Factors associated with inadequate treatment of syphilis during pregnancy: an integrative review

ABSTRACT Objectives: to analyze the evidence available in literature on factors associated with inadequate treatment of syphilis in pregnant women. Methods: an integrative review, carried out in the LILACS, CINAHL, Web of Science, Scopus, PubMed and EMBASE databases, with controlled descriptors therapeutic and prenatal syphilis. Results: nine publications composed the interpretative analysis, in which low education, income and maternal age, temporary lack of medication and HIV infection were associated with inadequate treatment of syphilis during pregnancy, in addition to delay or absence of prenatal care and receiving the 1st dose of penicillin, lack of tests or treatment less than 30 days before childbirth, and partners’ low compliance with treatment. Final Considerations: among the main factors associated with inadequate treatment, clinical and sociodemographic aspects stand out, as well as failures in drug dispensing, prescription and monitoring of treatment of pregnant women and their partners by the health system.


INTRODUCTION
Syphilis is a millennial sexually transmitted infection (STIs) caused by the bacterium Treponema pallidum, transmitted sexually and vertically during pregnancy or childbirth, when the treatment regimen of the diagnosed mother occurs inappropriately or does not occur. Vertical transmission of syphilis depends on the stages of maternal infection, the risk of which is higher during the primary and secondary stages of infection, being 70% to 100% in pregnant women who do not receive treatment and/or are treated inappropriately, with reduction in the latent and late phases (30%) (1)(2) .
Among the main outcomes of gestational syphilis, evidenced in literature, there is an increased risk of fetal death by up to 21%, neonatal death, prematurity, underweight or congenital malformations (3)(4) . It is worth mentioning that all adverse events of syphilis during pregnancy can be avoided with appropriate treatment during prenatal care, which consists in Brazil of penicillin G benzayene administration in a dose appropriate to the clinical phase diagnosed and started up to 30 days before childbirth, in addition to monthly follow-up to verify decreased titration. Pregnant women who do not meet these criteria are considered inadequately treated (5) .
Although it is a disease with affordable, effective and effective treatment, it still exhibits high incidence rates, representing a challenge for public health. The estimated worldwide prevalence of maternal syphilis in 2016 was 0.69%, 988,000 cases, with an overall congenital syphilis rate of 473 per 100,000 live births and 661,000 total cases (6) . In Brazil, in 2019, there were 61,127 cases of syphilis in pregnant women, a detection rate of 20.8 per 1,000 live births, and 24,130 cases of congenital syphilis, an incidence rate of 8.2 per 1,000 live births (7) .
Thus, in May 2016, the World Health Organization (WHO), through the World Health Assembly, adopted the global strategy 2016-2021, which defined priority actions to achieve goals for eliminating STIs by 2030, including congenital syphilis, and the expansion of evidence-based interventions and services to control STIs and reduce their impact as a public health concern (7)(8) .
Some countries have already been certified by who as free of vertical transmission of syphilis. Among them, Cuba was the first country in the world to receive validation in 2015, later, in 2016 and 2017, about six Caribbean countries and territories such as Anguilla, Antigua and Barbuda, Bermuda, Cayman Islands, Montserrat and Saint Kitts and Nevis, plus the Americas, Thailand, Republic of Moldova and Belarus in 2016 and Malaysia in 2018 (9) .
In Brazil, based on the criteria established by the Pan American Health Organization (PAHO) and WHO, adapted to the Brazilian reality, Boa Vista da Aparecida, municipality of Paraná State, achieved the Mother-to-child Congenital Syphilis Transmission Elimination Certificate. To this end, the municipality has reached the impact indicators in the last three years (incidence rate of syphilis ≤ 2.5 /1,000 live births in children under one year and less than 25% of children under one year with congenital syphilis) and process in the last 2 years (90% of pregnant women with four or more prenatal consultations, 90% of pregnant women diagnosed with syphilis who received a dose or more of penicillin and 50% or more of pregnant women diagnosed in the first trimester of pregnancy), in addition to assisting the others stipulated criteria (10) .
As a strategy to combat congenital syphilis, in 2021, Brazil launched the National Campaign to Combat Acquired and Congenital Syphilis, with the warning about the importance of prevention and early treatment, including as a target audience for pregnant women and their partners. As combat actions, the Mother-to-Child HIV and/or Syphilis Transmission Elimination Guide was launched, with the objective of standardizing the certification procedure in municipalities with 100 thousand or more inhabitants and in states, and a course on Comprehensive Care to People with STIs was conducted, with the purpose of offering professional qualification online (11) . Therefore, given the data presented, including the high incidences of gestational syphilis, it is of paramount importance to recognize the factors associated with the occurrence of inadequate treatment, since it may direct public policies to certain risk groups. Thus, it is urgent to add a synthesis on the subject in question in a single study, in order to direct policies to improve prenatal care for pregnant women and their partners, thus reducing the number of cases of syphilis during pregnancy, with a consequent reduction in congenital syphilis and complications related to newborns.

OBJECTIVES
To analyze the evidence available in literature on factors associated with inadequate treatment of syphilis in pregnant women.

Study design
This is an integrative literature review, developed according to the following steps: selection of a question for review; sampling (search for studies according to inclusion and exclusion criteria); extraction of characteristics from primary research (data extraction); data analysis; interpretation of results; review report (12) . The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations (13) were followed.

Data collection and organization
To elaborate the research question, the PICo strategy (P-Population) was used; I-Interest; Co-Context) was used. Subsequently, the Descriptors in Health Sciences (DeCS/BIREME) and the Medical Subject Headings (MeSH terms) were consulted, according to Chart 1. Thus, the following research question was constructed: what are the factors associated with inadequate treatment of syphilis in pregnant women?
The search for articles that made up this review took place in July 2021 in six databases, such as Latin American and Caribbean Literature in Health Sciences (LILACS), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, Sci Verse Scopus (Scopus), PubMed and EMBASE. For this, searches were performed respecting the singularities of each database, using the combination of Boolean operator "AND" between descriptors and Boolean operator "OR" between synonymous words. The search strategy employed for all databases was [("Syphilis") AND ("pregnant women" OR "pregnancy") AND ("therapeutics") AND ("Prenatal Care")].
of Factors associated with inadequate treatment of syphilis during pregnancy: an integrative review Torres PMA, Reis ARP, Santos AST, Negrinho NBS, Meneguetti MG, Gir E.
Articles available in full with research results that answered the question of the study and in all languages were included. Secondary studies (literature reviews, experience reports, reflection articles, editorials and letters), duplicate publications (duplicate manuscripts were considered only once) and productions not related to the purpose of this study were excluded. For the selection of articles, there was no time frame.
The results found in the searches were entered into the Rayyan web application, developed by Qatar Computing Research Institute (QCRI) (14) , to assist in article organization and selection. The reading of articles' titles and abstracts and their selection were performed by two independent researchers. Subsequently, the selected articles were read in full in the first stage, and the relevant information was extracted with the help of an adapted instrument (15) containing the following information: title; year of publication; objective; method (study design and site, participants, data collection and data analysis); main results of each article; and conclusion. It is worth noting that the disagreements between the selection of articles were resolved through agreement among researchers in the two stages.
The articles' level of evidence was ordered through assessment of its methodological design, using the classification of seven levels: level I -evidence from a systematic review or meta-analysis of multiple randomized controlled clinical trials; level II -evidence from at least one well-designed randomized controlled clinical trial; level III -evidence derived from well-designed clinical trials without randomization; level IV -evidence derived from well-designed cohort and case-control research; level V -evidence from a systematic review using descriptive and qualitative methodologies; level VI -evidence from only one descriptive or qualitative study; level VII -evidence originating from authority concepts and/or expert committees report (16) .

Data analysis
For data analysis, an analytical framework was constructed that allowed gathering and synthesizing the main information of included articles, as presented later. Data were interpreted and compared and later synthesized descriptively.

RESULTS
The selection of articles found through the different word crosses followed PRISMA recommendations (13) , as shown in Figure 1.  The final sample consisted of nine articles that assessed the factors associated with inadequate treatment of syphilis in pregnant women. Most, seven, (77.7%) were published in international scientific journals, and only two (22.2%), in Brazilian journals. There was a predominance of eight (88.8%) studies with a quantitative approach, while only one (11.1%) was qualitative, and 66.6% had level VI evidence and were in English.
Still, regarding the study site, the largest portion, seven (77.7%), was developed outside Brazil, namely: Argentina, United States, Thailand, two in China and two in South Africa. In Brazil, two (22.2%) were carried out in the Northeast, in the states of Pernambuco and in Rio Grande do Norte.
The characteristics of articles included in this review, regarding the authors, journal, objectives, method and level of evidence, are described in Chart 2. The main results regarding the definition of adequate and inadequate treatment and factors associated with inadequate treatment, as well as the prevalence or incidence found and the profile of participants, are shown in Chart 3. To be continued Based on the findings, it is noted that articles (17)(18)(21)(22)25) bring as factors associated with inadequate treatment of syphilis during pregnancy clinical variables related to pregnant women, such as syphilis treatment before the current pregnancy and HIV infection. Articles (19)(20)(21)(22) point out sociodemographic aspects, such as low education, income and maternal age, which sometimes imply ignorance about the disease and, consequently, inadequate treatment.
Additionally, other studies (17,(23)(24)(25) indicate the issues of dispensing the drug, prescription and follow-up of treatment, such as temporary lack of medication, failures in prenatal care, including delay or absence of it, delay in receiving the 1 st dose of penicillin, lack of tests or treatment performed less than 30 days before childbirth/ miscarriage and inappropriate prescribing, in terms of dosage and regimen. Partners' low treatment compliance, including the report of being painful, was pointed out in two articles (19,23) .
of Factors associated with inadequate treatment of syphilis during pregnancy: an integrative review Torres PMA, Reis ARP, Santos AST, Negrinho NBS, Meneguetti MG, Gir E.

DISCUSSION
This review showed factors associated with inadequate treatment of syphilis during pregnancy related to clinical variables, sociodemographic aspects and care failures.
Inadequate prenatal care was indicated as the main factor responsible for the high incidence of congenital syphilis in a study conducted in Belo Horizonte, Minas Gerais (26) . The same was found in national study developed in 2011 and 2012, who pointed out cases of congenital syphilis associated with lower education, later initiation of prenatal care, that is, fewer consultations and fewer serological tests. It was found that pregnant women without any prenatal consultation are the ones with the highest prevalence of syphilis during pregnancy (27) , corroborating the findings of eight of articles analyzed in this study.
In another study carried out at the Maternity Hospital of Malvinas, Argentina, it was pointed out that the risk of having some type of failure in the diagnosis of maternal syphilis was related to specific factors, such as low maternal education and insufficient number of prenatal exams. Moreover, pregnancy before the age of 18 and having less than 5 prenatal consultations are factors that affect failure of gestational syphilis treatment (28) .
Research identified the occurrence of syphilis in pregnancy associated with less than eight years of education, 7.4 times more likely in women who did not have prenatal care, inadequate or not performed treatment (53.7%) and 64.0% of the cases there was no treatment of their sexual partners (4) .
The epidemiological bulletin of HSD/MoH, brings that in 2020, 41.8% of women were diagnosed in the first trimester, 21.9% in the second trimester, and 30.1%, in the third. Still considering 2020, it was observed that more than half (56.4%) of pregnant women were between 20 and 29 years old when diagnosed with the disease, 23.3% between 15 and 19 years old and 17.3% aged between 30 and 39 years. Regarding education, most notifications (26.3%) were "ignored" the information, followed by 25.3% of pregnant women with elementary education (29) .
Maternal syphilis diagnosed late during pregnancy is considered a significant risk factor for congenital syphilis, as it implies late treatment or lack of treatment during pregnancy. It is reinforced that screening, diagnosis and timely treatment of syphilis are fundamental for the prevention of congenital syphilis and its adverse outcomes in pregnancy (1) .
Cases of congenital syphilis can be avoided by screening and treating pregnant women early, in addition to another assessments at the beginning of the third trimester to check for infections acquired during pregnancy (30) . Of the analyzed articles, only one (24) indicated as a factor associated with inadequate treatment the lack of prenatal examinations less than 30 days before childbirth.
Regarding the maternal variables related to cases of congenital syphilis the maternal age of 20 to 25 years was evidenced, predominance of mothers with incomplete elementary education, at the height of menacme and residents of the urban area (31)(32) . On the other hand, a study showed that almost all cases of syphilis in pregnant women had good compliance with prenatal care (96.6%), but despite this, almost 40% of pregnant women had the diagnosis during childbirth, and those who were diagnosed during prenatal care, less than half completed treatment less than 30 days before childbirth (32) .
Regarding partners' treatment, only two articles (19,23) addressed partners' low compliance as a factor associated with inadequate treatment of syphilis in pregnant women, considering the definition of adequate treatment brought by the articles. In Brazil, despite the current Information Note 2 -SEI/2017 -DIAHV/ HSD/MoH (5) not considering the treatment of mothers' sexual partners for the purpose of defining adequate treatment and a case of congenital syphilis, it is essential to consider that there is a risk of reinfection for pregnant women who are not treated concomitantly with partners.
A study conducted in Minas Gerais showed that only 34.3% of pregnant women and 19.8% of partners who underwent treatment for syphilis were considered adequately treated. It is emphasized that 176 (65.7%) of pregnant women had inadequate treatment or were not attended during prenatal care examinations. Patients with adequate treatment had lower rates of congenital syphilis when compared to those who were not treated (33) . Similar data were found in a study with secondary data in the city of Salvador, Bahia, where 49.3% of pregnant women did not undergo treatment properly, despite prenatal care and diagnosis during pregnancy. The article also states that 18.3% of pregnant women had incomplete elementary school and 39.6% of partners did not undergo treatment (34) .
Such findings converge with the articles analyzed in this review, which found, in most cases, high rates of inadequate treatment among pregnant women with syphilis, observing that structural problems still persist and limit the fight against congenital syphilis, which is a worrying fact that requires attention during prenatal care by health professionals in order to identify and minimize the factors that contribute to these results.

Study limitations
Although the objective proposed by the study has been achieved, there are some limitations. The studies aggregated in this review refer to different cultural, social and economic realities and contexts that reflect in different actions and policies, as identified in the different definitions of inadequate treatment highlighted, in addition to the methodological variety, which made the comparative analysis of publications difficult. This review showed that most studies focus on factors related to the prevalence of congenital syphilis in children of pregnant women who did not undergo treatment or did so improperly. However, it can be seen that a small number of articles directly, specifically and in depth on factors associated with inadequate treatment of pregnant women, the focus of our study, are mostly addressed in isolation and punctually. Therefore, it is necessary to expand research in this area in the various national and international scenarios that use homogeneous methodologies and representative samples in order to achieve a greater degree of evidence, thus filling in such gaps found in the preparation of this study.

Contributions to nursing, health and public policies
Despite these limitations, by compiling and identifying the main factors related to inadequate treatment, the study presents advances for health and nursing, as it allows collaborating in the construction of improvement plans for prenatal care, allowing intervention in the face of the identification of such factors in practice with families during prenatal care, thus ensuring early treatment of syphilis both in pregnant women and in partners, and therefore preventing congenital syphilis. Finally, it is expected that the present study will foster further investigations, in order to fill the gaps found in the preparation of this study.

FINAL CONSIDERATIONS
The findings pointed out as the main factors associated with inadequate treatment of syphilis during pregnancy, the clinical and sociodemographic aspects of pregnant women, as well as failures in drug dispensing, prescription and monitoring of treatment by the health system. Among these, coinfection (syphilis -HIV), history of treatment of the disease prior to current pregnancy, low education, maternal income and age, and low partner compliance with treatment stand out, in addition to temporary lack of medication, failures in prenatal care (absence or delay), including delay in receiving the 1 st dose of penicillin, lack of tests or treatment performed less than 30 days before childbirth/abortion and failures in prescriptions.
Thus, aiming to reduce the still high numbers of inadequate treatment of syphilis during pregnancy, with a consequent reduction in congenital syphilis and complications related to newborns, an integral and quality prenatal care is essential. To this end, policies to improve this assistance are necessary in order to guarantee, mainly, syphilis prevention, in addition to the early diagnosis and treatment of pregnant women and their partners.