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Syphilis Screening and Treatment During Pregnancy

This is an interim intervention report. We have spent limited time to form an initial view of this program and, at this point, our views are preliminary. We plan to consider undertaking additional work on this program in the future.

Summary

  • What is the program? Syphilis screening and treatment during pregnancy can prevent the complications of syphilis infection for the child and mother. Rapid point-of-care (POC) testing allows pregnant women to be tested and treated in a single visit at low cost. Interventions promoting rapid POC testing intend to increase treatment rates and decrease the harmful outcomes of congenital syphilis in low- and middle-income countries.
  • What is its evidence of effectiveness? Rapid POC tests have good accuracy, and benzathine penicillin G is highly effective in treating syphilis according to observational studies and a long history of clinical use. We identified three randomized-controlled trials (RCTs) on the impact of programs that promote rapid POC testing. Two trials found beneficial effects on outcomes of interest, including treatment and testing rates and risk of congenital syphilis. One trial found no effect on treatment rates or infant mortality.
  • How cost-effective is it? We have completed a cost-effectiveness analysis of Evidence Action’s syphilis screening and treatment program in Liberia, which appears to be in the range of cost-effectiveness of programs we would consider directing funding to. We do not have an estimate on the cost-effectiveness of syphilis screening and treatment in pregnancy programs in general because the costs of implementing such programs through technical assistance vary widely depending on the context of the specific funding opportunity.
  • Does it have room for more funding? We believe that there may be roughly $20-$30 million in room for more funding for one-time grants to scale up syphilis screening and treatment programs in countries other than Liberia.
  • Bottom line: The intervention appears promising, but we would need to conduct additional research to assess the cost-effectiveness of programs that promote syphilis testing and treatment and identify funding opportunities with room for more funding.

Published: August 2018; Last updated: May 2021 (2018 version)

What is the problem?

Syphilis is a sexually-transmitted disease caused by the bacterium Treponema pallidum subspecies pallidum. The early stages of infection involve a sore and rashes, after which it becomes asymptomatic for many years and sometimes re-emerges with damage to multiple organ systems.1

Syphilis in pregnancy often causes severe health consequences for the fetus and newborn if untreated. Disease Control Priorities 3 states that “syphilis in pregnancy can lead to a wide range of adverse outcomes, including stillbirth, fetal loss, neonatal death, premature and low-birthweight infants, and infection or disease in newborns.”2

The World Health Organization (WHO) estimates that in 2008, 36.4 million people globally were infected with syphilis, and 10.6 million new cases occurred annually.3 It also estimates that in 2008, 1.4 million pregnant women were infected with syphilis, and 212,327 stillbirths or early fetal deaths, 91,764 neonatal deaths, 65,267 preterm or low birth weight infants, and 151,547 syphilis-infected newborns could be attributed to the disease.4 Sixty-six percent of those adverse events impacted women who received antenatal care but were not tested or treated for syphilis.5

The highest reported rates of syphilis in pregnant women occur in parts of sub-Saharan Africa, but substantial rates also occur in Asia and South America.6

According to our conversations with representatives of WHO and the Bill and Melinda Gates Foundation, funding for syphilis control in pregnancy is neglected relative to its importance.7

What is the program?

There are several approaches for controlling syphilis transmission8; we chose to focus on control of congenital syphilis (infection of unborn children or newborns) via testing and treatment, due to its large burden, apparent tractability, and evidence base.

Syphilis infection can be diagnosed using rapid point-of-care (POC) tests that allow testing and treatment in the same visit, do not require specialized equipment, and have accuracy comparable to laboratory-based tests.9 Syphilis and HIV can also be diagnosed in tandem using a dual rapid POC test, raising the possibility that syphilis control can be paired with more widespread HIV control efforts for greater coverage and cost-effectiveness.10 Once diagnosed, syphilis is treated using injected benzathine penicillin G.11

Researchers have evaluated interventions to increase screening and treatment rates in low- and middle-income countries with a high prevalence of congenital syphilis. These tend to implement “health systems strengthening,” including promoting the use of rapid POC tests and same-day treatment, typically via training, providing testing and treatment materials, supply chain management, and/or monitoring.12

WHO is currently leading efforts on the elimination of mother-to-child transmission (EMTCT) of HIV and syphilis by encouraging the systematic testing and treatment of pregnant women in target countries.13

Does the program have strong evidence of effectiveness?

We reviewed two types of evidence for this program:

  1. Evidence on the effectiveness of syphilis screening tests and treatments. Rapid POC syphilis screening tests and benzathine penicillin G have strong evidence of effectiveness.
  2. Evidence on the effectiveness of interventions to increase syphilis screening and treatment rates in pregnant women in low- and middle-income countries. Three RCTs have evaluated the effectiveness of interventions promoting rapid POC testing and treatment. One trial did not find an impact on treatment rates or infant mortality. A second trial found an increase in testing and treatment rates and a substantial reduction in the risk of congenital syphilis. A third trial found an increase in testing and treatment rates but did not report on perinatal outcomes. We have not investigated the reasons for the different outcomes on treatment rates found in these trials.

Effectiveness of tests and treatments

Currently available rapid POC tests, including dual syphilis/HIV tests, show acceptable sensitivity and specificity for diagnosing syphilis infection.14

Given the consensus that benzathine penicillin G effectively treats syphilis, no RCTs of this drug in treating congenital syphilis exist, so evidence supporting its effectiveness in treating congenital syphilis comes primarily from observational studies. A 2011 meta-analysis of observational studies by Blencowe et al.15 reported that treating infected pregnant women with at least 2.4 million units of benzathine penicillin G was associated with:

  • A 97 percent reduction in the risk of giving birth to an infant infected with syphilis
  • An 82 percent reduction in the risk of stillbirth
  • A 64 percent reduction in the risk of preterm birth
  • An 80 percent reduction in the risk of neonatal death16

Although direct evidence is primarily observational, the very large effect size; simple, plausible mechanism of action; and long history of clinical use together provide strong evidence that benzathine penicillin G is effective for treating congenital syphilis.17

Effectiveness of interventions to increase screening and treatment rates in pregnant women in low- and middle-income countries

Via a medium-depth literature search, we identified three RCTs of interventions intended to increase rates of syphilis screening and treatment during pregnancy in low- and middle-income countries:

  1. Myer et al. 2003 divided fourteen South African clinics into seven matched pairs and randomly assigned one clinic from each pair to implement rapid POC syphilis screening and testing, while the other continued with off-site laboratory testing and later follow-up. The trial did not find a statistically significant effect on syphilis treatment rates or infant mortality rates.18
  2. Munkhuu et al. 2009 randomized fourteen Mongolian clinics to implement rapid POC syphilis screening and treatment vs. off-site laboratory testing and later follow-up. The trial found that the intervention significantly increased syphilis testing and treatment rates and reduced cases of congenital syphilis by 94 percent (95 percent confidence interval of 66 to 99 percent).19
  3. Betrán et al. 2018 performed a stepped-wedge RCT including ten antenatal care clinics in Mozambique. Clinics were randomized to receive “kits with medical supplies, a cupboard to store these supplies, a tracking sheet to monitor stocks, and a one-day training session” at different times. Kits included rapid POC syphilis tests. The trial found that the intervention increased the rate of syphilis testing from 66 to 96 percent and the rate of syphilis treatment from 61 to 86 percent, both statistically significant. The trial did not report on pregnancy or postnatal outcomes.20

Internal and external validity adjustments

In our cost-effectiveness model, we make several adjustments to academic estimates of the treatment effectiveness of benzathine penicillin G (taken from Blencowe et al. 2011) and rates of adverse pregnancy outcomes due to syphilis (taken from Gomez et al. 2013), in order to apply this evidence to the Evidence Action program of screening and treatment in Liberia.21

We have applied adjustments for "internal validity" (i.e., the likelihood that the results of the studies we rely on are accurate) to account for several factors:

  • Some of the studies in Gomez et al. 2013 include a large proportion of patients with asymptomatic or latent infections,22 for which we expect the likelihood of adverse pregnancy outcomes to be lower than for active infections. Because of this, we believe that Gomez et al. 2013 may underestimate the likelihood of adverse pregnancy outcomes for typical syphilis cases, and we apply an upward internal validity adjustment.
  • We apply a downward adjustment to account for the fact that many of the studies reviewed in Blencowe et al. 2011 did not control for potential confounding factors.23

See this spreadsheet, "IV adjustments" sheet, for more detail on the reasoning behind our internal validity adjustments.

We have not made any adjustments for "external validity" (i.e., the likelihood that the academic estimates are applicable to the Liberian context) because our impression is that there is high consistency across studies of syphilis treatment in pregnancy in various contexts,24 and we have no particular reason to believe the program will be more or less effective in Liberia. See this spreadsheet, "EV adjustments" sheet, for more detail on our reasoning for not making an external validity adjustment.

How cost-effective is the program?

We do not have an estimate on the cost-effectiveness of syphilis screening and treatment in pregnancy programs in general. Our impression is that the costs of implementing such a program through technical assistance vary widely depending on the context of the specific funding opportunity.

We have developed a cost-effectiveness analysis of Evidence Action’s syphilis screening and treatment program in Liberia, to which we recommended a grant of $3.9 million in August 2020. This program appears to be in the range of cost-effectiveness of other programs we would consider directing funding to.25 Read more about our cost-effectiveness analysis for Evidence Action’s syphilis screening and treatment program in Liberia here.

Room for more funding

In August 2020, we recommended a grant of $3.9 million to Evidence Action to provide technical assistance to the Liberian government in order to support its switch from HIV rapid tests to dual HIV/syphilis rapid tests in routine antenatal care.

Although WHO prequalified the first dual HIV/syphilis rapid test in 2015, few countries have made the switch from HIV single rapid tests to dual HIV/syphilis rapid tests.26 Evidence Action anticipates that there are four to five additional countries where (a) syphilis screening and treatment in pregnancy has not yet been implemented, (b) the political climate is favorable to such implementation, and (c) the baseline prevalence of syphilis is sufficiently high to make this a worthwhile investment.27 Based on this, we guess that there is roughly $20-$30 million in room for more funding for one-time grants to scale up this program in other countries.28

Focus of further investigation

The primary focus of further investigation on syphilis screening and treatment during pregnancy will be to understand the impact of our recent grant to Evidence Action to provide technical assistance to Liberia to switch to dual tests, in order to inform our decision on whether or not to fund additional grants to expand the program to other countries.

Questions we will aim to answer when following up on the grant include the following:

  • What was the achieved impact and cost-effectiveness of the grant?
  • Are facility-reported data accurate and reliable enough for us to estimate screening and treatment coverage rates among pregnant people?
  • How successful was the transitioning of the program to the government?
  • What were the biggest implementation challenges of this program? Are those challenges likely to apply to other implementation settings?
  • How accurate was the forecasted budget for this program?

Other questions we plan to ask as part of further investigation include the following:

  • How promising does screening and treating pregnant people using dual syphilis/HIV tests appear to be in countries other than Liberia, in terms of counterfactual impact, cost-effectiveness, and implementation feasibility?
  • Are there other organizations we should consider supporting to expand the program’s scope?

Our process

We searched WHO, US Centers for Disease Control, and Disease Control Priorities publications for general information on syphilis and global syphilis control efforts. We performed medium-depth literature searches for meta-analyses and primary studies evaluating the effectiveness of syphilis screening methods, treatments, and screening/treatment promotion programs. We performed a medium-depth literature search for cost-effectiveness analyses of syphilis screening and treatment approaches, and we spoke with representatives of WHO and the Bill and Melinda Gates Foundation.

We conducted a grant investigation for Evidence Action’s program providing technical assistance to the Liberian government to support a switch from the use of single HIV rapid tests in antenatal care to the use of dual HIV/syphilis rapid tests. More details on the grant investigation and Evidence Action’s program in Liberia can be found here.

Sources

Document Source
Betrán et al. 2018 Source (archive)
Blencowe et al. 2011 Source (archive)
Clinton Health Access Initiative, 2018 Slide deck Source (archive)
Evidence Action, Back-of-the-envelope-calculation cost-effectiveness analysis, 2020 Unpublished
GiveWell's non-verbatim summary of a conversation with Melanie Taylor, June 2, 2020 Source
GiveWell's non-verbatim summary of a conversation with Melanie Taylor, Medical Officer, Department of Reproductive Health and Research, World Health Organization, April 24, 2018 Source
GiveWell’s non-verbatim summary of a conversation with Dr. Jerker Liljestrand, Lee Pyne-Mercier, and Jillian Foote, May 11, 2018 Source
Gliddon et al. 2017 Source (archive)
Gomez et al. 2013 Source (archive)
Hawkes et al. 2011 Source
Holmes et al. 2017 Source (archive)
Jafari et al. 2013 Source (archive)
Munkhuu et al. 2009 Source
Myer et al. 2003 Source
Newman et al. 2013 Source (archive)
Raatikainen, Heiskanen, and Heinonen 2007 Source (archive)
Terris-Prestholt et al. 2015 Source (archive)
US Centers for Disease Control and Prevention, Syphilis - CDC Fact Sheet (Detailed), 2021 Source (archive)
World Health Organization, Department of Reproductive Health and Research Annual Technical Report, 2013 Source (archive)
World Health Organization, Global guidance on criteria and processes for validation: Elimination of mother-to-child transmission of HIV and syphilis, 2017 Source (archive)
World Health Organization, Global incidence and prevalence of selected curable sexually transmitted infections, 2008 Source (archive)
World Health Organization, Information note on the use of dual HIV/syphilis rapid diagnostic tests, 2017 Source (archive)
  • 1.

  • 2.

    Holmes et al. 2017, Pg. 208.

  • 3.

  • 4.
    • WHO cites these figures in its 2013 Department of Reproductive Health and Research Annual Technical Report, writing "An estimated 1.4 million pregnant women are infected with syphilis each year, and ... there are over 300,000 stillbirths or neonatal deaths per year." World Health Organization, Department of Reproductive Health and Research Annual Technical Report, 2013 Pg. 13.
    • These figures appear to be drawn from Newman et al. 2013, a global estimate of syphilis in pregnancy produced by WHO staff and published in PLOS Medicine. For the remainder of this section we rely on Newman et al. 2013. “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.” Newman et al. 2013, abstract.

  • 5.

    “Approximately 66% of adverse outcomes occurred in ANC attendees who were not tested or were not treated for syphilis.” Newman et al. 2013, abstract.

  • 6.

    Newman et al. 2013, figure 2.

  • 7.

  • 8.

    See Holmes et al. 2017, chapters 6 and 10.

  • 9.
    • “In recent years, syphilis rapid and point-of-care (POC) tests which detect antibodies to T. pallidum antigen have become popular due to their many advantages. In order to define the ideal characteristics of a rapid and POC test, the WHO Sexually Transmitted Diseases Diagnostic Initiative (SDI) established the ASSURED criteria: Affordable, Sensitive, Specific, User-friendly, Rapid and robust, Equipment free, and Deliverable to those who need them. Rapid and POC tests are performed on one patient at a time with results communicated to the patient within 20 minutes, saving time, preventing loss to follow up and allowing for same day treatment administration.” Jafari et al. 2013, Pg. 2..
    • “Rapid and POC treponemal tests reported sensitivity and specificity estimates comparable to laboratory-based treponemal tests.” Jafari et al. 2013, abstract.

  • 10.
    • “A dual POC test for HIV and syphilis has become available that detects both treponemal and nontreponemal antibodies and is both sensitive and specific, with good test performance for the diagnosis of active syphilis (Yin and others 2013). The dual POC test is a pragmatic and attractive approach to promoting integration of PMTCT of HIV-syphilis programs (Kiarie and others 2015).” Holmes et al. 2017, Pg. 121.
    • “Of 1914 identified papers, 18 were included for the meta-analysis of diagnostic accuracy for HIV and syphilis. All diagnostic accuracy evaluation studies showed a very high sensitivity and specificity for HIV and a lower, yet adequate, sensitivity and specificity for syphilis, with some variation among types of test. Dual screening for HIV and syphilis was more cost effective than single rapid tests for HIV and syphilis and prevented more adverse pregnancy outcomes.” Gliddon et al. 2017, abstract.

  • 11.

    “The recommended treatment for adults and adolescents with primary, secondary, or early latent syphilis is Benzathine penicillin G 2.4 million units administered intramuscularly in a single dose. The recommended treatment for adults and adolescents with late latent syphilis or latent syphilis of unknown duration is Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units administered intramuscularly each at weekly intervals. The recommended treatment for neurosyphilis and ocular syphilis is Acqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units intravenously every 4 hours or continuous infusion, for 10-14 days. Treatment will prevent disease progression, but it might not repair damage already done.” US Centers for Disease Control and Prevention, Syphilis - CDC Fact Sheet (Detailed), 2021.

  • 12.
    • “Nine studies included an element of health-systems strengthening (training, laboratory support, supply chain management, or monitoring). Hawkes et al. 2011, Pg. 688.
    • Hawkes et al. 2011, table 4, pg. 687.

  • 13.

    One of the criteria for validating EMTCT in a country is “Coverage of HIV and/or syphilis testing of pregnant women of ≥95%”. World Health Organization, Global guidance on criteria and processes for validation: Elimination of mother-to-child transmission of HIV and syphilis, 2017, Pg. 16.

  • 14.
    • “Rapid and POC treponemal tests reported sensitivity and specificity estimates comparable to laboratory-based treponemal tests.” Jafari et al. 2013, abstract.
    • “A dual POC test for HIV and syphilis has become available that detects both treponemal and nontreponemal antibodies and is both sensitive and specific, with good test performance for the diagnosis of active syphilis (Yin and others 2013). The dual POC test is a pragmatic and attractive approach to promoting integration of PMTCT of HIV-syphilis programs (Kiarie and others 2015).” Holmes et al. 2017, Pg. 121.
    • “Of 1914 identified papers, 18 were included for the meta-analysis of diagnostic accuracy for HIV and syphilis. All diagnostic accuracy evaluation studies showed a very high sensitivity and specificity for HIV and a lower, yet adequate, sensitivity and specificity for syphilis, with some variation among types of test. Dual screening for HIV and syphilis was more cost effective than single rapid tests for HIV and syphilis and prevented more adverse pregnancy outcomes.” Gliddon et al. 2017, abstract.

  • 15.

    Blencowe et al. 2011 is the most recent meta-analysis we found and the only one cited by the Disease Control Priorities 3 report.

  • 16.

    “Moderate quality evidence (3 studies) supports a reduction in the incidence of clinical congenital syphilis of 97% (95% c.i 93 - 98%) with detection and treatment of women with active syphilis in pregnancy with at least 2.4 MU penicillin. The results of meta-analyses suggest that treatment with penicillin is associated with an 82% reduction in stillbirth (95% c.i. 67 - 90%) (8 studies), a 64% reduction in preterm delivery (95% c.i. 53 - 73%) (7 studies) and an 80% reduction in neonatal deaths (95% c.i. 68 - 87%) (5 studies).” Blencowe et al. 2011, abstract.

  • 17.
    • “However, given these large observed effects and a clear biological mechanism for effectiveness the GRADE recommendation is strong.” Blencowe et al. 2011, abstract.
    • “Parenteral penicillin was identified as effective in the treatment of syphilis shortly after its introduction in 1943, and is still the recommended drug for treatment of syphilis, whether acquired sexually or through transmission from mother to child during pregnancy [14]. Studies have established that penicillin is treponemocidal at fairly low serum concentrations (>0.1 mug/ml), and that longer duration regimens are more effective than shorter duration regimens, even those achieving higher concentrations [15]. These provide the therapeutic rationale for use of relatively low doses of longer acting penicillin G formulations (e.g. 2.4 million units benzathine penicillin).” Blencowe et al. 2011, Pg. 2.

  • 18.
    • “We conducted a cluster randomised controlled trial among seven pairs of primary healthcare clinics in rural South Africa, comparing on-site testing complemented by laboratory confirmation versus laboratory testing alone. Intervention clinics used the on-site test conducted by primary care nurses, with results and treatment available within an hour. Control clinics sent blood samples to the provincial laboratory, with results returned 2 weeks later.” Myer et al. 2003, abstract.
    • “Of 7134 women seeking antenatal care with available test results, 793 (11.1%) tested positive for syphilis. Women at intervention clinics completed treatment 16 days sooner on average (95% confidence interval: 11 to 21), though there was no significant difference in the proportion receiving adequate treatment at intervention (64%) and control (69%) clinics. There was also no significant difference in the proportion experiencing perinatal loss (3.3% v 5.1%; adjusted risk difference: -0.9%; 95% CI -4.4 to 2.7).” Myer et al. 2003, abstract.

  • 19.
    • “Out of 14 antenatal clinics in 6 districts of Ulaanbaatar, 7 were randomly selected for the one-stop service and the remaining for the conventional service. Intervention clinics provided on-site rapid syphilis testing and immediate treatment for positive cases and their partners. In control clinics, syphilis screening services with routine off-site rapid plasma regain testing and case management were followed.” Munkhuu et al. 2009, abstract.
    • “Of 3850 antenatal women recruited in each group, the proportion of syphilis testing at the first visit and third trimester was over 99% in the intervention group and 79.6% and 61.5% in the control group, respectively (P <0.001 for both periods). Correspondingly, syphilis cases detected in the intervention group were 73 (1.9%) and 20 (0.5%) for the first visit and third trimester, respectively, and 27 (0.9%) and 2 (0.08%) in the control group; and 98.9% (92/93) of the detected cases in the intervention group and 89.6% (26/29) in the control group were adequately treated (P = 0.02). The corresponding treatment rates for sexual partners were 94.6% and 55.2% (P <0.001). One congenital syphilis case out of 3632 deliveries in the intervention group, compared to 15 of 3552 in the control group, was diagnosed, a reduction of 93.5% (95% confidence interval, 66.0%-98.6%).” Munkhuu et al. 2009, abstract.

  • 20.

  • 21.

    For more details, see our cost-effectiveness model, "Treatment effects" sheet.

  • 22.

    For example, Ingraham, 1940-49, studied women who were asymptomatic. Characteristics of each of the studies analyzed in Gomez et al. 2013 are described in Table 1, pp. 220-221.

  • 23.
    • Blencowe et al. 2011, p. 10, Table 1 reports that the studies used to estimate treatment effectiveness of benzathine penicillin G for each of our outcomes of interest (stillbirth, neonatal mortality, preterm birth, and congenital syphilis) had “no or insufficient controlling for important potential confounding variables.”
    • We expect that pregnant people who attend early antenatal care and are screened and treated for syphilis may differ from those who do not in key ways that affect their risk for adverse pregnancy outcomes. "Under- or non-attendance associated with social and health behavioral risk factors: unmarried status, lower educational level, young maternal age, smoking and alcohol use." Raatikainen, Heiskanen, and Heinonen 2007, Abstract.
    • We also expect that attending antenatal care provides additional benefits outside of syphilis screening and treatment that are likely to reduce the likelihood of adverse pregnancy outcomes. More frequent antenatal care attendance appears to be correlated with fewer adverse pregnancy outcomes, and the difference appears to be large, though we have not looked deeply into the literature. "After logistic regression analyses, controlling for confounding, there were significantly more low birth weight infants in under- and non-attenders (OR:s with 95% CI:s: 9.18 (6.65–12.68) and 5.46 (3.90–7.65), respectively) more fetal deaths (OR:s 12.05 (5.95–24.40) and 5.19 (2.04–13.22), respectively) and more neonatal deaths (OR:s 10.03 (3.85–26.13) and 8.66 (3.59–20.86), respectively). . . . Even when birth takes place in hospital, non- or under-attendance at antenatal care carries a substantially elevated risk of severe adverse pregnancy outcome." Raatikainen, Heiskanen, and Heinonen 2007, Abstract.

  • 24.

    For example, Blencowe et al. 2011 found that the effect estimates of benzathine penicillin G treatment "were large and remarkably consistent across studies." Abstract.

  • 25.

  • 26.

  • 27.

    Evidence Action, Back-of-the-envelope-calculation cost-effectiveness analysis, 2020 (unpublished).

  • 28.

    Our rough estimate of $20-30 million is based on the budget for implementing the program in Liberia for five years, which was $3.9 million, multiplied by the four to five countries where Evidence Action anticipates the program could be implemented. We have added approximately 50% to that estimate to account for the possibility that the budget needed for implementing the program in countries larger than Liberia would be greater than $3.9 million.