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SYPHILIS SCREENING IN PREGNANCY: A SYSTEMATIC REVIEW AND META-ANALYSIS

Friday, 17th of June 2011

‘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.’

 

Best viewed at http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(11)70104-9/fulltext

 

The Lancet Infectious Diseases, Early Online Publication, 16 June 2011

doi:10.1016/S1473-3099(11)70104-9 Cite or Link Using DOI

Effectiveness of interventions to improve screening for syphilis in pregnancy: a systematic review and meta-analysis

Original Text

Dr Sarah Hawkes PhD a , Nashaba Matin MRCP b, Nathalie Broutet PhD c, Prof Nicola Low MD d

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.

According to WHO estimates, more than 2 million pregnant women have active syphilis every year (ie, positive for both reaginic and non-reaginic tests), most of whom live in low-income and middle-income countries.1 Active syphilis infection in pregnancy, when untreated or inadequately treated, is estimated to result in adverse pregnancy outcomes in up to 69% of infected women.2—4 Historical and present data suggest that untreated syphilis in pregnancy can cause late abortion (after 16 weeks) or stillbirth in 25% of cases, prematurity or low birthweight in 13%, neonatal death in 11%, and classic symptoms and signs of an infected syphilitic infant in 20%.1—3,5

Adverse pregnancy outcomes caused by syphilis are avoidable.6 The WHO global initiative to eliminate congenital syphilis7 recommends several preventive strategies, including (1) reducing the overall prevalence of syphilis in the adult population; (2) delivering integrated sexual and reproductive health programmes (which, for example, meet the unmet need for family planning services); (3) promoting and ensuring access to high quality antenatal care for all pregnant women; and (4) provision of syphilis screening and treatment within antenatal care services. Most countries have policies for antenatal syphilis screening in place and have often had these in place for decades, but implementation of the policy is often poor.8, 9 As a result, fewer than one in eight of all pregnant women is estimated to get screened for syphilis at any point in their pregnancy,10 despite the known low costs of both screening and treatment.11

Evidence of the optimum components and the size of the potential beneficial and harmful effects of screening programmes for antenatal syphilis is needed to improve delivery and outcomes. Conclusions from previous reviews of syphilis screening and treatment were that no intervention studies showing an effect on preterm birth existed,12 that available studies provided only low grade evidence,13 and that further randomised trials would be unethical.12, 13 Whereas placebo-controlled trials of the efficacy of penicillin or other antibiotics are unethical, important information can be obtained from studies that compare the effectiveness of interventions that aim to improve the delivery of screening for antenatal syphilis with usual care. The objectives of this study were to systematically review evidence for the effectiveness of interventions that strengthen antenatal syphilis screening programmes, and to identify components of interventions that contribute to this effectiveness.

Search strategy and selection criteria

We used a protocol to define our study questions and methods. We searched Medline, Embase, the Allied and Complementary Medicine Database (AMED), and the Cochrane Library for studies published in English from January, 1974, to December, 2009. We developed a specific search strategy that combined thesaurus terms for syphilis and prenatal care with free text terms to identify potentially relevant interventions (OR “program*”, “screening”, “intervention”, “study”, “trial”). We searched the reference lists of articles included in the review and asked experts in the specialty to identify additional studies.

Two of the authors (SH and NM) screened titles and abstracts to identify potentially relevant articles. Full text reports of these articles were then screened independently to assess whether they answered any of the following questions about the effectiveness of antenatal 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.

Role of the funding source

There was no funding source for this study. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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

 

Figure 1 Full-size image (17K) Download to PowerPoint

Flow chart of included studies

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;26table 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 controlled for changes in conditions over time (table 3). No study reported blinding of outcome assessment.

Table 1Table image  

Descriptive characteristics of included studies of antenatal syphilis screening interventions

Table 2Table image  

Risk of bias in randomised controlled trials

Table 3Table image  

Risk of bias in non-randomised controlled studies

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.

Table 4Table image  

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

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 rapid treponemal test,23 and one used both.20 All except Swain and colleagues28 promoted same-day treatment. Six studies reported explicit efforts to encourage partner notification and treatment19—23,25 and four studies19, 22, 23, 28 included serological testing for syphilis in the third trimester (table 4).

Nine studies included an element of health-systems strengthening (training, laboratory support, supply chain management, or monitoring).19—23,25—28 Additionally, two studies examined interventions to modify the structure of the health system: Potter and colleagues27 reported on the effect of introducing new standards for programmes of HIV prevention of mother-to-child transmission (HIV-PMTCT) and research on pre-existing screening programmes for syphilis in Zambia. Swain and colleagues28 in the USA used a public—private collaboration to educate and inform private-practice physicians about incidence of congenital syphilis in their area.28

Only one study22 reported the effect of an intervention on the percentage of women who had their first antenatal visit before 16 weeks of gestation. Hira and colleagues22 showed that, in the intervention group, first-trimester testing increased from 68 (9·4%) of 723 women to 194 (42·5%) of 457. Five studies22,23,25—27 reported rates of syphilis testing in intervention and control groups. The results were very heterogeneous (I2 99·9%; figure 2). In the randomised trial in South Africa,26 the coverage of antenatal syphilis testing was as high in the control group, in which blood samples were obtained in the clinic and sent to a central laboratory, as in the intervention group, in which on-site testing was done (figure 2).26 Results from the non-randomised study by Hira and colleagues22 in Zambia showed the lowest uptake in the intervention group (473 [59%] of 806) but showed the greatest increase by comparison with the control group (182 [14%] of 1092). In the study by Potter and colleagues27 in Zambia, only an intervention combining both research and improved HIV-PMTCT services was associated with an increase in testing.

 

Figure 2 Full-size image (34K) Download to PowerPoint

Studies reporting proportion of women receiving screening for antenatal syphilis in intervention group compared with control group

*Research only versus normal care. †Prevention of mother-to-child transmission of HIV only versus normal care. ‡Research and improved prevention of mother-to-child transmission of HIV versus normal care.

Three studies19, 23, 28 reported on syphilis screening in the third trimester or at delivery.19, 22, 23 Bique Osman and colleagues19 studied women with syphilis: of 384 women followed through to delivery, 157 (41%) had seroreverted and were RPR-negative at the time of delivery, compared with only 73 (24%) of the 383 women in the control group (p<0·0001). Munkhuu and colleagues23 showed that 3670 (95·3%) of 3850 women randomised to intervention clinics were retested in the third trimester and 20 (0·5%) were RPR-positive, compared with 2357 (61·2%) of 3850 women retested in control clinics, of whom two (0·08%) were RPR-positive. Hira and colleagues22 reported that 15·1% of women in intervention clinics and 1·6% of women in control clinics were tested in the third trimester. Swain and colleagues28 promoted an intervention to encourage women to have three serological tests during pregnancy, but did not report uptake rates.

Treatment regimens (one or three doses of penicillin) and definitions of adequate treatment (at least two or all three doses of a three-dose regimen) differed between studies. The most consistently reported outcome was the percentage of women receiving at least one dose of penicillin, reported in six studies,20—22,24,26,27 all including point-of-care testing and same-day treatment in the intervention. Results were heterogeneous (I2 78·2%, figure 3). The smallest effect was seen in the randomised trial,26 with no difference between groups. However, in that study, the average time to completion of adequate treatment (at least two doses) was shorter in the intervention than in the control group (risk difference 16 days, 95% CI 11—21]. In the other four non-randomised studies,20—22,24 women in the intervention group were more likely to receive any penicillin (at least one dose of 2·4 million IUs of benzathine penicillin) than those in the control group. Three studies19, 22, 23 reported on the percentage of sex partners notified and treated. In all three studies, more partners of women in the intervention groups than those of women in the control group were treated (Bique Osman and colleagues19 reported 76% of partners invited vs “virtually” none; Munkhuu and colleagues23 reported 94·6% vs 55·2% fully treated; Hira and colleagues22 reported 29 [39·2%] of 74 vs 3 [8·3%] of 36 spouses brought for treatment). None of these studies reported whether or not partner notification resulted in the woman having any adverse events.30

 

Figure 3 Full-size image (38K) Download to PowerPoint

Studies reporting proportion of women receiving at least one dose of penicillin in intervention group compared with control group

*Research only versus normal care. †Prevention of mother-to-child transmission of HIV versus normal care. ‡Research and improved prevention of mother-to-child transmission of HIV versus normal care.

Seven studies19,21—24,26,28 reported on the incidence of any adverse pregnancy outcome, such as congenital syphilis, perinatal death, stillbirth, low birthweight, or abortion (figure 4). Munkhuu and colleagues23 used the WHO criteria31 for definition of cases of congenital syphilis. Fitzgerald and colleagues21 used the definition from the US Centers for Disease Control and Prevention (CDC).32 Neither Hira and colleagues22 nor Swain and colleagues28 gave case definitions for congenital syphilis. In three studies,19, 24, 26 perinatal death was defined as either stillbirth or neonatal death in the first week of life.

 

Figure 4 Full-size image (108K) Download to PowerPoint

Studies reporting adverse pregnancy outcomes in women in intervention group compared with those in control group.

(A) Proportion of women with a child with congenital syphilis, apart from Fitzgerald and colleagues,21 who 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 centre. (C) Proportion of women having a stillbirth.

Incidence of congenital syphilis (ie, infection in a live-born infant) were reported in four studies (figure 4A); all showed a lower incidence in the intervention group, but with heterogeneous results (I2=75·1%).21—23,28 The largest effect was recorded in the randomised trial by Munkhuu and colleagues23 in Mongolia. Perinatal death was reported in three studies, one randomised trial26 and two non-randomised studies19, 24 (figure 4B). The pooled estimate showed a 54% (95% CI 18—74, I2=0·0%) reduction in the incidence of perinatal death in clinics with antenatal syphilis screening interventions (figure 4B). Stillbirth was reported as a separate outcome in three non-randomised studies (figure 4C).19, 22, 24 The pooled estimate showed a reduction of 58% (95% CI 7—81, I2=0·0%). Two non-randomised studies19, 22 reported on preterm birth. Results from both studies showed a slight reduction (pooled risk ratio 0·79, 95% CI 0·53—1·19, I2=0·0%). No combination of intervention components could be clearly linked to the size of outcome effects.

This systematic review included ten studies of interventions to improve the outcomes of antenatal syphilis screening. All interventions in low-income and middle-income countries, where most of congenital syphilis is reported, assessed the effects of introducing point-of-care testing and same-day treatment, with or without additional elements to improve case management. Effects on the uptake of testing for and treatment of antenatal syphilis were heterogeneous, but all in the direction of increased frequency. In studies measuring clinical outcomes, the incidence of perinatal death and stillbirth was decreased. Rates of congenital syphilis were lower in four studies, with high heterogeneity between studies.

The strengths of this systematic review are the focus on screening for antenatal syphilis as complex interventions, the assessment of both process and clinical outcomes, and the systematic methods used to identify, select, assess, and synthesise studies. We documented the components of intervention packages and described them according to where they acted in the health-care system. One limitation is that we might have missed eligible studies. A highly sensitive search strategy that used any one of the possible indexing terms gave an unmanageable number of items. We therefore supplemented our specific strategy by searching reference lists and asking experts in the field. This strategy identified more studies than did another recent systematic review,12 which identified “no intervention studies showing an effect of syphilis screening and treatment on preterm birth”.12 However, information in study reports was insufficient to identify the potential harms of screening, which might include gender-based violence when women inform their partners of a positive result,33 lack of reduction in risky sexual behaviours in women who screen negative, or adverse events related to treatment.34

We believe this to be the first systematic review that provides quantitative estimates of the potential effectiveness of an antenatal syphilis screening programme in preventing adverse pregnancy outcomes. All but one included studies addressed at least two of the 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 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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a Institute of Global Health, University College London, London, UK

b International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh, and Mortimer Market Centre, Camden Primary Care Trust, London, UK

c Department of Reproductive Health Research, World Health Organization, Geneva, Switzerland

d Division of Clinical Epidemiology and Biostatistics, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland

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