Article Text
Abstract
Introduction Consistent definitions of congenital syphilis are critical for determining true incidences and setting up targets of elimination. This study aimed to assess the evaluation and management of infants at high risk of congenital syphilis with an antenatal syphilis-screening programme in the Shenzhen SEZ and to develop feasible definitions for the detection of congenital syphilis in China.
Methods A retrospective study was conducted of all standardised records of pregnant women with positive syphilis between 2003 and 2007. Infants at high risk of congenital syphilis were evaluated by laboratory tests at birth and longitudinal follow-up. A screening test-positive congenital syphilis case was defined based on a positive 19S-IgM-FTA-ABS result at birth. Assuming that 19S-IgM-FTA-ABS was the gold standard, the sensitivity and specificity of the ascertainment methods were calculated.
Results During the study period, 1010 live infants were born to women with active syphilis during pregnancy. 19S-IgM-FTA-ABS detected 42 screening-positive congenital syphilis cases and another nine cases were identified by longitudinal follow-up only. Using 19S-IgM-FTA-ABS as the gold standard, ‘fourfold rapid plasma reagin (RPR) titres’ had the highest sensitivity and specificity compared with the other two follow-up methods.
Discussion 19S-IgM-FTA-ABS makes congenital syphilis case classification simpler and faster for newborns. In areas where 19S-IgM-FTA-ABS is not available, comparing newborn RPR titres with maternal titres can be an alternative method. Meanwhile, positive follow-up results act as treatment indicators for older infants. As congenital syphilis definitions vary over the country, the Shenzhen programme suggested a practical model for surveillance and treatment in areas with or without available 19S-IgM-FTA-ABS testing.
- Intervention studies
- pregnancy
- screening
- sexually transmitted disease surveillance
- syphilis
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China has been experiencing a syphilis epidemic over the past two decades, showing a rise in incidence from 0.2 per 100 000 in 1993 to 21.1 per 100 000 in 2008.1 2 An increasing seroprevalence with a median of 0.45% of syphilis infection among pregnant women has also been reported.3 Shenzhen, a special economic zone (SEZ), is a newly developed city located on the southern coast of China with a population of over 10 million. Syphilis started to emerge in the city in the early 1980s and the incidence increased to 66.2 per 100 000 by 1999.4
Congenital syphilis is caused by Treponema pallidum, which is passed from mother to child during fetal development or birth. If infected, 40% of the fetuses can present as fetal loss, such as stillbirth, spontaneous abortion and perinatal death, and another 40% can have syphilitic lesions leading to many paediatric disorders.5 The World Health Organization (WHO) proposed an Action plan for global elimination of congenital syphilis in 2007.6 Penicillin is a cheap and readily available antibiotic that is effective against T pallidum7 and prevents 98% of vertical transmissions.8 Therefore, antenatal screening for syphilis followed by treatment with penicillin is cost-effective in developed and developing countries.9
Consistent definitions of congenital syphilis are critical for determining true incidences and setting up targets of elimination. However, diagnosis and evaluation of congenital syphilis is puzzling.10–12 The Centers for Disease Control and Prevention's (CDC) definitions of congenital syphilis cases13 have been widely used by many studies8 14 15; however, these may not be practical for use in a Chinese setting. The purpose of this study was to assess the evaluation and management of infants at high risk of congenital syphilis with an antenatal syphilis-screening programme in Shenzhen and to develop feasible definitions for the detection of congenital syphilis in China.
Methods
Screening and management for maternal syphilis
Supported by a governmental fund, a free universal antenatal syphilis-screening programme was initiated in Shenzhen in July 2002. By the end of 2007, the programme covered 79 antenatal care clinics and over 95% of all pregnant women in the city. For every mother presenting for her first visit at an antenatal care clinic, a rapid plasma reagin (RPR) test or a toluidine red unheated serum test (TRUST) is used for syphilis screening. All positive non-treponemal test results are confirmed with a T pallidum particle agglutination (TPPA) test before being reported to the Shenzhen Center for Chronic Disease Control (SZCCC).
When diagnosis is confirmed, patients are advised to accept standardised treatment and follow-up visits according to the Diagnostic criteria and management of syphilis guidelines (Ministry of Health, China)16 and the Guidelines for the prevention and control of congenital syphilis (CDC, USA).17 After being given the results of their congenital syphilis risk evaluations, the mothers decide whether to continue their pregnancies.
For each pregnant woman with maternal syphilis, information on demographic characteristics, clinical findings and sexual behaviours, as well as follow-up information of both mothers and newborns was collected. The whole programme was implemented based on the principle of first consultation responsibility and verbal consents were obtained before the screening. Ethical approval of the programme was granted by the Research Ethics Committees of SZCCC.
Congenital syphilis case investigation
The congenital syphilis cases were investigated, reported and treated according to the algorithm in figure 1. A confirmed congenital syphilis case was defined as a liveborn infant or child in whom T pallidum was identified by darkfield microscopy or direct fluorescent antibody. A screening test-positive case was defined as an infant with a positive fluorescent treponemal antibody absorption (19S-IgM-FTA-ABS) result at birth. The cases were reported to SZCCC and treated with penicillin when detected. Preventive treatment should also be provided to infants with a fourfold or greater rise in RPR titres at birth compared with maternal titres. All seroreactive infants (or infants whose mothers were seroreactive at delivery) should be carefully followed up and tested with RPR and TPPA every 3 months until the tests become non-reactive. A reactive non-treponemal (RPR) or treponemal test (TPPA) that does not revert to non-reactive in 6 or 18 months, respectively, should identify presumptive congenital syphilis cases for treatment. Syphilitic stillbirths were not included in the case definitions in the current programme.
Study design and data collection
A retrospective study was conducted of all standardised records of pregnant women who were positively screened for syphilis in the Shenzhen SEZ between January 2003 and December 2007. The data were reviewed by an epidemiologist using a structured data abstraction form. Maternal demographic information, clinical information regarding the intervention of maternal syphilis, and data regarding the diagnosis, follow-up and evaluation of infants were extracted from the records.
Statistical analysis
The data were inputted with Epidata 3.1 software and analysed using SPSS 15.0 software. Consistencies between congenital syphilis detection methods were tested by κ statistical analysis. The sensitivity and specificity of the ascertainment methods were calculated based on the assumptions that 19S-IgM-FTA-ABS was the gold standard for congenital syphilis case identification and all true cases were identified by at least one detection method.
Results
Maternal characteristics
From January 2003 to December 2007, 1375 women with active syphilis during pregnancy were reported in the Shenzhen SEZ. Of these pregnancies, 1010 live births (73.5%) were delivered. Among the 974 mothers with complete demographic records, the mean age at delivery was 27.9 years, 91.1% were married during pregnancy, 13.7% had a permanent registered residence in Shenzhen, the majority (89.9%) held lower than bachelor degrees and approximately half were unemployed (51.7%). The median gestational age at the syphilis screening was 17 weeks, with a range of 4–42 weeks. Of the 1010 syphilis mothers, 30.6% (n=309) received no or inadequate treatment before delivery.
Newborn evaluation and management
Newborns were evaluated based either on laboratory test results at birth or from longitudinal follow-up records. Of the 1010 liveborn infants, no congenital syphilis case was clinically diagnosed by darkfield microscopy or direct fluorescent antibody, 51 (5.0%) cases were identified as presumptive congenital syphilis and 18 (1.8%) were classified as unclear due to incomplete follow-up records. Figure 2 shows that the rate of congenital syphilis among all live births was frighteningly high compared with the national incidence at the start of the programme (109.3 per 100 000 live births in 2003) and has decreased remarkably over the 5-year period (15.1 per 100 000 live births in 2007). Among the 51 congenital syphilis presumptive cases, eight (15.7%) premature births, one (2.0%) post-term birth and five (9.8%) perinatal deaths were observed. Seventy-nine stillbirths were reported during the study; however, syphilitic stillbirth was not included in the case definitions of the programme.
Of the 51 presumptive cases, 50 (98.0%) received laboratory evaluation at birth, nine (17.6%) of which did not return for follow-up. Only 32 (62.7%) were evaluated adequately by undergoing 19S-IgM-FTA-ABS, having compared RPR titres at birth with maternal titres, and returning for follow-up until RPR/TPPA reverted to non-reactive.
Among the 51 presumptive cases, 42 (82.4%) were defined as screening test-positive cases (a positive 19S-IgM-FTA-ABS result at birth), among whom 12 (23.5%) also revealed a fourfold or greater rise in RPR titres compared with maternal titres. The remaining nine (17.6%) cases were identified by longitudinal follow-up only, including eight (15.7%) with reactive RPR results after 6 months. Attention should be given to one case (1.9%) in which the TPPA test did not revert to non-reactive after 18 months, whereas it was ascertained positively neither at birth nor after 6 months' follow-up with RPR. Moderate consistency was observed between 19S-IgM-FTA-ABS and the ‘fourfold RPR titres’ (κ=0.565, p=0.000), whereas the two follow-up methods were not consistent with each other (κ=0.217, p=0.041).
Among the mothers of the presumptive congenital syphilis newborns, the mean gestational age at the syphilis screening was 29.5 weeks, ranging from 6 to 40 weeks, which was almost 10 weeks later (p=0.001) than that of mothers of healthy infants (mean gestation 19.6 weeks, ranging from 4 to 42 weeks). However, information regarding treatment regimens was not recorded in detail.
Sensitivity and specificity of ascertainment methods
For all the presumptive cases, 19S-IgM-FTA-ABS had a detection rate (84.0%) more than three times that of the ‘fourfold RPR titres’ (27.9%) and the 18-month TPPA follow-up (25.6%), and approximately two times that of the 6-month RPR follow-up (47.6%). Assuming that 19S-IgM-FTA-ABS is the gold standard for congenital syphilis case identification, the sensitivity and specificity of the other three ascertainment methods were evaluated. As presented in table 1, the method of comparing newborn RPR titres with maternal RPR titres had the highest sensitivity and specificity compared with the other two follow-up methods. The sensitivities and specificities of the three evaluations did not vary by infant RPR titres at birth.
Discussion
Congenital syphilis is a serious public health problem in China. As reported by Chen et al,1 the incidence of congenital syphilis increased with an average yearly rise of 71.9% from 0.01 cases per 100 000 live births in 1991 to 19.68 cases per 100 000 live births in 2005. To prevent congenital syphilis effectively, the true incidence must be ascertained, diagnostic methods have to be improved and mother-to-child transmission needs to be controlled. In 1988, the US CDC developed a surveillance case definition.18 According to this definition, all infants born to mothers with untreated or inadequately treated syphilis should be considered potentially infected. However, it is difficult to apply the US definition to China as it relies largely on detailed documentation of maternal treatment and serological status that may not be achievable for clinicians in the affected areas. To develop feasible definitions for congenital syphilis detection in a Chinese setting, records from a 5-year span of the antenatal screening programme were reviewed.
According to our knowledge, this is the first study regarding newborn evaluation and the longitudinal follow-up of infants at high risk of congenital syphilis in China. During the study period, no cases met the confirmed congenital syphilis case criteria. Based on positive neonatal 19S-IgM-FTA-ABS results, 42 screening-positive cases were reported and nine additional cases, which were negative for 19S-IgM-FTA-ABS, were identified by longitudinal follow-up. While assuming 19S-IgM-FTA-ABS as the gold standard for congenital syphilis ascertainment, ‘fourfold RPR titres’ had a sensitivity of 100%.
The interpretation of seroreactive tests for syphilis in infants is complicated because of the transplacental transfer of maternal non-treponemal and treponemal IgG antibodies to the fetus. Although 19S-IgM-FTA-ABS was used as the gold standard for congenital syphilis identification by many studies,19 20 its limitations were also revealed. As 19S-IgM-FTA-ABS is a subjective test and hard to standardise,10 false-positive and false-negative results may occur.11 12 However, the false-positive rate of 19S-IgM-FTA-ABS in newborns was much lower compared with that of other treponemal tests, such as TPPA or T pallidum haemagglutination antibody.12 Meyer and others have reported a false-positive rate of 19S-IgM-FTA-ABS as 2% in newborns and 15% in elder infants.12 This indicates that 19S-IgM-FTA-ABS is more reliable for the congenital syphilis evaluation of newborns than for that of older infants. As very few congenital syphilis cases are clinically asymptomatic at birth, 19S-IgM-FTA-ABS makes case classification simpler and faster if done during the immediate post-delivery period. Moreover, having congenital syphilis surveillance data available can help to improve the ability of programme planners and practitioners to grasp the true local incidences and trace high-risk women of childbearing age.
The evaluation method of ‘fourfold RPR titres’ had a high sensitivity of 100% when 19S-IgM-FTA-ABS was used as a gold standard. This suggests that comparing newborn RPR titres with maternal titres can be an alternative method for congenital syphilis case identification and a treatment indicator in areas where 19S-IgM-FTA-ABS is not available. Longitudinal follow-up identified nine additional cases (17.6%) that had negative 19S-IgM-FTA-ABS results at birth. This indicates that positive follow-up results act as treatment indicators for older infants, thus longitudinal follow-up for RPR and TPPA should always be conducted for the management of infants at high risk for congenital syphilis. As congenital syphilis definitions vary a lot over the country, the Shenzhen programme suggested a practical model for surveillance and treatment in areas either with or without available 19S-IgM-FTA-ABS testing. Meanwhile, using strict diagnostic criteria but wide inclusion criteria for treatment can largely reduce the incidence of syphilis infection.
Based on different models, the annual global number of congenital syphilis cases was estimated to be between 713 600 and 1 575 000.21 Among children under 5 years of age, 1.3% of deaths were attributed to congenital syphilis (WHO Global Burden of Disease, 2000).22 More newborns were affected by mother-to-child transmission of syphilis than any other infections including HIV. It has been seen that screening for maternal syphilis and treatment of seropositive mothers is cost-effective, affordable and feasible for the prevention of congenital syphilis.23 However, in most parts of China, antenatal screening and intervention for maternal syphilis is not practised as routine care due to insufficient governmental awareness.
During the antenatal syphilis-screening programme in the Shenzhen SEZ, more than 95% of all pregnant women in the city were screened, and the incidence of congenital syphilis decreased sharply although national incidence has increased. It can be considered that Shenzhen has achieved the goal of the WHO plan for the elimination of congenital syphilis, in which the incidence of congenital syphilis falls below 0.5 per 1000 live births and screening covers more than 90% of pregnant women.6 However, efforts should also be made to promote effective antenatal syphilis screening according to the WHO plan. Shenzhen is a young city in which 76.7% of its population have a floating residence.24 Special attention should be paid to this group to ensure that all pregnant women in the city, having undergone or not undergone antenatal care, are screened, and that all infected women and their partners are adequately treated. In this study, the median gestational age at screening was high at 17 weeks and the mean gestational age at screening of mothers of congenital syphilis cases was 10 weeks later than that of mothers of healthy infants. It is suggested that further research should focus on the determinants of the uptake of antenatal syphilis screening to guide the promotion of syphilis screening in early gestation.
One limitation of the congenital syphilis definitions in this programme is that they do not include syphilitic stillbirths. Corrections need to be made in the future in order to avoid underestimation of the incidence of congenital syphilis and to improve the surveillance system. In addition, it is of concern that only 62.7% (n=32) of all presumptive cases were evaluated adequately by both laboratory tests at birth and longitudinal follow-up methods, and that there were 18 infants classified unclearly because of incomplete records. It is suggested that SZCCC strengthens the training of clinicians and public health workers in the use of the congenital syphilis case definitions and improves the monitoring and evaluation systems of the programme. In addition, clinical presentations of congenital syphilis cases need to be recorded in detail for a better understanding of the effectiveness of the current screening programme and areas where effective intervention could be targeted.
Key messages
The study is based on a free universal antenatal syphilis-screening programme, which covered 95% of all pregnant women in the Shenzhen SEZ, South China.
This is the first study regarding newborn evaluation and longitudinal follow-up of infants at high risk of congenital syphilis in China.
Of the 1010 live births born to women with active syphilis during pregnancy during the study period, 51 (5.0%) presumptive congenital syphilis cases were detected.
19S-IgM-FTA-ABS detected 42 screening-positive congenital syphilis cases and the remaining nine cases were identified by longitudinal follow-up only.
The study suggested a practical model for surveillance and treatment in areas either with or without available 19S-IgM-FTA-ABS testing in China.
Acknowledgments
The authors would like to thank Professor Chen Xiang-Sheng, deputy director of the National Center for STD Control, China, for his valuable comments on the objectives, study design, data collection and statistical methods of this study. The author also thank clinicians in the 79 antenatal clinics who are responsible for the diagnosis, treatment, follow-up and records documentation of mothers with syphilis infection and their infants, and they are also grateful to all pregnant women who participated for their cooperation to make this study possible.
References
Footnotes
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the the Research Ethics Committees of Shenzhen Center for Chronic Disease Control.
Provenance and peer review Not commissioned; externally peer reviewed.
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