Articles
Effectiveness of interventions to improve screening for
Lancet Infect Dis 2011;
11: 684–91
Published Online
June 16, 2011
DOI:10.1016/S1473-
3099(11)70104-9
See Comment page 654
Institute of Global Health,
University College London,
London, UK (S Hawkes PhD);
International Centre for
Diarrhoeal Disease Research,
Dhaka, Bangladesh, and
Mortimer Market Centre,
Camden Primary Care Trust,
London, UK (N Matin MRCP);
Department of Reproductive
Health Research, World Health
Organization, Geneva,
Switzerland (N Broutet PhD);
and Division of Clinical
Epidemiology and
Biostatistics, Institute of Social
and Preventive Medicine,
University of Bern, Bern,
Switzerland (Prof N Low MD)
Correspondence to:
Dr S Hawkes, Reader in Global
Health, UCL Institute for Global
Health and Centre for
International Health and
Development, University College
London, London WC1N 1EH, UK
s.hawkes@ucl.ac.uk
684
syphilis in pregnancy: a systematic review and meta-analysis
Sarah Hawkes, Nashaba Matin, Nathalie Broutet, Nicola Low
Summary
Background About 2·1 million pregnant women have active syphilis every year. Without screening and treatment,
69% of these women will have an adverse outcome of pregnancy. The objectives of this study were to review the
literature systematically to determine the effectiveness of screening interventions to prevent congenital syphilis and
other adverse pregnancy outcomes.
Methods We searched four electronic databases and selected studies to examine evidence for effectiveness of
interventions on three outcomes: increased uptake of syphilis testing, increased treatment rates, and reduction in
adverse pregnancy outcomes. We used fixed effects meta-analysis to estimate pooled relative risks if no or little
evidence of heterogeneity between trials existed.
Findings Ten studies met the inclusion criteria, including two randomised trials. Only two studies aimed to encourage
women to seek care earlier in pregnancy. Nine studies included decentralisation of screening and treatment. The
effects of the interventions on uptake of testing for antenatal syphilis and receiving at least one dose of penicillin were
variable and could not be combined statistically. Study interventions were associated with a reduction in perinatal
death (pooled risk ratio [RR] from three studies 0·46, 95% CI 0·26–0·82) and stillbirth (pooled RR from three
studies 0·42, 95% CI 0·19–0·93). The incidence of congenital syphilis was reduced in all four studies that measured
this outcome with heterogeneous results.
Interpretation Interventions to improve the coverage and effect of screening programmes for antenatal syphilis could
reduce the syphilis-attributable incidence of stillbirth and perinatal death by 50%. The resources required to roll out
antenatal screening programmes would be a worthwhile investment for reduction of adverse pregnancy outcomes
and improvement of neonatal and child survival.
Funding None.
Introduction policies for antenatal syphilis screening in place and
According to WHO estimates, more than 2 million have often had these in place for decades, but
pregnant women have active syphilis every year implementation of the policy is often poor.8,9 As a result,
(ie, positive for both reaginic and non-reaginic tests), fewer than one in eight of all pregnant women is
most of whom live in low-income and middle-income estimated to get screened for syphilis at any point in
countries.1 Active syphilis infection in pregnancy, when their pregnancy,10 despite the known low costs of both
untreated or inadequately treated, is estimated to result screening and treatment.11
in adverse pregnancy outcomes in up to 69% of infected Evidence of the optimum components and the size of
women.2–4 Historical and present data suggest that the potential beneficial and harmful effects of screening
untreated syphilis in pregnancy can cause late abortion programmes for antenatal syphilis is needed to improve
(after 16 weeks) or stillbirth in 25% of cases, prematurity delivery and outcomes. Conclusions from previous
or low birthweight in 13%, neonatal death in 11%, and reviews of syphilis screening and treatment were that no
classic symptoms and signs of an infected syphilitic intervention studies showing an effect on preterm birth
infant in 20%.1–3,5 existed,12 that available studies provided only low grade
Adverse pregnancy outcomes caused by syphilis are evidence,13 and that further randomised trials would be
avoidable.6 The WHO global initiative to eliminate unethical.12,13 Whereas placebo-controlled trials of the
congenital syphilis7 recommends several preventive efficacy of penicillin or other antibiotics are unethical,
strategies, including (1) reducing the overall prevalence important information can be obtained from studies that
of syphilis in the adult population; (2) delivering compare the effectiveness of interventions that aim to
integrated sexual and reproductive health programmes improve the delivery of screening for antenatal syphilis
(which, for example, meet the unmet need for family with usual care. The objectives of this study were to
planning services); (3) promoting and ensuring access systematically review evidence for the effectiveness of
to high quality antenatal care for all pregnant women; interventions that strengthen antenatal syphilis screening
and (4) provision of syphilis screening and treatment programmes, and to identify components of interventions
within antenatal care services. Most countries have that contribute to this effectiveness.
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Methods
Search strategy and selection criteria 787 total number of references

We used a protocol to define our study questions and

27 excluded
methods. We searched Medline, Embase, the Allied and 27 duplicates
Complementary Medicine Database (AMED), and the
Cochrane Library for studies published in English from 760 unique references
January, 1974, to December, 2009. We developed a
specific search strategy that combined thesaurus terms 651 excluded
for syphilis and prenatal care with free text terms to 550 not relevant to study questions
95 study design not relevant
identify potentially relevant interventions (OR 6 not obtained
“program*”, “screening”, “intervention”, “study”,
“trial”). We searched the reference lists of articles
109 full text articles
included in the review and asked experts in the specialty 106 from databases
to identify additional studies. 3 from reference lists
Two of the authors (SH and NM) screened titles and
abstracts to identify potentially relevant articles. Full text
99 excluded
reports of these articles were then screened independently 96 not relevant to study questions
to assess whether they answered any of the 3 demonstration project with
following questions about the effectiveness of antenatal no comparison data

interventions: (1) has the uptake of syphilis testing in

pregnant women increased? (2) is successful treatment
of syphilis in pregnancy more frequent? or (3) has the
incidence of congenital syphilis and other adverse
pregnancy outcomes decreased?
We included randomised trials and non-randomised
studies with either a parallel control group or historical
data from the same population. We excluded prevalence
surveys, economic assessments and modelling studies,
and studies that only examined the effectiveness of
antibiotic treatment or the performance of diagnostic
tests. We reached consensus on which reports to include
by discussion or by asking a third reviewer to adjudicate.
Data about study design and population, components of
the intervention and control groups, outcomes and
the risk of bias were extracted onto prepiloted
structured forms.
Data analysis
We did descriptive analyses to document components of
study interventions acting at different stages of health
care provision: increase of access to antenatal care;
decentralised testing, treatment and case management;
or strengthening of health systems. We also examined
evidence of effectiveness for outcomes related to every
review question. Where more than two studies reported
the same outcome, we displayed effect estimates in
forest plots. We used fixed effects meta-analysis to pool
relative risks (RR) and estimate a common effect (with
95% CIs) if no or little evidence of heterogeneity between
trials existed (I² statistic <25%).14,15 If the I² statistic was
25% or higher, indicating moderate or high heterogeneity
caused by reasons other than chance,14 we did not pool
results; we did not consider it clinically meaningful to
estimate either a common (fixed effects model) or an
average (random-effects model) intervention effect.15
Instead, we described results and considered reasons
for heterogeneity.
10 articles included
2 randomised controlled trial 3 non-randomised, parallel 5 non-randomised, historical
control group control group
Figure 1: Flow chart of included studies
Role of the funding source
There was no funding source for this study. The For the protocol see
corresponding author had full access to all the data in the http://www.ispm.ch/journal-
downloads
study and had final responsibility for the decision to
submit for publication.
Results
We identified 760 unique references and screened
109 full text articles (figure 1). We excluded 99 articles;
there were disagreements between reviewers for
nine,16–24 of which three were excluded after adjudication
by the third reviewer.16–18 Ten full-text articles met the
inclusion criteria.19–28
The included studies enrolled a total of 41 049 women
from 1986 to 2008. Two studies were cluster randomised
trials (from Mongolia23 and South Africa;26 table 1). A risk
of bias existed in both because the assessment of outcomes
was not reported to have been blinded. Additionally, the
process of randomisation in the trial in Mongolia was not
explained (table 2). Two studies were non-randomised
studies with parallel comparison groups in Mozambique19
and South Africa.20 Five studies compared outcomes
before and after implementation of the intervention in
Haiti,21 Kenya,25 Zambia,27 USA,28 and South Africa.24 Hira
and colleagues22 in Zambia reported on both parallel
comparison groups and before-and-after comparisons in
intervention and control groups. A risk of bias existed in
all non-randomised studies (table 3); no study with parallel
groups controlled for differences between intervention
and control clinics, and no before-and-after study

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Country Study design Dates of Study population Settings, Pregnant women Mean Syphilis at Review
enrolment number in enrolled, number gestational enrolment questions*
intervention/ intervention/ age at
control control enrolment,
weeks
Bique Mozambique Non-randomised August 1996– Pregnant women making first Antenatal clinics, Not reported I: 20·7/C: 20·3 100% 3
Osman (Maputo) parallel group July, 1998 antenatal visit 2/2 (453/383 with
et al19 syphilis)
Bronzan South Africa Non-randomised December, 2001– Pregnant women attending Antenatal clinics, 1285/1456 I: 26.6 I: 6·3% 2
et al20 (Eastern Cape) parallel group March, 2002 antenatal clinic, no previous 8/8
syphilis test
Fitzgerald Haiti Non-randomised January, 1996– Pregnant women making first Antenatal clinics Not reported Not reported 6% 2, 3
et al21 (Artibonite before–after December, 1999 antenatal visit linked to NGO (50/34 with
region) hospital, 12 syphilis)
Hira et al22 Zambia Non-randomised February, 1986– Sexually active women attending Periurban health 806/1427 9·4% before I: 8·0% 1, 2, 3
(Lusaka) parallel group January, 1987 MCH clinics; sexually active centres, 3/3 16 weeks
and before–after women attending general OPD;
elderly men and women
attending general OPD
Jenniskens Kenya (Nairobi) Non-randomised Early 1989– Pregnant women making first Antenatal clinics, 13131/540 Before: 23 6·5% 2
et al25† before–after August, 1993 antenatal visit 9/13
Munkhuu Mongolia Randomised August, 2007– Pregnant women making first Antenatal clinics 3850/3850 I: 12·0/C: 14·1 I: 1·9%/ 2, 3
et al23 (Ulaanbaatar) controlled trial August, 2008 antenatal visit with a single linked district C: 0·9%
pregnancy hospitals, 7/7
Myer et al26‡ South Africa, Randomised October, 1998– Pregnant women making first Primary care 5201/2417 I: 23·7/C: 24·2 7·5% 2, 3
(KwaZulu-Natal) controlled trial January, 2000 antenatal visit clinics, 7/7
Potter et al27 Zambia Non-randomised January, 1997– Pregnant women making first Antenatal clinics, 5333 Not reported 6% 2
before–after December, 2004 antenatal visit 22
Swain et al28 USA Non-randomised January, 1992– Pregnant women attending Whole city Not reported Not reported 100% 1, 3
(Milwaukee) before–after December, 1996 antenatal care; high-risk women (67/168 with
having pregnancy tests; physicians syphilis)
Wilkinson South Africa Non-randomised January, 1996– Pregnant women attending Mobile nursing 398/200 Not reported Before: 2
et al23‡ (KwaZulu-Natal) before–after December, 1996 antenatal care service, 1 6·5%

I=intervention centres. NGO=non-governmental organisation. MCH=maternal and child health. OPD=outpatient department. C=control centres. *(1) Increasing uptake of antenatal syphilis screening;
(2) increasing successful treatment rates; (3) reducing incidence of adverse pregnancy outcomes. †Additional details about comparison group from Temmerman and colleagues.29 ‡Wilkinson and colleagues24 is
pilot study for Myer and colleagues.26

Table 1: Descriptive characteristics of included studies of antenatal syphilis screening interventions

Generation of Concealment Blinding of Withdrawals from Intention-to- Valid Clustering Risk of bias
allocation of allocation outcome analysis treat analysis outcome taken into
sequence assessment measures account
Munkhuu et al23 Not reported Not reported Not reported Only for loss to follow- Yes Yes Yes Yes, moderate
up (intervention 5·7%,
control 7·4%)
Myer et al26 ”Independent No Not reported Only for loss to follow- Yes Yes Yes Yes, moderate
scientist…toss up (intervention 9%,
of a coin” control 7%)

Table 2: Risk of bias in randomised controlled trials

controlled for changes in conditions over time (table 3).
No study reported blinding of outcome assessment.
We studied the components of the interventions
assessed in every study (table 4). With regards to
promotion of early antenatal care, Hira and colleagues22
in Zambia used various methods to increase community
awareness about the importance of early antenatal care
(before 16 weeks of pregnancy). They targeted sexually
active women at primary care clinics, and men and
women who were sexually active or elderly people
attending general outpatient clinics. Swain and
colleagues28 in the USA worked with physicians in public
and private sectors to educate “prenatal patients [and]
identify high risk patients not yet receiving prenatal care”
to participate in a screening programme with serological
tests at booking, 28 weeks’ gestation, and delivery.
All studies in low-income and middle-income countries
investigated at least one component of decentralised
testing and treatment (table 4). Eight used a rapid-plasma-
reagin (RPR) test at the point of care,19–22,24–27 one used a

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Intervention and control centres similar Blinded outcome Confounding factors Confounding Clustering Risk of bias
assessment measured factors accounted for in
controlled for analysis
Bique Osman et al19 ”similar suburban antenatal clinics” and “assuming the Not reported No No No High
populations covered by the four clinics are comparable”
Bronzan20 Intervention ”clinics chosen to represent the range of Random 20% No No No High
rural Eastern Cape clinics” and “for comparison
18 clinics in same districts selected as ‘standard practice
clinics’”
Fitzgerald et al21 Same clinics in before–after comparison Not reported No No No High
Hira et al22 ”comparable in size and socio-economic status” Not reported Age, parity, income, lifetime No No High
partners, marital status,
occupation, education
Jenniskens et al25 Not known if same clinics analysed before and after Not reported Not reported No No High
Potter et al27 Same clinics in each before–after comparison Not reported Not reported No No High
Swain et al28 Whole city data compared before and after Not reported No No Not applicable High
Wilkinson et al24 Same mobile antenatal clinic in before–after Not reported No No Not applicable High
comparison

Table 3: Risk of bias in non-randomised controlled studies

Earlier Decentralisation of testing and treatment and improved case management Health system strengthening Comparison
antenatal groups
care
Community Point Same day Single dose Partner notification Patient Third Training Laboratory Supply chain Monitoring
recruitment of care treatment treatment counselling trimester support management
test* test
Bique Osman, 200019 No 1 Yes Yes “Partners were invited No Yes Yes No Yes No Laboratory
to come any afternoon RPR, 3 doses
as soon as possible” penicillin
Bronzan, 200720 No 5 Yes No “Partner notification Yes No Yes No Yes Yes Laboratory
cards” RPR/TPHA
Fitzgerald, 200321 No 1 Yes No “Encouraged to notify No No Yes Yes No Yes Laboratory
sexual partners” testing
Hira, 199022 Yes 2 Yes Yes “Special messages Yes Yes Yes No No No Routine
passed through the antenatal
woman” care,
laboratory
RPR
Jenniskens, 199525 No 1 Yes Yes “Partner was invited to Yes No Yes Yes Yes Yes Laboratory
come to the clinic for testing
reasons related to the
pregnancy”
Munkhuu, 200923 No 4 Yes No “Husbands/ sexual Yes Yes Yes No Yes No Routine
partners invited to antenatal
come at their earliest care,
convenience” laboratory
RPR
Myer, 200326 No 3 Yes No No No No Yes No No Yes Routine
antenatal
care,
laboratory
RPR
Potter, 200827 No 1 Yes Not No No No Yes No Yes No ··
reported
Swain, 199828 Yes 0 No Not No No Yes Yes No No Yes ··
reported
Wilkinson, 199824 No 1 Yes No No No No No No No No Laboratory
RPR

RPR=rapid plasma reagin. TPHA=Trepanoma Pallidum Haemagglutination. *0=no point of care test used. 1=RPR alone, on serum. 2=RPR with laboratory treponemal test. 3=RPR with laboratory RPR test. 4=rapid
treponemal test with laboratory confirmation. 5=rapid treponemal test or RPR (alternating every 2 weeks).

Table 4: Content of antenatal syphilis screening interventions in included studies, in alphabetical order

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Risk ratio (95% CI)

(42·5%) of 457. Five studies22,23,25–27 reported rates of
syphilis testing in intervention and control groups. The
Hira et al (1990)22 4·11 (3·55–4·76)
Jenniskens et al (2000)25 1·62 (1·52–1·73) results were very heterogeneous (I² 99·9%; figure 2). In
Munkhuu et al (2009)23 1·26 (1·24–1·28) the randomised trial in South Africa,26 the coverage of
Myer et al (2003)26 0·98 (0·97–0·99) antenatal syphilis testing was as high in the control
Potter 1 et al (2008)27* 0·96 (0·89–1·04) group, in which blood samples were obtained in the
Potter 2 et al (2008)27† 0·92 (0·89–0·96)
clinic and sent to a central laboratory, as in the intervention
Potter 3 et al (2008)27‡ 1·28 (1·22–1·35)
group, in which on-site testing was done (figure 2).26
0·75 1·0 2·0 3·0 4·0 Results from the non-randomised study by Hira and
Fewer women screened for More women screened for colleagues22 in Zambia showed the lowest uptake in the
syphilis in intervention group syphilis in intervention group
intervention group (473 [59%] of 806) but showed the
Figure 2: Studies reporting proportion of women receiving screening for greatest increase by comparison with the control group
antenatal syphilis in intervention group compared with control group (182 [14%] of 1092). In the study by Potter and colleagues27
*Research only versus normal care. †Prevention of mother-to-child in Zambia, only an intervention combining both research
transmission of HIV only versus normal care. ‡Research and improved
prevention of mother-to-child transmission of HIV versus normal care.
and improved HIV-PMTCT services was associated with
an increase in testing.
Three studies19,23,28 reported on syphilis screening in the
Risk ratio (95% CI) third trimester or at delivery.19,22,23 Bique Osman and
Bronzan et al (2007)20 1·47 (1·22–1·78) colleagues19 studied women with syphilis: of 384 women
Fitzgerald et al (2003)21 1·35 (0·91–2·01) followed through to delivery, 157 (41%) had seroreverted
Hira et al (1990)22 2·30 (1·22–4·33) and were RPR-negative at the time of delivery, compared
Myer et al (2003)26 0·99 (0·91–1·08)
with only 73 (24%) of the 383 women in the control group
Potter 1 et al (2008)27* 1·32 (0·97–1·80)
Potter 2 et al (2008)27† 0·91 (0·78–1·06)
(p<0·0001). Munkhuu and colleagues23 showed that
Potter 3 et al (2008)27‡ 1·20 (0·90–1·60) 3670 (95·3%) of 3850 women randomised to intervention
Wilkinson et al (1998)24 1·24 (1·01–1·52) clinics were retested in the third trimester and 20 (0·5%)
were RPR-positive, compared with 2357 (61·2%) of
0·5 0·75 1·0 2·0 3·0 4·0
Fewer women receive penicillin More women receive penicillin
3850 women retested in control clinics, of whom two
in intervention group in intervention group (0·08%) were RPR-positive. Hira and colleagues22 reported
that 15·1% of women in intervention clinics and 1·6% of
Figure 3: Studies reporting proportion of women receiving at least one dose women in control clinics were tested in the third trimester.
of penicillin in intervention group compared with control group
Swain and colleagues28 promoted an intervention to
*Research only versus normal care. †Prevention of mother-to-child
transmission of HIV versus normal care. ‡Research and improved prevention of encourage women to have three serological tests during
mother-to-child transmission of HIV versus normal care. pregnancy, but did not report uptake rates.
Treatment regimens (one or three doses of penicillin)
rapid treponemal test,23 and one used both.20 All except and definitions of adequate treatment (at least two or all
Swain and colleagues28 promoted same-day treatment. Six three doses of a three-dose regimen) differed between
studies reported explicit efforts to encourage partner studies. The most consistently reported outcome was the
notification and treatment19–23,25 and four studies19,22,23,28 percentage of women receiving at least one dose of
included serological testing for syphilis in the third penicillin, reported in six studies,20–22,24,26,27 all including
trimester (table 4). point-of-care testing and same-day treatment in the
Nine studies included an element of health-systems intervention. Results were heterogeneous (I² 78·2%,
strengthening (training, laboratory support, supply chain figure 3). The smallest effect was seen in the randomised
management, or monitoring).19–23,25–28 Additionally, two trial,26 with no difference between groups. However, in
studies examined interventions to modify the structure that study, the average time to completion of adequate
of the health system: Potter and colleagues27 reported on treatment (at least two doses) was shorter in the
the effect of introducing new standards for programmes intervention than in the control group (risk difference
of HIV prevention of mother-to-child transmission 16 days, 95% CI 11–21]. In the other four non-randomised
(HIV-PMTCT) and research on pre-existing screening studies,20–22,24 women in the intervention group were more
programmes for syphilis in Zambia. Swain and likely to receive any penicillin (at least one dose of
colleagues28 in the USA used a public–private collaboration 2·4 million IUs of benzathine penicillin) than those in
to educate and inform private-practice physicians about the control group. Three studies19,22,23 reported on the
incidence of congenital syphilis in their area.28 percentage of sex partners notified and treated. In all
Only one study22 reported the effect of an intervention three studies, more partners of women in the intervention
on the percentage of women who had their first antenatal groups than those of women in the control group were
visit before 16 weeks of gestation. Hira and colleagues22 treated (Bique Osman and colleagues19 reported 76% of
showed that, in the intervention group, first-trimester partners invited vs “virtually” none; Munkhuu and
testing increased from 68 (9·4%) of 723 women to 194 colleagues23 reported 94·6% vs 55·2% fully treated; Hira

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and colleagues22 reported 29 [39·2%] of 74 vs 3 [8·3%] of

36 spouses brought for treatment). None of these studies A Risk ratio (95% CI) % weight

reported whether or not partner notification resulted in Hira et al (1990)22 0·35 (0·02–7·12) 7·58
Munkhuu et al (2009)23 0·02 (0–0·18) 14·39
the woman having any adverse events.30
Swain et al (1998)28 0·53 (0·33–0·84) 39·49
Seven studies19,21–24,26,28 reported on the incidence of any Fitzgerald et al (2003)21 0·25 (0·15–0·42) 38·53
adverse pregnancy outcome, such as congenital syphilis,
perinatal death, stillbirth, low birthweight, or abortion 0·03 0·125 0·25 0·5 1·0 2·0 4·0
Fewer infants with congenital More infants with congenital
(figure 4). Munkhuu and colleagues23 used the WHO syphilis in intervention group syphilis in intervention group
criteria31 for definition of cases of congenital syphilis.
Fitzgerald and colleagues21 used the definition from the B
US Centers for Disease Control and Prevention (CDC).32 Bique Osman et al (2000)19 0·31 (0·11–0·85) 43·05
Neither Hira and colleagues22 nor Swain and colleagues28 Myer et al 1 (2003)26 1·95 (0·26–14·56) 5·12
Myer et al 2 (2003)26 0·59 (0·11–3·08) 9·21
gave case definitions for congenital syphilis. In three
Myer et al 3 (2003)26 0·08 (0–1·50) 15·31
studies,19,24,26 perinatal death was defined as either stillbirth Myer et al 4 (2003)26 0·64 (0·04–9·77) 3·64
or neonatal death in the first week of life. Myer et al 5 (2003)26 0·63 (0·03–12·86) 2·46
Incidence of congenital syphilis (ie, infection in a live- Myer et al 6 (2003)26 (No events) 0
born infant) were reported in four studies (figure 4A); all Myer et al 7 (2003)26 (No events) 0
showed a lower incidence in the intervention group, but Wilkinson et al (1998)24 0·57 (0·18–1·77) 21·21
Overall (I2=0%, p=0·643) 0·46 (0·26–0·82) 100·00
with heterogeneous results (I²=75·1%).21–23,28 The largest
effect was recorded in the randomised trial by Munkhuu 0·25 0·5 1·0 2·0 4·0
and colleagues23 in Mongolia. Perinatal death was Fewer perinatal deaths More perinatal deaths
reported in three studies, one randomised trial26 and two in intervention group in intervention group
non-randomised studies19,24 (figure 4B). The pooled C
estimate showed a 54% (95% CI 18–74, I²=0·0%) Bique Osman et al (2000)19 0·50 (0·16–1·50) 43·05
reduction in the incidence of perinatal death in clinics Hira et al (1990)22 0·17 (0·02–1·47) 7·58
with antenatal syphilis screening interventions Wilkinson et al (1998)24 0·51 (0·12–2·20) 21·21
(figure 4B). Stillbirth was reported as a separate outcome Overall (I2=0%, p=0·660) 0·42 (0·19–0·93) 100·00
in three non-randomised studies (figure 4C).19,22,24 The
0·25 0·5 1·0 2·0 4·0
pooled estimate showed a reduction of 58% (95% CI Fewer stillbirths More stillbirths
7–81, I²=0·0%). Two non-randomised studies19,22 reported in intervention group in intervention group
on preterm birth. Results from both studies showed a
slight reduction (pooled risk ratio 0·79, 95% CI 0·53–1·19, Figure 4: Studies reporting adverse pregnancy outcomes in women in intervention group compared with
I²=0·0%). No combination of intervention components those in control group.
(A) Proportion of women with a child with congenital syphilis, apart from Fitzgerald and colleagues,21 who
could be clearly linked to the size of outcome effects. compared proportions of children with congenital syphilis after intervention versus before the intervention.
(B) Proportion of women having perinatal death. Myer 1–7: results for this outcome presented separately for every
Discussion centre. (C) Proportion of women having a stillbirth.
This systematic review included ten studies of
interventions to improve the outcomes of antenatal One limitation is that we might have missed eligible
syphilis screening. All interventions in low-income and studies. A highly sensitive search strategy that used any
middle-income countries, where most of congenital one of the possible indexing terms gave an unmanageable
syphilis is reported, assessed the effects of introducing number of items. We therefore supplemented our specific
point-of-care testing and same-day treatment, with or strategy by searching reference lists and asking experts in
without additional elements to improve case the field. This strategy identified more studies than did
management. Effects on the uptake of testing for and another recent systematic review,12 which identified “no
treatment of antenatal syphilis were heterogeneous, but intervention studies showing an effect of syphilis
all in the direction of increased frequency. In studies screening and treatment on preterm birth”.12 However,
measuring clinical outcomes, the incidence of perinatal information in study reports was insufficient to identify
death and stillbirth was decreased. Rates of congenital the potential harms of screening, which might include
syphilis were lower in four studies, with high gender-based violence when women inform their partners
heterogeneity between studies. of a positive result,33 lack of reduction in risky sexual
The strengths of this systematic review are the focus on behaviours in women who screen negative, or adverse
screening for antenatal syphilis as complex interventions, events related to treatment.34
the assessment of both process and clinical outcomes, We believe this to be the first systematic review that
and the systematic methods used to identify, select, provides quantitative estimates of the potential
assess, and synthesise studies. We documented the effectiveness of an antenatal syphilis screening
components of intervention packages and described them programme in preventing adverse pregnancy outcomes.
according to where they acted in the health-care system. All but one included studies addressed at least two of the

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three health-system foci that we used to classify the
interventions: uptake of early antenatal care,
decentralisation and clinical management; and health-
systems strengthening. However, the effects of specific
intervention components could not be determined. This
review adds to observational evidence of the benefits of
single interventions such as penicillin for the treatment
of diagnosed syphilis in pregnancy2,35 and of the diagnostic
efficacy of rapid point-of-care tests.36 We showed the
levels of benefit that could be achieved at a population
level, when single interventions are combined and
delivered as a comprehensive programme.
Our study suggests that antenatal syphilis screening
interventions could reduce the incidence of perinatal death
and stillbirth attributable to syphilis by about 50%.19,22,24,26
The incidence of congenital syphilis (ie, an infected live-
born infant) could also be reduced, but results of the four
studies21–23,28 reporting this outcome were too heterogeneous
to quantify the effect in meta-analysis, perhaps in part
owing to different study populations and settings, different
diagnostic criteria, and the difficulties of ascertainment.37
The estimated level of benefit should take into account the
risk of biases in results of individual studies that would
tend to overestimate the effects of the interventions; only
two studies23,26 were randomised trials and these were also
at risk of bias. Moreover, study settings that could contribute
to heterogeneity also differed substantially. Myer and
colleagues26 in South Africa showed no statistical evidence
of differences in testing or treatment between intervention
(RPR testing on-site) and control (RPR testing in a
reference laboratory) clinics. This was thought to be due,
partly, to the “relatively high quality of laboratory services
provided in the control arm”. The reduction in perinatal
death was, however, consistent with other studies.19,24 The
studies included did not allow assessment of the optimum
timing for screening for syphilis in pregnancy. Moreover,
there was a paucity of information about the outcomes of
partner treatment and of repeat screening in the third
trimester to reduce the risk of reinfection. The WHO
strategy recommends promoting early antenatal care,
ensuring all women are tested at their first antenatal visit,
repeat testing in the third trimester, and treatment of
partners of infected women.7
Empirical evidence on how to increase early attendance
frequency in antenatal care is needed to ensure that the
first antenatal visit takes place early enough in pregnancy
for interventions to be optimally effective. Delayed
screening and treatment of syphilis in pregnancy
increases the likelihood of congenital syphilis.38,39 The
randomised trial by Munkhuu and colleagues23 in which
the effect on congenital syphilis rates was the strongest,
was the only study in which the average gestational age at
booking was in the first trimester.23 Service delivery data,
however, show that few of first antenatal visits in Africa
and Asia are in the first trimester.10 Furthermore, although
syphilis screening has been proposed to be integrated
into HIV-PMTCT programmes,7 we found little evidence
690
on how to address the structural issues within the health
system that are important for effective intervention
delivery within integrated programmes.40 We found only
one relevant study.27 In this study, Potter and colleagues27
reported no evidence that HIV-PMTCT programmes
improved syphilis screening in the absence of resource-
intensive researcher inputs.
The call for provision of a comprehensive package of
antenatal care interventions41 carries substantial resource
implications for both the health systems and the women
who use the services, but the question of who pays for
syphilis screening was not addressed in any of the reports
selected in this study. Although antenatal care is delivered
free as a global public good in many settings,10
interventions such as screening tests are sometimes
charged to the end-user (the pregnant woman in this
case). Cheng and colleagues noted, in a non-comparative
study16 in southern China, that provision of free screening
resulted in an annual increase in the number of women
being screened in one city.16 The resource implications of
this finding need further analysis if antenatal screening
is to be made more widely available.
Our study shows that antenatal syphilis screening
interventions can reduce adverse pregnancy outcomes,
particularly rates of stillbirth and perinatal death. Taking
screening for congenital syphilis programmes to scale
will necessitate both a better understanding of the actual
interventions that work in a range of settings and
contexts, a willingness to address health-financing issues
and persuade policy makers of the benefit of eliminating
this preventable disease. This study suggests that the
resources needed to roll out programmes for antenatal
screening will be a worthwhile investment for reduction
of adverse pregnancy outcomes and improvement of
neonatal and child survival.
Contributors
SH, NB, and NL planned the sudy. NM did the literature search. SH and
NM undertook the data extraction. NL did the meta-analysis. SH, NL,
and NM drafted the manuscript with input from NB.
Conflicts of interest
NB is a staff member of the WHO. She alone is responsible for the
views expressed in this publication and they do not necessarily represent
the decisions, policy or views of the WHO. We declare that we have no
conflicts of interest.
Acknowledgements
We acknowledge Shelagh Redmond for her help in the searches and
design of the data extraction form.
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