied in depth.

It is important to bring the impacts related to congenital syphilis to society.

For a broader look at the real epidemiological and operational situation of syphilis control, the analyses should include the quality of prenatal care in the public and private sectors. This aspect should be discussed.

Expand the debate on the ethnic-racial clippings performed, as differentials in the three arches analyzed.

Include the debates on recently published articles:

Saes MO, Duro SMS, Gonçalves CS, Tomasi E, Facchini LA. Assessment of the appropriate management of syphilis patients in primary health care in different regions of Brazil from 2012 to 2018. Cad Saude Publica. 2022 May 16;38(5):EN231921. doi: 10.1590/0102-311XEN231921. PMID: 35584428.

Ramos AN Jr. Persistence of syphilis as a challenge for the Brazilian public health: the solution is to strengthen SUS in defense of democracy and life. Cad Saude Publica. 2022 May 16;38(5):PT069022. doi: 10.1590/0102-311XPT069022. PMID: 35584431.

Reiterate the relevance of PMAQ-AB as an innovative and useful action to induce quality improvement of PHC in SUS. This program was interrupted by the federal government in 2019 within the process of deconstruction of public health policies, having been replaced by the PREVINE Brazil Program. The authors need to discuss the effect of this change, implying a considerable setback in the process of evaluation and financing of PHC.

For the abstract, it is recommended to qualify the description of border arcs, to better situate the analyzed scenarios. The objectives of the study should have been clearly listed, as in the introduction. Thus, the objectives of the study are partially articulated with a clear testable hypothesis stated. In principle, the focus is on the spatial and temporal description in Brazilian municipalities in border contexts. The conclusions of the abstract as well as of the manuscript should be adjusted to this perspective: the epidemiological and operational patterns of syphilis control are not satisfactory. The way it is described gives the wrong message of assumed control.

The introduction needs to be enhanced with better-contextualized data in operational and epidemiological terms of syphilis control in the country and in border areas, especially over the period 2010 to 2020. In Brazil, the changes in the definition of syphilis case for compulsory notification purposes delimited the temporal scope of the study. It is important to signal which changes were undertaken and their impacts, particularly the change in the definition of appropriate treatment of pregnant women with syphilis, excluding as a criterion the concomitant treatment of the sexual partner, in terms of the sensitivity/specificity of the case definition criteria.

In the introduction, the authors should be clearer when referring to the fact that discussions about the border have intensified in recent decades due to regionalization processes, including more consistent references.

The description of the study design needs to be qualified. In principle, the study design is appropriate to address the possible objective.

In addition, a detailed map of the study area could have been presented, while in the text, the indication of the territorial and population, as well as the economic relevance of this territorial cut-out adopted in the study.

It is recommended to detail the scope of the syphilis indicator panel with its linked databases, as well as the Health Information System for Primary Health Care, clearly demonstrating the role of care and surveillance and to what extent the interfaces between these systems. The population is clearly described and appropriate for the hypothesis being tested.

Qualify correctly and better the reference in the text to SPSS version 20.0 and TabWin (version???), according to the developers' specification. The correct statistical analysis is used to support conclusions.

There are concerns about ethical requirements being met.

The results are clearly and completely presented. The figures (Tables, Images) are of sufficient quality for clarity.

In the discussion, the reduction seen in the last two years analyzed does not allow one to clearly establish that there was a reduction in the detection rates analyzed. The limitations of the analysis are clearly described.

The authors discuss partially how these data can be helpful to advance our understanding of the topic under study.

The public health relevance is addressed. However, the conclusions are partially supported by the data presented.

**********

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Reviewer #1: Yes: Fred Luciano Neves Santos

Reviewer #2: No

Reviewer #3: 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.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2022 Oct 25;17(10):e0275253. doi: 10.1371/journal.pone.0275253.r002

Author response to Decision Letter 0


16 Aug 2022

Response to comments to the Journal Requirements and reviewers

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

RESPONSE: We reviewed the document and organized it according to the requirements

2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.

RESPONSE: Thank you for this comment, we clarified it in the text. The need for informed consent was waived by the ethics committee as this is a study used public and anonymous secondary data. Privacy and confidentiality were ensured at all stages of the project by codification performed before we had access to data. The databases were analyzed without the identification of the subjects. This study was conducted with the authorization of the Department of Chronic Diseases and Sexually Transmitted Infections of the Brazilian Ministry of Health. The study was submitted to the Research Ethics Committee of the Center for Health Sciences of the Federal University of Espírito Santo, as recommended by resolution no. 466/2012 of the National Health Council and approved under the number 4,719,557/2021.

3. Thank you for stating the following financial disclosure:

"The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

At this time, please address the following queries:

a) Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.

RESPONSE: The study did not receive any funds. We used secondary databases, and it was part of a PhD thesis. The student was responsible for the analysis and was supervised by the mentors.

b) State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

RESPONSE: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

c) If any authors received a salary from any of your funders, please state which authors and which funders.

RESPONSE: No author received funds for this project.

d) If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

RESPONSE: We included this statement in the manuscript. The authors received no specific funding for this work.

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

RESPONSE: We included the statement as requested. The Ministry of Health responsible for the program signed it. Amended statements are attached

4. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

RESPONSE: All data are available at:

The data are accessible in:

Border municipalities:

https://geoftp.ibge.gov.br/organizacao_do_territorio/estrutura_territorial/municipios_da_faixa_de_fronteira/2020/Municipios_da_Faixa_de_Fronteira_2020.xls

Epidemiological indicators: http://indicadoressifilis.aids.gov.br/

Primary care indicators: https://sisab.saude.gov.br/

Primary care coverage:

https://egestorab.saude.gov.br/paginas/acessoPublico/relatorios/relHistoricoCoberturaAB.xhtml

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

RESPONSE: We included the database used for the project analysis.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

RESPONSE: There are no ethical restrictions for database sharing. It was included in the submitted documents.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

5. Please amend your list of authors on the manuscript to ensure that each author is linked to an affiliation. Authors’ affiliations should reflect the institution where the work was done (if authors moved subsequently, you can also list the new affiliation stating “current affiliation:….” as necessary).

RESPONSE: We updated it and the statement reflects the information we provide in your cover letter.

6. We note that Figures 1, 4-5 in your submission contain [map/satellite] images which may be copyrighted. All PLOS content is published under the Creative Commons Attribution License (CC BY 4.0), which means that the manuscript, images, and Supporting Information files will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution. For these reasons, we cannot publish previously copyrighted maps or satellite images created using proprietary data, such as Google software (Google Maps, Street View, and Earth). For more information, see our copyright guidelines: http://journals.plos.org/plosone/s/licenses-and-copyright.

We require you to either (1) present written permission from the copyright holder to publish these figures specifically under the CC BY 4.0 license, or (2) remove the figures from your submission:

RESPONSE: We included the written permission from the copyright holder. The responsible director in the MoH signed the document.

As we said before, Tabwin/Tabnet is an application provided by the Ministry of Health of Brazil, with the purpose of enabling the analysis of information at the various points of the care network. This program has a public license for free and free use, available at: https://datasus.saude.gov.br/transferencia-de-arquivos/

a. You may seek permission from the original copyright holder of Figures 1, 4-5 to publish the content specifically under the CC BY 4.0 license.

RESPONSE: We included the written permission from the copyright holder.

We recommend that you contact the original copyright holder with the Content Permission Form (http://journals.plos.org/plosone/s/file?id=7c09/content-permission-form.pdf) and the following text:

“I request permission for the open-access journal PLOS ONE to publish XXX under the Creative Commons Attribution License (CCAL) CC BY 4.0 (http://creativecommons.org/licenses/by/4.0/). Please be aware that this license allows unrestricted use and distribution, even commercially, by third parties. Please reply and provide explicit written permission to publish XXX under a CC BY license and complete the attached form.”

RESPONSE: We included the written permission from the copyright holder We contacted them, and the authorization is attached.

Please upload the completed Content Permission Form or other proof of granted permissions as an "Other" file with your submission.

In the figure caption of the copyrighted figure, please include the following text: “Reprinted from [ref] under a CC BY license, with permission from [name of publisher], original copyright [original copyright year].”

RESPONSE: We uploaded the content permission form with our submission.

a. If you are unable to obtain permission from the original copyright holder to publish these figures under the CC BY 4.0 license or if the copyright holder’s requirements are incompatible with the CC BY 4.0 license, please either i) remove the figure or ii) supply a replacement figure that complies with the CC BY 4.0 license. Please check copyright information on all replacement figures and update the figure caption with source information. If applicable, please specify in the figure caption text when a figure is similar but not identical to the original image and is therefore for illustrative purposes only.

The following resources for replacing copyrighted map figures may be helpful:

USGS National Map Viewer (public domain): http://viewer.nationalmap.gov/viewer/

The Gateway to Astronaut Photography of Earth (public domain): http://eol.jsc.nasa.gov/sseop/clickmap/

Maps at the CIA (public domain): https://www.cia.gov/library/publications/the-world-factbook/index.html and https://www.cia.gov/library/publications/cia-maps-publications/index.html

NASA Earth Observatory (public domain): http://earthobservatory.nasa.gov/

Landsat: http://landsat.visibleearth.nasa.gov/

USGS EROS (Earth Resources Observatory and Science (EROS) Center) (public domain): http://eros.usgs.gov/#

Natural Earth (public domain): http://www.naturalearthdata.com/

RESPONSE: It does not apply. We obtained permission from the original copyright holder to publish these figures.

Response to general 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

Reviewer #2: Partly

Reviewer #3: Partly

RESPONSE: Thank you for the comment. We reviewed the manuscript and tried to improve it and focused the conclusions to the presented data. We changed it in the abstract and in the end of the discussion.

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

RESPONSE: Thank you for the comment.

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: No

Reviewer #2: Yes

Reviewer #3: Yes

RESPONSE: We attached the databases in the submission.

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

Reviewer #2: Yes

Reviewer #3: Yes

RESPONSE: Thank you for the comment.

5. Review Comments to the Author

Response to reviewer #1:

In this manuscript, the distribution of acquired syphilis, syphilis in pregnancy, and congenital syphilis was analyzed at the Brazilian border with other nine countries from 2010 to 2020. The results show that the number of cases for all three variables is increasing throughout the Brazilian border area. This is nothing new, as the number of syphilis cases has increased dramatically worldwide in recent years. However, given the lack of data on developing country borders, I believe that this manuscript should be considered for publication after some modifications as described below:

Abstract:

I suggest inserting a space between several words: pregnancy (SP), syphilis (CS), syphilis (AS), Brazil(38.4%), North(18.3%), South(65.7%), 427(72.6%), 441(75.3%), 422(72%).

RESPONSE: Thank you for the comment. We made the requested corrections in the text.

Introduction:

- Why "Discussions about the border have intensified in recent decades due to the regionalization processes"?

RESPONSE: We changed it. Now you can read the new explanation on page 2, lines 57 to 60 AND lines 63 to 65.

- About "Despite the importance of the border region in Brazil and the congenital syphilis as a public health problem, few studies explored the epidemiology of this infection in the region." Are AS and SP a public health problem in Brazil? Or not?

RESPONSE: Thank you for the comment. We added a paragraph in introduction. It is stated on page 3, lines 77 to 84.

Results:

- Note Figures 2 and 3. In the text below the figure, words are underlined. What does "2010 a 2020" mean?

RESPONSE: Thank you for the comment. We correct it, now it is 2010 to 2020.

- "Syphilis in pregnancy was reported in 61.4% (361) of border municipalities and 27.8% (164) have a detection rate ≥ national rate (21.6/1000 LB). Most municipalities, 67.5% (397), did not report cases of congenital syphilis in 2020 and 14.3% (84 municipalities ) have an incidence of congenital syphilis ≥ 7.7/1000 LB (Figure 5)." Define LB.

RESPONSE: Thank you for the comment. We wrote it down. LB = live births

Discussion:

- Italianize Treponema pallidum: "CS is the result of the transmission of the spirochete of the Treponema pallidum from the infected pregnant woman's ..."

RESPONSE: Thank you for the comment. We corrected it.

Reviewer #2:

The manuscript is of relevance, it points out updated aspects with the syphilis theme. However, it presents internal and external biases.

Title: adequate; Abstract: incomplete with the need for adaptation of items as presented throughout the text; Introduction: presents issues that belong to another topic such as the research scenario, the knowledge gap is fragile, without articulation with the uniqueness of the research.

RESPONSE: We rewrote the abstract to attend your suggestions.

Methods: The research design is inadequate. According to Morgenstern (2011), ecological studies can be divided into: multiple group designs (exploratory and etiological), time trend designs (exploratory and etiological), mixed designs (between multiple groups and time trend, but also with sub-classifications between exploratory and etiological). By the detailing of the methods, the study is more articulated with an exploratory ecological study with multiple group designs.

RESPONSE: Following your suggestion, we change the terminology of research design to be clear regarding what we did.

Results: are very well designed, but not validated with explanatory tests. The statistics are simple and make the text uncompetitive.

RESPONSE: We used secondary data and proposed to a descriptive exploratory study to have a general idea of the situation in the border areas. Even if we did not used exploratory tests, we think we have important data about syphilis in a region where there are not available data. We identified a problem to be approach by public health strategies in the border area. We agree that you had an important point and we intend to do it in a next proposal using primary data.

MORGENSTERN, Hal. Ecologic Study. In: ROTHMAN, Kenneth L.; GREENLAND, Sander; LASH, Timothy L. Modern Epidemiology, 3rd Edition, 2008.

Discussion: well elaborated with the inclusion of limitations. However, limited to the results, which in fact is not inconsistent, but does not address aspects related to the health model, the treatment of partners who are in another border country, the mobility of the standardization of treatment and availability of supplies among other aspects that interfere in the occurrence of the grievance in all its scopes, acquired syphilis, in pregnant women and congenital. I hope that the comments provided will help you with the publication elsewhere or to resubmit after adaptations.

RESPONSE: Thank you for the comment. We included this topic in the third paragraph of the discussion (page 13, lines 283-289). It is important to point out that we had difficulties for obtaining epidemiological information from neighboring countries.

Reviewer #3:

Syphilis represents a highly relevant issue globally. It remains a global challenge, the second most commonly reported STI. In Brazil, syphilis persists as a public health problem, particularly due to limited access to timely diagnosis and treatment, as well as limited monitoring of cases in the Unified Health System health care network, especially in Primary Health Care. The challenge is amplified when the critical political and institutional moment of the country is recognized. One of the great challenges has been to implement these health care actions integrated with surveillance and control, ensuring wide access to diagnosis, treatment, and monitoring in the Primary Health Care setting. These aspects are even more critical in border areas in the context of South America.

There is great variation in the operational performance of disease control in the country. This variation has been associated with operational factors such as access to testing via rapid tests, but also to the lower use of condoms, the reduced use of penicillin in routine PHC, and the period in which there was a shortage of the drug. These aspects should have been better described in the manuscript.

RESPONSE: It is an important topic. We tried to be clear when explain it. You can read on page 16-17, lines 402-407.

Moreover, both acquired syphilis, syphilis in pregnant women, and congenital syphilis are compulsorily notifiable diseases in the country but have registered systematic under-reporting, which compromises health planning actions, despite the improvement over time. This aspect should have been studied in depth.

RESPONSE: It is an important point to be mentioned. We included it in the limitations of the study. We worked with the official data and included all the information available in the databases. It is stated on page 16, lines 389-391.

It is important to bring the impacts related to congenital syphilis to society.

For a broader look at the real epidemiological and operational situation of syphilis control, the analyses should include the quality of prenatal care in the public and private sectors. This aspect should be discussed.

RESPONSE: We agree with the reviewer that these are important topics, but it was not our goal to approach this question because this information is not included in the databases. It will be important to design a qualitative study or a quali-quantitative study to approach these situations. We plan to do it after the evaluation of the actual picture of the situation. We included it in the discussion section the impacts related to congenital syphilis to society and the importance of prenatal care evaluation.

Expand the debate on the ethnic-racial clippings performed, as differentials in the three arches analyzed. Include the debates on recently published articles:

RESPONSE: Thank you for the comment. We included some of these references in our discussion.

Reiterate the relevance of PMAQ-AB as an innovative and useful action to induce quality improvement of PHC in SUS. This program was interrupted by the federal government in 2019 within the process of deconstruction of public health policies, having been replaced by the PREVINE Brazil Program. The authors need to discuss the effect of this change, implying a considerable setback in the process of evaluation and financing of PHC.

RESPONSE: Thank you for the comment. It is an important topic. As our data goes from 2010 to 2020 and the Previne Brasil was launched in the end of 2019 and it has been implemented in 2020 and then. We think the replacement of public health policies for primary care did not affect our data. Although we included a topic in the discussion section about the importance of the PMAQ-AB as a policy.

For the abstract, it is recommended to qualify the description of border arcs, to better situate the analyzed scenarios.

RESPONSE: We tried to clarify the information about the arches, but we needed to explore more these data in the methods section because of the words limits.

The objectives of the study should have been clearly listed, as in the introduction. Thus, the objectives of the study are partially articulated with a clear testable hypothesis stated. In principle, the focus is on the spatial and temporal description in Brazilian municipalities in border contexts. The conclusions of the abstract as well as of the manuscript should be adjusted to this perspective: the epidemiological and operational patterns of syphilis control are not satisfactory. The way it is described gives the wrong message of assumed control.

RESPONSE: Thank you for the comment. We adjusted the conclusions to the perspective of the objectives and tried to be clearer in the language.

The introduction needs to be enhanced with better-contextualized data in operational and epidemiological terms of syphilis control in the country and in border areas, especially over the period 2010 to 2020. In Brazil, the changes in the definition of syphilis case for compulsory notification purposes delimited the temporal scope of the study. It is important to signal which changes were undertaken and their impacts, particularly the change in the definition of appropriate treatment of pregnant women with syphilis, excluding as a criterion the concomitant treatment of the sexual partner, in terms of the sensitivity/specificity of the case definition criteria.

RESPONSE: We did not find published data about syphilis in pregnant women and congenital syphilis at the borders, and information about acquired syphilis was limited and very specific. Trying to improve the discussion, we included a phrase on page 13-14, lines 306-309

In the introduction, the authors should be clearer when referring to the fact that discussions about the border have intensified in recent decades due to regionalization processes, including more consistent references. The description of the study design needs to be qualified. In principle, the study design is appropriate to address the possible objective. In addition, a detailed map of the study area could have been presented, while in the text, the indication of the territorial and population, as well as the economic relevance of this territorial cut-out adopted in the study.

RESPONSE: We rewrote this topic to attend your suggestions. The new text is on page 2, lines 57-60 AND 63-65. The territories are described on the Methods Section and in Figure 1.

It is recommended to detail the scope of the syphilis indicator panel with its linked databases, as well as the Health Information System for Primary Health Care, clearly demonstrating the role of care and surveillance and to what extent the interfaces between these systems. The population is clearly described and appropriate for the hypothesis being tested.

RESPONSE: The information contained in the indicators comes from the National Notification System, after performing the database linkage.

Qualify correctly and better the reference in the text to SPSS version 20.0 and TabWin (version???), according to the developers' specification. The correct statistical analysis is used to support conclusions.

RESPONSE: We included the version for the TABWIN. It was the 3.6. Added the SPSS and STATA were for windows.

There are concerns about ethical requirements being met.

RESPONSE: We did not understand why the reviewer has concerns about ethical requirements. The Project was submitted and approved by the Ethics Committee in the Federal University of Espirito Santo. We had added the approved letter to our submission. We can ensure you that we follow all the ethical procedures necessary to guarantee the quality and suitability of the data.

The results are clearly and completely presented. The figures (Tables, Images) are of sufficient quality for clarity.

RESPONSE: Thank you for the comment.

In the discussion, the reduction seen in the last two years analyzed does not allow one to clearly establish that there was a reduction in the detection rates analyzed. The limitations of the analysis are clearly described.

RESPONSE: Agreed. Thank you for the comment.

The authors discuss partially how these data can be helpful to advance our understanding of the topic under study. The public health relevance is addressed. However, the conclusions are partially supported by the data presented.

RESPONSE: We changed the conclusions and tried to be clearer regarding to the public health relevance. We tried to be clear when explain it. You can read on page 16-17, lines 402-407.

This article proposes to evaluate syphilis, a complex problem, through secondary data, in an extremely dynamic border scenario. To support improvements, changes in public policy, the first step is to know the situation through the available data. In this context we observe that syphilis in the region is a problem, the detection rates of the disease in pregnant women are higher than in other parts of Brazil, highlighting the importance of improving screening and access to diagnosis.

Decision Letter 1

Everton Falcão de Oliveira

13 Sep 2022

Gestational and congenital syphilis across the international border in Brazil

PONE-D-22-16035R1

Dear Dr. Miranda,

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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,

Everton Falcão de Oliveira, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 #1: 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?

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

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. 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

Reviewer #3: Yes

**********

5. 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

Reviewer #3: Yes

**********

6. 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: The authors have made all suggested changes, so the manuscript can be accepted for publication in Plos One.

Reviewer #3: The authors made the suggested changes, which improved this version. I have no additional suggestions for changes to the article.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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: Yes: Fred Luciano Neves Santos

Reviewer #3: No

**********

Acceptance letter

Everton Falcão de Oliveira

27 Sep 2022

PONE-D-22-16035R1

Gestational and congenital syphilis across the international border in Brazil

Dear Dr. Miranda:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Everton Falcão de Oliveira

Academic Editor

PLOS ONE


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