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. As transplacental transmission can occur at any time during pregnancy and at any stage of maternal disease,13 the WHO launched a global initiative to eliminate mother-to-child transmission of syphilis in 2007, by performing antenatal screenings during the first and third trimester for every 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 during the third trimester.
Syphilis in Korean adults decreased to 0.2% in 2000 compared to 2.5% in 1977. However, in recent years CS has re-emerged, both in developing and higher income countries including the USA and Canada.14,15 The number of CS cases declined between 2008–2012, followed by another sharp increase from 2012–2014, representing an increase in rate from 8.4 to 11.6 cases per 100,000 live births.16 From our data in the last 5 years, the number of syphilis patients tended to decrease but considering the decreasing annual birth total, the prevalence of CS fluctuated around 1.4–3.8% for the past five years, which can be related to the increasing prevalence of international marriage.5
Seoul and its surrounding area showed a lower incidence of syphilis compared to other areas. Disease prevalence tended to increase as with further distance from the capital and surrounding area. It can be related to the diversity of the antenatal care system and patient’s compliance to antenatal care. Increasing incidence of CS in immigrant mothers were reported due to the failure of prenatal care.5 Gestational syphilis was shown with a higher proportion of more vulnerable women with low schooling, and women of color.17,18 In this study, no socioeconomic data were included, and only trends by region could be seen.
Intrauterine infection may 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 is noted and the prevalence of preterm births was 0.495 per 10000 births, compared to 2.976 per 10000 births for term birth. There were no cases of mortality after birth. For the last 5 years, male patients showed a non-significantly higher prevalence (53%), which agrees with 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 Among 14 patients (2.5%) with neurosyphilis, mental retardation occurred in one case, and hearing impairment occurred in 6 cases (43%). We emphasized the importance of screening for syphilis in the central nervous system even if symptoms are lacking for a diagnosis of syphilis, because the central nervous system is crucial for neurodevelopmental outcomes. Early diagnosis and treatment are important to prevent late manifestations of the infection.
While the prognosis is considered to be very good for infants treated during the first two months of life, if left untreated, progressive disease may result in death or disability in children.24 In our study, no death was noted; however, over 20% 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, considering the timepoint of data collection. Patients who received aqueous penicillin G had more complications and neurosyphilis compared to those who received Benzathine penicillin G. Gender and preterm infants were not significantly associated with complication risk. Besides high-quality antenatal screening and care, early detection of neurosyphilis and appropriate treatment indications with Benzathine penicillin G can improve prognosis.
The recommended treatment for definite or probable CS is intravenous penicillin G for a total duration of 10 days. If more than one day of therapy is missed, the entire course should be restarted. In infants with possible syphilis, 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 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 whether to continue treatment.26 In this study, the number of tests during serial follow-up varied from 1 to 4. Method of test are also variable. Reverse sequence testing is emerging as a high throughput and cost effective method for syphilis screening.27 however it is still limited in clinics. Different algorithms of follow-up tests between sites are reflected in our data. The management seems to deviate from the different algorithms of diagnosis and clinical judgement. Considering the scarce prevalence, it is important to share a standardized algorithm for the evaluation and treatment of CS at the national level to improve outcomes.
In Korea, CS cases have been reported occasionally in specific case reports. There are no published data with yearly long-term follow-up. Differences in numbers reported in the CDC(10–33 infants with proven CS) and NHIS databases indicates the clinical complexity of diagnosis and limitations of self-reporting at the proper time. A strength of this 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 are 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 subjects. There is a discrepancy between 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. The information about the residence of beneficiaries may not be reliable because HIRA data is collected based on the location of providers. A beneficiary may have received healthcare services in a different area from where they actually reside.