Objectives To determine the effectiveness of treatment in improving pregnancy outcomes among women with syphilis.
Methods This is a retrospective study based on the provincial prevention of mother-to-child transmission of syphilis database. All women with syphilis with singleton pregnancies were recruited. We evaluated their pregnancy outcomes by group-specific analyses according to their treatment time and adequacy.
Results The syphilis prevalence among pregnant women was 0.3% (4214/1 338 739) in Zhejiang Province, China, during 2013–2014, considering all live births and abortions. Women with singleton pregnancies (3767) were included in the study, including live births and stillbirths (≥28 weeks). The treatment coverage for all women with syphilis was 80.2% (3022/3767), and 68.2% (2062/3022) of the women were treated adequately. Of 745 infants born to untreated pregnant women with syphilis, 1.2% manifested pneumonia, 2.7% asphyxia, 1.6% birth defects, 3.8% congenital syphilis (CS), 14.2% were preterm, 10.1% had low birth weight (LBW) and 3.1% experienced perinatal death. The risks of asphyxia (OR=2.7), CS (OR=3.1), preterm birth (OR=1.5), LBW (OR=1.9) and perinatal death (OR=3.1) were much higher in infants born to mothers treated inadequately than from those treated adequately. Moreover, mothers with syphilis who initiated treatment in the third trimester suffered an increased risk for asphyxia (OR=3.0), CS (OR=6.0) and LBW (OR=1.7) compared with those who initiated treatment in the first trimester.
Conclusions Early and adequate treatment could improve the adverse pregnancy outcomes among women with syphilis.
- INFECTIOUS DISEASES
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Globally, syphilis continues to be an urgent public health issue. In 2008, the WHO estimated that there were approximately 1.36 million pregnant women with active syphilis and that nearly 66% of adverse outcomes occurred in those who were not tested or untreated.1 Untreated maternal syphilis is strongly associated with a wide range of adverse pregnancy outcomes, such as spontaneous abortion, stillbirth, low birth weight (LBW), preterm birth, prenatal death and congenital syphilis (CS).1–4 In addition, CS is a life-threatening infection that can result in growth retardation, multiple organ dysfunction and neonatal death.5–7 Strengthening the prevention of mother-to-child transmission (PMTCT) of syphilis has drawn worldwide attention. The WHO has even advocated the global elimination of CS for the achievement of the Millennium Development Goal.8 Although the screening and treatment of maternal syphilis are feasible and cost effective in many regions, meeting the global goal will still involve considerable efforts for the large proportion of untreated or inadequately treated women and the associated adverse influences on their offspring.1–8
In China, the most recent estimate of the entire population aged 15–49 years old with syphilis was 2 979 422 (1 504 000–6 063 309) in 2011, including 70 062 pregnant women.9 As the number of syphilis cases continues to soar in many regions, a national programme on integrated PMTCT of syphilis, HIV and hepatitis B was launched at the end of 2010; this included uptake of counselling and screening and strengthening of healthcare for infected mothers and their infants.10 The programme has achieved great success in reducing the incidence of CS in pilot areas such as Shenzhen, where the CS incidence decreased from 115/100 000 in 2002 to 10/100 000 (live births) in 2011.11 However, China still faces great pressure from the increasing CS burden with respect to social inequalities and other gaps in access to healthcare services. The national incidence of CS increased 28.1% annually since 2000, which reached 69.9/100 000 (live births) in 2013.12 In China, studies on maternal syphilis and CS have rarely been conducted, and they have focused mainly on Southern China or on large cities.13–15 As a country with a vast territory and a large population, data on maternal syphilis are needed for the development of policy decisions and interventional guidance.
Zhejiang Province is located on the southeastern coast of China, and syphilis has placed a huge burden on this area. According to data from provincial sexual surveillance centres, the incidences of adult syphilis and CS have undergone an upward trend.16–18 In 2011, a provincial PMTCT programme was initiated locally. A clearer understanding of the epidemiology of maternal syphilis and the effects of their treatment in high-prevalence settings is necessary with respect to healthcare providers and policy makers. The purpose of this study was to determine the prevalence of maternal syphilis, treatment effectiveness and syphilis-associated pregnancy outcomes.
According to China's national PMTCT programme, syphilis testing and counselling are routinely offered to all pregnant women when they have their first antenatal care appointment. Women in pregnancy with positive results in the Toluidine Red Unheated Serum Test (TRUST)/syphilis rapid plasma reagin (RPR) and Treponemal pallidum particle agglutination (TPPA)/pallidum particle agglutination (TPHA) tests were diagnosed with syphilis infection.19 All pregnant women were required to be screened again in the third trimester during pregnancy or at delivery. More frequent screening was performed among women at high risk for syphilis. If women chose to continue pregnancies, they were provided free treatment with two courses of penicillin injections in the first trimester and the third trimester, respectively, such as 2.4 million units of benzathine penicillin by weekly injection for 3 weeks or 0.8 million units of procaine penicillin by daily injection for 15 days per treatment course. Erythromycin or ceftriaxone was provided to those women who were allergic to penicillin, or we suggested that they considered the termination of their pregnancies.
All exposed infants were required to undergo testing for CS at birth and they were followed up every 3 months until they were diagnosed or excluded. CS was diagnosed in infants who met any one of the following criteria: (1) infants with a titre in the TRUST or RPR tests four or more times higher than his or her mother's values during labour (however, the absence of a fourfold increase could not exclude CS); (2) infants with abnormal physical examinations consistent with syphilis infection; (3) infants with positive TPPA/TPHA tests lasting until 18 months after birth or (4) infants with positive IgM or T. pallidum. Infants born to mothers with syphilis were immediately given free prophylaxis with benzathine penicillin in order to prevent CS.
The follow-up and healthcare services for mothers and their infants were provided by the local Women's and Children's Hospitals. All the information was recorded online using the PMTCT information system. A series of quality control actions was then performed by local and provincial experts each year. The Women's Hospital School of Medicine Zhejiang University was in charge of the provincial programme, including training healthcare providers, supervising the information system and providing guidance.
Data were from the provincial syphilis PMTCT database and were linked with the birth database. All pregnant women with syphilis who delivered between 1 January 2013 and 31 December 2014 were enrolled. We recorded women's pregnancy outcomes, including live births and perinatal deaths (stillbirth at ≥28 weeks and 0–7 days for neonatal deaths). Women who terminated their pregnancies voluntarily, who had multiple pregnancies or suffered early miscarriage (<28 weeks) and without clear treatment information were excluded from the study. We categorised women according to treatment regimens: whether treated or not, whether treated adequately or inadequately and the trimester of treatment initiation. The treated group included all women with syphilis who received at least one dose of penicillin/erythromycin/ceftriaxone during pregnancy. Women who did not receive treatment during the entire pregnancy period were considered the untreated group. Women with two courses of penicillin injections and at least 2 weeks off between the two courses were categorised in the adequate treatment group. Others who received non-penicillin treatment or were treated with fewer than two courses were classified in the inadequate- treatment group.
Data were exported in Excel 2007 and analysed using SPSS software V.16.0 for Windows. Categorical variables were presented as numbers and frequencies. The demographic characteristics of these infected women were described. The OR values and 95% CIs of the factors were estimated to compare the pregnancy outcomes in groups of women with syphilis, according to their time of treatment and adequacy of their treatment. We listed adverse pregnancy outcomes as pneumonia, asphyxia, birth defects, CS, preterm birth, LBW and perinatal death. In this study, infants were diagnosed with asphyxia if their Apgar scores were under 7 at birth. Perinatal deaths were recorded only as stillbirths (≥28 weeks stillbirth) and early neonatal deaths (0–7 days).
We collected data using a routine information questionnaire. All infected mothers were required to complete the questionnaire when they received their first antenatal care or at birth. The clinical diagnosis and treatment information were obtained from medical records. The study was approved by the ethics committee to link two routinely collected data sets as a provincial PMTCT database and a birth database using the mother's ID card and name. In the final database, only the special numbers for mothers and infants were listed. All information was kept confidential.
Demographic characteristics and pregnancy outcomes
A total of 1 338 739 pregnant women were screened and 4214 were identified with syphilis infection during 2013–2014. The total prevalence of syphilis among pregnant women was 0.3%. Women (3767) with singleton pregnancies were analysed in this study, including 3757 live births and 10 stillbirths (≥28 weeks). The treatment coverage for all women with syphilis was 80.2% (3022/3767). In the treatment group, only 68.2% (2062/3022) of women had adequate treatment. In the adequately treated group, the numbers of women who initiated treatment in the first, second and third trimesters were 799, 1146, and 117, respectively. In the inadequately treated group, the corresponding data were 104 in the first trimester, 236 in the second trimester and 620 in the third trimester. Generally, there were 903 women treated in the first trimester, 1382 in the second trimester and 737 in the third trimester (figure 1).
Table 1 shows the demographic characteristics and pregnancy outcomes of women with syphilis during pregnancy. In our study, the majority of women with syphilis were from outside of Zhejiang Province, including two who were foreign born. Most of the women were young, poorly educated, unemployed and unaware of their infection status during pregnancy. Of these infected women, 99.7% had live births. Some women were reported to be coinfected with HIV and hepatitis B. The total number of perinatal deaths was 52, including 10 stillbirths and 42 early new infant deaths (table 1).
Syphilis treatment and pregnancy outcomes
The diagnoses of CS were unreported for 22 infants (15 were born to treated mothers and 7 were born to untreated mothers). There were five perinatal deaths missing from the data (three were born to treated mothers and two were born to untreated mothers). The infants born to untreated mothers were at significantly higher risk for pneumonia, asphyxia, birth defects, CS, preterm birth, LBW and perinatal death than were those born to the treated mothers. The greater risks of asphyxia, CS, preterm birth, LBW and perinatal death were also observed in infants born to mothers treated inadequately compared with those treated adequately. The risks of asphyxia, CS and LBW were higher in infants exposed to mothers who initiated treatment in the third trimester than for those who initiated treatment in the first trimester (table 2).
As the prevalence of syphilis in China has risen since the 1990s, to prevent syphilis transmission from mother to child has become a priority.10 ,16 In this study, the overall prevalence of maternal syphilis was much higher than in other parts of the world, such as Europe (0.16%), the Mediterranean (0.06%) and slightly higher than the Chinese national average (0.24%).1 ,9 Additionally, the prevalence in our study was similar to those in Shenzhen and Shanghai, China, where both were estimated at 0.30%, but it was lower than those in rural parts of Southern China (0.39%), Latin America (1.1%) and India (0.57–0.78%).4 ,13–15 ,20 This largely conformed to the general population epidemiology and geographic distribution of syphilis in China.16
Although the government provided free syphilis screening to all pregnant women, 100% coverage has not been achieved for several reasons. Most of these mothers with syphilis in our study were migrants, unemployed or illiterate, which might have increased the risk of infection and the likelihood of missed active interventions. Moreover, syphilis was subjected to HIV/STD coinfection as previously reported.21 Stigma and isolation might pose obstacles to screening and antenatal care. Therefore, we found a high proportion of women (17.6%) identified at or after delivery and less than 90% received treatment. Even among those women treated during pregnancy, only 68.2% received adequate treatment. Syphilis prevention is available and treatable since the advent of penicillin; nevertheless, deferred diagnoses usually lead to delayed treatment or even lack of treatment entirely. These findings were comparable with current studies.1 ,22–24 It was estimated that globally approximately 20% of women with syphilis did not attend antenatal care.1 In some areas, over 70% of women were diagnosed at late trimester and only half of women received treatment, and in Oliveira's study, the proportion of inadequate treatment for maternal syphilis arrived at 77.6%.20 ,22 ,23 This reinforces the concept of antenatal care correlates with effective intervention.
We found herein that untreated or inadequately treated maternal syphilis remained an important risk factor for a series of adverse pregnancy outcomes, which agreed with a wide range of published studies.1–4 In a recent meta-analysis performed by Qin et al2 that involved a large number of pregnant women with and without syphilis, the prevalence of adverse results among the untreated group was 36.0% for CS, 23.2% for preterm delivery, 23.4% for LBW and 26.4% for stillbirth or fetal loss. The latest meta-analysis performed by Gomez et al3 showed 17.2% for stillbirth and fetal loss, 6.6% for neonatal death and 6.6% for prematurity or LBW among women with untreated syphilis. In general, the above figures were much higher than the untreated group in our study, which were 3.8% for CS, 14.2% for prematurity and 10.1% for LBW. Owing to variations in study design, study origin, stage of maternal infection, treatment regimens and inclusion criteria across different researches, the potential bias with regard to comparisons should be considered. In the present study, the majority of infected women were asymptomatic and had mild cases, and the data on exact disease progression in Qin and Gomez’s studies were not presented. Besides that, we only investigated the adverse pregnancy outcomes of women with syphilis with singleton births, calculated the stillbirths over 28 weeks and reported the identification of CS at 0–7 days after birth. In this way, we might have underestimated the specific adverse pregnancy outcomes. However, in Qin's study, they excluded the HIV-infected population and provided data that included all women with early fetal loss and miscarrage, and in both Qin and Gomez’s studies, prematurity and LBW and stillbirth and fetal loss were all combined.2 ,3
We observed that the treatment initiated in the first trimester reduced the risk of asphyxia, CS and LBW more than the treatment initiated in the third trimester. Conversely, no significant differences were observed in the prevalence of birth defects, preterm birth and perinatal death between women who initiated treatment in the third trimester and the first trimester. The OR values for preterm birth and perinatal death approximated the cut-off, which attracted our attention. These findings were supported by a systematic review that reported an overall OR for any adverse outcome in women treated only during the third trimester at 2.24 compared with those women treated at first and second trimesters.25 Importantly, every week of delay in treatment increased the risk for adverse pregnancy outcomes by 2.82-fold.13 The call for early treatment should be strengthened in order to promote the treatment adequacy as non-penicillin treatment exerted minimal impact on incomplete treatment in our setting.
CS is a disabling infection that can destroy multiple organ systems and present various symptoms.5–7 Among those infants with CS, 50 infants were reported with titres in the TRUST or RPR tests four or more times higher than their mothers, four infants were detected with the Treponema and others were reported to be positive for IgM. Thirteen out of 62 infants with CS showed differential clinical manifestations, such as skin pimples (eight cases), chondritis (one case), anaemia (two cases), pneumonia (three cases) and hepatosplenomegaly (three cases). Of them, four infants were reported with various clinical features. In our study, 45.2% (28/62) received no treatment for syphilis among mothers with infants with CS, which was similar to a study in USA.5 Nevertheless, among treated mothers with infants with CS, 58.8% (20/34) received inadequate treatment for syphilis, which was much higher than the data (30.0%) reported in the same study from the USA.5 Although we only presented the prevalence of CS among perinatals, CS was preventable and curable when mothers received early and adequate treatment.
Pneumonia, asphyxia, birth defects, CS, preterm birth and LBW all increased the risk of perinatal death, and the interplay between these elements was promoted to some extent. In Arnesen's study, women with gestational syphilis had increased odds of stillbirth (OR=6.87).24 Based on the report from the USA, no or inadequate treatment for maternal syphilis, infants with CS born alive at <28 weeks' gestation or born weighing <1500 g all increased the likelihood of a dead case.26 Here, we reviewed the causes of 42 new infant deaths and noticed that pneumonia, asphyxia, LBW and CS contributed greatly. Despite the unknown infection status for some of the dead infants, it was deduced that CS was an independent risk factor because the dead infants had been born to untreated or incompletely treated mothers.
There are several limitations to the present study. First, we did not provide data for all pregnant women; thus, we could not compare outcomes between women with and without syphilis. Second, we only focused on selected adverse pregnancy outcomes of women with syphilis with singleton births according to their treatment. Improved data on early fetal loss as well as complete estimate for CS and outcomes of multiple births should be addressed. Lastly, we did not analyse the mother's stage of syphilis infection and partner's infection status due to limited data, and this might negatively influence the women's health or treatment effects.
In summary, this is the first systematic investigation of syphilis prevention and pregnancy outcomes in Zhejiang Province, China. The results suggested that treatment, especially adequate and early treatment, improves pregnancy outcomes and promotes the health of offspring. This may be achievable in Zhejiang because of the integrated PMTCT services and the presence of a government-driven programme, but there are still some barriers to the complete success. Improving the coverage with regard to early screening and adequate treatment among pregnant women should be the goal for future strategies, particularly by stressing prenatal healthcare early among key segments of the population.
Treatment coverage, rates of early treatment and adequate treatment for maternal syphilis were all suboptimal..
Neonates born to women with untreated syphilis experienced a high burden of morbidity.
Improved delivery of early and adequate treatment is likely to improve pregnancy outcomes.
We thanked all the staff of PMTCT programme and mother–infants health service in Zhejiang Province.
Abstract in Chinese
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
- Abstract in Chinese - Online abstract
Xiao-Hui Zhang and Jian Xu are equal contributors to this study.
Handling editor Jackie A Cassell
Contributors X-HZ carried out the statistical analysis and drafted the manuscript; JX and D-QC conceived the study and revised the paper and L-FG helped in data collection and cleaning. L-QQ was responsible for the whole programme. All authors read and approved the final manuscript.
Funding This work were funded by “He Sheng Yuan mother and infants health program (2015FYH001)” and “Provincial medical and health science and technology project(2016KYA121)” initiated by National Center for Women and Children's Health, Chinese Center for Disease Control and Health and Family Planning Commission of Zhejiang Province.
Competing interests None declared.
Ethics approval Ethical clearance was obtained from the Women's Hospital School of Medicine Zhejiang University (2016-0005).
Provenance and peer review Not commissioned; externally peer reviewed.