Screening for Bacterial Vaginosis in Pregnant Adolescents and Women to Prevent Preterm Delivery: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force | Guidelines | JAMA | JAMA Network
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Figure 1.  Analytic Framework: Screening for Bacterial Vaginosis in Pregnant Adolescents and Women to Prevent Preterm Delivery
Analytic Framework: Screening for Bacterial Vaginosis in Pregnant Adolescents and Women to Prevent Preterm Delivery

Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display key questions addressed by the review to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate interventions to outcomes. A dashed line indicates an outcome that precedes subsequent outcomes. Refer to the USPSTF Procedure Manual for further details.10

Figure 2.  Literature Search Flow Diagram: Screening for Bacterial Vaginosis in Pregnant Adolescents and Women to Prevent Preterm Delivery
Literature Search Flow Diagram: Screening for Bacterial Vaginosis in Pregnant Adolescents and Women to Prevent Preterm Delivery

KQ indicates key question; USPSTF, US Preventive Services Task Force.

Figure 3.  Effect of Treatment of Bacterial Vaginosis Among the General Obstetric Population
Effect of Treatment of Bacterial Vaginosis Among the General Obstetric Population

Mixed-methods test of moderators for all-cause vs spontaneous preterm delivery: P = .054 for absolute risk difference and P = .002 for risk ratio. OM indicates oral metronidazole; PTD, preterm delivery; VC, intravaginal clindamycin.

aIncludes spontaneous late abortion (≥16 weeks).

Figure 4.  Effect of Treatment of Bacterial Vaginosis Among Women With Prior Preterm Delivery
Effect of Treatment of Bacterial Vaginosis Among Women With Prior Preterm Delivery

Mixed-methods test of moderators for all-cause vs spontaneous preterm delivery at less than 37 weeks’ gestation (P = .14). For Hauth et al,47 data from the subgroup of participants with bacterial vaginosis and history of prior preterm delivery were used. For Carey et al,45 data from the subgroup of participants with a history of prior preterm delivery were used. For McDonald et al,52 data from the subgroup of participants with bacterial vaginosis and history of prior preterm delivery were used. For Vermeulen and Bruinse,57 data from the subgroup of participants with bacterial vaginosis were used. OC indicates oral clindamycin; OM, oral metronidazole; VC, intravaginal clindamycin.

Table 1.  Accuracy of Tests Used for Screening for Bacterial Vaginosis, Compared With Gram Stain Reference Standard
Accuracy of Tests Used for Screening for Bacterial Vaginosis, Compared With Gram Stain Reference Standard
Table 2.  Study Characteristics of Randomized Clinical Trials Reporting Benefits of Treating Bacterial Vaginosis
Study Characteristics of Randomized Clinical Trials Reporting Benefits of Treating Bacterial Vaginosis
Table 3.  Summary of Evidence for Screening for Bacterial Vaginosis in Pregnant Adolescents and Women to Prevent Preterm Delivery
Summary of Evidence for Screening for Bacterial Vaginosis in Pregnant Adolescents and Women to Prevent Preterm Delivery
Supplement.

eMethods

eTable 1. Study Characteristics of Diagnostic Accuracy Studies (Key Question 2)

eTable 2. Study Quality Ratings for Diagnostic Accuracy Studies: Part 1

eTable 3. Study Quality Ratings for Diagnostic Accuracy Studies: Part 2

eTable 4. Study Quality Ratings for Diagnostic Accuracy Studies: Part 3

eTable 5. Study Quality Ratings for Diagnostic Accuracy Studies: Part 4

eTable 6. Study Quality Ratings for Diagnostic Accuracy Studies: Part 5

eTable 7. Study Quality Ratings for Diagnostic Accuracy Studies: Part 6

eTable 8. Additional Study Characteristics of Randomized, Controlled Trials of Treatment of Bacterial Vaginosis to Prevent Preterm Delivery (KQs 4 and 5)

eTable 9. Study Quality Ratings for Randomized, Controlled Trials: Part 1

eTable 10. Study Quality Ratings for Randomized, Controlled Trials: Part 2

eTable 11. Study Quality Ratings for Randomized, Controlled Trials: Part 3

eTable 12. Study Quality Ratings for Randomized, Controlled Trials: Part 4

eTable 13. Study Quality Ratings for Randomized, Controlled Trials: Part 5

eTable 14. Study Quality Ratings for Randomized, Controlled Trials: Part 6

eTable 15. Benefit Outcomes From Randomized, Controlled Trials of Treatment of Bacterial Vaginosis to Prevent Preterm Delivery (Key Question 4)

eTable 16. Study Quality Ratings for Observational Studies- Controlled Cohort Studies: Part 1

eTable 17. Study Quality Ratings for Observational Studies- Controlled Cohort Studies: Part 2

eTable 18. Study Quality Ratings for Observational Studies- Controlled Cohort Studies: Part 3

eTable 19. Study Quality Ratings for Observational Studies- Controlled Cohort Studies: Part 4

eTable 20. Study Quality Ratings for Observational Studies- Controlled Cohort Studies: Part 5

eTable 21. Study Quality Ratings for Observational Studies- Controlled Cohort Studies: Part 6

eTable 22. Study Quality Ratings for Observational Studies- Controlled Cohort Studies: Part 7

eTable 23. Study Quality Ratings for Observational Studies- Controlled Cohort Studies: Part 8

eTable 24. Study Quality Ratings for Observational Studies- Case Control Studies: Part 1

eTable 25. Study Quality Ratings for Observational Studies- Case Control Studies: Part 2

eTable 26. Study Quality Ratings for Observational Studies- Case Control Studies: Part 3

eTable 27. Study Quality Ratings for Observational Studies- Meta-Analyses: Part 1

eTable 28. Study Quality Ratings for Observational Studies- Meta-Analyses: Part 2

eTable 29. Study Quality Ratings for Observational Studies- Meta-Analyses: Part 3

eTable 30. Study Quality Ratings for Observational Studies- Meta-Analyses: Part 4

eTable 31. Study Quality Ratings for Observational Studies- Meta-Analyses: Part 5

eTable 32. Study Quality Ratings for Observational Studies- Meta-Analyses: Part 6

eTable 33. Maternal Harm Outcomes From Randomized, Controlled Trials of Treatment of Bacterial Vaginosis to Prevent Preterm Delivery (Key Question 5)

eTable 34. Study Characteristics and Outcomes of Observational Studies and Meta-Analyses Reporting Harms in Children Related to In Utero Metronidazole Exposure (Key Question 5)

eFigure 1. Summary Receiver Operating Characteristics Curve for Diagnostic Test Accuracy of the BD Affirm VP III Test

eFigure 2. Summary Receiver Operating Characteristics Curve for Complete Amsel’s Clinical Criteria Compared With Gram Stain

eFigure 3. Summary Receiver Operating Characteristics Curve for Diagnostic Test Accuracy of Modified Amsel’s Clinical Criteria

eFigure 4. Absolute Risk Difference of Various Preterm Delivery Outcomes from Treatment of Bacterial Vaginosis Among a General Obstetric Population

eFigure 5. Risk Ratio for Various Pregnancy-related Outcomes from Treatment of Bacterial Vaginosis Among a General Obstetric Population

eReferences

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US Preventive Services Task Force
Evidence Report
April 7, 2020

Screening for Bacterial Vaginosis in Pregnant Adolescents and Women to Prevent Preterm Delivery: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

Author Affiliations
  • 1RTI International–University of North Carolina at Chapel Hill Evidence-based Practice Center
  • 2RTI International, Research Triangle Park, North Carolina
  • 3School of Medicine, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill
  • 4School of Medicine, Department of Family Medicine, University of North Carolina at Chapel Hill
JAMA. 2020;323(13):1293-1309. doi:10.1001/jama.2020.0233
Abstract

Importance  Preterm delivery results in adverse outcomes; identifying and treating bacterial vaginosis may reduce its occurrence.

Objective  To update the evidence on screening and treatment of asymptomatic bacterial vaginosis in pregnancy for the US Preventive Services Task Force.

Data Sources  MEDLINE, Cochrane Library, and trial registries through May 29, 2019; bibliographies from retrieved articles, experts, and surveillance of the literature through December 31, 2019.

Study Selection  Fair- or good-quality English-language studies evaluating diagnostic accuracy of tests feasible within primary care; randomized clinical trials (RCTs); nonrandomized controlled intervention studies (for harms only); or meta-analyses of metronidazole or clindamycin.

Data Extraction and Synthesis  Two reviewers independently assessed titles/abstracts and full-text articles, extracted data, and assessed study quality; when at least 3 similar studies were available, meta-analyses were conducted.

Main Outcomes and Measures  Sensitivity, specificity, preterm delivery, maternal adverse effects, congenital birth defects, childhood cancer.

Results  Forty-four studies (48 publications) were included. No studies evaluated the benefits or harms of screening. Twenty-five studies (n = 15 785) evaluated the accuracy of screening tests; across individual studies and tests, sensitivity ranged from 0.36 to 1.0 and specificity ranged from 0.49 to 1.0. Among trials reporting findings from general obstetric populations (n = 7953), no significant association was observed between treatment and spontaneous delivery before 37 weeks (pooled absolute risk difference [ARD], –1.44% [95% CI, −3.31% to 0.43%]; 8 RCTs, n = 7571) or any delivery before 37 weeks (pooled ARD, 0.20% [95% CI, −1.13% to 1.53%]; 6 RCTs, n = 6307). Among 5 trials reporting findings among women with a prior preterm delivery, findings were inconsistent; 3 showed a significant beneficial effect, while 2 did not. Maternal adverse events from treatment were infrequent and minor (eg, candidiasis) but were slightly more common with active treatment compared with placebo across 8 RCTs. Two meta-analyses of observational studies reported no significant association between metronidazole exposure and congenital malformations (odds ratio, 0.96 [95% CI, 0.75 to 1.22]; odds ratio, 1.08 [95% CI, 0.90 to 1.29]). One cohort study reported no significantly increased incidence of childhood cancer among metronidazole-exposed children (adjusted relative risk, 0.81 [95% CI, 0.41 to 1.59]). However, studies of in utero exposure had important limitations.

Conclusions and Relevance  Accuracy of screening tests for bacterial vaginosis varies. The evidence suggests no difference in the incidence of preterm delivery and related outcomes from treatment for asymptomatic bacterial vaginosis in a general obstetric population but was inconclusive for women with a prior preterm delivery. Maternal adverse events from treatment appear to be infrequent and minor, but the evidence about harms from in utero exposure was inconclusive.

Introduction

Bacterial vaginosis is a common lower genital tract syndrome defined as a shift from normal hydrogen peroxide–producing lactobacilli to mixed anaerobes.1,2 Studies conducted between 1983 and 2006 estimate that only 25% to 50% of women with bacterial vaginosis report symptoms.3-5 Research has suggested bacterial vaginosis as a risk factor for preterm delivery; a 2007 meta-analysis of 32 studies estimated a pooled odds ratio for the risk of preterm delivery in the presence of asymptomatic bacterial vaginosis of 2.16 (95% CI, 1.56 to 3.00).6 The causal mechanism is not fully understood.7,8

Early identification and treatment of bacterial vaginosis may reduce the incidence of preterm delivery and its associated morbidity and mortality. This review was conducted to inform the US Preventive Services Task Force (USPSTF) for its update of the 2008 recommendation on screening and treatment of bacterial vaginosis in pregnancy to prevent preterm delivery.9 In 2008, the USPSTF recommended against screening for bacterial vaginosis in asymptomatic pregnant women at low risk for preterm delivery (D recommendation) and concluded that the evidence was insufficient for asymptomatic pregnant women at high risk for preterm delivery (I statement).

Methods
Scope of the Review

The analytic framework and key questions (KQs) that guided the review are shown in Figure 1. Detailed methods, evidence tables, sensitivity analyses, and contextual information are available in the full evidence report at http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/bacterial-vaginosis-in-pregnant-adolescents-and-women-to-prevent-preterm-delivery-screening.

Data Sources and Searches

PubMed, the Cochrane Library, and EMBASE were searched for English-language articles published from January 1, 2006, through May 29, 2019. Because the previous reviews for the USPSTF did not include a systematic search for KQ2 (diagnostic test accuracy), a separate PubMed search from inception through December 31, 2005, was conducted to supplement the main search for this update. ClinicalTrials.gov, the Cochrane Clinical Trials Registry, and the World Health Organization International Clinical Trials Registry Platform were also searched. To supplement systematic electronic searches (eMethods in the Supplement), reference lists of pertinent articles and studies suggested by reviewers were searched. Ongoing surveillance was conducted through article alerts and targeted searches of journals to identify major studies published in the interim that may affect the conclusions or understanding of the evidence and the related USPSTF recommendation. The last surveillance was conducted on December 31, 2019.

Study Selection

Two investigators independently reviewed titles, abstracts, and full-text articles using prespecified inclusion criteria for each KQ (eMethods in the Supplement); disagreements about inclusion were resolved by a third reviewer. Briefly, for KQ1, KQ3, and KQ4, randomized clinical trials (RCTs) and relevant systematic reviews of RCTs, conducted in pregnant women or adolescents, were selected; for KQ1 and KQ3, participants had to be asymptomatic with respect to vaginal symptoms of bacterial vaginosis. For KQ1 and KQ3, studies that compared screening with no screening and reported health outcome benefits (eg, reduction in preterm delivery) or harms (eg, anxiety) were selected. For KQ2, studies that reported on diagnostic test accuracy for Amsel clinical criteria (vaginal pH >4.5, clue cells, discharge, amine odor)3 or laboratory-based tests in commercial use or feasible for use in primary care settings were selected. Participants were not required to be pregnant in studies selected for KQ2. For KQ4 and KQ5, trials that compared treatment with metronidazole or clindamycin vs placebo or no treatment in symptomatic or asymptomatic pregnant women with bacterial vaginosis and that reported health outcomes related to preterm delivery or other adverse pregnancy outcomes were selected. For KQ5, observational studies that reported on outcomes related to fetal exposure to metronidazole or clindamycin, such as carcinogenesis or congenital malformations, were eligible.

English-language studies that met all study selection criteria, were fair or good methodological quality, and were conducted in countries categorized as very highly developed by the 2017 United Nations Human Development Index were included.11 Studies included in the prior 2008 review were reassessed against the study selection and methodological quality criteria for this update.

Data Extraction and Quality Assessment

For each included study, 1 reviewer abstracted relevant study characteristics (ie, population, intervention, comparator) and data for eligible outcomes into a structured form. A second reviewer checked all data for completeness and accuracy. Some study authors were contacted to clarify data. Two senior reviewers independently assessed each study’s methodological quality using predefined criteria established by the USPSTF (eMethods in the Supplement) and others.12-16 Disagreements in study quality ratings were resolved through discussion or with an independent assessment from a third senior investigator. Studies reporting multiple outcomes may have been assigned different quality ratings for different outcomes.

Data Synthesis and Analysis

For diagnostic test accuracy (KQ2), data related to sensitivity, specificity, and likelihood ratios were synthesized in tabular and narrative formats. When at least 3 studies using the same index test and test threshold were available, a quantitative synthesis was performed by fitting the bivariate model described by Reitsma et al17 with the metandi package in Stata version 15 (StataCorp) to generate a summary receiver operating characteristics curve and a pooled summary point estimate of sensitivity and specificity. For benefits of treatment (KQ4), findings were synthesized using both absolute risk differences (ARDs) and relative risk (RR) ratios. For harms of treatment (KQ5), odds ratios (ORs) were also used. When a quantitative synthesis was possible, a random-effects model with the inverse-variance weighted method of DerSimonian and Laird with the metafor package in R version 2.0-0 (R Foundation for Statistical Computing) was used.18 Significance testing was based on the exclusion of the null value by the 95% CI around the pooled estimate.

The strength of evidence was assessed based on the Agency for Healthcare Quality and Research Methods Guide for Effectiveness and Comparative Effectiveness Reviews, which specifies the assessment of study limitations, directness, consistency, precision, and reporting bias for each intervention comparison and major outcome of interest.19 Two senior reviewers independently developed initial strength of evidence assessments for each relevant outcome and comparison across the KQs; disagreements were resolved through discussion and the independent assessment of a third senior reviewer.

Results

Forty-four studies from 48 publications were included (Figure 2). Twenty-five studies of test accuracy (KQ2),20-44 13 RCTs evaluating the benefits of treatment with respect to preterm delivery and related pregnancy outcomes (KQ4),45-57 and 14 studies evaluating the harms of treatment (KQ5)45,48,49,51,52,55-63 were identified.

Benefits of Screening

Key Question 1. Does screening for bacterial vaginosis in asymptomatic pregnant adolescent and women reduce preterm delivery and related morbidity and mortality?

No studies were identified.

Accuracy of Screening

Key Question 2. What is the diagnostic accuracy of tests used to screen for bacterial vaginosis?

Twenty-five cross-sectional diagnostic test accuracy studies (n = 15 785) reported test accuracy for laboratory assays and for Amsel clinical criteria (complete or modified). Study characteristics are reported in eTable 1 in the Supplement, and individual study methodological quality is described in eTables 2 through 7 in the Supplement. Six studies were assessed as good methodological quality23,25,26,31,37,43; the others were assessed as fair quality generally because of unclear enrollment procedures and unclear information regarding blinding of index and reference test results. The reference standard assessed in nearly all studies was a Gram stain of vaginal secretions, most often interpreted using Nugent criteria, a scoring system based on quantity and morphotypes of organisms present.64,65 Two studies enrolled exclusively pregnant or asymptomatic women.23,40 Table 1 summarizes the accuracy of various tests; across individual studies and tests, sensitivity ranged from 0.36 to 1.0 and specificity ranged from 0.49 to 1.0.

Harms of Screening

Key Question 3. What are the harms of screening for bacterial vaginosis in asymptomatic pregnant adolescents and women?

No studies were identified.

Benefits of Treatment

Key Question 4. Does treatment of bacterial vaginosis during pregnancy reduce preterm delivery and related morbidity and mortality?

Thirteen RCTs (n = 8751) reported findings related to preterm delivery, other pregnancy outcomes, or clearance of bacterial vaginosis.45-57 Study characteristics are summarized in Table 2, with additional characteristics described in eTable 3 in the Supplement. Nine RCTs45,46,48,50,52,53,55-57 were assessed as good methodological quality, and 4 RCTs47,49,51,54 were assessed as fair quality, primarily because of concerns related to lack of information on allocation concealment and lack of information to assess adequacy of randomization,51 lack of treatment blinding,49,51 post hoc subgroup analyses,47,49 or lack of intent-to-treat analyses.54 Individual study methodological quality is described in eTable 4 in the Supplement. No studies reported subgroup findings by maternal or gestational age, race or ethnicity, HIV status, or other population characteristics specified by the KQs.

Four studies were conducted in the US45,47,53,54; the others were conducted in Australia52 and various countries in Europe.46,48-51,55-57 Ten of the 13 studies (n = 7953) were conducted among general obstetric populations, meaning that patients were enrolled without regard to their risk for preterm delivery.45,46,48-53,55,56 The percentage of participants with a prior preterm delivery in these studies ranged from 0% to 10.9%. Two of these studies (n = 194) also reported findings among subgroups considered at high risk for preterm delivery because of a prior preterm delivery.45,52 Three of the 13 studies (n = 279) were conducted solely among participants considered at high risk for preterm delivery.47,54,57 All 3 defined high risk as a previous preterm delivery; however, 1 study also considered women with a prepregnancy weight less than 50 kg and no previous preterm delivery as high risk.47 Most studies identified asymptomatic patients during routine prenatal visits and enrolled participants during the second trimester, although criteria for enrollment varied. Three studies enrolled participants without regard to bacterial vaginosis status but reported findings for the subgroup of participants testing positive for bacterial vaginosis at study entry. Study findings are only reported in this article from the subgroups with bacterial vaginosis.47,49,57

Three studies evaluated the use of oral metronidazole,45,52,54 2 studies evaluated oral clindamycin,55,56 1 study evaluated oral metronidazole and erythromycin,47 and 7 evaluated intravaginal clindamycin.46,48-51,53,57 The dosages and durations of treatment varied across studies, and most, but not all, used a placebo control. Two studies repeated treatment if the test of a cure demonstrated persistent bacterial vaginosis,49,52 and 3 studies repeated dosing at a later follow-up point without regard to results from a test of cure for some or all participants.45,55,57 Twelve of the 13 RCTs45-56 reported findings related to preterm delivery prior to 37 weeks’ gestational age; 1 RCT57 only reported preterm delivery defined as delivery prior to 34 weeks. Detailed results are summarized in eTable 5 in the Supplement.

Preterm Delivery in General Obstetric Populations

Ten RCTs conducted among general obstetric populations reported preterm delivery outcomes (Figure 3). The absolute risk of delivery prior to 37 weeks’ gestational age in the placebo groups ranged from 3.1% to 15.7%. Among the 6 studies reporting all-cause preterm delivery, the pooled ARD comparing active treatment with control was 0.20% (95% CI, −1.13% to 1.53%; 6307 participants; I2 = 0%), and the pooled RR was 1.02 (95% CI, 0.86 to 1.20).45,46,51-53,55 No individual studies reported a significant difference between active treatment and control. Among the 8 studies reporting spontaneous preterm deliveries, the pooled ARD comparing active treatment with control was −1.44% (95% CI, −3.31% to 0.43%; 7571 participants; I2 = 61.9%), and the pooled RR was 0.78 (95% CI, 0.56 to 1.07).45,48-52,55,56 Two of the 8 studies reported statistically significant reductions in spontaneous preterm delivery for active treatment compared with control,50,56 while the other 6 reported no significant differences between active treatment and control. One of the studies that reported a significant reduction in spontaneous preterm delivery enrolled participants (n = 409) with either bacterial vaginosis or intermediate flora50; other population or intervention characteristics that might explain this inconsistency could not be identified.

Three RCTs reported the incidence of preterm delivery prior to 32 weeks’ completed gestation among a general obstetric population (eFigures 4 and 5 in the Supplement).45,51,55 The pooled ARD was −0.30% (95% CI, −0.97% to 0.38%; 5564 participants; I2 = 15.4%), and the pooled RR was 0.87 (95% CI, 0.54 to 1.42). All 3 studies observed no significant differences between active treatment and control. One RCT also reported no significant difference in preterm delivery at less than 34 weeks’ gestation (ARD, −0.04% [95% CI, −2.0% to 1.92%]; RR, 1.0 [95% CI, 0.7 to 1.5]).45

Other pregnancy-related outcomes in a general obstetric population for which a pooled summary estimate was calculatable are provided in eFigures 4 and 5 in the Supplement. No significant association between treatment and low birth weight, very low birth weight, or premature rupture of membranes was observed. Studies also reported outcomes for which pooled summary estimates could not be generated, including maternal peripartum infection,48 stillborn fetus,49 preterm labor,53 and neonatal mortality55; authors observed no significant differences between active treatment and control for these outcomes.

Preterm Delivery in Women With Prior Preterm Delivery

Five RCTs reported preterm delivery outcomes in this subgroup; 3 reported incidence of preterm delivery at less than 37 weeks,45,47,52,54 1 reported incidence of preterm delivery at less than 34 weeks,57 and 1 reported incidence of preterm delivery at both less than 37 weeks and less than 34 weeks.39 Findings for this subgroup were not pooled because of heterogenous outcome measures.

In the 4 RCTs (n = 451) conducted among participants with a previous preterm delivery or that reported subgroup findings for such women, the incidence of preterm delivery at less than 37 weeks’ gestation in control groups ranged from 22.5% to 57.1% (Figure 4).45,47,52,54 Carey et al45 and Hauth et al47 reported all-cause preterm delivery, and Morales et al54 and McDonald et al52 reported spontaneous preterm delivery. Three of the 4 RCTs reported a statistically significant favorable treatment effect (ARDs ranging from –18.3% to –29.4%),47,52,54 while Carey et al45 (subgroup n = 160) observed no significant treatment effect (ARD, 7.50% [95% CI, −6.09% to 21.09%]). The inconsistency in findings could not be explained based on study or population characteristics (further details are reported in the eResults in the Supplement).

Two RCTs reported the incidence of preterm delivery at less than 34 weeks’ gestation among participants with a prior preterm delivery (Figure 4).54,57 In Morales et al (n = 80),54 4 participants (11%) in the placebo group and 2 participants (4.6%) in the oral metronidazole group had a spontaneous preterm delivery at less than 34 weeks (calculated ARD, −6.57% [95% CI, −18.5% to 5.40%]). Vermeulen and Bruinse57 reported the incidence of all-cause preterm delivery at less than 34 weeks’ gestation among a subgroup of 22 participants with bacterial vaginosis and observed 1 event in both the vaginal clindamycin and the placebo group.

With respect to other pregnancy outcomes, Morales et al (n = 80)54 reported a significant treatment effect on preterm labor (calculated ARD, −50.51% [95% CI, −69.41% to −31.60%]), premature rupture of membranes (calculated ARD, −28.79% [95% CI, −45.37% to −12.21%]), and birth weight less than 2500 g (calculated ARD, −19.7% [95% CI, −38.13% to −1.26%]). Vermeulen and Bruinse (n = 22)57 reported no significant treatment effect on neonatal sepsis.

Preterm Delivery Based on Bacterial Vaginosis Clearance Status

Some studies conducted among a general obstetric population reported preterm delivery outcomes for subgroups of participants who had documented clearance or persistence of bacterial vaginosis after treatment. Among a subgroup of participants who had follow-up Gram staining after initial testing and treatment, Carey et al (n = 1704)45 reported no significant difference in preterm delivery among women with clearance of bacterial vaginosis (incidence, 10.6%) vs those with persistence of bacterial vaginosis (incidence, 10.7%) (P = .95). Kekki et al48 also reported no significant difference in preterm delivery between active treatment and control among a subgroup (n = 121) of women with documented clearance of bacterial vaginosis 1 week after treatment (calculated ARD, 2.30% [95% CI, −1.45% to 6.06%]).

Harms of Treatment

Key Question 5. What are the harms of treatment of bacterial vaginosis in pregnant adolescents and women?

Fourteen studies reported on the harms of treatment. Eight RCTs reported on maternal adverse events,45,48,49,51,52,55-57 and 6 studies reported on adverse outcomes in children exposed to medication in utero.58-63 eTable 6 in the Supplement provides an assessment of individual study methodological quality.

Maternal Adverse Events

Among the 13 RCTs reporting on the benefits of treatment for bacterial vaginosis during pregnancy (KQ4), 8 (n = 7758) reported on maternal adverse events. These 8 RCTs included 4 trials of intravaginal clindamycin,48,49,51,57 2 trials of oral clindamycin,55,56 and 2 trials of oral metronidazole.45,52 Results from individual studies are presented in eTable 7 in the Supplement. Across this body of evidence, maternal adverse events from treatment with oral clindamycin or oral metronidazole generally occurred at a higher incidence compared with control treatment but were not severe (eg, gastrointestinal symptoms, candida infection). For example, in Carey et al (n = 1704; oral metronidazole),45 the ARD for gastrointestinal symptoms was 12.5%, and in Subtil et al (n = 2860; oral clindamycin),55 the ARD was 1.2%. Adverse events from intravaginal clindamycin were infrequent and mild (eg, vaginal itching).

Adverse Childhood Outcomes Associated With In Utero Exposure to Medication

Six studies (eTable 8 in the Supplement) reporting adverse childhood outcomes associated with in utero exposure to metronidazole were included.58-63 Three observational studies (n = 62 271)60-62 and 2 meta-analyses58,59 reported on outcomes related to congenital abnormalities and malformations, and 1 observational study (n = 328 846)63 reported on incidence of childhood cancer. One study was assessed as poor methodological quality because of confounding and because of a large amount of missing data61; however, it was retained for continuity with the previous review. All other studies were assessed as fair methodological quality.

The studies included for this KQ did not provide information about the indication for metronidazole treatment; the setting of treatment (ie, inpatient vs outpatient); or the dose, duration, and route of treatment. Furthermore, the populations were not limited to women exposed to metronidazole specifically for the treatment of bacterial vaginosis in pregnancy, which may limit applicability; however, those studies were retained in this update for continuity with the previous review.

The 2 included meta-analyses found no significant association between metronidazole and congenital malformations (OR, 0.96 [95% CI, 0.75 to 1.22; N not reported]58 and OR, 1.08 [95% CI, 0.90 to 1.29; n = 199 451]59). Similarly, 2 of the 3 observational studies60-62 found no association between metronidazole and congenital abnormalities. The exception was reported by Czeizel and Rockenbauer.60 This fair-quality study (n = 47 963) found a significant association between congenital anomalies and exposure to metronidazole during the first month of gestation (OR, 2.24 [95% CI, 1.30 to 3.85]) but not for the second through third months or fourth through ninth months.60 The authors noted that because the first month of gestation is counted from the first day of the last menstrual period, several of these weeks of exposure may be before conception or during the all-or-none phase of fetal development; thus, this finding may be spurious or the result of recall bias or uncontrolled confounding.60

One cohort study among women enrolled in Tennessee Medicaid did not find an association between metronidazole exposure during pregnancy and diagnosis of first cancer before age 5 years among exposed children (n = 328 846; adjusted RR, 0.81 [95% CI, 0.41 to 1.59]).63

Discussion

This evidence report reviewed studies on the diagnostic accuracy of screening tests for bacterial vaginosis and studies evaluating the benefits and harms of metronidazole or clindamycin treatment in pregnancy. Table 3 summarizes the evidence by KQ and provides an assessment of the strength of evidence. Compared with the 2008 review for the USPSTF on this topic, 2 RCTs were added and 2 RCTs were excluded. Despite this change in the evidence base, the overall conclusions about no benefit in a general obstetric population remain unchanged from the prior report.

For diagnostic accuracy (KQ2), the strength of evidence was assessed as low for adequate accuracy for all tests evaluated because of fair methodological quality and inconsistency. Most studies were conducted among symptomatic, nonpregnant women; thus, the applicability to asymptomatic pregnant women is not clear. For complete Amsel and modified Amsel clinical criteria, the sensitivities observed in the 2 studies23,40 conducted exclusively among pregnant women were lower than the pooled summary estimates, suggesting that the physiologic changes that occur in the vaginal environment during pregnancy may affect the sensitivity of 1 or more of the clinical criteria used to identify bacterial vaginosis. Furthermore, a lower sensitivity was not observed for the BD Affirm test in the 1 study conducted exclusively in pregnant women.41 Although no formal comparative assessment was conducted, the tests varied somewhat in accuracy. The laboratory-based tests (BD Affirm VPIII [Becton, Dickinson], BD Max, OSOM BVBLUE [Sekisui Diagnostics]) had higher sensitivities than those based on Amsel clinical criteria but lower specificities.

Among a general obstetric population, the strength of evidence was moderate for no benefit of treatment on all-cause preterm delivery because of imprecision and low for no benefit of treatment on spontaneous preterm delivery because of imprecision and inconsistency. With respect to precision, although most studies were powered for the outcome of preterm delivery, either a lower control group risk was observed than was expected or the treatment effect observed was smaller than expected, resulting in imprecise estimates. Regarding spontaneous preterm delivery, the strength of evidence was also influenced by methodological considerations. The consequences related to preterm delivery generally do not differ for medically indicated deliveries vs spontaneous deliveries, and treatment could result in a medical complication that results in delivery after randomization but before the outcome reporting window that would not be captured. In addition, because an indicated preterm delivery is a competing risk to a spontaneous preterm delivery, use of spontaneous delivery outcomes could introduce informative censoring.

Among women with a prior preterm delivery, the strength of evidence for preterm delivery at less than 37 weeks was insufficient because of inconsistency and imprecision. Furthermore, its applicability is limited to treatment with oral metronidazole. A source for the inconsistency in findings could not be identified. Findings from 3 of the 4 studies were based on subgroup analyses, some of which were post hoc. The 2 studies reporting preterm delivery at less than 34 weeks did not observe any significant differences between groups, but results were very imprecise.

Compared with placebo, the strength of evidence for serious maternal adverse events related to treatment was moderate for no difference for oral metronidazole and both oral and intravaginal clindamycin. Compared with placebo, the strength of evidence for minor adverse events was moderate for no difference for intravaginal clindamycin and was moderate for an increase in minor events for both oral metronidazole and oral clindamycin. These bodies of evidence were rated as moderate because of imprecision due to relatively infrequent events.

The strength of evidence for congenital malformations and incidence of cancer among children exposed to metronidazole in utero was insufficient. This evidence comprises observational studies with no more than fair methodological study quality, and despite large sample sizes, the incidence of these types of events was rare, resulting in imprecise estimates. This evidence applies to metronidazole exposure during pregnancy across a range of medical indications and is not specific to treatment for bacterial vaginosis.

Limitations

This review has several limitations. First, no available evidence that directly evaluated the health benefits and harms of screening (KQ1 and KQ3) was identified. Second, for diagnostic test accuracy (KQ2), limited evidence was available for pregnant, asymptomatic populations. Most studies were of only fair methodological quality, and for most tests, moderate to substantial heterogeneity was observed. Most studies used Gram stain as a reference standard; however, in light of the advances in the molecular and microbiological understanding of bacterial vaginosis, this may be an imperfect standard.

Third, for benefits of treatment (KQ4) and adverse maternal events (KQ5), studies varied with respect to dose and duration of treatment, use of a test of cure, and methodological quality. The findings in women with a prior preterm delivery were inconsistent, and a source for this inconsistency could not be identified. Fourth, with respect to harms, trials were underpowered for maternal adverse events, and the comparative harms of treatment were not assessed.

Fifth, this review was limited to treatment with only metronidazole and clindamycin. Although other treatments for bacterial vaginosis are available, they have not been studied in pregnant women. Sixth, only observational studies were available to assess the harms to children related to in utero exposure to medications (KQ5), and all of these studies included women exposed to metronidazole for any indication, including but not limited to bacterial vaginosis. Given the infeasibility of conducting randomized studies large enough and over a long enough duration to provide definitive evidence on in utero exposure, it is unlikely that this body of evidence will become stronger. However, these medications have had widespread and longstanding use in clinical practice.

Conclusions

Accuracy of screening tests for bacterial vaginosis varies. The evidence suggests no difference in the incidence of preterm delivery and related outcomes from treatment for asymptomatic bacterial vaginosis in a general obstetric population but was inconclusive for women with a prior preterm delivery. Maternal adverse events from treatment appear to be infrequent and minor, but the evidence about harms from in utero exposure was inconclusive.

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Article Information

Corresponding Author: Leila C. Kahwati, MD, MPH, RTI International, 3040 E Cornwallis Rd, Research Triangle Park, NC 27709 (Lkahwati@rti.org).

Accepted for Publication: January 8, 2020.

Author Contributions: Dr Kahwati had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kahwati, Clark, Urrutia, Zeng, Viswanathan.

Acquisition, analysis, or interpretation of data: Kahwati, Clark, Berkman, Urrutia, Patel, Zeng.

Drafting of the manuscript: Kahwati, Clark, Urrutia, Patel.

Critical revision of the manuscript for important intellectual content: Kahwati, Berkman, Urrutia, Zeng, Viswanathan.

Statistical analysis: Kahwati, Clark, Viswanathan.

Obtained funding: Kahwati, Viswanathan.

Administrative, technical, or material support: Kahwati, Clark, Berkman, Patel, Viswanathan.

Supervision: Kahwati, Viswanathan.

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was funded under contract HHSA-290-2015-00011-I, Task Order 11, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Heath and Human Services, under a contract to support the US Preventive Services Task Force (USPSTF).

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Contributions: We thank the following individuals for their contributions to this project: AHRQ staff, Tina Fan, MD, MPH, and Tracy Wolff, MD; former AHRQ staff, Quyen Ngo-Metzger, MD, MPH; current and former members of the USPSTF who contributed to topic deliberations; RTI International–University of North Carolina Evidence-based Practice Center staff, B. Lynn Whitener, DrPH; Carol Woodell, BSPH; Sharon Barrell, MA; and Loraine Monroe. USPSTF members, peer reviewers, and federal partner reviewers did not receive financial compensation for their contributions.

Additional Information: A draft version of the full evidence report underwent external peer review from 4 content experts (Mark Klebanoff, MD, MPH, Nationwide Children’s Hospital; John Thorp, MD, University of North Carolina; Valerie J. King, MD, MPH, Oregon Health & Science University; and Julie van Schalkwyk, MD, University of British Columbia) and 2 additional federal partner reviewers (National Institutes of Health; Centers for Disease Control and Prevention). None of the reviewers received compensation for their role in reviewing the report. Comments from reviewers were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence report.

Editorial Disclaimer: This evidence report is presented as a document in support of the accompanying USPSTF Recommendation Statement. It did not undergo additional peer review after submission to JAMA.

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