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Management of Bacterial Vaginosis During Pregnancy
DARON G. FERRIS, M.D.
Medical College of Georgia
Augusta, Georgia

From a clinician's perspective of diligent diagnosis and proper treatment, bacterial vaginosis may be the most innocently ignored and improperly managed vaginal infection. Diagnosis involves consideration of microbiologic, cytologic, clinical and chemical factors. The most sensitive chemical parameter (abnormally elevated pH) is never considered by 95 percent of health care professionals. In contrast with other types of vaginitis, simple microscopic recognition of a unique pathogen does not confirm bacterial vaginosis infection.

No one knows what causes the virtual banishment of Lactobacillus acidophilus from the vagina and the preponderance of a diverse mixture of opportunistic microorganisms within the vagina. Because the true etiology of bacterial vaginosis remains unknown, therapeutic agents are not universally effective. As a consequence of imprecisely directed treatment (i.e., treating the expression of bacterial vaginosis and not the exact cause), the recurrence of bacterial vaginosis infection is exceedingly common.

See Article in this issue.

Yet, data from studies of pregnant women with bacterial vaginosis demonstrate substantial twofold or greater increased risk for serious complications, including preterm birth, low-birth-weight infants, premature rupture of the membranes, amniotic fluid infection, chorioamnionitis, and post-cesarean and postpartum endometritis. Although bacterial vaginosis has been shown to be an independent risk factor for these complications, many health care professionals still consider bacterial vaginosis more of a nuisance than a genuine fetal-maternal threat. Even though widely disseminated educational efforts should rectify misunderstandings with regard to pregnancy outcome and bacterial vaginosis, many other critical questions concerning this topic remain unanswered. Should asymptomatic pregnant women with bacterial vaginosis be treated? Is there a role for screening pregnant women for bacterial vaginosis? Which antibiotics effectively reduce the risk for pregnancy-related complications of bacterial vaginosis?

Clearly, a casual approach to pregnant women with symptoms or clinical signs of bacterial vaginosis appears unjustified. Symptomatic pregnant women with confirmed bacterial vaginosis should be treated.¹ Whether asymptomatic pregnant women deserve, and would benefit from, therapy is less well defined. More than one half of all women with bacterial vaginosis have no symptoms of the lower genital tract; nevertheless, they are still afflicted. One could easily argue that treatment should be implemented for pregnant women because of the increased probability of serious complications, regardless of the absence of symptoms.

Several researchers have demonstrated that treatment of bacterial vaginosis in pregnant women reduces the rate of preterm birth.^2,3 Hauth and colleagues² showed that pregnant women who had bacterial vaginosis and an increased risk for preterm delivery (previous history of preterm delivery or low prepregnant weight of less than 50 kg [110 lb]), and who received metronidazole (Flagyl) and erythromycin therapy, had significantly reduced rates of preterm delivery when compared with women given placebo (39 percent versus 57 percent). Morales and colleagues³ demonstrated that oral metronidazole therapy reduced the rate of preterm births for pregnant women with bacterial vaginosis and a previous history of preterm birth when compared with women who received placebo (18 percent versus 39 percent).

Of particular importance is the fact that both of these studies^2,3 demonstrated therapeutic efficacy for only pregnant women considered at high risk for preterm delivery. It is not clearly understood if low-risk pregnant women with no underlying increased risk factors for preterm birth would benefit equally as well from treatment of bacterial vaginosis. Similarly, claims of benefit from treatment of asymptomatic pregnant women with bacterial vaginosis have not been properly substantiated. Recent guidelines from the Centers for Disease Control and Prevention (CDC) recommend treating asymptomatic high-risk pregnant women with bacterial vaginosis.⁴ It may also be prudent to treat symptomatic low-risk pregnant women with bacterial vaginosis to eliminate their symptoms.⁴

The effectiveness of screening patients to prevent potentially serious sequelae depends on the prevalence of the condition in the population at risk, readily available and accurate diagnostic tests, consequences of the untreated condition, effective therapy and the overall cost-effectiveness of such intervention. In support of screening pregnant women for bacterial vaginosis are the following factors: the condition is exceedingly common (a prevalence rate of up to 30 percent); reasonably reliable tests are available; the potential consequences of not treating bacterial vaginosis are severe for the mother and the fetus; and moderately effective therapy is available. While these factors bolster screening, many questions regarding screening pregnant women for bacterial vaginosis exist.

If screening is done, when should it be conducted, second or third trimester?

It appears that infection with bacterial vaginosis in early pregnancy (second trimester) conveys a greater risk for complications than infection with bacterial vaginosis in late pregnancy.⁵ However, a positive test for bacterial vaginosis in early pregnancy may be a poor predictor for the development of preterm birth, preterm labor and premature rupture of the membranes (positive predictive values: 4 percent to 11 percent).⁶ Based on increased risk, current CDC guidelines recommend screening early in the second trimester.⁴

Should all pregnant women be screened, or only women considered to be at increased risk for fetal-maternal complications?

While treatment of high-risk pregnant women with bacterial vaginosis reduces the risks for fetal-maternal complications,^2,3 no data are available to compare bacterial vaginosis treatment outcomes for both women at low risk and women at high risk of fetal-maternal complications. Therefore, currently only women determined to be at high risk for preterm delivery should be considered candidates for screening for bacterial vaginosis.^1,4

How should screening be performed--using simple clinical evaluation and Amsel's criteria, Gram stain, gas-liquid chromatography (GLC) or fibronectin assay?

Screening by Amsel's criteria (three of four findings: pH of more than 4.5, amine odor on adding KOH, presence of clue cells, adherent off-white vaginal discharge) is readily available to all clinicians but is also the least accurate method of diagnosing bacterial vaginosis. The other tests are considerably more expensive and are not readily available, but they offer more accurate diagnosis or assessment of increased risk for potential complications. Whether screening would be cost-effective is controversial,^7,8 because data based on outcomes from randomized controlled screening trials are not available. Screening guidelines may evolve from the BV/TV trials sponsored by the National Institutes of Health, but initial data will not be available until 1999. As such, no guidelines currently recommend universal screening of pregnant women for bacterial vaginosis.

Some limited data are available to help guide clinicians in the selection of antibiotics for bacterial vaginosis in pregnant women. Topical clindamycin vaginal cream is ineffective in reducing the rates of preterm birth.^9,10 In fact, such treatment actually increases the presence of vaginal Escherichia coli, an organism known to increase the risk for preterm birth. Topical metronidazole gel (Metrogel) has not been evaluated in the context of bacterial vaginosis during pregnancy. Topical antibiotics usually eradicate local bacterial vaginosis infection, but do not reduce prematurity sequelae because of the lack of access to the upper genital tract. Therefore, systemic antibiotics are probably required to adequately reduce the risk of pregnancy-related complications.

Oral metronidazole and metronidazole combined with erythromycin have been shown to reduce pregnancy complications associated with bacterial vaginosis.^2,11 But because metronidazole use is contraindicated during the first trimester, only women in mid to late pregnancy should be treated with the drug. Alternatively, oral clindamycin (Cleocin) could be used, but limited data are available on its use,¹² particularly in the context of treating women without a current or past history of pregnancy-related complications. A test of cure evaluation one month following treatment of bacterial vaginosis may be beneficial because treatment failures are common.^4,13

In summary, women with bacterial vaginosis during pregnancy should be aggressively evaluated and effectively treated. This is particularly true for women considered at high risk for pregnancy-related complications. Asymptomatic pregnant women with bacterial vaginosis may also benefit from therapy. Systemic antibiotics appear to afford both effective treatment for bacterial vaginosis and minimization of pregnancy-related complications.

Universal screening of pregnant women for bacterial vaginosis is not currently recommended, but women at high risk for preterm birth may benefit from early second trimester screening for bacterial vaginosis. Casual clinical recognition of bacterial vaginosis in asymptomatic pregnant women should prompt proper diagnosis and treatment. Although pregnant women with bacterial vaginosis obviously have an increased risk for pregnancy-related complications, it is unknown whether therapeutic intervention decreases the rate of specific fetal-maternal problems for all pregnant women. Evidence-based guidelines for proper management of pregnant women with bacterial vaginosis await the outcomes of clinical trials currently being conducted.

Dr. Ferris is associate professor of the Department of Family Medicine at the Medical College of Georgia, Augusta.

REFERENCES

1. Bacterial vaginosis screening for prevention of preterm delivery. ACOG Committee Opinion No. 198. American College of Obstetricians and Gynecologists, Washington, D.C., 1998.
2. Hauth JC, Goldenberg RL, Andrews WW, DuBard MB, Copper RL. Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med 1995;333:1732-6.
3. Morales WJ, Schorr S, Albritton J. Effect of metronidazole in patients with preterm birth in preceding pregnancy and bacterial vaginosis: a placebo-controlled, double-blind study. Am J Obstet Gynecol 1994;171:345-9.
4. Centers for Disease Control and Prevention. 1998 Sexually transmitted diseases treatment guidelines. Morb Mort Wkly Rep 1998;47:70-4.
5. 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.
6. Kurki T, Sivonen A, Renkonen OV, Savia E, Ylikorkala O. Bacterial vaginosis in early pregnancy and pregnancy outcome. Obstet Gynecol 1992;80: 173-7.
7. Bloom BS, Lee DW. Bacterial vaginosis and preterm birth. N Engl J Med 1996;334:1338-9.
8. Oleen-Burkey MA, Hillier SL. Pregnancy complications associated with bacterial vaginosis and their estimated costs. Infect Dis Obstet Gynecol 1995; 3:149-57.
9. Joesoef MR, Hillier SL, Wiknjosastro G, Sumampouw H, Linnan M, Norojono W, et al. Intravaginal clindamycin treatment for bacterial vaginosis: effects on preterm delivery and low birth weight. Am J Obstet Gynecol 1995;173: 1527-31.
10. McGregor JA, French JI, Jones W, Milligan K, McKinney PJ, Patterson E, 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.
11. McGregor JA, French JI, Parker R, Draper D, Paterson E, Jones W, 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.
12. 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.
13. Ferris DG, Litaker MS, Woodward L, Mathis D, Hendrich J. Treatment of bacterial vaginosis: a comparison of oral metronidazole, metronidazole vaginal gel and clindamycin vaginal cream. J Fam Pract 1995;41:443-9.

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Family Physicians and the Tuberculosis Epidemic
ROBERT HIGGINS, M.D.
Anacortes, Washington

In 1995, more people in the world died of tuberculosis than in any other year in history.¹ The incidence of tuberculosis is increasing, even in the United States. From 1953, when national statistics on tuberculosis were first kept, until 1981, a 5 percent annual decrease in the number of cases of tuberculosis was recorded, and from 1981 until 1985, a 6 to 7 percent annual decrease was reported. However, from 1985 until 1993, there was an almost 10 percent increase in the number of cases of tuberculosis. From 1993 until 1994, a small decrease in the number of cases occurred, perhaps because of enhanced interest in the problem.² A level of neglect regarding the seriousness of tuberculosis through the 1970s and 1980s worldwide has resulted in the spread of tuberculosis that we now see. Medical schools under-emphasized the public health aspects of tuberculosis control, ministries of health minimized tuberculosis control, and it was disregarded by most funding agencies. The result is that tuberculosis has a higher mortality rate in adults than any other infectious disease worldwide. The tuberculosis epidemic has become a global emergency, and it will not go away on its own. In 1995, for each person who died of the Ebola virus, 12,000 people died of tuberculosis.¹ If tuberculosis were a new disease like Ebola, the world would spare little expense to fight it, but tuberculosis has been around for centuries and has become an old, familiar enemy that we have learned to overlook. It is easy to understand why the tuberculosis epidemic is getting worse: For each person who has tuberculosis and is improperly treated, 10 to 15 other people per year may be infected.

The epidemiology of tuberculosis is changing in the United States and around the world. As the number of cases increases in developing nations, the threat to people in the United States increases because of air travel and immigration. The most significant change in the epidemiology has been the number of cases diagnosed in people infected with human immunodeficiency virus (HIV) infection. Another very worrisome change has been the recent outbreaks of multidrug-resistant tuberculosis.

In the United States, more than two thirds of cases of tuberculosis occur in nonwhite racial and ethnic groups. More than one fourth of all cases in the United States occur in foreign-born individuals, and about one third of these people have been residing in the United States less than one year.³ It is of interest that nearly one third of the cases of tuberculosis in the United States occur in persons in the middle- and upper-income groups, despite the popular notion that tuberculosis is a problem of only the poor.

Infectious diseases in general are thriving as the world's population becomes more mobile. Global trade has multiplied sixfold since 1960, and people from all parts of the world fly from country to country on business, on vacation or to attend school. The United States is now receiving over 20 million foreign visitors annually, and U.S. citizens are taking nearly 60 million trips annually to foreign countries. The public health implications of this increased travel have not been fully appreciated. This increased mobility can place your patients at risk of exposure to tuberculosis and other infectious diseases through contact while flying, contact while in a foreign country or contact with foreign visitors to this country. This increased mobility also means that every country is vulnerable to the inferior tuberculosis treatment practices of other countries.

Worldwide, more HIV-infected people die from tuberculosis than from any other cause; tuberculosis is the cause of death in about one third of those who die from acquired immunodeficiency syndrome. Those people who are immunosuppressed because of HIV or because of other causes are 30 times more likely than nonimmunosuppressed individuals to acquire tuberculosis when exposed to it and will develop the disease more rapidly. Yet they can be cured of tuberculosis if diagnosed in time and treated appropriately. The seriousness of this combination of immunosuppression and tuberculosis has led the Advisory Committee for the Elimination of Tuberculosis of the Centers for Disease Control and Prevention to recommend that all patients in whom tuberculosis has been diagnosed be offered counseling and HIV testing, and that all HIV-infected individuals, with or without AIDS, should be given a tuberculin skin test.⁴

We face a very serious threat that tuberculosis will become impossible to cure in the future. The increase in the number of cases of multidrug-resistant tuberculosis is seen worldwide, and although the extent of this problem is not known, it is estimated that 50 million people are infected with a drug-resistant form of tuberculosis. In this country, several outbreaks have been investigated, and most of the exposed people who developed multidrug-resistant tuberculosis were known to be infected with HIV. The case-fatality rate among these individuals was extraordinarily high--72 to 89 percent.^5,6 In developing countries, people with multidrug-resistant tuberculosis usually die because effective treatment is often impossible in poor settings, but even in more affluent countries, up to 50 percent of people with multidrug-resistant tuberculosis may die because of the expense and difficulty of proper treatment. Multidrug-resistant tuberculosis is created by prescribing the wrong drugs or the wrong combination of drugs in the treatment of tuberculosis. It can also occur if the right drugs are prescribed but are not taken consistently or for a full course of treatment. Multidrug-resistant tuberculosis has the potential to return humanity to an era when the diagnosis of tuberculosis was a virtual death sentence.

We know from the past that tuberculosis is controllable if appropriate measures are taken and sufficient interest in doing so exists. These measures include identification of cases, proper treatment regimens, contact identification and follow-up, and proper preventive treatment of those exposed to the disease. Most people with tuberculosis are identified either because they seek medical treatment for their symptoms or because they are being treated for other conditions and are found to have concurrent tuberculosis infection. Family physicians are among the most important identifiers of people with tuberculosis, but because of the nonspecific manifestations of the disease, a high index of suspicion must be maintained, especially in those individuals who are at greatest risk. Evaluation of the contacts of people with infectious tuberculosis is one of the most productive methods of identifying persons with infection and disease. We must ensure that local authorities are doing this effectively. Proper treatment is critical to containing this epidemic, and the key is that patients not only be treated but that they also be cured. Patients frequently forget to take their medicines or stop treatment when they begin to feel better. The treatment strategy that has proved most effective is called directly observed treatment course (DOTS). This strategy uses a combination of four drugs to kill the tuberculosis bacteria within six to eight months, and it virtually guarantees a cure because health workers actually watch patients swallow their medicines and evaluate their patients' progress. Widespread use of DOTS would soon reverse the course of this worldwide tuberculosis epidemic. Family physicians must continue to take an active role in helping curb this epidemic and must remain knowledgeable about tuberculosis as the epidemiology evolves and treatment regimens change.

Dr. Higgins is a family physician and president-elect of WONCA, the World Organization of Family Doctors. He is a former chair of the Board of the American Academy of Family Physicians and a former AAFP president.

REFERENCES

1. Expanded tuberculosis surveillance and tuberculosis morbidity-United States, 1993. MMWR Morb Mortal Wkly Rep 1994;43:361-6.
2. Tuberculosis morbidity--United States, 1994. MMWR Morb Mortal Wkly Rep 1995;44:387-95.
3. McKenna MT, McCray E, Onorato I. The epidemiology of tuberculosis among foreign-born persons in the United States, 1986-93. N Engl J Med 1995; 322:1071-6.
4. Tuberculosis and human immunodeficiency virus infection: recommendations of the Advisory Committee for the Elimination of Tuberculosis. MMWR Morb Mortal Wkly Rep 1989;38:236-50.
5. Management of persons exposed to multidrug-resistant tuberculosis. MMWR Morb Mortal Wkly Rep 1992;41:1-8.
6. American Thoracic Society. Control of tuberculosis in the United States. Am Rev Resp Dis 1992;146: 1623-33.