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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki; Helsinki City Health Department, Helsinki; Department of Obstetrics and Gynecology, Oulu University Central Hospital, Oulu; and Vihti Health Center, Vihti, Finland.
Address reprint requests to: M. Kekki, MD Helsinki University Central Hospital Department of Obstetrics and Gynecology Haartmaninkatu 2 Helsinki, 00290 Finland E-mail: minnamaija.kekki{at}hus.fi
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Abstract |
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Methods: In this multicenter, randomized, double-masked, placebo-controlled intervention trial, screening for BV was performed by vaginal Gram stain obtained from 5432 healthy women with singleton pregnancies during the first antenatal clinic visit at 10–17 weeks’ gestation. Bacterial vaginosis-positive women with no past history of preterm delivery were randomized to a single course of treatment with either 2% vaginal clindamycin cream or identical placebo cream for 7 days. Repeat Gram stains were taken 1 week after treatment and at 30–36 weeks’ gestation. Preterm delivery was defined as spontaneous delivery before 37 gestational weeks. Peripartum infectious morbidity was defined as postpartum endometritis, postpartum sepsis, postcesarean wound infection, or episiotomy wound infection, necessitating antimicrobial therapy. According to the power analysis, 180 patients were needed for both treatment arms to show a three-fold difference in the rates of preterm births.
Results: The overall prevalence of BV was 10.4%. Of all BV-positive women, 375 (66%) were randomized to the treatment arms. The primary cure rate was 66% in the clindamycin group; in the placebo group, 34% spontaneously cleared BV (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.3, 2.8). The rate of preterm deliveries was 5% in the clindamycin group and 4% in the placebo group (OR 1.3, 95% CI 0.5, 3.5). The rate of peripartum infectious morbidity was 11% in the clindamycin group and 18% in the placebo group (OR 1.6, 95% CI 0.9, 2.8). Bacterial vaginosis recurred in 7% of women. The rate of preterm deliveries was 15% in this subgroup compared with 2% among women who remained BV negative (OR 9.3, 95% CI 1.6, 53.5).
Conclusion: Vaginal clindamycin did not decrease the rate of preterm deliveries or peripartum infections, but recurrent or persistent BV increased the risk for these complications.
Preterm birth and peripartum infections are still major problems in obstetrics. Preterm birth is a complex syndrome with known or suspected risk factors including biochemical, immunologic, histopathologic, and anatomic factors, and infections.1 Data suggest that there is a link between ascending infection of the maternal genital tract and preterm birth.2,3 Bacterial vaginosis (BV) has been identified as a risk factor for preterm delivery by multiple studies, with an odds ratio (OR) that varies from 1.4 to 6.9.4–10 However, it is not clear whether BV is a cause of preterm delivery or just an association.
Randomized, controlled trials in high-risk populations have provided some evidence that treatment of BV during pregnancy can reduce preterm deliveries,11–13 but studies conducted among women with moderate risk for preterm birth have been conflicting.14,15 A recent meta-analysis concluded that there is no benefit of screening and treating BV in pregnancy in the general population (Guise JM, Aickin M, Helfand M, Peipert J, Westoff C: ACOG 48th Annual Clinical Meeting, May 20–24, 2000, San Francisco, CA). However, no randomized, controlled trial has shown so far whether treating BV can reduce preterm deliveries or other BV-associated outcomes of delivery in truly low-risk populations. The purpose of this multicenter study was to evaluate whether clindamycin given intravaginally decreases the rates of preterm birth and peripartum infections in a low-risk population.
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Materials and Methods |
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A vaginal smear was taken from the posterior vaginal fornix during the first antenatal clinic visit between 10 and 17 weeks’ gestation and Gram stained. According to the Gram stain findings, the appearance of BV was quantified using a semiquantitative scale as described.6 During the same visit, cervical specimens for Chlamydia trachomatis and Neisseria gonorrhoeae were taken. A repeat vaginal Gram-stained smear was taken 1 week after the treatment, and again during the third trimester (range 30–36 weeks’ gestation). Cure was defined by Gram stain criteria.
Block randomization was used within each centre, and the treatment group allocations were kept in sealed opaque envelopes. The investigators who read the Gram stains were blinded as to whether or not patients received clindamycin. Those who agreed to participate were randomly assigned by a previously generated randomization list to receive either 2% clindamycin phosphate vaginal cream or an identical-appearing placebo vaginal cream once daily for 7 days. Treatment was double masked. A total of 188 women were randomized to the placebo arm, and 187 women were randomized to the clindamycin arm (Figure 1
). Of the 375 patients randomized to the treatment arms, 93 patients from Oulu have been included in another report from the same multicenter study.17
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Vaginal smears were evaluated as previously described.6 Briefly, Gram-stained slides were examined under oil immersion (x1000), and bacteria were quantitated according to Spiegel et al18 as scanty (1+) (less than one to five bacteria per field), moderate (2+) (six to 30 bacteria per field), or abundant (3+) (more than 30 bacteria per field). Gram stain findings were classified into three categories: normal, ie, bacteria consisting totally (3+) or mainly (2+) of nonsporeforming gram-positive rods (Lactobacillus morphotype); BV, ie, Lactobacillus-morphotype bacteria being absent or diminished (1+) compared with other bacteria, especially gram-negative and gram-variable rods (Gardnerella morphotype); or intermediate, ie, small number of bacteria (1+), or bacteria consisting of a mixture of different morphotypes none dominating. Yeast cells, two or more, were also included in this category.
Cervical swabs were tested by MicroTrak II Chlamydia EIA (Behring Diagnostics Inc., Cupertino, CA) antigen test for C. trachomatis. All enzyme immunoassay positive samples were confirmed by direct fluorescent antibody Syva MicroTrak C. trachomatis Direct Specimen Test (Behring Diagnostics Inc.). Cervical swab samples were placed in transport media (Transpocult, Oriola Oy, Helsinki, Finland) and cultured for N. gonorrhoeae.
Power analysis showed that approximately 180 patients were needed for both treatment arms to show a three-fold difference in the number of preterm births (ie, 4% compared with 12%; two-sided test) with 80% power at P level of .05. Odds ratios with 95% confidence intervals (CI) were calculated.19 The treatment results were analyzed according to the intention-to-treat principle.20 The four-fold tables were analyzed using Fisher’s exact probability test.
The interobserver agreement of the Gram stain diagnosis of BV between the study centers was 93% as tested by kappa statistics (data not shown). A total of 104 slides were independently reviewed in masked fashion by two observers who reviewed all slides in the study. Disagreements were resolved by consensus agreement.
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Results |
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). Overall, 171 women refused to participate in the study, and 19 women were excluded because of various other reasons, including multiple pregnancies (n = 2), history of preterm birth (n = 4), move to another city (n = 8), or induced (n = 1) or spontaneous abortion (n = 4) (Figure 1).
Selected clinical characteristics of the study population are shown in Table 1. There was center-to-center variation in the prevalence of BV and in the rate of preterm deliveries between the centers, as shown in Table 1. Ten (3%) of the 375 BV-positive women were positive for C. trachomatis. None had N. gonorrhoeae. The cure rate 1 week after the treatment was 66% (119 of 181) in the clindamycin group. In the placebo group, 34% (62 of 181) cleared BV spontaneously (OR 1.9, 95% CI 1.3, 2.8). Thirteen patients did not attend the first follow-up visit.
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). It was 5% (nine of 187) in the clindamycin group and 4% (seven of 188) in the placebo group (OR 1.3, 95% CI 0.5, 3.5).
The overall rate of peripartum infections was 14% (54 of 375) (Table 1). These included postpartum endometritis (n = 25), postpartum sepsis (n = 3), cesarean wound infection (n = 5), episiotomy wound infection (n = 17), endometritis with episiotomy wound infection (n = 2), and endometritis with cesarean wound infection (n = 2). The rate of peripartum infections was 11% (21 of 187) in the clindamycin group and 18% (33 of 188) in the placebo group (OR 1.6, 95% CI 0.9, 2.8) (Table 1).
Bacterial vaginosis persisted in 31% (115 of 375) and recurred in 7% (26 of 375) of the study population. The overall rate of preterm deliveries and peripartum infections was almost three times higher in the study groups in which BV persisted or recurred during the pregnancy (40 of 141, 28%) compared with the group in which BV was cured (12 of 121, 10%) (OR 2.9, 95% CI 1.3, 5.2). However, there was no overall difference between the clindamycin and placebo arms (Table 2).
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We next performed a subgroup analysis of the rate of preterm deliveries among women who attended both follow-up visits excluding women with intermediate Gram stain findings. The rate of preterm deliveries was 15% (four of 26) in the subgroup in which BV was first cured but later recurred, but only 2% (two of 121) in the subgroup in which BV did not recur (OR 9.3, 95% CI 1.6, 53.5) (Table 3).
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Discussion |
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The efficacy of intravaginal clindamycin has been reported to be up to 90% and it is similar to oral metronidazole in the treatment of BV in nonpregnant women.21,22 In this study, the efficacy of the treatment was only 66%, which is somewhat lower than in the study by Carey et al (78%).15 However, it is not unexpected that the cure rate with topical clindamycin is lower than with systemic metronidazole.
The natural history of BV in pregnant women has been reasonably well studied. Bacterial vaginosis seems to resolve in up to 50% of cases during pregnancy.23 In our placebo arm, BV resolved spontaneously in 34% of cases as also previously reported.24 This suggests that BV does not necessarily persist throughout pregnancy, and therefore single screening in early pregnancy may not be the best diagnostic strategy.
The overall prevalence of BV in this study was lower (10%) than in our earlier study with nulliparous women (21%), although the same diagnostic criteria for BV were used in both studies. This difference is difficult to explain, but may indicate just some biologic fluctuation in the prevalence of BV taking place over time, or that women with previous full-term births were also included in the present study.
In light of other recent reports from moderate-risk or high-risk populations,11–15 it is not surprising that intravaginal clindamycin did not decrease the overall rate of spontaneous preterm deliveries or peripartum infections. Our results are also in accordance with another study showing that topical treatment in early pregnancy only reduced vaginal fluid mucinase and sialidase activities, but did not reduce the rate of preterm births.25 Another explanation for the poor efficacy of intravaginal clindamycin is the possibility that infection already exists in the choriodecidual interface unreachable to topical therapy.26 However, systemic antibiotic treatment of pregnant women has also failed to decrease the rate of preterm births,14,15 suggesting that eradication of BV during pregnancy is difficult and other treatment strategies should be considered.27 Alternatively, BV can be just a surrogate risk marker of another yet undefined and more specific risk factor for preterm delivery.
The overall recurrence rate of BV was 7%, and the infectious morbidity in this subgroup was strikingly high. In fact, recurrent BV increased the risk for preterm delivery nine-fold when compared with women who remained BV negative through the rest of the gestation.
Intravaginal clindamycin not only was ineffective in decreasing the rate of preterm deliveries, but seemed to increase the rate. It has been suggested that intravaginal clindamycin might select Escherichia coli and other virulent Gram-negative bacteria to grow in the vagina, which can actually increase the risk for preterm delivery.21
It is possible that BV causes an invasive ascending infection to the fetal membranes already in early pregnancy.26,28 Therefore, intravaginal treatment may only temporarily suppress BV leaving the upper genital tract infection untreated. If so, BV should be retreated as early in pregnancy as possible or perhaps even before pregnancy.27 Retreatment later in pregnancy has not been very successful in previous studies.14,15,29 Another possibility would be to apply a biochemical marker such as insulin-like growth factor binding protein-1, which can identify those BV-positive pregnant women who have the highest risk for infectious complications during pregnancy and the puerperium.26 Such a secondary risk marker could be useful in identifying susceptible women who should receive effective therapy early.27 However, as stated in recent reviews,27,28 more studies are clearly needed in this important area before it can be definitively concluded that screening and treatment of BV in pregnancy can reduce the rate of preterm deliveries.
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Footnotes |
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Received August 15, 2000. Received in revised form January 2, 2001. Accepted January 8, 2001.
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References |
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2. Minkoff H. Prematurity: Infection as an etiologic factor. Obstet Gynecol 1983;62:137–44.
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9. Meis PJ, Goldenberg RL, Mercer B, Moawad A, Das A, McNellis D, et al. The preterm prediction study: Significance of vaginal infections. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 1995;173:1231–5.[Medline]
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15. 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.
16. Charles D, Larsen B. Puerperal sepsis. In: Turnbull A, Chamberlein G, eds. Obstetrics. Edinburgh: Churchill Livingstone, 1989:917–32.
17. Kurkinen-Räty M, Vuopala S, Koskela M, Kekki M, Kurki T, Paavonen J, et al. A randomized controlled trial of vaginal clindamycin for early pregnancy bacterial vaginosis. Br J Obstet Gynaecol 2000;107:1427–32.
18. Spiegel CA, Amsel R, Eschenbach DA, Schoenknecht F, Holmes KK. Diagnosis of bacterial vaginosis by direct Gram stain of vaginal fluid. J Clin Microbiol 1983;18:170–7.
19. Morris J, Gardner M. Calculating confidence intervals for relative risks, odds ratios, and standardized ratios and rates. In: Gardner M, Altman D, eds. Statistics with confidence. London: British Medical Journal, 1989:50–63.
20. Hollis S, Cambell F. What is meant by intention to treat analysis? Survey of published randomized controlled trials. BMJ 1999;319: 670–4.
21. Hillier S, Krohn MA, Watts DM, Wolner-Hanssen P, Eschenbach D. Microbiologic efficacy of intravaginal clindamycin cream for the treatment of bacterial vaginosis. Obstet Gynecol 1990;76:407–13.
22. Andres FJ, Parker R, Hosein I, Benrubi GI. Clindamycin vaginal cream versus oral metronidazole in the treatment of bacterial vaginosis: A prospective double-blind clinical trial. South Med J 1992;85:1077–80.[Medline]
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25. 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.[Medline]
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29. 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 randomized placebo-controlled double-blind trial. Br J Obstet Gynaecol 1999;106:652–7.[Medline]
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