Antenatal lower genital tract infection screening and treatment programs for preventing preterm delivery
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effectiveness and complications of antenatal lower genital tract infection screening and treatment programs in reducing preterm birth and subsequent morbidity.
Background
Preterm birth, defined as birth occurring prior to 37 weeks of gestation occurs in 5% to 10% of all pregnancies and is the most common cause of perinatal morbidity and mortality in the world. Moreover, preterm birth is implicated in at least two‐thirds of early infant deaths (Cunningham 1997) and causes 60% of perinatal mortality and nearly half of long‐term neurologic disability, including cerebral palsy, and is associated with admission to neonatal intensive care, severe morbidity in the first weeks of life, prolonged hospital stay after birth, and readmission to hospital in the first year of life (Cunningham 2001; Goldenberg 1998; Roberts 2000; Wood 2000). Surviving infants, especially those born before 32 weeks, have a substantially increased risk of chronic lung disease, and major and minor impairments (Doyle 1996; Saigal 2000). Whatever the result, the emotional impact on the family can be enormous.
A wide spectrum of causes and demographic factors have been implicated in the birth of preterm infants. These can be categorized into four groups:
(1) medical and obstetric complications ‐ there are associations with placental hemorrhage and hypertensive disorders in about one‐third of cases (Meis 1995);
(2) lifestyle factors ‐ there is an association with alcohol abuse, low maternal age, and occupational factors (Henriksen 1995; Holzman 1995; Satin 1994);
(3) amniotic fluid infection caused by a variety of micro‐organisms located in the genital tract ‐ approximately one‐third of preterm births are associated with chorioamniotic infection (Lettieri 1993); and
(4) asymptomatic cervical dilatation (Papiernik 1986).
Many micro‐organisms cause both symptomatic and asymptomatic infection and may result in preterm prelabour rupture of membranes, preterm labour, or both. For example, bacterial vaginosis (including Gardnerella vaginalis, Bacteroides species, Mobiluncus species, Ureaplasma urealyticum, and Mycoplasma hominis) (Hillier 1995; McDonald 1994; McGregor 1990; Meis 1995), Chlamydia trachomatis (Gravett 1986), Trichomonas vaginalis (Cotch 1997), Neisseria gonorrhoeae (Elliott 1990), Group B streptococci (Regan 1981), Staphylococcus aureus (McGregor 1990), syphilis (McFarlin 1995), HIV (Temmerman 1994), enteropharyngeal bacteria and Peptostreptococcus species (McDonald 1994) have been associated with an increased risk of preterm birth. Candida species, however, has not been associated with preterm birth (Cotch 1998).
A possible mechanism for the link between infection and preterm birth is the bacterial stimulation of the biosynthesis of prostaglandins, either directly via phospholipase A2 and C (Bejar 1981) or bacterial endotoxin introduced into the amniotic fluid stimulating decidual cells to produce cytokines and prostaglandins that initiate labour (Cox 1989). Indirect links via substances such as interleukin‐1, tumour necrosis factor and platelet activating factor, all of which may be found in infected amniotic fluid, have also been identified (Romero 1992; Yoon 2000).
A program of screening for and treating asymptomatic vaginal infections has been associated with a reduction in preterm birth (Kiss 2006). There are differences in the screening methods of different types of organisms. There is scant evidence that can be used to determine the optimal screening regimen appropriate for each organism in pregnancy. Therefore, it is unclear whether all women should be routinely screened, how often the screening should occur, and which tests should be used.
Chlamydia trachomatis has been identified by multiple tests from different specimen sources. The tests may be analysed by three types of DNA‐based test: ligase chain reaction, polymerase chain reaction (PCR) and enzyme immuno‐assay (Watson 2002). DNA amplification techniques are providing highly sensitive and specific tests (Black 1997). The screening test can detect Chlamydia on genital secretions, urine specimens, endocervical and vaginal or urethral samples (Domeika 1999; Gulmezoglu 2002; Shrier 2004). Nucleic acid amplification tests are more sensitive than cell culture (Jespersen 2005).
Trichomoniasis may be asymptomatic in up to 50% of infected women (Wolner‐Hanssen 1989). The diagnosis is usually made on clinical findings and laboratory procedures (Petrin 1998) such as direct microscopy and culture. The gold standard for diagnosis of trichomoniasis is a culture (Borchardt 1991). Most frequently, the saline wet‐mount preparation is used for observation of motile organisms under the light microscope. Wet‐mount smear is a cheap and quick method but more sensitive techniques are culture, immunofluorescence and enzyme immunoassay (Lossick 1991). Different staining techniques include Gram stain, Giemsa stain, Papanicolaou smear, acridine orange (Borchardt 1991; Rein 1990), and diverse molecularly‐based diagnostic methods (hybridization assay and PCR). These vary widely in sensitivities and specificities for screening Trichomoniasis (DeMeo 1996; Madico 1998; Mayta 2000; Muresu 1994).
Bacterial vaginosis is a clinical syndrome; the microbiology of bacterial vaginosis is complex and is composed of Gardnerella vaginalis, Mycoplasma hominis and anaerobic bacteria (Amsel 1983). The diagnosis is usually made on clinical Amsel criteria findings (Amsel 1983) and laboratory tests. Vaginal pH testing may be a valuable screening tool as it is a quick and inexpensive test (Gjerdingen 2000). Vaginal swab Gram stain with quantification of the microbial flora has high sensitivity and specificity and is accepted as an alternative method (Nugent 1991).
Screening tests for other organisms including syphilis have been identified by multiple tests. Screening tests such as Treponema pallidum hemagglutination assay, Treponema pallidum particle agglutination assay, and enzyme‐linked immunosorbent assays (ELISAs) are more reliable than Venereal Disease Research Laboratory testing, the fluorescent treponemal antibody absorption test, and immunoblot assays (Muller 2006). The screening test for Neisseria gonorrhoeae, usually made from a culture, remains accurate when transport conditions are suitable. The tests could be used with cervical, urine and vaginal swabs. DNA amplification techniques provide highly sensitive and specific tests (Carroll 1998; Koumans 1998; Livengood 2001). Diagnosis of HIV infection can be obtained from enzyme‐linked immunosorbent assay (ELISA), Western blot, and RNA PCR testing (Kleinman 1998). The HIV‐p24 Ag was tested for early diagnosis of an acute HIV infection (Thies 1994). Strategies for the diagnosis of Group B streptococcus (GBS) include obtaining vaginal or both vaginal and anorectal GBS cultures (Quinlan 2000) and a rapid enrichment cum antigen detection test (Das 2003).
Other Cochrane protocols and reviews have addressed a number of issues regarding treatment of infection in pregnancy. Antibiotic treatment of chlamydial, trichomonas, bacterial vaginosis and gonorrhoeal infection in pregnancy appears to be effective to clear organisms (Brocklehurst 1998; Brocklehurst 2002; Gulmezoglu 2002; McDonald 2005) but it is not known whether treatment of trichomonas will have any effect on pregnancy outcomes (Gulmezoglu 2002). There is little evidence to show that screening and treatment in all asymptomatic pregnant women for bacterial vaginosis can prevent preterm birth (McDonald 2005). Antibiotic prophylaxis in pregnancies with a previous preterm birth associated with bacterial vaginosis can reduce preterm delivery (Thinkhamrop 2002). There is insufficient evidence to treat ureaplasmas to reduce preterm birth (Raynes‐Greenow 2004). There is no evidence that antiretrovirals and the treatment of syphilis influence the incidence of premature delivery (Brocklehurst 2006; Walker 2001). None of these reviews are concerned primarily with the screening program for antenatal lower genital tract infection. There is unclear evidence for the effectiveness of screening programs of lower genital tract infection to prevent preterm birth.
Objectives
To assess the effectiveness and complications of antenatal lower genital tract infection screening and treatment programs in reducing preterm birth and subsequent morbidity.
Methods
Criteria for considering studies for this review
Types of studies
We will include all published and unpublished randomised controlled trials evaluating any described method of antenatal lower genital tract infection screening. We will include quasi‐controlled trials.
Types of participants
Pregnant women with a gestational age of less than 37 weeks, who are not in labour, have no vaginal bleeding and are without symptoms of lower genital tract infection.
Types of interventions
Any lower genital tract infection screening and treatment programs compared with no screening. The screening programs are defined as screening tests such as wet mount, Gram stain and culture of vaginal secretions and are followed by appropriate treatment after a positive screening test, or a screening test followed by no treatment after a negative screening test. No screening is defined as pregnant women receiving routine antenatal care but without being given a screening program.
Types of outcome measures
Primary outcomes
(1) Preterm birth (less than 37 weeks)
Secondary outcomes
(1) Birthweight less than 2500 g
(2) Neonatal morbidity: sepsis, respiratory distress syndrome, intraventricular haemorrhage, necrotizing enterocolitis, seizures
(3) Duration of admission to neonatal intensive care unit/hospital
(4) Death: stillbirth, neonatal mortality, infant mortality
(5) Side‐effects of treatment including drug resistance
(6) Persistent infection
(7) Recurrent infection
(8) Economic analysis (cost effectiveness, cost utility)
(9) False positive/negative of the screening programme
(10) Women's satisfaction
Search methods for identification of studies
We will contact the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group's Trials Register.
The Cochrane Pregnancy and Childbirth Group's Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
(1) quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
(2) monthly searches of MEDLINE;
(3) handsearches of 30 journals and the proceedings of major conferences;
(4) weekly current awareness search of a further 37 journals.
Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the 'Search strategies for identification of studies' section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are given a code (or codes) depending on the topic. The codes are linked to review topics. The Trials Search Co‐ordinator searches the register for each review using these codes rather than keywords.
In addition, we will search the Central Register of Controlled Trials (The Cochrane Library) using the following search strategy:
#1 Pregnancy (explode MeSH)
#2 Pregnancy Complications (explode MeSH)
#3 pregnan*
#4 (preterm or premature) near (labour or labor)
#5 Infection (explode MeSH)
#6 infect*
#7 Mass Screening (explode MeSH)
#8 screen*
#9 (#1 or #2 or #3 or #4)
#10 (#5 or #6)
#11 (7 or #8)
#12 (#9 and #10 and #11)
We will adapt the above search strategy to search MEDLINE (January 1966 to current) and EMBASE (January 1985 to current) by selecting appropriate MeSH and/or keywords from their respective thesauri.
If necessary, we will contact researchers to provide further information. We will contact experts in the field for additional and ongoing trials. We will also search the reference lists of trials and review articles.
We will not apply any language restrictions.
Data collection and analysis
Selection of studies
Using the inclusion criteria, one review author, Ussanee Swadpanich (US), will assess all studies for inclusion in the review, and a second author, Witoon Prasertcharoensook (WP), will independently duplicate the process. In addition, any study that can not be classified by the first author will be independently assessed by the second. A third author, Pisake Lumbiganon, will be consulted to resolve any disagreement.
Data extraction and management
We will design a form to extract data. Both authors (US, WP) will extract the data using the agreed form. We will resolve discrepancies through discussion. We will use the Review Manager software (RevMan 2003) to double enter all the data or a subsample.
When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.
Assessment of methodological quality of included studies
We will assess the validity of each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005). Methods used for generation of the randomisation sequence will be described for each trial.
(1) Selection bias (randomisation and allocation concealment)
We will assign a quality score for each trial, using the following criteria:
(A) adequate concealment of allocation: such as telephone randomisation, consecutively numbered, sealed opaque envelopes;
(B) unclear whether adequate concealment of allocation: such as list or table used, sealed envelopes, or study does not report any concealment approach;
(C) inadequate concealment of allocation: such as open list of random number tables, use of case record numbers, dates of birth or days of the week.
(2) Attrition bias (loss of participants ‐ for example, withdrawals, dropouts, protocol deviations)
We will assess completeness to follow up using the following criteria:
(A) less than 5% loss of participants;
(B) 5% to 9.9% loss of participants;
(C) 10% to 19.9% loss of participants;
(D) more than 20% loss of participants.
We will exclude the trials have more than 20% loss of participants because of the risk of bias.
(3) Performance bias (blinding of participants, researchers and outcome assessment)
We will assess blinding using the following criteria:
(1) blinding of participants (yes/no/unclear);
(2) blinding of caregiver (yes/no/unclear);
(3) blinding of outcome assessment (yes/no/unclear).
Measures of treatment effect
We will carry out statistical analysis using the Review Manager software (RevMan 2003). We will use a fixed‐effect meta‐analysis for combining data in the absence of significant heterogeneity if trials are sufficiently similar. If heterogeneity is found, this will be explored by a sensitivity analysis followed by random‐effects if required.
Dichotomous data
For dichotomous data (for example, preterm birth, birthweight less than 2500 grams), we will present results as summary relative risks with 95% confidence intervals.
Continuous data
For continuous data (for example, duration of admission to neonatal intensive care unit or hospital), we will use the weighted mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods. If there is evidence of skewness, this will be reported.
Unit of analysis issues
Cluster‐randomised trials
We will include cluster‐randomised trials, in which the unit of randomisation was a group of participants rather than individual participants in the analyses, along with individually‐randomised trials. Their sample sizes will be adjusted using the methods described in Gates 2005 using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), or from another source. If ICCs from other sources are used, this will be reported and sensitivity analyses conducted to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually‐randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely. We will also acknowledge heterogeneity in the randomisation unit and perform a separate meta‐analysis. Therefore, the meta‐analysis will be performed in two parts as well.
Dealing with missing data
We will analyse data on all participants with available data in the group to which they are allocated, regardless of whether or not they received the allocated intervention. If in the original reports participants are not analysed in the group to which they were randomised, and there is sufficient information in the trial report, we will attempt to restore them to the correct group.
Assessment of heterogeneity
We will apply tests of heterogeneity between trials, if appropriate, using the I‐squared statistic. If we identify high levels of heterogeneity among the trials, (exceeding 50%), we will explore it by prespecified subgroup analysis and perform sensitivity analysis. A random‐effects meta‐analysis will be used as an overall summary if this is considered appropriate.
Subgroup analyses
If we have a large number of trials included, we will conduct planned subgroup analyses classifying whole trials by interaction tests as described by Deeks 2001. We are aware of different screening methods and treatment practices for the same micro‐organisms. If we have a large number of included trials, we will do subgroup analyses related to the same screening method following the same treatment practice for each type of organism. However, if we have a small number of trials, we will describe each trial with different screening and treatment practices separately.
We plan to carry out the following subgroup analyses:
(a) types of abnormal vaginal flora compared with each other;
(b) recurrent infection versus persistent infection;
(c) singleton versus multiple pregnancy;
(d) gestational age at screening (less than 12, 13 to 27, 28 to 36 weeks);
(e) effect of treatment of various abnormal vaginal flora on preterm birth rate;
(f) low‐income and high‐income settings;
(g) screening following with treatment versus screening following without treatment.
Sensitivity analyses
We will carry out sensitivity analyses to explore the effect of trial quality. This will involve analyses based on an A, B, C, or D rating of selection bias and attrition bias. Studies of poor quality will be excluded from the analyses (those rated B, C, or D) in order to assess any substantive difference to the overall result. We will then analyse the impact the inclusion of quasi‐controlled trials has had on trial quality. If cluster trials have been incorporated with an estimate of the ICC borrowed from a different trial, we will perform a sensitivity analysis to see what the effect of different values of the ICC on the results of the analysis would be.
