Bacterial vaginosis in pregnancy.

Bacterial vaginosis is a clinical condition caused by replacement of the normal hydrogen peroxide producing Lactobacillus sp. in the vagina with high concentrations of characteristic sets of aerobic and anaerobic bacteria. Bacterial vaginosis is the most prevalent cause of vaginal discharge or malodor, although 50 percent of women who meet the criteria for this condition are asymptomatic. Bacterial vaginosis is reported in 10 to 41 percent of women, and new evidence has shown association with maternal and fetal morbidity. Studies have shown that spontaneous abortion, preterm labor, premature birth, preterm premature rupture of the membranes, amniotic fluid infection, postpartum endometritis, and postcesarean wound infections are increased because of infection with bacterial vaginosis during pregnancy. Clinical trials demonstrated important reductions in many of these adverse events with appropriate screening and antimicrobial treatment protocols. New low-cost, diagnostic, point-of-care screening tools are available for rapid screening of patients, affording the physician the opportunity to potentially make a dramatic clinical and cost impact in preventing preterm birth and the costly sequelae of prematurity. Practicing physicians need to be aware of current guidelines for screening and treating pregnant patients for bacterial vaginosis. The authors recommend that all pregnant women be screened and treated with the Centers for Disease Control and Prevention (CDC-P) recommended oral regimens early in pregnancy. Each treated women should be evaluated for "test of cure" 1 month after treatment. Mothers likely to benefit from "screen and treat" approaches include 1) those with the highest concentrations of genital anaerobes and mycoplasmas, 2) women with prior preterm birth or who have low body mass (BMI < 19.8 kg/m2), 3) those with evidence of endometritis before pregnancy, and 4) those who are treated with oral agents effective for both presumed intrauterine mycoplasmas and other bacterial vaginosis flora (i.e., oral clindamycin or erythromycin and metronidazole).

Gestational bleeding, bacterial vaginosis, and common reproductive tract infections: risk for preterm birth and benefit of treatment.

OBJECTIVE: To examine associations between bacterial vaginosis and other prevalent lower genital tract infections and clinically recognized first-trimester bleeding; possible independent and joint effects of gestational bleeding and bacterial vaginosis or other prevalent infections on preterm birth and premature rupture of membranes; and effects of antimicrobial treatment on reducing risks of preterm birth among these women. METHODS: A secondary analysis was conducted of 1100 pregnant women enrolled in a prospective observational study that examined the effects of standardized diagnosis and treatment of lower genital tract infections to prevent preterm birth. RESULTS: Sixty percent of women with first-trimester bleeding had one or more study infections detected at the initial examination. First-trimester bleeding was associated independently with the presence of bacterial vaginosis (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.0, 2.3), Trichomonas vaginalis (OR 2.3, 95% CI 1.3, 4.2), and Chlamydia trachomatis (OR 2.7, 95% CI 1.4, 5.1). Preterm birth was increased among women with first-trimester bleeding and bacterial vaginosis (relative risk [RR] 4.4, 95% CI 2.0, 9.5) and bacterial vaginosis and T vaginalis (RR 3.0, 95% CI 1.0, 8.8). Systemic antimicrobial treatment reduced the rate of preterm birth among women with bacterial vaginosis without first-trimester bleeding (RR 0.37, 95% CI 0.16, 0.88). Treatment of women with both first-trimester bleeding and bacterial vaginosis reduced preterm birth (RR 0.52, 95% CI 0.18, 1.55), but not significantly. CONCLUSION: First-trimester bleeding was increased among women with bacterial vaginosis, T vaginalis, C trachomatis, and combinations of these infections. Women with bacterial vaginosis who also experienced first-trimester bleeding were at heightened risk for preterm birth. Treatment of studied infections reduced significantly the risks of preterm birth among women without first-trimester bleeding.

Pathogenesis to treatment: preventing preterm birth mediated by infection.

Prevention of preterm birth and subsequent newborn immaturity is a primary goal of obstetrical care worldwide. Accumulated evidence shows that 1) as many as 25-50% of preterm births are caused by common genital tract infections and subsequent maternal/fetal inflammatory responses; 2) microbial and maternal host factors (phospholipases, proteases, etc.) play roles in preterm labor and preterm premature rupture of membranes (pPROM); 3) integrated aspects of maternal and fetal host responses (inflammation, altered immune adaptations, endocrine and paracrine mechanisms) play increasingly understood roles in premature activation of parturition; and 4) identification and systemic treatment of common genitourinary infections, most importantly bacterial vaginosis (BV), reduce the risks of preterm delivery and PROM.

Infection and prematurity: evidence-based approaches.

The real cost savings arising from effectively preventing or treating preterm birth ascribable to prevalent reproductive tract infections are demonstrated in the lives of children saved from premature death and personal, biologic and economic impairment. Three meta-analyses demonstrate neonatal and maternal benefits from adjunctive antibiotic treatment of mothers suffering preterm premature rupture of membranes. The effects of adjunctive antibiotic treatment of women with preterm labor are inconsistent, but single-agent regimens using erythromycin and clindamycin are effective and provide coverage for group B streptococcus. Providers and payers now have evidence-based, clinically proven and cost-saving opportunities to prevent important numbers of preterm births, as well as preventing individual children suffering from being 'born too soon'.

The pathobiology of premature rupture of membranes.

Premature rupture of membranes arises from what are likely multifaceted and multistep pathogenic pathways. Pathophysiological processes may involve both endogenous and exogenous fetal and maternal factors. This article reviews and analyzes information regarding, first, the form and function of fetal membranes; second, how membranes physically fail (rupture) at term and preterm gestations; and third, evaluates if we can reduce risks of rupture using physiological understanding and evidence-based clinical studies.

Prevention of premature birth by screening and treatment for common genital tract infections: results of a prospective controlled evaluation.

OBJECTIVE: Our purpose was to analyze (1) the effects of prevalent lower reproductive tract infections and (2) the effect of systematic diagnosis and treatment to reduce risks of early pregnancy loss (< 22 weeks), preterm premature rupture of membrances, and overall preterm birth. STUDY DESIGN: A prospective, controlled treatment trial was conducted on 1260 women. During the first 7 months of the program (observation, phase I), women were examined at initiation of prenatal care for a panel of lower genital tract microorganisms and bacterial vaginosis. Women were followed up with reexaminations at 22 to 29 weeks and after 32 weeks' gestation. The recommended treatments of the Centers for Disease Control (i.e., 300 mg of clindamycin orally twice daily for 7 days for bacterial vaginosis) were used for infected women during the second 8 months of the study (treatment, phase II). Data were analyzed according to intent to treat by means of univariate and multivariate methods. RESULTS: Overall, presence of bacterial vaginosis (32.5%) at enrollment was associated with pregnancy loss at < 22 weeks' gestation (relative risk 3.1, 95% confidence interval 1.4 to 6.9). Among women in the observation phase bacterial vaginosis was associated with increased risk of both preterm birth (relative risk 1.9, 95% confidence interval 1.2 to 3.0) and preterm premature rupture of membranes (relative risk 3.5, 95% confidence interval 1.4 to 8.9). Within this population (phase I) 21.9% of preterm birth overall (43.8% premature rupture of membranes) is estimated as attributable to bacterial vaginosis. Among women with bacterial vaginosis phase II (treatment) was associated with reduced preterm birth (relative risk 0.5, 95% confidence interval 0.3 to 0.9); there was a similar reduction for women with preterm premature rupture of membranes (relative risk 0.5, 95% confidence interval 0.2 to 1.4). Women with both bacterial vaginosis and trichomoniasis were at highest risk of preterm birth (28%); treatment of both conditions (phase II) reduced preterm birth (17%) but did not eliminate this risk. Earlier patient enrollment and oral antibiotic treatment were associated with reduced preterm birth. CONCLUSIONS: This prospective, controlled trial confirms that the presence of bacterial vaginosis is associated with increased risks of pregnancy loss at < 22 weeks, preterm premature rupture of membranes, and preterm birth. Orally administered clindamycin treatment is associated with a 50% reduction of bacterial vaginosis-linked preterm birth and preterm premature rupture of membranes. Women at risk for preterm birth or preterm premature rupture of membranes because of bacterial vaginosis or common genital tract infections should be screened, treated, reevaluated for cure, and re-treated if necessary.

Trichomonas vaginalis Weakens human Amniochorion in an in vitro model of premature membrane rupture.

OBJECTIVE: Trichomonas vaginalis (TV) infection is associated with preterm rupture of membranes (PROM) and preterm birth. We evaluated the effects of TV growth and metabolism on preparations of human amniochorion to understand and characterize how TV may impair fetal-membrane integrity and predispose to PROM and preterm birth. METHODS: Term fetal membranes were evaluated using an established in vitro fetal-membrane model. Fresh TV clinical isolates were obtained from pregnant women. The protozoa (5.0x10(5) to 1.5x10(6)/ml) were incubated with fetal membranes in modified Diamond's medium for 20 h at 37 degrees C in 5% CO2.The effects of fetal-membrane strength (bursting tension, work to rupture, and elasticity) were measured using a calibrated Wheatstone-bridge dynamometer. Tests were also performed to evaluate the effects of 1) inoculum size; 2) metronidazole (50 microg/ml); and 3) cell-free filtrate. RESULTS: The TV-induced membrane effects were 1) isolate variable; 2) inoculum dependent; 3) incompletely protected by metronidazole; and 4) mediated by both live organisms as well as protozoan-free culture filtrates. Six of 9 isolates significantly reduced the calculated work to rupture (P < or = 0.02); 7 of 9 reduced bursting tension; and 1 of 9 reduced elasticity. One isolate significantly increased the work to rupture and bursting tension (P < or = 0.002). CONCLUSIONS: In vitro incubation of fetal membranes with TV can significantly impair the measures of fetal-membrane strength. This model may be used to delineate the mechanisms of TV-induced membrane damage. This study suggests that there are enzyme-specific effects as well as pH effects.

Bacterial vaginosis is associated with prematurity and vaginal fluid mucinase and sialidase: results of a controlled trial of topical clindamycin cream.

OBJECTIVE: The pathogenesis of preterm birth and other adverse pregnancy outcomes linked with reproductive tract infection remains poorly understood. Mucolytic enzymes, including mucinases and sialidases (neuraminidase), are recognized virulence factors among enteropathogens and bacteria that cause periodontal infection. Perturbation of maternal cervicovaginal mucosa membrane host defenses by such enzyme-producing microorganisms may increase the risk of subclinical intrauterine infection during pregnancy and thus increase risks of preterm birth. STUDY DESIGN: We prospectively evaluated vaginal fluid mucinase and sialidase and selected cervicovaginal bacteria along with pregnancy outcomes in 271 women. Within this study, women with bacterial vaginosis (16 to 27 week' gestation) were treated with 2% clinadmycin vaginal cream or placebo. Enzyme, microbial findings, treatment effects, and pregnancy outcomes were compared among drug- and placebo-treated women and control women without bacterial vaginosis. RESULTS: Presence of bacterial vaginosis at intake was associated with increased risk of preterm birth (relative risk 3.3, 95% confidence interval 1.2 to 9.1, p = 0.02), premature rupture of membranes (relative risk 3.8, 95% confidence interval 1.6 to 9.0, p = 0.002), and preterm premature rupture of membranes. Mucinase and sialidase activities were more commonly identified, and they occurred in higher concentrations, if present, in women with bacterial vaginosis (mucinase: 44.3% with bacterial vaginosis vs 27.4% without, p = 0.007; sialidase: 45% with bacterial vaginosis vs 12% without p < 0.001). Sialidase activity was associated with bacterial vaginosis-linked organisms (Gardnerella vaginalis, Mobiluncus spp, and Mycoplasma hominis) and Chlamydia trachomatis and yeast species; mucinase activity was associated only with bacterial vaginosis-linked microorganisms. Clindamycin, 2% cream, was effective treatment for bacterial vaginosis and temporarily reduced mucinase and sialidase activities. Topical treatment of bacterial vaginosis did not reduce risks of perinatal morbidity. Women with persistent or recurrent sialidase 8 weeks after treatment were at increased risk of preterm birth (15.6% vs 7.4%) premature rupture of membranes (30% vs 15%), and low birth weight (20% vs 3%, relative risk 6.8, 95% confidence interval 1.6 to 28.1). CONCLUSIONS: Persistence of sialidase-producing vaginal microorganisms in numbers sufficient to increase vaginal fluid sialidase activity may be a risk factor for possibly preventable subclinical intrauterine infection and preterm birth. This study confirms and further informs our understanding of the association of bacterial vaginosis and preterm birth; studies to evaluate whether systemic treatment for bacterial vaginosis can effectively reduce vaginal mucolytic enzymes and risks of prematurity and other morbid outcomes are continuing.

Premature rupture of membranes and bacterial vaginosis.

OBJECTIVE: Critically review obstetric, epidemiologic, microbiologic, and pathophysiologic information regarding the possible casual associations of bacterial vaginosis with premature rupture of membranes. METHODS: Observational and experimental studies are reviewed and correlated with in vitro and clinical, microbiologic, and pathophysiologic experiments in an effort to define possibly casual relationships with bacterial vaginosis and premature rupture of membranes and its maternal and perinatal sequelae. RESULTS: Considerable information shows that bacterial vaginosis, a common vaginal microbe-associated condition of reproductive age women, can be strongly (risk ratios up to 7.3, confidence interval 95%, 1.8 to 29.4) associated with preterm premature rupture of membranes as well as preterm labor and birth. Microorganisms of bacterial vaginosis produce factors including proteases (IgAse, collagenase, etc.) that can facilitate transport of bacteria to fetal membranes and impair fetal membrane integrity in experimental models. CONCLUSIONS: Controlled investigations are required to evaluate if treatment of bacterial vaginosis is associated with reduction of premature rupture of membranes and preterm birth.

Association of cervicovaginal infections with increased vaginal fluid phospholipase A2 activity.

OBJECTIVE: The purpose of this study was to determine if phospholipase A2 was detectable within vaginal fluid and to correlate its presence with the presence of common lower genital tract infection or microbial conditions. STUDY DESIGN: Pregnant women were examined at the first prenatal visit with standard clinical evaluations and microbiologic cultures or tests. Vaginal fluid samples were evaluated for phospholipase A2 activity by means of a standardized enzyme fluorometric assay. Data were stratified to control for coexisting infections. RESULTS: Phospholipase A2 activity was detected among 29.8% of women and was independently associated with the presence of bacterial vaginosis (p < 0.001), Trichomonas. vaginalis (p < 0.04), and Chlamydia trachomatis (p < 0.02). The percentage of women with phospholipase A2 activity and the level of activity was increased in the presence of more than one infection. CONCLUSIONS: Elevated reproductive tract phospholipase A2 concentrations among pregnant women may play roles in the pathogenesis of preterm labor and birth. Identification of pregnant women with increased concentrations in vaginal fluid may allow for development of effective intervention strategies to reduce the risk of preterm birth.

Use of antibiotics for preterm premature rupture of membranes. Rationales and results.

PPROM is directly associated with 30% to 40% of preterm births. Reproductive tract infection, inflammation, or both may be primary causes or occur secondarily after PPROM and hasten the onset of labor. Recent carefully controlled trials demonstrate that antibiotic treatment (erythromycin, ampicillin) can significantly lengthen the "beneficial latency period" and reduce perinatal and maternal morbidity, as well as the costs.

Fetal monitoring in perinatal sepsis.

To evaluate the utility of conventional electronic fetal monitoring in detection of established perinatal sepsis, we conducted a case-controlled study of fetal monitor results in 18 patients delivering newborns with sepsis. Eleven of the 18 newborns (61%) demonstrated clinically reassuring fetal heart rate patterns, not significantly different from controls (p = 0.80). No pattern predictive of presumed perinatal sepsis could be identified. Obstetric factors traditionally associated with increased risk of perinatal infection, such as long duration of labor, use of internal fetal monitoring, and increased number of vaginal examinations were not significantly different from controls. Preterm rupture of membranes greater than 24 hours occurred in less than 50% of the cases. Clinical diagnosis of chorioamnionitis was established in only one third of the patients who delivered newborns with sepsis. In this study, use of conventional electronic fetal monitoring did not accurately identify newborns with presumed intrauterine infection.

Preterm birth is associated with increased risk of maternal and neonatal infection.

Much information suggests that maternal reproductive tract infections, both recognized and unrecognized, account for an important and possibly preventable portion of preterm births. If such infections do mediate instances of preterm labor and premature rupture of the membranes (PROM), then associated risks of subsequent maternal and neonatal infections would be increased, even after controlling for confounding variables. To evaluate possible associations between preterm birth and maternal and neonatal infections, we conducted a retrospective study of 9642 births at the University of Colorado Health Sciences Center between July 1980 and June 1985. Clinical chorioamnionitis occurred more frequently among women delivering before term with intact membranes at the onset of labor (5.8% preterm versus 1.7% term) and among women with PROM (26.5% preterm versus 6.7% term). Among the women delivered by cesarean, the incidence of postpartum endometritis was higher in those with preterm PROM than in those with term rupture of membranes. The incidence of neonatal infection increased significantly as the gestational age of the neonates decreased (P less than .01). The rate of culture-proven neonatal infection was significantly higher following PROM (P less than .01) than after birth without PROM. Both neonatal infection and perinatal mortality were increased in association with chorioamnionitis in both preterm and term pregnancies. These consistent observations complement and support suggestions that reproductive tract infection plays a possibly preventable role in the pathogenesis of preterm birth.

Adjunctive clindamycin therapy for preterm labor: results of a double-blind, placebo-controlled trial.

A double-blind, placebo-controlled, randomized trial was conducted to evaluate the efficacy, safety, and tolerance of a course of clindamycin (administered for 3 days intravenously and 4 days orally) among hospitalized women with preterm labor at less than or equal to 34 weeks' gestation who were treated with tocolytics. One hundred three woman-perinate pairs were analyzed. Univariate analysis demonstrated that pregnancies were continued longer in women treated with clindamycin than in women who received placebo (clindamycin-treated group, 35 days; placebo-treated group, 25 days; p = 0.02). Survival analysis showed that pregnancy continued at least 35.5 days in 50% of clindamycin-treated women versus 20 days for control women (p = 0.03). Obstetric and microbiologic parameters associated with treatment outcomes were also sought. Women with bacterial vaginosis more often delivered preterm (p = 0.03; relative risk, 1.4; 95% confidence interval, 1.04 to 2.0). Among women with bacterial vaginosis, trends for increased duration of pregnancy (clindamycin-treated group, 36 days; placebo-treated group, 19 days), increased birth weight (clindamycin-treated group, 2634 gm; placebo-treated group, 2256 gm), and increased mean gestational age at delivery (clindamycin-treated group, 35 weeks; placebo-treated group, 34 weeks) were associated with clindamycin treatment. Women with either group B streptococcus, Chlamydia trachomatis, Trichomonas vaginalis, or Staphylococcus aureus were more likely to have preterm premature rupture of membranes (p = 0.01). Clindamycin treatment of these women reduced the incidence of preterm premature rupture of membranes to that of uninfected subjects. Stratification by gestational age at enrollment showed clindamycin treatment to be associated with an increased interval to delivery only among mothers enrolled before 33 weeks' gestation (clindamycin-treated group, 40 days; placebo-treated group, 28 days; p less than 0.05). Treatment with clindamycin appeared safe and well tolerated, with benefits limited to women who were less than or equal to 32 weeks' gestation.

A new proline aminopeptidase assay for diagnosis of bacterial vaginosis.

Bacterial vaginosis is one of the most common occurring vaginal conditions among women of reproductive age. A rapid and reliable laboratory test for diagnosis of bacterial vaginosis would be helpful in the clinical detection of this disease. Elevated proline aminopeptidase activity has been identified as a reliable marker enzyme for bacterial vaginosis. A proline aminopeptidase assay has been shown to predict accurately women with a clinical diagnosis of bacterial vaginosis. However, this assay has significant practical disadvantages, the most notable of which is the production of a carcinogenic end product, alpha-naphthylamine. We have developed a modified assay for this bacterial vaginosis marker enzyme with L-proline p-nitroanilide, a substrate that does not yield a carcinogenic end-product. The new proline aminopeptidase assay is a one-step test that is analyzed colorimetrically with microsomal leucine aminopeptidase used as a standard enzyme (linear from 3 to 125 mU per well). We have determined the activity of proline aminopeptidase in vaginal wet preparations from 57 patients with both assay methods. In addition, vaginal smears were examined with Gram's stain and analyzed for bacterial vaginosis with the Spiegel method. When compared with the Spiegel method, the two proline aminopeptidase assay methods were similar with respect to assay sensitivity (93%), specificity (91% to 93%), and the predictive value of a positive result (78% to 82%) or a negative result (97% to 98%). Vaginal wash samples also were assessed for proline aminopeptidase activity. Values for samples identified as bacterial vaginosis positive were significantly different (p less than 0.0001) from those that were negative according to the Spiegel analysis of Gram's stain: negative results, 66 +/- 41 mU/ml; positive results, 704 +/- 145 mU/ml. These findings indicate that this improved proline aminopeptidase assay will offer a rapid, sensitive, and objective laboratory method for the diagnosis of bacterial vaginosis.