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Metronidazole treatment of asymptomatic bacterial vaginosis did not reduce the preterm delivery rate
OB S T E TR ICS
Metronidazole treatment of asymptomatic bacterial vaginosis did not reduce the preterm delivery rate Carey JC, Klebanoff MA, Hauth JC, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 2000;342:534d540
OBJECTIVE To determine if metronidazole treatment of asymptomatic bacterial vaginosis in pregnant women prevents preterm delivery. DESIGN Multicentre, randomized, double-blind, placebo-controlled trial. Allocation was computer-generated and stratified by centre, using coded medications. The study had sufficient power to detect an absolute difference of 4.5% in preterm delivery rate. SETTING Network of Maternal-Fetal Medicine Units in the USA. SUBJECTS 1963 women, mean age 23 years, who were 16–23 (mean 20) weeks pregnant and were asymptomatic, but had bacterial vaginosis on screening. Women were excluded if they had received antibiotics or tested positive for Trichomonas vaginalis or other infections. 11% of women had had a previous preterm delivery. Outcome data were missing for (2% of women. INTERVENTION 966 women were randomized to receive oral metronidazole 250 mg/capsule, and 987 women to receive placebo. The women took the first course of 8 capsules at the clinic and another 8 capsules 48 hours later. At least 2 weeks later, treatment with the two-dose regimen was repeated. MAIN OUTCOME MEASURES Preterm birthweight, resolution of bacterial vaginosis.
delivery,
Commentary With an enrolment of 1953 women, this important study is the largest of the randomised, placebo-controlled trials of antibiotic treatment of bacterial vaginosis during pregnancy. This sample size was sufficient to detect a relative reduction of at least 47% in spontaneous preterm delivery in women with bacterial vaginosis, in a population with an untreated rate of 5.7%. The primary outcomes in this study were preterm delivery (37 weeks’ gestation, birthweight and resolution of bacterial vaginosis. However, the most important outcome measure is preterm delivery following spontaneous preterm labour. The rates of this outcome were 5.1% in the metronidazole group and 5.7% in the placebo group (not statistically significant). The authors concluded that treatment of pregnant women with asymptomatic bacterial vaginosis with oral metronidazole in the second trimester did not reduce the occurrence of preterm delivery at (37 weeks or (32 weeks. However, it would have been useful to compare the rates of spontaneous preterm birth at (32 weeks, especially for women with a previous spontaneous preterm delivery. This study did not find evidence that treatment of bacterial vaginosis in women with a previous spontaneous preterm delivery reduced the preterm ((37 weeks) birth rate. However, a power calculation shows that the small size of this subgroup (80 per treatment group) provided power to detect only very large reductions in preterm birth rate, i.e. a relative reduction of at least 74% from the placebo rate of 22.5% to 5.9% or lower. In studies such as this one, it is very difficult to recruit the required sample size. In this case, the number of participating centres was large, although we were not told the exact number. Recruitment rates, demographic characteristics of the subjects, and preterm birth rates at each centre were not provided. Also, the recruitment rate of 30% of
86
Evidence-based Obstetrics and Gynecology (2000) 2, 86 doi:10.1054/ebog.2000.0189, available online at http://www.idealibrary.com on
MAIN RESULTS Preterm delivery at (37 weeks gestation occurred in 12.2% of the metronidazole group and 12.5% of the placebo group (P"0.81*, relative risk (RR) 1.0, 95% CI 0.8–1.2). Preterm delivery occurred as a result of spontaneous labour in 5.1 and 5.7%, respectively (P"0.59*, RR 0.9, CI 0.6–1.3) and as a result of spontaneous rupture of the membranes in 4.2 and 3.7%, respectively, (P"0.60*, RR 1.1, CI 0.7–1.8). There was no significant difference between groups in the proportions of women who delivered before 35 weeks (5.0 vs 5.1%, RR 1.0, CI 0.7–1.5) or before 32 weeks (2.3 vs 2.7%, RR 0.9, CI 0.5–1.5). The rate of low-birthweight infants ((2500 g) was 10.9% in the metronidazole group and 11.4% in the placebo group (P"0.74*) and the rates of very low-birthweight infants ((1500 g) were 2.0 and 2.7%, respectively (P"0.31*). 90% of women returned for the second clinic visit. 22% of women in the metronidazole group and 9% in the placebo group reported side-effects, mainly gastrointestinal symptoms (P(0.0001). Resolution of bacterial vaginosis by the second clinic visit occurred in 78 and 37% of women, respectively (P(0.0001), but the presence of infection had no effect on preterm delivery. CONCLUSION In pregnant women with asymptomatic bacterial vaginosis, oral metronidazole treatment in midgestation did not reduce the risk of preterm delivery. *Calculated from data in article.
potentially eligible subjects was low. Another difficulty lies in the late timing of randomisation and treatment, being up to 8 weeks after the detection of bacterial vaginosis, at which time one-quarter of the women in each group had a negative test for bacterial vaginosis. This high rate of spontaneous resolution would reduce any therapeutic effect of antibiotic treatment. All these factors may have contributed to the failure to achieve a significant reduction in preterm delivery rate in the treatment group. In considering the implications for clinical practice, it should be remembered that, as in previous studies, women with symptomatic bacterial vaginosis or concurrent Trichomoniasis were excluded from the study. These women are at highest risk of associated adverse outcomes. Whilst the current evidence does not support screening and treatment of all pregnant women for asymptomatic bacterial vaginosis, symptomatic women should be treated. In this study, antibiotic treatment was given during the second trimester. As the authors suggested, this stage of pregnancy may be too late to prevent adverse effects; the ideal time for treatment of bacterial vaginosis may be prior to conception. Although this study did not provide evidence to justify screening all pregnant women for bacterial vaginosis, current research is focused on identifying subgroups of women at the highest risk for adverse sequelae of infection. This study does not change the current recommendation for clinical practice, that women with a previous preterm birth should be screened and treated for bacterial vaginosis during pregnancy.1 Helen McDonald, PhD Women’s and Children’s Hospital, Adelaide, Australia
Literature cited 1. Lamont RF. Antibiotics for the prevention of preterm birth. N Engl J Med 2000; 342:581d582
^ 2000 Harcourt Publishers Ltd
Metronidazole treatment of asymptomatic bacterial vaginosis did not reduce the preterm delivery rate Carey JC, Klebanoff MA, Hauth JC, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 2000;342:534d540
OBJECTIVE To determine if metronidazole treatment of asymptomatic bacterial vaginosis in pregnant women prevents preterm delivery. DESIGN Multicentre, randomized, double-blind, placebo-controlled trial. Allocation was computer-generated and stratified by centre, using coded medications. The study had sufficient power to detect an absolute difference of 4.5% in preterm delivery rate. SETTING Network of Maternal-Fetal Medicine Units in the USA. SUBJECTS 1963 women, mean age 23 years, who were 16–23 (mean 20) weeks pregnant and were asymptomatic, but had bacterial vaginosis on screening. Women were excluded if they had received antibiotics or tested positive for Trichomonas vaginalis or other infections. 11% of women had had a previous preterm delivery. Outcome data were missing for (2% of women. INTERVENTION 966 women were randomized to receive oral metronidazole 250 mg/capsule, and 987 women to receive placebo. The women took the first course of 8 capsules at the clinic and another 8 capsules 48 hours later. At least 2 weeks later, treatment with the two-dose regimen was repeated. MAIN OUTCOME MEASURES Preterm birthweight, resolution of bacterial vaginosis.
delivery,
Commentary With an enrolment of 1953 women, this important study is the largest of the randomised, placebo-controlled trials of antibiotic treatment of bacterial vaginosis during pregnancy. This sample size was sufficient to detect a relative reduction of at least 47% in spontaneous preterm delivery in women with bacterial vaginosis, in a population with an untreated rate of 5.7%. The primary outcomes in this study were preterm delivery (37 weeks’ gestation, birthweight and resolution of bacterial vaginosis. However, the most important outcome measure is preterm delivery following spontaneous preterm labour. The rates of this outcome were 5.1% in the metronidazole group and 5.7% in the placebo group (not statistically significant). The authors concluded that treatment of pregnant women with asymptomatic bacterial vaginosis with oral metronidazole in the second trimester did not reduce the occurrence of preterm delivery at (37 weeks or (32 weeks. However, it would have been useful to compare the rates of spontaneous preterm birth at (32 weeks, especially for women with a previous spontaneous preterm delivery. This study did not find evidence that treatment of bacterial vaginosis in women with a previous spontaneous preterm delivery reduced the preterm ((37 weeks) birth rate. However, a power calculation shows that the small size of this subgroup (80 per treatment group) provided power to detect only very large reductions in preterm birth rate, i.e. a relative reduction of at least 74% from the placebo rate of 22.5% to 5.9% or lower. In studies such as this one, it is very difficult to recruit the required sample size. In this case, the number of participating centres was large, although we were not told the exact number. Recruitment rates, demographic characteristics of the subjects, and preterm birth rates at each centre were not provided. Also, the recruitment rate of 30% of
86
Evidence-based Obstetrics and Gynecology (2000) 2, 86 doi:10.1054/ebog.2000.0189, available online at http://www.idealibrary.com on
MAIN RESULTS Preterm delivery at (37 weeks gestation occurred in 12.2% of the metronidazole group and 12.5% of the placebo group (P"0.81*, relative risk (RR) 1.0, 95% CI 0.8–1.2). Preterm delivery occurred as a result of spontaneous labour in 5.1 and 5.7%, respectively (P"0.59*, RR 0.9, CI 0.6–1.3) and as a result of spontaneous rupture of the membranes in 4.2 and 3.7%, respectively, (P"0.60*, RR 1.1, CI 0.7–1.8). There was no significant difference between groups in the proportions of women who delivered before 35 weeks (5.0 vs 5.1%, RR 1.0, CI 0.7–1.5) or before 32 weeks (2.3 vs 2.7%, RR 0.9, CI 0.5–1.5). The rate of low-birthweight infants ((2500 g) was 10.9% in the metronidazole group and 11.4% in the placebo group (P"0.74*) and the rates of very low-birthweight infants ((1500 g) were 2.0 and 2.7%, respectively (P"0.31*). 90% of women returned for the second clinic visit. 22% of women in the metronidazole group and 9% in the placebo group reported side-effects, mainly gastrointestinal symptoms (P(0.0001). Resolution of bacterial vaginosis by the second clinic visit occurred in 78 and 37% of women, respectively (P(0.0001), but the presence of infection had no effect on preterm delivery. CONCLUSION In pregnant women with asymptomatic bacterial vaginosis, oral metronidazole treatment in midgestation did not reduce the risk of preterm delivery. *Calculated from data in article.
potentially eligible subjects was low. Another difficulty lies in the late timing of randomisation and treatment, being up to 8 weeks after the detection of bacterial vaginosis, at which time one-quarter of the women in each group had a negative test for bacterial vaginosis. This high rate of spontaneous resolution would reduce any therapeutic effect of antibiotic treatment. All these factors may have contributed to the failure to achieve a significant reduction in preterm delivery rate in the treatment group. In considering the implications for clinical practice, it should be remembered that, as in previous studies, women with symptomatic bacterial vaginosis or concurrent Trichomoniasis were excluded from the study. These women are at highest risk of associated adverse outcomes. Whilst the current evidence does not support screening and treatment of all pregnant women for asymptomatic bacterial vaginosis, symptomatic women should be treated. In this study, antibiotic treatment was given during the second trimester. As the authors suggested, this stage of pregnancy may be too late to prevent adverse effects; the ideal time for treatment of bacterial vaginosis may be prior to conception. Although this study did not provide evidence to justify screening all pregnant women for bacterial vaginosis, current research is focused on identifying subgroups of women at the highest risk for adverse sequelae of infection. This study does not change the current recommendation for clinical practice, that women with a previous preterm birth should be screened and treated for bacterial vaginosis during pregnancy.1 Helen McDonald, PhD Women’s and Children’s Hospital, Adelaide, Australia
Literature cited 1. Lamont RF. Antibiotics for the prevention of preterm birth. N Engl J Med 2000; 342:581d582
^ 2000 Harcourt Publishers Ltd