Globally, nearly 1.4 million pregnant women in 2008 had probable active syphilis infection and were at risk of transmitting the disease perinatally to their unborn children. This is lower than previously reported 1997–2003 WHO estimates of approximately 2 million pregnant women annually with untreated syphilis infection, and suggests some progress may have been made over the past decade in syphilis prevention and control. However, the extent of progress is difficult to determine, as the estimates used differing methodological approaches. In comparison to the 1997–2003 estimates, the 2008 estimates were intended to take into account existing treatment services, remove background mortality and morbidity unrelated to syphilis, and better account for the anticipated increasing availability of testing and treatment over time. In addition, because of the paucity of published cross-sectional survey data since 2003 on syphilis in pregnancy, the 2008 estimates were based on data reported to WHO routinely by countries through the HIV Universal Access reporting system rather than on data from a literature review.
Despite differences in methodology, both the 1997–2003 and the 2008 estimates indicate that syphilis in pregnancy continues to be an important cause of mortality and morbidity in pregnancy. This is unsettling given the fact that universal syphilis screening in ANC and prompt treatment of women testing positive are basic interventions that have been proven to be cost-effective even in low prevalence settings. Additionally, rapid point-of-care syphilis tests allowing testing and treatment in almost any clinical setting were not widely available in 2003, but certainly should have been by 2008. These 2008 estimates support that countries in every region of the world should scale up screening and treatment for syphilis in pregnancy, and that doing so could substantially reduce preventable perinatal death and disability.
Our estimates suggest that over 520,000 adverse pregnancy outcomes due to syphilis occurred in 2008, of which approximately 215,000 were stillbirths or early fetal deaths, 90,000 were neonatal deaths, 65,000 were premature or low birth weight infants, and another 150,000 were infected newborns. Our estimates do not include additional deaths that would be expected to occur after the first month of life due to prematurity, low birth weight, or congenital infections, estimated in one study to result in approximately 10% mortality by 1 y (i.e., approximately 21,500 additional infant deaths) 
Approximately one-fifth (20%) of all pregnant women with syphilis did not attend ANC. Thus, efforts to ensure universal access to early ANC are fundamental in eliminating congenital syphilis, as well as other causes of preventable infant mortality. But importantly, our data suggest that two-thirds of the adverse outcomes due to syphilis occurred in women who had attended ANC at least once, but either were not screened or, if they were screened and tested positive, did not receive appropriate treatment with intramuscular benzathine penicillin. The vast majority of outcomes that occurred in 2008 could have been prevented had the women received quality early ANC that included syphilis testing and access to effective therapies, as recommended by WHO. Syphilis testing and treatment are relatively inexpensive compared with other interventions, with tests typically costing less than US$1, and treatment slightly less than that. To reduce cases of congenital syphilis, it will be important to incorporate syphilis testing and treatment into routine procurement and distribution systems to ensure that pregnant women receive an essential minimal package of ANC interventions.
Existing health care services were able to avert one out of every four expected adverse outcomes in 2008. However, if the proposed testing and treatment targets for 2015 outlined in the Initiative for the Global Elimination of Congenital Syphilis had been reached in 2008, over half of all expected adverse outcomes could have been averted. Further research is needed to define how many cases and what level of service delivery is needed to attain the ultimate goal of “elimination of congenital syphilis as a public health problem.” However, given that screening and treatment for preventing MTCT of syphilis is not 100% effective, primary prevention of syphilis in pregnant women is also an important strategy that needs to be addressed to truly eliminate congenital syphilis.
While substantial progress has been made in the utilization of ANC (in 2009 WHO estimated that approximately 81% of all pregnant women had attended at least one ANC visit) 
, congenital syphilis still occurred for a variety of reasons: many of these visits were too late to avert an adverse outcome, clinics may not have offered testing, testing may not have been affordable, women may not have followed up or received their test results, treatment may not have been available, or treated women may have been reinfected by untreated sexual partners 
Our estimates are subject to some limitations. First, there are no global data on estimated numbers of early fetal deaths; national estimates of early fetal deaths had to be crudely extrapolated from estimated numbers of stillbirths using a correction factor based mainly on data from high-income countries. Improved data on early fetal death, in particular in low- and middle-income countries, is necessary to understand the full extent of the impact of this limitation.
In addition, these estimates rely on data reported through the HIV Universal Access reporting system and do not include separate published studies of syphilis seropositivity, as was previously done for the 1997–2003 estimates. The advantage of HIV Universal Access data is that they are reported by most developing countries on a routine basis, involve a larger sample size than most published studies, and are less subject to a publication bias. However, several countries did not report through the HIV Universal Access system, including some high-income countries in North America, Europe, and the Mediterranean with low syphilis seropositivity, as well as some particularly low resource countries without organized screening programs and with high syphilis seropositivity. It is unclear how this underreporting would affect the overall estimates.
Although countries are asked to report nationally representative data, it is possible that these data are over-representative of urban populations with greater access to syphilis prevention and treatment services than rural populations. If syphilis seropositivity is higher in rural settings (and programs are less effective), our calculations may underestimate the true burden of syphilis-associated adverse outcomes.
In addition, HIV Universal Access data do not include information on testing methodologies, test titer, stage of disease, or treatment history, and therefore it is unclear whether or not a country's data includes women with latent or previously treated disease. This analysis applied a correction factor for “probable active” disease to the entire dataset to account for this; however, adjustment may not have been necessary in all cases and may have led to underestimation of the true burden of active disease.
Because of a lack of representative data on current testing and treatment coverage, these estimates relied on expert opinion of current testing and treatment coverage, and the experts may have miscalculated. In order to explore the validity of these estimates, we present a basic sensitivity analysis of testing and treatment coverage to account for the uncertainty related to this approximation. Although WHO is working to improve collection of data on syphilis testing and treatment through the HIV Universal Access reporting system, these testing and treatment data are not yet felt to be accurate and representative at a global level (the highest performing countries are more likely to report service delivery indicators). Thus, more work with countries to strengthen surveillance and monitoring systems is needed.
Finally, these estimates do not account for the timing of treatment of syphilis in pregnancy. Although syphilis transmission has been documented to occur very early in pregnancy, existing data suggest that catastrophic outcomes due to syphilis require development of the fetal immune system (i.e., after 18–20 wk gestation) 
. It is also recognized that the effectiveness of screening and treatment is lower in the third trimester than in the first and second trimesters 
The limitations of these estimates highlight the urgent need for improved data through stronger national surveillance and monitoring systems. All countries should know at least the three core indicators related to MTCT of syphilis in their population: what proportion of ANC attendees are tested for syphilis, what proportion are seropositive, and what proportion of syphilis seropositive ANC attendees are adequately treated 
. WHO hopes to work with countries to improve capacity to monitor and report on these three core indicators through the WHO HIV Universal Access reporting system. Better national data are also needed on how early pregnant women seek care and how many women have early fetal deaths, as well as how estimates of adverse outcomes such as congenital syphilis and stillbirth attributable to syphilis compare to actual reported cases of congenital syphilis and stillbirth attributable to syphilis.
In summary, this analysis indicates that syphilis continues to be an important cause of adverse outcomes of pregnancy, including substantial numbers of perinatal deaths and disabilities. Given that an increasing proportion of the infant mortality that Millennium Development Goal 4 aims to address by 2015 occurs during the first month of life, investing in elimination of MTCT of syphilis is a low-hanging fruit for reducing neonatal mortality, as well as stillbirths. Primary prevention of syphilis in people of reproductive age is an important first step towards reducing these deaths. Better data are needed to raise local awareness of the burden of syphilis in pregnancy, an old scourge that is often overlooked in modern day public health programs. Countries also need to ensure that quality-assured syphilis testing is available in all ANC settings, now possible even in remote care settings with the introduction of rapid point-of-care diagnostics. In addition, efforts are needed to ensure universal access to early ANC, as well as improved quality of ANC, so that all pregnant women receive an essential package of services that includes routine and early access to point-of-care testing and adequate treatment for syphilis if seropositive. MTCT of syphilis can only be eliminated if decision-makers at all levels prioritize the provision and quality of this basic ANC service.
Elimination of MTCT of syphilis directly supports attainment of Millennium Development Goals 4, 5, and 6 through reduction in infant mortality, improved maternal health, and primary prevention of HIV 
. With just a short amount of time left to achieve the Millennium Development Goals, the United Nations Secretary-General launched the Global Strategy for Women's and Children's Health, which calls for improved coordination around maternal and newborn health issues 
. Bringing ministries of health and partners together to provide universal coverage of antenatal syphilis screening and to ensure treatment of all pregnant women infected with syphilis is a specific example of an activity that would greatly support the Global Strategy for Women's and Children's Health.