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Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI
Dr. Allen reports she receives grant/research support from Bayer and is a consultant for Merck.
SYNOPSIS: In this randomized, controlled trial from France, screening for and treatment of bacterial vaginosis in pregnant women at low risk for preterm birth with oral clindamycin or placebo did not reduce the rate of spontaneous preterm birth between 16 and 36 weeks.
SOURCE: Subtil D, Brabant G, Tilloy E, et al. Early clindamycin for bacterial vaginosis in pregnancy (PREMEVA): A multicentre, double-blind, randomised controlled trial. Lancet 2018;392:2171-2179.
This randomized, double-blind, placebo-controlled trial was conducted at 40 centers in France between 2006 and 2011. Researchers screened adult women for bacterial vaginosis (BV) during the first trimester of pregnancy. Self-collected samples were sent to the laboratory for Gram staining, and Nugent scores were calculated (7 or higher defined BV). Women with BV, no history of second trimester pregnancy loss (16 to 21 6/7 weeks), and no history of preterm delivery (22 to 36 6/7 weeks) were invited to participate in the trial. Exclusion criteria included gestational age 15 weeks or greater, allergy to clindamycin, vaginal bleeding within the week of screening for BV, or planning to deliver in a different region of France. Participants were assigned randomly to either a single-course clindamycin (300 mg orally twice a day for four days × 1 with placebo for the remaining two months), triple-course clindamycin (300 mg orally twice a day for four days every month for three months), or placebo for three months. Women with BV at high risk for preterm delivery (history of second trimester pregnancy loss or preterm delivery) were offered participation in a subtrial and were randomized to either single-course clindamycin or triple-course clindamycin without a placebo arm. The primary outcome was the rate of spontaneous delivery between 16 and 32 weeks.
A total of 2,869 women were assigned randomly to groups in the low-risk trial (943 single-course clindamycin, 968 triple-course clindamycin, and 958 placebo) and 236 in the high-risk trial (122 single-course, 114 triple-course). Half of the participants were nulliparous, and the median gestational age at randomization was 12 4/7 weeks. Ninety-five percent of women began treatment before 15 weeks’ gestation. A total of 1.2% of women in the clindamycin group and 1.0% of women in the placebo group delivered spontaneously between 16 and 32 weeks (P = 0.82). Preterm delivery between 22 and 36 6/7 weeks also was similar between the groups (4.8% vs. 4.1%; P = 0.40). A repeat analysis measuring compliance with the regimen by counting pills showed no difference. The most common adverse event in the clindamycin group was diarrhea (1.6%). The high-risk subtrial also showed no differences in preterm delivery between 16 and 32 weeks with the two regimens of clindamycin (triple-course 4.4% vs. single-course 6.6%; P = 0.47), but there was no placebo arm.
BV occurs when the vaginal microbiome is disrupted with an overgrowth of anaerobic bacteria (Gardnerella vaginalis and other species) and an absence of vaginal lactobacilli.1 BV can be diagnosed with a Gram stain of vaginal flora (Nugent score), a wet prep to evaluate for clue cells, elevated vaginal pH and a positive whiff test, or a DNA probe assay for detecting G. vaginalis when present at a high concentration. BV now is recognized as a biofilm infection, and it has been found that this biofilm can ascend into the uterine cavity.1 This may explain the association of BV with adverse outcomes such as preterm birth, chorioamnionitis, endometritis after delivery or abortion, and pelvic inflammatory disease.
The relationship between BV and preterm birth has been well documented. Previous meta-analyses have shown an association between BV and preterm birth before 37 weeks, especially when BV was present early in gestation.2 Researchers surmise that ascending bacteria early in pregnancy could predispose certain patients to preterm birth. However, several studies and meta-analyses on screening for and treatment of BV in pregnant women at low risk for preterm delivery have yielded conflicting results.3 Similarly, in pregnant women at high risk for preterm delivery, screening for and treatment of BV has been controversial.1 The Centers for Disease Control and Prevention (CDC) currently states, “Evidence is insufficient to recommend routine screening for BV in asymptomatic pregnant women at high or low risk for preterm delivery for the prevention of preterm birth.”3
Subtil et al wanted to perform a large trial to finally answer the question about the utility of this intervention in pregnant women at low risk for preterm birth. The study has several strengths, including the large sample size, objective criteria for diagnosis of BV, and randomization. It is not clear how the authors determined which BV treatment regimen to use. Oral clindamycin 300 mg twice daily for four days is not a regimen endorsed by the CDC in the United States, but perhaps it is common in France. The CDC classifies oral clindamycin 300 mg twice daily for seven days as an alternative regimen, not a preferred one. Nevertheless, the authors of previous trials of clindamycin for preterm birth used the same dosing for five days and showed eradication of BV in more than 90% of cases.
The study clearly showed no benefit for low-risk women. Interestingly, for the high-risk group that participated in the subtrial, the authors noted that French ethics guidelines prevented them from including a placebo arm. Unfortunately, the lack of the placebo arm prevents us from drawing any conclusions about the efficacy of the intervention in preventing preterm birth in that population. I do not think that including a placebo arm would have been unethical given the uncertainty of the benefits of the intervention. More research is needed to elucidate which populations of women should be screened and treated for BV in pregnancy to prevent adverse sequelae. There may be a genetic component that increases susceptibility to BV-associated preterm birth that we have not yet elucidated. For now, however, it is clear that although symptomatic pregnant women with BV should be diagnosed and treated, there is no evidence for screening and treating asymptomatic pregnant women.
Financial Disclosure: OB/GYN Clinical Alert’s Editor Jeffrey T. Jensen, MD, MPH, reports that he is a consultant for and receives grant/ research support from ObstetRx, Bayer, Merck, and Sebela; he receives grant/research support from Abbvie, Mithra, and Daré Bioscience; and he is a consultant for CooperSurgical and the Population Council. Peer Reviewer Catherine Leclair, MD; Nurse Planner Marci Messerle Forbes, RN, FNP; Editorial Group Manager Terrey L. Hatcher; Executive Editor Leslie Coplin; and Editor Jonathan Springston report no financial relationships relevant to this field of study.