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.