Congenital syphilis (CS) is a sexually transmitted disease acquired in utero, resulting from vertical transmission from mother to fetus during pregnancy or during the peripartum period through contact with the mother's genital lesions. Vertical transmission can occur within the first 4 years after infection, with a fetal mortality rate about 30–40%. The fetus can be infected by the untreated mother, being more likely in the early stages. Infection of the fetus during the initial four months of pregnancy is rare, so early miscarriages attributable to CS are not common. The consequences of infection can result in miscarriage, neonatal death, neonatal disease, or latent infection; two-thirds of newborns are born asymptomatic but will develop signs in the following weeks, predominantly osteochondral and mucocutaneous. Treatment of the mother during the first 4 months of pregnancy generally prevents the fetus from being born infected. The likelihood of vertical transmission is most associated with untreated primary syphilis infections during pregnancy (95%) and early latent syphilis (40%), and is considered unlikely in cases of late latent syphilis (10%).1,2,3

For pregnant women with early syphilis, it is recommended to administer, in order of preference, a single dose of 2.4 million IU of intramuscular Penicillin G benzathine (PGB) or 1.2 million IU of intramuscular procaine penicillin once daily for 10 days. If the period of infection is unknown or latent syphilis is suspected in pregnant women, it is advised to administer 2.4 million IU of intramuscular PGB once weekly for three consecutive weeks or 1.2 million IU of intramuscular procaine penicillin for 20 days.1,4

Macrolides are not recommended in pregnant women due to their inadequate cross through the placental barrier. Benzathine penicillin G is the only antibiotic recommended, reporting an effectiveness in reducing stillbirths of up to 82% and an 80% reduction in neonatal mortality when administered at least 28 days prior to birth with a single dose of 2.4 million IU intramuscularly.1,4

The treatment of probable or confirmed congenital syphilis, crystalline sodium penicillin G 50,000 IU/kilogram/dose intravenously every 12 hours during the first 7 days of life and every 8 hours after the seventh day of life until completing 14 days, within the first 4 weeks of life. For children older than 4 weeks, treatment consists of the same antibiotic intravenously every 6 hours lasting 14 days. In the management of asymptomatic newborns, full treatment should be provided. If adequate follow-up appointments outside the hospital can be ensured, PGB 50,000 IU/kg intramuscularly as a single dose may be administered to the newborn.5,6,7,1

Several studies conducted during 2001 and 2012, in Mexico, report a national prevalence of acquired syphilis in pregnant women of 0.26-2.3%. Currently, the 2021 morbidity annals with an incidence of congenital syphilis of 2.3 per 100,000 live births (LBN) and 62.84 per 100,000 children under 1 year of age, classifying it as a low-prevalence area according to the World Health Organization. Despite this, in some states, including Sonora, the rate is 1.37/100,000 IMSS beneficiaries, contributing 16.3% to the national statistics. 8,9,10

Within Mexican protocols, the following lines of action are summarized: detection of syphilis cases in pregnant women (regardless of their clinical stage) throughout the first 12 weeks of gestation, at the time of the first gynecological consultation. In cases where prenatal care was not provided, prenatal or postpartum screening tests will be performed, with follow-up during each trimester and/or at 3, 6, and 12 months postpartum. The newborn will remain under surveillance for abnormal maternal results or clinical symptoms of the disease. Follow-up care for children born from mothers with syphilis should be provided at 2, 4, 6, and 12 months.1,11,12

As of 2016, Mexico was not at risk for Benzathine Penicillin G shortages; however, with annual incidences on the rise (121 cases in 2017 to 667 cases in 2021), it is of utmost importance to maintain supplies and agreements for the medication.9

Based on the above, we aimed to analyze the impact of the treatment administered to mothers of newborns with congenital syphilis prior to birth.

An observational, descriptive-analytical, retrospective, was carried out at the Regional General Hospital No. 1 in Ciudad Obregón at the Mexican Social Security Institute, between January 1, 2016 and May 1, 2023. Hospital records and epidemiological studies completed by treating medical personnel or epidemiologists were taken, entered into a database (Access) for Congenital Syphilis and the Epidemiological Card of the unit, in the periods expanding through January 1, 2016 to May 1, 2023. The calculation was made for finite samples, considering the prevalence of Congenital Syphilis varies from 0.26 - 2.3% as established according to the reviewed reference of studies in the pregnant population in Mexico; which yielded a sample of n=35. Patients were included if they were recruited by the attending physician or epidemiologist from the congenital syphilis databases, the unit's epidemiological record, which had received clinical-hospital care at Regional General Hospital No. 1, Ciudad Obregón, Sonora of both sexes, were newborns (≤30 days old), had a diagnosis of a probable case of congenital syphilis (symptomatic or asymptomatic) in the cases form 2021 onward. Due to the changes in the criteria for the scrutiny of cases, prior to 2021 newborns of mothers positive to any treponemal and non-treponemal tests were included.

Patient records were excluded if their final classification was based on clinical symptoms, cases without confirmatory laboratory tests (Western Blot IgM or FTA-ABS), and if their birth and completion of the clinical/epidemiological study form were in another unit.

Patient records were eliminated if their information in the congenital syphilis epidemiological study was incomplete.

The variables included treatment for syphilis acquired during pregnancy, neonatal age, neonatal sex, maternal risk factors, and positive and negative confirmatory tests for syphilis.

The research was authorized by the local health research committee in accordance with international and national guidelines.

Statistical analysis included relative and absolute frequency measurements for qualitative variables, and measures of central tendency (mean, median, mode) and dispersion (range, standard deviation, and variance) for quantitative variables.

Normality was determined using the Kolmogorov-Smirnov normality test. Hypothesis tests were analyzed as appropriate, using Student's t-test for quantitative variables, and categorical variables were analyzed using the Chi-square test or Fisher's exact test. Additionally, the risk ratio was examined using the Odds Ratio, applying a confidence interval (95% CI). A P value of less than 0.05 was considered statistically significant. Finally, the impact was measured with attributable risk, risk difference, or Spearman correlation, all using the SPSS version 26 statistical package.

An observational, descriptive, retrospective, and cross-sectional study was conducted, covering the months of January 2016 to May 2023. From a total of 75 records that met the inclusion, exclusion, and elimination criteria, 67 cases formed the study sample.

Categorical variables were analyzed based on their frequency, as shown in Table 1. In the distribution of cases by sex, males predominated, accounting for 55% (37) of the cases, while females accounted for 45% (30) of the observations.

The study elements were categorized based on the following parameters: initial diagnosis as a probable case of asymptomatic congenital syphilis in 70% (47) of the observations and symptomatic in 30% (20); the classification method was expert opinion (42% (28)) or laboratory test (58% (39). For the final classification of cases, the categorization was carried out into four groups: confirmation by expert opinion predominated at 39% (26), followed by laboratory-based exclusion at 36% (24), laboratory-based confirmation at 22% (15), and finally, exclusion by expert opinion at 3% (2), as shown in Table 1.

Clinical and treatment variables differ based on maternal factors such as risky activities and treatment received during pregnancy for probable cases. Likewise, as described in Table 1, the most prevalent maternal risk factor on the study was “having more than one sexual partner” in the last year, at 63% (42). Maternal treatment during pregnancy shows the distribution with superiority in the application of a scheme with 2.4 million IU of PGB 34% (23) of which 100% presented adherence to what was established in the guides and manuals, followed by the scheme with > 2.4 million IU of PGB 33% (22) with 63% of the treatments according to what was established, 21% (14) were not treated, and the prevalence of an alternative scheme or a scheme < 2.4 million IU of PGB is 6% (4) each respectively. Of the cases studied, the clinical data not specific for congenital syphilis are reported in Table 2.

The maternal age distribution, shown in Table 3, shows a mean of 25 years, median of 25, mode of 26, standard deviation of 5.27, variance of 27.8, range of 25, minimum range of 15, and maximum of 40. The Kolmogorov-Smirnov normality test was 0.142 and a p-value of 0.002.

The summary of laboratory results for treponemal and non-treponemal tests is shown in Table 4.

Table 5 presents the statistical results for hypothesis testing, association, and correlation of variables of interest in the study. They were categorized according to groups or associations of interest: non-treponemal tests at the onset of symptoms in newborns, maternal risk factors and laboratory classification of newborns, treatment variables, and case negativity. The maternal VDRL and neonatal VDRL variables obtained a point statistic of 95.733 (p = 0.319) and ρ(ro) = 0.299 (p = 0.015).

Several epidemiological studies have found a significant association between the risk of syphilis and exposure to different sexual partners during or one year prior to the pregnancy, with women with multiple sexual partners having a higher risk of contracting syphilis compared to those with only one sexual partner (23-26). In contrast, in our study, we found no association between a history of multiple sexual partners and T. pallidum seropositivity.

The only factor with statistical power was the ρ(r0) among women who reported "no history of risk" and the decrease in test positivity. The strength of the association was moderate (-0.31), with a negative impact (the higher the frequency of the history, the lower the risk) and a p-value of 0.05. However, both the hypothesis test and the OR yielded results that were not statistically significant, rendering these findings inconsistent. In summary, sexual risk factors are not associated with the confirmation or exclusion of congenital syphilis.

Research complementary to the referenced publications provided little information regarding the sexual risk history of the incident mothers, and we affirm the independence of maternal sexual risk factors and laboratory confirmation.

In recent years, the change in the operational definition of variables has led to more cases being studied than previously recorded, as the minimum maternal titer ratio has changed from 1:4 to qualitative, as many children are asymptomatic. However, no association is evident between the clinical manifestation of cases and titers below 1:4.

For the maternal VDRL and neonatal VDRL variables, a point statistic of 95.733 (p 0.319) and ρ(ro) 0.299 (p 0.015) was obtained, despite being represented in numerical values for analysis purposes, the variable is considered categorical, ordinal, polytomous, with a titration scale, so the central tendency measures are not performed. We found that the prevalence of symptomatic patients is consistent with the literature, and there is a lack of association between clinical presentation and maternal and neonatal VDRL values at dilutions of 1:4 and 1:2, respectively. This is as described in a study conducted in Uruguay by Moraes M. and Estevan M. (2011). They refute the association between symptoms with maternal titers lower than 1:16 and neonatal titers at 1:32. The lowest maternal titers recorded with symptoms were 1:8 with moderate association [ρ(ro) 0.334 (p 0.004)] but no causality. However, lack of treatment with benzathine penicillin G or temporality was also a cofactor.

The clinical presentation of probable cases of congenital syphilis did not correlate with laboratory confirmation of cases.

The purpose of our research was to analyze the impact of treatment on mothers of newborns with congenital syphilis. We observed that receiving any treatment, whether adequate or inadequate, is not statistically associated with the prevention of congenital syphilis.

The implementation of appropriate regimens for primary or latent syphilis achieved an adherence rate of 55%, with the percentage attributable to lack of confirmation due to the dose of benzathine penicillin being remarkably low (15.4%), as evidenced by the binary logistic regression model applied (B -0.302, Wald 3.732, p 0.05, Exp(B) 0.74, R2 Nagelkerke 0.154). Similarly, the model reveals the statistical significance of each intervention in maternal treatment and covariates. It is highlighted that, when exceeding 2.4 million International Units of benzathine penicillin G, the probability of confirmation decreases. This finding is supported by moderate correlation strength and a negative impact direction, indicating that as the dose increases, laboratory confirmation decreases. Consistent with what was found in the article by Gao J., Chen X., Yang M., Wu Y. et al. (2023), where standardized treatments are protective and predictive factors for congenital syphilis.

Despite finding a correlation between the dose of Benzathine Penicillin G administered to mothers, with a higher dose (>2.4 million IU) lowering the probability, the purpose of the study was to identify standardized treatments with negative results, with doses of 2.4 million IU (administered in cases of primary syphilis) not statistically significant.

While the Mexican statutes recommend confirming and ratifying screening tests for sexually transmitted infections, specifically syphilis, before the implementation of eradication treatment; in our healthcare system it typically experiences a delay of at least one month. Considering international guidelines and recommendations, and given the uncertainty in classifying maternal infection, the optimal treatment scheme would be administering 7.2 million IU of Benzathine Penicillin G divided into three doses, one dose each week, starting from the moment the infection is suspected based on a rapid test. As previously demonstrated, transmission rates decrease significantly when treatment is initiated following detection during the gestational trimester. Consequently, an investment in the mother results in reduced vertical transmission, improved neonatal health outcomes, and enhanced postnatal follow-up.

According to Herrera-Ortiz A., López-Gatell H., García-Cisneros S., et al. (2019), "to achieve the elimination of congenital syphilis, it is essential to have an updated regulatory framework focused on the mother-child relationship." Currently, the state of Sonora has guidelines for the diagnosis and treatment of gestational syphilis and the prevention of congenital syphilis; however, this guideline dates from 2012 and has not been recently updated. It is based on WHO and CDC treatment guidelines.

Adherence to care, primary and secondary prevention of syphilis in pregnant women has an impact on the incidence and confirmation of probable cases of congenital syphilis.

The study’s lower prevalence than the national average raises the question of whether the sharp increase in cases is due to an improvement in case detection and recruitment processes. In many Latin American countries, detection and prevention measures are not consistently implemented, and as a result, data on syphilis infection during pregnancy and congenital syphilis are unreliable.

Strengthening activities that ensure quality care and subsequently the perinatal transmission of these diseases could impact case detection, incidence, and therefore the allocation of resources.

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