Complications, clinical manifestations of congenital syphilis, and aspects related to its prevention: an integrative review

Objectives: to identify the scientific evidence about the clinical complications and manifestations of congenital syphilis and aspects related to its prevention. Methods: integrative review after a search in the databases LILACS and MEDLINE, carried out in March 2018, using the descriptors “syphilis, congenital”, “complications”, and “signs and symptoms”, leading to the selection of 27 researches. Results: the publications found were published from 1966 to 2017, and most of them were from Latin America and Africa. Negative outcomes, laboratory changes, and the clinical manifestations in congenital syphilis, whether early or delayed, were, respectively: low weight at birth, anemia, hepatosplenomegaly, and dental alterations. The lack of treatment of the pregnant women in the prenatal was the most common occasion in which the opportunity to prevent the complications of congenital syphilis was lost. Conclusions: the scientific evidences analyzed showed serious complications of congenital syphilis that could be avoided if early opportunities of diagnosing and treating the pregnant women are not lost during the prenatal. Descriptors: Congenital Syphilis; Sings and Symptoms; Complications; Syphilis; Prenatal Care. Conclusiones: las evidencias científicas analizadas presentan graves complicaciones de la sífilis congénita que serían evitadas desde que oportunidades precoces de diagnóstico y tratamiento de la embarazada no fueran perdidas durante el prenatal. Descriptores: Sífilis Congénita; Signos y Síntomas; Complicaciones; Sífilis; Atención Prenatal.


INTRODUCTION
Despite all attempts to eliminate congenital syphilis (CS) as a public health problem, estimates show that the disease affects a million pregnant women every year throughout the world. When it is not adequately treated, it can cause more than 300 thousand fetal and neonate deaths, putting nearly 200 thousand children under the risk of an untimely death (1)(2)(3) .
The morbidity and mortality by CS are avoidable and sensible to the health care conditions of women and children. An in-depth investigation about the aspects involved in the transmission of syphilis from mother to child is useful to identify the facts that determine and put children under the risk of sequelae and death, not to mention that an investigation of the kind could aid in the development of strategies to prevent and control the disease.
Brazil is a subscriber of the United Nations Sustainable Development Goals (SDG) (4) , which include controlling CS and eliminating the avoidable deaths of newborns and children below 5 years old. In countries where the prevalence of CS is high, the eradication of such a public health problem would have a positive impact, helping to achieve these goals.
The importance of controlling CS is especially related to the complications that this infection can cause in babies (5)(6)(7) . Although most children are asymptomatic at the time of birth (8) , CS can manifest early, up to their second year of age, or late, after this period. The symptoms usually can be dermatological, osseous, ophthalmic, auricular, neurological, or dental, in addition to alterations that can be found by laboratory exams (9) .
Considering the problem posed to the world by the current CS epidemic, it is extremely important to divulge the clinical complications and manifestations that this infection can cause in babies, including identifying factors that can help avoiding them.

OBJECTIVES
To identify the scientific evidence about the complications and clinical manifestations of CS and the aspects related to prevention.

METHODS
This is an integrative literature review, designed with the following steps: definition of a research question, search or sampling in literature (after defining inclusion and exclusion criteria), categorization of the information extracted, evaluation of the studies selected, interpretation of the results, and, finally, presentation of a review/synthesis of the knowledge provided (10)(11) .
The problem addressed by the review (the research question) was determined using the PICO strategy: P (population): pregnant women and children; I (interest): congenital syphilis; O (outcome): clinical complications and manifestations. The letter C, representing "comparison", does not apply to this research. As a result, the following guiding question was formed: What are the scientific evidences about complications and clinical CS manifestations, and what other studies have found about aspects related to prevention?
The online search was carried out in the Virtual Health Library (VHL), in the databases Latin American and Caribbean Health Sciences Literature (LILACS) and Medical Literature Analysis and Retrieval System Online (MEDLINE). Studies were selected in March 2018, using two crossed pairings of the three health descriptors (DeCS/MeSH: 1) "syphilis, congenital" AND "complications"; 2) "syphilis, congenital" AND "signs and symptoms". The limiting boolean operator "AND" was used to restrict the search only to findings about CS complications and clinical manifestations.
The inclusion criteria considered the following characteristics: original articles, available in full, and published in Portuguese, English, or Spanish. The systematic review and meta-analysis articles were also included, since some journals consider these to be original articles. Since syphilis has existed for millennia, with repercussions all around the globe, the year of publication of the investigations was not restricted, allowing for a broad survey of literature. Abstracts, editorials, letters to the editors, technical information, previous notes, repeated articles, and those that were not in accordance with the objective of this study were excluded.
The initial search for articles found 1,982 results. From these, 1,390 were excluded because they were not available in-full or were not in Portuguese, English, nor Spanish. Furthermore, 77 were duplicates, and as a result, were discarded. The titles and abstracts were read and, when the article seemed to be a potential inclusion, its results were skimmed. This allowed for the selection of 27 articles to be read in full and categorized for an analysis. The results were interpreted, and the final presentation of the review took place ( Figure 1).  To diminish potential biases, two researchers selected, independently, studies for the analysis. A third researcher was also participating, to help deciding on the inclusion or inclusion of articles whenever there were disagreements.
The studies were presented using tables that included identification data, methodological characteristics, evidence levels (12) , results, and conclusions. Considering the variety of complications and clinical manifestations that were identified, the description of the results, as well as the descriptive analysis carried out to present the findings of this analysis were compiled, based on the following findings: negative outcomes, laboratory changes and radiological changes, and early and late CS manifestations.

RESULTS
Data from the studies selected for analysis show a diversity of negative outcomes, laboratory and/or radiological alterations, and early and late CS manifestations. Publications from 1966 to 2017 were found, but the interval between the earlier publications was of approximately 10 years; from 2013 on, their frequency was higher, and their number increased. Most publications originated from Latin-American (n = 11) and African countries (n = 5). It stands out that the most recent studies were carried out in Brazil (E1, E2, E3, E4, E6).
Most studies were descriptive and cross-sectional (n = 21). From the studies analyzed, only four showed some type of follow up with the children (E9, E12, E17, and E19). Two (E8 and E14) were systematic reviews, and, as a result, their level of evidence was I (Chart 1).
From the 27 studies analyzed, 18 focused on the negative outcomes of CS, such as low weight at birth (n = 11), stillbirths (n = 9), or neonate death (n = 9). With the exception of E8, all others had more than one outcome, including miscarriage (n = 7), prematurity (n = 8), or post-neonate death (n = 3). Only E14 had, in the scope of its investigation, all outcomes observed in this review (miscarriage, stillbirth, death, prematurity, and low weight at birth) (Chart 2).
To be continued Chart 1 -Characterization of articles according to authorship, year of publication, title, country, journal, level of evidence and type of study Fourteen articles found children with laboratory and/or radiological alterations related to CS. The most common alteration was anemia, which was detected in 11 studies, followed by thrombocytopenia (n = 8), and leukocytosis (n = 7). It stands out that, in half of these articles, there were high levels of proteins and/or leukocytes in the newborns' liquor, and the Venereal Disease Research Laboratory (VDRL) was reactive. Regarding radiological findings, ten publications found changes in long bones, such as periostitis, osteochondritis, osteomyelitis, or Wimberger's sign (Chart 2).
Clinical CS manifestations were the focus of 18 studies. It stands out that the CS manifested early in 15 cases and late in 3. In this context, data relative to the early infection symptoms were predominant (n = 16), such as hepatomegaly and/or splenomegaly (n =14), in addition to skin lesions with desquamation, consistent with palmoplantar pemphigus (n = 12). Other traits that stand out are the presence of jaundice (n = 9); purulent, serosanguineous and thick nose secretions (n = 7); perioral or perianal fissures/tears (n = 5); and petechia, purpura, and/or rashes (n = 5). Regarding late CS, it manifested in ophthalmic (interstitial keratitis), auricular (neurological deafness/ hearing loss), osseous (frontal bossing and saddle nose), and dental (Hutchinson's teeth and mulberry molars) issues. Only E12, a cohort, discussed both types of manifestation (Chart 2). In the 27 articles analyzed, an attempt was made to identify information about the actions that could avoid clinical complications and manifestations of CS in newborns. In 21 studies, it was found that, during prenatal care, many opportunities to prevent against grave outcomes of this infection in the child are not taken advantage off.
The main opportunities for this prevention that were lost were the non-treatment of the pregnant woman during the prenatal (n = 9), the late diagnoses of pregnant women (n = 4), the late start of the prenatal (n = 3), pregnant women that were not properly treated for the disease (n = 3), and women with high titer levels at time of birth, according to the VDRL (n = 3) (Chart 3).

Complications, clinical manifestations of congenital syphilis, and aspects related to its prevention: an integrative review
Rocha AFB, Araújo MAL, Barros VL, Américo CF, Silva Jr GB.

DISCUSSION
Although syphilis has existed for millennia and there are studies that bring knowledge about CS, this infection is still a serious public health problem, especially in poor and developing countries. Most findings in the babies were related to lost opportunities to provide assistance to the mother.
Even with the high number of published studies, the actual magnitude of the damage this infection brings to Brazil may still be unknown (14) . Stillbirths and neonate death are among the most common negative outcomes in the articles found, and the systematic review and meta-analyses included show that this outcome is more likely in pregnant women with syphilis (5)(6)(7) , and in those who were not treated or who were not treated properly (19) .
Regarding laboratory and radiologic changes in the children, it stands out that all children whose mothers with syphilis were not treated or not treated properly must undergo the VDRL test, a hemogram, a radiography of the long bones, and liquor puncturing, even if they show no symptoms at birth (36) . A study carried out in Porto Alegre, in Rio Grande do Sul (RS), Brazil, showed that 25% of the children who were born with no symptoms had an alteration in at least one of these exams (8) .
Radiographic findings have an important role in the diagnosis of CS. In the Netherlands, a study found radiologic changes in eight out of ten children with CS signs (3) . These changes varied from a light periosteal reaction through the decalcification of the long bones to characteristics consistent of osteomyelitis. In Brazil, the proportions of changes in radiographies of long bones were of 1.6% in the state of Paraná (PR) (15) and 9.6% in Rio de Janeiro (RJ) (13) .
It is important for health professionals to be attentive to other findings that are not typical of children with CS. These findings, despite not being specific of these cases, can indicate complications or associated pathologies. This review found cases of children with CS who showed signs of liver dysfunction (16) , kidney problems consistent with nephrotic syndrome (35) , increased creatinine, and histopathological lesions in kidney biopsies (16,(33)(34) .
Another important aspect is identifying early clinical manifestations of CS by a minute physical examination of the newborn, aiding in the diagnostic and in providing a timely response. This contributes for a reduction of sequelae from the infection, especially considering that children who are symptomatic at birth are more likely to die when compared to asymptomatic ones (14) .
Regarding late CS manifestations, a case study carried out in India with two children showed that the only CS evidences were Hutchinson's teeth and mulberry molars (21) . These manifestations present as deformed upper middle incisors, in the form of screwdrivers, little flags, or beveled, generally accompanied by molars that are similar to mulberries due to their multiple cuspids. The authors alert that the presence of mulberry molars makes them highly susceptible to cavities and can lead to the early loss of teeth. As a result, these children need dental evaluation and monitoring (21,24) .
Other findings, such as frontal bossing and saddle nose, in addition to delays in development, were found by a research from Porto Alegre, Rio Grande do Sul, Brazil (8) . In that study, children who presented laboratory changes at birth were 20 times more likely to develop late CS sequelae. Considering the above, it is noteworthy that there are still late diagnoses for CS. The causes for this may indicate shortcomings in the strategies of prevention and treatment of the different levels of attention (37) .
Most studies evaluated the newborns during the ten days of hospitalization in the maternity for CS treatment, maybe due to the difficulties in getting to these children after their hospital discharge. Outpatient follow up seems to be challenging, and the few researches on it show that these children often interrupt their follow up. In Merseyside, England, in 1985, 2 out of 7 children with CS, who should be monitored in outpatient clinics up to their 3rd year of age, only came to their evaluation once (32) . More recently, in Brazil, studies in the cities of Porto Alegre (RS) (8) and Curitiba (Paraná -PR) (15) showed that the proportion of children who were not present in the health services for their follow up is large.
All studies that analyzed clinical findings in children with early CS showed some shortcoming in the management of care to the pregnant woman, especially when related to tracking, diagnosing, and providing proper treatment to the mothers as soon as possible (8,28,32) . Researches carried out in Chile, Mexico, and England exposed cases of early CS in which the mothers were only reactive to the second test applied to them or during birth (22)(23)(27)(28)32) . These women may have been infected during pregnancy and present high titer levels at the moment of birth, corresponding to an early stage of the infection.
Once the opportunities to prevent CS are lost during the prenatal care, its late complications in the newborns can be prevented, as long as these babies are properly managed when they are born. In the state of Minas Gerais (MG), Brazil, a study showed that the VDRL was not carried out for 25.8% of babies, while 42.2% did not undergo a hemogram, radiographies of the long bones, or liquor puncturing (17) . The health services may present difficulties to the guarantee all exams necessary to diagnose CS, which, in the long term, may lead to the increase in the cases of children with serious sequelae.
The transmission of syphilis to the baby is related to the clinical stage of the mother's infection, and can reach 100% when the infection is recent (38)(39) . High titer levels in non-treponemal tests in the mother indicate that the infection is recent and increase the likelihood of negative outcomes. In Shanghai, China, pregnant women whose titer levels were ≥ 1:16 in reacting to the Rapid Plasma Reagin (RPR) exam showed higher levels of CS when compared to those with ≥ 1:8 titer levels (24) . Furthermore, in Africa, stillbirth is associated with high VDRL titration (26,29) .
These findings call our attention to how important it is to improve both the prenatal coverage and the early tracking of the pregnant women; in these occasions, the opportunity to test and treat cannot be lost. Diagnosing and starting to treat syphilis as early as possible, preferably in the first trimester of pregnancy, avoids the prolonged exposure of the baby to the treponema. As a result, it should be mentioned that improving prenatal care is essential to prevent negative CS outcomes, considering that a study carried out using the World Health Organization database found that 66% of adverse effects involved children whose mothers went to prenatal examinations (6) .
In the United States, a study found how important it is to treat pregnant women with syphilis to prevent complications in the newborn. Through ultrasonography, it was possible to find that 8 of Complications, clinical manifestations of congenital syphilis, and aspects related to its prevention: an integrative review Rocha AFB, Araújo MAL, Barros VL, Américo CF, Silva Jr GB.
the number of abnormal findings (hepatomegaly, placentomegaly, polyhydramnios, ascites, and changes in the doppler evaluation of the middle cerebral artery) in fetuses after the mother was treated (20) . It should be noted that, even when there are shortcomings in the attention to the pregnant woman, it is possible to reduce CS complications when the newborn is diagnosed and treated as early as possible. A cohort carried out in SC followed cases of children up to 5 years old and found that some children showed alterations at birth, but did not develop sequelae because they started their treatment in their first seven days of life (8) .

Study limitations
A limiting factor of this study is the fact that literature was not exhaustively analyzed, since many researches were not openly available in full. Furthermore, some studies were case reports, which reduces their scope and/or the relevance of the inferences that can be made from these individual findings.

Contributions to the fields of Nursing, Health or Public Policy
This study is an important contribution, as it compiles and presents the complications from CS, indicating that they could be avoided. As a result, it can be an asset in the elaboration of public health policies that could help improving the quality of prenatal care. It can also give support to health workers in the identification of clinical manifestations, helping to provide early diagnoses, to adequately manage the newborn, and to reduce grave CS sequelae.

CONCLUSIONS
The scientific evidence analyzed here shows severe negative outcomes of CS, such as stillbirths, neonate deaths, and low weight at birth, in addition to radiological and laboratory changes, and a high diversity of early and late clinical manifestations. These outcomes could be avoided, considering that opportunities to diagnose early and treat the pregnant woman were lost during prenatal care.