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1.  Global Estimates of Syphilis in Pregnancy and Associated Adverse Outcomes: Analysis of Multinational Antenatal Surveillance Data 
PLoS Medicine  2013;10(2):e1001396.
Using multinational surveillance data, Lori Newman and colleagues estimate global rates of active syphilis in pregnant women, adverse effects, and antenatal coverage and treatment needed to meet WHO goals.
The World Health Organization initiative to eliminate mother-to-child transmission of syphilis aims for ≥90% of pregnant women to be tested for syphilis and ≥90% to receive treatment by 2015. We calculated global and regional estimates of syphilis in pregnancy and associated adverse outcomes for 2008, as well as antenatal care (ANC) coverage for women with syphilis.
Methods and Findings
Estimates were based upon a health service delivery model. National syphilis seropositivity data from 97 of 193 countries and ANC coverage from 147 countries were obtained from World Health Organization databases. Proportions of adverse outcomes and effectiveness of screening and treatment were from published literature. Regional estimates of ANC syphilis testing and treatment were examined through sensitivity analysis. In 2008, approximately 1.36 million (range: 1.16 to 1.56 million) pregnant women globally were estimated to have probable active syphilis; of these, 80% had attended ANC. Globally, 520,905 (best case: 425,847; worst case: 615,963) adverse outcomes were estimated to be caused by maternal syphilis, including approximately 212,327 (174,938; 249,716) stillbirths (>28 wk) or early fetal deaths (22 to 28 wk), 91,764 (76,141; 107,397) neonatal deaths, 65,267 (56,929; 73,605) preterm or low birth weight infants, and 151,547 (117,848; 185,245) infected newborns. Approximately 66% of adverse outcomes occurred in ANC attendees who were not tested or were not treated for syphilis. In 2008, based on the middle case scenario, clinical services likely averted 26% of all adverse outcomes. Limitations include missing syphilis seropositivity data for many countries in Europe, the Mediterranean, and North America, and use of estimates for the proportion of syphilis that was “probable active,” and for testing and treatment coverage.
Syphilis continues to affect large numbers of pregnant women, causing substantial perinatal morbidity and mortality that could be prevented by early testing and treatment. In this analysis, most adverse outcomes occurred among women who attended ANC but were not tested or treated for syphilis, highlighting the need to improve the quality of ANC as well as ANC coverage. In addition, improved ANC data on syphilis testing coverage, positivity, and treatment are needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Syphilis—a sexually transmitted bacterial infection caused by Treponema pallidum—can pass from a mother who is infected to her unborn child. Screening pregnant women for syphilis during routine antenatal care by looking for a reaction to T. pallidum in the blood (seropositivity) and then treating any detected infections with penicillin injections has been feasible for many years, even in low-resource settings. However, because coverage of testing and treatment of syphilis remains low in many countries, mother-to-child transmission of syphilis—“congenital syphilis”—is still a global public health problem. In 2007, the World Health Organization (WHO) estimated that there were 2 million syphilis infections among pregnant women annually, 65% of which resulted in adverse pregnancy outcomes: the baby's death during early or late pregnancy (fetal death and stillbirth, respectively) or soon after birth (neonatal death), or the birth of an infected baby. Babies born with syphilis often have a low birth weight and develop problems such as blindness, deafness, and seizures if not treated.
Why Was This Study Done?
In 2007, WHO launched an initiative to eliminate congenital syphilis that set targets of at least 90% of pregnant women being tested for syphilis and at least 90% of seropositive pregnant women receiving adequate treatment by 2015. To assess the initiative's progress and to guide policy and advocacy efforts, accurate global data on the burden of syphilis in pregnancy and on associated adverse outcomes are needed. Unfortunately, even in developed countries with good laboratory facilities, definitive diagnosis of congenital syphilis is difficult. Estimates of the global burden can be obtained, however, using mathematical models. In this study, the researchers generate global and regional estimates of the burden of syphilis in pregnancy and associated adverse outcomes for 2008 using a health services delivery model.
What Did the Researchers Do and Find?
The researchers developed a mathematical model to estimate the number of syphilis-infected pregnant women in each country and in each region, and to estimate the regional and global numbers of adverse pregnancy outcomes associated with syphilis. They used national syphilis seropositivity data and information on antenatal care coverage from WHO and estimates of the effectiveness of screening and treatment from published literature. Using these data and their model, the researchers estimated that, in 2008, 1.4 million pregnant women, 80% of whom had attended antenatal care services, had an active syphilis infection. Assuming a scenario in which the percentage of pregnant women tested for syphilis and adequately treated ranged from 30% for Africa and the Mediterranean region to 70% for Europe (a scenario defined in consultation with WHO advisors), the researchers estimated that maternal syphilis caused 520,000 adverse outcomes in 2008, including 215,000 stillbirths or fetal deaths, 90,000 neonatal deaths, 65,000 preterm or low birth weight infants, and 150,000 infants with congenital disease. About 66% of these adverse effects occurred in women who had attended antenatal care but were either not tested or not treated for syphilis. Finally, the researchers estimated that in 2008, clinical services averted 26% of all adverse outcomes.
What Do These Findings Mean?
These findings, which update and extend previous estimates of the global burden of congenital syphilis, indicate that syphilis continues to affect a large number of pregnant women and their offspring. The current findings, which cannot be directly compared to previous estimates because of the different methodologies used, are likely to be affected by the accuracy of the data fed into the researchers' model. In particular, the data on the percentage of the population infected with syphilis in individual countries used in this study came from the HIV Universal Access reporting system and may not be nationally representative. Nevertheless, these findings suggest that syphilis continues to be an important cause of adverse outcomes of pregnancy, partly because pregnant women often do not receive syphilis screening and prompt treatment during routine antenatal care. The researchers recommend, therefore, that all countries should ensure that all pregnant women receive an essential package of high-quality antenatal care services that includes routine and easy access to syphilis testing and treatment. Congenital syphilis, they conclude, can only be eliminated if decision-makers at all levels prioritize the provision, quality, and monitoring of this basic antenatal care service, which has the potential to reduce infant mortality and improve maternal health.
Additional Information
Please access these websites via the online version of this summary at
The World Health Organization provides information on sexually transmitted diseases, including details of its strategy for the global elimination of congenital syphilis, the investment case for the elimination of mother-to-child transmission of syphilis, and regional updates on progress towards elimination (some information is available in several languages)
The Pan American Health Organization provides information on efforts to eliminate congenital syphilis in Latin America (in English and Spanish), and the Asia-Pacific Prevention of Parent-to-Child Transmission Task Force provides information on efforts to eliminate congenital syphilis in Asia Pacific
The US Centers for Disease Control and Prevention has a fact sheet on syphilis (in English and Spanish)
The UK National Health Service Choices website also has a page on syphilis
MedlinePlus provides information on congenital syphilis and links to additional syphilis resources (in English and Spanish)
The London School of Hygiene and Tropical Medicine provides a toolkit for the introduction of rapid syphilis tests
Haiti: Congenital Syphilis on the Way Out is a YouTube video describing the introduction of rapid diagnostic tests for syphilis in remote parts of Haiti
PMCID: PMC3582608  PMID: 23468598
2.  Congenital syphilis in the Russian Federation: magnitude, determinants, and consequences 
Sexually Transmitted Infections  2003;79(2):106-110.
Objectives: Reported cases of congenital syphilis in the Russian Federation increased 26-fold from 1991–9. Our objectives were to describe the frequency, risk factors, and consequences of delivering an infant with congenital syphilis among pregnant women with active syphilis.
Methods: In a retrospective record review using consecutive sampling of logs at maternity hospitals in five geographic areas, data were abstracted for 850 women with active syphilis during pregnancy who had completed ≥20 weeks' gestation. Further information was abstracted from records in antenatal clinics, dermatovenereology clinics, and paediatric hospitals. We assessed the frequency of confirmed or probable congenital syphilis, used logistic modelling to identify independent predictors for delivering a baby with congenital syphilis, and calculated the proportion of infants with congenital syphilis who experienced late fetal death (20–27 weeks), stillbirth (≥28 weeks), or infant death.
Results: A total of 64% (n=544) of 850 pregnant syphilis infected women delivered an infant with confirmed or probable congenital syphilis; 40% of the sample had no prenatal care. Among women with no prenatal care, 77% received either no treatment or inadequate treatment and 86% delivered an infant with congenital syphilis. Important independent and modifiable risk factors for delivery of an infant with congenital syphilis included receiving no prenatal care (adjusted OR 2.8, 95% CI 1.7 to 4.7) and having the first test for syphilis at ≥28 weeks' gestation (adjusted OR 4.0, 95% CI 2.6 to 6.0). Fatal outcomes were observed in 26% of infants with congenital syphilis, including late fetal death (7%), stillbirth (16%), or neonatal death (3%).
Conclusions: In the Russian Federation, the frequency of congenital syphilis is high, risk factors for congenital syphilis are modifiable, and the consequences of congenital syphilis are severe.
PMCID: PMC1744638  PMID: 12690129
3.  Syphilis intervention in pregnancy: Zambian demonstration project. 
Genitourinary Medicine  1990;66(3):159-164.
Despite availability of simpler serologic tests for syphilis and near cure with penicillin, unacceptably high prevalence of infectious maternal syphilis exist in many developing countries, including Zambia. It is the foremost risk factor for mid-trimester abortions, stillbirths, prematurity and morbidity and mortality among infants born with congenital syphilis in Zambia. An intervention project was conducted in Lusaka aimed at demonstrating the effectiveness of new health education methods and prenatal screening for syphilis in reducing the adverse outcomes during pregnancy. During pre-intervention phase, approximately 150 consecutive pregnant women from each of the three study and the three control centres were recruited when they presented in labour at the University Teaching Hospital. The intervention phase lasted for one year at the three study centres during which new methods of health education were introduced to improve early attendances during pregnancy. Also, on-site syphilis screening was performed twice during pregnancy and seroreactive women, and in many cases their sexual partners, were treated by the existing prenatal clinic staff. During the post-intervention phase the steps of pre-intervention phase were repeated to evaluate the impact of intervention. Overall, 8.0% of women were confirmed seroreactive for syphilis; there was no difference between the study and the control centres (p greater than 0.05). Fifty seven percent (132/230) of syphilitic pregnancies ended with an adverse outcome, that is, abortion (RR 5.0), stillbirth (RR 3.6), prematurity (RR 2.6) and low birth weight (RR 7.8). The overall risk of adverse outcomes due to syphilis was 8.29 (95% confidence interval 6.53, 10.53). The new methods of health education were effective and the percentage of women who had their first prenatal visit under 16 weeks of gestation improved from 9.4 to 42.5. Although screening and treatment during intervention was suboptimal, the adverse outcomes attributable to syphilis were reduced to 28.3%; this is almost a two-third reduction when compared with 72.4% of adverse outcomes at control centres (p < less than 0.001). The intervention is culturally and politically acceptable in Zambia. The cost of each prenatal screening is US$0.60 and of averting each adverse outcome US$12. In countries with high rates of syphilis, there is an urgent need for STD control and Maternal and Child Health (MCH) programmes to pool their resources together to revitalise the prenatal care.
PMCID: PMC1194495  PMID: 2370060
4.  Cost-Effectiveness of Rapid Syphilis Screening in Prenatal HIV Testing Programs in Haiti 
PLoS Medicine  2007;4(5):e183.
New rapid syphilis tests permit simple and immediate diagnosis and treatment at a single clinic visit. We compared the cost-effectiveness, projected health outcomes, and annual cost of screening pregnant women using a rapid syphilis test as part of scaled-up prenatal testing to prevent mother-to-child HIV transmission in Haiti.
Methods and Findings
A decision analytic model simulated health outcomes and costs separately for pregnant women in rural and urban areas. We compared syphilis syndromic surveillance (rural standard of care), rapid plasma reagin test with results and treatment at 1-wk follow-up (urban standard of care), and a new rapid test with immediate results and treatment. Test performance data were from a World Health Organization–Special Programme for Research and Training in Tropical Diseases field trial conducted at the GHESKIO Center Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes in Port-au-Prince. Health outcomes were projected using historical data on prenatal syphilis treatment efficacy and included disability-adjusted life years (DALYs) of newborns, congenital syphilis cases, neonatal deaths, and stillbirths. Cost-effectiveness ratios are in US dollars/DALY from a societal perspective; annual costs are in US dollars from a payer perspective. Rapid testing with immediate treatment has a cost-effectiveness ratio of $6.83/DALY in rural settings and $9.95/DALY in urban settings. Results are sensitive to regional syphilis prevalence, rapid test sensitivity, and the return rate for follow-up visits. Integrating rapid syphilis testing into a scaled-up national HIV testing and prenatal care program would prevent 1,125 congenital syphilis cases and 1,223 stillbirths or neonatal deaths annually at a cost of $525,000.
In Haiti, integrating a new rapid syphilis test into prenatal care and HIV testing would prevent congenital syphilis cases and stillbirths, and is cost-effective. A similar approach may be beneficial in other resource-poor countries that are scaling up prenatal HIV testing.
Analyzing data from Haiti, Bruce Schackman and colleagues report that scale-up of prenatal HIV testing programs provides a cost-effective opportunity to prevent congenital syphilis through rapid testing.
Editors' Summary
Congenital syphilis (syphilis that is passed on from a woman infected with the disease to her unborn baby) is a major preventable public health problem. Around half of all pregnancies among women infected with syphilis result in stillbirth or death of the baby shortly after birth. However, it should be possible to reduce the health burden of congenital syphilis if infections among pregnant women could be quickly and accurately diagnosed. In resource-poor countries, many syphilis infections go undiagnosed, because the tests that are normally used involve sending samples away to a laboratory for processing. This means that the diagnosis can only be confirmed, and treatment started, at the next available visit. As a result, there is a delay in starting antibiotic treatment, and some women may never receive their intended treatment at all if they cannot return for their follow-up visit. However, new tests are available that don't involve cold storage of reagents or electrical equipment, and these can be used to give an immediate result about syphilis infection even in rural or resource-poor settings. Currently, global initiatives are underway to ensure many more pregnant women are tested for HIV and to reduce the risk of HIV being passed on from a woman to her baby. These initiatives could provide an important opportunity for carrying out widespread immediate screening for syphilis during pregnancy as well. Such screening might then help reduce infant deaths substantially.
Why Was This Study Done?
Field trials evaluating rapid syphilis tests have already been carried out by the World Health Organization's Special Programme for Research and Training in Tropical Diseases. One such trial, carried out in Port-au-Prince, Haiti, evaluated the success of three different rapid syphilis tests as compared to two “gold standard” tests (older tests that are generally considered reliable, but which don't give an immediate result). These researchers wanted to use data from these trials to compare costs and predicted health outcomes of including different types of syphilis screening as part of scaled-up prenatal care. Specifically, the researchers wanted to find out whether including rapid syphilis testing as part of universal prenatal care would be cost-effective and whether it would reduce the rate of stillbirths and congenital syphilis.
What Did the Researchers Do and Find?
This research was based on data from the field trials previously carried out in Haiti. The data from these trials were used to create a model comparing three different strategies for screening pregnant women for syphilis infections. The three strategies were as follows: checking for the symptoms of syphilis (assumed to be the standard of care in rural areas); standard testing for antibody response to the syphilis bacterium, after which treatment can be provided at follow-up a week later (assumed to be the standard of care in urban areas); and, finally, rapid testing that gives an immediate result. For each strategy, the researchers predicted what the health outcomes would be. These outcomes are summarized in “disability-adjusted life years” (DALYs) that reflect the number of years of healthy life lost due to congenital syphilis among newborn babies, the number of stillbirths, and the number of neonatal deaths. Cost-effectiveness of each strategy was also worked out by dividing the additional costs of testing and treatment for each strategy by the number of DALYs avoided using that screening method compared to the next most expensive alternative. Under the model, urban and rural settings were looked at separately. Immediate testing was more expensive than either standard testing or checking for symptoms, but emerged as more cost-effective than standard testing in rural settings; the immediate test would cost an additional $7–$10 per disability-adjusted life year compared to the current rural or urban standard of care. The researchers predicted that if immediate syphilis testing were provided to all pregnant women in Haiti who currently have access to prenatal care, over 1,000 congenital syphilis cases would be avoided, along with over 1,000 stillbirths and neonatal deaths, at a yearly cost of $525,000.
What Do These Findings Mean?
This model suggests that including rapid syphilis testing as part of current global initiatives for preventing mother-to-child transmission of HIV could substantially reduce infant deaths. The strategy is also likely to be cost-effective.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia entry on congenital syphilis
Information from the World Health Organization about congenital syphilis, including information about screening programs and new screening tests
A report is also available from the Special Programme for Research and Training in Tropical Diseases regarding rapid syphilis tests
AVERT, an international AIDS charity, provides information about preventing mother-to-child transmission of HIV
PMCID: PMC1880854  PMID: 17535105
5.  Prioritizing Congenital Syphilis Control in South China: A Decision Analytic Model to Inform Policy Implementation 
PLoS Medicine  2013;10(1):e1001375.
Nicholas Tan and colleagues use a decision analytic model to quantify the impact of the ten-year national syphilis control plan in China and conclude that earlier and more extensive screening are also necessary for reaching policy goals.
Syphilis is a major public health problem in many regions of China, with increases in congenital syphilis (CS) cases causing concern. The Chinese Ministry of Health recently announced a comprehensive 10-y national syphilis control plan focusing on averting CS. The decision analytic model presented here quantifies the impact of the planned strategies to determine whether they are likely to meet the goals laid out in the control plan.
Methods and Findings
Our model incorporated data on age-stratified fertility, female adult syphilis cases, and empirical syphilis transmission rates to estimate the number of CS cases associated with prenatal syphilis infection on a yearly basis. Guangdong Province was the focus of this analysis because of the availability of high-quality demographic and public health data. Each model outcome was simulated 1,000 times to incorporate uncertainty in model inputs. The model was validated using data from a CS intervention program among 477,656 women in China. Sensitivity analyses were performed to identify which variables are likely to be most influential in achieving Chinese and international policy goals. Increasing prenatal screening coverage was the single most effective strategy for reducing CS cases. An incremental increase in prenatal screening from the base case of 57% coverage to 95% coverage was associated with 106 (95% CI: 101, 111) CS cases averted per 100,000 live births (58% decrease). The policy strategies laid out in the national plan led to an outcome that fell short of the target, while a four-pronged comprehensive syphilis control strategy consisting of increased prenatal screening coverage, increased treatment completion, earlier prenatal screening, and improved syphilis test characteristics was associated with 157 (95% CI: 154, 160) CS cases averted per 100,000 live births (85% decrease).
The Chinese national plan provides a strong foundation for syphilis control, but more comprehensive measures that include earlier and more extensive screening are necessary for reaching policy goals.
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, 1.5 million pregnant women are infected with syphilis, a bacterial infection that is usually transmitted during sexual contact but that can also pass from a mother to her unborn child. In many of these women, the disease is detected through routine antenatal testing and is successfully treated with penicillin. But among those women who are not treated, about half experience adverse outcomes—the death of their baby during early or late pregnancy (fetal death and stillbirth, respectively) or soon after birth (neonatal death), or the birth of an infected baby. Babies born with syphilis (congenital syphilis) often fail to thrive and can develop problems such as blindness, deafness, and seizures if not treated. In 2008, syphilis in pregnancy contributed to 305,000 fetal deaths, stillbirths, and neonatal deaths, and 215,000 babies were affected by other adverse consequences of congenital syphilis. Yet congenital syphilis is simple and cheap to eliminate—a few injections of penicillin can clear the infection in a pregnant woman, and screening all pregnant women for syphilis is feasible even in low-resource settings.
Why Was This Study Done?
Congenital syphilis has recently reemerged in China. In the 1990s, there were very few cases of congenital syphilis in China, but by 2009, the reported incidence of congenital syphilis had risen to 139 cases per 100,000 live births. In 2010 the Chinese Ministry of Health announced a ten-year National Syphilis Prevention and Control Plan (NSCP) that, in line with World Health Organization (WHO) recommendations, aims to reduce the incidence of congenital syphilis to fewer than 30 cases per 100,000 live births by 2015 and to fewer than 15 cases per 100,000 live births by 2020. China's strategy for achieving these targets includes increasing prenatal syphilis screening coverage to 80% in urban areas and 60% in rural areas, increasing treatment rates among infected women to 90% in urban areas and 70% in rural areas, and increasing syphilis awareness among adults. But will this strategy be sufficient? Here, the researchers develop a mathematical model to quantify the likely impact of the NSCP's strategy on the incidence of congenital syphilis in southern China.
What Did the Researchers Do and Find?
The researchers developed a decision analytic model in which women move through a sequence of health states from uninfected, through infection and pregnancy, and to the development of congenital syphilis, and fed data collected in Guangdong Province between 2005 and 2008 on women's fertility, female syphilis cases, and syphilis transmission rates into the model. The researchers checked that their model provided estimates of the incidence of congenital syphilis that matched the reported incidence for Guangdong Province (internal validation) and the reported incidence in a congenital syphilis intervention program in Shenzhen, Guangdong (external validation). They then used their model to identify which parts of the NSCP strategy are likely to have the greatest effect on the incidence of congenital syphilis. Increasing prenatal screening coverage was the single most effective strategy for the reduction of congenital syphilis, but neither this strategy alone nor implementation of the whole NPSC strategy achieved the plan's target outcomes. By contrast, a four-pronged approach (95% coverage of prenatal screening, 75% of screening during the first two-thirds of pregnancy, 95% treatment completion, and having an accurate screening test) reduced the estimated incidence of congenital syphilis cases to 27 per 100,000 live births.
What Do These Findings Mean?
These findings suggest that although the NSCP is a strong foundation for control of congenital syphilis in China, more comprehensive measures will be needed to reach the plan's policy goals. In particular, the findings suggest that earlier and more extensive screening will be needed to reduce the incidence of congenital syphilis to below 30 cases per 100,000 live births, WHO's benchmark for congenital syphilis control. The accuracy of these findings is limited by the assumptions included in the model and by the data fed into it. Moreover, because the data included in the model came from Guangdong Province, these findings may not apply elsewhere in China or in other countries. Nevertheless, this study illustrates the importance of using multi-pronged approaches to address the complex problem of congenital syphilis control and identifies some strategies that are likely to improve the control of this important public health problem.
Additional Information
Please access these websites via the online version of this summary at
The World Health Organization provides information on sexually transmitted infections, including details of its strategy for the global elimination of congenital syphilis, the investment case for the elimination of mother-to-child transmission of syphilis, and regional updates on progress towards elimination (some information is available in several languages)
The US Centers for Disease Control and Prevention has a fact sheet on syphilis
The UK National Health Service Choices website also has a page on syphilis
MedlinePlus provides information on congenital syphilis and links to additional syphilis resources (in English and Spanish)
Haiti: Congenital Syphilis on the Way Out is a YouTube video describing the introduction of rapid diagnostic tests for syphilis in remote parts of Haiti
PMCID: PMC3551934  PMID: 23349624
6.  Antenatal Syphilis Screening Using Point-of-Care Testing in Sub-Saharan African Countries: A Cost-Effectiveness Analysis 
PLoS Medicine  2013;10(11):e1001545.
Yukari Manabe and colleagues evaluate the cost-effectiveness and budget impact of antenatal syphilis screening for 43 countries in sub-Saharan Africa and estimate the impact of universal screening on averted stillbirths, neonatal deaths, congenital syphilis, and DALYs.
Please see later in the article for the Editors' Summary
Untreated syphilis in pregnancy is associated with adverse clinical outcomes for the infant. Most syphilis infections occur in sub-Saharan Africa (SSA), where coverage of antenatal screening for syphilis is inadequate. Recently introduced point-of-care syphilis tests have high accuracy and demonstrate potential to increase coverage of antenatal screening. However, country-specific cost-effectiveness data for these tests are limited. The objective of this analysis was to evaluate the cost-effectiveness and budget impact of antenatal syphilis screening for 43 countries in SSA and estimate the impact of universal screening on stillbirths, neonatal deaths, congenital syphilis, and disability-adjusted life years (DALYs) averted.
Methods and Findings
The decision analytic model reflected the perspective of the national health care system and was based on the sensitivity (86%) and specificity (99%) reported for the immunochromatographic strip (ICS) test. Clinical outcomes of infants born to syphilis-infected mothers on the end points of stillbirth, neonatal death, and congenital syphilis were obtained from published sources. Treatment was assumed to consist of three injections of benzathine penicillin. Country-specific inputs included the antenatal prevalence of syphilis, annual number of live births, proportion of women with at least one antenatal care visit, per capita gross national income, and estimated hourly nurse wages. In all 43 sub-Saharan African countries analyzed, syphilis screening is highly cost-effective, with an average cost/DALY averted of US$11 (range: US$2–US$48). Screening remains highly cost-effective even if the average prevalence falls from the current rate of 3.1% (range: 0.6%–14.0%) to 0.038% (range: 0.002%–0.113%). Universal antenatal screening of pregnant women in clinics may reduce the annual number of stillbirths by up to 64,000, neonatal deaths by up to 25,000, and annual incidence of congenital syphilis by up to 32,000, and avert up to 2.6 million DALYs at an estimated annual direct medical cost of US$20.8 million.
Use of ICS tests for antenatal syphilis screening is highly cost-effective in SSA. Substantial reduction in DALYs can be achieved at a relatively modest budget impact. In SSA, antenatal programs should expand access to syphilis screening using the ICS test.
Please see later in the article for the Editors' Summary
Editors' Summary
Syphilis is a sexually transmitted infection caused by a bacterium called Treponema pallidum. In many countries, the screening and treatment program for syphilis in pregnancy is inadequate, leading to babies being affected. It is estimated that between 2.5% and 17% of pregnant women in sub-Saharan Africa are infected with syphilis; recent estimates suggest that more than 535,000 pregnancies occur in women with active syphilis each year. Maternal syphilis in pregnancy has been estimated to cause approximately half a million adverse outcomes in babies, including stillbirths, neonatal deaths, preterm or low-birth-weight babies, and congenital infections. If a pregnant woman is tested, and given penicillin if positive, then many of these harmful outcomes can be avoided. The best time to screen and treat is in the first half of pregnancy.
Until recently, tests for syphilis were done in a laboratory as an enzyme immunoassay, requiring technical staff. Recently, rapid tests for syphilis became available for use at the point of care. There are considerable advantages to this approach: the tests can be undertaken using a finger prick to obtain a small amount of blood, and require minimal staff training and no specialist laboratory equipment. A result can be given within minutes, avoiding the need for a return visit in settings where antenatal care is infrequent.
Why Was This Study Done?
Although the advantages to the mother and baby of testing seem clear, the cost-effectiveness of a screening and treatment program using rapid point-of-care tests has not previously been assessed for most sub-Saharan African countries. The program has the greatest potential value in settings where syphilis is common. In local guidelines, testing is often recommended, but uncertainty over the costs and technical requirements has meant that antenatal syphilis screening has not been comprehensively introduced. The aim of this study was to assess whether antenatal syphilis screening was cost-effective for 43 countries in sub-Saharan Africa by estimating the extent of infant mortality and disability that could be prevented if maternal syphilis was diagnosed and treated.
What Did the Researchers Do and Find?
The researchers created a model that allowed them to determine the cost-effectiveness of antenatal syphilis screening and treatment. They included many factors including the performance of the test, how common syphilis is in each country, the number of births, the likelihood of harmful outcomes, the effectiveness of penicillin therapy, the cost of an antenatal visit, and the cost of the test and the penicillin treatment, if positive. Then they calculated how many deaths and how much disability could be prevented by screening and treatment. The results were expressed in disability-adjusted life years (DALYs), which give the number of years affected by ill health, disability, or early death. The study found that screening was highly cost-effective, with each DALY prevented on average costing only US$11.
What Do These Findings Mean?
Across sub-Saharan Africa, only about 40% of women are screened for syphilis during one of their antenatal care visits. These findings suggest that it would be an efficient use of health care resources to scale up antenatal screening programs for syphilis using the rapid point-of-care test. Comparing these results to those for other health care interventions in resource-limited settings suggests that screening pregnant women for syphilis in sub-Saharan Africa could achieve a substantial improvement in public health at relatively little cost. The researchers propose that combining HIV and syphilis tests into one antenatal screening package could be an efficient way of introducing a care package into settings where uptake is currently limited.
Additional Information
Please access these websites via the online version of this summary at
The World Health Organization provides information on syphilis in pregnant women
The London School of Hygiene & Tropical Medicine has information on efforts to reduce congenital syphilis and a rapid syphilis test toolkit
The US Centers for Disease Control and Prevention's STD Curriculum includes materials on syphilis
PMCID: PMC3818163  PMID: 24223524
7.  Syphilis in pregnancy 
Syphilis can seriously complicate pregnancy and result in spontaneous abortion, stillbirth, non-immune hydrops, intrauterine growth restriction, and perinatal death, as well as serious sequelae in liveborn infected children. While appropriate treatment of pregnant women often prevents such complications, the major deterrent has been inability to identify the infected women and get them to undergo treatment. Screening in the first trimester with non-treponemal tests such as rapid plasma reagin (RPR) or venereal disease research laboratory (VDRL) test combined with confirmation of reactive individuals with treponemal tests such as the fluorescent treponemal antibody absorption (FTA-ABS) assay is a cost effective strategy. Those at risk should be retested in the third trimester. Treatment during pregnancy should be with penicillin. In determining a penicillin regimen, the clinician must consider the stage of the maternal infection and the HIV status of the mother. Patients who are allergic to penicillin should be desensitised before treatment. Despite appropriate treatment, as many as 14% will have a fetal death or deliver infected infants. Treatment may further be complicated by the Jarich–Herxheimer reaction, a complex allergic response to antigens released from dead micro-organisms, which can cause fetal distress and uterine contractions. Thanks to effective intervention strategies and inexpensive penicillin, syphilis rarely complicates pregnancy in the Western world today. In parts of the world where the traditional sexually transmitted diseases have not been controlled, the magnitude of problems associated with syphilis during pregnancy is reminiscent of that faced by the West during the early 1900s.
Key Words: syphilis; pregnancy
PMCID: PMC1758294  PMID: 10858706
8.  Prenatal syphilis infection is a possible cause of preterm delivery among immigrant women from eastern Europe 
Sexually Transmitted Infections  2007;83(2):102-105.
To evaluate the prevalence of maternal syphilis at delivery and neonatal syphilis infection in an Italian urban area, in connection with the increased flow of immigration.
Study design
A prospective surveillance study was carried out in Bologna, Italy, from November 2000 to March 2006. All pregnant women were screened for syphilis at delivery. Infants born to seropositive mothers were enrolled in a prospective follow‐up.
During the study period 19 205 women gave birth to 19 548 infants. A total of 85 women were seropositive for syphilis at delivery. The overall syphilis seroprevalence in pregnant women was 0.44%, but it was 4.3% in women from eastern Europe and 5.8% in women from Central–South America. Ten women were first found positive at delivery, as they did not receive any prenatal care. Nine of these were from eastern Europe. All their infants were asymptomatic, but six had both reactive immunoglobulin (Ig)M western blot and rapid plasma reagin tests and were considered prenatally infected. Three of six were preterm (gestational age <37 weeks).
In Italy, congenital syphilis infection is strictly related to immigration from eastern Europe. Although it is asymptomatic, it could cause premature delivery. Therefore, it is necessary to perform serological tests during the third trimester in mothers coming from endemic areas to adequately treat syphilis in pregnancy and prevent congenital infection. If the mother's test results are not available at delivery, it is necessary to investigate the newborn, especially if it is born prematurely.
PMCID: PMC2598605  PMID: 17098768
9.  Prevalence of syphilis in pregnancy and prenatal syphilis testing in Brazil: Birth in Brazil study 
Revista de Saúde Pública  2014;48(5):766-774.
Determine the coverage rate of syphilis testing during prenatal care and the prevalence of syphilis in pregnant women in Brazil.
This is a national hospital-based cohort study conducted in Brazil with 23,894 postpartum women between 2011 and 2012. Data were obtained using interviews with postpartum women, hospital records, and prenatal care cards. All postpartum women with a reactive serological test result recorded in the prenatal care card or syphilis diagnosis during hospitalization for childbirth were considered cases of syphilis in pregnancy. The Chi-square test was used for determining the disease prevalence and testing coverage rate by region of residence, self-reported skin color, maternal age, and type of prenatal and child delivery care units.
Prenatal care covered 98.7% postpartum women. Syphilis testing coverage rate was 89.1% (one test) and 41.2% (two tests), and syphilis prevalence in pregnancy was 1.02% (95%CI 0.84;1.25). A lower prenatal coverage rate was observed among women in the North region, indigenous women, those with less education, and those who received prenatal care in public health care units. A lower testing coverage rate was observed among residents in the North, Northeast, and Midwest regions, among younger and non-white skin-color women, among those with lower education, and those who received prenatal care in public health care units. An increased prevalence of syphilis was observed among women with < 8 years of education (1.74%), who self-reported as black (1.8%) or mixed (1.2%), those who did not receive prenatal care (2.5%), and those attending public (1.37%) or mixed (0.93%) health care units.
The estimated prevalence of syphilis in pregnancy was similar to that reported in the last sentinel surveillance study conducted in 2006. There was an improvement in prenatal care and testing coverage rate, and the goals suggested by the World Health Organization were achieved in two regions. Regional and social inequalities in access to health care units, coupled with other gaps in health assistance, have led to the persistence of congenital syphilis as a major public health problem in Brazil.
PMCID: PMC4211581  PMID: 25372167
Syphilis Serodiagnosis; Pregnant Women; Prenatal Care; Socioeconomic Factors; Health Inequalities; Infectious Disease Transmission, Vertical
10.  Reported Estimates of Adverse Pregnancy Outcomes among Women with and without Syphilis: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(7):e102203.
To estimate probability of adverse pregnancy outcomes (APOs) among women with and without syphilis through a systematic review of published literatures.
Methodology/Principal Findings
Chinese and English literatures were searched for studies assessing pregnancy outcomes in the presence of maternal syphilis through August 2013. The prevalence estimates were summarized and analyzed by meta-analysis. Fifty-four literatures involving 11398 syphilitic women and 43342 non-syphilitic women were included from 4187 records initially found. Among untreated mothers with syphilis, pooled estimates were 76.8% for all APOs, 36.0% for congenital syphilis, 23.2% for preterm, 23.4% for low birth weight, 26.4% for stillbirth or fetal loss, 14.9% for miscarriage and 16.2% for neonatal deaths. Among syphilitic mother receiving treatment only in the late trimester (>28 weeks), pooled estimates were 64.4% for APOs, 40.6% for congenital syphilis, 17.6% for preterm, 12.4% for low birth weight, and 21.3% for stillbirth or fetal loss. Among syphilitic mothers with high titers (≥1∶8), pooled estimates were 42.8% for all APOs, 25.8% for congenital syphilis, 15.1% for preterm, 9.4% for low birth weight, 14.6% for stillbirth or fetal loss and 16.0% for neonatal deaths. Among non-syphilitic mothers, the pooled estimates were 13.7% for all APOs, 7.2% for preterm birth, 4.5% for low birth weight, 3.7% for stillbirth or fetal loss, 2.3% for miscarriage and 2.0% for neonatal death. Begg's rank correlation test indicated little evidence of publication bias (P>0.10). Substantial heterogeneity was found across studies in the estimates of all adverse outcomes for both women with syphilis (I2 = 93.9%; P<0.0001) and women without syphilis (I2 = 94.8%; P<0.0001).
Syphilis continues to be an important cause of substantial perinatal morbidity and mortality, which reminds that policy-makers charged with resource allocation that the elimination of mother-to-child transmission of syphilis is a public health priority.
PMCID: PMC4099012  PMID: 25025232
11.  Congenital syphilis in The Netherlands: cause and parental characteristics. 
Genitourinary Medicine  1988;64(5):298-302.
During 1982-5 the 19S (IgM) fluorescent treponemal antibody absorption (19S (IgM) FTA-ABS) test gave positive results in 19 children. The parental histories were analysed. As five of the children were adopted, 14 pregnancies were evaluated. Mothers of foreign origin and extramarital pregnancies were found to be over-represented. Of 13 women who attended for pregnancy checkup, three were not serologically screened for syphilis. In four the infection had developed late in the course of pregnancy. In at least four treatment had not been given or had been inadequate or too late. At least two had positive 19S (IgM) FTA-ABS test results that did not indicate congenital syphilis. The possibility of false positive 19S (IgM) FTA-ABS test results is pointed out. As the male sexual partners of four of the 14 mothers had presented elsewhere with early syphilis at the time of their partner's pregnancy, adequate contact tracing appears to be important to prevent congenital syphilis in future.
PMCID: PMC1194247  PMID: 3203930
12.  An IgM capture enzyme linked immunosorbent assay to detect IgM antibodies to treponemes in patients with syphilis. 
Genitourinary Medicine  1989;65(2):79-83.
A new IgM capture enzyme linked immunosorbent assay (ELISA) was compared with the 19S(IgM) fluorescent treponemal antibody absorption (19S(IgM)FTA-ABS) test for detecting IgM antibodies to treponemes. Serum samples from 180 people, 109 with various stages of untreated syphilis, 45 with treated syphilis, and 26 non-infected, were investigated. In all diagnostic groups of syphilis the reactivity of the IgM capture ELISA was similar to that of the 19S(IgM)FTA-ABS test except in untreated neurosyphilis, for which the IgM capture ELISA was significantly less sensitive. The IgM capture ELISA was very sensitive in congenital (100%, 5/5) and primary (82%, 18/22) syphilis, but less sensitive in secondary (60%, 12/20), latent (53%, 16/30), neurosyphilis (34%, 11/32), and treated (11%, 5/45) syphilis. False positive IgM capture ELISA results were not found in five people who gave false positive Venereal Disease Research Laboratory (VDRL) reactions or in 21 neonates born to mothers adequately treated for syphilis before or during pregnancy. This indicated that the IgM capture ELISA was very specific. The course of antitreponemal IgM reactivity after treatment of early infectious syphilis was followed up in six patients. The quantity of IgM antibody declined in nearly all patients after treatment, but still remained detectable in five patients up to six months after treatment. In contrast, non-treponemal antibodies measured by the VDRL test disappeared in four out of six patients within five months from starting treatment. In conclusion, the IgM capture ELISA may be useful for easy and sensitive detection of IgM antibodies to treponemes in patients with congenital and primary syphilis. A positive test result in these cases indicates that patients should receive treatment if they have not been treated recently. The test is not, however, recommended to replace the VDRL test to monitor patients treated for syphilis.
PMCID: PMC1194291  PMID: 2666303
13.  Serological screening tests for syphilis in pregnancy: results of a five year study (1983-87) in the Oxford region. 
Journal of Clinical Pathology  1989;42(12):1281-1284.
Between 1983 and 1987, 62 out of 76519 pregnancies in 51 mothers had a positive miniaturised Treponema pallidum haemagglutination assay (TPHA) test--1 in 1234, or 0.81 per 1000 births. About two thirds of these mothers had syphilis and the remainder non-venereal treponematoses such as yaws or pinta. Antenatal screening identified 13 patients with previously unknown acquired syphilis, 11 of whom were given antibiotics during pregnancy. There were six fetal losses among the 62 TPHA positive pregnancies, but none had evidence of congenital syphilis. No live born child in this study group showed stigmata of congenital syphilis. It is concluded that despite the current low incidence of syphilis in the United Kingdom it is imperative to continue antenatal serological screening and to emphasise the importance of early adequate treatment of the infection.
PMCID: PMC502058  PMID: 2515214
14.  Early congenital syphilis still occurs. 
Archives of Disease in Childhood  1985;60(12):1128-1133.
Seven cases of early congenital syphilis have been recorded in the past 10 years in the Mersey Regional Health Authority. Antenatal serology was initially negative in five mothers, who were either incubating or acquired the infection later, and treatment had probably failed in two women given erythromycin for syphilis during pregnancy. Serology should be repeated later in pregnancy in those at high risk. Social factors that define this group include women who book for antenatal care late in pregnancy, have a past history of sexually transmitted disease, and have multiple consorts. Clinical signs in the infant such as failure to thrive, hepatosplenomegaly, symmetrical rash, rhinitis, and osteochondritis should alert the clinician to the possibility of congenital syphilis. Adequate management of mother and baby requires close liaison between the genitourinary physician, microbiologist, obstetrician, and paediatrician. Penicillin remains the treatment of choice.
PMCID: PMC1777673  PMID: 3841473
15.  A Road Map for the Global Elimination of Congenital Syphilis 
Congenital syphilis is the oldest recognized congenital infection, and continues to account for extensive global perinatal morbidity and mortality today. Serious adverse pregnancy outcomes caused by maternal syphilis infection are prevented with screening early in pregnancy and prompt treatment of women testing positive. Intramuscular penicillin, an inexpensive antibiotic on the essential medicine list of nations all over the world, effectively cures infection and prevents congenital syphilis. In fact, at a cost of $11–15 per disability adjusted life year (DALY) averted, maternal syphilis screening and treatment is among the most cost-effective public health interventions in existence. Yet implementation of this basic public health intervention is sporadic in countries with highest congenital syphilis burden. We discuss the global burden of this devastating disease, current progress and ongoing challenges for its elimination in countries with highest prevalence, and next steps in ensuring a world free of preventable perinatal deaths caused by syphilis.
PMCID: PMC2913802  PMID: 20706693
16.  Retrospective Analysis of the Serologic Response to the Treatment of Syphilis During Pregnancy 
Objective: The purpose of this study was to assess the effect of several maternal variables on the serologic response following the treatment of syphilis in pregnancy.
Methods: A 5-year chart review identified 95 patients coded with syphilis at Hermann Hospital. Inclusion criteria were 1) serologically confirmed syphilis infection during the index pregnancy, 2) complete treatment during the index pregnancy, and 3) minimum of one follow-up rapid plasma reagin (RPR) titer. Forty-nine of 95 patients met the inclusion criteria. Treatment response was evaluated by comparing each post-treatment titer of a patient to her pretreatment titer. Each comparison was considered an “observation.” Each observation was classified as either a positive response (≥4-fold titer decline) or a negative response (<4-fold titer decline). Maternal variables assessed included 1) prior history of syphilis untreated or incompletely treated prior to the index pregnancy, 2) gestational age, 3) titer level, 4) unknown duration, 5) positive response at 1 month, 6) positive response at 2 months, 7) positive response at >3 months, and 8) race.
Results: A positive response following treatment was significantly more likely if there was no prior history of syphilis or if there was a high initial RPR titer (>32). Only 33/54 (61%) observations at or greater than 3 months had a positive response.
Conclusions: Our study suggests that an absence of a history of syphilis and an initial high RPR titer are predictive of a positive response following appropriate treatment. Given the low percentage of observations with a positive response at 3 months, we speculate that we may be undertreating our pregnant patients with syphilis infection.
PMCID: PMC2364528  PMID: 18476130
17.  Congenital syphilis in newborn rabbits: immune functions and susceptibility to challenge infection at 2 and 5 weeks of age. 
Infection and Immunity  1991;59(5):1869-1871.
Experiments were performed to further elaborate on our congenital syphilis rabbit model. Attempts were made to determine whether in utero exposure to Treponema pallidum would stimulate immune reactivity and whether this activity would, in turn, affect lesion development upon challenge infection. Newborn rabbits aged 2 or 5 weeks were obtained from control does or from does infected intravenously with T. pallidum during pregnancy. Congenitally infected newborns exhibited increased immunologic functions. Concanavalin A-induced T-lymphocyte proliferation was elevated at both 2 and 5 weeks. In addition, macrophage Ia expression and RPR antibody titers were increased at 5 weeks. In separate experiments, newborn rabbits from control does or from does infected during pregnancy were challenged intradermally with viable organisms at either 2 or 5 weeks of age. Subsequent lesion severity was markedly increased in those newborns previously exposed to treponemes in utero. These observations further strengthen our model for congenital transmission of T. pallidum during pregnancy. We propose that at least some of the tissue pathology in syphilitic infection is associated with activated host defenses.
PMCID: PMC257930  PMID: 2019448
18.  Syphilis in pregnant women in Zambia. 
Because of the high incidence of congenital syphilis at the University Teaching Hospital, Lusaka, Zambia, the potential risks of congenital infection and fetal loss due to syphilis were assessed by screening 202 antenatal patients, 340 pregnant women admitted to the hospital whose pregnancies ended in either spontaneous abortion or stillbirth, and 469 consecutive babies delivered at the hospital. Primary serological screening was performed with the rapid plasma reagin test, and reactive sera were confirmed by the Treponema pallidum haemagglutination test. In all cases detailed histories were obtained and patients were examined for clinical signs of syphilis. The TPHA test result was reactive in 12.5% of antenatal patients and in 42% of women who aborted in the later half of pregnancy. Among 469 consecutive babies delivered at the hospital, 30 had reactive results to the TPHA test; of these two were stillborn and four had signs of congenital syphilis at birth. Thus, syphilis appears to affect adversely an appreciably high number of pregnant women in Zambia. For this reason a special campaign to screen adequately and treat pregnant women and neonates is needed.
PMCID: PMC1046100  PMID: 6756542
19.  Laboratory diagnosis and interpretation of tests for syphilis. 
The lack of a method for demonstrating the presence of Treponema pallidum by growth necessitates the use of alternative methods. Traditionally, these methods are divided into direct detection methods (animal inoculation, dark-field microscopy, etc.) and serologic tests for the presence of patient antibody against T. pallidum. Serologic methods are further divided into two classes. One class, the nontreponemal tests, detects antibodies to lipoidal antigens present in either the host or T. pallidum; examples are the Venereal Disease Research Laboratory and rapid plasma reagin and tests. Reactivity in these tests generally indicates host tissue damage that may not be specific for syphilis. Because these tests are easy and inexpensive to perform, they are commonly used for screening, and with proper clinical signs they are suggestive of syphilis. The other class of test, the treponemal tests, uses specific treponemal antigens. Confirmation of infection requires a reactive treponemal test. Examples of the treponemal tests are the microhemagglutination assay for antibodies to T. pallidum and the fluorescent treponemal antibody absorption test. These tests are more expensive and complicated to perform than the nontreponemal tests. On the horizon are a number of direct antigen, enzyme-linked immunosorbent assay, and PCR techniques. Several of these techniques have shown promise in clinical trials for the diagnosis of congenital syphilis and neurosyphilis that are presently difficult to diagnose.
PMCID: PMC172846  PMID: 7704889
20.  Syphilis in pregnant women and their children in the United Kingdom: results from national clinician reporting surveys 1994-7 
BMJ : British Medical Journal  1998;317(7173):1617-1619.
To measure the incidence of syphilis detected in pregnancy and congenital syphilis in the United Kingdom.
Surveys through consultants in genitourinary medicine and paediatricians with active surveillance.
United Kingdom, 1994-7.
Women treated for syphilis in pregnancy, and children with early congenital syphilis born in the United Kingdom.
Over 3 years 139 women were diagnosed with and treated for syphilis in pregnancy; 121 were detected through antenatal screening. Thirty one had confirmed or probable congenitally transmissible syphilis, putting their pregnancies at risk. These were minimum figures but are compatible with the 90 to 100 women newly diagnosed annually as having infectious or early latent syphilis. A universal screening policy would require 18 600 and 55 700 women (maximum numbers) to be screened, respectively, to detect one woman needing treatment and to prevent one case of congenital syphilis. Nine presumptive cases of children with congenital syphilis born in the United Kingdom were reported. Mothers requiring treatment for syphilis were found in almost every health region but were more prevalent in London and the south east. Being born abroad and belonging to an ethnic minority group were strong risk factors, but 14% (19 of 121) of cases treated and six of 31 definite or probably transmissible cases occurred in white women born in the United Kingdom.
Congenitally transmissible syphilis continues to occur among pregnant women in the United Kingdom. Cases would be missed and stillbirths and congenitally infected babies would occur if antenatal screening was abandoned.
Key messagesInfectious syphilis and other forms of congenitally transmissible syphilis continue to be found among pregnant women in the United KingdomNew cases of infectious syphilis are being detected through antenatal screeningRisk factors for infectious syphilis in pregnant women comprise living in London and the south east, belonging to an ethnic minority group, and having been born abroadA substantial minority of mothers with congenitally transmissible syphilis also occur among white women born in the United KingdomAbandonment of universal screening for syphilis would probably result in stillbirths and cases of congenital syphilis
PMCID: PMC28738  PMID: 9848899
21.  Prenatal Treatment for Serious Neurological Sequelae of Congenital Toxoplasmosis: An Observational Prospective Cohort Study 
PLoS Medicine  2010;7(10):e1000351.
An observational study by Ruth Gilbert and colleagues finds that prenatal treatment of congenital toxoplasmosis could substantially reduce the proportion of infected fetuses that develop serious neurological sequelae.
The effectiveness of prenatal treatment to prevent serious neurological sequelae (SNSD) of congenital toxoplasmosis is not known.
Methods and Findings
Congenital toxoplasmosis was prospectively identified by universal prenatal or neonatal screening in 14 European centres and children were followed for a median of 4 years. We evaluated determinants of postnatal death or SNSD defined by one or more of functional neurological abnormalities, severe bilateral visual impairment, or pregnancy termination for confirmed congenital toxoplasmosis. Two-thirds of the cohort received prenatal treatment (189/293; 65%). 23/293 (8%) fetuses developed SNSD of which nine were pregnancy terminations. Prenatal treatment reduced the risk of SNSD. The odds ratio for prenatal treatment, adjusted for gestational age at maternal seroconversion, was 0.24 (95% Bayesian credible intervals 0.07–0.71). This effect was robust to most sensitivity analyses. The number of infected fetuses needed to be treated to prevent one case of SNSD was three (95% Bayesian credible intervals 2–15) after maternal seroconversion at 10 weeks, and 18 (9–75) at 30 weeks of gestation. Pyrimethamine-sulphonamide treatment did not reduce SNSD compared with spiramycin alone (adjusted odds ratio 0.78, 0.21–2.95). The proportion of live-born infants with intracranial lesions detected postnatally who developed SNSD was 31.0% (17.0%–38.1%).
The finding that prenatal treatment reduced the risk of SNSD in infected fetuses should be interpreted with caution because of the low number of SNSD cases and uncertainty about the timing of maternal seroconversion. As these are observational data, policy decisions about screening require further evidence from a randomized trial of prenatal screening and from cost-effectiveness analyses that take into account the incidence and prevalence of maternal infection.
Please see later in the article for the Editors' Summary
Editors' Summary
Toxoplasmosis is a very common parasitic infection. People usually become infected with Toxoplasma gondii, the parasite that causes toxoplasmosis, by eating raw or undercooked meat that contains the parasite, but it can also be contracted by drinking unfiltered water or by handling cat litter. Most people with toxoplasmosis never know they have the disease. However, if a pregnant woman becomes infected with T. gondii, she can transmit the parasite to her unborn baby (fetus). Overall, about a quarter of women who catch toxoplasmosis during pregnancy transmit the parasite to their fetus. If transmission occurs early during pregnancy, the resultant “congenital toxoplasmosis” increases the risk of miscarriage and the risk of the baby being born with brain damage, epilepsy, deafness, blindness, or developmental problems (“serious neurological sequelae”). In the worst cases, babies may be born dead or die soon after birth. Congenital toxoplasmosis caught during the final third of pregnancy may not initially cause any health problems but eyesight problems often develop later in life.
Why Was This Study Done?
Clinicians can find out if a woman has been infected with T. gondii during pregnancy by looking for parasite-specific antibodies (proteins made by the immune system that fight infections) in her blood. If the pattern of antibodies suggests a recent infection, the woman can be given spiramycin or pyrimethamine-sulfonamide, antibiotics that are thought to reduce the risk of transmission to the fetus and the severity of toxoplasmosis in infected fetuses. In some countries where toxoplasmosis is particularly common (for example, France), pregnant women are routinely screened for toxoplasmosis and treated with antibiotics if there are signs of recent infection. But is prenatal treatment an effective way to prevent the serious neurological sequelae or postnatal death (SNSD) associated with congenital toxoplasmosis? In this observational study, the researchers examine this question by studying a group of children identified as having congenital toxoplasmosis by prenatal or neonatal screening in six European countries. An observational study measures outcomes in a group of patients without trying to influence those outcomes by providing a specific treatment.
What Did the Researchers Do and Find?
The researchers followed 293 children in whom congenital toxoplasmosis had been identified by prenatal screening (in France, Austria, and Italy) or by neonatal screening (in Denmark, Sweden, and Poland) for an average 4 years. Two-thirds of the children received prenatal treatment for toxoplasmosis and 23 fetuses (8% of the fetuses) developed SNSD; nine of these cases of SNSD were terminated during pregnancy. By comparing the number of cases of SNSD among children who received prenatal treatment with the number among children who did not receive prenatal treatment, the researchers estimate that prenatal treatment reduced the risk of SNSD by three-quarters. They also estimate that to prevent one case of SNSD after maternal infection at 10 weeks of pregnancy, it would be necessary to treat three fetuses with confirmed infection. To prevent one case of SNSD after maternal infection at 30 weeks of pregnancy, 18 fetuses would need to be treated. Finally, the researchers report that the effectiveness of pyrimethamine-sulfonamide and spiramycin (which is less toxic) was similar, and that a third of live-born infants with brain damage that was detected after birth subsequently developed SNSD.
What Do These Findings Mean?
These findings suggest that prenatal treatment of congenital toxoplasmosis could substantially reduce the proportion of infected fetuses that develop SNDS and would be particularly effective in fetuses whose mothers acquired T. gondii during the first third of pregnancy. These findings should be interpreted with caution, however, because of the small number of affected fetuses in the study and because of uncertainty about the timing of maternal infection. Furthermore, these findings only relate to the relatively benign strain of T. gondii that predominates in Europe and North America; further studies are needed to test whether prenatal treatment is effective against the more virulent strains of the parasite that occur in South America. Finally, because this study is an observational study, its findings might reflect differences between the study participants other than whether or not they received prenatal treatment. These findings need to be confirmed in randomized controlled trials of prenatal screening, therefore, before any policy decisions are made about routine prenatal screening and treatment for congenital toxoplasmosis.
Additional Information
Please access these Web sites via the online version of this summary at
The US Centers for Disease Control and Prevention provides detailed information about all aspects of toxoplasmosis, including toxoplasmosis in pregnant women (in English and Spanish)
The UK National Health Services Choices website has information for patients about toxoplasmosis and about the risks of toxoplasmosis during pregnancy
KidsHealth, a resource maintained by the Nemours Foundation (a not-for-profit organization for children's health), provides information for parents about toxoplasmosis (in English and Spanish)
Tommy's, a nonprofit organization that funds research on the health of babies, also has information on toxoplasmosis
MedlinePlus provides links to other information on toxoplasmosis (in English and Spanish)
EUROTOXO contains reports generated by a European consensus development project
Uptodate provides information about toxoplasmosis and pregnancy
PMCID: PMC2953528  PMID: 20967235
22.  Immune Evasion and Recognition of the Syphilis Spirochete in Blood and Skin of Secondary Syphilis Patients: Two Immunologically Distinct Compartments 
The clinical syndrome associated with secondary syphilis (SS) reflects the propensity of Treponema pallidum (Tp) to escape immune recognition while simultaneously inducing inflammation.
To better understand the duality of immune evasion and immune recognition in human syphilis, herein we used a combination of flow cytometry, immunohistochemistry (IHC), and transcriptional profiling to study the immune response in the blood and skin of 27 HIV(-) SS patients in relation to spirochetal burdens. Ex vivo opsonophagocytosis assays using human syphilitic sera (HSS) were performed to model spirochete-monocyte/macrophage interactions in vivo.
Despite the presence of low-level spirochetemia, as well as immunophenotypic changes suggestive of monocyte activation, we did not detect systemic cytokine production. SS subjects had substantial decreases in circulating DCs and in IFNγ-producing and cytotoxic NK-cells, along with an emergent CD56−/CD16+ NK-cell subset in blood. Skin lesions, which had visible Tp by IHC and substantial amounts of Tp-DNA, had large numbers of macrophages (CD68+), a relative increase in CD8+ T-cells over CD4+ T-cells and were enriched for CD56+ NK-cells. Skin lesions contained transcripts for cytokines (IFN-γ, TNF-α), chemokines (CCL2, CXCL10), macrophage and DC activation markers (CD40, CD86), Fc-mediated phagocytosis receptors (FcγRI, FcγR3), IFN-β and effector molecules associated with CD8 and NK-cell cytotoxic responses. While HSS promoted uptake of Tp in conjunction with monocyte activation, most spirochetes were not internalized.
Our findings support the importance of macrophage driven opsonophagocytosis and cell mediated immunity in treponemal clearance, while suggesting that the balance between phagocytic uptake and evasion is influenced by the relative burdens of bacteria in blood and skin and the presence of Tp subpopulations with differential capacities for binding opsonic antibodies. They also bring to light the extent of the systemic innate and adaptive immunologic abnormalities that define the secondary stage of the disease, which in the skin of patients trends towards a T-cell cytolytic response.
Author Summary
Syphilis, a sexually transmitted disease caused by the spirochetal bacterium Treponema pallidum, affects close to 10 million people per year worldwide. Despite the robust nature of the humoral and cellular immune responses associated with the disease, weeks to months may elapse before the host gains control of the infection. Moreover, in the absence of antibiotic treatment, containment is often incomplete and relapses are common. Herein we studied aspects of the immune response in the blood and skin of patients with secondary syphilis to better understand the factors that determine whether the bacterium evades host defenses or is cleared in its natural human host. Our findings support the importance of the macrophage as a primary means of bacterial killing in the skin, while suggesting that the extent of bacterial clearance is determined by the bacterial loads present in either the blood or skin of patients and the appearance of spirochetes which are resistant to uptake (phagocytosis) by the macrophages. Study results underscore the extent of the systemic immunologic abnormalities triggered by the bacterium and provide new insights regarding the complexity of the immune response in the skin of untreated patients.
PMCID: PMC3398964  PMID: 22816000
23.  Congenital syphilis after treatment of maternal syphilis with a penicillin regimen exceeding CDC guidelines. 
BACKGROUND: Although congenital syphilis usually occurs as a result of a failure to detect and treat syphilis in pregnant women, failures of the currently recommended regimen to prevent congenital syphilis have been reported. CASE: This report describes an infant with congenital syphilis despite maternal treatment with a regimen exceeding current CDC guidelines. CONCLUSION: Regardless of the regimen used to treat syphilis during pregnancy, clinicians should recognize the possibility of occasional treatment failures and the importance of adequate follow-up of infants at risk for congenital syphilis.
PMCID: PMC1784788  PMID: 9785110
24.  Syphilis in adults 
Sexually Transmitted Infections  2005;81(6):448-452.
Syphilis is a sexually transmitted disease with protean manifestations resulting from infection by Treponema pallidum. It is systemic early from the outset, the primary pathology being vasculitis. Acquired syphilis can be divided into primary, secondary, latent, and tertiary stages. The infection can also be transmitted vertically resulting in congenital syphilis, and occasionally by blood transfusion and non-sexual contact. Diagnosis is mainly by dark field microscopy in early syphilis and by serological tests. The management in the tropics depends on the diagnostic facilities available: in resource poor countries, primary syphilis is managed syndromically as for anogenital ulcer. The introduction of rapid "desktop" serological tests may simplify and promote widespread screening for syphilis. The mainstay of treatment is with long acting penicillin. Syphilis promotes the transmission of HIV and both infections can simulate and interact with each other. Treponemes may persist despite effective treatment and may have a role in reactivation in immunosuppressed patients. Partner notification, health education, and screening in high risk populations and pregnant women to prevent congenital syphilis are essential aspects in controlling the infection.
PMCID: PMC1745064  PMID: 16326843
25.  IgM rheumatoid factor removal and performance of the FTA-ABS (IgM) test in congenital syphilis. 
Genitourinary Medicine  1992;68(4):249-253.
OBJECTIVE--To determine the performance of the FTA-ABS (IgM) test in congenital syphilis after eliminating interference by IgM rheumatoid factor (RF) and preventing competitive inhibition by IgG. DESIGN--The FTA-ABS (IgM) test was carried out before and after RF removal (achieved by immunoprecipitation of the IgG) in infants with congenital syphilis and controls. SETTING--Newborns delivered in the Peninsula Maternal and Neonatal Services in Cape Town and infants presenting at Red Cross War Memorial Children's Hospital. SUBJECTS--Infants with congenital syphilis aged 0-4 months were divided into those with clinical signs at presentation and those who were asymptomatic at delivery. In addition, patients without congenital syphilis but with similar clinical signs at presentation were investigated as were control infants. OUTCOME MEASURE--The diagnosis of congenital syphilis was based on the criteria suggested by Kaufman et al (1977). RESULTS--Amongst symptomatic infants with congenital syphilis the FTA-ABS (IgM) test was positive in 34 (92%) of 37 cases prior to abolishing the RF effect and in 29 (78.4%) of 37 cases afterwards (p = 0.19). In 12 cases of congenital syphilis who were asymptomatic at birth, 10 had positive FTA-ABS (IgM) tests before RF removal and only three had positive tests afterwards (p = 0.006). False positive tests were not found amongst 15 symptomatic infants whose clinical features mimicked those of the infants with congenital syphilis. Among 51 healthy infants the test had a false-positive rate of 2% in newborns and 13% in older infants. The false positive reactions were eradicated by IgG precipitation. CONCLUSIONS--Following IgG and RF removal there was an improvement in the specificity of the FTA-ABS (IgM) test but this was at the expense of a loss of sensitivity, particularly in asymptomatic newborns. For newborns, if the FTA-ABS (IgM) test was positive, the patient was likely to require treatment for congenital syphilis, regardless of whether the result was due to the presence of RF or specific IgM.
PMCID: PMC1194883  PMID: 1398661

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