- Email: [email protected]
Closing discussion by Dr Carey
Carey and Klebanoff
References 1. Goldenberg RL, Rouse DJ. The prevention of premature birth. N Engl J Med 1998;339:313-20. 2. Cotch MF, Pastorek JG, Nugent RP, Hillier SL, Gibbs RS, Martin DH, et al. Trichomonas vaginalis associated with low birth weight and preterm delivery. The Vaginal Infections and Prematurity Study Group. Sex Transm Dis 1997;24:353-60. 3. Elder HA, Santamarina BAG, Smith S, Kass EH. The natural history of asymptomatic bacteriuria during pregnancy: the effect of tetracycline on the clinical course and the outcome of pregnancy. Am J Obstet Gynecol 1971;111:441-61. 4. 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. 5. Andrews WW, Sibai BM, Thom EA, Dudley D, Ernest JM, McNeffis D, et al. Randomized clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal fibronectin-positive women. Obstet Gynecol 2003;101:847-55. 6. Klebanoff MA, Carey JC, Hauth JC, Hillier SL, Nugent RP, Thom EA, et al. Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl J Med 2001;345:487-93. 7. Kigozi GG, Brahmbhatt H, Wabwire-Mangen F, Wawer MJ, Serwadda D, Sewankambo N, et al. Treatment of Trichomonas in pregnancy and adverse outcomes of pregnancy: a subanalysis of a randomized trial in Rakai, Uganda. Am J Obstet Gynecol 2003;189:l398-400. 8. Carey JC, Klebanoff MA. Is a change in the vaginal flora associated with an increased risk of preterm birth? Am J Obstet Gynecol 2005;192:1341-7. 9. Carey JC, Yaffe SJ, Catz C. The Vaginal Infections and Prematurity Study: an overview. Clin Obstet Gynecol 1993;36:809-20.
DR CAREY (Closing). We initially analyzed gestational age as a continuous variable, and performed multiple analyses of variance using PROC GLM on SAS for the PC. We found that an increase in E coli or K pneumoniae was associated with lower mean gestational age after controlling for prepregnancy weight !100 pounds, vaginal pH >5.0, ethnicity, metronidazole before 32 weeks, primigravidity, and a change in other organisms (P = .02). We chose to present the data as a series of odds ratios for ease in comprehension. The P values for preterm birth with an acquisition of E coli was .0012, for K pneumoniae was .0014, and for either was ! .0001. It is highly unlikely that these are chance observations. The relationship between previous preterm birth and metronidazole therapy in the index pregnancy is complex. Women who were treated with metronidazole before 32 weeks were more likely to have a previous preterm birth (37/229 (16.2%) vs 1303/13,708 (9.5%), P ! .01). However, the increased risk of preterm birth
1347 Table
Recurrent preterm birth and metronidazole therapy Percent preterm birth
Metronidazole !32 wk
Yes
No
Previous preterm birth
9/37 (24.3%) 28/192 (14.6%)
279/1244 (22.4%) 1210/11,835 (10.2%)
No Previous preterm birth
with metronidazole therapy was seen primarily in those who did not have a previous preterm birth (see Table). The remarkable similarity between the results of the randomized trials of metronidazole therapy for bacterial vaginosis or T vaginalis and this study, and the fact that we did not see an increased risk of preterm birth in women with bacterial vaginosis in either study, strongly suggest that the effect seen is one of metronidazole therapy and not a surrogate marker for any other factor such as previous preterm birth. From this data set, we cannot prove that the increased risk of preterm birth seen in women treated with metronidazole before 32 weeks is caused by an increase in E coli or K pneumoniae in the vagina. We did not have enough women who were treated with metronidazole before 32 weeks and had delivery cultures to adequately analyze the association. Activation of decidual macrophages is thought to be a common inciting event for both preterm contractions and effacement of the cervix. Endotoxins1,2 and lipopolysaccharides3 produced by Gram-negative rods have been shown to increase placental production of interleukins and other cytokines, and the presence of endotoxin in the amniotic fluid is strongly associated with preterm birth.2 An increase in Gram-negative rods could well lead to an increase in endotoxins and activation of the cytokine pathway, leading to preterm labor.
References 1. Menon R, Swan KF, Lyden TW, Rote NS, Fortunato SJ. Expression of inflammatory cytokines (interleukin-1 beta and interleukin-6) in amniochorionic membranes. Am J Obstet Gynecol 1995;172:493-500. 2. Romero R, Sirtori M, Oyarzun E, Avila C, Mazor M, Callahan R, et al. Infection and labor. V. Prevalence, microbiology, and clinical. Am J Obstet Gynecol 1989;161:817-24. 3. Okada T, Matsuzaki N, Sawai K, Nobunaga T, Shimoya K, Suzuki K, et al. Chorioamnionitis reduces placental endocrine functions: the role of bacterial lipopolysaccharide and superoxide anion. J Endocrinol 1997;155:401-10.
References 1. Goldenberg RL, Rouse DJ. The prevention of premature birth. N Engl J Med 1998;339:313-20. 2. Cotch MF, Pastorek JG, Nugent RP, Hillier SL, Gibbs RS, Martin DH, et al. Trichomonas vaginalis associated with low birth weight and preterm delivery. The Vaginal Infections and Prematurity Study Group. Sex Transm Dis 1997;24:353-60. 3. Elder HA, Santamarina BAG, Smith S, Kass EH. The natural history of asymptomatic bacteriuria during pregnancy: the effect of tetracycline on the clinical course and the outcome of pregnancy. Am J Obstet Gynecol 1971;111:441-61. 4. 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. 5. Andrews WW, Sibai BM, Thom EA, Dudley D, Ernest JM, McNeffis D, et al. Randomized clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal fibronectin-positive women. Obstet Gynecol 2003;101:847-55. 6. Klebanoff MA, Carey JC, Hauth JC, Hillier SL, Nugent RP, Thom EA, et al. Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl J Med 2001;345:487-93. 7. Kigozi GG, Brahmbhatt H, Wabwire-Mangen F, Wawer MJ, Serwadda D, Sewankambo N, et al. Treatment of Trichomonas in pregnancy and adverse outcomes of pregnancy: a subanalysis of a randomized trial in Rakai, Uganda. Am J Obstet Gynecol 2003;189:l398-400. 8. Carey JC, Klebanoff MA. Is a change in the vaginal flora associated with an increased risk of preterm birth? Am J Obstet Gynecol 2005;192:1341-7. 9. Carey JC, Yaffe SJ, Catz C. The Vaginal Infections and Prematurity Study: an overview. Clin Obstet Gynecol 1993;36:809-20.
DR CAREY (Closing). We initially analyzed gestational age as a continuous variable, and performed multiple analyses of variance using PROC GLM on SAS for the PC. We found that an increase in E coli or K pneumoniae was associated with lower mean gestational age after controlling for prepregnancy weight !100 pounds, vaginal pH >5.0, ethnicity, metronidazole before 32 weeks, primigravidity, and a change in other organisms (P = .02). We chose to present the data as a series of odds ratios for ease in comprehension. The P values for preterm birth with an acquisition of E coli was .0012, for K pneumoniae was .0014, and for either was ! .0001. It is highly unlikely that these are chance observations. The relationship between previous preterm birth and metronidazole therapy in the index pregnancy is complex. Women who were treated with metronidazole before 32 weeks were more likely to have a previous preterm birth (37/229 (16.2%) vs 1303/13,708 (9.5%), P ! .01). However, the increased risk of preterm birth
1347 Table
Recurrent preterm birth and metronidazole therapy Percent preterm birth
Metronidazole !32 wk
Yes
No
Previous preterm birth
9/37 (24.3%) 28/192 (14.6%)
279/1244 (22.4%) 1210/11,835 (10.2%)
No Previous preterm birth
with metronidazole therapy was seen primarily in those who did not have a previous preterm birth (see Table). The remarkable similarity between the results of the randomized trials of metronidazole therapy for bacterial vaginosis or T vaginalis and this study, and the fact that we did not see an increased risk of preterm birth in women with bacterial vaginosis in either study, strongly suggest that the effect seen is one of metronidazole therapy and not a surrogate marker for any other factor such as previous preterm birth. From this data set, we cannot prove that the increased risk of preterm birth seen in women treated with metronidazole before 32 weeks is caused by an increase in E coli or K pneumoniae in the vagina. We did not have enough women who were treated with metronidazole before 32 weeks and had delivery cultures to adequately analyze the association. Activation of decidual macrophages is thought to be a common inciting event for both preterm contractions and effacement of the cervix. Endotoxins1,2 and lipopolysaccharides3 produced by Gram-negative rods have been shown to increase placental production of interleukins and other cytokines, and the presence of endotoxin in the amniotic fluid is strongly associated with preterm birth.2 An increase in Gram-negative rods could well lead to an increase in endotoxins and activation of the cytokine pathway, leading to preterm labor.
References 1. Menon R, Swan KF, Lyden TW, Rote NS, Fortunato SJ. Expression of inflammatory cytokines (interleukin-1 beta and interleukin-6) in amniochorionic membranes. Am J Obstet Gynecol 1995;172:493-500. 2. Romero R, Sirtori M, Oyarzun E, Avila C, Mazor M, Callahan R, et al. Infection and labor. V. Prevalence, microbiology, and clinical. Am J Obstet Gynecol 1989;161:817-24. 3. Okada T, Matsuzaki N, Sawai K, Nobunaga T, Shimoya K, Suzuki K, et al. Chorioamnionitis reduces placental endocrine functions: the role of bacterial lipopolysaccharide and superoxide anion. J Endocrinol 1997;155:401-10.