Incremental cost-effectiveness ratios—the net additional cost per additional unit of health benefit gained (measured as USD per averted CS case)—provide decision-makers with a tool to assess the additional resources required to attain a desired public health outcome. Adopting off-site RPR/TPHA would, compared to no program, avert 18 of the 33 expected CS cases per 1000 pregnancies at a cost of USD82 per case. Averting all but 6 of the CS cases per 1000 pregnancies could be realized through adoption of the on-site ICS strategy; averting 9 additional cases (compared to off-site RPR/TPHA) with an incremental cost-effectiveness ratio of USD104 per case.
One-way and multiway sensitivity analyses demonstrated the results to be stable over a wide range of probability and cost estimates. In one-way analyses, the modeled effectiveness of ANC screening approaches was most affected by test sensitivity of on-site ICS in detecting high- and low-titer maternal infections. Even at lower extremes of test sensitivity values for on-site ICS, however, the number of averted congenital syphilis cases exceeds that of other screening approaches. In multiway sensitivity analyses, only extreme assumptions would drive effectiveness of on-site ICS below that of other screening approaches. Sensitivity of on-site ICS would need to be less than 65% for detection of both high-titer and low-titer maternal infections, and the sensitivity of on-site RPR would need to exceed 87% in detecting high-titer infections for on-site ICS to be supplanted as the most effective of the screening approaches. Other variables shown to influence screening effectiveness—probability of mother-to-child transmission, probability of accepting presumptive treatment, syphilis prevalence rates, penicillin treatment efficacy—did not significantly alter the relative effectiveness of the 3 strategies.
The factors most influential in determining the relative cost-effectiveness of the screening strategies were prevalence of maternal syphilis and the relative distribution of active and past disease. While these variables did not impact the effectiveness of the screening approaches in detecting maternal infections, they did influence cost and, hence, cost-effectiveness measures. As estimates of maternal prevalence increased, on-site ICS became more cost-effective. For example, at the upper boundary of the confidence interval for maternal prevalence, 7.8%, the incremental cost-effectiveness of on-site ICS decreased from USD104 to USD85. At a prevalence rate of 10%, the incremental cost-effectiveness would decrease further to USD57. On-site ICS was sensitive to the prevalence of past disease, implying that relative cost-effectiveness would increase as rates of past disease increased, driven by the costs of unnecessary treatment following misdiagnosis. At the upper-bound prevalence estimate for past disease, 8.1%, the incremental cost of on-site ICS increased to USD122 per additional case averted.
We also evaluated the effect of assuming the rate of congenital transmission for low-titer infections to be zero, reflecting the findings of a recent study.5,12 With the assumption of zero probability of congenital transmission of low-titer infections, on-site ICS would remain the most effective of the screening approaches, averting 14 of the 16 adverse outcomes estimated to occur in the absence of a screening and treatment program. Off-site RPR/TPHA would avert 8 of the expected adverse outcomes and on-site RPR would avert 9. On-site RPR would also be somewhat less expensive than off-site RPR/TPHA, implying that off-site RPR/TPHA would be dominated by the on-site screening strategies. Compared to no program, the cost per case averted for on-site RPR would be $213. The incremental cost-effectiveness ratio of on-site ICS, compared to on-site RPR would be $218, approximately double that estimated in the base model. Incorporating a further assumption of decreased likelihood of adverse outcomes resulting from high-titer active infections had no significant impact on the relative effectiveness of the screening strategies but would increase the incremental cost-effectiveness ratios of the strategies.
Our study found that screening ANC patients using on-site ICS resulted in the largest proportion of infected patients receiving the recommended course of treatment. On-site ICS also averted the greatest portion of CS cases, preventing 82% of the CS cases that would be expected with no screening program. The next most effective screening strategy, off-site RPR/TPHA, averted 55% of expected CS cases. Screening with on-site RPR proved the least effective of the 3 approaches. The greater effectiveness of on-site ICS, however, entailed higher program costs than the other screening approaches evaluated. The incremental cost effectiveness of off-site RPR/TPHA of USD82 per CS case averted was somewhat lower than the USD104 for each of the additional CS cases averted using on-site ICS. While the additional cost is not trivial, especially in resource-poor settings, the advantages in terms of lower perinatal death rates, averting of CS-related lifetime disability, and prevention of late-stage maternal disease are substantial.
The on-site RPR screening approach proved to be least effective of the 3 approaches because of relatively low sensitivity in detecting both high- and low-titer maternal syphilis infections. The low field sensitivity of the test reflects the greater difficulty in accurately interpreting test results, a limitation exacerbated by frequent staff turnover in the study clinics. Test performance was not a factor in the standard-practice clinics, where off-site RPR/TPHA was used, because sensitivity and specificity were assumed to be equal to those of the study reference laboratory. The factor limiting the effectiveness of off-site RPR/TPHA was the loss to follow-up of ANC patients who did not return to the clinics for test results and treatment.
A recent study of adverse birth outcomes associated with maternal syphilis infection in Tanzania suggested that no adverse outcomes were associated with low-titer active maternal infections.5,12 Because this was a retrospective study of women presenting for delivery, spontaneous abortion was not one of the considered adverse outcomes of infection; as a result, data from the Tanzania study may not be fully applicable to the adverse outcomes modeled in the current study. Nonetheless, we considered the impact of these findings on cost-effectiveness measures. In the end, consideration of these findings from Tanzania would influence incremental cost-effectiveness ratios but does not impact the dominant effectiveness of on-site ICS relative to other screening strategies.
The primary disadvantage of on-site ICS stemmed from the inability of the treponemal test to distinguish active from past infections. The lower specificity of on-site ICS testing approach in identifying active infections, which would result in some overtreatment of tested ANC patients, should be weighed against the high sensitivity of the test in detecting both high- and low-titer infections and the opportunity to treat infected patients while they are still in the clinic.
The cost-effectiveness of on-site ICS will depend on the particular epidemiological context. As rates of high- and low-titer syphilis infections increase, the on-site ICS becomes increasingly cost-effective relative to other approaches. The cost-effectiveness of on-site ICS will also depend on the distribution of active and past syphilis infections. As rates of past infections in a population increase, the proportion of women who are unnecessarily treated will increase also. In contrast, the off-site RPR/TPHA approach and on-site RPR are largely insensitive to differences in rates of past infection. The impact of syphilis rates, and the distribution of disease between active and past infections, will influence the relative magnitude of differences in cost-effectiveness measures. Because the epidemiology of maternal syphilis infections may vary by population and time-period, the impact of these variables should be considered in assessing the relative advantages and cost-effectiveness of these interventions.
Because we assumed off-site RPR/TPHA to perform with perfect sensitivity and specificity, the cost-effectiveness study was designed such that any bias in cost-effectiveness measures would favor the off-site RPR/TPHA strategy. Should the off-site laboratories prove less accurate, then estimates of averted and treated disease would have been overestimated and measures of cost per case averted or cured would have been underestimated. If this were to be the case, the relative performance of both on-site ICS and on-site RPR would improve.
Another source of potential bias in estimates of performance of the standard-practice clinic strategy stems from the difficulty in locating standard-practice clinics comparable to the study clinics and representative of ANC clinics in the rural Eastern Cape.14 Because antenatal syphilis testing in the province was rare before the study period, clinics where antenatal screening was already in place were disproportionately located in urban or periurban areas. As a result, our study may have underestimated transportation difficulties that would adversely impact the effectiveness of this screening approach, including off-site evaluation of specimens, timely return of test results, and presentation of ANC patients at clinics to receive results and treatment. A more representative group of clinics doing off-site evaluation might have lower rates of successful treatment and less favorable cost-effectiveness ratios than were predicted in the model. If so, the relative estimated performance of on-site ICS and on-site RPR would improve.
Because we adopted the perspective of the Provincial Ministry of Health for the analysis, we did not consider patient costs. Because patient time and travel costs were excluded under this perspective, our study underestimated the value of being able to treat patients at their initial screening visit and therefore the relative cost of the off-site RPR/TPHA. No user fees associated with ANC syphilis screening in the Eastern Cape; in a context where user fees were assessed, we would expect the uptake of the more expensive on-site ICS to be negatively affected if user fees reflected relative test costs. We also underestimated the value of averting CS cases, because lost productivity costs of parents that would be incurred in caring for CS-affected infants were not included. Considering these costs would improve the relative cost-effectiveness of on-site ICS testing compared to off-site RPR/TPHA.
To avert adverse congenital syphilis events and to effectively treat syphilis infections of patients seeking antenatal care in high-prevalence settings, implementation of on-site screening with ICS may be a highly effective approach. The next most effective of the approaches evaluated relied on evaluation of specimens at an off-site laboratory using RPR/TPHA. On-site RPR was the least effective of the 3 approaches considered and was dominated on cost-effectiveness measures. While the incremental cost-effectiveness of off-site RPR/TPHA was marginally less than that of on-site ICS, both screening strategies may be considered cost-effective, depending on the available resources of the relevant funding authority and public priorities for syphilis control in mothers and infants.
1. Radolf JD, Sanchez PJ, Schulz KF, et al. Congenital syphilis. In: Holmes KK, Sparling PF, Mardh P-A, et al., eds. Sexually Transmitted Diseases. New York: McGraw-Hill; 1999:1165–1190.
2. Hira SK, Bhat GJ, Chikamata DM, et al. Syphilis intervention in pregnancy: Zambian demonstration project. Genitourin Med 1990; 66:159–164.
3. McDermott J, Steketee R, Larsen S, et al. Syphilis-associated perinatal and infant mortality in rural Malawi. Bull World Health Organ 1993; 71:773–780.
4. Schulz KF, Schulte JM, Berman SM. Maternal health and child survival: Opportunities to protect both women and children from the adverse consequences of reproductive tract infections. In: Germain A, ed. Reproductive Tract Infections: Global Impact and Priorities for Women’s Reproductive Health. New York: Plenum; 1992:145–182.
5. Watson-Jones D, Changalucha J, Gumodoka B, et al. Syphilis in pregnancy in Tanzania. I. Impact of maternal syphilis on outcome of pregnancy. J Infect Dis 2002; 186:940–947.
6. Pham-Kanter GB, Steinberg MH, Ballard RC. Sexually transmitted diseases in South Africa. Genitourin Med 1996; 72:160–171.
7. Sturm AW, Wilkinson D, Ndovela N, et al. Pregnant women as a reservoir of undetected sexually transmitted diseases in rural South Africa: Implications for disease control. Am J Public Health 1998; 88:1243–1245.
8. Wilkinson D, Abdool Karim SS, Harrison A, et al. Unrecognized sexually transmitted infections in rural South African women: A hidden epidemic. Bull World Health Organ 1999; 77:22–28.
9. Karuhije P. A pilot study on the feasibility, cost and cost-effectiveness of transporting specimens from clinics to the nearest laboratory. Northern Transkei, Eastern Cape Province, Republic of South Africa: National Health Laboratory Service; 2003.
10. Alexander JM, Sheffield JS, Sanchez PJ, et al. Efficacy of treatment for syphilis in pregnancy. Obstet Gynecol 1999; 93:5–8.
11. Sheffield JS, Sanchez PJ, Morris G, et al. Congenital syphilis after maternal treatment for syphilis during pregnancy. Am J Obstet Gynecol 2002; 186:569–573.
12. Watson-Jones D, Gumodoka B, Weiss H, et al. Syphilis in pregnancy in Tanzania. II. The effectiveness of antenatal syphilis screening and single-dose benzathine penicillin treatment for the prevention of adverse pregnancy outcomes. J Infect Dis 2002; 186:948–957.
13. Wilkinson D, Sach M. Improved treatment of syphilis among pregnant women through on-site testing: An intervention study in rural South Africa. Trans R Soc Trop Med Hyg 1998; 92:348.
14. Bronzan R, Mwesigwa-Kayongo D, Narkunas D, et al. Onsite rapid antenatal syphilis screening with an immunochromotagraphic strip improves case detection and treatment in rural South African clinics, in press.
15. Ingraham NR. The value of penicillin alone in the prevention and treatment of congenital syphilis. Acta Demato-Venereologica 1951; 31:60–88.
16. Schulz KF, Cates W Jr, O’Mara PR. Pregnancy loss, infant death, and suffering: Legacy of syphilis and gonorrhoea in Africa. Genitourin Med 1987; 63:320–325.
© Copyright 2007 American Sexually Transmitted Diseases Association
17. Temmerman M, Lopita MI, Sanghvi HC, et al. The role of maternal syphilis, gonorrhoea and HIV-1 infections in spontaneous abortion. Int J STD AIDS 1992; 3:418–422.