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Click here to sign up. Download Free PDF. Re-emergence of syphilis in women of reproductive age and its association with the increase in congenital syphilis in Mexico during — an ecological study BMC Infectious Diseases.
A short summary of this paper. Download Download PDF. Translate PDF. The objective of this study was to examine trend in syphilis, congenital syphilis, and neonatal deaths among the Mexican population during — The variables were described considering age, sex, Mexican state, and year.
Cases of congenital syphilis increased from 62 cases in to cases in ; furthermore, the increase in syphilis cases among women aged 20 to 24 years was associated with an increase in cases of congenital syphilis. Between and , 83 neonatal deaths were reported, with the highest incidence in 0. As a consequence of the reemergence of syphilis among the population of reproductive age, it is necessary to address and treat syphilis in various population groups. BMC Infect Dis Page 2 of 8 8 20 Congenital syphilis incidence per , new born 18 7 Syphilis women 16 Syphilis incidencce per , inhabitans 6 Syphilis man 14 Congenital syphilis 5 12 4 10 8 3 6 2 4 1 2 0 0 Fig.
The bars show the incidence of syphilis in Mexico between and , stratified by sex. The line shows the incidence of congenital syphilis. In , , and , the incidence of congenital syphilis was 0. Later, there is a latency phase that lacks clini- and through the information available in the cal manifestation, but nontreponemal serological tests General Directorate of Epidemiology of the Ministry of remain positive; this stage can last up to 20 years.
Infec- Health of Mexico. In persons living with HIV, the natural his- Directorate of Epidemiology of the Ministry of Health of tory of syphilis is different: there are more patients with Mexico from to No administrative permis- tertiary syphilis, patients are diagnosed earlier with Aids, sions were required to access the data; the information and the presence of syphilis increases the transmission of was freely accessible.
The information about the inci- HIV [4, 5]. The number of neo- estimated to be From to inhabitants worldwide and 2. Furthermore, syphilis caused , for all years was obtained from the National Institute of stillbirths and deaths worldwide, making it one of the Statistics and Geography of Mexico. In the present study, leading causes of newborn death.
In the Americas, an neonatal death was considered death in children under 1 estimated 22, cases of mother-to-child syphilis trans- year of age. In Mexico, an increase in the incidence women, syphilis incidence among men, congenital of syphilis was observed between and , espe- syphilis incidence, and syphilis incidence stratified by cially among men aged 20—24 years and 25—44 years [8].
The figure shows the change in the incidence of syphilis by age group and sex from to Linear regression was analyses were carried out with the statistical program evaluated with standardized residual plots and R square GraphPad Subsequently, infor- women; the average increase among men was 0.
An increase in congenital syphilis aged 15—19 years and 20—24 years as well as the corre- was observed, with a rate of 2. Spearman correlation test. Cases of congenital syphilis by state Aguascalientes 0 0 0 0 0 0 3 5 5 16 Baja California 17 20 8 12 15 24 38 30 24 79 Baja Cal. Cord blood testing is not recommended because of the high rate of false positive results 7. A diagnosis of maternal syphilis during the year after a women gives birth should lead to testing of the infant.
Immigrant parents and children including foreign adoptees from regions of the world with a high incidence of syphilis should be screened for syphilis or congenital syphilis in the case of children when first presenting for medical care. Because the incidence of congenital syphilis is extremely low in Canada, the detection rate is likely to be highest in this group.
The treatment for syphilis in pregnancy is identical to that of adults who are not pregnant, except that penicillin is the only agent that is appropriate for use during pregnancy 9.
Tetracyclines are contraindicated in pregnancy because of their effect on fetal bone and tooth development. Erythromycin has inconsistent placental transfer, and treatment failures have been reported 9. For primary, secondary or early latent syphilis, 2. Some experts recommend a second dose of BPG for pregnant women due to the possibility of treatment failures and transmission to the fetus, especially for secondary syphilis 11 , For the treatment of late latent syphilis or disease of unknown duration, 2.
Women with a documented penicillin allergy should undergo desensitization and treatment with penicillin Individuals with neurosyphilis should receive 3 to 4 million units of crystalline penicillin G intravenously every 4 h for 10 to 14 days Individuals infected with the human immunodeficiency virus HIV should undergo investigation for neurosyphilis before treatment. Following adequate therapy for primary or secondary syphilis, the required monthly follow-up testing should show at least a fourfold decline in titre three to four months after treatment.
Women in whom titres fail to decline as predicted require investigation and management for neurosyphilis lumbar puncture for cell count, protein and VDRL , and further therapy. All pregnant women should receive appropriate counselling and recommendations for HIV testing Women who are diagnosed with syphilis during pregnancy should receive HIV testing if this has not been performed previously; hepatitis B surface antigen and hepatitis C antibody testing should also be performed.
Chlamydia and gonorrhea cultures are also recommended. Diagnosis and treatment of syphilis in the HIV-infected individual may be problematic because serology may be falsely negative or positive, seroconversion may be delayed and response to treatment may be suboptimal due to abnormalities in cell-mediated immunity 8 , There may be an increased risk of transplacental HIV transmission to the fetus in syphilis coinfection resulting from placental inflammation HIV infection may also enhance syphilis transmission due to impaired cell-mediated immunity Infants with congenital syphilis may present with typical signs and symptoms or they may be completely asymptomatic at birth.
Clinical findings may become obvious in the first few months of life; however, infection may remain undetected in some children until the signs of late congenital syphilis are apparent. Clinical findings related to congenital syphilis in children younger than one year of age. Symmetrical longbone lesions that are more common in the lower than the upper extremities. Metaphyseal osteochondritis with mild to destructive lesions that develop within five weeks of infection.
Diaphyseal periostitis with periosteal new bone formation that develops after 16 weeks of infection. Untreated neurosyphilis may lead to chronic meningovascular syphilis with hydrocephalus, cerebral infarctions and cranial nerve palsies. Renal involvement: nephrotic syndrome immune complex mediated after two to three months of infection. Clinical findings related to late congenital syphilis in children older than one year of age.
Sensorineural hearing loss due to osteochondritis of otic capsule and cochlear degeneration. Short maxilla, high palatal arch and saddle nose deformity syphilitic nasal chondritis. The surveillance case definition for congenital syphilis is presented in Table 3. A diagnostic algorithm for congenital syphilis is presented in Figure 2. When the diagnosis of congenital syphilis is suspected before or during delivery based on the maternal history , ideally, an histological examination of the placenta and cord should be performed for typical pathological changes and spirochetes Snuffles are more likely to occur in infants at one to three months of age.
Identification of spirochetes in specimens from lesions or tissue is required for a definitive diagnosis of congenital syphilis Table 3. In addition to a thorough physical examination, all infants potentially exposed to syphilis in utero should undergo serological testing for syphilis, regardless of maternal treatment.
Asymptomatic infants whose mothers receive appropriate treatment should be followed monthly until their nontreponemal antibody disappears. Transplacentally acquired nontreponemal VDRL or RPR antibody will be present in most infants, but it disappears in uninfected infants by six months of age. Algorithm for the treatment and diagnosis of congenital syphilis. CSF Cerebrospinal fluid. A complete diagnostic evaluation, including long bone radiographical examination and lumbar puncture for cell count, protein and VDRL, is warranted in the following situations 11 :.
It has been argued that the results of long bone radiography in most infected children do not affect decisions regarding therapy However, abnormalities on x-ray may provide the most expeditious evidence of infection, even before serology is available. The usefulness of cerebrospinal fluid CSF examination in the diagnosis of congenital syphilis has also been debated. While there is controversy in the literature regarding the usefulness of both long bone films and CSF examinations, these tests remain the standard of care There is no test which, at birth, will identify the asymptomatic baby with normal long bone examination as definitively infected or uninfected.
Most infected babies are asymptomatic at birth. Review of maternal serology and follow-up of the infant will, over time, indicate whether infection has occurred. In most cases, the diagnosis is presumptive, and is based on serological and clinical features. Many laboratories will perform an immunoglobulin Ig M assay, most commonly a Western blot, to detect IgM to multiple treponemal proteins 5. Because IgM does not cross the placenta, a positive IgM is consistent with congenital infection.
Detection of treponemal DNA in tissues or fluids eg, amniotic fluid, CSF by polymerase chain reaction has been evaluated but is not routinely available 5. Ultimately, a presumptive serological diagnosis may also be made when:. This is increased to every 8 h after seven days of life, for 10 to 14 days. The management of an asymptomatic, exposed infant is controversial. Some experts give a full course of penicillin to infants who are asymptomatic with normal CSF and radiographic examination and have an inadequate maternal treatment history, including no maternal treatment; insufficient penicillin treatment eg, single dose of benzathine penicillin G for late latent syphilis ; failed penicillin therapy inadequate response to treatment ; adequate therapy that is given less than one month before delivery; or treatment with a nonpenicillin regimen.
The alterative to immediate treatment is close follow-up with initiation of therapy when the signs or symptoms of congenital syphilis develop, or when nontreponemal titres increase or fail to decline. Single dose benzathine penicillin G is recommended by some experts for this scenario, especially when follow-up cannot be assured However, failures have occurred using this treatment regimen Therefore, if adequate follow-up of an exposed, asymptomatic infant cannot be guaranteed, consideration should be given to a full course of therapy for the child before discharge from the hospital.
Infants born to mothers who are HIV coinfected and in whom follow-up cannot be assured, should be treated for 10 to 14 days, regardless of maternal treatment history and symptomatology because the response to maternal treatment is unpredictable.
In CS cases, more than Additionally, less than It is noteworthy that some of these variables presented high percentages of ignored information; highlighting up to In the database Supplementary Material 2 , there were null values in The models with Poisson probability distribution, both non-inflated and zero-inflated models, showed an overdispersion and were disregarded. The results presented here refer to the modeling using zero-inflated and non-zero-inflated negative binomial probability distributions.
Table 1 presents the deviance information criteria DIC for these models. For the models with covariates, the lowest DIC was the one with a non-zero inflated negative binomial distribution. For CS, the intercept and random-effects model with the lowest DIC was the one with non-zero inflated negative binomial distribution and the DIC of the covariate models were close.
From these results, we considered the non-zero inflated negative binomial probability distribution for the SPW and CS models. We commenced with the intercept and random-effects models for both diseases, presenting first the temporal relative risks RR , spatial RR, and predicted RR, and then the results of the models with the inclusion of covariates.
Between and , there was an increase in the temporal RR of CS although it was slightly less pronounced , while there was a decrease in Between and , the RR increased 6. The spatial RR for CS ranged from 0. We obtained these values through the intercept random-effects models considering the spatial and temporal autocorrelations and the interactions between them; therefore, the predicted RR were adjusted taking these into account. Similarly, with CS, the gross RR ranged from 0 to Figure 6 , which presents the predicted RR for both diseases per year using box plots indicates the dimension of the increase in the occurrence of SPW and CS.
Furthermore, this growth was widespread, occurring in all the municipalities of SP. After presenting the results of the intercept plus random-effects models, we finalized the results with the inclusion of covariates in these models. The exploratory analyses of the covariates showed that the proportion of women between 18 and 24 years old with no education or an incomplete first cycle of elementary school, proportion of people between 15 and 19 years old who did not work or study, proportion of LB to adolescent mothers, proportion of mothers with fewer than four antenatal care consultations, acquired immunodeficiency syndrome AIDS incidence rate, supplementary health care coverage, number of inhabitants, and demographic density presented outlier values.
To address this issue, we transformed the first six covariates using the square root and the last two using the logarithm. The collinearity analysis with the variance inflation factor VIF revealed the necessity of removing the covariates average household income per capita, proportions of people with incomes below half the minimum wage, and demographic density.
We considered a spatio-temporal architecture; therefore, the results for the covariates were adjusted for spatial and temporal autocorrelations and the interactions between them; the items of significance are highlighted in bold in Table 2. We also found significant results for the interaction between the logarithm of the number of inhabitants and the square root of the AIDS incidence rate, for both SPW and CS.
Supplementary Material 3 presents the descriptive analysis of the covariates considered in the models. Moreover, this increase occurred en bloc in approximately all the municipalities of SP. This occurred in the richest and most populated state of Brazil.
In the analyses of the socioeconomic and demographic conditions, link to health services, and presence of transmissible comorbidities such as AIDS, which also indirectly involved aspects related to programmatic vulnerability, we observed that the increase in SPW was influenced by teenage pregnancy, municipalities with a large number of inhabitants, and AIDS incidence.
The conditions that influenced the increase of CS were municipalities with a large number of inhabitants, incomplete antenatal care, and AIDS incidence. This study had limitations and issues of concern.
We used secondary data with the possibility of underreported cases. Another limitation was the inability to consider variables indicative of programmatic vulnerability, such as penicillin availability in PHC and testing coverage for syphilis, due to the lack of free access to this type of data.
This information would have facilitated our discussion on aspects that could be related to the persistence of congenital syphilis. Issues of concern included the presence of temporal and spatial correlation in our response variables, the existence of numerous municipalities with small populations, and small numbers of LB generating random fluctuations in SPW and CS rates and RR. Part of these deficiencies in the data were overcome by the modeling framework we used. We developed our study with a space—time architecture that accounted for the spatial and temporal dependence.
This aspect was considered through the use of Bayesian latent Gaussian models, so that the results obtained were adjusted for the spatial and temporal autocorrelations and the interactions between them 9 , Since space and time were part of the modeling, the Bayesian inference allowed us to obtain the RR describing the behavior of the diseases studied according to time years , space municipalities , and space—time municipalities according to years.
These last two results, related to the mapping of diseases and their risks, are invaluable tools in view of the possibility of knowledge of areas with higher risks, assisting in health decision-making, interpreting the implementation of existing actions, and intervening to reduce injuries through prevention programs 8.
Moreover, the consideration of neighborhood relationships in the models allowed the generation of smooth RR for the municipalities, avoiding random fluctuations that could be present in those with reduced numbers of LB. The ecological design we used could be considered as a weakness of our study as we did not evaluate the response variable at the individual level, but aggregated on space and time.
On the other hand, it is also a strength, considering that ecological studies set the stage for examining causal mechanisms and provide a better approach for exploring exposures that are easier to measure in groups than at the individual level Furthermore, inferences were uniformly made for aggregates and not individuals to avoid ecological fallacy. We interpreted our results based on the characteristics of the regions and not individually in relation to pregnant women and LB.
Since these two diseases display a synergistic behavior, an increase in the second 5 can lead to management difficulties in the first This demonstrated the importance of studies on this dynamic. An analysis of the global load of SPW and CS showed that Europe was the only region that presented a level close to elimination, despite estimates of declines in Southeast Asia. This incidence can be explained by the expansion of the coverage of tests to detect diseases and the improvement in surveillance In Brazil, the availability of a rapid test for syphilis increased from 31, in to 3,, in In SP, this increase was greater: from tests being available in to 1,, in A study conducted in Brazil confirmed this tendency, showing that the increase in the capacity to identify asymptomatic cases of syphilis resulted in an increase in the notifications of acquired, gestational, and congenital syphilis It is important to highlight that the identification of cases through proper testing must target all groups vulnerable to this health problem.
A recent study 5 pointed out that the increase in SPW and CS is closely related to the expressive increase in AS rates in the general population and people socially vulnerable to human immunodeficienvy virus HIV and sexually transmitted infections STI , such as men who have unprotected sex with men; and those not covered by the search actions, such as those in the antenatal care protocol.
Furthermore, researches 14 , 25 , 26 demonstrated the importance of adequate antenatal care, syphilis screening, and correct and timely treatment for the prevention of syphilis. For Kimball et al. The increase in SPW and CS incidence was also influenced by the decreased use of condoms and loss of opportunity for treatment when penicillin was not administered in PHC, as well as the global crisis supply shortages between and This evidence was consistent with the results of this research, which showed a positive association between SPW and the proportion of LB to adolescent mothers, municipalities with a large number of inhabitants, and the incidence rate of AIDS.
The evidence was also consistent with the results obtained for CS, which showed a positive association with the proportion of pregnant women with inadequate antenatal care, proportion of mothers with fewer than four antenatal care consultations, municipalities with a large number of inhabitants, and AIDS incidence rate. Some of the variables associated with CS were also associated with SPW, highlighting the finding of a previous study that the control of CS is directly linked to the management of SPW during antenatal care Other factors that influenced the spread of syphilis were related to the accelerated urbanization process seen in recent decades in Brazil.
Consequently, there is increased social exclusion, generating segregated populations, difficulties in accessing urban services and infrastructure, greater exposure to violence, racial discrimination, and discrimination against women and children These situations, among others, affect the way a person falls ill and the health needs of a population Nevertheless, in terms of health, larger populations can provide the impetus for a municipality to present a more comprehensive care network with greater investments due to greater demand However, municipalities with larger population sizes present greater disparities in their social determinants of health, including access to health services On one hand, People are diverse in terms of culture and education, and they move indistinctly from the capital to the interior or vice versa The intervening factors in the current scenario of SPW and CS are probably related to access and capacity of prenatal care.
Nonetheless, in spite of the many obstacles, Brazilian PHCs contributed to the control of syphilis. Major challenges that need to be overcome on a worldwide scale are the issues related to the incorrect treatment of syphilis during pregnancy and the lack of audits to identify flaws in the care process and the adequacy of the qualifications of health professionals.
The lack of knowledge and the importance of health monitoring during pregnancy have been associated with populations of greater social vulnerability, low education, and non-white skin color.
Women with low education have less access to information, which limits their knowledge of health care, particularly on the prevention of sexually transmitted diseases such as syphilis infection 35 , Equally, it is worth mentioning the existence of more vulnerable population groups in each municipality, especially with regard to adolescents, as evidenced by the results. A study in the United Kingdom indicated that young people were more likely to become unemployed, use drugs and alcohol, be involved in crimes, have poor health, and become pregnant in adolescence According to the literature, people infected with other STI, including syphilis, are three to five times more likely to acquire HIV Moreover, the prevalence of syphilis also occurs more frequently among HIV-positive pregnant women than among HIV-negative women, because pregnant women living with HIV may have a weaker immune systems than other pregnant women Considering that this study followed all the precepts of ecological design, it is necessary to indicate the need for research that can analyze, as robustly as this study, issues directly related to individual characteristics and can contribute to the evaluation of the persistence of SPW and CS, as well as the facilitation of qualified audits to assess programmatic vulnerabilities involving their management, care and prevention.
Although Brazil has an extensive range of technical materials and well-established clinical protocols that regulate the management of SPW and CS, it is still necessary to standardize the therapeutic conduct of health professionals and identify treatments with alternative drugs that can be used in periods of worldwide shortages of penicillin, among other factors.
The results obtained in this study may also be useful in the design of new studies for the evaluation of SPW and CS surveillance and control in SP, both from a spatial and temporal point of view. The en bloc increase in the occurrence of both diseases indicates that actions are required in almost all the municipalities of SP.
However, the identification of municipalities and RDSs at the greatest risk for these diseases, in addition to the identification of their characteristics, also points to priority areas for the development and implementation of these actions. If, on one hand, the growing tendency of SPW points to difficulties in its control, the reversal of the temporal tendency of CS, even if not statistically significant, can be an indication of the resoluteness of the actions that have been developed.
It is also important to highlight that these actions to control SPW and CS strengthen the strategic surveillance systems and cooperate with the sustainable development goals. This ecological study was based on secondary data with spatial and temporal components. SP occupies an area of , km 2 and in it had a population of 43,, inhabitants.
Based on the population census, the human development index for SP was 0. Between and , infant mortality rates and the proportions of pregnant women who had more than six consultations evolved from The notified cases of SPW and CS, presented by municipality and year, constituted the two response variables in this study.
We also used the data obtained from the SINAN to characterize women with gestational syphilis and congenital syphilis. Possible factors associated with the occurrence of the conditions studied were socioeconomic, demographic, and health care variables.
We considered the proxies for the socioeconomic and demographic conditions the following variables obtained for each of the municipalities: proportion of women of childbearing age 15 to 49 years ; proportion of women between 18 and 24 years of age with no education or with an incomplete first cycle of elementary school; average household income per capita in Reais the Brazilian currency ; Gini index; proportion of people with an income below a quarter and half of the minimum wage; proportion of people between 15 and 19 years of age who did not work or study; proportion of people between 15 and 19 years of age who did not attend school; number of inhabitants; and demographic density.
This information was obtained from the Population Census database provided by the Brazilian Institute of Geography and Statistics In this group, we also considered the presence of prisons in the municipality. It was a categorical variable with a unique value yes or no for each municipality during the entire study period.
We considered the following proxies for the factors related to health care: the proportion of pregnant women with inadequate antenatal care, proportion of LB to adolescent mothers aged 19 years or less , municipality that performed deliveries categorical: yes or no , and proportion of mothers with less than four antenatal care consultations.
This information was obtained from the Live Birth Information System For the construction of the variable proportion of pregnant women with inadequate antenatal care we considered information for the year , which was the median year period and the first year for which information was available. In the calculation, the number of pregnant women with inadequate antenatal care women who began antenatal care after the first trimester of pregnancy and those who, although they had started antenatal care until the third month of gestation, had less than three consultations was uses as the numerator, and the number of LB as the denominator.
The variable proportion of LB to adolescent mothers, municipality that performed deliveries, and proportion of mothers with less than four antenatal care consultations were obtained for each year of the study period and for each municipality. We also considered, as part of the conditions related to healthcare, the AIDS incidence rate and the primary and supplementary health care coverages.
The AIDS incidence was calculated by dividing the number of notified AIDS cases by the population cases per , inhabitants for each municipality and year of the study period. Primary and supplementary health care coverages for each municipality and year were obtained from the e-Gestor AB website 43 and the ANS Tabnet website 44 , respectively. Based on the information presented, a database was constructed containing the numbers of cases of SPW and CS in each municipality and for each year, and the expected cases of the two diseases by municipality and year.
These were calculated from the global rates of detection of SPW and the incidence of CS per thousand LB-years for the entire study period. The expected values of SPW and CS were obtained for each year and municipality by multiplying the global rates by the number of LB and dividing the result by These values represented the expected number of SPW and CS cases in a specified municipality in a given year, if the city had the same rates as the entire study area.
To this database, socioeconomic, demographic, and health care variables presented above were added and were considered as covariates. This database is available in Supplementary Material 2. We performed a descriptive analysis to characterize SPW and CS cases considering the socioeconomic and access variables for the first and the last year of our study period.
For SPW, we evaluated age, skin color, education, pregnancy trimester at the time of diagnosis, and treatment information. For CS, we evaluated maternal characteristics, such as age, skin color, education, prenatal care, time of diagnosis, treatment, and partner's treatment.
An exploratory analysis was conducted to assess the existence of outliers and quantities of zeros in the response variables, identify collinearity between the covariates, and evaluate relationships between the two outcomes and each of the covariates.
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