Christina Bougatsos

Evidence on the Benefits and Harms of Screening and Treating Pregnant Women Who Are Asymptomatic for Bacterial Vaginosis: An Update Review for the U.S. Preventive Services Task Force

Bacterial vaginosis is the most common lower genital tract syndrome in women of reproductive age (1). It involves an imbalance in the vaginal bacterial ecosystem, such that hydrogen peroxideproducing lactobacilli are diminished and Gardnerella vaginalis, anaerobes, and mycoplasmata are abundant. Symptoms can include vaginal discharge, pruritus, or malodor, although approximately half of women with bacterial vaginosis are asymptomatic (24). Once the condition is diagnosed, the microflora imbalance can be altered with a short course of antibiotic therapy; however, recurrence is common. The natural history of bacterial vaginosis in pregnant women has shown that up to 50% of cases of bacterial vaginosis resolve spontaneously during pregnancy (5, 6). Although several antibiotic treatment regimens have been shown to effectively eradicate bacterial vaginosis in pregnant women (7), the treatments recommended in pregnancy by the Centers for Disease Control and Prevention are oral metronidazole (250 mg 3 times daily for 7 days) or oral clindamycin (300 mg twice daily for 7 days) (8, 9). Researchers have documented the associations between bacterial vaginosis and adverse pregnancy outcomes, focusing on preterm birth and, more recently, the timing of treatment (4, 1020). This epidemiologic evidence has been used as a rationale for screening asymptomatic pregnant women. The prevalence of bacterial vaginosis in pregnant women seen in community settings is not well studied. In several large, prospective, longitudinal studies, the rate of bacterial vaginosis has ranged from 9% to 23% (1113, 2123). Nearly one quarter of white women in an NHANES (National Health and Nutrition Examination Survey) probability sample had Gram stains consistent with bacterial vaginosis (24). Bacterial vaginosis in pregnancy may be more common among minority women, those of low socioeconomic status, and those who have previously delivered low-birthweight infants (12, 25, 26). The National Institute of Child Health and Human Development MaternalFetal Medicine Units Network study found that nearly 50% of pregnant African-American women had bacterial vaginosis (17), similar to the rate found in nonpregnant African American women in NHANES (24). Recently, concerns have been raised that metronidazole, the most common antibiotic used to treat bacterial vaginosis, may increase preterm births in certain populations. In studies that focus on treatment with metronidazole (often at higher doses for treatment of Trichomonas vaginalis), treated pregnant women were up to twice as likely to have a preterm birth as their untreated counterparts (27, 28). The juxtaposition of these data, along with epidemiologic evidence associating bacterial vaginosis with preterm birth, leads to considerable confusion for clinicians and researchers alike. Whether to screen or treat multiple times, when to start, and at what interval during pregnancy are unanswered questions, as bacterial vaginosis may not necessarily persist throughout pregnancy. This review was conducted for the U.S. Preventive Services Task Force (USPSTF) to update its 2001 recommendations (2931) by examining the chain of evidence regarding the value of screening for and treating bacterial vaginosis in reducing adverse pregnancy outcomes for asymptomatic women at low, average, and high risk for preterm delivery. Methods Figure 1 presents the analytic framework and key questions used to guide this updated review. Figure 1. Analytic framework and key questions. KQ = key question. Data Sources We searched the Cochrane Central Registry of Controlled Trials, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effects to identify relevant studies through September 2007 (Appendix Table 1 and Appendix Table 2). In addition, we conducted question-specific searches in Ovid MEDLINE for studies from 1996 to September 2007 and Ovid MEDLINE Database of In-Process and Other Non-Indexed Citations for studies from 2000 to September 2007 to identify otherwise nonindexed studies relevant to any key question. We downloaded and stored captured titles and abstracts in an EndNote database for systematic review and tracking throughout the project. We conducted additional targeted keyword searches and compared the results with the existing database, reviewing unique citations relating to all key questions for inclusion. We obtained additional articles by comparing reference lists of other systematic reviews, individual studies, editorials, reports, and Web sites and by consulting experts. Appendix Table 1. Overall Searches Appendix Table 2. Specific Searches per Key Question* Study Selection We included systematic reviews and individual randomized, controlled trials that evaluated screening, treatment, pregnancy outcomes, or adverse effects for asymptomatic women with bacterial vaginosis. Two investigators independently reviewed captured abstracts by using predefined inclusion and exclusion criteria, and we retrieved any title or abstract that either reviewer marked for inclusion. Two reviewers also independently reviewed full-text papers according to specific criteria. Investigators met to resolve any discrepancies. For a screening trial to be included, we required a comparison of pregnancy outcomes for 2 distinct groups of women: 1 group was screened and treated, and the other was unscreened. We defined asymptomatic patients as those who presented for routine prenatal visits and not specifically for evaluation of vaginal discharge, odor, or itching. Under this definition, asymptomatic patients could include both patients who had no symptoms and those who were unaware of symptoms. We felt this population was most reflective of that encountered in everyday practice. Eligible studies were conducted in settings where pregnant women went for prenatal and obstetric care. Study participants were categorized as having low, average (general population), or high risk for preterm delivery. Women who had not had a previous preterm delivery or had no other risk factors for preterm delivery (for example, nulliparous women) were considered to be low-risk. The general population, or average-risk, category included all pregnant women presenting to the clinic or study site regardless of risk status. This would include a mix of women at low, average, and high risk for preterm delivery. Women who had a previous preterm delivery due to spontaneous rupture of membranes or spontaneous preterm labor were categorized as high-risk. We excluded studies of nonpregnant women or those symptomatic for bacterial vaginosis or other infections, as well as studies lacking pregnancy outcomes, animal studies, and nonEnglish-language studies. We reviewed randomized, controlled trials that matched all other criteria except for including multiple infections to ascertain whether bacterial vaginosisonly data were available for any pregnancy outcome, and we excluded studies that only included outcome data for multiple infections. Data Extraction and Quality Assessment Two independent reviewers read and extracted data on study design, number of persons who enrolled in and completed the study, setting, patient demographic characteristics, inclusion and exclusion criteria, diagnostic methods, and risk factors. We abstracted all pregnancy outcome data provided. Preterm delivery (that is, the probability of delivery before 37 weeks) may be further subdivided into spontaneous preterm delivery and indicated preterm delivery. Other abstracted outcomes included low birthweight (defined as <2500 g); preterm, premature rupture of membranes; preterm labor; spontaneous abortion; postpartum endometritis; neonatal sepsis; and intrauterine, neonatal, or perinatal death. We extracted treatment data on reported gestational age at screening and treatment, type of treatment, dose, regimen, administration route, and number of treatment rounds. We documented and summarized all data on adverse effects of treatment, including drug tolerability, study discontinuation related to drug effects, and adverse pregnancy outcomes. We applied a best-evidence approach, in which studies with the highest quality and most rigorous designs are emphasized (32). Two investigators separately evaluated the assessment of relevance and appraisal of internal validity by using the predefined study quality criteria of the USPSTF (33) (Appendix Table 3) and the Jadad (34) rating systems for individual studies (Appendix Table 4 and Appendix Table 5). Raters noted the appropriateness of procedures for patient recruitment and selection, random assignment, blinding, reporting of withdrawals and dropouts, and analyses. Experts in the field suggested that we also abstract study characteristics related to internal validity assessment that are specific to this body of literature. These included patient and provider blinding at second bacterial vaginosis test and second round of treatment, timing and number of dating sonograms obtained before or after random assignment, and types and rates of coinfection. We assigned studies with discrepant quality ratings to a third reviewer and discussed them until we reached consensus. The overall body of evidence for each key question is rated (33) and summarized (35) in a systematic review used by the USPSTF in making their recommendations for preventive services. Appendix Table 3. U.S. Preventive Services Task Force Quality Rating Criteria Appendix Table 4. Jadad Scale Criteria Appendix Table 5. Jadad Score Calculation Data Synthesis and Analysis Meta-analysis When appropriate, we performed a series of meta-analyses that included new trials identified from this search, as well as from studies identified from the previous review, to estimate the effect of treatment on preterm delivery (<37 weeks, <34 weeks, or <32 weeks); low birthweight; and preterm, premature rupture of membranes. The primary measure of effect of bacterial vaginosis treatment was the absolu