Despite the expansion of antenatal syphilis screening programs over the past few decades, syphilis continues to be a major public health concern worldwide. This is the first nationwide study on the manifestation and treatment of CS in Korea. Given the chances of transplacental transmission during pregnancy at any stage of maternal disease,13 the WHO launched a global initiative against mother-to-child transmission of syphilis in 2007, by promoting antenatal screenings in the first and third trimesters in all pregnant woman. Currently in Korea, pregnant women are routinely tested for syphilis at the beginning of pregnancy, and those who are at high risk of syphilis are advised to take an additional test in the third trimester. However, in recent years, CS has re-emerged in both developing and higher income countries, including the United States and Canada.14,15
Syphilis in Korean adults decreased from 2.5% in 1977 to 0.2% in 2000. The number of CS cases declined between 2008 and 2012, followed by another sharp increase from 2012 to 2014, with an increase from 8.4 to 11.6 cases per 100,000 live births.16 Based on our data over the last 5 years, we noted that while the number of syphilis patients has tended to decrease, the prevalence of CS has fluctuated, ranging between 1.4 to 3.8% for the past 5 years, which could be attributed to the increasing prevalence of marriages between Koreans and non-Koreans.5
Seoul and its surrounding areas showed a lower incidence of syphilis compared to other regions. The disease prevalence tended to be removed with further distance from the capital and surrounding areas. This could be related to variations in antenatal care systems and patient compliance to antenatal care. Indeed, a higher incidence of CS in immigrant mothers has been reported due to failure of prenatal care.5 Also, a higher incidence of gestational syphilis was observed in women of lower socioeconomic status and women with lower education.17,18 In this study, socioeconomic data were not included, and only trends by region could be seen.
Intrauterine infection can result in spontaneous abortion, hydrops fetalis, preterm birth, and low birth weight. Clinical manifestations in infected infants within the first 1-2 months of age include hepatosplenomegaly, lymphadenopathy, rash, mucocutaneous lesions, copious nasal secretions, pneumonia, hemolytic anemia, thrombocytopenia, and skeletal involvement.19 Due to the limited maternal information in the current study, syphilis-related stillbirths/abortions were not included. Only one case of hydrops fetalis was noted, and the prevalence of preterm births was 0.495 per 10,000 births, compared to 2.976 per 10,000 births for term births. There was no case of mortality after birth. Over the last 5 years, male patients showed a non-significantly higher prevalence (53%), similar to temporal studies conducted in the United Kingdom and Brazil.20,21
The surveillance of neurosyphilis, an uncommon but severe consequence of syphilis, is complex.22,23 Out of 14 patients (2.5%) with neurosyphilis, mental retardation occurred in one case, and hearing impairment occurred in six patients (43%). As early diagnosis and treatment are important to prevent late manifestations of the infection, we wish to emphasize the importance of screening for neurosyphilis in asymptomatic patients, even if symptoms are lacking for a diagnosis of syphilis, as the central nervous system is crucial for neurodevelopmental outcomes.
While the prognosis is considered to be very good for infected infants treated during the first 2 months of life, if left untreated, disease progression may lead to death or disability in children.24 In our study, no death was noted; however, over 20% of the subjects suffered from complications such as mental retardation, eye and renal involvement, and hearing impairment. The presence of complications led to a prolonged duration of treatment. Complication rates were similar throughout the 5 years, except in 2018, potentially reflecting the timepoint of data collection. Patients who received aqueous penicillin G had more complications and neurosyphilis compared to those who received benzathine penicillin G. Sex and preterm infants were not significantly associated with complication risk. In addition to high-quality antenatal screening and care, early detection of neurosyphilis and appropriate treatment indications with benzathine penicillin G can also improve the prognosis.
The recommended duration of treatment for definite or probable CS is intravenous penicillin G for 10 days. If more than 1 day of therapy is missed, the whole course must be started again. In infants with possible syphilis, a single intramuscular dose of benzathine penicillin is an alternative treatment choice in select circumstances, but only if follow-up is assured.25 According to our data, benzathine penicillin G is prescribed more frequently than aqueous crystalline penicillin G, with a variable treatment duration. Four patients underwent re-treatment with various manifestations, treatment regimens, and durations, which may be due to the rare prevalence of the disease and site differences. This reflects the lack of standard guidelines for evaluation and therapeutic measures of CS.
Once CS is diagnosed, serial laboratory follow-up is required to assess the duration of treatment.26 In this study, the number of tests during serial follow-up varied from one to four. Testing methods also varied. Reverse sequence testing is emerging as a high throughput and cost-effective method for screening syphilis;27 however, it is still limited in the clinical setting. Meanwhile, out data have shown different algorithms of follow-up tests between sites. Considering the scarce prevalence of CS, it is important to share a standardized algorithm for the evaluation and treatment of CS at the national level to improve treatment outcomes.
In Korea, cases of CS have been reported occasionally in specific case reports. There are no published data with yearly long-term follow-up. Differences in the numbers reported in the Centers for Disease Control (10-33 infants with proven CS) and NHIS databases indicate the clinical complexity of diagnosis and limitations of self-reporting. A strength of our study was that it used nationwide accumulative data with updates on recent rates of CS, including long-term complications.
A limitation of this study was that it depended on infant claim data; therefore, maternal information, including adequate treatment, spontaneous abortion, and stillbirths, were not included. Data analysis after 2018 can add some additional trends and outcomes of CS. The data did not have records collected from laboratories, notably on the severity of conditions and health behavior of beneficiaries. Since the information was obtained from the diagnosis code entered by each hospital, there could be data omission or limited detailed information about the diseases of each subject. There could be a discrepancy between the diagnoses entered in the database and the actual diseases that the patients had. Furthermore, as the claims data were generated to reimburse healthcare services eligible for coverage, non-covered healthcare services were not assessed. Information about the residence of beneficiaries may not be reliable, since HIRA data are collected based on the location of providers; therefore, a beneficiary may have received healthcare services in a different area from where they actually reside.
Another limitation of our study was that it only included infants born in Korea, and the results may not be generalizable to other regions in the world.