# 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. Two of three randomized controlled trials (RCTs) suggest that interventions promoting rapid POC testing can increase testing and treatment rates; one suggests that it can substantially reduce rates of congenital syphilis, while a third did not report a significant impact on treatment rates or infant mortality. We have not investigated the reasons for their divergent outcomes.
• How cost-effective is it? Our initial cost-effectiveness estimate suggests that syphilis screening and treatment (vs. no action) may be in the range of cost-effectiveness of our current top charities. We have not evaluated the cost-effectiveness of interventions that intend to increase syphilis screening and treatment rates.
• Does it have room for more funding? We have not identified charities that directly fund congenital syphilis screening and treatment efforts, and we have not yet explored other possible funding options.
• 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

## 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 the 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

The 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 impact treatment rates or infant mortality, a second trial increased testing and treatment rates and substantially reduced the risk of congenital syphilis, and a third trial increased testing and treatment rates but did not report on perinatal outcomes. We have not investigated the reasons for the divergent outcomes of 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 intervention did not increase syphilis treatment rates or reduce infant mortality.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 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 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. They did not report pregnancy or postnatal outcomes.20

Of the three RCTs, one did not impact treatment rates or infant mortality, a second trial increased testing and treatment rates and substantially reduced the risk of congenital syphilis, and a third trial increased testing and treatment rates but did not report on perinatal outcomes. We have not investigated the reasons for the divergent outcomes of these trials.

## How cost-effective is the program?

We reviewed academic cost-effectiveness analyses of maternal syphilis testing and treatment in low- and middle-income countries, and we conducted our own. Both suggest that the intervention is highly cost-effective, and the latter suggests a cost-effectiveness similar to our top charities. We did not have enough information to conduct cost-effectiveness calculations on programs that intend to increase screening and testing rates in pregnant women.

Academic cost-effectiveness analyses suggest that rapid POC screening and treatment of pregnant women is highly cost-effective, ranging from $11 to$54 per disability-adjusted life-year averted.21 However, we did not encounter cost-effectiveness analyses of interventions to increase screening and treatment rates in pregnant women in low- and middle-income countries.

We created a rough cost-effectiveness estimate of screening and treatment of pregnant women for syphilis based on observed and modeled data from 20 clinics in Peru, Tanzania, and Zambia (see our model here).22 Our analysis suggests that syphilis screening and treatment of pregnant women in low- and middle-income countries may be in the range of cost-effectiveness of our top charities.

Note that our cost-effectiveness analyses are simplified models that do not take into account a number of factors. There are limitations to this kind of cost-effectiveness analysis, and we believe that cost-effectiveness estimates such as these should not be taken literally, due to the significant uncertainty around them. We provide these estimates (a) for comparative purposes and (b) because working on them helps us ensure that we are thinking through as many of the relevant issues as possible.

Major uncertainties in our model include the following:

• It does not include benefits to mothers of eliminating syphilis.
• It does not include benefits to children of preventing low birth weight.
• It does not consider potential cost-effectiveness gains of testing for syphilis and HIV at the same time.
• It does not include patient costs.
• We have not vetted cost estimates.
• We have not put much thought into how to model the postnatal effects of syphilis infection in infants and we are highly uncertain about our current moral value estimate.

We were unable to model the cost-effectiveness of interventions to increase screening and treatment rates in pregnant women in low- and middle-income countries because we did not encounter cost data in the meta-analysis or three RCTs we considered. However, Betrán et al. 2018 state that they “have been engaged in an assessment of the cost-effectiveness and implementation options for scaling up the use of antenatal care supply kits in Mozambique,”23 potentially providing a future opportunity for cost-effectiveness analysis, although the intervention applied in this trial was broader than syphilis screening and treatment.

## Organizations and room for more funding

Dr. Melanie Taylor is currently the only full-time staff member working on syphilis control at the WHO.24 According to Dr. Taylor, the WHO does not currently receive charitable funding for its syphilis control efforts, and its total funding for this program is very limited.25 In conversations with Dr. Taylor and representatives of the Bill and Melinda Gates Foundation, we did not identify charities that currently directly fund congenital syphilis screening and treatment efforts.26 However, we have not yet explored other possible funding options.

## Focus of further investigation

Questions we would ask as part of further investigation include:

• What accounts for differences in the outcomes of RCTs of interventions that promote syphilis testing and treatment of pregnant women?
• How does the timing of treatment impact the risk of perinatal complications?
• How much does syphilis prevalence vary between countries, and how does this impact the cost-effectiveness of syphilis control interventions?
• What is the long-term burden of children who survive congenital syphilis?
• What is the cost-effectiveness of screening and treating pregnant women using dual syphilis/HIV tests?
• What are the costs and cost-effectiveness of interventions that promote syphilis testing and treatment of pregnant women?
• Are there funding opportunities we may have missed or that may be available in the future?

## 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 the WHO and the Bill and Melinda Gates Foundation.

## Sources

Document Source
Betrán et al. 2018 Source
Blencowe et al. 2011 Source
Disease Control Priorities 3, volume 6 Source
GiveWell’s non-verbatim summary of a conversation with Dr. Jerker Liljestrand, Lee Pyne-Mercier, and Jillian Foote, May 11, 2018 Source
GiveWell's non-verbatim summary of a conversation with Melanie Taylor, Medical Officer, Department of Reproductive Health and Research, World Health Organization, April 24th, 2018 Source
Gliddon et al. 2017 Source
Hawkes et al. 2011 Source
Jafari et al. 2013 Source
Munkhuu et al. 2009 Source
Myer et al. 2003 Source
Newman et al. 2013 Source
Terris-Prestholt et al. 2015 Source
US Centers for Disease Control, Syphilis - CDC Fact Sheet (Detailed) Source
WHO, Department of Reproductive Health and Research Annual Technical Report Source
WHO, Global guidance on criteria and processes for validation: Elimination of Mother-to-Child Transmission of HIV and Syphilis Source
WHO, Global incidence and prevalence of selected curable sexually transmitted infections Source
• 1.
• 2.

Disease Control Priorities 3, volume 6, Pg. 208.

• 3.
• 4.
• The 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." WHO, 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 Disease Control Priorities 3, volume 6, 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).” Disease Control Priorities 3, volume 6, 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, Syphilis - CDC Fact Sheet (Detailed).

• 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%”. WHO, 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).” Disease Control Priorities 3, volume 6, 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.

Disease Control Priorities 3, volume 6, table 6.6, Pg. 128.

• 22.

Data are from Terris-Prestholt et al. 2015.

• 23.

Betrán et al. 2018, Pg. e63.

• 24.

"Dr. Taylor is the only WHO staff member working on congenital syphilis prevention and spends approximately 75% of her time on this work." GiveWell's non-verbatim summary of a conversation with Melanie Taylor, Medical Officer, Department of Reproductive Health and Research, World Health Organization, April 24th, 2018, Pg. 2.

• 25.
• 26.