Jurnal Evidanbased

Strategies of testing for syphilis during pregnancy (Review)
Shahrook S, Mori R, Ochirbat T, Gomi H
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2014, Issue 10
http://www.thecochranelibrary.com
Strategies of testing for syphilis during pregnancy (Review)

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 29
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Strategies of testing for syphilis during pregnancy (Review) i

[Intervention Review]
Strategies of testing for syphilis during pregnancy
Sadequa Shahrook1 , Rintaro Mori1 , Tumendemberel Ochirbat2 , Harumi Gomi3

1 Department of Health Policy, National Center for Child Health and Development, Tokyo, Japan. 2 Global Health Policy, Graduate
School of Medicine, University of Tokyo, Bunkyo-ku, Japan. 3 Center for Global Health, Mito Kyodo General Hospital, University of
Tsukuba, Mito, Japan
Contact address: Rintaro Mori, Department of Health Policy, National Center for Child Health and Development, 2-10-1 Okura,
Setagaya-ku, Tokyo, Tokyo, 157 8535, Japan. [email protected].
Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: New, published in Issue 10, 2014.
Review content assessed as up-to-date: 30 September 2014.
Citation: Shahrook S, Mori R, Ochirbat T, Gomi H. Strategies of testing for syphilis during pregnancy. Cochrane Database of Systematic
Reviews 2014, Issue 10. Art. No.: CD010385. DOI: 10.1002/14651858.CD010385.pub2.
ABSTRACT
Background
Each year about two million pregnant women are infected with preventable syphilis infection, mostly in developing countries. Despite
the expansion of antenatal syphilis screening programmes over the past few decades, syphilis continues to be a major public health
concern in developing countries. Point-of-care syphilis testing may be a useful strategy to substantially prevent syphilis-associated
perinatal mortality and other negative consequences in resource-poor settings. However, the evidence on effectiveness has been generated
mostly from observational study designs or has been reported as a mixed-intervention effect.
Objectives
To assess the effectiveness of antenatal syphilis screening in improving the uptake of screening tests and treatment, and reducing perinatal
mortality.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (30 September 2014) and the reference lists of retrieved
studies.
Selection criteria
Randomised (individual and cluster) controlled trials comparing different screening tests conducted during routine antenatal check-
ups versus no screening test. Cross-over trials and quasi-randomised experimental study designs were not eligible for inclusion.
Data collection and analysis
Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked for accuracy.
Main results
We included two cluster-randomised controlled trials (three reports). Both trials assessed point-of-care syphilis testing with conventional
testing methods and together involved a total of 8493 pregnant women. Data from these trials were not amenable to meta-analysis as
the measure of effectiveness was assessed in a non-comparable way.
One trial randomised 14 antenatal clinics (including 7700 pregnant women) and was carried out at in Ulaanbaatar, Mongolia. The
trial assessed one-stop syphilis testing using a rapid treponemal test, and was judged to have unclear methods of random sequence
Strategies of testing for syphilis during pregnancy (Review) 1
generation, allocation concealment, selective reporting, and other bias and low risk of bias for incomplete outcome data. Blinding was
not reported and was assessed as high risk. The point-of-care testing provided screening, test results and treatment within the same day.
The trial appears to have adjusted their results to account for clustering. We entered the data into RevMan using the generic inverse
variance method. The incidence of congenital syphilis was lower in the clusters receiving on-site screening (adjusted odds ratio (AOR)
0.09, 95% confidence interval (CI) 0.01 to 0.71) and the proportion of women tested for syphilis was higher in the clusters receiving
on-site screening at both the first antenatal visit and at the third trimester visit (OR 989.80, 95% CI 16.27 to 60233.05; OR 617.88,
95% CI 13.44 to 28399.01). Adequate treatment and partner treatment was higher with the on-site screening (AOR 10.44, 95% CI
1.00 to 108.99; AOR 18.17, 95% CI 3.23 to 101.20) and more syphilis cases were detected at first and third trimester visits with the
on-site screening (AOR 2.45, 95% CI 1.44 to 4.18; AOR 6.27, 95% CI 1.47 to 26.69). Perinatal mortality, incidence of HIV/AIDS,
obstacles in uptake of screening, any other adverse effects, or healthcare resource usage were not reported in this trial.
The second trial divided clinics into seven matched pairs (including 7618 pregnant women, although results were only presented for
the positive cases (793 women)), and within each pair one clinic was randomised to receive the on-site screening and the other to
continue routine laboratory testing. The trial was conducted in primary healthcare clinics in KwaZulu-Natal, South Africa. Random
sequence generation were judged to be at low risk of bias, but allocation concealment and incomplete outcome data were judged to
be high risk. Other bias and selective reporting bias remain unclear. Blinding was not reported and was assessed as high risk of bias.
This trial assessed the primary outcome of this review (perinatal mortality) and the secondary outcomes (adverse outcomes; adequate
treatment; syphilis prevalence) in the subset of women (793 women) who tested positive for syphilis. Only one outcome, adequate
treatment, was adjusted to account for cluster design. However, not enough information was provided to include this in an analysis
using the generic inverse variance method. Where possible, results have therefore been presented in forest plots (perinatal mortality;
adequate treatment), as if the data are from a parallel randomised controlled trial. These results should therefore be interpreted with
caution.
The trial reported on perinatal mortality in women with positive test results and showed that on-site screening using a rapid plasma
reagin test had no clear evidence of an effect on perinatal mortality reduction (odds ratio (OR) 0.63; 95% CI 0.27 to 1.48; 18/549
(3.3%) versus 8/157 (5.1%)). After loss to follow up, 396/618 (64.1%) women with positive test results received adequate treatment
(two or more doses of 2.4 mega units of benzathine penicillin) in the intervention cluster versus 120/175 (68.6%) in the control (OR
0.82; 95% CI 0.57 to 1.17). It was not possible to include any other data on reported outcomes in forest plots (adverse outcomes;
syphilis prevalence). Incidence of congenital syphilis, proportion of women test for syphilis, incidence of HIV/AIDS, obstacles in
uptake of screening, partner treatment, or healthcare resource usage were not reported in this trial.
Authors’ conclusions
This review included evidence from two cluster-randomised trials at high or unclear risk of bias for most of the ’Risk of bias’ domains.
Data were not combined in meta-analysis because the trials used non-comparable measures of effectiveness.
Point-of-care syphilis testing showed some promising results for syphilis detection and treatment rates and for use in different settings.
In Mongolia point-of-care testing was found to be effective in increasing the proportion of pregnant women tested for syphilis and
treatment provided, reducing congenital syphilis, and improving access to treatment for both women and their partners. In contrast,
in rural South Africa, among women with positive test results, there was no clear evidence of an effect of point-of-care syphilis testing
in increasing adequate syphilis treatment rates, and reducing perinatal mortality, but point-of-care testing was found to reduce delay
in seeking treatment.
More trials are therefore warranted to determine the effectiveness of available testing strategies for improving syphilis-associated adverse
outcomes in pregnant women and neonates, especially in high-risk regions.
PLAIN LANGUAGE SUMMARY

Antenatal screening tests for the prevention and treatment of syphilis
Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum. A major public health issue in developing
countries, the condition develops over four stages and is potentially fatal if untreated. A pregnant woman with syphilis can transmit the
infection to her baby, which may result in a severe condition in liveborn infants, stillbirth, or neonatal death. Syphilis infection can be
transmitted by direct person-to-person contact via open sores on the lips, mouth, genitals and other areas, and during vaginal, anal or
oral sexual intercourse. Open sores also increase the risk of human immunodeficiency virus (HIV) infection. Universal syphilis screening
within an existing antenatal care program has been advocated as an effective way to reduce syphilis-associated adverse outcomes.
However, despite decades of syphilis-testing programs and substantial advances in screening technology, successful prevention and
treatment of syphilis have been limited. This is largely due to delays in the identification and treatment of infected women. Technical
and logistical difficulties with testing, lack of antenatal care, and poor-quality services are possible contributing factors. It is therefore
crucial to investigate available randomised controlled trials to determine which test strategies are most effective in developing countries.
Two included trials assessed point-of-care syphilis testing against conventional testing methods. The first trial was carried out in
Mongolia and compared the rapid treponemal test with conventional testing. The point-of-care testing provided screening, test results
and treatment within the same day. The trial reported a marked improvement in screening coverage, case detection and treatment,
both at the first visit and in the third trimester, compared with conventional screening. The second trial was conducted at primary
healthcare clinics in rural South Africa. On-site screening using the rapid plasma reagin (RPR) test was compared with conventional
testing. Among women who tested positive for syphilis, no clear reduction in perinatal deaths was observed in those who had RPR
testing compared with conventional testing, and technical and logistical difficulties were reported.
Both trials were mainly at high risk or unclear risk of bias. In one trial, in Mongolia, on-site screening was better at detecting syphilis
cases. More trials are warranted, especially in regions where the disease burden is increasing and HIV co-infection is probable due to
high HIV/AIDs prevalence.
BACKGROUND In approximately 69% of pregnant women with inadequately

treated or untreated syphilis, the infection will be transmitted to
Syphilis is a potentially fatal, sexually transmitted infection (STI) the fetus causing severe birth outcomes such as spontaneous abor-
that can be transmitted from a pregnant woman to the fetus. tion, prematurity, stillbirth, low birthweight, neonatal death, or se-
Though preventable, each year about two million pregnant women rious sequelae in liveborn infants (Hawkes 2011). However, these
become infected with syphilis globally, the majority of whom live adverse outcomes are preventable, and existing approaches such as
in developing countries (Schmid 2004). The yearly toll of ad- incorporated sexual and reproductive health programs, antenatal
verse birth outcomes associated with untreated maternal syphilis syphilis screening, and timely treatment have been suggested as a
is 730,000 to 1,500,000, of which nearly 650,000 deaths occur way to reduce syphilis-attributable perinatal deaths and stillbirth
in fetuses and newborns (Schmid 2007; WHO 2010). Maternal incidence by about 50% (Bique 2000; Hawkes 2011; Myer 2003;
syphilis is less of a concern in developed countries than in devel- Wilkinson 1998). Routine antenatal check-ups have been widely
oping countries. For example, the seroprevalence of women with promoted to pregnant women in developing countries (UNICEF
syphilis attending antenatal care is estimated to be highest in Latin 2009; WHO 2007), however despite the existence of antenatal
America (3.90%) and Africa (1.98%) (Schmid 2007). In sub-Sa- screening policies in most countries, policy implementation is typ-
haran Africa, mother-to-child transmission of syphilis is responsi- ically lacking (Gloyd 2001; Hossain 2007).
ble for significant proportion of perinatal mortality count (21%)
(Shafii 2008) and associated morbidities e.g. stillbirth and low
birthweight (25%) (Watson-Jones 2002), serious neonatal infec- Additionally, the control and elimination of syphilis is hindered
tion (20%) (Schulz 1987) and neonatal death (35%) (McDermott by a lack of testing among the majority of infected women. Of
1993). Furthermore, concern is deepening in countries such as the women who are tested, most women do not undergo prompt
China where an increase in disease incidence has already been ob- treatment or are missed entirely (Newman 2013; WHO 2007;
served (Cheng 2007; Tucker 2010). For example, in 2008 an av- WHO 2010). Despite the availability of various improved diag-
erage of more than one baby was born per hour with congenital nostic tools and cost-effective prevention therapy (Peeling 2004;
syphilis among 9480 total cases; the observed amplification rate WHO 2010), attempts to prevent and eliminate syphilis are pre-
was by a factor of 12 during the five preceding years (Tucker 2010). dominantly disrupted by the complex natural history of the dis-
Moreover, people with human immunodeficiency virus (HIV) are ease and the absence of precise clinical presentation in infected
more likely to acquire syphilis infection and vice versa (Walker patients (Peeling 2004). It has also been suggested that the absence
2001). As a result, the rise in congenital syphilis in many countries of antenatal care, and poor-quality services are likely to be impor-
in Sub-Saharan Africa has been aggravated by HIV as this region tant factors in the increase of congenital syphilis (Walker 2002;
is highly burdened by HIV infection (WHO 2010). Wilkinson 1998).
Scientific efforts to prevent and eliminate congenital syphilis have congenital syphilis are usually born premature and classic signs of
been accelerated by the development of reliable and improved the condition include marasmus (acute malnutrition), pot belly,
diagnostic tools such as on-site syphilis testing, which provides and wrinkled skin, especially on the face (Walker 2001). The sever-
rapid results and immediate therapy for seropositive women in pri- ity of adverse birth outcomes associated with congenital syphilis
mary care settings. In addition to laboratory testing, on-site testing is usually determined by the length of the maternal infection as
might be a useful strategy to curb congenital syphilis and its associ- well as the stage of pregnancy. The majority of pregnant women
ated adverse outcomes by reducing treatment delays and increasing with syphilis as well as infected newborns at time of birth, are
the numbers of seropositive women receiving treatment (Delport asymptomatic (Peeling 2004). Therefore, if not treated immedi-
1998; Fonn 1996; Jenniskens 1995). Although the effects of on- ately, within a few weeks the disease progression can be fatal (CDC
site testing in observational studies (Bique 2000; Temmerman 2010).
2000) were positive, one randomised controlled study found no
effective impact on either treatment rates or perinatal mortality
reduction (Myer 2003). Despite the presence of laboratory access Description of the intervention
in some developing areas, the number of infected women who
Early detection and administration of appropriate therapies are
receive a full course of treatment remains low (Wilkinson 1997).
at the centre of syphilis prevention strategies: undergoing syphilis
Furthermore, in developing countries, useful screening tools such
screening tests at the first antenatal check-up within the first
as treponemal tests are often obtained only at reference laboratories
trimester and again in the late stage of pregnancy followed by
or large regional centres (Peeling 2004). Hence, syphilis screening
prompt treatment of sero-positive women with a single dose of
has been constrained by varying dynamics and largely due to delays
long-acting penicillin before the second trimester (WHO 2010).
in diagnosis and treatment of infected women (Rotchford 2000).
Serologic testing is the core strategy of syphilis screening and diag-
It is therefore crucial to identify from randomised controlled trials
nosis (Hook 1992; Peeling 2004). The two main types of serologic
the most effective strategies for antenatal syphilis testing in order
tests are non-treponemal tests and treponemal tests. Non-trepone-
to improve the uptake of testing and treatment, and to reduce
mal tests identify active infection by detecting antibodies to im-
perinatal mortality.
precise antigens, e.g. cardiolipin present in the sera of patients with
syphilis. Non-treponemal tests such as the RPR test are easy to per-
form, sensitive, and relatively cheap (Peeling 2004). Furthermore,
Description of the condition the non-treponemal test is quantitative and the treatment response
Syphilis is caused by the bacterium Treponema pallidum. The dis- can be monitored over time (Fiumara 1978). On the other hand,
ease has protean clinical manifestations that may involve any or- treponemal tests are more specific than the former but in most
gans and a range of severe health outcomes (CDC 2010). Syphilis cases, treponemal tests continue to be positive, regardless of treat-
infection is transmitted via direct person-to-person contact with ment administration. In addition, treponemal tests, e.g. enzyme
an open syphilitic sore, and during vaginal, anal or oral sexual immunoassay (EIAs) are more costly than non-treponemal tests
intercourse. The external genitals, vagina, rectum or anus are the and can be difficult to perform (Peeling 2004). Seroprevalence
main organs where sores usually occur, as well as the lips and inside data from antenatal screening programmes are used as one of the
the mouth. The risk of acquiring HIV infection in an individual proxy indicators to track the prevalence of sexually transmitted
with syphilis is two- to five-fold if exposed when an ulcer is present, infections (Peeling 2004). Non-treponemal tests such as RPR can
and consequently, individuals involved in high-risk sexual behav- be performed at a local laboratory but one of the major limita-
ior are likely to have a higher risk of syphilis and HIV co-infection. tions is that RPR cannot be carried out on whole blood. Con-
Furthermore, the syphilis bacterium can be vertically transmitted versely, although useful to obtain prevalence rates and surveillance
to the fetus of a pregnant woman who has a syphilis infection, facts, confirmatory assays such as EIAs are usually only available at
with at least two-thirds of all newborns infected with maternal reference or large regional laboratories in resource-poor settings.
syphilis (Zenker 1990). The likelihood of fetal involvement occurs Currently, numerous improved sero-diagnostic tools are available
among women with active syphilis infection (i.e. rapid plasma rea- for the control and treatment of syphilis; for example, RPR and
gin (RPR) titre greater than 1:4), specifically, with inadequately or reagents of the Venereal Disease Research Laboratory (VDRL) test
untreated infection acquired in the five years prior to pregnancy can be stored at room temperature. In addition, existing solar-
(Blencowe 2011). Sixty-nine per cent of women with active infec- energy powered rotators have provided the means to carry out
tion may experience a variety of adverse birth outcomes (Ingraham these tests in resource-poor settings where there is a lack of, or no
1950; McDermott 1993), i.e. late miscarriage (after 16 weeks) or electricity (Peeling 2004). Rapid and easy treponemal tests using
stillbirth in 25% cases, neonatal death at term in 11%, preterm or whole blood, serum or plasma can be stored at room temperature
low birthweight in 13%, and classic symptoms and clinical signs for six to 12 months, are cost-effective (Peeling 2004), and overall
of congenital syphilis in 20% (Ingraham 1950; McDermott 1993; have a performance comparable to laboratory tests (Fears 2001;
Schmid 2004; Watson-Jones 2002). Symptomatic newborns with Lien 2000). It is noteworthy that syphilis screening and treatment

are estimated to be the most economical public health interven- Criteria for considering studies for this review
tions available (WHO 2007).
Types of studies
How the intervention might work We planned to include all randomised (individual and clustered)
Prevention success lies in the early detection of syphilis in preg- controlled trials that compared different screening test strategies
to detect and treat syphilis infection in pregnant women during
nant women and prompt treatment management before the sec-
routine antenatal check-ups. The unit of randomisation could be
ond trimester (WHO 2010). As recommended by the WHO,
either the individual pregnant woman or any formal healthcare
all pregnant women should undergo antenatal syphilis screening
facilities, e.g. health posts/clinics. We identified and included only
tests; however, women without test results at delivery should also
two cluster-randomised trials. Studies presented only as abstracts
be tested or re-tested. Women should also be well informed about
the importance of being tested for HIV infection. Additionally, were considered, only if accompanied with appropriate publica-
tion status. Cross-over trials and quasi-randomised experimental
HIV testing should also be offered to their partners and treatment
study designs were not eligible for inclusion.
planning should be primed in order to protect their infants at
birth. Screening pregnant women in the early stage of pregnancy
(preferably prior to 24 weeks of gestational age) can substantially
avert the burden of associated adverse birth outcomes in many Types of participants
developing countries. Intial screening at routine antenatal check- Eligible participants were either pregnant women at any stage of
ups in the first trimester and again in the late stage of pregnancy, their pregnancy or healthcare facilities/clinics depending on the
as well as prompt treatment of seropositive women is the desired randomisation unit in each of the included trials.
approach to syphilis prevention. Once diagnosed, syphilis can be
cured with a single dose of long-acting penicillin, which prevents
transmission to the unborn infant. Depending on the stage of Types of interventions
disease progression, one (primary or secondary disease) or three Antenatal syphilis screening tests versus no screening tests or stan-
(latent disease) doses of penicillin can effectively treat maternal dard screening. We also considered trials investigating the effect of
syphilis (WHO 2010). combined screening strategies, only if the difference between arms
was that of strategies for testing syphilis i.e. syphilis and HIV/
AIDs testing versus HIV/AIDs testing.
Why it is important to do this review
Evidence from randomised controlled trials on the effectiveness of Types of outcome measures
screening strategies for the detection and treatment of maternal
syphilis is scarce, and most knowledge is derived from observa-
tional studies. Moreover, earlier reviews of syphilis screening and
Primary outcomes
treatment did not detect an intervention effect on preterm birth
reduction (Barros 2010), nor a high grade of evidence (Menezes • Perinatal mortality
2009). Therefore, in this review we attempted to accumulate qual- • Incidence of congenital syphilis**
ity evidence on the effectiveness of syphilis screening strategies in • Proportion of pregnant women tested for syphilis and
pregnant women and their neonates. treatment provided
Secondary outcomes
• Incidence of HIV/AIDs in pregnant women and neonates
OBJECTIVES • Obstacles/challenges in the uptake of antenatal syphilis
screening tests e.g. availability of the useful syphilis tests and
To assess the effectiveness of antenatal syphilis screening in im-
living far from the antenatal clinic (ANC) service spots
proving the uptake of screening tests and treatment, and reducing
• Any other adverse outcomes reported in the included
perinatal mortality.
studies (summarised)
• Adequate treatment*
• Partner treatment*
METHODS • Syphilis prevalence*

Economic data for the use of healthcare resources Data collection and analysis
The following methods are based on a standard template used by
the Cochrane Pregnancy and Childbirth Group.
Pregnant women
• Antenatal hospital admission Selection of studies
Two review authors, S Shahrook (SS) and R Mori (RM), inde-
pendently assessed all potential studies identified by the search
Neonates methods to determine whether they met all inclusion criteria. Any
• Special care/intensive care admission disagreement was resolved through discussion.
* Outcome not prespecified in our protocol.

Data extraction and management
** Outcome was prespecified in our protocol as a secondary out- For eligible studies, SS and RM independently extracted data using
come. a specified form. We resolved discrepancies through discussion.
We entered data into Review Manager software (RevMan 2014)
and checked for accuracy.
Search methods for identification of studies When information regarding any of the above was unclear, we
The following methods are based on a standard template used by contacted authors of the original reports to provide further details.
the Cochrane Pregnancy and Childbirth Group.
Assessment of risk of bias in included studies

Electronic searches SS and RM independently assessed risk of bias for each study us-
We contacted the Trials Search Co-ordinator to search the ing the criteria outlined in the Cochrane Handbook for Systematic
Cochrane Pregnancy and Childbirth Group’s Trials Register (30 Reviews of Interventions (Higgins 2011). We resolved any disagree-
September 2014). ment by discussion.
The Cochrane Pregnancy and Childbirth Group’s Trials Register
is maintained by the Trials Search Co-ordinator and contains trials
identified from: (1) Random sequence generation (checking for possible
1. monthly searches of the Cochrane Central Register of selection bias)
Controlled Trials (CENTRAL); We described for each included study the method used to generate
2. weekly searches of MEDLINE; the allocation sequence in sufficient detail to allow an assessment
3. weekly searches of Embase; of whether it should produce comparable groups.
4. handsearches of 30 journals and the proceedings of major We assessed the method as:
conferences; • low risk of bias (any truly random process, e.g. random
5. weekly current awareness alerts for a further 44 journals number table; computer random number generator);
plus monthly BioMed Central email alerts. • high risk of bias (any non-random process, e.g. odd or even
Details of the search strategies for CENTRAL, MEDLINE and date of birth; hospital or clinic record number);
Embase, the list of handsearched journals and conference pro- • unclear risk of bias.
ceedings, and the list of journals reviewed via the current aware-
ness service can be found in the ‘Specialized Register’ section
within the editorial information about the Cochrane Pregnancy (2) Allocation concealment (checking for possible selection
and Childbirth Group. bias)
Trials identified through the searching activities described above We described for each included study the method used to con-
are each assigned to a review topic (or topics). The Trials Search ceal allocation to interventions prior to assignment and assessed
Co-ordinator searches the register for each review using the topic whether intervention allocation could have been foreseen in ad-
list rather than keywords. vance of, or during recruitment, or changed after assignment.
We assessed the methods as:
• low risk of bias (e.g. telephone or central randomisation;
Searching other resources
consecutively numbered sealed opaque envelopes);
We checked the reference lists of retrieved studies. • high risk of bias (open random allocation; unsealed or non-
We did not apply any language restrictions. opaque envelopes, alternation; date of birth);

• unclear risk of bias. • high risk of bias (where not all the study’s pre-specified
outcomes have been reported; one or more reported primary
outcomes were not pre-specified; outcomes of interest are
(3.1) Blinding of participants and personnel (checking for reported incompletely and so cannot be used; study fails to
possible performance bias) include results of a key outcome that would have been expected
We described for each included study the methods used, if any, to to have been reported);
blind study participants and personnel from knowledge of which • unclear risk of bias.
intervention a participant received. We considered studies to be
at low risk of bias if they were blinded, or if we judged that the
lack of blinding would be unlikely to affect results. We assessed (6) Other bias (checking for bias due to problems not
blinding separately for different outcomes or classes of outcomes. covered by (1) to (5) above)
We assessed the methods as: We described for each included study any important concerns we
• low, high or unclear risk of bias for participants; have about other possible sources of bias.
• low, high or unclear risk of bias for personnel. We assessed whether each study was free of other problems that
could put it at risk of bias:
• low risk of other bias;
(3.2) Blinding of outcome assessment (checking for possible
• high risk of other bias;
detection bias)
• unclear whether there is risk of other bias.
We described for each included study the methods used, if any, to
blind outcome assessors from knowledge of which intervention a
participant received. We assessed blinding separately for different (7) Overall risk of bias
outcomes or classes of outcomes. We made explicit judgements about whether studies were at high
We assessed methods used to blind outcome assessment as: risk of bias, according to the criteria given in the Cochrane Hand-
• low, high or unclear risk of bias. book (Higgins 2011). With reference to (1) to (6) above, we as-
sessed the likely magnitude and direction of the bias and whether
we considered it is likely to impact on the findings. We explored
(4) Incomplete outcome data (checking for possible attrition
the impact of the level of bias through undertaking sensitivity
bias due to the amount, nature and handling of incomplete
analyses - see Sensitivity analysis.
outcome data)
We described for each included study, and for each outcome or
class of outcomes, the completeness of data including attrition and Measures of treatment effect
exclusions from the analysis. We stated whether attrition and ex-
clusions were reported and the numbers included in the analysis at
each stage (compared with the total randomised participants), rea- Dichotomous data
sons for attrition or exclusion where reported, and whether miss- For dichotomous data, we have presented results as odds ratio with
ing data were balanced across groups or were related to outcomes. 95% confidence intervals.
We assessed methods as:
• low risk of bias (e.g. no missing outcome data; missing
outcome data balanced across groups); Continuous data
• high risk of bias (e.g. numbers or reasons for missing data For continuous data, we would have used the mean difference
imbalanced across groups; ‘as treated’ analysis done with if outcomes were measured in the same way between trials. We
substantial departure of intervention received from that assigned planned to use the standardised mean difference to combine trials
at randomisation); that measured the same outcome, but used different methods.
• unclear risk of bias.
Unit of analysis issues

(5) Selective reporting (checking for reporting bias)
We described for each included study how we investigated the
possibility of selective outcome reporting bias and what we found. Cluster-randomised trials
We assessed the methods as: We included two cluster-randomised trials in the analyses. We were
• low risk of bias (where it is clear that all of the study’s pre- unable to pool the summary effect as the measure of effectiveness
specified outcomes and all expected outcomes of interest to the was assessed in different ways. In one trial (Munkhuu 2009) the
review have been reported); results appear to have been adjusted to account for clustering.

The adjusted odds ratios [AOR] and P values were presented ( mary outcome which is irreversible, such as mortality as described
Table 1) and we used these to calculate the log odds ratio and in the Cochrane Handbook for Systematic Reviews of Interventions
standard error and entered these into RevMan 2014 using the section 16.4.
generic inverse-variance method. In the other trial (Myer 2003),
only one outcome, adequate treatment, was adjusted to account for
the cluster design. However, not enough information was provided Dealing with missing data
to include this in an analysis using the generic inverse variance For included studies, we noted levels of attrition. In future updates,
method. we will explore the impact of including studies with high levels of
In future updates of this review, if more cluster-randomised trials missing data in the overall assessment of treatment effect by using
are found, we will use effect estimates and their standard errors sensitivity analysis.
from correct analyses of cluster-randomised trials and use these For all outcomes, we carried out analyses, as far as possible, on
in meta-analysis using the generic inverse-variance method. How- an intention-to-treat basis, i.e. we attempted to include all partic-
ever, if the trials fail to report an appropriate correct analysis, we ipants randomised to each group in the analyses, and all partici-
will approximate analyses of cluster-randomised trials to take ac- pants were analysed in the group to which they were allocated, re-
count of the design effect. We plan to adjust their sample sizes gardless of whether or not they received the allocated intervention.
using the methods described in the Cochrane Handbook using an The denominator for each outcome in each trial was the number
estimate of the intracluster correlation co-efficient (ICC) derived randomised minus any participants whose outcomes are known
from the trial (if possible), from a similar trial or from a study of to be missing.
a similar population. If we use ICCs from other sources, we will
report this and conduct sensitivity analyses to investigate the effect
of variation in the ICC. If we identify both cluster-randomised Assessment of heterogeneity
trials and individually-randomised trials, we plan to synthesise the We were unable to conduct meta-analysis combining the two in-
relevant information. We will consider it reasonable to combine cluded trials. However, in future updates of this review, we plan
the results from both if there is little heterogeneity between the to assess statistical heterogeneity in each meta-analysis using the
study designs and the interaction between the effect of interven- Tau², I² and Chi² statistics. We will regard heterogeneity as sub-
tion and the choice of randomisation unit is considered to be un- stantial if an I² is greater than 30% and either a Tau² is greater
likely. than zero, or there is a low P value (less than 0.10) in the Chi² test
We plan to acknowledge heterogeneity in the randomisation unit for heterogeneity.
and perform a sensitivity analysis to investigate the effects of the
randomisation unit.
Assessment of reporting biases
Trials with more than two treatment groups In future updates of this review, if there are 10 or more studies
We planned to include trials with more than two intervention in a meta-analysis, we plan to investigate reporting biases (such
groups (multi-arm studies), if identified. In future updates of this as publication bias) using funnel plots. We will assess funnel plot
review, if trials with more than two intervention groups are iden- asymmetry visually. If asymmetry is suggested by a visual assess-
tified, only directly relevant arms will be included. If studies with ment, we will perform exploratory analyses to investigate it.
various relevant arms are identified, groups will be combined to
generate a single pair-wise comparison (Higgins 2011), and the
Data synthesis
disaggregated data in the corresponding subgroup category will
be included. If the control group is shared by two or more study We carried out statistical analysis using the Review Manager soft-
arms, the control group over the number of relevant subgroup cat- ware (RevMan 2014). We were unable to meta-analyse the results
egories will be divided to avoid double-counting the participants as the measure of treatment effectiveness was assessed in a non-
(for dichotomous data, we will divide the events and the total pop- comparable way. In one trial (Munkhuu 2009), the results appear
ulation, and for continuous data, we will assume the same mean to have been adjusted to account for clustering. The adjusted odds
and standard deviation but will divide the total population). The ratios [AOR] and P values were presented (Table 1) and we used
details will be described in the Characteristics of included studies these to calculate the log odds ratio and standard error and en-
tables. tered these into RevMan 2014 using the generic inverse-variance
method. In the other trial (Myer 2003), only one outcome, ade-
quate treatment, was adjusted to account for cluster design. How-
Cross-over trials ever, not enough information was provided to include this in an
For this review cross-over trials have been judged invalid as they analysis using the generic inverse variance method. We presented
are generally considered to be inappropriate while measuring a pri- some of these data in forest plots, as if for a parallel randomised-

controlled trial, and for the remaining data used a narrative syn- 4. Syphilis screening strategies including HIV/AIDs versus
thesis of the data and presented them in a consistent manner as without HIV/AIDs screening.
described in the Cochrane Handbook (section 11.7.2). The following outcomes will be used in subgroup analysis.
In future updates of this review, we plan to use fixed-effect meta- • Perinatal mortality.
analysis for combining data where it is reasonable to assume that • Incidence of congenital syphilis.
studies are estimating the same underlying treatment effect: i.e. • Proportion of pregnant women tested for syphilis and
where trials are examining the same intervention, and the trials’ treatment provided.
populations and methods are judged sufficiently similar. If there
We will assess subgroup differences by interaction tests available
is clinical heterogeneity sufficient to expect that the underlying
within RevMan (RevMan 2014). We will report the results of
treatment effects differ between trials, or if substantial statistical
subgroup analyses quoting the Chi² statistic and P value, and the
heterogeneity is detected, we will use random-effects meta-anal-
interaction test I² value.
ysis to produce an overall summary if an average treatment ef-
fect across trials is considered clinically meaningful. The random-
effects summary will be treated as the average range of possible Sensitivity analysis
treatment effects and we will discuss the clinical implications of
We were unable to conduct a sensitivity analysis to investigate the
treatment effects differing between trials. If the average treatment
robustness of the results as too few trials were detected. However, in
effect is not clinically meaningful, we will not combine trials.
future updates of this review, sensitivity analyses will be performed
If we use random-effects analyses in future updates of this review,
to assess the risk of bias effects (trials with low or unclear sequence
we plan to present results as the average treatment effect with its
generation and allocation concealment and either high levels of
95% confidence interval, and the estimates of Tau² and I².
attrition or inadequate blinding) on the analyses, by omitting trials
rated as ’high risk of bias’ for these components.
Subgroup analysis and investigation of heterogeneity

RESULTS
We were unable to conduct either an investigation of heterogeneity
or pre-specified subgroup analyses as only two trials were included.
Investigation of publication bias presentation using a funnel plot
was also not possible due to the small number of trials. However, Description of studies
in future updates of this review, if we identify substantial hetero-
geneity, we plan to investigate it using subgroup analyses and sen-
sitivity analyses. We plan to consider whether an overall summary Results of the search
is meaningful by using a random-effects analysis. In future updates The search of the Pregnancy and Childbirth Group’s Trials Reg-
of this review, if sufficient or appropriate data are available, we ister retrieved three reports of two studies (Munkhuu 2009 based
plan to carry out the following subgroup analyses. in Mongolia; Myer 2003 based in South Africa) meeting all the
1. Low-income versus middle-income countries. inclusion criteria for this review. Rotchford 2000 reported base-
2. Study settings, i.e. antenatal clinics versus other healthcare line findings of the trial carried out in South Africa (Myer 2003)
facilities. where perinatal mortality was estimated through modelling (See:
3. HIV/AIDs status of pregnant women and neonates. Figure 1).

Figure 1. Study flow diagram.

million units of intramuscular benzathine penicillin, and coun-
Included studies
selling before and after the test. The trial included 14 antenatal
clinics randomly assigning seven clinics each to the intervention
and control group using clinics as the unit of randomisation. In
Design the intervention group, the on-site rapid treponemal test was as-
Both of the included trials investigated point-of-care syphilis test- sayed with SD Bioline Syphilis 3.0 (Standard Diagnostics Inc.,
ing effect during routine antenatal check-ups for the detection and Kyunggi-do, Korea) as per the manufacturer’s specifications, and
treatment of syphilis infection in pregnant women, using cluster- the results were available the same day and within 10 to 15 min-
randomised trials (C-RCTs) design. The trials were published be- utes. Blood specimens of the women with sero-positive test re-
tween 2000 and 2009. sults were further collected and sent to the reference laboratory for
confirmation testing, which was carried out using RPR tests, with
further testing for the positive samples by TPHA if required. After
Sample size both tests, seropositive women were subsequently administered
The trial by Munkhuu 2009 included 7700 pregnant women in two free doses of benzathine penicillin at weekly intervals. Women
14 clinics; whereas, in Myer 2003, 7618 pregnant women were who tested negative on the rapid assays received post-test coun-
eligible, although results were only presented for the positive cases selling by antenatal service providers and were invited for a second
(793 women). screening during the third trimester of pregnancy. Providers in the
intervention clinics received two days of workshop training which
covered various aspects of antenatal syphilis screening, such as de-
Setting centralisation of services, case detection and management. After
The Munkhuu 2009 trial was conducted in antenatal clinics in admission to the control clinics, pregnant women were asked to
Ulaanbaatar, Mongolia. The Myer 2003 study was a primary visit any District General Hospital or the National Center of In-
healthcare setting-based intervention carried out in KwaZulu-Na- fectious Diseases for free initial testing with RPR and/or TPHA
tal, South Africa. confirmation test. Providers in the control clinics also received two
days of training but on different aspects of the program, such as
the project overview and refresher training.
Participants Myer 2003 went on to assess the effectiveness of on-site syphilis
In the Mongolian trial (Munkhuu 2009), all pregnant women testing using the RPR test complemented by laboratory confir-
with a single pregnancy attending their first antenatal care were mation, and compared this strategy with routine testing at the
included. Statistical adjustments were made for the significant dif- provincial reference laboratory. Using clinics as the unit of ran-
ferences in participants’ characteristics, i.e. gestational age at first domisation, seven matched clinic pairs were each randomly as-
antenatal visit and multiple sexual partners. In Myer 2003, preg- signed to the intervention and control group. In the intervention
nant women attending their first antenatal care with a positive group, test results and treatment (the first of three recommended
syphilis test were offered treatment and were followed up and anal- weekly intramuscular injections of 2.4 mega units of benzathine
ysed (793 women). penicillin) were available on the same day and were administered
within an hour by clinic nurses. In this test, cells were separated
from plasma by standing the samples for 30 minutes, and serum
Interventions was mixed with RPR antigen using a battery powered rotator as
per the manufacturer’s instructions. Positive or negative test re-
Both of the trials assessed the on-site syphilis testing strategy per-
sults were reported by the clinic nurses using colour photographs
formed during antenatal check-ups and compared it with tradi-
as a reference standard. Nurses at the intervention clinics were
tional laboratory testing.
provided with a one-day training workshop on a range of on-site
Munkhuu 2009 assessed on-site syphilis screening using rapid tre-
syphilis testing operations, including logistics information, spec-
ponemal tests at the first antenatal visit and at the third trimester
of gestation, and compared on-site screening with conventional imen handling and maintenance, and supervised practice. Con-
tinued monitoring of test performance and refresher training for
testing using rapid plasma reagin (RPR), and where necessary, Tre-
new clinic staff were also provided throughout the trial. In the
ponema pallidum haemagglutination assay (TPHA) at any district-
control group, blood specimens were sent to the provincial refer-
level health facilities. The other elements of their one-stop service
ence laboratory for routine testing and results were available upon
included: immediate on-site treatment for sero-positive women
returning to the laboratory two weeks following the test. Upon
and their sexual partners, including the administration of G 2.4

returning, sero-positive women were counselled on the effective and maternal syphilis were not pre-specified in the protocol but
doses of the treatment regimen and received their first penicillin were considered later in this review as important outcome data.
injection. All women with RPR positive results (on-site or labora- None of the trials examined obstacles/challenges in the uptake
tory tests) were advised to return to the clinics for two follow-up of antenatal syphilis screening tests (review secondary outcome)
injections at weekly intervals. and incidence of HIV/AIDs in pregnant women and neonates,
including economic data on healthcare resource usage, which was
a secondary outcome of this review. Other adverse outcomes (re-
Outcomes view secondary outcome) was reported in one trial (Myer 2003).
Comparison with a pooled effect estimate was constrained due to
Many pre-specified outcomes of this review were not reported in
the incomparable modes of action (see also Subgroup analysis and
the two included trials. Munkhuu 2009 reported two pre-specified
investigation of heterogeneity); however, we presented results in
primary outcomes: the proportion of women tested for syphilis
individual forest plots.
and treatment provided at the first antenatal visit and again at the
third trimester of gestation, and congenital syphilis (number of
cases). In addition to reporting adequate treatment rates (percent- Excluded studies
age of sero-positive cases completing three doses of benzathine There are no excluded studies in this review.
penicillin before delivery), the trial also reported the proportion of
completely treated sexual partners of seropositive women (reported
as a non-pre-specified review outcome). One of the reports from
Risk of bias in included studies
South Africa by Rotchford 2000 used modelling to estimate the The two included cluster-randomised controlled trials (C-RCTs)
reduction of perinatal mortality risk based on the number of peni- were judged to be at unclear to high risk of bias overall. A summary
cillin doses. However, Myer 2003 reported one of the pre-specified of the risk of bias for the two included trials is provided in Figure
review primary outcomes of perinatal mortality. Treatment delay 2 and Figure 3.
Figure 2. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.

Figure 3. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included
study.
Allocation
Allocation concealment
Allocation concealment bias is unclear in the trial by Munkhuu

2009. The authors did not report whether allocation concealment
was used and therefore we cannot discard the possibility of baseline
Generation of sequence imbalance, in spite of the unlikelihood of C-RCTs to suffer from
allocation bias. Also, randomisation of the clusters was not pair-
Munkhuu 2009 reported that the groups were randomised but matched or stratified but baseline characteristics of the groups were
the randomisation method was not reported, and therefore, the reported to be well-balanced. Since allocation in Myer 2003 was
risk of bias is unclear. However, sequence generation was adequate unblinded, we cannot rule out the possibility of high risk of bias.
in Myer 2003, where clinics were randomised through a coin-toss However, we assume that the baseline imbalance in this trial was
method. reduced due to pair-matched randomisation of the clusters.

Blinding Effects of interventions
We assume both of the trials (Munkhuu 2009; Myer 2003) to Both trials assessed point-of-care syphilis testing with conventional
be at high risk of performance and detection bias since they did testing methods and together involved a total of 8493 pregnant
not report on blinding of participants, clinicians and outcome women. Meta-analysis of the two included trials was not possible
assessors. as the measure of intervention effectiveness was assessed in a non-
comparable way. It is for this reason that the results have been
presented separately as different comparisons.
Incomplete outcome data In one trial (Munkhuu 2009) the results appear to have been
Only losses to follow-up were reported: in Munkhuu 2009, the adjusted to account for clustering. The adjusted odds ratios [AOR]
rates were 5.7% versus 7.4% (intervention versus control) and and P values were presented (see Table 1) and these were used to
this was judged to be at low risk of bias. However, in Myer 2003, calculate the log odds ratio and standard error and we entered these
of 7134 women seeking antenatal care with available results, 793 into RevMan 2014 using the generic inverse-variance method.
(11.1%) tested positive for syphilis and the results are presented In the other trial (Myer 2003), only one outcome, adequate treat-
only for this subgroup of women. It is not clear why outcome data ment, was adjusted to account for cluster design. However, not
are presented only for those women where syphilis was detected. enough information was provided to include this in an analysis
The denominator here should be the number of women in each using the generic inverse variance method. Where possible, results
trial arm (5201 onsite versus 2417 control clinic). For this reason have therefore been presented in forest plots, as if the data are
we judged incomplete outcome data to be at high risk of bias for from a parallel randomised controlled trial. These results should
Myer 2003. therefore be interpreted with caution, as no adjustments have been
made to account for clustering.
Selective reporting
The risk of reporting bias for the included trials is unclear On-site syphilis screening test using rapid treponemal
(Munkhuu 2009; Myer 2003). With no access to the protocols tests versus conventional laboratory testing with
for both, it was not possible to determine whether outcome data rapid plasma reagin (RPR) or treponema pallidum
for all prespecified outcomes were reported. hemagglutination (TPHA)
Other potential sources of bias Primary outcomes

The risk of recruitment bias, baseline imbalance, loss of clusters,
early termination of the trial, and incorrect analysis were assessed
in both trials. In Munkhuu 2009, the trial appears to have ad- Perinatal mortality
justed for the main outcomes using univariate and multivariate This outcome was not reported by Munkhuu 2009.
analysis. All antenatal care (ANC) service providers in the catch-
ment were included in the randomisation except the Maternal and
Child Health (MCH) Centre and two out of 16 ANC clinics. The Incidence of congenital syphilis (non-prespecified outcome)
MCH centre was excluded because it is responsible for the whole The number of congenital syphilis cases was reported in the
country, and the two ANC clinics had small attendance. The study Munkhuu 2009 trial in which one-stop antenatal syphilis screen-
groups were reported to be well-balanced for the distribution of ing found a 93.5% (95% confidence interval (CI), 66.0% to
baseline characteristics, including statistical adjustment made for 98.6%) reduction in congenital syphilis, and detected only one
participants’ characteristics such as mean age and marital status. In congenital syphilis case out of 3632 deliveries in the intervention
Myer 2003, baseline imbalance due to one very busy clinic in the group compared to 15 out of 3552 in the control (P = 0.002),
intervention arm was reported in terms of participants’ age and (adjusted odds ratio (AOR) 0.09, 95% CI 0.01 to 0.71), Analysis
gravidity. However, adjusted analyses (not shown in the paper) did 1.1.
not alter the trial’s findings substantially, as was reported by the
authors. We also assumed that the differences in the groups were
somewhat reduced by pair-matched randomisation of the clusters. Proportion of pregnant women tested for syphilis and
Nevertheless, contamination between groups in both of the C- treatment provided
RCTs cannot be excluded as allocation concealment was either Munkhuu 2009 reported syphilis testing and treatment as primary
not reported (Munkhuu 2009) or was unblinded (Myer 2003). outcomes. Both were assessed twice, at the first antenatal visit and
Therefore, the quality of the trials’ designs were judged to be at again, at the third trimester of gestation; the following changes
unclear risk of other bias. were detected in the intervention group.

The one-stop syphilis screening intervention significantly achieved Perinatal mortality
better testing and treatment coverage than the conventional Perinatal mortality, defined as either stillbirth (death at or after 28
screening test: of 3850 pregnant women recruited in each group, weeks’ gestation) or early neonatal death (death up to seven days
99.9% (intervention) and 79.6% (control) were screened at the postpartum), was reported in Myer 2003 but significant on-site
first visit (AOR 989.80, 95% CI 16.27 to 60233.05), Analysis 1.2. syphilis testing effect on the reduction of perinatal loss was not
Of the remaining participants, 3683 and 3796 pregnant women detected. Among the 618 pregnant women with syphilis in the
(excluding loss to follow-up) from the intervention and control intervention clinics, pregnancy outcomes were available for 561,
respectively revisited at the third trimester, 99.7% (intervention) of which 549 full-term pregnancies were reported. In the control
and 62.1% (control) had the second test (AOR 617.88, 95% CI clinics, pregnancy outcomes were available for 162/175, of which
13.44 to 28399.01; P= < 0.001), Analysis 1.3. 157 pregnancies were at full term. Overall, 3.3% perinatal deaths
were observed in the intervention group (18/549) versus 5.1% (8/
157) in the control (OR: 0.63; 95% CI: 0.27 to 1.48), Analysis
Secondary outcomes 2.1.
Obstacles/challenges in the uptake of antenatal syphilis screen-
ing testing was not investigated in Munkhuu 2009. Similarly,
Munkhuu 2009 did not report data on the incidence of HIV/ Proportion of pregnant women tested for syphilis and
AIDs in pregnant women and neonates, any adverse outcomes or treatment provided
healthcare resource usage. On-site syphilis testing was insignificant to effectively treat mater-
nal syphilis in South Africa (Myer 2003). Out of the 7134 women
with available test reports, 793 (11.1%) were detected to be sero-
Adequate treatment (non-prespecified outcome) positive and enrolled in the trial, of which 618 women were al-
One-stop screening also showed significant impact on improv- located to the intervention group and 175 to the control (Myer
ing treatment rates in pregnant women and their sexual partners 2003). After losses to follow-up, 396/618 (64.1%) women with
(Munkhuu 2009). The proportion of women who received ade- positive test results received adequate treatment (two or more doses
quate treatment (three doses of G 2.4 million units of intramuscu- of 2.4 mega units of benzathine penicillin) in the intervention
lar benzathine penicillin) was 98.9% (92/93) in the intervention cluster versus 120/175 (68.6%) in the control cluster (odds ratio
versus 89.6% (26/29) in the control group AOR 10.44, 95% CI (OR): 0.82; 95% CI 0.57 to 1.17), Analysis 2.2. The proportion
1.00 to 108.99; P= 0.05), Analysis 1.4. of women receiving inadequate treatment (defined as one dose or
no treatment) was reported as 125/618 (20.2%) in the interven-
tion versus 34/175 (19.4%) in the control (OR: 1.05; 95% CI
Partner treatment (non-prespecified outcome) 0.69 to 1.60), Analysis 2.2. Among the infected women receiving
On-site testing significantly improved the completion of recom- inadequate treatment in the intervention clinics, 63/125 needed
mended treatment doses in sexual partners of seropositive women: to receive the recommended treatment dosages (based upon lab-
94.6% (88/93) in the intervention versus 55.2% (16/29) in the oratory test reports or clinical decision); however, none obtained
control clinics (AOR 18.17, 95% CI 3.23 to 101.20; P = < 0.001), the recommended dosages but were found negative in on-site test-
Analysis 1.5, ing (50%). Conversely, 17% of women who received a minimum
of one penicillin dosage showed negative results in on-site testing
(86/493). These findings therefore led the authors (Myer 2003) to
Syphilis prevalence (non-prespecified outcome) conclude that women’s negative sero-positivity at on-site testing
had a strong influence on whether they remained untreated (ARD,
Munkhuu 2009 reported maternal syphilis cases at the first ANC
intervention minus control, 28%; 95% CI: 20 to 36).
visit: 73/3849 in the intervention versus 27/3065 in the control
The included trial did not report data on the incidence of con-
(AOR 2.45, 95% CI 1,44 to 4.18; P = < 0.001) Analysis 1.6; and
genital syphilis.
at the third trimester, 20/3670 versus 2/2357, respectively (AOR
6.27, 95% CI 1.47 to 26.69), Analysis 1.7.
Secondary outcomes
On-site syphilis testing with rapid plasma reagin

(RPR) test versus routine laboratory testing with RPR
Adverse outcomes
Obstacles/challenges in the uptake of antenatal syphilis screening
tests (a secondary outcome of this review) were not investigated in
Primary outcomes
any of the included trials (Myer 2003); however, important and

relevant information discussed in the papers is included in our required for women to be completely tested, in addition to fur-
discussion section. Other adverse outcomes were reported in Myer ther visits to receive their test results. This approach possibly de-
2003. Of the 723 women who tested positive and for whom avail- ters a large number of pregnant women from pursuing screen-
able pregnancy outcome data were available (91%), 12 women in ing and treatment. Conversely, the decentralised testing services
the intervention arm (2.1%) and 5 in the control (3.1%) reported provide screening, test results and treatment within the same day.
miscarriages, and were excluded from the perinatal mortality anal- The one-stop approach offers greater convenience to women, and
ysis, Analysis 2.3. has been indicated by the authors as one of the influencing fac-
The included trial did not report data on the incidence of HIV/ tors to increase coverage at both testing points during pregnancy.
AIDs in pregnant women and neonates, or healthcare resource However, the intervention was implemented within a relatively
usage. well-developed antenatal care system with linkages to district gen-
eral hospitals and a MCH centre (excluded from the sampling),
which was likely a key factor in determining the success of this
Syphilis prevalence (non-prespecified outcome) approach. The characteristics of the screening test used might also
Myer 2003 reported the prevalence of laboratory-confirmed be influential, for instance, useful screening tools such as rapid
syphilis as 7.5% which was similar in both intervention and con- treponemal tests are often obtainable only at reference laborato-
trol clinics, after accounting for the matched-pair design of the ries or large regional centres; perhaps because they are more costly
study. In both on-site and laboratory testing, positive syphilis rates compared to the non-treponemal test and can be difficult to per-
were 5% (246) in the intervention versus 6% (149) laboratory- form (Peeling 2004). Furthermore, women screened at the first
confirmed cases in the control clinics, Analysis 2.4. Myer 2003 also trimester of gestational age were significantly different at base-
reported RPR titre data determined from 346 women (55%) from line, as were those with multiple sexual partners. It has been sug-
the intervention group and 134 women (75%) from the control gested that gestational age could be one of the predictors of the
group, and observed that a median titre level of 1:16 or higher was risks associated with congenital syphilis, which might be reduced
documented among 20% of women. On-site syphilis testing sig- by early screening and prompt treatment of women (Liu 2010),
nificantly reduced treatment delays in South Africa (Myer 2003). for which supporting evidence was offered by Munkhuu 2009.
Women in the intervention clinics completed syphilis treatment Additionally, one-stop services showed promise in the notifica-
an average of 16 days earlier compared to women attending con- tion and treatment of sexual partners, and doctors’ active coun-
trol clinics (95% CI 11 to 21; P= < 0.001), Analysis 2.5. selling was identified as a key catalyst to achieve success in this
area. Partner notification and treatment is also considered useful
for the prevention of syphilis reinfection risks and associated ad-
verse outcomes, and can be achieved through the delivery of exist-
DISCUSSION ing antenatal screening programmes (WHO 2007; WHO 2010).
However, negative consequences of partner notification may oc-
cur, such as domestic violence. Although not addressed in either
Summary of main results of the included trials (Munkhuu 2009; Myer 2003), a cross-sec-
tional study (Díaz-Olavarrieta 2007) documented both women’s
We included two cluster-randomised controlled trials (totaling
fear of negative reactions from their partners and underreporting
8493 pregnant women) assessing point-of-care syphilis testing to
of syphilis infection. Future screening programmes may consider
improve maternal and perinatal outcomes. The trials were based
integration of effective counselling services to identify potential
in Mongolia (Munkhuu 2009) and South Africa (Myer 2003)
risk of domestic violence and develop partner notification strate-
and judged overall to be of a high/unclear risk of bias. Meta-
gies that protect the safety of pregnant women.
analysis of the two included trials was not possible as the measure of
The trial by Myer 2003 was conducted in primary care clinics in
intervention effectiveness was assessed in a non-comparable way.
rural South Africa. No statistical differences between the interven-
It is for this reason that the results have been presented separately
tion and control groups were found in terms of testing or treat-
as different comparisons.
ment, for which “the relatively high quality of laboratory services
The Mongolian trial (Munkhuu 2009) reported on syphilis test-
provided in the control arm” was indicated as a possibility. The
ing in the first trimester and retesting in the third trimester-a
trial found no effect on perinatal mortality reduction, though a
useful strategy to remedy the risk of syphilis reinfection as sug-
50% reduction was assumed at baseline (Rotchford 2000). As one
gested by experts in the field (Newman 2013; WHO 2007). The
of the possibilities of this insignificant effect, failure in treating
trial’s one-stop intervention package was successful in improving
larger proportion of women in the intervention clinics mainly due
the use of antenatal syphilis screening, syphilis case detection and
to technical and logistical difficulties was pointed out. Such dif-
treatment for infected women and their sexual partners, including
ficulties were related to the relatively complex process of on-site
congenital syphilis cases. Conventional screening approaches are
diagnosis using rapid plasma reagin (RPR) testing, e.g. separating
often inconvenient; in Mongolia, at least one additional visit is

the serum from the cells and mixing the serum with RPR anti- Quality of the evidence
gen. Although a battery powered rotator was used for this pro-
Munkhuu 2009 was judged to have unclear methods of random
cess, the test performance could also have been restricted by the
sequence generation, allocation concealment, selective reporting,
fact that in most cases RPR reagents require refrigeration (Peeling
and other bias. However, outcome data were addressed adequately
2004). Furthermore, high workloads, limited staffing, and diffi-
with intention-to-treat analysis and multilevel regression mod-
culty in maintaining a daily supply of testing materials and hold-
elling. Losses to follow-up were reported at random only due to lo-
ing admitted women in clinics while they awaited test results have
gistical and technical difficulties. In the second trial (Myer 2003),
also been identified as critical challenges in achieving optimally
methods of random sequence generation were adequate, but allo-
effective results. The trial distributed standard partner notification
cation concealment was judged to be inadequate. Incomplete out-
cards to seropositive women, but partners’ treatment was not re-
come data were an issue, because of 7134 women seeking antenatal
ported. Also, miscarriages were documented in both study groups.
care with available results, 793 (11.1%) tested positive for syphilis
We contacted Myer 2003 for additional information but did not
and results are presented only for this subgroup of women. It is
receive any reply.
not clear why outcome data are presented only for those women
Neither trial reported data on healthcare resource use, but both
where syphilis was detected and why the denominator was not
were able to detect a greater number of syphilis cases. Also, nei-
the number of women in each trial arm (5201 onsite versus 2417
ther trial reported whether the participants were encouraged to be
control clinic). For this reason, we judged incomplete outcome
screened for HIV infection, which is another viable approach for
data to be at high risk of bias for Myer 2003. Selective reporting
the prevention of sexually transmitted infections (WHO 2007;
bias (no published version of the protocol was found) and other
WHO 2010) since individuals with HIV/AIDs are highly suscep-
bias (baseline imbalance was reported due to a particularly busy
tible to syphilis co-infection and vice versa (Walker 2001). The tri-
clinic in the intervention group) remain unclear. Blinding was not
als’ findings indicate that the effectiveness of point-of-care syphilis
reported in either trial, however it might not have been possible
testing might depend on varying dynamics such as the setting in
due to the nature of the study design.
which a particular screening test is implemented, as well as the
existing service delivery system. Even though the Mongolian trial
was carried out in a well-functioning antenatal service delivery sys-
tem, and support for health systems strengthening was provided
Potential biases in the review process
in both trials through training, laboratory support and other ac- This review evidence is based on two cluster-randomised con-
tivities, success rates varied between both trials, and it was difficult trolled trials identified through an inclusive search strategy. How-
to determine exactly which component/s were effective, and for ever, we cannot eliminate the possibility that additional published
which particular outcomes. or unpublished trials on this topic exist and were not detected.
If any such trials are identified, we will include them in future
updates of this review.
Overall completeness and applicability of Agreements and disagreements with other

evidence studies or reviews
Three of the pre-specified review primary outcomes (proportion Our review confirms that the evidence effectiveness of point-of-
of pregnant women tested for syphilis and treatment provided, care syphilis testing varies for different outcomes tested under dif-
congenital syphilis and perinatal mortality) were reported in the ferent settings. While point-of-care testing was effective in the
two included trials. Although we were unable to provide an overall Mongolian setting to improve syphilis case detection, treatment
summary effect through data pooling, point-of-care syphilis test- rates for both women and their partners, and congenital syphilis,
ing showed effectiveness in different aspects of syphilis prevention it showed non-significant intervention effect for increased testing
in both included trials. While the one-stop service in Mongolia sig- and treatment or perinatal mortality reduction in the rural con-
nificantly improved the screening coverage, case detection of ma- text of South Africa, although treatment delay was reduced. Gen-
ternal syphilis, treatment quality in seropositive women including erally, evidence from randomised controlled trials on the effec-
their partners (Munkhuu 2009), and reduced congenital syphilis tiveness of antenatal syphilis testing for the detection, treatment
cases, the addition of on-site testing in South Africa did not im- and management of associated adverse outcomes is sparse, with
prove treatment rates or perinatal deaths, although treatment de- current knowledge mostly derived from observational studies. No
lays were markedly decreased (Myer 2003). In future updates of Cochrane review has previously attempted to accumulate evidence
this review, we aim to provide a further complete assessment in this on effectiveness. Conclusions from other systematic reviews em-
critical area of maternal and neonatal health as more data become ploying rigorous methods were mixed: for instance, one systematic
available. review concluded that 50% of syphilis-associated stillbirth and

perinatal deaths could be averted if effectiveness in both cover- pregnant women remaining unscreened and hence untreated. Nei-
age and screening of available antenatal syphilis testing strategies ther of the included trials (Munkhuu 2009; Myer 2003) assessed
were improved (Hawkes 2011); while other reviews failed to detect the determinants of syphilis testing and treatment uptake; how-
any effect of syphilis screening on preterm birth reduction (Barros ever, in the South African trial (Myer 2003), pregnant women
2010), or a high grade of evidence (Menezes 2009). with negative on-site testing results were more likely to remain
untreated. Therefore, an examination of the potential factors that
may drive or prevent women from using syphilis screening ser-
vices would be necessary. Also, an assessment of the technical and
AUTHORS’ CONCLUSIONS logistical difficulties in on-site diagnosis using rapid plasma reagin
(RPR) testing, e.g. separating the serum from cells and mixing
Implications for practice with RPR antigen, has great potential to enhance syphilis detection
and treatment in resource-poor settings. Furthermore, it would
Reported primary outcomes were different between trials and also be useful to investigate whether women are charged a fee for
point-of-care syphilis testing showed promising results for the de- screening services and if so, how much the fee costs, whether it is
tection and treatment of syphilis infection and congenital syphilis affordable and finally, what effect the fee has on screening uptake.
(Mongolia), and treatment delay (South Africa). Both trials were Although antenatal care is usually provided free, syphilis screening
of high to unclear risk of bias. More trials are warranted to be may incur out-of-pocket payments in some settings, and elimina-
able to further determine the effectiveness of testing strategies, tion of such expenses could result in an increase in screening at-
especially for the prevention of syphilis and HIV co-infection in tendance (Cheng 2007). Future trials may also consider following
regions with high HIV/AIDs endemicity. a checklist for good quality reporting such as a modified Consol-
idated Standards Of Reporting Trials (CONSORT) for cluster-
Implications for research randomised trials (Campbell 2004) to ensure better quality and
This review includes two cluster-randomised controlled trials and generation of important information.
offers a basis for the integration of future trials investigating ante-
natal syphilis testing strategies that are indispensable in improving
the adverse outcomes of the disease. This is particularly significant
for developing context, especially in those locations with a high
prevalence of syphilis and HIV/AIDs, a lack of laboratory test- ACKNOWLEDGEMENTS
ing, or poor-quality antenatal clinic (ANC) services. Future trials
should take greater care to avoid common risks of bias and report We are thankful for the support provided by the Cochrane Preg-
all important associated outcomes (e.g. HIV/AIDs), including a nancy and Childbirth Group during the development process of
sufficient number of observations. Provision of HIV screening in this review.
syphilis trials would be of immense importance to generate valu- As part of the pre-publication editorial process, this review has been
able data to prevent syphilis and HIV/AIDs co-infection. More- commented on by two peers (an editor and referee who is external
over, assessment of the obstacles/challenges of screening uptake to the editorial team), a member of the Pregnancy and Childbirth
that pregnant women plausibly face both at the individual and Group’s international panel of consumers and the Group’s Statis-
health system levels would be important. For example, lack of tical Adviser.
knowledge or awareness of syphilis infection and screening tests
(Munkhuu 2006), living far from antenatal clinics, and poor qual- We would also like to thank Marty Richardson for her statistical
ity of ANC services (Walker 2002; Wilkinson 1998) lead to many support.

REFERENCES
References to studies included in this review Delport 1998

Delport SD, van den Berg JH. On-site screening for
Munkhuu 2009 {published data only} syphilis at an antenatal clinic. South African Medical Journal
Munkhuu B, Liabsuetrakul T, Chongsuvivatwong V, 1998;88(1):43–4.
McNeil E, Janchiv R. One-stop service for antenatal Díaz-Olavarrieta 2007
syphilis screening and prevention of congenital syphilis in Díaz-Olavarrieta C, García SG, Feldman BS, Polis AM,
Ulaanbaatar, Mongolia: a cluster randomized trial. Sexually Revollo R, Tinajeros F, et al. Maternal syphilis and
Transmitted Diseases 2009;36(11):714–20. intimate partner violence in Bolivia: a gender-based analysis
of implications for partner notification and universal
Myer 2003 {published data only}
screening. Sexually Transmitted Diseases 2007;34(7 Suppl):
∗
Myer L, Wilkinson D, Lombard C, Zuma K, Rotchford K,
S42–S46.
Karim SS. Impact of on-site testing for maternal syphilis on
treatment delays, treatment rates, and perinatal mortality in Fears 2001
rural South Africa: a randomised controlled trial. Sexually Fears MB, Pope V. Syphilis fast latex agglutination test, a
Transmitted Infections 2003;79(3):208–13. rapid confirmatory test. Clinical and Diagnostic Laboratory
Rotchford K, Lombard C, Zuma K, Wilkinson D. Impact Immunology 2001;8(4):841–2.
on perinatal mortality of missed opportunities to treat Fiumara 1978
maternal syphilis in rural South Africa: baseline results from Fiumara NJ. Treatment of early latent syphilis of less than
a clinic randomized controlled trial. Tropical Medicine & one year’s duration: an evaluation of 275 cases. Sexually
International Health 2000;5(11):800–4. Transmitted Diseases 1978;5(3):85-8.
Additional references Fonn 1996

Fonn S. A blood-result turn-around time survey to improve
congenital syphilis prevention in a rural area. South African
Barros 2010
Medical Journal 1996;86(1):67–71.
Barros F, Bhutta ZA, Batra M, Hansen T, Victora CG,
Rubens CE. Global report on preterm birth and stillbirth Gloyd 2001
(3 of 7): evidence for effectiveness of interventions and the Gloyd S, Chai S, Mercer MA. Antenatal syphilis in
GAPPS Review Group. BMC Pregnancy and Childbirth sub-Saharan Africa: missed opportunities for mortality
2010;10(Suppl 1):S3. reduction. Health Policy and Planning 2001;16(1):29–34.
Bique 2000 Hawkes 2011

Bique Osman N, Challis K, Folgosa E, Cotiro M, Hawkes S, Matin N, Broutet N, Low N. Effectiveness of
Bergström S. An intervention study to reduce adverse interventions to improve screening for syphilis in pregnancy:
pregnancy outcomes as a result of syphilis in Mozambique. a systematic review and meta-analysis. Lancet Infectious
Sexually Transmitted Infections 2000;76(3):203–7. Diseases 2011;11(9):684–91.
Higgins 2011
Blencowe 2011
Higgins JPT, Green S, editors. Cochrane Handbook for
Blencowe H, Cousens S, Kamb M, Berman S, Lawn
Systematic Reviews of Interventions Version 5.1.0 [updated
JE. Lives Saved Tool supplement detection and treatment
March 2011]. The Cochrane Collaboration, 2011.
of syphilis in pregnancy to reduce syphilis related stillbirths
Available from www.cochrane-handbook.org.
and neonatal mortality. BMC Public Health 2011;13(11
Suppl 3):S9. Hook 1992
Hook EW 3rd, Marra CM. Acquired syphilis in adults.
Campbell 2004 New England Journal of Medicine 1992;326(16):1060–9.
Campbell MK, Elbourne DR, Altman DG for the
CONSORT Group. CONSORT statement: extension to Hossain 2007
cluster randomised trials. BMJ 2004;328:702-8. Hossain M, Broutet N, Hawkes S. The elimination of
congenital syphilis: a comparison of the proposed World
CDC 2010 Health Organization action plan for the elimination of
CDC. Sexually Transmitted Diseases (STDs). Syphilis - congenital syphilis with existing national maternal and
CDC Fact Sheet. Available from http://www.cdc.gov/std/ congenital syphilis policies. Sexually Transmitted Diseases
syphilis/stdfact-syphilis.htm 2010. 2007;34(7 Suppl):S22–S30.
Cheng 2007 Ingraham 1950
Cheng JQ, Zhou H, Hong FC, Zhang D, Zhang YJ, Ingraham NR Jr. The value of penicillin alone in the
Pan P, et al. Syphilis screening and intervention in 500, prevention and treatment of congenital syphilis. Acta
000 pregnant women in Shenzhen, the People’s Republic of Dermato-Venereologica Supplementum (Stockh) 1950;31
China. Sexually Transmitted Infections 2007;83(5):347–50. (Suppl 24):60–87.
Jenniskens 1995 a clinic randomized controlled trial. Tropical Medicine &
Jenniskens F, Obwaka E, Kirisuah S, Moses S, Yusufali International Health 2000;5(11):800–4.
FM, Achola JO, et al. Syphilis control in pregnancy: Schmid 2004
decentralization of screening facilities to primary care level, Schmid G. Economic and programmatic aspects of
a demonstration project in Nairobi, Kenya. International congenital syphilis prevention. Bulletin of the World Health
Journal of Gynaecology and Obstetrics 1995;48 Suppl: Organization 2004;82(6):402–9.
S121–S128.
Schmid 2007
Lien 2000
Schmid GP, Stoner BP, Hawkes S, Broutet N. The need and
Lien TX, Tien NT, Chanpong GF, Cuc CT, Yen VT,
plan for global elimination of congenital syphilis. Sexually
Soderquist R, et al.Evaluation of rapid diagnostic tests for
Transmitted Diseases 2007;34(7 Suppl):S5–S10.
the detection of human immunodeficiency virus types 1
and 2, hepatitis B surface antigen, and syphilis in Ho Chi Schulz 1987
Minh City, Vietnam. American Journal of Tropical Medicine Schulz KF, Cates W Jr, O’Mara PR. Pregnancy loss, infant
and Hygiene 2000;62(2):301–9. death, and suffering: legacy of syphilis and gonorrhoea in
Africa. Genitourinary Medicine 1987 Oct;63(5):320–5.
Liu 2010
Liu JB, Hong FC, Pan P, Zhou H, Yang F, Cai YM, et Shafii 2008
al. A risk model for congenital syphilis in infants born to Shai T, Radolf JD, Sanchez PJ, Schulz KF, Murphy FK.
mothers with syphilis treated in gestation: a prospective Congenital syphilis. Sexually Transmitted Diseases. Fourth.
cohort study. Sexually Transmitted Infections 2010;86(4): New York: McGraw Hill Medical, 2008:1577–612.
292–6. Temmerman 2000
McDermott 1993 Temmerman M, Gichangi P, Fonck K, Apers L, Claeys
McDermott J, Steketee R, Larsen S, Wirima J. Syphilis- P, Van Renterghem L, et al. Effect of a syphilis control
associated perinatal and infant mortality in rural Malawi. programme on pregnancy outcome in Nairobi, Kenya.
Bulletin of the World Health Organization 1993;71(6): Sexually Transmitted Infections 2000;76(2):117–21.
773–80.
Tucker 2010
Menezes 2009 Tucker JD, Chen XS, Peeling RW. Syphilis and social
Menezes EV, Yakoob MY, Soomro T, Haws RA, Darmstadt upheaval in China. New England Journal of Medicine 2010;
GL, Bhutta ZA. Reducing stillbirths: prevention and 362(18):1658–61.
management of medical disorders and infections during
UNICEF 2009
pregnancy. BMC Pregnancy and Childbirth 2009;9(Suppl
UNICEF. The state of the world’s children 2009: maternal
1):S4.
and newborn health. Available from http://www.unicef.org/
Munkhuu 2006 publications/index˙47127.html.
Munkhuu B, Liabsuetrakul T, Chongsuvivatwong V,
Geater A, Janchiv R. Coverage of antenatal syphilis Walker 2001
screening and predictors for not being screened in Walker GJA. Antibiotics for syphilis diagnosed during
Ulaanbaatar, Mongolia. Sexually Transmitted Diseases 2006; pregnancy. Cochrane Database of Systematic Reviews 2001,
33(5):284–8. Issue 3. [DOI: 10.1002/14651858.CD001143]
Newman 2013 Walker 2002
Newman L, Kamb M, Hawkes S, Gomez G, Say L, Walker DG, Walker GJ. Forgotten but not gone: the
Seuc A, et al. Global estimates of syphilis in pregnancy continuing scourge of congenital syphilis. Lancet Infectious
and associated adverse outcomes: analysis of multinational Diseases 2002;2(7):432-6.
antenatal surveillance data. PLoS Medicine 2013;10(2): Watson-Jones 2002
e1001396. Watson-Jones D, Changalucha J, Gumodoka B, Weiss
Peeling 2004 H, Rusizoka M, Ndeki L, et al. Syphilis in pregnancy
Peeling RW, Ye H. Diagnostic tools for preventing and in Tanzania. I. Impact of maternal syphilis on outcome
managing maternal and congenital syphilis: an overview. of pregnancy. Journal of Infectious Diseases 2002;186(7):
Bulletin of the World Health Organization 2004;82(6): 940–7.
439–46. WHO 2007
RevMan 2014 WHO. The global elimination of congenital
The Nordic Cochrane Centre, The Cochrane Collaboration. syphilis: rationale and strategy for action, 2007.
Review Manager (RevMan). 5.3. Copenhagen: The Nordic http://whqlibdoc.who.int/publications/2007/
Cochrane Centre, The Cochrane Collaboration, 2014. 9789241595858˙eng.pdf (accessed 19 November, 2012).
Rotchford 2000 The World Health Organization.
Rotchford K, Lombard C, Zuma K, Wilkinson D. Impact WHO 2010
on perinatal mortality of missed opportunities to treat WHO. World Health Organization and Department of
maternal syphilis in rural South Africa: baseline results from Reproductive Health and Research: Investment case for

eliminating congenital syphilis: promoting better maternal Royal Society of Tropical Medicine and Hygiene 1998;92(3):
and child health outcomes and stronger health systems. 348.
World Health Organization 2010. Zenker 1990
Zenker PN, Rolfs RT. Treatment of syphilis, 1989. Reviews
Wilkinson 1997 of Infectious Diseases 1990;12(Suppl 6):S590-S609.
Wilkinson D, Sach M, Connolly C. Epidemiology of
syphilis in pregnancy in rural South Africa: opportunities References to other published versions of this review
for control. Tropical Medicine and International Health
1997;2(1):57-62. Shahrook 2013
Shahrook S, Mori R, Ochirbat T, Gomi H. Strategies of
Wilkinson 1998 testing for syphilis during pregnancy. Cochrane Database
Wilkinson D, Sach M. Improved treatment of syphilis of Systematic Reviews 2013, Issue 2. [DOI: 10.1002/
among pregnant women through on-site testing: an 14651858.CD010385]
intervention study in rural South Africa. Transactions of the ∗
Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Munkhuu 2009
Methods Cluster-randomised trial. Unit of randomisation: antenatal clinics
Participants Number of participants: 14 ANC clinics randomised to 7 intervention (3850 pregnant

women) and 7 control group (3850 pregnant women)
Mean Age: 27 years (SD 7.5) versus 26.9 years (SD 5.5) in the intervention and control
Setting: Ulaanbaatar, Mongolia.
Recruitment: August 2007 to August 2008.
Inclusion criteria: all new ANC attendees with a single pregnancy.
Exclusion criteria: women unable to return for the scheduled ANC visit, living outside
Ulaanbaatar, unwilling to give informed consent, and absence of a willing guardian
(under-aged women)
Interventions 1-stop syphilis screening service (n = 3850)

On-site screening with rapid treponemal tests at the 1st and 3rd trimester visits; imme-
diate on-site treatment for sero-positive women including sexual partners; and pre- and
post-test counselling.
Conventional syphilis screening (n = 3850)
Free testing (e.g. at district hospital) with rapid plasma reagin (RPR) and Treponema
pallidum hemagglutination (TPHA) confirmation tests, where necessary
Outcomes Primary: utilisation of antenatal syphilis screening (at 1st and 3rd trimester of gestational
visits); detected syphilis cases; number of congenital syphilis cases
Secondary: adequate treatment and % of completely treated sexual partners
Notes Training: intervention clinic providers received a 2-day training workshop on case detec-
tion and management; control clinics had 2-day training on other aspects of the screen-
ing
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Unclear risk The groups were reported to be randomised
bias) but the randomisation method was not re-
ported
Allocation concealment (selection bias) Unclear risk Not reported. However, since clusters in C-
RCTs were randomised at once, lack of con-
cealment of an allocation sequence is un-
likely to influence the outcomes
Blinding of participants and personnel High risk Not reported. However, blinding might
(performance bias) not be possible due to the nature of the
All outcomes study design

Munkhuu 2009 (Continued)
Blinding of outcome assessment (detection High risk Not reported. However, blinding might
bias) not be possible due to the nature of the
Incomplete outcome data (attrition bias) Low risk Only losses to follow-up were reported (in-
All outcomes tervention 5.7%; control 7.4%). No drop-
outs, withdrawals or lost of clusters were
reported
Selective reporting (reporting bias) Unclear risk With no access to a trial protocol, it was
not possible to determine if outcome data
for all prespecified outcomes were reported
Other bias Unclear risk The risk of recruitment bias, baseline im-
balance, loss of clusters, early termination
of the trial, and incorrect analysis were as-
sessed
Recruitment bias: 1 centre responsible for
whole country was excluded from the sam-
pling of clusters and 2 other antenatal clin-
ics were excluded due to small attendance -
may introduce bias. A total of 14 of a pos-
sible total of 16 antenatal clinics were in-
cluded in the sample of clusters
Baseline imbalance: the study groups were
well balanced for distribution of baseline
characteristics (see table 1, page 718); sta-
tistical adjustment made for gestational age
at the 1st visit and multiple sexual part-
ners. Nevertheless, contamination between
groups cannot be excluded as allocation
concealment was not reported
Loss of clusters: no clusters were lost, but
218 out of 3850 women lost to follow-up
from intervention group (6%) and 286 out
of 3850 women lost from the control group
(7%)
Incorrect anal-
ysis: no stratified or pair-matched cluster
randomisation approached. The following
adjustments were made: “Since the main
outcomes were nested within clinics, Rao
and Scott’s Chi² test in survey package was
used in the univariate analysis. For mul-
tivariate analysis, a multilevel analysis was
carried out having individual women at the
first (lower level) and the clinic at the sec-

Munkhuu 2009 (Continued)
ond level (higher) using “lme4” package.

Women’s characteristics were independent,
explanatory variables.” A statistician would
need to confirm whether this is a correct
analysis
Comparability with individually-ran-
domised trial: only 2 trials included, both
cluster, so not an issue.
Myer 2003
Methods Cluster-randomised trial. Unit of randomisation: primary healthcare clinics
Participants Number of participants: 14 primary healthcare clinics randomised to 7 intervention

(5201 pregnant women) and 7 control group (2417 pregnant women) and pair-matched.
Mean Age: 25.8 years (intervention); 27.0 years (control).
Setting: rural Hlabisa district in KwaZulu-Natal, South Africa.
Recruitment: October 1998 to January 2000.
Inclusion criteria: pregnant women attending 1st antenatal care tested positive.
Exclusion criteria: not reported.
Interventions On-site syphilis testing (n = 5201)

RPR test plus laboratory confirmation, same-day results and treatment within the hour.
Routine antenatal syphilis testing (n = 2417)
Routine laboratory testing, results returned 2 weeks later.
Outcomes Primary: perinatal death or early neonatal death.

Secondary: treatment rates-inadequate and adequate; treatment delay.
Notes Training: 1-day training for intervention clinics; refresher training, etc. for new staff
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Low risk “An independent scientist randomised the
bias) clinics through toss of a coin.”
Allocation concealment (selection bias) High risk “Allocation was unblinded.”

However, since clusters in C-RCTs were
randomised at once, lack of concealment of
an allocation sequence is unlikely to influ-
ence the outcomes
Blinding of participants and personnel High risk Not reported. However, blinding might
(performance bias) not be possible due to the nature of the

Myer 2003 (Continued)
Blinding of outcome assessment (detection High risk Not reported. However, blinding might
bias) not be possible due to the nature of the
Incomplete outcome data (attrition bias) High risk Of 7134 women seeking antenatal care
All outcomes with available results, 793 (11.1%) tested
positive for syphilis and results are pre-
sented only for this subgroup of women
It is not clear why outcome data are
presented only for those women where
syphilis was detected. The denominator
here should be the number of women in
each trial arm (5201 onsite versus 2417
control clinic)
Selective reporting (reporting bias) Unclear risk With no access to the protocol, it was not
possible to determine if outcome data for
all prespecified outcomes were reported
Other bias Unclear risk The risk of recruitment bias, baseline im-
balance, loss of clusters, early termination
of the trial, and incorrect analysis were as-
sessed
Recruitment bias: there was an imbalance
in the numbers recruited between the 2
arms of the trial because of 1 very busy
clinic. No early termination of the study
reported
Baseline imbalance: contamination be-
tween groups may exist. Allocation con-
cealment was not reported, limiting the as-
sumption about baseline imbalances which
was reported as “There was an imbalance
in the numbers recruited between the two
arms of the trial because of one very busy
clinic in the intervention arm. Participants
attending intervention clinics were slightly
younger and of lower mean gravidity than
those attending control clinics, but there
were no differences in gestational age or
previous pregnancy loss. In adjusted anal-
yses (not shown), the baseline differences
in age and gravidity did not alter substan-
tially trial findings and as a result only un-
adjusted results are presented here”
Loss of clusters: none apparent. However,
numbers in intervention and control clinic
matched pairs are very different, e.g. Pair

Myer 2003 (Continued)
1 (large perirural clinics near main road,

intervention total births = 234 versus con-
trol total births = 38). Also, results are only
reported for subset of women who tested
positive
Incorrect analysis: pair-matched cluster
randomisation might decrease baseline im-
balances. Statistical adjustment was made
for cluster design based on a weighted aver-
age of the risk difference within each clinic
pair. Early termination of the study not re-
ported
ANC: antenatal clinic

C-RCT: cluster-randomised controlled trial
SD: standard deviation

DATA AND ANALYSES
Comparison 1. On-site syphilis screening test using rapid treponemal tests versus conventional laboratory testing
with RPR or TPHA
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Incidence of congenital syphilis 1 Odds Ratio (Fixed, 95% CI) 0.09 [0.01, 0.71]
2 Proportion of pregnant women 1 Odds Ratio (Fixed, 95% CI) 989.80 [16.27,
tested for syphilis - 1st 60233.05]
antenatal visit
3 Proportion of pregnant women 1 Odds Ratio (Fixed, 95% CI) 617.88 [13.44,
tested for syphilis - 3rd 28399.01]
trimester
4 Adequate treatment 1 Odds Ratio (Fixed, 95% CI) 10.44 [1.00, 108.99]
5 Partner treatment 1 Odds Ratio (Fixed, 95% CI) 18.17 [3.23, 102.20]
6 Syphilis prevalence - 1st 1 Odds Ratio (Fixed, 95% CI) 2.45 [1.44, 4.18]
antenatal visit
7 Syphilis prevalence - 3rd 1 Odds Ratio (Fixed, 95% CI) 6.27 [1.47, 26.69]
trimester
Comparison 2. On-site syphilis testing with rapid plasma reagin (RPR) test versus routine laboratory testing with
RPR
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Perinatal mortality 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
2 Syphilis treatment 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
2.1 Adequate treatment 1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.2 Inadequate treatment 1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
3 Adverse outcomes Other data No numeric data
4 Syphilis prevalence Other data No numeric data
5 Treatment delay Other data No numeric data

ADDITIONAL TABLES
Table 1. Munkhuu 2009 - Associations between main outcomes and the intervention analysed by multilevel logistic model
Outcome Intervention n/N (%) Control n/N (%) Adjusted OR* P
Congenital syphilis 1/3632 (0.03) 15/3564 (0.42) 0.09 0.022
Coverage at 1st antenatal 3849/3850 (99.9) 3065/3850 (79.6) 989.84 < 0.001
visit
Coverage at 3rd 3670/3683 (97.7) 2357/3796 (62.1) 617.88 < 0.001

trimester
Syphilis case at 1st visit 73/3849 (1.9) 27/3065 (0.9) 2.45 < 0.001
Syphilis case at 3rd 20/3670 (0.5) 2/2357 (0.08) 6.27 0.013

trimester
Adequate treatment 92/93 (98.9) 26/29 (89.6) 10.44 0.05
Partner treatment 88/93 (94.6) 16/29 (55.2) 18.17 < 0.001

* Adjusted for significant independent variables such as gestational age at 1st antenatal visit and multiple sexual partners with a random
effect for antenatal clinics.
OR: odds ratio.
CONTRIBUTIONS OF AUTHORS
Sadequa Shahrook (SS) conceived, designed, co-ordinated, and drafted the review with advice from Rintaro Mori (RM). SS and RM
independently applied study selection criteria and extracted data from the included studies. SS abstracted and analysed the data with
advice from RM. SS wrote the initial draft of the review and all authors contributed to the draft and all subsequent drafts. All authors
read and approved the final version of this review.
DECLARATIONS OF INTEREST
None known.
SOURCES OF SUPPORT

Internal sources
• National Center for Child Health and Development, Japan.
External sources
• Ministry of Health, Labour and Welfare, Japan.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

Deviations from the protocol published in 2013, Issue 2
• We added ’congenital syphilis’ as one of the primary outcomes and ’obstacles/challenges in the uptake of antenatal syphilis
screening tests’ as a secondary outcome.
• ’Coverage of different syphilis screening tests for the detection and treatment of syphilis infection’ (primary outcome) has been
rephrased as ’Proportion of pregnant women tested for syphilis and treatment provided.’
• ’Adequate treatment’, ’partner treatment’, and ’syphilis prevalence’ were not included in the protocol but have been added as
important outcome data.
• Odds ratio (OR) has been reported rather than risk ratio (RR), as was specified in the protocol.
INDEX TERMS
Medical Subject Headings (MeSH)

∗ Point-of-Care Systems; Pregnancy Complications, Infectious [∗ diagnosis]; Prenatal Diagnosis [∗ methods]; Randomized Controlled
Trials as Topic; Syphilis [∗ diagnosis]; Syphilis, Congenital [diagnosis]
MeSH check words

Female; Humans; Pregnancy


Jurnal Evidanbased

Uploaded by

Copyright:

Available Formats

Jurnal Evidanbased

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Jurnal Evidanbased

Uploaded by

Copyright:

Available Formats

Strategies of testing for syphilis during pregnancy (Review)

Shahrook S, Mori R, Ochirbat T, Gomi H

Strategies of testing for syphilis during pregnancy (Review)

Strategies of testing for syphilis during pregnancy (Review) i

Strategies of testing for syphilis during pregnancy

Sadequa Shahrook1 , Rintaro Mori1 , Tumendemberel Ochirbat2 , Harumi Gomi3

Editorial group: Cochrane Pregnancy and Childbirth Group.

PLAIN LANGUAGE SUMMARY

BACKGROUND In approximately 69% of pregnant women with inadequately

Strategies of testing for syphilis during pregnancy (Review) 4

Strategies of testing for syphilis during pregnancy (Review) 5

* Outcome not prespecified in our protocol.

Assessment of risk of bias in included studies

Strategies of testing for syphilis during pregnancy (Review) 6

Unit of analysis issues

Strategies of testing for syphilis during pregnancy (Review) 7

Strategies of testing for syphilis during pregnancy (Review) 8

Subgroup analysis and investigation of heterogeneity

Strategies of testing for syphilis during pregnancy (Review) 9

Strategies of testing for syphilis during pregnancy (Review) 10

Strategies of testing for syphilis during pregnancy (Review) 11

Strategies of testing for syphilis during pregnancy (Review) 12

Allocation concealment bias is unclear in the trial by Munkhuu

Strategies of testing for syphilis during pregnancy (Review) 13

Other potential sources of bias Primary outcomes

Strategies of testing for syphilis during pregnancy (Review) 14

On-site syphilis testing with rapid plasma reagin

Strategies of testing for syphilis during pregnancy (Review) 15

Strategies of testing for syphilis during pregnancy (Review) 16

Overall completeness and applicability of Agreements and disagreements with other

Strategies of testing for syphilis during pregnancy (Review) 17

Strategies of testing for syphilis during pregnancy (Review) 18

References to studies included in this review Delport 1998

Additional references Fonn 1996

Bique 2000 Hawkes 2011

Strategies of testing for syphilis during pregnancy (Review) 20

Strategies of testing for syphilis during pregnancy (Review) 21

Characteristics of included studies [ordered by study ID]

Methods Cluster-randomised trial. Unit of randomisation: antenatal clinics

Participants Number of participants: 14 ANC clinics randomised to 7 intervention (3850 pregnant

Interventions 1-stop syphilis screening service (n = 3850)

Bias Authors’ judgement Support for judgement

Strategies of testing for syphilis during pregnancy (Review) 22

Strategies of testing for syphilis during pregnancy (Review) 23

ond level (higher) using “lme4” package.

Methods Cluster-randomised trial. Unit of randomisation: primary healthcare clinics

Participants Number of participants: 14 primary healthcare clinics randomised to 7 intervention

Interventions On-site syphilis testing (n = 5201)

Outcomes Primary: perinatal death or early neonatal death.

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) High risk “Allocation was unblinded.”

Strategies of testing for syphilis during pregnancy (Review) 24

Strategies of testing for syphilis during pregnancy (Review) 25

1 (large perirural clinics near main road,

ANC: antenatal clinic

Strategies of testing for syphilis during pregnancy (Review) 26

Strategies of testing for syphilis during pregnancy (Review) 27

Outcome Intervention n/N (%) Control n/N (%) Adjusted OR* P

Congenital syphilis 1/3632 (0.03) 15/3564 (0.42) 0.09 0.022

Coverage at 3rd 3670/3683 (97.7) 2357/3796 (62.1) 617.88 < 0.001