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Obstetrics & Gynecology 2004;104:114-119
© 2004 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Natural History of Bacterial Vaginosis and Intermediate Flora in Pregnancy and Effect of Oral Clindamycin

Austin Ugwumadu, MRCOG, Fiona Reid, MSc, Phillip Hay, MRCP and Isaac Manyonda, PhD, MRCOG

From Department of Obstetrics and Gynecology and Department of Genitourinary Medicine, St. George's Hospital; and Department of Community Health Sciences, St George's Hospital Medical School, Cranmer Terrace, London, United Kingdom.

Address reprint requests to: Austin Ugwumadu, Department of Obstetrics & Gynecology, St. George's Hospital, Blackshaw Road, London SW17 0QT United Kingdom; e-mail: augwumad{at}sghms.ac.uk.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: We sought to describe the natural history of abnormal vaginal flora in pregnancy and estimate the efficacy of oral clindamycin in eradicating it and preventing relapse.

METHODS: This was a subanalysis of a randomized trial of oral clindamycin for abnormal vaginal flora in pregnancy. All 494 enrolled women were asked to provide a vaginal smear 2 weeks after treatment and every second participant to provide further smears at 20, 24, 28, 32, and 36 weeks of gestation. We used Nugent score of Gram-stained smears to assess the cure rate among the clindamycin group and the rate of spontaneous resolution among the placebo group.

RESULTS: Posttreatment smears were available for 462 women (231 in each of the clindamycin and placebo arms). The prevalence of abnormal flora posttreatment was 10% (22 of 231) in the clindamycin group compared with 93% (214 of 231) in the placebo group (P < .001). Two hundred nineteen women obtained 4 weekly smears; slides for 84 women were lost, and results were available for 135 women (69 clindamycin, 66 placebo). In the clindamycin group, the prevalence of abnormal flora was 15% at 20 weeks of gestation and 17% at 36 weeks of gestation compared with 69% at 20 weeks of gestation and 43% at 36 weeks of gestation in the placebo group.

CONCLUSION: Oral clindamycin eradicated abnormal flora in 90% of treated pregnant women and maintained a normal flora in two thirds of women throughout pregnancy. Almost one third of untreated women in our study had spontaneous resolution of abnormal flora by 20 weeks of gestation. Because previous research has shown that spontaneous resolution does not modify the risk of preterm birth, early screening is essential.

LEVEL OF EVIDENCE: I

Bacterial vaginosis and intermediate flora (abnormal vaginal flora) increase the risks of chorioamnionitis,1 midtrimester miscarriage, and preterm birth.2–4 Although the natural history of abnormal vaginal flora in pregnancy is poorly understood, there are reports of spontaneous resolution in late pregnancy,5,6 which may be explained in part by an increase in the concentration of protective Lactobacillus species in the vagina and a decrease in the populations of potentially pathogenic anaerobic bacteria that is known to occur in normal pregnancy.7 This resolution, however, does not appear to alter the risk of preterm delivery,6,8 suggesting that the risk of adverse outcome may be established early and therefore may not be reversible by subsequent spontaneous resolution or by late antibiotic treatment. This hypothesis might explain the failure of late oral metronidazole to reduce preterm delivery,9,10 whereas oral and topical clindamycin therapy initiated early in the second trimester significantly reduced second-trimester miscarriage and preterm birth.11,12 Knowledge of the natural history of abnormal vaginal flora in pregnancy is therefore important to further refine the optimal time to screen and treat women.

At present, there is no consensus on the antibiotic of choice for the treatment of abnormal vaginal flora in pregnancy, the optimal route and timing of therapy, and whether to treat persistent and recurrent cases. The aim of this study was to trace the natural history of abnormal vaginal flora in pregnancy in a group of placebo-treated pregnant women and estimate the cure rate of abnormal flora after oral clindamycin therapy and the risk of recurrence throughout pregnancy.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This study was a subanalysis of a larger randomized trial of oral clindamycin versus placebo initiated at a mean gestational age of 15.6 weeks for the treatment of abnormal vaginal flora in pregnancy.11 In summary, pregnant women attending their first antenatal visit at St. George's Hospital, London, and St. Helier Hospital, Surrey, from November 1, 1996, through February 1, 1999, were offered screening for abnormal vaginal flora if they were between 12 and 22 weeks pregnant according to their menstrual date or early ultrasound scan. Women who had positive test results were invited to participate, and those consenting and meeting the study's inclusion criteria were randomly assigned to a treatment group. Women were excluded from randomization if they had multiple pregnancy; needed or had cervical cerclage; had a history of cone biopsy; had a uterine, cervical, or fetal anomaly; had diabetes, renal disease, lupus, antiphospholipid syndrome, or hypertension; had an allergy to clindamycin; were aged less than 16 years; or reported a fishy-smelling vaginal discharge, in which case they received treatment and further genitourinary screening for sexually transmitted pathogens.

We used a computer program to randomly assign the numbers 1 to 500 to clindamycin or placebo treatment. A trial pharmacist used this randomized list to package bottles of 5-day courses of either clindamycin (300 mg) or placebo to be taken twice daily. The clindamycin capsules were identical to and indistinguishable from the placebo capsules and masked to the participants and investigators. The investigators allocated the bottles consecutively to the participants. The trial pharmacist retained the code for group allocation within a sealed envelope until all of the study data had been collected and analyzed. A total of 494 women was randomly assigned. The Local Research Ethics Committees at both centers approved the study.

Each participant received instruction on the technique of obtaining a self-administered vaginal smear. This was performed by inserting a Dacron swab approximately 4–5 cm into the vagina. The swab was left in the vagina for 10–15 seconds, rolled round through 360 degrees before withdrawal, and then smeared on a plain glass slide and air-dried. The slides were Gram stained and examined at the end of the study by 2 of the investigators (A.U. and P.H.) using the Nugent scoring system.13 Nugent scores of 0–3 were graded as normal flora, 4–6 as intermediate flora, and scores of 7–10 were classified as bacterial vaginosis.5 The 2 observers had previously examined 700 Gram-stained slides of vaginal smears together until the interobserver variation between them was negligible.

All participants were given a swab and a slide and asked to obtain a vaginal smear for Gram stain assessment of the efficacy of treatment at 14 days after a 5-day course of oral clindamycin 300 mg or placebo twice daily. Each slide was labeled with the subject's trial number for identification and marked as "post treatment smear."

Because of resource constraints, every second participant enrolled in the randomized trial was invited to take part in a separate longitudinal follow-up study and instructed to obtain further vaginal smears at 5 time points (20, 24, 28, 32, and 36 weeks of gestation). Each slide was prelabeled with the participant's trial number and the gestational age at sampling. If a participant declined, the invitation was extended to the next one. The slides were stored in a plastic slide carrier case by the participant until 36 weeks of gestation or earlier if preterm delivery occurred.

Abnormal vaginal flora is defined as persistent if the Nugent score of Gram-stained vaginal smear is 4 or greater at posttreatment assessment and at all time points of the longitudinal study. If normal flora was documented posttreatment, the subsequent detection of a Nugent score of 4 or greater by 36 weeks of pregnancy was counted as a relapse or recurrence.

Sample sizes originally were calculated to give sufficient power for the comparison of pregnancy outcomes between clindamycin and placebo groups within the randomized clinical trial.11 A post hoc power calculation for this study indicates that the number of women who provided posttreatment vaginal smears (231 in each group) was sufficient to detect a difference of 10% in posttreatment cure rates between placebo-treated women (7%, observed) and clindamycin-treated women (17%), with 90% power at a 5% significance level. The Fisher exact test was used to compare categorical variables, and the t test used to compare continuous variables between the clindamycin and placebo groups.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of the 494 randomly assigned women, posttreatment vaginal smears and Nugent scores were available from 462, of whom 231 were in the clindamycin group and 231 in the placebo group. Table 1 shows the baseline characteristics of these women, who were well matched between the treatment and placebo groups for age, parity, ethnic origin, gestation at randomization, and pretreatment Nugent scores. Of the 32 women without Nugent scores, 15 failed to return their slides, 9 slides could not be evaluated because of poor quality, 2 women miscarried before the time for posttreatment smear, 1 woman had elective termination of pregnancy, and no reason was documented for the remaining 5 women. At the posttreatment assessment (Table 2), only 10% (n = 22) in the clindamycin group compared with 93% (n = 214) in the placebo group had abnormal vaginal flora (difference = 83%, 95% confidence interval 78–88%, P < .001).


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  		Table 1. Baseline Characteristics of the Treatment and Placebo Groups for All Women Providing Posttreatment Vaginal Smears

 

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  		Table 2. Posttreatment Nugent Scores

 

Two hundred nineteen women (105 clindamycin, 114 placebo) participated in the longitudinal study, providing up to 5 slides at 20, 24, 28, 32, and 36 weeks of gestation. The slides for 84 women (36 clindamycin, 48 placebo) stored together were lost during the process of office relocation. The baseline characteristics of the remaining 135 women (69 clindamycin, 66 placebo), who provided one or more follow-up Nugent scores, were well balanced between the clindamycin group and the placebo group (Table 3). The results of the follow-up study of these women are presented in Table 4 and Figure 1. Not all women provided a full set of follow-up slides, and posttreatment scores were unavailable for 3 of these women (clindamycin group). Three women (1 clindamycin, 2 placebo) received antibiotic therapy for other indications but were included in the analysis.


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  		Table 3. Follow-Up Nugent Scores for the Clindamycin and Placebo Groups

 

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  		Table 4. Baseline Characteristics of the Women Providing Follow-Up Smears Every 4 Weeks

 


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  		Fig. 1. Prevalence of bacterial vaginosis, intermediate flora, and normal flora in the (A) clindamycin and (B) placebo groups.

Ugwumadu. Bacterial Vaginosis in Pregnancy. Obstet Gynecol 2004.

 

In the clindamycin group, the low prevalence of abnormal vaginal flora achieved at 20 weeks of gestation (15%) was maintained throughout pregnancy (17% at 36 weeks of gestation). The prevalence of abnormal vaginal flora in the placebo group was 69% at 20 weeks of gestation (indicating spontaneous resolution in 31% of women by this time), steadily reducing to 43% at 36 weeks of gestation.

Of the 55 women in the clindamycin group who were cured posttreatment and also provided 1 or more follow-up slides, 12 (22%) showed evidence of recurrence at some point throughout the pregnancy, of whom 4 had intermediate flora, and 2 relapsed in gestational week 36 only. Forty-one women in the clindamycin group provided a posttreatment slide and a complete set of 5 follow-up slides: 4 (10%) had persistent abnormal vaginal flora (all of whom had term deliveries) and 27 (66%) had normal flora at all time points. Four women in this group showed improvement to normal flora, 3 deteriorated, and the remaining 3 subjects had fluctuating results over the course of time. In the placebo group, 49 women provided complete data, of whom 15 (31%) had persistent abnormal vaginal flora and 8 (16%) had normal flora at all time points. Seventeen women in this group improved over time without relapse, whereas the remaining 9 had fluctuating results.


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Fourteen days after treatment with a 5-day course of oral clindamycin, 90% of pregnant women with bacterial vaginosis or intermediate vaginal flora reverted to normal flora compared with 7% of women who were treated with placebo. This cure rate is substantially higher than the 40–77% cure rates achieved with a 2-day course of oral metronidazole 400 mg taken twice a day and 2-g stat doses taken 48 hours apart.10,14 It is also higher than the 60–80% elimination rates reported in studies that used topical clindamycin.15–17 Furthermore, the prevalence of bacterial vaginosis throughout pregnancy is lower for oral clindamycin (7–14%) than the 38–58% reported in a comparable study that used oral metronidazole.14 Available data suggest that women with persistent or recurrent bacterial vaginosis after topical treatment in pregnancy have a higher risk of preterm delivery than women treated with placebo.8 Two controlled trials of oral metronidazole9,10 and 4 of 5 such trials using intravaginal clindamycin therapy in pregnancy did not show a reduction in the risk of preterm delivery.8,12,15,17,18 Thus, we would suggest that oral clindamycin be considered the drug of choice for women with abnormal vaginal flora in pregnancy. It reduces the risk of late miscarriage and spontaneous preterm birth,11 maintains normal vaginal flora in two thirds of treated women throughout pregnancy, and is well tolerated.

This study confirms the progressive decline in the prevalence of bacterial vaginosis in untreated pregnant women reported by previous studies5,6,14 and extends this observation by documenting the earlier onset of spontaneous resolution in pregnancy. The 31% reduction in the prevalence of abnormal vaginal flora observed between recruitment (mean, 15.6 weeks) and 20 weeks of gestation suggests that approximately one third of women with abnormal vaginal flora would have a false-negative result if screening was initiated at 20 weeks of gestation or later, emphasizing the importance of early screening. This is further underpinned by the finding that the risk of preterm delivery associated with bacterial vaginosis is 2- to 6.9-fold higher in studies where bacterial vaginosis was detected before 20 weeks of gestation2,4,19 compared with 1.4- to 1.9-fold increase reported in studies where it was diagnosed after 26 weeks of pregnancy.6,20,21 It is probable that some abnormal flora might already have undergone spontaneous resolution even before the mean 15.6 weeks of gestation of randomization in this trial, raising the question of the optimal time to screen for and treat women for abnormal flora during pregnancy. A recent community-based study in south London screened women for bacterial vaginosis at less than 10 weeks of gestation. There was a significant association between bacterial vaginosis and miscarriage between 13 and 16 weeks of gestation but a nonsignificant trend for miscarriage between 10 and 13 weeks of gestation.22

We followed up women with vaginal smears 2 weeks after treatment and then every 4 weeks from 20 weeks of gestation. Changes other than those detected at the times of sampling could have occurred in the vaginal flora between the sampling times. Furthermore, we do not know for certain that women treated with oral clindamycin were subsequently recolonized by the protective H2O2-producing strains of lactobacilli or that organisms within the endometrial cavity were definitely eradicated. We lost 84 sets of slides in an unfortunate office accident and were unable to compare the baseline characteristics of these women, thus raising the possibility of bias. The baseline characteristics of the remaining 66 women in the placebo group were, however, almost identical to those of the 69 women in the clindamycin group.

Our results suggest that screening for abnormal vaginal flora, if indicated, should be undertaken very early in pregnancy, perhaps at the beginning of the second trimester at the latest. Further studies are required to characterize the pregnancy specific stimuli that elicit the spontaneous resolution of abnormal vaginal flora in pregnancy, and the time of onset of their effect. Such data might hold the key for the development of effective interventions in future.


   Footnotes
 
Received February 2, 2004. Received in revised form March 25, 2004. Accepted April 1, 2004.

Supported by the NHS Executive London, Research and Development Program. The authors thank Phamacia Upjohn for donating the clindamycin and placebo used in the study.

Financial Disclosure Phillip Hay has received payment for lectures and consultancy from Osmetech, 3M, and Pharmacia and Upjohn and has received funding for trials and to attend conferences from these companies.

10.1097/01.AOG.0000130068.21566.4e


   REFERENCES
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Hillier SL, Martius J, Krohn M, Kiviat N, Holmes KK, Eschenbach DA. A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988;319:972–8.[Abstract]

2. Hay PE, Lamont RF, Taylor-Robinson D, Morgan DJ, Ison C, Pearson J. Abnormal bacterial colonization of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 1994;308:295–8.[Abstract/Free Full Text]

3. Llahi-Camp JM, Rai R, Ison C, Regan L, Taylor-Robinson D. Association of bacterial vaginosis with a history of second trimester miscarriage. Hum Reprod 1996;11:1575–8.[Abstract/Free Full Text]

4. Kurki T, Sivonen A, Renkonen OV, Savia E, Ylikorkala O. Bacterial vaginosis in early pregnancy and pregnancy outcome. Obstet Gynecol 1992;80:173–7.[Abstract/Free Full Text]

5. Hay PE, Morgan DJ, Ison CA, Bhide SA, Romney M, McKenzie P, et al. A longitudinal study of bacterial vaginosis during pregnancy. Br J Obstet Gynaecol 1994;101:1048–53.[Medline]

6. Gratacos E, Figueras F, Barranco M, Vila J, Cararach V, Alonso PL, et al. Spontaneous recovery of bacterial vaginosis during pregnancy is not associated with an improved perinatal outcome. Acta Obstet Gynecol Scand 1998;77:37–40.[Medline]

7. Goplerud CP, Ohm MJ, Galask RP. Aerobic and anaerobic flora of the cervix during pregnancy and the puerperium. Am J Obstet Gynecol 1976;126:858–68.[Medline]

8. Rosenstein IJ, Morgan DJ, Lamont RF, Sheehan M, Dore CJ, Hay PE, et al. Effect of intravaginal clindamycin cream on pregnancy outcome and on abnormal vaginal microbial flora of pregnant women. Infect Dis Obstet Gynecol 2000;8:158–65.[Medline]

9. McDonald HM, O'Loughlin JA, Vigneswaran R, Jolley PT, Harvey JA, Bof A, et al. Impact of metronidazole therapy on preterm birth in women with bacterial vaginosis flora (Gardnerella vaginalis): a randomized, placebo controlled trial. Br J Obstet Gynaecol 1997;104:1391–7.[Medline]

10. Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 2000;342:534–40.[Abstract/Free Full Text]

11. Ugwumadu A, Manyonda I, Reid F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised controlled trial. Lancet 2003;361:983–8.[Medline]

12. Lamont RF, Duncan SL, Mandal D, Bassett P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol 2003;101:516–22.[Abstract/Free Full Text]

13. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol 1991;29:297–301.[Abstract/Free Full Text]

14. McDonald HM, O'Loughlin JA, Vigneswaran R, Jolley PT, McDonald PJ. Bacterial vaginosis in pregnancy and efficacy of short-course oral metronidazole treatment: a randomized controlled trial. Obstet Gynecol 1994;84:343–8.[Abstract/Free Full Text]

15. Kekki M, Kurki T, Pelkonen J, Kurkinen-Raty M, Cacciatore B, Paavonen J. Vaginal clindamycin in preventing preterm birth and peripartal infections in asymptomatic women with bacterial vaginosis: a randomized, controlled trial. Obstet Gynecol 2001;97:643–8.[Abstract/Free Full Text]

16. Vermeulen GM, van Zwet AA, Bruinse HW. Changes in the vaginal flora after two percent clindamycin vaginal cream in women at high risk of spontaneous preterm birth. BJOG 2001;108:697–700.[Medline]

17. 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.[Medline]

18. Vermeulen GM, Bruinse HW. Prophylactic administration of clindamycin 2% vaginal cream to reduce the incidence of spontaneous preterm birth in women with an increased recurrence risk: a randomised placebo-controlled double-blind trial. Br J Obstet Gynaecol 1999;106:652–7.[Medline]

19. 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.[Medline]

20. Meis PJ, Goldenberg RL, Mercer B, Moawad A, Das A, McNellis D, et al. The preterm prediction study: significance of vaginal infections. Am J Obstet Gynecol 1995;173:1231–5.[Medline]

21. Hillier SL, Nugent RP, Eschenbach DA, Krohn MA, Gibbs RS, Martin DH, et al. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant: The Vaginal Infections and Prematurity Study Group. N Engl J Med 1995;333:1737–42.[Abstract/Free Full Text]

22. Oakeshott P, Hay P, Hay S, Steinke F, Rink E, Kerry S. Association between bacterial vaginosis or chlamydial infection and miscarriage before 16 weeks’ gestation: prospective community based cohort study. BMJ 2002;325:1334–8.[Abstract/Free Full Text]




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