Syphilis is a potentially fatal, sexually transmitted disease (STD) that can be transmitted to the fetus of a pregnant woman infected with syphilis. Though preventable, globally, each year about two million pregnant women become infected with syphilis, the majority of whom live in developing countries (WHO 2011). The yearly toll of adverse birth outcomes associated with untreated maternal syphilis is 730,000 to 1500,000, of which nearly 650,000 deaths occur in fetuses and newborns (Schmid 2007; WHO 2010). Maternal syphilis is less of a concern in developed countries than in developing countries. For example, in congenital syphilis (mother-to-child transmission), the seroprevalence of women with syphilis attending antenatal care is estimated to be highest in Latin America (3.90%) and Africa (1.98%) (Schmid 2007). In Africa alone, syphilis causes nearly 400,000 stillbirths and newborn deaths in a single year (Anonymous 2012). Furthermore, concern is deepening in countries such as China where an increase in the disease incidence has already been observed (Cheng 2007; Tucker 2010). In China in 2008, among 9480 total cases, on average, more than one baby per hour was born with congenital syphilis; the observed amplification rate was by a factor of 12 during the five preceding years (Tucker 2010). Moreover, people with the human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDs) usually become infected with syphilis and vice versa (Walker 2001). As a result, the rise in congenital syphilis in many countries in Sub-Saharan Africa has been aggravated by HIV/AIDs as this region is highly burdened by HIV/AIDs infection (WHO 2010).
The World Health Organization (WHO) has estimated that about 50% of pregnant women with untreated syphilis will transmit the infection to the fetus causing severe birth outcomes such as spontaneous abortion, prematurity, stillbirth, low birthweight, neonatal death, or serious sequelae in liveborn infected children (WHO 2011). However, these adverse outcomes are preventable, and existing health programs such as incorporated sexual and reproductive health programs, antenatal syphilis screening, and timely treatment have been suggested as a means to curtail syphilis-attributable perinatal deaths and stillbirth incidence by about 50% (Bique 2000; Hawkes 2011; Myer 2003; Wilkinson 1998). Hence, every pregnant woman has been urged to undergo routine antenatal check-up (UNICEF 2009; WHO 2007). Yet, for decades, in spite of the existence of an antenatal screening policy in the majority of the countries, policy implementation is typically lacking (Gloyd 2001; Hossain 2007).
Additionally, the control and elimination of syphilis is hindered by the fact that the majority of infected women are not tested; nearly every one of those who is tested either does not undergo prompt treatment or is missed entirely (WHO 2011). Despite the availability of various improved diagnostic tools and cost-effective prevention therapy (Peeling 2004; WHO 2010), the prevention and elimination of syphilis is predominantly disrupted by the complexity of the natural disease history, coupled with the absence of precise clinical presentation in infected patients (Peeling 2004). It has also been suggested that the absence of antenatal care, and poor quality services are likely to be important factors in raising the number of mothers giving birth to newborns with congenital syphilis (Walker 2002; Wilkinson 1998).
Scientific efforts for the prevention and elimination of congenital syphilis have been accelerated by the development of reliable and improved diagnostic tools such as on-site syphilis testing, providing rapid results and immediate therapy for sero-positive women in primary care settings. In addition to laboratory testing, on-site testing might be a useful strategy to curb congenital syphilis and its associated adverse outcomes by reducing treatment delays and increasing the numbers of sero-positive women treated (Delport 1998; Fann 1996; Jenniskens 1995). Although the effects of on-site testing in observational studies (Bique 2000; Temmerman 2000) were positive, one randomised controlled study found no effective impact on either treatment rates or perinatal mortality reduction (Myer 2003). Indeed, in spite of the presence of laboratory access in some developing areas, the number of infected women treated fully is still in the minority (Wilkinson 1997). Furthermore, in developing countries, useful screening tools such as treponemal tests are often obtainable only at reference laboratories or large regional centres (Peeling 2004). Hence, syphilis screening has been constrained by varying dynamics and largely due to the delays in the identification and treatment of the infected women (Rotchford 2000). Therefore, it is crucial to assess the effectiveness of available screening strategies for the detection of syphilis infection in pregnant women.
Description of the condition
Syphilis is caused by the bacterium Treponema pallidum. The disease manifestation is protean; involvement of any organs in this disease is possible and it may appear with multiple clinical manifestations resulting in a range of severe health outcomes (CDC 2010). Syphilis infection is transmitted via person-to-person direct contact with a syphilis sore, and during vaginal, anal or oral sexual intercourse. The external genitals, vagina, rectum or anus are the main organs where sores usually occur, including lips and inside the mouth. The risk of acquiring HIV infection in an individual with syphilis is two- to five-fold if exposed when an ulcer is present, and consequently, individuals involving in high-risk sexual behavior are likely to suffer from syphilis and HIV co-infection. Furthermore, the syphilis bacterium can be vertically transmitted to the fetus of a pregnant woman who has a syphilis infection; reportedly, at least two-thirds of all newborns are infected from maternal syphilis (Zenker 1990). The likelihood of fetal involvement occurs among women with active syphilis infection (i.e. rapid plasma reagin (RPR) titre greater than 1:4), specifically, insufficient or untreated infection acquired within the five years prior to the pregnancy (Hannah 2011). Sixty-nine per cent of such women with active infection may experience a variety of adverse birth outcomes (Ingraham 1950; McDermott 1993), i.e. late miscarriage (after 16 weeks) or stillbirth in 25% cases, neonatal death at term in 11%, preterm or low birthweight in 13%, and classic symptoms and clinical signs of congenital syphilis in 20% (Ingraham 1950; McDermott 1993; Schmid 2004; Watson-Jones 2002). Classically, newborns with congenital syphilis are severely infected premature infants with marasmus, a pot belly, 'old man faces’ and withered skin (Walker 2001). The severity of the adverse birth outcomes associated with congenital syphilis is usually determined by the length of the maternal infection as well as pregnancy stage. The majority of the pregnant women with syphilis are asymptomatic and so are many infected newborns at the time of their birth (Peeling 2004). Therefore, if not treated immediately, within a few weeks the disease progression can be fatal (CDC 2010).
Description of the intervention
Early detection and administration of appropriate therapies are at the centre of syphilis prevention strategies: undergoing syphilis screening tests at the first antenatal check-up within the first trimester and again in late stage of pregnancy followed by prompt treatment of sero-positive women with a single dose of long-acting penicillin before the second trimester (WHO 2010).
Serologic testing is the core strategy of syphilis screening and diagnosis (Hook 1992; Peeling 2004). The are two main types of serologic tests: non-treponemal tests and treponemal tests. Non-treponemal tests identify antibodies to reagin, a cholesterol-lecithin-cardiolipin antigen that cross-reacts with antibodies present in the sera of patients with syphilis. Non-treponemal tests such as the RPR test are easy to perform, sensitive, and relatively cheap (Peeling 2004). Furthermore, the non-treponemal test is quantitative and treatment response can be followed over time (Fiumara 1978). On the other hand, in most cases, the treponemal tests remain positive indefinitely, whether the person has been treated or not. In addition, treponemal tests, e.g. enzyme immunoassay (EIAs) are more costly than non-treponemal tests and can be difficult to perform (Peeling 2004). Seroprevalence data from antenatal screening programmes are used as one of the proxy indicators for monitoring the prevalence of sexually transmitted infections (Peeling 2004). Non-treponemal tests such as RPR can be performed at a local laboratory but one of the major limitations is that RPR can not be carried out on whole blood. Conversely, confirmatory assays such as EIAs, although useful to obtain prevalence rates and surveillance facts, are usually available only at reference or large regional laboratories in resource-poor settings. Currently, numerous improved sero-diagnostic tools are available for the control and treatment of syphilis. For example, nowadays RPR and Venereal Diseases Research Laboratory test (VDRL) reagents can be stored at room-temperature. In addition, existing solar-energy powered rotators have provided the means to carry out these tests in resource-poor settings where there is a lack of, or no electricity (Peeling 2004). Rapid and easy treponemal tests using whole blood, serum or plasma can be stored at room temperature for six to 12 months, are cost-effective (Peeling 2004), and the performance of some of these tests is comparable to laboratory tests (Fears 2001; Lien 2000). It is noteworthy that syphilis screening and treatment are estimated to be the most cost-effective public health interventions in existence (WHO 2007).
How the intervention might work
Prevention success lies in the early detection of syphilis in pregnant women and prompt treatment management before the second trimester (WHO 2010). As recommended by the WHO, all pregnant women should undergo antenatal syphilis screening tests; however, by some means, women without test results at delivery should also be tested or re-tested. Women should also be well informed about the importance of being tested for HIV infection. Additionally, this treatment should also be offered to their partners and treatment planning should be primed in order to protect their infants at birth. Screening of pregnant women in the early stage of their pregnancy (preferably prior to 24 weeks of gestational age) can substantially avert the burden of associated adverse birth outcomes in many parts of the developing world. Screening pregnant women at the routine antenatal check-up, in the first trimester, and again in the late stage of pregnancy, and finally the prompt treatment of those women detected with syphilis sero-positive results are desirable. Syphilis is curable by administering a single dose of long-acting penicillin, and prevents related consequences in the unborn babies. Either one (primary or secondary disease) or three (latent disease) penicillin doses can be effective to treat maternal syphilis, depending on the disease stage.
Why it is important to do this review
Evidence on the effectiveness of screening strategies for the detection and treatment of maternal syphilis is scarce from randomised controlled trials, and most of the knowledge is derived from observational studies. Moreover, earlier reviews of syphilis screening and treatment detected either no intervention effect on preterm birth reduction (Barros 2010), or high grade of evidence (Menezes 2009). Therefore, this review will attempt to accumulate quality evidence on the effectiveness of syphilis screening strategies in pregnant women and their neonates.