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Preventing Adverse Sequelae of Bacterial Vaginosis: A Public Health Program and Research Agenda

KOUMANS, EMILIA H. MD, MPH* AND; KENDRICK, JULIETTE S. MDfor the CDC Bacterial Vaginosis Working Group

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Background The cause of bacterial vaginosis remains poorly understood. Recent evidence strengthens the association between bacterial vaginosis and serious medical complications.

Goal To review the evidence linking bacterial vaginosis with adverse pregnancy outcomes, complications after gynecologic procedures, and HIV infection, and to identify prevention strategies.

Methods In March 1999, the Centers for Disease Control and Prevention organized a conference to accomplish this goal.

Results Better understanding is needed concerning the etiology, epidemiology, and natural history of bacterial vaginosis. More efficacious treatment of bacterial vaginosis and strategies to reduce maternal complications associated with bacterial vaginosis, such as premature rupture of the fetal membranes, chorioamnionitis, premature labor and delivery, postdelivery endometritis, and postpartum infant complications should be developed. Recent evidence shows that screening and treatment of bacterial vaginosis before abortion reduces postabortion pelvic inflammatory disease, and that anaerobic coverage during hysterectomy reduces postoperative complications. Better understanding concerning the relation of bacterial vaginosis to acquisition of sexually transmitted diseases and HIV infection are needed as well as possible prevention strategies.

Conclusions A national prevention effort should be guided by the results of research that addresses current knowledge gaps.

From the *Division of STD Prevention, National Center for HIV, STD, and TB Prevention, the †Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia

Correspondence and reprint requests: Emilia H. Koumans, MD, MPH, 1600 Clifton Road, Mailstop E-02, Atlanta, GA 30333. E-mail: exk0@cdc.gov

Received for publication July 6, 2000, revised October 6, 2000, and accepted October 18, 2000.

The BV working group members (listed in alphabetical order) were Carol Bruce, MPH, BSN, Epidemiologist, Pregnancy and Infant Health Branch, Division of Reproductive Health, CDC; Vijaya Hogan, DrPH, MPH, Epidemiologist, Pregnancy and Infant Health Branch, Division of Reproductive Health, CDC; Riduan Joesoef, MD, PhD, Medical Epidemiologist, International Activities, Division of STD, CDC; Juliette S. Kendrick, MD, Medical Epidemiologist, Pregnancy and Infant Health Branch, Division of Reproductive Health, CDC; Emilia H. Koumans, MD, MPH, Medical Epidemiologist, Epidemiology and Surveillance Branch, Division of STD, CDC, and Clinical Assistant Professor of Pediatrics, Emory University, Atlanta, Georgia; Lauri Markowitz, MD, Medical Epidemiologist, Chief, Epidemiology Research Section, Epidemiology and Surveillance Branch, Division of STD, CDC; George Schmid, MD, Medical Epidemiologist, Program Development and Support Branch, Division of STD, CDC; Johannes Schmidt, MD, EIS Officer, Division of Reproductive Health; Anne Schuchat, MD, Chief, Respiratory Diseases Branch, Division of Bacterial and Mycotic Diseases, CDC; Michael St. Louis, MD, Chief, Epidemiology and Surveillance Branch, Division of STD, CDC; Madeline Sutton, MD, MPH, EIS Officer, Epidemiology and Surveillance Branch, Division of STD, CDC, and Clinical Instructor, Department of Obstetrics and Gynecology, Morehouse School of Medicine, Atlanta, Georgia; Kimberly Workowski, MD, Chief, Clinical Guidelines Unit, Epidemiology and Surveillance Branch, Division of STD, CDC, and Assistant Professor of Medicine, Emory University, Atlanta, Georgia.

BACTERIAL VAGINOSIS is a common condition of poorly understood etiology. It is characterized by alterations in vaginal flora. Normally, lactobacilli constitute 95% of the bacteria in the vagina. In women with bacterial vaginosis (BV), lactobacilli are absent or severely reduced and the concentration of other bacteria increased by 102 to 104. 1 Bacterial vaginosis is associated with the production of a malodorous discharge with an increased pH relative to normal vaginal fluid. No single bacterial agent consistently predominates. Microorganisms associated with BV include Gardnerella vaginalis, Ureaplasma urealyticum, Mycoplasma hominis, Mobiluncus species, Prevotella species, and other anaerobes. Both the microbiology of the microbes and the products they produce differ considerably between individuals with BV. 2,3 Likely, the risk for upper genital tract infection also varies between individuals.

Evidence associating BV with serious medical complications has accumulated. These complications include premature rupture of the fetal membranes, 4 chorioamnionitis, 5 amniotic fluid infection, 5–7 premature labor and delivery, 8–19 post-cesarean delivery endometritis, 20 and postpartum complications in the infant. 21 The bacteria typical of BV have been found in the upper genital tract of nonpregnant women with endometritis, 22 post-abortion endometritis, 23 and nonchlamydial, nongonococcal pelvic inflammatory disease. 24–26 In addition, new evidence shows that BV increases women’s risk of acquiring and transmitting HIV infection. 25–31

Bacterial vaginosis may be responsible for many adverse health sequelae in women and their infants. Although the nationwide prevalence is unknown, BV prevalence ranges from 10% to 40% depending on the population of women studied. Bacterial vaginosis is almost three times more common among black than white women. 11,32 The reasons for the higher prevalence of BV among black women are unknown. Each year in the United States approximately 4 million births occur, nearly 11% of which involve premature deliveries. In 1997, the percentage of black infants born preterm was 17.5% as compared to 10.2% for white infants. Bacterial vaginosis could account for as much as 30% of the racial difference in premature birth and infant mortality. 32 Assuming a population-attributable risk of 30% for premature delivery and 3.9 million births in the United States each year, the premature births and infant mortality associated with BV have been estimated as follows: 93,600 premature births and 12,225 infants with serious morbidity or mortality, 32 at a cost of $1 billion. 33 In addition, an estimated 300,000 cases of local or systemic infections after delivery and 1.1 million cases of pelvic inflammatory disease occur annually.

Recognizing the need to review existing data and identify prevention strategies, in March 1999, the Centers for Disease Control and Prevention (CDC) organized a 2-day conference for the review of evidence linking BV with certain adverse sequelae, specifically, adverse pregnancy outcomes, complications after gynecologic procedures, and HIV infection. The conference brought together national and international experts in the fields of microbiology, clinical medicine, epidemiology, and policy as well as representatives from interested public and private groups to address a series of key questions. The intent was to assess the evidence linking BV with adverse health consequences, to identify areas in which further research is needed, to identify prevention strategies that could be implemented, and to discuss whether changes for the sexually transmitted disease (STD) treatment guidelines should be recommended. This article reports the key points identified in this meeting.

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Discussion

Primary and Secondary Prevention of Bacterial Vaginosis

Because the etiology of BV is poorly understood, approaches to primary and secondary prevention of BV are difficult to identify. A better understanding of the etiology, epidemiology, and natural history of BV is needed. Increased attention to surveillance activities is needed, in addition to epidemiologic studies to determine risk factors for BV and for upper tract infection with BV-related organisms.

Participants in the CDC meeting noted that current therapy for BV is less than optimal. The effectiveness of CDC-recommended therapies for BV at 3 to 4 weeks is approximately 80%. 34 Recurrences are common (up to 20% of women) within 1 month after therapy. 34 In contrast, the effectiveness of therapy for most bacterial STDs is nearly 100%. 35 Priority should be given to evaluation of new BV prevention strategies, including those directed at restoring normal vaginal flora through the use of exogenous vaginal lactobacilli. Studies to determine optimal methods for diagnosing, treating, and preventing upper tract infection also are important. In addition, trials are needed to determine whether BV screening and treatment decreases the incidence of pelvic inflammatory disease.

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Bacterial Vaginosis and Adverse Outcomes of Pregnancy

Participants in the CDC meeting agreed on the apparent existence of a causal relation between BV and adverse pregnancy outcomes, particularly preterm birth, which is supported by substantial and consistent epidemiologic and biologic evidence. 1–24 The relation between BV and preterm birth has been demonstrated in at least 12 epidemiologic studies conducted on five continents among pregnant women at different gestation ages. 8–19 The risk of premature birth does not appear to be reduced if BV resolves spontaneously. 10,12,19 Despite incomplete understanding of how vaginal bacteria overgrowth characteristic of BV relates to upper tract complications, microbes can provoke an inflammatory response in the cervix, uterus, and vagina and enter the uterine cavity. 36–37 Any of these occurrences may lead to a cascade of events that results in adverse pregnancy outcomes. The relative risk for the most common outcome measured, premature birth (before 37 weeks gestation), ranges from 1.4 to 6.9. 8–19

Intervention trials targeting BV to reduce preterm birth have yielded inconsistent results. 38–41 Three studies have reported that treating BV may reduce preterm birth among high-risk women (e.g., women with a previous premature birth or prepregnancy weight less than 50 kg). 38–41 Two of the three studies used a long regimen of BV treatment (7 days of therapy), 38,39 and the third used a 2-day regimen. 40 However, a recent large randomized controlled trial did not demonstrate reductions among high- or low-risk women enrolled at 16 to 23 weeks gestation. 41 This trial compared placebo with a short regimen (two 2-g doses) of metronidazole separated by 48 hours and repeated 2 to 3 weeks later. Participants thought that differences in study design and medication regimen could account for the differences in the trial results.

Priority should be given to studies that determine effective screening and treatment strategies before pregnancy or in early pregnancy to reduce adverse outcomes. Attention should be given to study design, medication regimen, BV diagnostic criteria, and the use of additional or alternative tests (microbiologic, inflammatory, biochemical).

Participants in the CDC meeting cited research showing that a higher relative risk for premature delivery is found among women with BV early in pregnancy, 10,14 and that BV has been associated with first-trimester miscarriage. 42 These observations led to the recommendation that further studies should evaluate the relation between BV and miscarriage.

The occurrence of postpartum infections related to organisms characteristic of BV is firmly established. 5,20,43–45 Because infectious complications of cesarean delivery (endometritis, bacteremia, and wound infection) are common (15–20% of deliveries), resulting in significant morbidity and economic cost, 5,20,43–45 participants in the CDC meeting recommended that trials evaluate whether BV screening and treatment before vaginal, and particularly before cesarean, delivery could prevent postpartum infectious complications. The participants recommended that studies among pregnant women should evaluate the effects of maternal BV on infants after delivery (i.e., culture negative sepsis syndrome, respiratory distress syndrome, necrotizing enterocolitis, infectious complications, and cerebral palsy).

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Bacterial Vaginosis and Infectious Complications of Gynecologic Procedures

The relation of BV to infections after vaginal or abdominal hysterectomy and induced abortion has been well demonstrated, 23,46–50 and prophylactic antimicrobials are commonly used during hysterosalpingography or intrauterine device insertion, although little data exist to support the practice. The participants cited two strategies that might reduce infectious complications after gynecologic procedures and delivery: (1) screen all women undergoing procedures or delivery and treat those with BV, or (2) treat all women empirically with prophylactic therapy that includes coverage for BV organisms.

The first strategy has been evaluated in two randomized clinical trials for prevention of postabortion complications. 51,52 The first trial evaluated BV screening of women undergoing induced abortion and treatment with metronidazole or placebo. The rate of postprocedure endometritis in the metronidazole group was reduced 50% to 75%. The second trial, which treated women 1 day before the procedure with 2% intravaginal clindamycin cream, also found a reduction in postabortion pelvic inflammatory disease. 52

The second strategy has been evaluated for prevention of infectious complications after abortion 53–55 and hysterectomy. 56–61 The administration of prophylactic antimicrobials with anaerobic coverage in these trials diminished subsequent infections 10% to 75%. 53–61

Priority should be given to trials evaluating either the screening or empirical coverage strategy before selected gynecologic procedures (e.g., hysterosalpingography, induced abortion, or hysterectomy) to prevent postoperative infectious complications.

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Bacterial Vaginosis and HIV Infection

The participants in the CDC meeting noted that BV is emerging as an important risk factor for HIV acquisition in women. Cross-sectional studies in North America, Asia, and Africa show that women with BV are more likely to have HIV infection. 25–31 Prospective studies demonstrate that BV or lack of lactobacilli is associated with an increased risk of HIV seroconversion and STD acquisition, and that STD acquisition is associated with an increased risk of HIV infection. 29,30 Evidence supporting the biologic plausibility of these findings is provided by in vitro studies indicating that H2O2-producing lactobacilli inhibit HIV, 62 and that BV organisms are associated with activation of HIV. 63 Participants noted that in populations with high BV prevalence, BV may be one of the most important risk factors for HIV infection in women.

Whereas only one study has evaluated treatment of BV to prevent HIV infection, 64 the mass treatment was found to be ineffective in changing the prevalence of BV, and the impact; thus the impact of reducing BV prevalence on HIV acquisition could not be assessed. Consultants have advised that studies be performed to evaluate the relation of BV to acquisition and transmission of HIV infection and other STDs, as well as trials to evaluate the prevention of BV-associated HIV and STD transmission.

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Implications for CDC Guidelines for Treatment of STDs

The participants in the CDC meeting discussed possible changes to the 1998 CDC Guidelines for Treatment of STD. The current recommendation is that symptomatic women be tested for BV, and that those with BV be treated. Also, high-risk pregnant women without symptoms of BV may be screened, and those with BV can be treated. 35 The recommended regimen is metronidazole 250 mg orally three times daily for 7 days. Alternative regimens are metronidazole 2 g orally in a single dose or clindamycin 300 mg orally twice daily for 7 days.

The participants thought data were insufficient to recommend changes in current CDC guidelines for screening pregnant women. Removal from the CDC Guidelines for Treatment of STD of the single 2-g metronidazole dose as an alternative treatment regimen for pregnant women should be considered. 35 This regimen is expected to be less effective than the repeated 2-g metronidazole regimen given twice, two weeks apart, which was found to be no more effective than a placebo in a recently completed randomized trial, 41 and which also is less effective for treating BV. 35

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Implications for Public Health Education

Controversy exists about the advisability of promoting widespread public awareness of BV and its associated risks given the lack of substantial evidence documenting the effectiveness of specific interventions. The participants in the CDC meeting disagreed about the need for a national campaign to inform the public about BV: what it is, how to recognize it, and how to treat it. Some thought that increased dissemination of information was important as a means of enabling individuals to make informed decisions about their health. Others believed that this effort would medicalize or stigmatize women, that risks for BV were poorly understood, and that current antimicrobial therapies were not effective enough for widespread use. Such use carrys the theoretical risk of causing increases in antimicrobial resistance. All the participants agreed that increased awareness of BV by funding agencies was needed to increase research in this important area.

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Summary

The CDC meeting addressed gaps in knowledge about the primary and secondary prevention of BV, and about the prevention of adverse sequelae of BV associated with pregnancy, gynecologic procedures, and HIV infection. The prevalence of BV among women in the United States is high. Bacterial vaginosis is associated with many adverse reproductive outcomes as well as HIV infection. There are large racial disparities in BV and its associated complications. The cost and burden of these complications is large. Further research is needed, particularly in the area of BV prevention. A national prevention effort should be guided by the results of research that addresses current knowledge gaps. The BV Meeting was made possible with support from the Division of STD Prevention, NCHSTP, the Division of Reproductive Health, CCDPHP, and the Office of Minority and Women’s Health, NCID.

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BV Meeting Invited Participants

Linda Alexander, PhD, FAAN, American Social Health Association; William (Bill) Andrews, MD, Associate Professor, University of Alabama at Birmingham; Jennifer Culhane, PhD, The Health Federation of Philadelphia; David A. Eschenbach, MD, Professor, Department of Obstetrics and Gynecology, University of Washington; Kevin Fiscella, MD, MPH, Professor of Family Medicine, University of Rochester; Robert L. Goldenberg, MD, Chairman, Department of Obstetrics and Gynecology, University of Alabama at Birmingham; Jeanne-Marie Guise, MD, MPH, Director, Clinical Research, Assistant Professor, OB/GYN Oregon Health Sciences University; John C. Hauth, MD, Professor, Department of Obstetrics and Gynecology, University of Alabama at Birmingham; Phillip E. Hay, MD, Department of Genito-Urinary Medicine, St. George’s Hospital, London, UK; Sharon L. Hillier, PhD, Director, Reproductive Infectious Disease Research, University of Pittsburgh; King K. Holmes, MD, PhD, Director, Center for AIDS and STD, University of Washington; Claudia Holzman, DVM, PhD, Michigan State University; Romina Kee, MD, Director, Chicago STD Clinic; Mark Klebanoff, MD, MPH, Prevention Research, NICHD; Luella Klein, MD, Professor of Gynecology and Obstetrics, Emory University; Ronald F. Lamont, MD, Northwick Park Hospital, Harrow, England, United Kingdom; Helen Margaret McDonald, PhD, Women’s Children Hospital, Microbiology and Infectious Diseases Department, North Adelaide, Australia; James A. McGregor, MD, CM, Denver Health Medical Center, Department of Obstetrics and Gynecology, Denver; Kenneth Schoendorf, MD, Infant and Child Health Studies Branch, Division of Health and Utilization Analysis, National Center for Health Statistics; Jay Schulkin, PhD, Director of Research, American College of OB/GYN; Jane R. Schwebke, MD, Division of Infectious Disease, University of Alabama at Birmingham; David Soper, MD, Department of Obstetrics and Gynecology, Medical University of South Carolina; Barbara Stoll, MD, Associate Professor of Pediatrics, Emory University; Maria Wawer, MD, MSc, Associate Professor, Columbia University. The BV Meeting was made possible with support from the Division of STD Prevention, NCHSTP, the Division of Reproductive Health, CCDPHP, and the Office of Minority and Women’s Health, NCID.

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