Objective
We assessed the effectiveness of vaginal probiotic capsules for recurrent bacterial vaginosis (BV) prevention.
Study Design
One hundred twenty healthy Chinese women with a history of recurrent BV were assigned randomly to daily vaginal prophylaxis with 1 capsule (Probaclac Vaginal; Nicar Laboratories, Inc, Blainville, Quebec, Canada) that contained 8 billion colony-forming units of Lactobacillus rhamnosus , L acidophilus , and Streptococcus thermophilus (n = 58 women) or 1 placebo capsule (n = 62 women) for 7 days on, 7 days off, and 7 days on.
Results
Probiotic prophylaxis resulted in lower recurrence rates for BV (15.8% [9/57 women] vs 45.0% [27/60 women]; P < .001) and Gardnerella vaginalis incidence through 2 months (3.5% [2/57 women] vs 18.3% [11/60 women]; P = .02). Between the 2- and 11-month follow-up period, women who received probiotics reported a lower incidence of BV and G vaginalis . Aside from vaginal discharge and malodor, no adverse events were reported in either study group.
Conclusion
Short-term probiotic prophylaxis is well tolerated and reduces BV recurrence and G vaginalis risk through 11 months after treatment.
Bacterial vaginosis (BV) is the most common vaginal infection in women of childbearing age, with a prevalence of 19-42%. This infection occurs when the normal Lactobacillus bacteria in the vagina are disrupted and subsequently replaced by predominantly anaerobic bacteria such as Gardnerella vaginalis and, to a lesser extent, Mycoplasma hominis , Prevotella , and Peptostreptococcus. Although most infected women are aymptomatic, BV increases the risk for pelvic inflammatory disease, mid-trimester miscarriage, preterm delivery, and other gynecologic complications.
The standard of care for BV treatment is oral or vaginal metronidazole or vaginal clindamycin. However, treatment success rates as low as 52% and recurrence rates of >50% within 6-12 months are common. The study of Swidsinski et al suggests that antibiotic treatment reduces vaginal bacteria metabolic activity, although a G vaginalis –rich biofilm persists, which likely contributes to BV relapse. Furthermore, a recent trial reported that all G vaginalis strains develop resistance to metronidazole in recurrent BV cases. Given the mediocre efficacy of antibiotic treatment for BV, there is a clear need to explore new BV therapies.
Lactobacilli are an alternative option for BV prevention and treatment because they produce acetic acid and hydrogen peroxide, thereby hindering pathogenic bacteria growth. Vaginal probiotic capsules are particularly appealing because of their ease of use and high satisfaction rates vs creams, gels, and oral yogurt consumption. Several trials have studied the efficacy of vaginal probiotic capsules on BV. However, no known trial has studied the prophylactic use of these capsules in women with a history of recurrent BV.
Therefore, the purpose of this study was to determine the efficacy of vaginal probiotic capsules for BV prophylaxis in healthy women with a history of recurrent BV. We hypothesized that women who are treated with vaginal probiotic capsules would have a lower incidence of BV and G vaginalis compared with treatment with placebo.
Materials and Methods
This single-center, double-blind, randomized, placebo-controlled trial was conducted at Yuyao/Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China). Enrollment occurred between December 2008 and January 2009. The research practices that were used in this trial were in accordance with the Declaration of Helsinki. The institutional review board at Yuyao/Xinhua Hospital approved this protocol (study no. 08-SC-NIC-01), and all subjects provided informed consent before any research activities were initiated.
Inclusion criteria for study participation were healthy women who were 18-55 years old, were currently free from BV, had had ≥2 BV episodes in the previous year, had had no antibiotic treatment within 1 week of study participation, and who were willing to refrain from other intravaginal products (eg, douche or spermicide). Exclusion criteria included the presence of other causes of vulvovaginitis (eg, candidiasis or Chlamydia trachomatis ), pregnant or lactating, history of daily fermented milk and/or yogurt consumption, allergy to study product ingredients, immunosuppressed state, systemic or intravaginal antibiotic or antifungal therapy within 7 days of study participation, intraepithelial neoplasia or cervical carcinoma that required treatment, and urogenital infection within 21 days of participation.
Subjects who met all study entry criteria and who provided informed consent were assigned randomly to BV prophylaxis (test group) with a proprietary vaginal probiotic capsule (Probaclac Vaginal; Nicar Laboratories, Inc, Blainville, Quebec, Canada) or a placebo capsule (control group) for 7 days on, 7 days off, and 7 days on. The randomization sequence that was used in this trial was generated by a computerized random-number generator (SAS, release 9.2; SAS Institute Inc, Cary, NC). Study products were delivered to the investigative site in identical containers that were labeled only with the lot number and a sequentially numbered patient identification code.
Probaclac Vaginal is a pharmaceutic grade probiotic complex that is produced with 3 DNA-certified proprietary lactic acid bacteria strains. Mother cultures were kept at –80°C to prevent any mutation of probiotic characteristics. Each strain was fermented individually then filtered, lyophilized, and ground into a powder before being blended into the final probiotic complex. Each probiotic vaginal capsule contained 8 billion colony-forming units of live lactic bacteria that included L rhamnosus (6.8 billion stabilized lactic ferments), L acidophilus (0.4 billion stabilized lactic ferments), and Streptococcus thermophilus (0.8 billion stabilized lactic ferments) and lactose. Placebo capsules were of identical appearance, smell, and texture and contained only lactose. Study products were kept secured and double verification was used to ensure correct product administration to study subjects.
Baseline evaluations included a physical examination, vaginal swabs, medical history, concomitant medication use, blood pressure, height, and weight. Each subject received instruction regarding appropriate use of the vaginal capsules. The study product was dispensed in a box that contained 7 vaginal capsules and a vaginal applicator. The women used the study product for 1 week and returned 1 week later to pick up the second box that contained a 1-week supply of capsules. The women returned for follow-up visits at 30 and 60 days after treatment. Follow-up evaluations included the collection of vaginal swabs, an assessment of vaginal flora, and a report of adverse events. The women were contacted by telephone at 10.8 ± 0.2 months after treatment and were asked to confirm or deny the presence of BV symptoms, diagnosis of BV or G vaginalis , and adverse events over the 2- to 11-month follow-up period. If a subject reported a diagnosis of BV, the research staff confirmed this diagnosis with the subject’s treating physician at Yuyao/Xinhua Hospital.
The primary endpoint of this study was BV that was diagnosed at any time during the 2-month follow-up period. BV was diagnosed in the presence of positive results with the Amsel Criteria, which confirms BV in the presence of at least 3 of the following 4 criteria: (1) vaginal pH >4.5, (2) clue cells on microscopy of saline solution wet mount, (3) release of fish amine odor on addition of 10% potassium hydroxide to a drop of vaginal discharge, and (4) characteristic thin, homogenous vaginal discharge. Vaginal swabs were collected and cultured on 5% blood agar, eosin methylene blue agar, and Sabouraud dextrose agar. The plates were evaluated after 24-48 hours incubation at 37°C in microaerophilic conditions.
This study was conducted with triple-blinding procedures. The study product was packaged and labeled by the manufacturer according to the study identification number and treatment assignment. Women were blinded to the treatment that was being received throughout the trial. Investigators and all involved clinicians were blinded to the treatment allocation throughout the course of the study. The blind was broken to investigators, but not patients, in cases of a positive BV diagnosis. Test subjects who experienced BV during the supplementation period continued using the study product. If the infection persisted for >1 week, treatment was supplemented with antibiotics at the physician’s discretion. Control subjects who had BV discontinued the placebo treatment and began a course of antibiotics at the physician’s discretion.
Data analysis
All data were recorded on case report forms, double-entered into a database, verified, and monitored independently for accuracy by Sprim China Ltd. (Shanghai, China). Clinical monitors and biostatisticians were blinded to treatment allocation throughout the entire clinical study and until after all analyses were completed.
Patient randomization was stratified by age (18-30, 31-40, 41-55 years) to minimize confounding age effects between groups. Sample size for this trial was estimated by assuming a 35% BV incidence in the control group, an anticipated 30% BV risk reduction in the test group, 90% statistical power, alpha level of .05, and a 17% attrition rate. Overall, 120 women (60 per group) were planned for enrollment.
Statistical analyses were performed with SAS/STAT software (release 9.2; SAS Institute Inc, Cary, NC). Baseline variables were analyzed with independent t tests to assess between-group differences. χ 2 and the Fisher’s exact test were used to compare BV and G vaginalis incidence between test and control groups. Odds ratios were calculated by logistic regression. Data are reported as mean ± SD or n (%). Statistical significance was set at a probability value of ≤ .05.
Results
Subject retention through the 2-month follow-up visit was 91% (53/58 women) in the test group and 90% (56/62 women) for the control group. All withdrawals were due to personal reasons and unrelated to the study. At the 11-month telephone follow-up interview, 81% of the test group (47/58 women) and 76% of the control group (47/62 women) were contacted ( Figure 1 ). No between-group differences in baseline characteristics were detected ( Table 1 ). All subjects reported either none or 1 sexual partner within the previous year. Most of the women (85%) were nonsmokers; 15% of them reported smoking 1-15 cigarettes each day.
