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SEARCH STRATEGY: We selected articles from a combination of the results of a MEDLINE search (1966-1996), a manual search of bibliographies, and contact with leading researchers.
SELECTION CRITERIA: We included case control and cohort studies evaluating the risk of preterm delivery, low birth weight, preterm premature rupture of membranes, or preterm labor for pregnant women who had bacterial vaginosis and those who did not.
DATA COLLECTION AND ANALYSIS: Two investigators independently conducted literature searches, applied inclusion criteria, performed data extraction, and critically appraised included studies. Summary estimates of risk were calculated as odds ratios (ORs) using the fixed and random effects models.
MAIN RESULTS: We included 19 studies in the final analysis. Bacterial vaginosis during pregnancy was associated with a statistically significant increased risk for all outcomes evaluated. The summary OR was 1.85 for preterm delivery (95% confidence interval [CI], 1.62-2.11), 1.57 for low birth weight (95% CI, 1.32-1.87), 1.83 for preterm premature rupture of membranes (95% CI, 1.39-2.44), and 2.19 for preterm labor (95% CI, 1.73-2.76). In the subanalyses for preterm delivery, bacterial vaginosis remained a significant risk factor. Pooling adjusted ORs yielded a 60% increased risk of preterm delivery given the presence of bacterial vaginosis.
CONCLUSION: Bacterial vaginosis is an important risk factor for prematurity and pregnancy morbidity. Further study will help clarify the benefits of treating bacterial vaginosis and the potential role of screening during pregnancy.
CLINICAL QUESTION
What is the association between bacterial vaginosis and preterm delivery?
Prematurity, whether defined by gestational age or birth weight, increases the risk of neonatal morbidity and mortality, as well as early childhood morbidity. Preterm birth, defined as delivery before 37 weeks’ gestation, accounts for 8% to 10% of all births1 and leads to nearly 75% of all neonatal mortality and 50% of all long-term neurologic damage in children.2 On average, first-year medical costs for infants born weighing less than 2500 grams exceed that of a full-term infant by $15,000.3
Between 25% and 60% of preterm births are thought to be attributable to maternal infections,4,5 and are thus considered preventable. Bacterial vaginosis (BV) has been suggested as one potentially treatable risk factor for preterm delivery. BV is fairly common, with a prevalence ranging from 10% to 30% in an typical obstetrical population6 to more than 50% in some high-risk groups.7
Although otherwise thought to be a fairly benign condition, in pregnancy BV is estimated to confer a two- to threefold increased risk of prematurity.4,8 Yet the relative risks from the literature range from09,10> to 6.9.11 These variations may be attributable to differences in study design, sample size, or confounders. The purpose of our meta-analysis was to estimate the magnitude of risk that BV poses on prematurity and pregnancy complications that may lead to prematurity.
Methods
Data Sources
To identify potential studies for inclusion, 2 independent investigators (CF and AH) conducted a MEDLINE search (1966-1996), using the terms “bacterial vaginosis,” “gardnerella” and “prematurity,” “labor-premature onset, ” “rupture of membranes-premature,” “preterm delivery,” or “preterm infant” as both medical subject headings and text words. The bibliographies of obstetric texts, all included studies, relevant reviews, and the Cochrane Library were also reviewed. Finally, we contacted several authors who had published articles on the subject in an attempt to identify any unpublished data.
Study Selection
Studies were included if they met the following criteria: (1) the population studied was pregnant women; (2) the risk factor considered was the presence of BV; (3) the outcomes measured included either gestational age or birth weight; secondary outcomes considered were preterm premature rupture of membranes and preterm onset of labor; and (4) study design was either case control or cohort trial evaluating the benefit of treating BV in pregnancy. Trials were included if sufficient data were available to compare the outcomes of those women who had BV with those who did not in the control cohort. Inclusion criteria were applied independently by the 2 investigators; differences were settled by consensus.
Non-English language papers and those containing duplication of previous data were excluded. For articles in which the data presentation prohibited the linking of BV to the outcomes of interest, we contacted the authors in writing for the original data. If the original data were unavailable, we excluded the study from final analysis.
Data Extraction
The 2 investigators also independently performed data extraction. Disagreements were settled by discussion and consensus.
The population data we collected included country, medical setting, and baseline risk of prematurity. We recorded inclusion and exclusion criteria, but those factors were insufficient to categorize the study population as either high, normal, or low risk. Therefore, baseline risk was determined by calculating the incidence of preterm delivery in the control group for each study. Since the standard incidence of preterm delivery is 8% to 10%, we considered as high risk those studies with rates greater than 10% in the non-BV group; those below were categorized as low or normal risk.
We recorded the method and timing of BV diagnosis. In studies with multiple methods of determining BV, we collected the results for each method. The gram stain/wet mount result was preferentially used in the final analysis, as this is the most relevant technique for clinical assessment of BV. Vaginal culture data could only be correlated to outcome by individual microbes, so we limited data recording to Gardnerella vaginalis only. We recorded the timing of the diagnosis of BV as presented (ie, weeks of gestational age, trimester, during labor), then grouped the data by trimester. If more than one sample was collected in an individual study, we recorded all results but used the earliest in the analysis.
We recorded outcome data dichotomously in 2 x 2 tables for all 4 study outcomes. Extracted information on the handling of confounding included the method used, the adjusted odds ratio with confidence interval, and the variables included in the final model.
In studies that reported preterm delivery results at multiple gestational age cutoffs, we used only the 37-week cutoff. If studies used a definition other than 37 weeks, their data were noted for subanalysis. Some case control studies defined cases as women in preterm labor, but reported data separately from those cases that delivered prematurely from those that delivered after 37 weeks. For the preterm delivery outcome, the preterm labor cases who delivered at term were included in the control group.
Validity Assessment
We used validity assessment worksheets that were developed specifically for this project using a summary of previously published criteria.12-14 Each included study was critically appraised independently by the 2 investigators, and their assessments were compared. A third investigator (LM) settled disagreements. We did not use validity criteria to exclude any study from analysis.
Data Synthesis
We calculated summary estimates of risk as odds ratios using both the fixed and random effects models.15-17 Additionally, we combined cohort studies to generate summary relative risk estimates using both models. Precision is reported as 95% confidence intervals for each statistic. These calculations were generated using Review Manager 3.0 software.18 We evaluated homogeneity using the chi-square statistic:15 the greater the P value, the more homogeneous the studies.
We conducted subanalyses by study design, baseline population risk of prematurity, method and timing of BV diagnosis, and country of study population. When the subgroupings resulted in any category having fewer than 3 studies, we did not calculate a summary statistic for that group. We excluded those studies and generated a new pooled risk assessment for the alternate groups only.
To address the issue of confounders, we used the general variance-based model15,19,20 to combine the adjusted odds ratios of individual studies into a summary odds ratio with its 95% confidence interval.
Results
Data Sources and Study Selection
Our literature review identified 233 studies; no unpublished data were discovered. Reviewing the abstracts identified 39 studies for possible inclusion (27 observational studies and 12 trials). We excluded 11 observational studies because they had an inadequate or no control group (2),21,22 no vaginal assessment of BV (2),23,24 repeated data (1),25 or the inability to link BV with pregnancy outcomes (6).9,26-30 Nine of the 12 trials did not present their control group cohort data in a way that distinguished the outcomes by the presence or absence of BV and were therefore excluded.31-39 We included 19 studies10,11,40-56 in the final analysis: 8 case control trials and 11 cohort studies. Three from this latter group consisted of the placebo group of randomized controlled trials.
We estimated the likelihood of publication bias by generating a funnel plot.15 The graph of study size versus the logarithm of the ratio results, although funnel-shaped, is not completely symmetric.* Data from small studies demonstrating a protective effect of BV in pregnancy are missing.
Data Extraction
Twelve of the 19 included studies drew patients from a university or tertiary care hospital setting; the 7 others were clinic based Table 1. Two studies were conducted in nonindustrialized countries (Nairobi and Indonesia). The remaining studies were performed in the United States (11), Australia (3), the United Kingdom (1), Sweden (1), and Finland (1). The baseline prevalence of preterm delivery ranged from 1.1% to 64.9%, with a mean of 20.0% and a median of 13.8%.
To diagnose bacterial vaginosis, 13 studies used gram stain alone or in combination with a wet mount, 2 used gas-liquid chromatography, and 4 used vaginal swab cultures. The timing of risk factor detection varied among the studies, ranging from the first prenatal visit to the time of labor. We grouped the studies by trimester as precisely as possible, resulting in 10 studies diagnosing BV in the first or second trimester, 4 with second or third trimester assessment, and 4 studies discovering BV in the third trimester only (which in most cases was at the time of labor).
In most studies, gestational age was determined by the best obstetric clinical estimate — using the date of the mother’s last menstrual period, detection of fetal heart tones, fundal heights, and obstetrical ultrasound. In one study, gestational age was determined only by pediatric assessment. Preterm delivery was evaluated as a dichotomous outcome in 18 of the 19 included studies. Two studies used 35 weeks’ gestation or less to define a preterm infant; one study used 36 weeks. All others adhered to the standard definition of preterm as any gestation with a duration of less than 37 weeks. Low birth weight was defined as an infant weighing less than 2500 grams [at birth] in all 6 studies that reported this outcome.
Of the 7 studies evaluating preterm premature rupture of membranes, 2 used 36 weeks as the cutoff for preterm; the other 5 used 37 weeks. Only 2 studies reported the method to determine membrane rupture (both used pH and ferning criteria). The time from rupture of membranes to labor onset varied from 1 to 6 hours in the 4 studies defining this period.
For the outcome of preterm onset of labor, all 9 studies defined preterm as gestational age less than 37 weeks. Most studies defined labor as regular painful uterine contractions; only 2 required cervical change. Two others considered treatment for preterm labor as the definition of preterm onset of labor.
Validity Assessment
Details about validity assessment and the effect of biases on the summary estimates of individual studies are available elsewhere.* Two biases were common. First was the misclassification of either the predictor or the outcomes, which tended to underestimate risk. Second was the issue of confounding variables, which tended to overestimate the odds ratio.
Data Synthesis
The Figure shows that women with BV were more likely to deliver a preterm infant (odds ratio, fixed effects model [OR<->FIXED<->] 1.85; 95% CI, 1.62-2.11) or an infant weighing less than 2500 grams (OR<->FIXED<-> 1.57; 95% CI, 1.32-1.87).
For the secondary outcomes of preterm premature rupture of membranes and preterm onset of labor, the resultant ORs<->FIXED <->were 1.83 (95% CI, 1.39-2.44) and 2.19 (95% CI, 1.73-2.76), respectively. The studies combined for preterm onset of labor met statistical requirements of homogeneity (P <\>>.25); those for preterm delivery, low birth weight, and preterm premature rupture of membranes did not. Recalculation of the odds ratio using the random effects model did not result in the loss of statistical significance for any of the main outcomes Table 2.
Pooling only cohort studies to generate a summary relative risk also resulted in a persistently elevated risk of prematurity for those mothers with BV, ranging from a 1.44- to a 2.86-fold increase Table 2, and homogeneity criteria were met for low birth weight, preterm premature rupture of membranes, and preterm onset of labor, (P <\>>.33) but not for preterm delivery. BV was significantly associated with preterm delivery in nearly all the subanalyses conducted Table 3.
Seven of the 18 studies evaluating preterm delivery did not perform regression analysis to evaluate for confounding; 4 others did this analysis but did not report an adjusted risk for BV. Thus, only 7 studies had controlled data available for a summary estimate. These studies, with their respective adjusted odds ratios and confounders considered, are listed in Table 5. As expected, the resultant summary estimate of the adjusted odds ratio was lower than that obtained from unadjusted data but remained significant clinically (OR = 1.60), as well as statistically (95% CI, 1.44-1.74).
Discussion
Our study pooled data representing more than 17,000 patients and the results show BV to be a significant risk factor for preterm and low birth weight deliveries. Additionally, BV is significantly associated with preterm onset of labor and preterm premature rupture of membranes. Summary relative risks calculated using cohort data only, although lower than the odds ratios, also showed a significant association between BV and all prematurity outcomes. Although often used interchangeably with relative risks, odds ratios tend to overestimate risk in cases of a positive association and a nonrare outcome. In our study, odds ratios exceeded relative risks for 3 of the 4 outcomes. This may reflect violation of the rare disease assumption or may simply be due to pooling a different subset of studies.
We believe the nearly twofold increase in prematurity with BV is especially robust for several reasons. First, the results are statistically significant regardless of the statistics used to generate them: odds ratio or relative risk, fixed or random effects models.
Second, decisions regarding data handling in our study were made to produce the most conservative estimate of association. For example, in case control studies that defined cases by the presence of preterm labor, those women with preterm onset of labor who gave birth at term were analyzed with the control group in the preterm delivery analysis. These women may be more likely to have BV, and moving them to the control group for the purpose of analysis would tend to underestimate the risk. In addition, for studies using vaginal cultures for diagnosing BV, we extracted data only for G vaginalis culture, which might lead to overdiagnosis, since the presence of G vaginalis can be a normal finding. This nondifferential error, as well as the potential imprecision of clinical estimates of gestational age, would tend to bias the summary estimate toward the null. Despite these potential underestimations, BV remained a significant risk factor for prematurity.
Finally, BV remained a significant risk for preterm delivery regardless of the subanalysis groupings. Pooling data from different populations with variable baseline risk or in different settings may lend confidence to the generalizability of these estimates. Caution is warranted, however, when drawing conclusions from any specific subanalysis.
All studies included in this analysis were observational in design, which raises 2 particular concerns: causality and confounding. Because neither the Mantel-Haenszel or DerSimonian and Laird methods for pooling risk estimates can incorporate confounding, we calculated separately the adjusted odds ratio pooled from risk estimates generated by regression analyses in individual studies. This summary of adjusted odds ratios still demonstrated a statistically significant elevated risk of 1.6 for preterm delivery in women with BV. This value may be overestimated, because 4 studies did not report regression results for the variable of BV. Presumably, these values were near the null but were likely not statistically significant, or they would have been reported. A lower summary adjusted odds ratio may have resulted were inclusion of these results possible.
Although causality cannot be proven by observational studies or by meta-analytic combination of such studies, several of the criteria suggesting causality are met.57,58 The strength of the association is relatively small, ranging from 1.4 to 2.4. Although it is possible that confounders account for all this association, we think that is unlikely given that the controlled summary odds ratio remained significant. This meta-analysis did not address the dose response question directly, although some individual studies reported a stronger association with prematurity outcomes for those who had heavier colonization or higher BV scores. In all but one study this risk factor preceded the outcome, although in some cases vaginal assessment was done at the time of labor. Results are consistent, as can be seen from the summary figures: No study found a protective effect, and only one had a null value. The presence of BV makes biological sense as a contributor to preterm labor and thus to preterm premature rupture of membranes and preterm delivery. One proposed mechanism for this association is the production of phospholipase by the bacteria associated with BV. These enzymes can initiate prostaglandin synthesis, which is one step in the physiology of normal labor activation.53 Infections in pregnancy are also associated with fetuses that were small for the gestational age,59 which is another mechanism for low birth weight. Taken together, these factors lend support to a causal association for BV and prematurity.
Identifying BV in pregnancy as a modifiable risk factor for prematurity raises the obvious question of intervention. Accumulating evidence demonstrates that treating pregnant women who have BV with certain oral antibiotics can decrease the risk of prematurity. Clindamycin taken orally by pregnant women with BV decreased preterm deliveries and low birth weight infants by approximately 50%.38,55 Hauth42 combined oral erythromycin and metronidazole and found a decreased rate in preterm births among a group of high-risk women with BV. Neither oral amoxicillin31 or intravaginal clindamycin33 have been shown to affect pregnancy outcomes.
Limitations
As with any meta-analysis, one major limitation of this work is the appropriateness of combining results from different studies. Statistical homogeneity was met in 1 of the 4 analyses for summary odds ratios (pooling all studies possible), but in 3 of the 4 analyses when only cohort studies were pooled. This discrepancy suggests that study design was likely a key source of heterogeneity in this review. In addition to study design differences, we expected heterogeneity given the range of risks reported in individual studies, the varying population risks, the disparate methods, the timing of BV diagnosis, and the different definitions for the measured outcomes. One method for addressing heterogeneity is to use the random effects model, which accounts for variability between studies when estimating the precision of the risk. When we analyzed the data using this method, none of our conclusions changed.
A second limitation of this project is the possibility of publication bias. Our funnel plot reflects the absence of studies finding that BV protects pregnant women from delivering preterm infants. By chance alone, some studies may find this result, but it is unlikely that such a study would be published. Using Orwin’s method60 to calculate a fail-safe N of 60 and our weighted summary effect size of 0.052 (number needed to harm [NNH] = 19), more than 75 studies showing no effect would be needed to drop the risk difference to 0.01 (NNH = 100). Given our systematic and complete search, we think it unlikely that publication bias accounts for our findings, despite the asymmetry of the funnel plot.
Implications for Future Research
The association of BV with prematurity remains at the disease-oriented level of evidence. Although neonatal and infant morbidity and mortality are increased with preterm delivery, the clinical impact of BV or its treatment on these patient-oriented outcomes remains unclear. Additionally, since approximately 50% of the pregnant women with BV are asymptomatic, some advocate universal screening for BV during pregnancy.61 A large randomized controlled trial evaluating patient-oriented health benefits as well as costs is warranted before this becomes a part of routine prenatal care.
Recommendations for clinical practice
BV in pregnancy is associated with a significant risk of preterm delivery. Evidence suggests that oral treatment with certain antibiotics can decrease this risk, especially in those with a previous preterm birth.62 Thus, if identified during pregnancy, BV should be treated. There is insufficient data to recommend screening for BV during pregnancy.
Acknowledgments
This project was done as part of Dr Flynn’s requirements for her master’s degree. She thanks the members of her thesis committee for their invaluable feedback. The authors also thank Shirley Killian for her assistance with article retrieval, Tangelia Pruitt for her assistance with bibliographic management, and Bill Grant for his statistical guidance.
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3. Lewit EM, Baker LS, Corman H, Shiono PH. The direct cost of low birth weight. Future Child 1995;5:35-56.
4. Reynolds HD. Bacterial vaginosis and its implication in preterm labor and premature rupture of membranes: a review of the literature. J Nurse Midwifery 1991;36:289-96.
5. Goldberg RL, Andrews WW. Intrauterine infection and why preterm prevention programs have failed. Am J Pub Health 1996;86:781-3.
6. Lamont RF, Fisk NM. The role of infection in the pathogenesis of preterm labor. In: Studd JWW, ed. Progress in obstetrics and gynaecology. London, England: Churchill Livingston; 1993;135-58.
7. Fiscella K. Racial disparities in preterm births: the role of urogenital infections. Pub Health Rep 1996;111:104-13.
8. Oleen-Burkey MK, Hillier SL. Pregnancy complications associated with bacterial vaginosis and their estimated costs. Inf Dis Obstet Gynecol 1995;3:149-57.
9. Minkoff H, Grunebaum AN, Schwarz RH, et al. Risk factors for prematurity and premature rupture of membranes: a prospective study of the vaginal flora in pregnancy. Am J Obstet Gynecol 1984;150:965-72.
10. Elliott B, Brunham RC, Laga M, et al. Maternal gonococcal infection as a preventable risk factor for low birth weight. J Infect Dis 1990;161:531-6.
11. Kurki T, Sivonen A, Renkonen O, Savia E. Bacterial vaginosis in early pregnancy and pregnancy outcome. Obstet Gynecol 1992;80:173-7.
12. Levine M, Walter S, Lee H, Haines T, Holbrook A, Moyer V. Users’ guides to the medical literature: how to use an article about harm. JAMA 1994;271:1615-9.
13. DuRant RH. Checklist for the evaluation of research articles. J Adoles Health 1994;15:4-8.
14. Hayden GF, Kramer MS, Horwitz RI. The case control study: a practical review for the clinician. JAMA 1982;247:326-31.
15. Petitti DB. Meta-analysis, decision analysis and cost-effectiveness analysis: methods for quantitative synthesis in medicine. New York, NY: Oxford University Press; 1994.
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17. DerSimonian R, Laird N. Meta-analysis in clinical trials. Contr Clin Trials 1986;7:177-88.
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19. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev 1987;9:1-30.
20. Prentice RL, Thomas DB. On the epidemiology of oral contraceptives and disease. Adv Cancer Res 1986;49:285-401.
21. Kass EH, McCormack WM, Lin JS, Rosner B, Munoz A. Genital mycoplasmas as a cause of excess premature delivery. Trans Assoc Am Phys 1981;94:261-6.
22. Lamont RF, Taylor-Robinson D, Newman M, Wigglesworth J. Spontaneous early preterm labour associated with abnormal genital bacterial colonization. Br J Obstet Gynecol 1985;43:804-10.
23. Gravett MG, Hummel D, Eschenbach DA, Holmes KK. Preterm labor associated with subclinical amniotic fluid infection and with bacterial vaginosis. Obstet Gynecol 1986;67:229-37.
24. Hillier SL, Krohn M, Kiviat N, Watts DH. Microbiologic causes and neonatal outcomes associated with chorioamnion infection. Am J Obstet Gynecol 1991;165:955-61.
25. Kurki T, Ylikorkala O. Coitus during pregnancy is not related to bacterial vaginosis or preterm birth. Am J Obstet Gynecol 1993;169:1130-4.
26. Carey JC, Blackwelder WC, Nugent RP, et al. Antepartum cultures for ureaplasma urealyticum are not useful in predicting pregnancy outcome. Am J Obstet Gynecol 1991;164:728-33.
27. Creatsas G, Pavlatos M, Lolis D, Aravantinos D, Kaskarelis D. Bacterial contamination of the cervix and premature rupture of membranes. Am J Obstet Gynecol 1981;139:522-5.
28. Hawkinson JA, Schulman H. Prematurity associated with cervicitis and vaginitis during pregnancy. Am J Obstet Gynecol 1966;94:898-902.
29. Hillier SL, Krohn MA, Cassen E, Easterling TR, Rabe LK. The role of bacterial vaginosis and vaginal bacteria in amniotic fluid infection in women in preterm labor with intact fetal membranes. Clin Infect Dis 1995;20 (suppl 2):S276-8.
30. Polk BF. Investigators of the John Hopkins Study of Cervicitis and Adverse Pregnancy Outcome. Association of chlamydia trachomatis and mycoplasma hominis with intrauterine growth retardation and preterm delivery. Am J Epidemiol 1989;129:1247-57.
31. Duff P, Lee M, Hillier S, Herd LM, Krohn MA, Eschenbach DA. Amoxicillin treatment of bacterial vaginosis during pregnancy. Obstet Gynecol 1991;77:431-5.
32. Eschenbach DA, Nugent RP, Rao AV, et al. A randomized placebo-controlled trial of erythromycin for the treatment of Ureaplasma urealyticum to prevent premature delivery. Am J Obstet Gynecol 1991;164:764-72.
33. Joesoef MR. Intravaginal clindamycin treatment for bacterial vaginosis: effects on preterm delivery and low birth weight. Am J Obstet Gynecol 1995;173:1527-31.
34. McCormack WM, Rosner B, Lee Y, Munoz A, Charles D, Kass EH. Effect on birth weight of erythromycin treatment of pregnant women. Obstet Gynecol 1987;69:202-7.
35. McGregor JA, French JI, Seo K. Adjunctive clindamycin therapy for preterm labor: results of a double-blind, placebo-controlled trial. Am J Obstet Gynecol 1991;165:867-75.
36. McGregor JA, French JI, Richter R, Vuchetich M, Bachus V. Cervicovaginal microflora and pregnancy outcome: results of a double-blind, placebo-controlled trial of erythromycin treatment. Am J Obstet Gynecol 1990;163:1580-91.
37. Morales W, Schorr S, Albritton J. Effect of metronidazole in patients with preterm birth in preceding pregnancy and bacterial vaginosis: a placebo-controlled, double-blinded study. Am J Obstet Gynecol 1994;171:345-9.
38. Morales WJ, Angel JL, O’Brien WF, Knuppel RA, Finazzo M. A randomized study of antibiotic therapy in idiopathic preterm labor. Obstet Gynecol 1988;72:829-33.
39. Newton E, Dinsmoor MJ, Gibbs RS, Newton E, Dinsmoor MJ, Gibbs RS. A randomized, blinded, placebo-controlled trial of antibiotics in idiopathic preterm labor. Obstet Gynecol 1989;74:562-6.
40. Eschenbach DA, Gravett MG, Chen KCS, Hoyme UB, Holmes KK. Bacterial vaginosis during pregnancy: an association with prematurity and post partum complications. Scand J Uro Nephro 1984;S86:213-22.
41. Gravett MG, Nelson P, DeRouen T, Critchlow C. Independent associations of bacterial vaginosis and chlamydia trachomatis infection with adverse pregnancy outcome. JAMA 1986;256:1899-903.
42. Hauth JC, Goldenberg RL, Andrews WW, DuBard MB. Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med 1995;333:1732-6.
43. Hay PE, Lamont RF, Taylor-Robinson D, Morgan DJ. Abnormal bacterial colonization of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 1994;308:295-8.
44. Hillier SL, Nugent RP, Eschenbach DA, Krohn MA. Association between bacterial vaginosis and preterm delivery of a low birth weight infant. N Engl J Med 1995;333:1737-42.
45. Hillier SL, Martius J, Krohn M, Kiviat N. A case control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988;319:972-8.
46. Holst E, Goffeng AR, Andersch B. Bacterial vaginosis and vaginal microorganisms in idiopathic premature labor and association with pregnancy outcome. J Clin Microbiol 1994;32:176-86.
47. Krohn MA, Hillier SL, Lee ML, Rabe LK, Eschenbach DA. Vaginal bacteriodes species are associated with an increased rate of preterm delivery among women in preterm labor. J Infect Dis 1991;164:88-93.
48. Martius J, Krohn MA, Hillier SL, Stamm WE. Relationships of vaginal lactobacillus species, cervical chlamydia trachomatis, and bacterial vaginosis to preterm birth. Obstet Gynecol 1988;71:89-95.
49. McDonald HM, O’Loughlin JA, Jolley P, Vigneswaran R, McDonald PJ. Changes in vaginal flora during pregnancy and associaton with preterm birth. J Infect Dis 1994;170:724-8.
50. McDonald HM, O’Loughlin JA, Jolley P, Vigneswaran R. Vaginal infection and preterm labour. Br J Obstet Gynecol 1991;98:427-35.
51. McGregor JA, French JI, Jones W, et al. Bacterial vaginosis is associated with prematurity and vaginal fluid mucinase and sialidase: results of a controlled trial of topical clindamycin cream. Am J Obstet Gynecol 1994;170:1048-60.
52. Meis PJ, Goldenberg RL, Mercer B, et al. The preterm prediction study: significance of vaginal infections. Am J Obstet Gynecol 1995;173:1231-5.
53. Riduan JM, Hillier SL, Utomo B, Wiknjosastro G, Linnan M, Kandun N. Bacterial vaginosis and prematurity in Indonesia: association in early and late pregnancy. Am J Obstet Gynecol 1993;169:175-8.
54. McDonald HM, O’Loughlin JA, Jolley P, Vigneswaran R. Prenatal microbiological risk factors associated with preterm birth. Br J Obstet Gynecol 1992;99:190-6.
55. McGregor J, French J, Richter R, et al. Antenatal microbiologic and maternal risk factors associated with prematurity. Am J Obstet Gynecol 1990;163:1465-73.
56. McGregor JA, French JI, Parker R, et al. Prevention of premature birth by screening and treatment for common genital tract infections: results of a prospective controlled evaluation. Am J Obstet Gynecol 1995;173:157-67.
57. Beaglehole R, Bonita R, Kjellstrom T. Causation in epidemiology. In: Basic epidemiology. Geneva, Switzerland: World Health Organization; 1993;71-81.
58. Greenberg RS. Interpretation of epidemiologic literature. In: Medical epidemiology. Norwalk, Conn: Appleton & Lange; 1996;167-78.
59. Germain M, Krohn MA, Hillier SL, Eschenbach DA. Genital flora in pregnancy and its association with intrauterine growth retardation. J Clin Microbiol 1994;32:2162-8.
60. Einarson TR, McGhan WF, Bootman JL, Sabers DL. Meta-analysis: quantitative integration of independent research results. Am J Hosp Pharm 1985;42:1957-64.
61. Frieden J. Not screening for bacterial vaginosis can be costly. Fam Pract News 1997;40-1.62. Brocklehurst P, Hannah M, McDonald H. The management of bacterial vaginosis in pregnancy. In: The Cochrane library. Oxford, England: Update Software; 1998.
SEARCH STRATEGY: We selected articles from a combination of the results of a MEDLINE search (1966-1996), a manual search of bibliographies, and contact with leading researchers.
SELECTION CRITERIA: We included case control and cohort studies evaluating the risk of preterm delivery, low birth weight, preterm premature rupture of membranes, or preterm labor for pregnant women who had bacterial vaginosis and those who did not.
DATA COLLECTION AND ANALYSIS: Two investigators independently conducted literature searches, applied inclusion criteria, performed data extraction, and critically appraised included studies. Summary estimates of risk were calculated as odds ratios (ORs) using the fixed and random effects models.
MAIN RESULTS: We included 19 studies in the final analysis. Bacterial vaginosis during pregnancy was associated with a statistically significant increased risk for all outcomes evaluated. The summary OR was 1.85 for preterm delivery (95% confidence interval [CI], 1.62-2.11), 1.57 for low birth weight (95% CI, 1.32-1.87), 1.83 for preterm premature rupture of membranes (95% CI, 1.39-2.44), and 2.19 for preterm labor (95% CI, 1.73-2.76). In the subanalyses for preterm delivery, bacterial vaginosis remained a significant risk factor. Pooling adjusted ORs yielded a 60% increased risk of preterm delivery given the presence of bacterial vaginosis.
CONCLUSION: Bacterial vaginosis is an important risk factor for prematurity and pregnancy morbidity. Further study will help clarify the benefits of treating bacterial vaginosis and the potential role of screening during pregnancy.
CLINICAL QUESTION
What is the association between bacterial vaginosis and preterm delivery?
Prematurity, whether defined by gestational age or birth weight, increases the risk of neonatal morbidity and mortality, as well as early childhood morbidity. Preterm birth, defined as delivery before 37 weeks’ gestation, accounts for 8% to 10% of all births1 and leads to nearly 75% of all neonatal mortality and 50% of all long-term neurologic damage in children.2 On average, first-year medical costs for infants born weighing less than 2500 grams exceed that of a full-term infant by $15,000.3
Between 25% and 60% of preterm births are thought to be attributable to maternal infections,4,5 and are thus considered preventable. Bacterial vaginosis (BV) has been suggested as one potentially treatable risk factor for preterm delivery. BV is fairly common, with a prevalence ranging from 10% to 30% in an typical obstetrical population6 to more than 50% in some high-risk groups.7
Although otherwise thought to be a fairly benign condition, in pregnancy BV is estimated to confer a two- to threefold increased risk of prematurity.4,8 Yet the relative risks from the literature range from09,10> to 6.9.11 These variations may be attributable to differences in study design, sample size, or confounders. The purpose of our meta-analysis was to estimate the magnitude of risk that BV poses on prematurity and pregnancy complications that may lead to prematurity.
Methods
Data Sources
To identify potential studies for inclusion, 2 independent investigators (CF and AH) conducted a MEDLINE search (1966-1996), using the terms “bacterial vaginosis,” “gardnerella” and “prematurity,” “labor-premature onset, ” “rupture of membranes-premature,” “preterm delivery,” or “preterm infant” as both medical subject headings and text words. The bibliographies of obstetric texts, all included studies, relevant reviews, and the Cochrane Library were also reviewed. Finally, we contacted several authors who had published articles on the subject in an attempt to identify any unpublished data.
Study Selection
Studies were included if they met the following criteria: (1) the population studied was pregnant women; (2) the risk factor considered was the presence of BV; (3) the outcomes measured included either gestational age or birth weight; secondary outcomes considered were preterm premature rupture of membranes and preterm onset of labor; and (4) study design was either case control or cohort trial evaluating the benefit of treating BV in pregnancy. Trials were included if sufficient data were available to compare the outcomes of those women who had BV with those who did not in the control cohort. Inclusion criteria were applied independently by the 2 investigators; differences were settled by consensus.
Non-English language papers and those containing duplication of previous data were excluded. For articles in which the data presentation prohibited the linking of BV to the outcomes of interest, we contacted the authors in writing for the original data. If the original data were unavailable, we excluded the study from final analysis.
Data Extraction
The 2 investigators also independently performed data extraction. Disagreements were settled by discussion and consensus.
The population data we collected included country, medical setting, and baseline risk of prematurity. We recorded inclusion and exclusion criteria, but those factors were insufficient to categorize the study population as either high, normal, or low risk. Therefore, baseline risk was determined by calculating the incidence of preterm delivery in the control group for each study. Since the standard incidence of preterm delivery is 8% to 10%, we considered as high risk those studies with rates greater than 10% in the non-BV group; those below were categorized as low or normal risk.
We recorded the method and timing of BV diagnosis. In studies with multiple methods of determining BV, we collected the results for each method. The gram stain/wet mount result was preferentially used in the final analysis, as this is the most relevant technique for clinical assessment of BV. Vaginal culture data could only be correlated to outcome by individual microbes, so we limited data recording to Gardnerella vaginalis only. We recorded the timing of the diagnosis of BV as presented (ie, weeks of gestational age, trimester, during labor), then grouped the data by trimester. If more than one sample was collected in an individual study, we recorded all results but used the earliest in the analysis.
We recorded outcome data dichotomously in 2 x 2 tables for all 4 study outcomes. Extracted information on the handling of confounding included the method used, the adjusted odds ratio with confidence interval, and the variables included in the final model.
In studies that reported preterm delivery results at multiple gestational age cutoffs, we used only the 37-week cutoff. If studies used a definition other than 37 weeks, their data were noted for subanalysis. Some case control studies defined cases as women in preterm labor, but reported data separately from those cases that delivered prematurely from those that delivered after 37 weeks. For the preterm delivery outcome, the preterm labor cases who delivered at term were included in the control group.
Validity Assessment
We used validity assessment worksheets that were developed specifically for this project using a summary of previously published criteria.12-14 Each included study was critically appraised independently by the 2 investigators, and their assessments were compared. A third investigator (LM) settled disagreements. We did not use validity criteria to exclude any study from analysis.
Data Synthesis
We calculated summary estimates of risk as odds ratios using both the fixed and random effects models.15-17 Additionally, we combined cohort studies to generate summary relative risk estimates using both models. Precision is reported as 95% confidence intervals for each statistic. These calculations were generated using Review Manager 3.0 software.18 We evaluated homogeneity using the chi-square statistic:15 the greater the P value, the more homogeneous the studies.
We conducted subanalyses by study design, baseline population risk of prematurity, method and timing of BV diagnosis, and country of study population. When the subgroupings resulted in any category having fewer than 3 studies, we did not calculate a summary statistic for that group. We excluded those studies and generated a new pooled risk assessment for the alternate groups only.
To address the issue of confounders, we used the general variance-based model15,19,20 to combine the adjusted odds ratios of individual studies into a summary odds ratio with its 95% confidence interval.
Results
Data Sources and Study Selection
Our literature review identified 233 studies; no unpublished data were discovered. Reviewing the abstracts identified 39 studies for possible inclusion (27 observational studies and 12 trials). We excluded 11 observational studies because they had an inadequate or no control group (2),21,22 no vaginal assessment of BV (2),23,24 repeated data (1),25 or the inability to link BV with pregnancy outcomes (6).9,26-30 Nine of the 12 trials did not present their control group cohort data in a way that distinguished the outcomes by the presence or absence of BV and were therefore excluded.31-39 We included 19 studies10,11,40-56 in the final analysis: 8 case control trials and 11 cohort studies. Three from this latter group consisted of the placebo group of randomized controlled trials.
We estimated the likelihood of publication bias by generating a funnel plot.15 The graph of study size versus the logarithm of the ratio results, although funnel-shaped, is not completely symmetric.* Data from small studies demonstrating a protective effect of BV in pregnancy are missing.
Data Extraction
Twelve of the 19 included studies drew patients from a university or tertiary care hospital setting; the 7 others were clinic based Table 1. Two studies were conducted in nonindustrialized countries (Nairobi and Indonesia). The remaining studies were performed in the United States (11), Australia (3), the United Kingdom (1), Sweden (1), and Finland (1). The baseline prevalence of preterm delivery ranged from 1.1% to 64.9%, with a mean of 20.0% and a median of 13.8%.
To diagnose bacterial vaginosis, 13 studies used gram stain alone or in combination with a wet mount, 2 used gas-liquid chromatography, and 4 used vaginal swab cultures. The timing of risk factor detection varied among the studies, ranging from the first prenatal visit to the time of labor. We grouped the studies by trimester as precisely as possible, resulting in 10 studies diagnosing BV in the first or second trimester, 4 with second or third trimester assessment, and 4 studies discovering BV in the third trimester only (which in most cases was at the time of labor).
In most studies, gestational age was determined by the best obstetric clinical estimate — using the date of the mother’s last menstrual period, detection of fetal heart tones, fundal heights, and obstetrical ultrasound. In one study, gestational age was determined only by pediatric assessment. Preterm delivery was evaluated as a dichotomous outcome in 18 of the 19 included studies. Two studies used 35 weeks’ gestation or less to define a preterm infant; one study used 36 weeks. All others adhered to the standard definition of preterm as any gestation with a duration of less than 37 weeks. Low birth weight was defined as an infant weighing less than 2500 grams [at birth] in all 6 studies that reported this outcome.
Of the 7 studies evaluating preterm premature rupture of membranes, 2 used 36 weeks as the cutoff for preterm; the other 5 used 37 weeks. Only 2 studies reported the method to determine membrane rupture (both used pH and ferning criteria). The time from rupture of membranes to labor onset varied from 1 to 6 hours in the 4 studies defining this period.
For the outcome of preterm onset of labor, all 9 studies defined preterm as gestational age less than 37 weeks. Most studies defined labor as regular painful uterine contractions; only 2 required cervical change. Two others considered treatment for preterm labor as the definition of preterm onset of labor.
Validity Assessment
Details about validity assessment and the effect of biases on the summary estimates of individual studies are available elsewhere.* Two biases were common. First was the misclassification of either the predictor or the outcomes, which tended to underestimate risk. Second was the issue of confounding variables, which tended to overestimate the odds ratio.
Data Synthesis
The Figure shows that women with BV were more likely to deliver a preterm infant (odds ratio, fixed effects model [OR<->FIXED<->] 1.85; 95% CI, 1.62-2.11) or an infant weighing less than 2500 grams (OR<->FIXED<-> 1.57; 95% CI, 1.32-1.87).
For the secondary outcomes of preterm premature rupture of membranes and preterm onset of labor, the resultant ORs<->FIXED <->were 1.83 (95% CI, 1.39-2.44) and 2.19 (95% CI, 1.73-2.76), respectively. The studies combined for preterm onset of labor met statistical requirements of homogeneity (P <\>>.25); those for preterm delivery, low birth weight, and preterm premature rupture of membranes did not. Recalculation of the odds ratio using the random effects model did not result in the loss of statistical significance for any of the main outcomes Table 2.
Pooling only cohort studies to generate a summary relative risk also resulted in a persistently elevated risk of prematurity for those mothers with BV, ranging from a 1.44- to a 2.86-fold increase Table 2, and homogeneity criteria were met for low birth weight, preterm premature rupture of membranes, and preterm onset of labor, (P <\>>.33) but not for preterm delivery. BV was significantly associated with preterm delivery in nearly all the subanalyses conducted Table 3.
Seven of the 18 studies evaluating preterm delivery did not perform regression analysis to evaluate for confounding; 4 others did this analysis but did not report an adjusted risk for BV. Thus, only 7 studies had controlled data available for a summary estimate. These studies, with their respective adjusted odds ratios and confounders considered, are listed in Table 5. As expected, the resultant summary estimate of the adjusted odds ratio was lower than that obtained from unadjusted data but remained significant clinically (OR = 1.60), as well as statistically (95% CI, 1.44-1.74).
Discussion
Our study pooled data representing more than 17,000 patients and the results show BV to be a significant risk factor for preterm and low birth weight deliveries. Additionally, BV is significantly associated with preterm onset of labor and preterm premature rupture of membranes. Summary relative risks calculated using cohort data only, although lower than the odds ratios, also showed a significant association between BV and all prematurity outcomes. Although often used interchangeably with relative risks, odds ratios tend to overestimate risk in cases of a positive association and a nonrare outcome. In our study, odds ratios exceeded relative risks for 3 of the 4 outcomes. This may reflect violation of the rare disease assumption or may simply be due to pooling a different subset of studies.
We believe the nearly twofold increase in prematurity with BV is especially robust for several reasons. First, the results are statistically significant regardless of the statistics used to generate them: odds ratio or relative risk, fixed or random effects models.
Second, decisions regarding data handling in our study were made to produce the most conservative estimate of association. For example, in case control studies that defined cases by the presence of preterm labor, those women with preterm onset of labor who gave birth at term were analyzed with the control group in the preterm delivery analysis. These women may be more likely to have BV, and moving them to the control group for the purpose of analysis would tend to underestimate the risk. In addition, for studies using vaginal cultures for diagnosing BV, we extracted data only for G vaginalis culture, which might lead to overdiagnosis, since the presence of G vaginalis can be a normal finding. This nondifferential error, as well as the potential imprecision of clinical estimates of gestational age, would tend to bias the summary estimate toward the null. Despite these potential underestimations, BV remained a significant risk factor for prematurity.
Finally, BV remained a significant risk for preterm delivery regardless of the subanalysis groupings. Pooling data from different populations with variable baseline risk or in different settings may lend confidence to the generalizability of these estimates. Caution is warranted, however, when drawing conclusions from any specific subanalysis.
All studies included in this analysis were observational in design, which raises 2 particular concerns: causality and confounding. Because neither the Mantel-Haenszel or DerSimonian and Laird methods for pooling risk estimates can incorporate confounding, we calculated separately the adjusted odds ratio pooled from risk estimates generated by regression analyses in individual studies. This summary of adjusted odds ratios still demonstrated a statistically significant elevated risk of 1.6 for preterm delivery in women with BV. This value may be overestimated, because 4 studies did not report regression results for the variable of BV. Presumably, these values were near the null but were likely not statistically significant, or they would have been reported. A lower summary adjusted odds ratio may have resulted were inclusion of these results possible.
Although causality cannot be proven by observational studies or by meta-analytic combination of such studies, several of the criteria suggesting causality are met.57,58 The strength of the association is relatively small, ranging from 1.4 to 2.4. Although it is possible that confounders account for all this association, we think that is unlikely given that the controlled summary odds ratio remained significant. This meta-analysis did not address the dose response question directly, although some individual studies reported a stronger association with prematurity outcomes for those who had heavier colonization or higher BV scores. In all but one study this risk factor preceded the outcome, although in some cases vaginal assessment was done at the time of labor. Results are consistent, as can be seen from the summary figures: No study found a protective effect, and only one had a null value. The presence of BV makes biological sense as a contributor to preterm labor and thus to preterm premature rupture of membranes and preterm delivery. One proposed mechanism for this association is the production of phospholipase by the bacteria associated with BV. These enzymes can initiate prostaglandin synthesis, which is one step in the physiology of normal labor activation.53 Infections in pregnancy are also associated with fetuses that were small for the gestational age,59 which is another mechanism for low birth weight. Taken together, these factors lend support to a causal association for BV and prematurity.
Identifying BV in pregnancy as a modifiable risk factor for prematurity raises the obvious question of intervention. Accumulating evidence demonstrates that treating pregnant women who have BV with certain oral antibiotics can decrease the risk of prematurity. Clindamycin taken orally by pregnant women with BV decreased preterm deliveries and low birth weight infants by approximately 50%.38,55 Hauth42 combined oral erythromycin and metronidazole and found a decreased rate in preterm births among a group of high-risk women with BV. Neither oral amoxicillin31 or intravaginal clindamycin33 have been shown to affect pregnancy outcomes.
Limitations
As with any meta-analysis, one major limitation of this work is the appropriateness of combining results from different studies. Statistical homogeneity was met in 1 of the 4 analyses for summary odds ratios (pooling all studies possible), but in 3 of the 4 analyses when only cohort studies were pooled. This discrepancy suggests that study design was likely a key source of heterogeneity in this review. In addition to study design differences, we expected heterogeneity given the range of risks reported in individual studies, the varying population risks, the disparate methods, the timing of BV diagnosis, and the different definitions for the measured outcomes. One method for addressing heterogeneity is to use the random effects model, which accounts for variability between studies when estimating the precision of the risk. When we analyzed the data using this method, none of our conclusions changed.
A second limitation of this project is the possibility of publication bias. Our funnel plot reflects the absence of studies finding that BV protects pregnant women from delivering preterm infants. By chance alone, some studies may find this result, but it is unlikely that such a study would be published. Using Orwin’s method60 to calculate a fail-safe N of 60 and our weighted summary effect size of 0.052 (number needed to harm [NNH] = 19), more than 75 studies showing no effect would be needed to drop the risk difference to 0.01 (NNH = 100). Given our systematic and complete search, we think it unlikely that publication bias accounts for our findings, despite the asymmetry of the funnel plot.
Implications for Future Research
The association of BV with prematurity remains at the disease-oriented level of evidence. Although neonatal and infant morbidity and mortality are increased with preterm delivery, the clinical impact of BV or its treatment on these patient-oriented outcomes remains unclear. Additionally, since approximately 50% of the pregnant women with BV are asymptomatic, some advocate universal screening for BV during pregnancy.61 A large randomized controlled trial evaluating patient-oriented health benefits as well as costs is warranted before this becomes a part of routine prenatal care.
Recommendations for clinical practice
BV in pregnancy is associated with a significant risk of preterm delivery. Evidence suggests that oral treatment with certain antibiotics can decrease this risk, especially in those with a previous preterm birth.62 Thus, if identified during pregnancy, BV should be treated. There is insufficient data to recommend screening for BV during pregnancy.
Acknowledgments
This project was done as part of Dr Flynn’s requirements for her master’s degree. She thanks the members of her thesis committee for their invaluable feedback. The authors also thank Shirley Killian for her assistance with article retrieval, Tangelia Pruitt for her assistance with bibliographic management, and Bill Grant for his statistical guidance.
SEARCH STRATEGY: We selected articles from a combination of the results of a MEDLINE search (1966-1996), a manual search of bibliographies, and contact with leading researchers.
SELECTION CRITERIA: We included case control and cohort studies evaluating the risk of preterm delivery, low birth weight, preterm premature rupture of membranes, or preterm labor for pregnant women who had bacterial vaginosis and those who did not.
DATA COLLECTION AND ANALYSIS: Two investigators independently conducted literature searches, applied inclusion criteria, performed data extraction, and critically appraised included studies. Summary estimates of risk were calculated as odds ratios (ORs) using the fixed and random effects models.
MAIN RESULTS: We included 19 studies in the final analysis. Bacterial vaginosis during pregnancy was associated with a statistically significant increased risk for all outcomes evaluated. The summary OR was 1.85 for preterm delivery (95% confidence interval [CI], 1.62-2.11), 1.57 for low birth weight (95% CI, 1.32-1.87), 1.83 for preterm premature rupture of membranes (95% CI, 1.39-2.44), and 2.19 for preterm labor (95% CI, 1.73-2.76). In the subanalyses for preterm delivery, bacterial vaginosis remained a significant risk factor. Pooling adjusted ORs yielded a 60% increased risk of preterm delivery given the presence of bacterial vaginosis.
CONCLUSION: Bacterial vaginosis is an important risk factor for prematurity and pregnancy morbidity. Further study will help clarify the benefits of treating bacterial vaginosis and the potential role of screening during pregnancy.
CLINICAL QUESTION
What is the association between bacterial vaginosis and preterm delivery?
Prematurity, whether defined by gestational age or birth weight, increases the risk of neonatal morbidity and mortality, as well as early childhood morbidity. Preterm birth, defined as delivery before 37 weeks’ gestation, accounts for 8% to 10% of all births1 and leads to nearly 75% of all neonatal mortality and 50% of all long-term neurologic damage in children.2 On average, first-year medical costs for infants born weighing less than 2500 grams exceed that of a full-term infant by $15,000.3
Between 25% and 60% of preterm births are thought to be attributable to maternal infections,4,5 and are thus considered preventable. Bacterial vaginosis (BV) has been suggested as one potentially treatable risk factor for preterm delivery. BV is fairly common, with a prevalence ranging from 10% to 30% in an typical obstetrical population6 to more than 50% in some high-risk groups.7
Although otherwise thought to be a fairly benign condition, in pregnancy BV is estimated to confer a two- to threefold increased risk of prematurity.4,8 Yet the relative risks from the literature range from09,10> to 6.9.11 These variations may be attributable to differences in study design, sample size, or confounders. The purpose of our meta-analysis was to estimate the magnitude of risk that BV poses on prematurity and pregnancy complications that may lead to prematurity.
Methods
Data Sources
To identify potential studies for inclusion, 2 independent investigators (CF and AH) conducted a MEDLINE search (1966-1996), using the terms “bacterial vaginosis,” “gardnerella” and “prematurity,” “labor-premature onset, ” “rupture of membranes-premature,” “preterm delivery,” or “preterm infant” as both medical subject headings and text words. The bibliographies of obstetric texts, all included studies, relevant reviews, and the Cochrane Library were also reviewed. Finally, we contacted several authors who had published articles on the subject in an attempt to identify any unpublished data.
Study Selection
Studies were included if they met the following criteria: (1) the population studied was pregnant women; (2) the risk factor considered was the presence of BV; (3) the outcomes measured included either gestational age or birth weight; secondary outcomes considered were preterm premature rupture of membranes and preterm onset of labor; and (4) study design was either case control or cohort trial evaluating the benefit of treating BV in pregnancy. Trials were included if sufficient data were available to compare the outcomes of those women who had BV with those who did not in the control cohort. Inclusion criteria were applied independently by the 2 investigators; differences were settled by consensus.
Non-English language papers and those containing duplication of previous data were excluded. For articles in which the data presentation prohibited the linking of BV to the outcomes of interest, we contacted the authors in writing for the original data. If the original data were unavailable, we excluded the study from final analysis.
Data Extraction
The 2 investigators also independently performed data extraction. Disagreements were settled by discussion and consensus.
The population data we collected included country, medical setting, and baseline risk of prematurity. We recorded inclusion and exclusion criteria, but those factors were insufficient to categorize the study population as either high, normal, or low risk. Therefore, baseline risk was determined by calculating the incidence of preterm delivery in the control group for each study. Since the standard incidence of preterm delivery is 8% to 10%, we considered as high risk those studies with rates greater than 10% in the non-BV group; those below were categorized as low or normal risk.
We recorded the method and timing of BV diagnosis. In studies with multiple methods of determining BV, we collected the results for each method. The gram stain/wet mount result was preferentially used in the final analysis, as this is the most relevant technique for clinical assessment of BV. Vaginal culture data could only be correlated to outcome by individual microbes, so we limited data recording to Gardnerella vaginalis only. We recorded the timing of the diagnosis of BV as presented (ie, weeks of gestational age, trimester, during labor), then grouped the data by trimester. If more than one sample was collected in an individual study, we recorded all results but used the earliest in the analysis.
We recorded outcome data dichotomously in 2 x 2 tables for all 4 study outcomes. Extracted information on the handling of confounding included the method used, the adjusted odds ratio with confidence interval, and the variables included in the final model.
In studies that reported preterm delivery results at multiple gestational age cutoffs, we used only the 37-week cutoff. If studies used a definition other than 37 weeks, their data were noted for subanalysis. Some case control studies defined cases as women in preterm labor, but reported data separately from those cases that delivered prematurely from those that delivered after 37 weeks. For the preterm delivery outcome, the preterm labor cases who delivered at term were included in the control group.
Validity Assessment
We used validity assessment worksheets that were developed specifically for this project using a summary of previously published criteria.12-14 Each included study was critically appraised independently by the 2 investigators, and their assessments were compared. A third investigator (LM) settled disagreements. We did not use validity criteria to exclude any study from analysis.
Data Synthesis
We calculated summary estimates of risk as odds ratios using both the fixed and random effects models.15-17 Additionally, we combined cohort studies to generate summary relative risk estimates using both models. Precision is reported as 95% confidence intervals for each statistic. These calculations were generated using Review Manager 3.0 software.18 We evaluated homogeneity using the chi-square statistic:15 the greater the P value, the more homogeneous the studies.
We conducted subanalyses by study design, baseline population risk of prematurity, method and timing of BV diagnosis, and country of study population. When the subgroupings resulted in any category having fewer than 3 studies, we did not calculate a summary statistic for that group. We excluded those studies and generated a new pooled risk assessment for the alternate groups only.
To address the issue of confounders, we used the general variance-based model15,19,20 to combine the adjusted odds ratios of individual studies into a summary odds ratio with its 95% confidence interval.
Results
Data Sources and Study Selection
Our literature review identified 233 studies; no unpublished data were discovered. Reviewing the abstracts identified 39 studies for possible inclusion (27 observational studies and 12 trials). We excluded 11 observational studies because they had an inadequate or no control group (2),21,22 no vaginal assessment of BV (2),23,24 repeated data (1),25 or the inability to link BV with pregnancy outcomes (6).9,26-30 Nine of the 12 trials did not present their control group cohort data in a way that distinguished the outcomes by the presence or absence of BV and were therefore excluded.31-39 We included 19 studies10,11,40-56 in the final analysis: 8 case control trials and 11 cohort studies. Three from this latter group consisted of the placebo group of randomized controlled trials.
We estimated the likelihood of publication bias by generating a funnel plot.15 The graph of study size versus the logarithm of the ratio results, although funnel-shaped, is not completely symmetric.* Data from small studies demonstrating a protective effect of BV in pregnancy are missing.
Data Extraction
Twelve of the 19 included studies drew patients from a university or tertiary care hospital setting; the 7 others were clinic based Table 1. Two studies were conducted in nonindustrialized countries (Nairobi and Indonesia). The remaining studies were performed in the United States (11), Australia (3), the United Kingdom (1), Sweden (1), and Finland (1). The baseline prevalence of preterm delivery ranged from 1.1% to 64.9%, with a mean of 20.0% and a median of 13.8%.
To diagnose bacterial vaginosis, 13 studies used gram stain alone or in combination with a wet mount, 2 used gas-liquid chromatography, and 4 used vaginal swab cultures. The timing of risk factor detection varied among the studies, ranging from the first prenatal visit to the time of labor. We grouped the studies by trimester as precisely as possible, resulting in 10 studies diagnosing BV in the first or second trimester, 4 with second or third trimester assessment, and 4 studies discovering BV in the third trimester only (which in most cases was at the time of labor).
In most studies, gestational age was determined by the best obstetric clinical estimate — using the date of the mother’s last menstrual period, detection of fetal heart tones, fundal heights, and obstetrical ultrasound. In one study, gestational age was determined only by pediatric assessment. Preterm delivery was evaluated as a dichotomous outcome in 18 of the 19 included studies. Two studies used 35 weeks’ gestation or less to define a preterm infant; one study used 36 weeks. All others adhered to the standard definition of preterm as any gestation with a duration of less than 37 weeks. Low birth weight was defined as an infant weighing less than 2500 grams [at birth] in all 6 studies that reported this outcome.
Of the 7 studies evaluating preterm premature rupture of membranes, 2 used 36 weeks as the cutoff for preterm; the other 5 used 37 weeks. Only 2 studies reported the method to determine membrane rupture (both used pH and ferning criteria). The time from rupture of membranes to labor onset varied from 1 to 6 hours in the 4 studies defining this period.
For the outcome of preterm onset of labor, all 9 studies defined preterm as gestational age less than 37 weeks. Most studies defined labor as regular painful uterine contractions; only 2 required cervical change. Two others considered treatment for preterm labor as the definition of preterm onset of labor.
Validity Assessment
Details about validity assessment and the effect of biases on the summary estimates of individual studies are available elsewhere.* Two biases were common. First was the misclassification of either the predictor or the outcomes, which tended to underestimate risk. Second was the issue of confounding variables, which tended to overestimate the odds ratio.
Data Synthesis
The Figure shows that women with BV were more likely to deliver a preterm infant (odds ratio, fixed effects model [OR<->FIXED<->] 1.85; 95% CI, 1.62-2.11) or an infant weighing less than 2500 grams (OR<->FIXED<-> 1.57; 95% CI, 1.32-1.87).
For the secondary outcomes of preterm premature rupture of membranes and preterm onset of labor, the resultant ORs<->FIXED <->were 1.83 (95% CI, 1.39-2.44) and 2.19 (95% CI, 1.73-2.76), respectively. The studies combined for preterm onset of labor met statistical requirements of homogeneity (P <\>>.25); those for preterm delivery, low birth weight, and preterm premature rupture of membranes did not. Recalculation of the odds ratio using the random effects model did not result in the loss of statistical significance for any of the main outcomes Table 2.
Pooling only cohort studies to generate a summary relative risk also resulted in a persistently elevated risk of prematurity for those mothers with BV, ranging from a 1.44- to a 2.86-fold increase Table 2, and homogeneity criteria were met for low birth weight, preterm premature rupture of membranes, and preterm onset of labor, (P <\>>.33) but not for preterm delivery. BV was significantly associated with preterm delivery in nearly all the subanalyses conducted Table 3.
Seven of the 18 studies evaluating preterm delivery did not perform regression analysis to evaluate for confounding; 4 others did this analysis but did not report an adjusted risk for BV. Thus, only 7 studies had controlled data available for a summary estimate. These studies, with their respective adjusted odds ratios and confounders considered, are listed in Table 5. As expected, the resultant summary estimate of the adjusted odds ratio was lower than that obtained from unadjusted data but remained significant clinically (OR = 1.60), as well as statistically (95% CI, 1.44-1.74).
Discussion
Our study pooled data representing more than 17,000 patients and the results show BV to be a significant risk factor for preterm and low birth weight deliveries. Additionally, BV is significantly associated with preterm onset of labor and preterm premature rupture of membranes. Summary relative risks calculated using cohort data only, although lower than the odds ratios, also showed a significant association between BV and all prematurity outcomes. Although often used interchangeably with relative risks, odds ratios tend to overestimate risk in cases of a positive association and a nonrare outcome. In our study, odds ratios exceeded relative risks for 3 of the 4 outcomes. This may reflect violation of the rare disease assumption or may simply be due to pooling a different subset of studies.
We believe the nearly twofold increase in prematurity with BV is especially robust for several reasons. First, the results are statistically significant regardless of the statistics used to generate them: odds ratio or relative risk, fixed or random effects models.
Second, decisions regarding data handling in our study were made to produce the most conservative estimate of association. For example, in case control studies that defined cases by the presence of preterm labor, those women with preterm onset of labor who gave birth at term were analyzed with the control group in the preterm delivery analysis. These women may be more likely to have BV, and moving them to the control group for the purpose of analysis would tend to underestimate the risk. In addition, for studies using vaginal cultures for diagnosing BV, we extracted data only for G vaginalis culture, which might lead to overdiagnosis, since the presence of G vaginalis can be a normal finding. This nondifferential error, as well as the potential imprecision of clinical estimates of gestational age, would tend to bias the summary estimate toward the null. Despite these potential underestimations, BV remained a significant risk factor for prematurity.
Finally, BV remained a significant risk for preterm delivery regardless of the subanalysis groupings. Pooling data from different populations with variable baseline risk or in different settings may lend confidence to the generalizability of these estimates. Caution is warranted, however, when drawing conclusions from any specific subanalysis.
All studies included in this analysis were observational in design, which raises 2 particular concerns: causality and confounding. Because neither the Mantel-Haenszel or DerSimonian and Laird methods for pooling risk estimates can incorporate confounding, we calculated separately the adjusted odds ratio pooled from risk estimates generated by regression analyses in individual studies. This summary of adjusted odds ratios still demonstrated a statistically significant elevated risk of 1.6 for preterm delivery in women with BV. This value may be overestimated, because 4 studies did not report regression results for the variable of BV. Presumably, these values were near the null but were likely not statistically significant, or they would have been reported. A lower summary adjusted odds ratio may have resulted were inclusion of these results possible.
Although causality cannot be proven by observational studies or by meta-analytic combination of such studies, several of the criteria suggesting causality are met.57,58 The strength of the association is relatively small, ranging from 1.4 to 2.4. Although it is possible that confounders account for all this association, we think that is unlikely given that the controlled summary odds ratio remained significant. This meta-analysis did not address the dose response question directly, although some individual studies reported a stronger association with prematurity outcomes for those who had heavier colonization or higher BV scores. In all but one study this risk factor preceded the outcome, although in some cases vaginal assessment was done at the time of labor. Results are consistent, as can be seen from the summary figures: No study found a protective effect, and only one had a null value. The presence of BV makes biological sense as a contributor to preterm labor and thus to preterm premature rupture of membranes and preterm delivery. One proposed mechanism for this association is the production of phospholipase by the bacteria associated with BV. These enzymes can initiate prostaglandin synthesis, which is one step in the physiology of normal labor activation.53 Infections in pregnancy are also associated with fetuses that were small for the gestational age,59 which is another mechanism for low birth weight. Taken together, these factors lend support to a causal association for BV and prematurity.
Identifying BV in pregnancy as a modifiable risk factor for prematurity raises the obvious question of intervention. Accumulating evidence demonstrates that treating pregnant women who have BV with certain oral antibiotics can decrease the risk of prematurity. Clindamycin taken orally by pregnant women with BV decreased preterm deliveries and low birth weight infants by approximately 50%.38,55 Hauth42 combined oral erythromycin and metronidazole and found a decreased rate in preterm births among a group of high-risk women with BV. Neither oral amoxicillin31 or intravaginal clindamycin33 have been shown to affect pregnancy outcomes.
Limitations
As with any meta-analysis, one major limitation of this work is the appropriateness of combining results from different studies. Statistical homogeneity was met in 1 of the 4 analyses for summary odds ratios (pooling all studies possible), but in 3 of the 4 analyses when only cohort studies were pooled. This discrepancy suggests that study design was likely a key source of heterogeneity in this review. In addition to study design differences, we expected heterogeneity given the range of risks reported in individual studies, the varying population risks, the disparate methods, the timing of BV diagnosis, and the different definitions for the measured outcomes. One method for addressing heterogeneity is to use the random effects model, which accounts for variability between studies when estimating the precision of the risk. When we analyzed the data using this method, none of our conclusions changed.
A second limitation of this project is the possibility of publication bias. Our funnel plot reflects the absence of studies finding that BV protects pregnant women from delivering preterm infants. By chance alone, some studies may find this result, but it is unlikely that such a study would be published. Using Orwin’s method60 to calculate a fail-safe N of 60 and our weighted summary effect size of 0.052 (number needed to harm [NNH] = 19), more than 75 studies showing no effect would be needed to drop the risk difference to 0.01 (NNH = 100). Given our systematic and complete search, we think it unlikely that publication bias accounts for our findings, despite the asymmetry of the funnel plot.
Implications for Future Research
The association of BV with prematurity remains at the disease-oriented level of evidence. Although neonatal and infant morbidity and mortality are increased with preterm delivery, the clinical impact of BV or its treatment on these patient-oriented outcomes remains unclear. Additionally, since approximately 50% of the pregnant women with BV are asymptomatic, some advocate universal screening for BV during pregnancy.61 A large randomized controlled trial evaluating patient-oriented health benefits as well as costs is warranted before this becomes a part of routine prenatal care.
Recommendations for clinical practice
BV in pregnancy is associated with a significant risk of preterm delivery. Evidence suggests that oral treatment with certain antibiotics can decrease this risk, especially in those with a previous preterm birth.62 Thus, if identified during pregnancy, BV should be treated. There is insufficient data to recommend screening for BV during pregnancy.
Acknowledgments
This project was done as part of Dr Flynn’s requirements for her master’s degree. She thanks the members of her thesis committee for their invaluable feedback. The authors also thank Shirley Killian for her assistance with article retrieval, Tangelia Pruitt for her assistance with bibliographic management, and Bill Grant for his statistical guidance.
1. Mason JO. Healthy people 2000: national health promotion and disease prevention objectives. DHHS publication no. (PHS) 91-50212. Washington, DC: Department of Health and Human Services; 1990;375-6.
2. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985;312:82-9.
3. Lewit EM, Baker LS, Corman H, Shiono PH. The direct cost of low birth weight. Future Child 1995;5:35-56.
4. Reynolds HD. Bacterial vaginosis and its implication in preterm labor and premature rupture of membranes: a review of the literature. J Nurse Midwifery 1991;36:289-96.
5. Goldberg RL, Andrews WW. Intrauterine infection and why preterm prevention programs have failed. Am J Pub Health 1996;86:781-3.
6. Lamont RF, Fisk NM. The role of infection in the pathogenesis of preterm labor. In: Studd JWW, ed. Progress in obstetrics and gynaecology. London, England: Churchill Livingston; 1993;135-58.
7. Fiscella K. Racial disparities in preterm births: the role of urogenital infections. Pub Health Rep 1996;111:104-13.
8. Oleen-Burkey MK, Hillier SL. Pregnancy complications associated with bacterial vaginosis and their estimated costs. Inf Dis Obstet Gynecol 1995;3:149-57.
9. Minkoff H, Grunebaum AN, Schwarz RH, et al. Risk factors for prematurity and premature rupture of membranes: a prospective study of the vaginal flora in pregnancy. Am J Obstet Gynecol 1984;150:965-72.
10. Elliott B, Brunham RC, Laga M, et al. Maternal gonococcal infection as a preventable risk factor for low birth weight. J Infect Dis 1990;161:531-6.
11. Kurki T, Sivonen A, Renkonen O, Savia E. Bacterial vaginosis in early pregnancy and pregnancy outcome. Obstet Gynecol 1992;80:173-7.
12. Levine M, Walter S, Lee H, Haines T, Holbrook A, Moyer V. Users’ guides to the medical literature: how to use an article about harm. JAMA 1994;271:1615-9.
13. DuRant RH. Checklist for the evaluation of research articles. J Adoles Health 1994;15:4-8.
14. Hayden GF, Kramer MS, Horwitz RI. The case control study: a practical review for the clinician. JAMA 1982;247:326-31.
15. Petitti DB. Meta-analysis, decision analysis and cost-effectiveness analysis: methods for quantitative synthesis in medicine. New York, NY: Oxford University Press; 1994.
16. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Nat Cancer Inst 1959;22:719-48.
17. DerSimonian R, Laird N. Meta-analysis in clinical trials. Contr Clin Trials 1986;7:177-88.
18. Update Software, Inc. Review Manager 3.0. Oxford, England; 1996.
19. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev 1987;9:1-30.
20. Prentice RL, Thomas DB. On the epidemiology of oral contraceptives and disease. Adv Cancer Res 1986;49:285-401.
21. Kass EH, McCormack WM, Lin JS, Rosner B, Munoz A. Genital mycoplasmas as a cause of excess premature delivery. Trans Assoc Am Phys 1981;94:261-6.
22. Lamont RF, Taylor-Robinson D, Newman M, Wigglesworth J. Spontaneous early preterm labour associated with abnormal genital bacterial colonization. Br J Obstet Gynecol 1985;43:804-10.
23. Gravett MG, Hummel D, Eschenbach DA, Holmes KK. Preterm labor associated with subclinical amniotic fluid infection and with bacterial vaginosis. Obstet Gynecol 1986;67:229-37.
24. Hillier SL, Krohn M, Kiviat N, Watts DH. Microbiologic causes and neonatal outcomes associated with chorioamnion infection. Am J Obstet Gynecol 1991;165:955-61.
25. Kurki T, Ylikorkala O. Coitus during pregnancy is not related to bacterial vaginosis or preterm birth. Am J Obstet Gynecol 1993;169:1130-4.
26. Carey JC, Blackwelder WC, Nugent RP, et al. Antepartum cultures for ureaplasma urealyticum are not useful in predicting pregnancy outcome. Am J Obstet Gynecol 1991;164:728-33.
27. Creatsas G, Pavlatos M, Lolis D, Aravantinos D, Kaskarelis D. Bacterial contamination of the cervix and premature rupture of membranes. Am J Obstet Gynecol 1981;139:522-5.
28. Hawkinson JA, Schulman H. Prematurity associated with cervicitis and vaginitis during pregnancy. Am J Obstet Gynecol 1966;94:898-902.
29. Hillier SL, Krohn MA, Cassen E, Easterling TR, Rabe LK. The role of bacterial vaginosis and vaginal bacteria in amniotic fluid infection in women in preterm labor with intact fetal membranes. Clin Infect Dis 1995;20 (suppl 2):S276-8.
30. Polk BF. Investigators of the John Hopkins Study of Cervicitis and Adverse Pregnancy Outcome. Association of chlamydia trachomatis and mycoplasma hominis with intrauterine growth retardation and preterm delivery. Am J Epidemiol 1989;129:1247-57.
31. Duff P, Lee M, Hillier S, Herd LM, Krohn MA, Eschenbach DA. Amoxicillin treatment of bacterial vaginosis during pregnancy. Obstet Gynecol 1991;77:431-5.
32. Eschenbach DA, Nugent RP, Rao AV, et al. A randomized placebo-controlled trial of erythromycin for the treatment of Ureaplasma urealyticum to prevent premature delivery. Am J Obstet Gynecol 1991;164:764-72.
33. Joesoef MR. Intravaginal clindamycin treatment for bacterial vaginosis: effects on preterm delivery and low birth weight. Am J Obstet Gynecol 1995;173:1527-31.
34. McCormack WM, Rosner B, Lee Y, Munoz A, Charles D, Kass EH. Effect on birth weight of erythromycin treatment of pregnant women. Obstet Gynecol 1987;69:202-7.
35. McGregor JA, French JI, Seo K. Adjunctive clindamycin therapy for preterm labor: results of a double-blind, placebo-controlled trial. Am J Obstet Gynecol 1991;165:867-75.
36. McGregor JA, French JI, Richter R, Vuchetich M, Bachus V. Cervicovaginal microflora and pregnancy outcome: results of a double-blind, placebo-controlled trial of erythromycin treatment. Am J Obstet Gynecol 1990;163:1580-91.
37. Morales W, Schorr S, Albritton J. Effect of metronidazole in patients with preterm birth in preceding pregnancy and bacterial vaginosis: a placebo-controlled, double-blinded study. Am J Obstet Gynecol 1994;171:345-9.
38. Morales WJ, Angel JL, O’Brien WF, Knuppel RA, Finazzo M. A randomized study of antibiotic therapy in idiopathic preterm labor. Obstet Gynecol 1988;72:829-33.
39. Newton E, Dinsmoor MJ, Gibbs RS, Newton E, Dinsmoor MJ, Gibbs RS. A randomized, blinded, placebo-controlled trial of antibiotics in idiopathic preterm labor. Obstet Gynecol 1989;74:562-6.
40. Eschenbach DA, Gravett MG, Chen KCS, Hoyme UB, Holmes KK. Bacterial vaginosis during pregnancy: an association with prematurity and post partum complications. Scand J Uro Nephro 1984;S86:213-22.
41. Gravett MG, Nelson P, DeRouen T, Critchlow C. Independent associations of bacterial vaginosis and chlamydia trachomatis infection with adverse pregnancy outcome. JAMA 1986;256:1899-903.
42. Hauth JC, Goldenberg RL, Andrews WW, DuBard MB. Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med 1995;333:1732-6.
43. Hay PE, Lamont RF, Taylor-Robinson D, Morgan DJ. Abnormal bacterial colonization of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 1994;308:295-8.
44. Hillier SL, Nugent RP, Eschenbach DA, Krohn MA. Association between bacterial vaginosis and preterm delivery of a low birth weight infant. N Engl J Med 1995;333:1737-42.
45. Hillier SL, Martius J, Krohn M, Kiviat N. A case control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988;319:972-8.
46. Holst E, Goffeng AR, Andersch B. Bacterial vaginosis and vaginal microorganisms in idiopathic premature labor and association with pregnancy outcome. J Clin Microbiol 1994;32:176-86.
47. Krohn MA, Hillier SL, Lee ML, Rabe LK, Eschenbach DA. Vaginal bacteriodes species are associated with an increased rate of preterm delivery among women in preterm labor. J Infect Dis 1991;164:88-93.
48. Martius J, Krohn MA, Hillier SL, Stamm WE. Relationships of vaginal lactobacillus species, cervical chlamydia trachomatis, and bacterial vaginosis to preterm birth. Obstet Gynecol 1988;71:89-95.
49. McDonald HM, O’Loughlin JA, Jolley P, Vigneswaran R, McDonald PJ. Changes in vaginal flora during pregnancy and associaton with preterm birth. J Infect Dis 1994;170:724-8.
50. McDonald HM, O’Loughlin JA, Jolley P, Vigneswaran R. Vaginal infection and preterm labour. Br J Obstet Gynecol 1991;98:427-35.
51. McGregor JA, French JI, Jones W, et al. Bacterial vaginosis is associated with prematurity and vaginal fluid mucinase and sialidase: results of a controlled trial of topical clindamycin cream. Am J Obstet Gynecol 1994;170:1048-60.
52. Meis PJ, Goldenberg RL, Mercer B, et al. The preterm prediction study: significance of vaginal infections. Am J Obstet Gynecol 1995;173:1231-5.
53. Riduan JM, Hillier SL, Utomo B, Wiknjosastro G, Linnan M, Kandun N. Bacterial vaginosis and prematurity in Indonesia: association in early and late pregnancy. Am J Obstet Gynecol 1993;169:175-8.
54. McDonald HM, O’Loughlin JA, Jolley P, Vigneswaran R. Prenatal microbiological risk factors associated with preterm birth. Br J Obstet Gynecol 1992;99:190-6.
55. McGregor J, French J, Richter R, et al. Antenatal microbiologic and maternal risk factors associated with prematurity. Am J Obstet Gynecol 1990;163:1465-73.
56. McGregor JA, French JI, Parker R, et al. Prevention of premature birth by screening and treatment for common genital tract infections: results of a prospective controlled evaluation. Am J Obstet Gynecol 1995;173:157-67.
57. Beaglehole R, Bonita R, Kjellstrom T. Causation in epidemiology. In: Basic epidemiology. Geneva, Switzerland: World Health Organization; 1993;71-81.
58. Greenberg RS. Interpretation of epidemiologic literature. In: Medical epidemiology. Norwalk, Conn: Appleton & Lange; 1996;167-78.
59. Germain M, Krohn MA, Hillier SL, Eschenbach DA. Genital flora in pregnancy and its association with intrauterine growth retardation. J Clin Microbiol 1994;32:2162-8.
60. Einarson TR, McGhan WF, Bootman JL, Sabers DL. Meta-analysis: quantitative integration of independent research results. Am J Hosp Pharm 1985;42:1957-64.
61. Frieden J. Not screening for bacterial vaginosis can be costly. Fam Pract News 1997;40-1.62. Brocklehurst P, Hannah M, McDonald H. The management of bacterial vaginosis in pregnancy. In: The Cochrane library. Oxford, England: Update Software; 1998.
1. Mason JO. Healthy people 2000: national health promotion and disease prevention objectives. DHHS publication no. (PHS) 91-50212. Washington, DC: Department of Health and Human Services; 1990;375-6.
2. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985;312:82-9.
3. Lewit EM, Baker LS, Corman H, Shiono PH. The direct cost of low birth weight. Future Child 1995;5:35-56.
4. Reynolds HD. Bacterial vaginosis and its implication in preterm labor and premature rupture of membranes: a review of the literature. J Nurse Midwifery 1991;36:289-96.
5. Goldberg RL, Andrews WW. Intrauterine infection and why preterm prevention programs have failed. Am J Pub Health 1996;86:781-3.
6. Lamont RF, Fisk NM. The role of infection in the pathogenesis of preterm labor. In: Studd JWW, ed. Progress in obstetrics and gynaecology. London, England: Churchill Livingston; 1993;135-58.
7. Fiscella K. Racial disparities in preterm births: the role of urogenital infections. Pub Health Rep 1996;111:104-13.
8. Oleen-Burkey MK, Hillier SL. Pregnancy complications associated with bacterial vaginosis and their estimated costs. Inf Dis Obstet Gynecol 1995;3:149-57.
9. Minkoff H, Grunebaum AN, Schwarz RH, et al. Risk factors for prematurity and premature rupture of membranes: a prospective study of the vaginal flora in pregnancy. Am J Obstet Gynecol 1984;150:965-72.
10. Elliott B, Brunham RC, Laga M, et al. Maternal gonococcal infection as a preventable risk factor for low birth weight. J Infect Dis 1990;161:531-6.
11. Kurki T, Sivonen A, Renkonen O, Savia E. Bacterial vaginosis in early pregnancy and pregnancy outcome. Obstet Gynecol 1992;80:173-7.
12. Levine M, Walter S, Lee H, Haines T, Holbrook A, Moyer V. Users’ guides to the medical literature: how to use an article about harm. JAMA 1994;271:1615-9.
13. DuRant RH. Checklist for the evaluation of research articles. J Adoles Health 1994;15:4-8.
14. Hayden GF, Kramer MS, Horwitz RI. The case control study: a practical review for the clinician. JAMA 1982;247:326-31.
15. Petitti DB. Meta-analysis, decision analysis and cost-effectiveness analysis: methods for quantitative synthesis in medicine. New York, NY: Oxford University Press; 1994.
16. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Nat Cancer Inst 1959;22:719-48.
17. DerSimonian R, Laird N. Meta-analysis in clinical trials. Contr Clin Trials 1986;7:177-88.
18. Update Software, Inc. Review Manager 3.0. Oxford, England; 1996.
19. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev 1987;9:1-30.
20. Prentice RL, Thomas DB. On the epidemiology of oral contraceptives and disease. Adv Cancer Res 1986;49:285-401.
21. Kass EH, McCormack WM, Lin JS, Rosner B, Munoz A. Genital mycoplasmas as a cause of excess premature delivery. Trans Assoc Am Phys 1981;94:261-6.
22. Lamont RF, Taylor-Robinson D, Newman M, Wigglesworth J. Spontaneous early preterm labour associated with abnormal genital bacterial colonization. Br J Obstet Gynecol 1985;43:804-10.
23. Gravett MG, Hummel D, Eschenbach DA, Holmes KK. Preterm labor associated with subclinical amniotic fluid infection and with bacterial vaginosis. Obstet Gynecol 1986;67:229-37.
24. Hillier SL, Krohn M, Kiviat N, Watts DH. Microbiologic causes and neonatal outcomes associated with chorioamnion infection. Am J Obstet Gynecol 1991;165:955-61.
25. Kurki T, Ylikorkala O. Coitus during pregnancy is not related to bacterial vaginosis or preterm birth. Am J Obstet Gynecol 1993;169:1130-4.
26. Carey JC, Blackwelder WC, Nugent RP, et al. Antepartum cultures for ureaplasma urealyticum are not useful in predicting pregnancy outcome. Am J Obstet Gynecol 1991;164:728-33.
27. Creatsas G, Pavlatos M, Lolis D, Aravantinos D, Kaskarelis D. Bacterial contamination of the cervix and premature rupture of membranes. Am J Obstet Gynecol 1981;139:522-5.
28. Hawkinson JA, Schulman H. Prematurity associated with cervicitis and vaginitis during pregnancy. Am J Obstet Gynecol 1966;94:898-902.
29. Hillier SL, Krohn MA, Cassen E, Easterling TR, Rabe LK. The role of bacterial vaginosis and vaginal bacteria in amniotic fluid infection in women in preterm labor with intact fetal membranes. Clin Infect Dis 1995;20 (suppl 2):S276-8.
30. Polk BF. Investigators of the John Hopkins Study of Cervicitis and Adverse Pregnancy Outcome. Association of chlamydia trachomatis and mycoplasma hominis with intrauterine growth retardation and preterm delivery. Am J Epidemiol 1989;129:1247-57.
31. Duff P, Lee M, Hillier S, Herd LM, Krohn MA, Eschenbach DA. Amoxicillin treatment of bacterial vaginosis during pregnancy. Obstet Gynecol 1991;77:431-5.
32. Eschenbach DA, Nugent RP, Rao AV, et al. A randomized placebo-controlled trial of erythromycin for the treatment of Ureaplasma urealyticum to prevent premature delivery. Am J Obstet Gynecol 1991;164:764-72.
33. Joesoef MR. Intravaginal clindamycin treatment for bacterial vaginosis: effects on preterm delivery and low birth weight. Am J Obstet Gynecol 1995;173:1527-31.
34. McCormack WM, Rosner B, Lee Y, Munoz A, Charles D, Kass EH. Effect on birth weight of erythromycin treatment of pregnant women. Obstet Gynecol 1987;69:202-7.
35. McGregor JA, French JI, Seo K. Adjunctive clindamycin therapy for preterm labor: results of a double-blind, placebo-controlled trial. Am J Obstet Gynecol 1991;165:867-75.
36. McGregor JA, French JI, Richter R, Vuchetich M, Bachus V. Cervicovaginal microflora and pregnancy outcome: results of a double-blind, placebo-controlled trial of erythromycin treatment. Am J Obstet Gynecol 1990;163:1580-91.
37. Morales W, Schorr S, Albritton J. Effect of metronidazole in patients with preterm birth in preceding pregnancy and bacterial vaginosis: a placebo-controlled, double-blinded study. Am J Obstet Gynecol 1994;171:345-9.
38. Morales WJ, Angel JL, O’Brien WF, Knuppel RA, Finazzo M. A randomized study of antibiotic therapy in idiopathic preterm labor. Obstet Gynecol 1988;72:829-33.
39. Newton E, Dinsmoor MJ, Gibbs RS, Newton E, Dinsmoor MJ, Gibbs RS. A randomized, blinded, placebo-controlled trial of antibiotics in idiopathic preterm labor. Obstet Gynecol 1989;74:562-6.
40. Eschenbach DA, Gravett MG, Chen KCS, Hoyme UB, Holmes KK. Bacterial vaginosis during pregnancy: an association with prematurity and post partum complications. Scand J Uro Nephro 1984;S86:213-22.
41. Gravett MG, Nelson P, DeRouen T, Critchlow C. Independent associations of bacterial vaginosis and chlamydia trachomatis infection with adverse pregnancy outcome. JAMA 1986;256:1899-903.
42. Hauth JC, Goldenberg RL, Andrews WW, DuBard MB. Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med 1995;333:1732-6.
43. Hay PE, Lamont RF, Taylor-Robinson D, Morgan DJ. Abnormal bacterial colonization of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 1994;308:295-8.
44. Hillier SL, Nugent RP, Eschenbach DA, Krohn MA. Association between bacterial vaginosis and preterm delivery of a low birth weight infant. N Engl J Med 1995;333:1737-42.
45. Hillier SL, Martius J, Krohn M, Kiviat N. A case control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988;319:972-8.
46. Holst E, Goffeng AR, Andersch B. Bacterial vaginosis and vaginal microorganisms in idiopathic premature labor and association with pregnancy outcome. J Clin Microbiol 1994;32:176-86.
47. Krohn MA, Hillier SL, Lee ML, Rabe LK, Eschenbach DA. Vaginal bacteriodes species are associated with an increased rate of preterm delivery among women in preterm labor. J Infect Dis 1991;164:88-93.
48. Martius J, Krohn MA, Hillier SL, Stamm WE. Relationships of vaginal lactobacillus species, cervical chlamydia trachomatis, and bacterial vaginosis to preterm birth. Obstet Gynecol 1988;71:89-95.
49. McDonald HM, O’Loughlin JA, Jolley P, Vigneswaran R, McDonald PJ. Changes in vaginal flora during pregnancy and associaton with preterm birth. J Infect Dis 1994;170:724-8.
50. McDonald HM, O’Loughlin JA, Jolley P, Vigneswaran R. Vaginal infection and preterm labour. Br J Obstet Gynecol 1991;98:427-35.
51. McGregor JA, French JI, Jones W, et al. Bacterial vaginosis is associated with prematurity and vaginal fluid mucinase and sialidase: results of a controlled trial of topical clindamycin cream. Am J Obstet Gynecol 1994;170:1048-60.
52. Meis PJ, Goldenberg RL, Mercer B, et al. The preterm prediction study: significance of vaginal infections. Am J Obstet Gynecol 1995;173:1231-5.
53. Riduan JM, Hillier SL, Utomo B, Wiknjosastro G, Linnan M, Kandun N. Bacterial vaginosis and prematurity in Indonesia: association in early and late pregnancy. Am J Obstet Gynecol 1993;169:175-8.
54. McDonald HM, O’Loughlin JA, Jolley P, Vigneswaran R. Prenatal microbiological risk factors associated with preterm birth. Br J Obstet Gynecol 1992;99:190-6.
55. McGregor J, French J, Richter R, et al. Antenatal microbiologic and maternal risk factors associated with prematurity. Am J Obstet Gynecol 1990;163:1465-73.
56. McGregor JA, French JI, Parker R, et al. Prevention of premature birth by screening and treatment for common genital tract infections: results of a prospective controlled evaluation. Am J Obstet Gynecol 1995;173:157-67.
57. Beaglehole R, Bonita R, Kjellstrom T. Causation in epidemiology. In: Basic epidemiology. Geneva, Switzerland: World Health Organization; 1993;71-81.
58. Greenberg RS. Interpretation of epidemiologic literature. In: Medical epidemiology. Norwalk, Conn: Appleton & Lange; 1996;167-78.
59. Germain M, Krohn MA, Hillier SL, Eschenbach DA. Genital flora in pregnancy and its association with intrauterine growth retardation. J Clin Microbiol 1994;32:2162-8.
60. Einarson TR, McGhan WF, Bootman JL, Sabers DL. Meta-analysis: quantitative integration of independent research results. Am J Hosp Pharm 1985;42:1957-64.
61. Frieden J. Not screening for bacterial vaginosis can be costly. Fam Pract News 1997;40-1.62. Brocklehurst P, Hannah M, McDonald H. The management of bacterial vaginosis in pregnancy. In: The Cochrane library. Oxford, England: Update Software; 1998.