Schmid, George P. MD, MSc*; Stoner, Bradley P. MD, PhD†; Hawkes, Sarah MBBS, PhD‡; Broutet, Nathalie MD, PhD§
IN EVERY SOCIETY, CONGENITAL SYPHILIS (CS) has significant medical, economic, societal, and emotional burdens.
Over 130 million infants are born each year, almost 8 million die before their first birthday, and, of these fatalities, about 3 million occur in the first week of life.1 An additional 3.3 million are stillborn.1 Many of these 6.3 million deaths are caused by syphilis (up to 26% of all stillbirths, in one review2), almost exclusively in the developing world.3
Although estimates of proportions vary, adverse pregnancy outcomes occur in up to 80% of women with active syphilis, including stillbirth (40%), perinatal death (20%), and serious neonatal infection (20%).4 Whichever of the several estimates that might be used, the morbidity is high.
Yet, a large reduction in CS is feasible with a relatively simple set of existing interventions focusing on maternal and newborn care. The building blocks for CS prevention are already in place in many countries: Policy guidelines for universal antenatal syphilis screening exist in most countries, levels of antenatal attendance are reasonably high, screening tests are low cost and technically feasible even at the primary health-care level, and treatment with penicillin is inexpensive and is on the essential medicines list of all countries. Despite these numerous facilitating factors, there is a great underappreciation of the burden of CS, and there are minimal advocacy or program intervention efforts at international and national levels. The numbers of deaths from CS annually rival those that will be caused by transmission of HIV from mother to child.5 Great attention is focused on preventing infants from becoming infected by HIV—why do we not have the same emphasis on preventing infection of the fetus and newborn by Treponema pallidum?
To heighten such emphasis, and to begin to address the problem, the World Health Organization (WHO) has, in the past 2 years, developed a program to eliminate CS. In this brief overview, we (1) present preliminary, new estimates of the numbers of cases of CS that occur annually; (2) review the importance of CS; and (3) describe the WHO initiative and global strategy to eliminate CS.
Estimates of the Numbers of Cases of CS
No reliable global estimates of the numbers of cases of CS exist. To determine the magnitude of the problem of CS, we estimated the numbers of cases of CS occurring annually and present preliminary results from an estimations process not yet completed.
We used a two-stage approach to determining the incidence of CS for a single year, using data collected from pregnant women, 1997–2003. Data were collected over this 7-year time because data are sparse, and our estimated incidence does not apply to any one specific year. The incidence of syphilis in pregnant women is unlikely to undergo marked change in this time in most settings, however, and thus the incidence would be representative of any given year over this time period.
For the first stage, data were abstracted from a WHO database, used for estimating the numbers of cases of sexually transmitted infections (STIs) acquired globally.6 This literature review acquired data from published and unpublished reports of serologically confirmed (positive reaginic test, confirmed by a treponemal test) maternal seroprevalence among antenatal care (ANC) populations sampled between 1997 and 2003, globally, which met criteria for inclusion in the data base (sample size ≥100, no apparent bias in sampling, reaginic and confirmatory treponemal tests performed). For efficiency reasons, we excluded the United States, Canada, Northern Europe, and Western Europe from our search because syphilis is rare in those countries and they would not contribute meaningful numbers of cases of CS. Because many countries lacked data, a regional approach was used, using the 6 WHO regions and the population-weighted mean of available seroprevalence data from countries within a region was applied to countries without data which, together with the country-specific data, were used to determine a mean seroprevalence for women attending ANC by region. The number of studies in the data base were sometimes sparse, and our calculated regional seroprevalences may differ from regional estimates made in different ways. We assumed that all women with positive serologic tests had untreated syphilis and, thus, had cases of maternal syphilis (MS). To estimate the annual number of MS cases, seroprevalence in a particular region was multiplied by 2004 United Nations population estimates of the annual number of births for that region.7 We did not include the numbers of births for United States, Canada, and Northern and Western Europe.
This method of calculating the numbers of cases of MS affected by syphilis will underestimate the true numbers of cases of pregnancy affected by syphilis. If there is early fetal loss from syphilis, as occurs in 17% to 40% of cases (Table 1), many of these women will not have attended ANC, and thus, the estimate of MS among ANC patients will not include these women. We did not adjust for this effect.
For the second stage, to estimate global annual CS morbidity, we reviewed studies that estimated morbidity accruing to women with untreated MS (Table 1). Since there were inconsistencies among all, we selected 3 recent studies to model the proportion of mothers with a positive serologic test who would have an adverse pregnancy outcome due to syphilis.4,11,12
1. In the study of Watson-Jones,12 only cases of MS with high titer RPR (≥1:8) suffered an adverse event. For this method, we multiplied the numbers of cases of MS by 73% (the proportion of cases of MS with a high titer) to determine the numbers of cases of MS at risk of having a case of congenital syphilis and then multiplied this resulting number by 49%, the proportion of all cases of MS with a high titer that developed CS.
2. In the study of Schulz et al.,4 we selected the midpoint (65%) of the estimated 50%–80% of cases of MS that were estimated to develop congenital syphilis. For this method, we multiplied the number of cases of MS by 65% to determine the numbers of cases of CS.
3. In the Global Burden of Disease method,11 an estimated 75% of cases of MS were estimated to develop CS. For this method, we multiplied the number of cases of MS by 75% to determine the numbers of cases of CS.
We found seroprevalence data from 31 countries (excluding the United States, Canada, Northern and Western Europe), with a total of 431,452 tested women. Seroprevalence was highest in the American region (3.90%), followed by the African region (1.98%), European region (1.50%), Southeast Asia region (1.48%), Eastern Mediterranean region (1.11%), and Western Pacific region (0.70%) (Fig. 1). Multiplying these proportions by the numbers of births yielded a total of 2,036,753 cases of MS annually, with the African region having the most cases of MS (705,725 cases) and the Western Pacific region the least (134,522 cases).
The estimated annual numbers of cases of CS varied by the proportion of cases of MS estimated to develop CS. Using figures of Watson-Jones et al., the estimated number of cases of CS was 728,547 annually; using figures of Schulz et al., the estimated number of cases of CS was 1,323,889 annually; and using the figures of the Global Burden of Disease, the estimated number of cases of CS was 1,527,565.
While our failure to adjust for stillbirths among women not seeking ANC would increase these numbers, the clinical importance of these numbers of cases will be decreased by screening programs. That is, even though a fetus might be infected in utero, an ANC program that detects and treats infected pregnant women early enough in pregnancy will treat the infected fetus and prevent the clinical expression of cases (see below). We did not adjust for this effect.
The Importance of CS
The number of cases of CS and their clinical morbidity have important economic and social implications.
As the incidence of syphilis has fallen in the industrialized world, numerous economic analyses there have examined the economic value of continued universal screening of pregnant women for syphilis. All have concluded that screening is cost-effective or cost-saving at prevalences considerably <1%.5,13 Although some have suggested targeted screening may be more cost-effective in very low-risk populations,14 others have found universal screening to be as cost-effective as targeted screening, easier to implement and more politically acceptable,15 and few industrialized countries do not recommend universal screening of pregnant women.
In the developing world, screening of pregnant women is an economic public health bargain. Converting fetal/neonatal consequences of maternal syphilis into disability-adjusted life years (DALYs), the cost per DALY saved is $4 to $19 in published studies.5 This figure compares very favorably with the figure set in 1993 by the World Bank, which defined cost-effective interventions as those costing <$193/DALY saved.16 A recent study from Tanzania found that preventing CS in live-born infants costs $110.03/DALY saved, but including fetal outcomes was very favorable ($10.56/DALY saved).17 Using newly developed immunochromatographic testing strips instead of RPR makes screening at point of care feasible,18,19 more accurate,18 and even more cost-effective than already cost-effective RPR testing on-site or at a referral laboratory.20 As health care systems increasingly concentrate on preventing HIV infection in infants born to mothers with HIV infection, it is inexplicable that they do not do the same for syphilis, as prevention of one DALY due to CS in a screening program for maternal syphilis using traditional testing methods is about 25 times as cost-effective as preventing one DALY among infants born to women who are HIV-positive.13
Societal and Emotional Implications
The high societal value of a child “drives” programs for the prevention of HIV in infants and for safe motherhood. The sparse scientific literature on the emotional and psychological reaction among parents to the loss of a fetus,21 with perhaps none from the developing world, describes for some a significant, traumatizing event, with feelings of guilt, blame, and depression.22 These feelings could be worse after the loss of a fetus or neonate to syphilis as, indeed, there may be justifiable parental reasons for guilt and blame, but safe pregnancy and country programs must also share guilt for not implementing their own policies. In considering the costs of CS prevention, decision makers must value the societal and emotional costs of allowing cases of CS to occur, even if, implicitly; such valuation will increase considerably the cost-effectiveness of CS prevention, as it has in the only economic evaluation to include such costs.23
Why CS Occurs
Although the concept of screening every pregnant woman for syphilis is simple, implementing the program may not be. In every society, the causes of CS are similar.5 In the industrialized world, failure to attend ANC is the most common cause of CS24,25 with late care (too late to prevent stillbirth) a major contributing factor. In the developing world, only an estimated 68% of pregnant women receive prenatal care,26 and, among these, the average time of first attendance is late—5 to 6 months.26 When ANC is accessed, testing must be available and accessible. Availability can be addressed by decentralization of testing; it is effective and cost-effective.18,19,27 “Accessibility” suggests testing and treatment that are free of charge, with cost to the patient being identified as the single greatest impediment to syphilis testing in sub-Saharan Africa.28
Why We Can Prevent CS
We know how to prevent CS. We have the tools and medicines needed, and they are improving. We know how to use them. Prevention of CS is at least cost-effective and in many situations cost saving. It is affordable to countries with limited health budgets, and, compared to preventing mother-to-child-transmission (PMTCT) of HIV, prevention of CS is inexpensive, simple, and highly cost-effective. Lack of political will and the absence of modest funding prevent us from eliminating CS.
The WHO Global Strategy to Eliminate CS
The Department of Reproductive Health and Research (RHR) at WHO recently published a series of “state-of-the-art” reviews on maternal and CS in the Bulletin of the World Health Organization to advocate for action for the elimination of CS worldwide.29 The Scientific Technical Advisory Group of RHR in WHO endorsed a strategy for the global elimination of CS, and elimination of CS was included in its 2004–2009 work plan.30 It is also highlighted in the Strategy for the Prevention and Control of Sexually Transmitted Infections adopted by the 59th World Health Assembly in 2006 and in the Making Pregnancy Safer Strategic Approach to Improving Maternal and Newborn Survival. Resources are currently being mobilized.
The broad goal of the WHO Strategy is the elimination of CS as a public health problem, with the specific goal of prevention of mother-to-child transmission of syphilis through early antenatal care for all women, treatment of all sexual partners of infected women, and prophylactic treatment with a single dose of penicillin of all neonates born to RPR-positive mothers. These together with the reduction of prevalence of syphilis in pregnant women as stated in the WHO strategy for the prevention and control of sexually transmitted infections will ensure sustainability of the elimination goal of CS.
The WHO Strategy at country level consists of 4 pillars:
1. Ensure sustained political commitment and advocacy—sustained political commitment to achieving the goal of eliminating CS. A review of the policies of maternal and CS control and available epidemiologic data from 13 countries was conducted to compare and contrast the approaches currently taken by countries with varying geographical, socioeconomic, and epidemiologic ranges.31 The countries showed varying degrees of success in decreasing MS levels. The review concluded that the policies are only as effective as the implementing health system and its users are or want them to be. Successful implementation of MS screening programs is dependant on identifying barriers to their implementation, e.g., lack of recognition of the problem or lack of policy, and then enhancing the health care system’s capacity to provide the services required. The results of the study highlighted the fact that the barriers faced by each country are remarkably similar, although the degree varies. Reflecting the diversity of policy implementation among and within countries, the range of coverage is wide. Screening ranged from 17% to 88% in Bolivia, 63.6% to 79% in Brazil, 51% to 81% in Kenya, 43.2% in Malawi, <5% to 40% in Mozambique, 83.2% in Tanzania, and 32% to 83.2% in the USA, a country that uniquely has a plan to eliminate syphilis.32 Political commitment, with resulting prioritization and resource allocation, can eliminate these disparities.
2. Increase access to, and quality of, maternal and newborn health services—ensuring that all pregnant women are screened and adequately treated and decreasing the frequency of missed opportunities for screening women outside maternal and newborn care, e.g., identifying and then testing for syphilis of a pregnant women who has not attended ANC but who is seeking care for another child in a pediatric clinic. In short, access to care, and the quality of care, should be improved.
3. Screen and treat all pregnant women—use of diagnostics that are effective, affordable, and require minimal logistic support, with effective management of all infected women and their partners, and the treatment of infants born to seropositive mothers. The development of rapid, inexpensive immunochromatographic test methods, as described elsewhere in this issue, highlights the promise that these tests have of bringing affordable, technically simple testing to all primary health care facilities.
4. Establish surveillance, monitoring, and evaluation systems—improving surveillance systems, developing indicators, and strengthening monitoring and evaluation systems. In the 13-country review, monitoring and evaluation were seldom part of the policy of screening all pregnant women but are vital to understanding the success of a control program.31
The 4 guiding principles for implementation include:
1. A country-driven process taking into account the wide range of cultures and readiness of health services in countries but having a common approach that can be adapted to local situations.
2. An integrated approach: The elimination of CS is not a vertical program but must form an integral part of other maternal and newborn health services. Thus, linking with other maternal and newborn health services, e.g., prevention of mother-to-child transmission of HIV or malaria screening in pregnancy, etc., as well as other reproductive health initiatives, e.g., Making Pregnancy Safer, a WHO program that, among other things, enhances access to and utilization of ANC, are essential to a coordinated, efficient and sustainable elimination program. Stated simply, integrating and not building vertical programs will efficiently offer better service and outcome.
3. A rights-based approach giving women the right to information, counseling, and confidentiality.
4. Partnership and collaboration: In resource-limited countries, the key to success will be cross-sectoral collaboration at the government level (Ministry of Health, Ministry of Education, school-based programs, etc.); collaboration and partnership with other reproductive health services; and community-based health programs run through nongovernmental organizations (that in some countries deliver 50% of all health care), bilateral donors and foundations, and other UN agencies.
To achieve success, WHO will work at the international, regional, and country level.
WHO will assume a leadership role, ensuring that the elimination of CS becomes an institutional priority and strengthening links within the organization and with other UN agencies and organizations working on maternal and child health; work to galvanize interest and support for the initiative at national, regional, and international levels; establish a general framework for elimination of CS, which should then be tailored by each country to its individual context; and support development of technical and generic training manuals.
WHO will assume a leadership role at regional level, providing many of the leadership activities described above. In addition, WHO will support countries in the development of national plans and actively promote the integration of prevention of CS and PMTCT programs.
WHO will provide technical assistance to countries (from headquarters, regional, or country offices), especially those with high maternal and infant mortality (or high rates of MS and CS). Included in such assistance will be support to the following:
* Ensure collaboration and partnership between programs such as Mother and Child Health, Sexual and Reproductive Health, STI and HIV (including PMTCT of HIV);
* Conduct situational analysis where an overview of the country’s political and health system willingness and capability to tackle CS elimination is performed to identify opportunities, needs, and gaps;
* Determine the burden of disease;
* Provide support to countries to identify and implement appropriate strategies aiming to eliminate CS;
* Provide training to build a skilled, motivated workforce;
* Develop and implement surveillance, and monitoring and evaluation, programs; and
* Help countries to identify strategies for increasing attendance of pregnant women to receive maternal and newborn health services.
No date has been set as a target for eliminating CS. Rather, interim goals have been set to operationally introduce programs to eliminate CS into countries. The first goal is to introduce a pilot countrywide CS elimination program into 2 countries by 2008, with success documented in at least 1 country by 2010. Subsequent goals will be set, depending upon the cost and evaluation of these programs.
Countries do not face insurmountable obstacles in attempts to achieve CS elimination. What they often lack are political commitment, evidence-based priority setting, and advocacy at all levels. There is little reason why the elimination of CS is not a priority, and many reasons why it should be.