Trends and Predictors of Syphilis Prevalence in the General Population: Global Pooled Analyses of 1103 Prevalence Measures Including 136 Million Syphilis Tests
Trends and Predictors of Syphilis Prevalence in the General Population: Global Pooled Analyses of 1103 Prevalence Measures Including 136 Million Syphilis Tests
Alex Smolak 2
Jane Rowley 1
Nico Nagelkerke 0
Nicholas J. Kassebaum 5 6
R. Matthew Chico 4
Eline L. Korenromp 3
Laith J. Abu-Raddad 2 7
0 Malawi-Liverpool Wellcome Trust , Blantyre , Malawi
1 London , United Kingdom
2 Infectious Disease Epidemiology Group, Weill Cornell Medicine-Qatar, Cornell University , Doha , Qatar
3 Avenir Health , Geneva , Switzerland
4 London School of Hygiene and Tropical Medicine , United Kingdom
5 Division of Pediatric Anesthesiology, Seattle Children's Hospital , Washington , USA
6 Institute for Health Metrics and Evaluation, University of Washington , USA
7 Department of Healthcare Policy and Research, Weill Cornell Medicine, Cornell University , New York , New York
Background. This study assessed levels, trends, and associations of observed syphilis prevalence in the general adult population using global pooled analyses. Methods. A standardized database of syphilis prevalence was compiled by pooling systematically gathered data. Randomeffects meta-analyses and meta-regressions were conducted using data from the period 1990-2016 to estimate pooled measures and assess predictors and trends. Countries were classified by World Health Organization region. Sensitivity analyses were conducted. Results. The database included 1103 prevalence measures from 136 million syphilis tests across 154 countries (85% from women in antenatal care). Global pooled mean prevalence (weighted by region population size) was 1.11% (95% confidence interval [CI], .99-1.22). Prevalence predictors were region, diagnostic assay, sample size, and calendar year interacting with region. Compared to the African Region, the adjusted odds ratio (AOR) was 0.42 (95% CI, .33-.54) for the Region of the Americas, 0.13 (95% CI, .09-.19) for the Eastern Mediterranean Region, 0.05 (95% CI, .03-.07) for the European Region, 0.21 (95% CI, .16-.28) for the South-East Asia Region, and 0.41 (95% CI, .32-.53) for the Western Pacific Region. Treponema pallidum hemagglutination assay (TPHA) only or rapid plasma reagin (RPR) only, compared with dual RPR/TPHA diagnosis, produced higher prevalence (AOR >1.26), as did smaller sample-size studies (<500 persons) (AOR >2.16). Prevalence declined in all regions; the annual AORs ranged from 0.84 (95% CI, .79-.90) in the Eastern Mediterranean to 0.97 (95% CI, .97-1.01) in the Western Pacific. The pooled mean male-to-female prevalence ratio was 1.00 (95% CI, .89-1.13). Sensitivity analyses confirmed robustness of results. Conclusions. Syphilis prevalence has declined globally over the past 3 decades. Large differences in prevalence persist among regions, with the African Region consistently the most affected.
In 2016, the World Health Assembly and its member states
adopted the World Health Organization’s (WHO) Global Health
Sector Strategy on Sexually Transmitted Infections (STIs),
]. The strategy aims to reduce syphilis and
gonorrhea incidence over 2018–2030 by 90%, and to reduce the
incidence of congenital syphilis to <50 cases per 100 000 live births
by 2030 [
]. However, levels and trends in adult and congenital
syphilis prevalence and incidence remain uncertain [
recent evidence suggesting increases [
], particularly among
men who have sex with men (MSM), where several countries
reported the largest increases in many years [
Our study had 5 aims to inform syphilis burden estimates:
(1) to create a global database of adult syphilis prevalence in
the general population post-1970; (2) to pool prevalence data
globally and by region; (3) to assess the association between
prevalence and region, surveyed general population type,
sex, and diagnostic assay; (4) to estimate the overall
temporal trend in prevalence by region; and (5) to inform model
assumptions and parameters, most notably the
SpectrumSTI model being developed to estimate national-level STI
We compiled a standardized global database of syphilis
prevalence in the adult general population (Global Syphilis Prevalence
Database), drawing data from the following:
1. Global AIDS Response Progress Reporting (GARPR) system,
more recently called the Global AIDS Monitoring system [
(last accessed in July 2016);
Other data sources included a major systematic review for STIs
in sub-Saharan Africa [
]; national surveillance reports
compiled by the ministries of health of Zimbabwe [
], and Mongolia (unpublished data), during pilot national
STI estimations using the Spectrum-STI model; and a national
human immunodeficiency virus (HIV)/syphilis household
survey conducted in 2016 in Zimbabwe [
The extracted GARPR data included prevalence measures
among women screened at antenatal care (ANC), and reported
by national health ministries based on either routine ANC
programmatic screening or nationally representative surveys.
The extracted IHME data were based on a PubMed
systematic search using broad search terms for post-1990 data, and
extraction of testing data from reports in the Global Health Data
] database maintained by IHME. Inclusion of data
was restricted to those in the general population with exclusion
of blood donors (because of exclusion of self-reported risks),
and high-risk and other nonrepresentative populations.
The extracted WHO-STI data included nationally or
subnationally representative general population surveys of sample
size >100 and published after 2000. Probable active syphilis
infection was defined as concurrent positive serology on both
nontreponemal and treponemal assays per the WHO [
IHME definitions. Nontreponemal laboratory diagnosis was
classified as “RPR” testing as it was done using rapid plasma
reagin (RPR) or the similar Venereal Disease Research Laboratory
(VDRL) assay [
]. The treponemal laboratory diagnosis was
classified as “TPHA” as it was usually done using the Treponema
pallidum hemagglutination assay (TPHA) or similar assay.
At least 1 reviewer evaluated each data point based on our
inclusion criteria: (1) specimens collected between 1970 and
2016; (2) study population considered representative of the
general population; (3) no apparent participant selection bias (eg,
patients seeking care for genital symptoms were excluded); and
(4) studies used nontreponemal and/or treponemal assays on
serum samples. Suspected duplicates were removed.
Information extracted included prevalence, sample size,
diagnostic assay, sex, and population type. The diagnostic
assay was categorized as RPR/TPHA; TPHA only, in ANC or
family planning (FP) population; TPHA only, in non-ANC/
non-FP population; RPR only; rapid treponemal-based assay;
and assay unknown. “TPHA only” was split into 2 categories
because TPHA positivity is a marker of cumulative exposure
that increases with age and thus should be lower in the younger
ANC/FP women compared with other women [
]. Sample size
was imputed for few ANC data points through linear
interpolation between years with reported sample sizes.
Countries were grouped by WHO region [
Region (AFRO) including most of Africa; Region of the
Americas (AMRO) including North/Central/South America;
South-East Asia Region (SEARO) including South Asia (eg,
India) and part of South-East Asia (eg, Indonesia); European
Region (EURO) including Europe and Central Asia; Eastern
Mediterranean Region (EMRO) including Middle East and
North Africa and part of the Horn of Africa; and Western
Pacific Region (WPRO) including East Asia (eg, China), part of
South-East Asia, Australia, and Oceania.
Global and regional mean syphilis prevalence (and corresponding
confidence intervals [CIs]) were estimated by pooling prevalence
measures. With the small number of measures pre-1990, these
data were excluded from main meta-analysis as they may not be
representative for 1970–1990. A meta-analysis including data over
46 years (1970–2016) was conducted as a sensitivity analysis.
The pooled means were estimated using DerSimonian and
Laird random-effects models [
]. This meta-analytic approach
accounts for sampling variation and heterogeneity in effect size
(here syphilis prevalence) [
]. The variances of prevalence
measures were stabilized using a Freeman-Tukey–type arcsine
square-root transformation [
], and then weighted using
the inverse-variance method [
]. The weights
accommodate for the variance arising from sampling variation as well as
distribution of true effect size [
Cochran’s Q-test was conducted to assess the existence of
heterogeneity in effect size [
]. The I2 measure was estimated
to assess the proportion of between-study variation in effect size
that is due to actual differences in effect size across studies rather
than chance. The prediction interval was estimated to assess the
distribution of true effects around the estimated mean [
The pooled mean male-to-female ratio of syphilis
prevalence was assessed using studies that reported prevalence in
men and women within the same population at the same time.
The ratio was estimated using random-effects meta-analyses as
Meta-analyses were conducted in R version 3.3.1 software
] using the package meta [
] except for the male-to-female
ratio, which was conducted using the package metafor [
Random-effects meta-regression models were used to identify
predictors of syphilis prevalence (and male-to-female
prevalence ratio) and sources of between-study heterogeneity.
Pre1990 data were excluded from main meta-regression, but a
meta-regression including all data (1970–2016) was conducted
as a sensitivity analysis.
The following independent variables and interaction were
specified a priori because of relevance to the study’s questions:
region, population type, sample size (dichotomized as ≥500 or
<500 persons), diagnostic assay, time (linear measure specified
Trends and Predictors of Syphilis Prevalence • CID 2018:66 (15 April) • 1185
by year, and then centered by mean year), and time´region
interaction. The time´region interaction was included to
measure the annual rate of decline in the odds of syphilis
positivity for each region separately, as opposed to a global rate
of decline. Syphilis prevalence was generally low; the annual
odds ratio for syphilis positivity can be interpreted
(approximately) as the average annual proportional decline in syphilis
prevalence, in the given region. Factors associated with
prevalence with P ≤ .1 in univariate analysis were included in the
final multivariable model. Factors associated with prevalence
with P ≤ .05 in the final multivariable model were considered
statistically significant. Inverse variance weighting was used in
For sensitivity analyses, to confirm identified trends given
the variation in data availability with time, we repeated the
same meta-regression analysis plan but excluded all pre-1995
and pre-2000 data. Also to confirm identified trends, we
conducted sensitivity analyses by excluding small sample-size
studies (<500) and studies using an assay besides RPR/TPHA.
All meta-regressions were conducted in R version 3.3.1
] using the package metafor [
Scope of Syphilis Prevalence Data
The database included 1103 prevalence measures from 154
countries carried out between 1972 and 2016. Year 2010 was
the median year. Of the 136 million syphilis tests, 1.4 million
(1.0%) were syphilis positive (Table 1). The median prevalence
was 1.4%. Most data were from ANC women (84.8%), including
both routine-care screening (44.3%) and ANC-based sentinel
surveys (40.5%). Just over 50% of surveys used RPR/TPHA dual
positivity for defining syphilis. AFRO had the largest number
of surveys, but WPRO had the largest number of people tested.
Most data were collected post-2000 (82.5%). Number of people
tested increased with time, peaking in 2014.
Meta-analyses of Syphilis Prevalence
Meta-analyses (for 1990–2016 data) estimated the pooled mean
regional syphilis prevalence at 3.04% (95% CI, 2.84%–3.24%) in
AFRO, 0.97% (95% CI, .82%–1.13%) in AMRO, 0.63% (95% CI,
.46%–.82%) in EMRO, 0.12% (95% CI, .09%–.15%) in EURO,
0.65% (95% CI, .56%–.75%) in SEARO, and 1.27% (95% CI,
1.18%–1.36%) in WPRO (Table 2). The global (unweighted)
mean prevalence was 1.61% (95% CI, 1.51%–1.71%). Weighted
by region population size, the global mean prevalence was lower
at 1.11% (95% CI, .99%–1.22%), reflecting lower prevalence in
populous regions such as SEARO. The meta-analysis including
all data (1970–2016) arrived at similar results (Supplementary
There was significant evidence for heterogeneity in effect size
(syphilis prevalence) within all regions; the P value was always
<.0001. Most variability was attributed to differences in effect
1186 • CID 2018:66 (15 April) • Smolak et al
size rather than chance (I2 > 99.5%). However, the prediction
intervals were relatively narrow, indicating only moderate
variation in prevalence across studies.
Meta-regression for Syphilis Prevalence
Univariate meta-regression analyses of syphilis prevalence
(1990–2016) data selected the variables region, sample size,
population type, diagnostic assay, and time´region
interaction for inclusion in the final multivariable model (Table 3). The
final model’s adjusted R2 was 47.16%. AFRO had the highest
prevalence. Relative to AFRO, the adjusted odds ratios (AORs)
were 0.42 (95% CI, .33–.54) for AMRO, 0.13 (95% CI, .09–.19)
for EMRO, 0.05 (95% CI, .03–.07) for EURO, 0.21 (95% CI, .16–
.28) for SEARO, and 0.41 (95% CI, .32–.53) for WPRO.
The meta-regression yielded adjustment factors for the
diagnostic assays. Compared to studies using RPR/TPHA for
diagnosis, studies diagnosing with TPHA only in the ANC/FP
populations had >2-fold higher odds of test positivity (AOR,
2.41 [95% CI, 1.36–4.22]). Studies diagnosing with TPHA only
in non-ANC/non-FP populations had nearly 3-fold higher
odds (AOR, 2.71 [95% CI, 1.39–5.27]). Studies utilizing RPR
only also had higher odds (AOR, 1.26 [95% CI, 1.04–1.53]).
Small study sample size (<500) was associated with higher
prevalence. The AOR was 2.16 (95% CI, 1.60–2.92).
The AORs for the time´region interaction term were all <1,
indicating declining syphilis prevalence in all regions, but this
decline was not statistically significant for EURO and WPRO.
AORs (per year) were 0.95 (95% CI, .93–.97) for AFRO, 0.92 (95%
CI, .88–.97) for AMRO, 0.84 (95% CI, .79–.90) for EMRO, 0.94
(95% CI, .87–1.03) for EURO, 0.90 (95% CI, .86–.94) for SEARO,
and 0.97 (95% CI, .93–1.01) for WPRO. An AOR of 0.95 implies
(approximately) a 5% annual decline in syphilis prevalence.
For sensitivity analyses, the above meta-regressions
were redone on data collected for all times (1970–2016;
Supplementary Table 2), post-1995 (Supplementary Table 3),
and post-2000 (Supplementary Table 4). These yielded similar
results for the trends and predictors, affirming the inherent
consistency of the results and confirming the temporal declines
in all regions. A meta-regression excluding studies with <500
sample size, and another excluding studies using an assay
besides RPR/TPHA, both yielded also similar trends and
predictors (Supplementary Tables 5 and 6).
Meta-analysis and Meta-regression for the Male-to-Female
Forty-three studies were identified (from 4 of the 6 regions) that
included data from the same population at the same time for
both men and women. The majority were from AFRO (67.4%),
72% had ≥500 sample size, and 72% used RPR/TPHA dual
positivity for diagnosis. Most studies were drawn from the
The pooled mean male-to-female prevalence ratio was
1.00 (95% CI, .89–1.13; Figure 1). The meta-regression
Abbreviations: AFRO, African Region; AMRO, Region of the Americas; ANC, antenatal care; EMRO, Eastern Mediterranean Region; EURO, European Region; FP, family planning; RPR, rapid
plasma reagin; SEARO, South-East Asia Region; TPHA, Treponema pallidum hemagglutination assay; WHO, World Health Organization; WPRO, Western Pacific Region.
analyses did not identify any significant predictor for this ratio
(Supplementary Table 7).
We presented analyses of 1103 syphilis prevalence measures
representing 136 million tests from 154 countries over 4
decades. Prevalence has been declining for 3 decades, if not more,
by several percentage points per year across the regions. While
the global mean weighted (1990–2016) prevalence was 1.11%,
regional prevalence varied widely, from 0.12% in EURO to
3.04% in AFRO. The analyses yielded adjustment factors for the
different diagnostic assays; diagnosis by other than RPR/TPHA
dual-positivity overestimated prevalence. Small sample-size
studies (<500) also overstated prevalence estimates. Prevalence
did not differ between men and women in the subanalysis that
investigated the male-to-female prevalence ratio.
The downward trends in prevalence in all regions were
remarkable. Though there were differences in the decline rates, the decline
was consistent in all regions, suggesting a global phenomenon.
Whether these declines reflect falls in incidence and/or shorter
durations of active infection is unclear. The incidence may have
Trends and Predictors of Syphilis Prevalence • CID 2018:66 (15 April) • 1187
fallen due to the expansion of HIV/STI response including
primary prevention interventions [
], declines in sexual risk
behavior in response to the threat of HIV infection , increased
HIV-associated mortality that may have disproportionally affected
people at higher STI risk [
], shorter duration of active infection
in sex partners [
], and possibly demographic, sociocultural,
Meta-regression Results for the Predictors of Adult Syphilis Prevalence Levels and Sources of Between-Study Heterogeneity, 1990–2016
Women and men survey
TPHA in ANC or FP population
TPHA in non-ANC or non-FP
Rapid treponemal-based assay
AFRO and year
AMRO and year
EMRO and year
EURO and year
SEARO and year
WPRO and year
No. of Studies, Surveys, and Years of
Routine ANC Screening
OR (95% CI)
AOR (95% CI)
R2 for the multivariable meta-regression model was 47.2%.
Abbreviations: AOR, adjusted odds ratio; AFRO, African Region; AMRO, Region of the Americas; ANC, antenatal care; CI, confidence interval; EMRO, Eastern Mediterranean Region;
EURO, European Region; FP, family planning; OR, odds ratio; RPR, rapid plasma reagin; SEARO, South-East Asia Region; TPHA, Treponema pallidum hemagglutination assay; WHO, World
Health Organization; WPRO, Western Pacific Region.
1188 • CID 2018:66 (15 April) • Smolak et al
and socioeconomic changes. Factors that may have contributed to
a shorter active-infection duration include progressive
improvements in coverage of syphilis screening and treatment (notably in
ANC), or more widespread use of antibiotics in general (including
for non-STI infections, which sometimes cure concurrent
syphilis). It was noteworthy that there are considerable and persistent
differences in prevalence by region, and that the prevalence in the
EURO region appears to be very low (and declining), two findings
that warrant further investigation.
While the evidence for the declines at the aggregate regional
level is robust, this may not necessarily reflect prevalence
declines in specific countries or specific subpopulations.
Surveillance data indicate that syphilis prevalence is
increasing among MSM [
]. It is possible that the declines in the
general population may reflect changes taking place in specific
sexual networks, such as in commercial heterosexual sex
networks, while prevalence could be increasing in other sexual
networks, such as among MSM. There is even some evidence in
Trends and Predictors of Syphilis Prevalence • CID 2018:66 (15 April) • 1189
few countries for increased incidence among reproductive-age
women, along with increases in congenital syphilis incidence
]. This highlights the need for continued vigilance in
syphilis testing and treatment as overall population prevalence
Our study has limitations. Although our database covered
all regions and 154 countries, availability of data varied by
region and country. While nearly all large countries contributed
data, there were exceptions (eg, Russia in EURO). Surveys may
have intentionally oversampled higher-STI or higher-risk areas
and populations for reasons of public health surveillance. The
availability of data increased with time, and the vast majority
of data were collected after 2000. This may have biased trend
estimates if earlier data were less representative. We could not,
given available data, assess possible effects of age and urban–
rural differences on prevalence.
The higher prevalence in AFRO may in part be inflated by the
higher rates of nonvenereal treponematoses infections in this
]. Serologic methods (RPR or TPHA and
combination) cannot differentiate syphilis from other treponematoses
]. More generally, syphilis diagnostic methods are imperfect.
TPHA only and RPR only provide inflated prevalence estimates.
TPHA positivity reflects ever exposure, and therefore not
necessarily current infection. RPR-only diagnosis can overestimate
prevalence with false positivity with conditions such as HIV
infection and pregnancy [
]. RPR/TPHA dual positivity, the
gold standard, unavoidably includes a small fraction of false
positives due to people whose syphilis infection was
successfully treated but who remain “serofast” [
]. We attempted to
address the diagnostic biases by including diagnostic type as
a variable, and showing similar results in a sensitivity analysis
that used only RPR/TPHA studies; nevertheless, the regional
prevalence estimates and time trends are still subject to some
bias associated with geographical and temporal variations in
test types used across the surveys.
While we assessed the average linear trends in prevalence, the
declines may have varied in intensity with time. We attempted
to assess the variation in the decline rates through a sensitivity
analysis (not shown) by incorporating a year-squared term in
the multivariable regression, but this did not result in a superior
The male-to-female prevalence ratio was assessed based on
a relatively small database (43 studies) from specific countries
from 4 of the 6 regions—the estimated ratio may not be
representative of the global ratio. There could be also variations in
this ratio by setting or region depending on the type of syphilis
Despite these limitations, our study has key strengths. This
syphilis database is, to our knowledge, the largest and most
comprehensive ever assembled. Much of included data was
collected through standardized protocols over years, enhancing
our ability to assess trends. Our sensitivity analyses confirmed
1190 • CID 2018:66 (15 April) • Smolak et al
the consistency and robustness of predictors and trends across
all regions and regardless of survey characteristics.
Our findings inform global and country-level STI
surveillance, burden estimation, and program target setting. The
results provided key parameter inputs for modeling, such
as for the Spectrum-STI surveillance tool [
]. First, our
results affirmed, based on empirical data, a 1:1
male-to-female prevalence ratio, a key modeling assumption. Second,
our results provided diagnostic-assay adjustment
factors. We found larger biases of TPHA-only and RPR-only
screening algorithms (Table 3) than previously assumed
(Supplementary Table 8) [
]. In contrast, the adjustment
factor for the rapid, treponemal-based assays was not
statistically different from 1. This supports WHO’s
recommendation to use this assay in settings where RPR/TPHA testing
is not feasible or not indicated . Third, after adjustment
for confounders, we found no difference in prevalence
between ANC/FP and other women (Table 3).
The WHO’s Global Health Sector Strategy on STIs, 2016–
2021 target of 90% reduction in syphilis incidence over
] corresponds to an average annual reduction
of 17%. This is substantially greater than the estimated
annual declines in prevalence (Table 3), the Spectrum-STI
estimates from national applications [
], and the 2015
Global Burden of Disease estimates . This suggests that
the Global STI Strategy target may be ambitious or that
insufficient resources have been made available to achieve the
target. It is clear also that major public health and
programmatic challenges remain on the road to elimination of
congenital syphilis by 2030.
Syphilis prevalence in the general population appears to be
declining in all regions. However, large differences across
regions persist, with sub-Saharan Africa continuing to be the
most affected region. The drivers and determinants of these
declines and heterogeneities merit further study, especially the
role that syphilis- and other STI-specific programs played.
Supplementary materials are available at Clinical Infectious Diseases online.
Consisting of data provided by the authors to benefit the reader, the posted
materials are not copyedited and are the sole responsibility of the authors,
so questions or comments should be addressed to the corresponding author.
Author contributions. E. L. K., L. A. R., and N. N. conceived the study
and developed the analysis plan. E. L. K., J. R., N. K., R. M. C., and
A. S. collated data. N. N., E. L. K., A. S., and L. A. R. designed the analysis
methodology. A. S. with L. A. R. conducted the analyses. A. S. and L. A. R. with
E. L. K. wrote the first draft of the article. All authors contributed to the
interpretation of the results and final version of the article.
Disclaimer. The views expressed in this article are those of the authors
and do not necessarily represent the position of Avenir Health, World
Health Organization (WHO), or other affiliated organization. The findings
achieved herein are solely the responsibility of the authors.
Financial support. The study was funded partially by WHO,
Department of Reproductive Health and Research, STI Program. We
thank Dr Teodora Wi and Dr Melanie Taylor, both from WHO, for
facilitation in compiling data reported through the Global AIDS Response
Progress Reporting system. This publication was partially made possible
by the National Priorities Research Program grant number 9-040-3-008
from the Qatar National Research Fund (a member of Qatar Foundation).
The authors are also grateful for support provided by the Biostatistics,
Epidemiology, and Biomathematics Research Core at Weill Cornell
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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