Bacterial vaginosis, the inflammatory response and the risk of preterm birth: a role for genetic epidemiology in the prevention of preterm birth

Abstract

This issue of the Journal contains a report stating that a “gene-environment interaction” determines risk for preterm birth. The importance of this observation was recognized with a Research Excellence Award by the Society for Maternal-Fetal Medicine and represents a major contribution by the team of Dr George Macones and Dr Jerome Strauss III at the University of Pennsylvania. Gene-environment interactions are central to the understanding of common complex diseases such as atherosclerosis, obesity, hypertension, depression, etc. Screening for bacterial vaginosis and treatment has been considered a strategy to reduce the rate of preterm birth. Yet, there is much controversy surrounding the issue. This Clinical Opinion will review key concepts of bacterial vaginosis, vaginal inflammation, the importance of genetic control of the inflammatory response in the context of microbial invasion, and the significance of the report of Dr Macones et al1.Macones G Parry S Elkousy M Clothier B Ural S.H Strauss III, J.F A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth.Am J Obstet Gynecol. 2004; : 1504-1508Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar contained in the current issue of the Journal.1. Bacterial vaginosisBacterial vaginosis, a condition characterized by a change in the microbial ecosystem of the vagina,2.Eschenbach D.A Hillier S Critchlow C Stevens C DeRouen T Holmes K.K Diagnosis and clinical manifestations of bacterial vaginosis.Am J Obstet Gynecol. 1988; 158: 819-828Abstract PubMed Google Scholar, 3.Spiegel C.A Bacterial vaginosis.Clin Microbiol Rev. 1991; 4: 485-502PubMed Google Scholar is present in up to 15% to 20% of pregnant women4.Eschenbach D.A Gravett M.G Chen K.C Hoyme U.B Holmes K.K Bacterial vaginosis during pregnancy: an association with prematurity and postpartum complications.Scand J Urol Nephrol Suppl. 1984; 86: 213-222PubMed Google Scholar, 5.Eschenbach D.A Bacterial vaginosis and anaerobes in obstetric-gynecologic infection.Clin Infect Dis. 1993; 16 Suppl 4: S282-S287Crossref PubMed Google Scholar, 6.McGregor J.A French J.I Bacterial vaginosis in pregnancy.Obstet Gynecol Surv. 2000; 55: S1-S19Crossref PubMed Google Scholar, 7.Ugwumadu A.H Bacterial vaginosis in pregnancy.Curr Opin Obstet Gynecol. 2002; 14: 115-118Crossref PubMed Scopus (29) Google Scholar, 8.Sobel J.D Bacterial vaginosis.Annu Rev Med. 2000; 51: 349-356Crossref PubMed Scopus (120) Google Scholar and is a risk factor for spontaneous preterm delivery,4.Eschenbach D.A Gravett M.G Chen K.C Hoyme U.B Holmes K.K Bacterial vaginosis during pregnancy: an association with prematurity and postpartum complications.Scand J Urol Nephrol Suppl. 1984; 86: 213-222PubMed Google Scholar, 5.Eschenbach D.A Bacterial vaginosis and anaerobes in obstetric-gynecologic infection.Clin Infect Dis. 1993; 16 Suppl 4: S282-S287Crossref PubMed Google Scholar, 9.Gibbs R.S Chorioamnionitis and bacterial vaginosis.Am J Obstet Gynecol. 1993; 169: 460-462Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 10.Hillier S.L Nugent R.P Eschenbach D.A Krohn M.A Gibbs R.S Martin D.H 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: 1737-1742Crossref PubMed Google Scholar, 11.Meis P.J Goldenberg R.L 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: 1231-1235Abstract Full Text PDF PubMed Scopus (238) Google Scholar, 12.Goldenberg R.L Thom E Moawad A.H Johnson F Roberts J Caritis S.N The preterm prediction study: fetal fibronectin, bacterial vaginosis, and peripartum infection. NICHD Maternal Fetal Medicine Units Network.Obstet Gynecol. 1996; 87: 656-660PubMed Google Scholar, 13.Goepfert A.R Goldenberg R.L Prediction of prematurity.Curr Opin Obstet Gynecol. 1996; 8: 417-427Crossref PubMed Google Scholar, 14.Carey J.C Klebanoff M.A What have we learned about vaginal infections and preterm birth?.Semin Perinatol. 2003; 27: 212-216Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 15.Flynn C.A Helwig A.L Meurer L.N Bacterial vaginosis in pregnancy and the risk of prematurity: a meta-analysis.J Fam Pract. 1999; 48: 885-892PubMed Google Scholar, 16.Riduan J.M Hillier S.L 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: 175-178Abstract Full Text PDF PubMed Google Scholar, 17.Kimberlin D.F Andrews W.W Bacterial vaginosis: association with adverse pregnancy outcome.Semin Perinatol. 1998; 22: 242-250Abstract Full Text PDF PubMed Google Scholar, 18.Paige D.M Augustyn M Adih W.K Witter F Chang J Bacterial vaginosis and preterm birth: a comprehensive review of the literature.J Nurse Midwifery. 1998; 43: 83-89Crossref PubMed Google Scholar, 19.Chaim W Mazor M Leiberman J.R The relationship between bacterial vaginosis and preterm birth: a review.Arch Gynecol Obstet. 1997; 259: 51-58Crossref PubMed Google Scholar, 20.Subtil D Denoit V Le Goueff F Husson M.O Trivier D Puech F The role of bacterial vaginosis in preterm labor and preterm birth: a case-control study.Eur J Obstet Gynecol Reprod Biol. 2002; 101: 41-46Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 21.Newton E.R Piper J Peairs W Bacterial vaginosis and intraamniotic infection.Am J Obstet Gynecol. 1997; 176: 672-677Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 22.Martius J Eschenbach D.A The role of bacterial vaginosis as a cause of amniotic fluid infection, chorioamnionitis and prematurity—a review.Arch Gynecol Obstet. 1990; 247: 1-13Crossref PubMed Scopus (67) Google Scholar, 23.Silver H.M Sperling R.S St Clair P.J Gibbs R.S Evidence relating bacterial vaginosis to intraamniotic infection.Am J Obstet Gynecol. 1989; 161: 808-812Abstract Full Text PDF PubMed Google Scholar, 24.Hay P.E Lamont R.F Taylor-Robinson D Morgan D.J Ison C Pearson J Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage.BMJ. 1994; 308: 295-298Crossref PubMed Google Scholar premature rupture of membranes,25.Gravett M.G Nelson H.P DeRouen T Critchlow C Eschenbach D.A Holmes K.K Independent associations of bacterial vaginosis and Chlamydia trachomatis infection with adverse pregnancy outcome.JAMA. 1986; 256: 1899-1903Crossref PubMed Google Scholar, 26.Reynolds H.D Bacterial vaginosis and its implication in preterm labor and premature rupture of membranes: a review of the literature.J Nurse Midwifery. 1991; 36: 289-296Crossref PubMed Google Scholar, 27.McGregor J.A French J.I Seo K Premature rupture of membranes and bacterial vaginosis.Am J Obstet Gynecol. 1993; 169: 463-466Abstract Full Text PDF PubMed Google Scholar, 28.Lamont R.F Recent evidence associated with the condition of preterm prelabour rupture of the membranes.Curr Opin Obstet Gynecol. 2003; 15: 91-99Crossref PubMed Scopus (18) Google Scholar and postpartum endometritis.4.Eschenbach D.A Gravett M.G Chen K.C Hoyme U.B Holmes K.K Bacterial vaginosis during pregnancy: an association with prematurity and postpartum complications.Scand J Urol Nephrol Suppl. 1984; 86: 213-222PubMed Google Scholar, 29.Jacobsson B Pernevi P Chidekel L Jorgen Platz-Christensen J Bacterial vaginosis in early pregnancy may predispose for preterm birth and postpartum endometritis.Acta Obstet Gynecol Scand. 2002; 81: 1006-1010Crossref PubMed Scopus (46) Google Scholar The change in the bacterial ecosystem is characterized by a decrease in the number of lactobacilli and overgrowth of several anaerobic or facultative bacteria (such as Mobiluncus species, Prevotella species, Gardnerella vaginalis, and genital Mycoplasmas: Mycoplasma hominis and Ureaplasma urealyticum).30.Kurki T Sivonen A Renkonen O.V Savia E Ylikorkala O Bacterial vaginosis in early pregnancy and pregnancy outcome.Obstet Gynecol. 1992; 79: 173-177PubMed Google Scholar, 31.French J.I McGregor J.A Bacterial vaginosis.in: Faro S Soper D.E Infectious diseases in women. WB Saunders, Philadelphia2001: 221-239Google Scholar Yet, despite the substantial microbial overgrowth, the conventional view has been that bacterial vaginosis is not associated with signs of inflammation (ie, vaginal fluid leukocytes),32.Donders G.G Bosmans E Dekeersmaecker A Vereecken A Van Bulck B Spitz B Pathogenesis of abnormal vaginal bacterial flora.Am J Obstet Gynecol. 2000; 182: 872-878Abstract Full Text Full Text PDF PubMed Google Scholar, 33.Hill L.V Anaerobes and Gardnerella vaginalis in non-specific vaginitis.Genitourin Med. 1985; 61: 114-119PubMed Google Scholar, 34.Blackwell A Barlow D Clinic diagnosis of anaerobic vaginosis (non-specific vaginitis): a practical guide.Br J Vener Dis. 1982; 58: 387-393PubMed Google Scholar and hence the condition is called “vaginosis” rather than “vaginitis.”31.French J.I McGregor J.A Bacterial vaginosis.in: Faro S Soper D.E Infectious diseases in women. WB Saunders, Philadelphia2001: 221-239Google Scholar, 32.Donders G.G Bosmans E Dekeersmaecker A Vereecken A Van Bulck B Spitz B Pathogenesis of abnormal vaginal bacterial flora.Am J Obstet Gynecol. 2000; 182: 872-878Abstract Full Text Full Text PDF PubMed Google Scholar The reason for the absence of a local inflammatory response in most women with bacterial vaginosis in spite of increased microbial load in vaginal fluid has yet to be determined. Clearly, the vaginal mucosa is capable of mounting an inflammatory response; infections with Trichomonas vaginalis and Candida species can cause an intense inflammation, which is clinically manifested as vaginitis.35.Steele C Fidel Jr., P.L Cytokine and chemokine production by human oral and vaginal epithelial cells in response to Candida albicans.Infect Immun. 2002; 70: 577-583Crossref PubMed Scopus (72) Google Scholar, 36.Sobel J.D Vaginitis.N Engl J Med. 1997; 337: 1896-1903Crossref PubMed Scopus (249) Google Scholar Bacterial vaginosis is asymptomatic in approximately 50% of patients.2.Eschenbach D.A Hillier S Critchlow C Stevens C DeRouen T Holmes K.K Diagnosis and clinical manifestations of bacterial vaginosis.Am J Obstet Gynecol. 1988; 158: 819-828Abstract PubMed Google Scholar, 36.Sobel J.D Vaginitis.N Engl J Med. 1997; 337: 1896-1903Crossref PubMed Scopus (249) Google ScholarThe cause of bacterial vaginosis is unknown, but the condition can be considered as “a microbial/mucosal immunity disorder” (see below). The standard method for the diagnosis of bacterial vaginosis is a Gram stain examination of vaginal fluid.37.Spiegel C.A Amsel R Holmes K.K Diagnosis of bacterial vaginosis by direct Gram stain of vaginal fluid.J Clin Microbiol. 1983; 18: 170-177PubMed Google Scholar Nugent et al38.Nugent R.P Krohn M.A Hillier S.L Reliability of diagnosing bacterial vaginosis is improved by a standardized method of Gram stain interpretation.J Clin Microbiol. 1991; 29: 297-301PubMed Google Scholar developed standardized criteria for the interpretation of the Gram stain based on the examination of 4 bacterial morphotypes. A score of 7 to 10 is considered diagnostic of bacterial vaginosis. This method is both highly reproducible and reliable,38.Nugent R.P Krohn M.A Hillier S.L Reliability of diagnosing bacterial vaginosis is improved by a standardized method of Gram stain interpretation.J Clin Microbiol. 1991; 29: 297-301PubMed Google Scholar, 39.Schwebke J.R Hillier S.L Sobel J.D McGregor J.A Sweet R.L Validity of the vaginal Gram stain for the diagnosis of bacterial vaginosis.Obstet Gynecol. 1996; 88: 573-576Crossref PubMed Scopus (132) Google Scholar, 40.Nelson D.B Macones G Bacterial vaginosis in pregnancy: current findings and future directions.Epidemiol Rev. 2002; 24: 102-108Crossref PubMed Scopus (30) Google Scholar and has been very helpful in advancing the state of knowledge of bacterial vaginosis. Gram stain diagnosis relies on changes of the microbial flora of the vagina and not the local host inflammatory response,41.Donder G.G Vereecken A Bosmans E Dekeersmaecker A Salembier G Spitz B Definition of a type of abnormal vaginal flora that is distinct from bacterial vaginosis: aerobic vaginitis.BJOG. 2002; 109: 34-43Crossref PubMed Scopus (130) Google Scholar which can be assessed by a leukocyte count or other parameters such as the cytokine profile. The relevance of this will be discussed below.2. Screening and treatment of bacterial vaginosis to prevent preterm deliveryThere is compelling evidence of a causal association between intrauterine infection and spontaneous preterm labor and delivery.42.Hillier S.L Martius J Krohn M Kiviat N Holmes K.K Eschenbach D.A A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity.N Engl J Med. 1988; 319: 972-978Crossref PubMed Google Scholar, 43.Romero R Sirtori M Oyarzun E Avila C Mazor M Callahan R et al.Infection and labor: V, prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes.Am J Obstet Gynecol. 1989; 161: 817-824Abstract Full Text PDF PubMed Google Scholar, 44.Gibbs R.S Romero R Hillier S.L Eschenbach D.A Sweet R.L A review of premature birth and subclinical infection.Am J Obstet Gynecol. 1992; 166: 1515-1528Abstract Full Text PDF PubMed Google Scholar, 45.Romero R Avila C Sepulveda W et al.The role of systemic and intrauterine infection in preterm labor.in: Fuchs A Fuchs F Stubblefield P Preterm birth: causes, prevention, and management. 2nd edition. McGraw-Hill, New York1993: 97-136Google Scholar, 46.McGregor J.A French J.I Witkin S Infection and prematurity: evidence-based approaches.Curr Opin Obstet Gynecol. 1996; 8: 428-432Crossref PubMed Google Scholar, 47.Andrews W.W Hauth J.C Goldenberg R.L Infection and preterm birth.Am J Perinatol. 2000; 17: 357-365Crossref PubMed Scopus (68) Google Scholar, 48.Gravett M.G Hitti J Hess D.L Eschenbach D.A Intrauterine infection and preterm delivery: evidence for activation of the fetal hypothalamic-pituitary-adrenal axis.Am J Obstet Gynecol. 2000; 182: 1404-1413Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 49.Goldenberg R.L Hauth J.C Andrews W.W Intrauterine infection and preterm delivery.N Engl J Med. 2000; 342: 1500-1507Crossref PubMed Scopus (1037) Google Scholar, 50.Hitti J Tarczy-Hornoch P Murphy J Hillier S.L Aura J Eschenbach D.A Amniotic fluid infection, cytokines, and adverse outcome among infants at 34 weeks' gestation or less.Obstet Gynecol. 2001; 98: 1080-1088Crossref PubMed Scopus (46) Google Scholar, 51.Hillier S.L Witkin S.S Krohn M.A Watts D.H Kiviat N.B Eschenbach D.A The relationship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis, and chorioamnion infection.Obstet Gynecol. 1993; 81: 941-948PubMed Google Scholar Yet, except for the treatment of asymptomatic bacteriuria,52.Romero R Oyarzun E Mazor M Sirtori M Hobbins J.C Bracken M Meta-analysis of the relationship between asymptomatic bacteriuria and preterm delivery/low birth weight.Obstet Gynecol. 1989; 73: 576-582PubMed Google Scholar, 53.Smaill F Antibiotics for asymptomatic bacteriuria in pregnancy.Cochrane Database Syst Rev. 2000; : CD000490PubMed Google Scholar prevention of preterm birth by administering antimicrobial agents to pregnant women has not been effective.54.King J Flenady V Prophylactic antibiotics for inhibiting preterm labour with intact membranes.Cochrane Database Syst Rev. 2002; : CD000246PubMed Google Scholar, 55.Kenyon S.L Taylor D.J Tarnow-Mordi W Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. ORACLE Collaborative Group.Lancet. 2001; 357: 989-994Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 56.Thorp Jr., J.M Hartmann K.E Berkman N.D Carey T.S Lohr K.N Gavin N.I et al.Antibiotic therapy for the treatment of preterm labor: a review of the evidence.Am J Obstet Gynecol. 2002; 186: 587-592Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar There are several potential explanations for this. One is that preterm parturition is a syndrome and that infection is only one of its causes.57.Romero R Mazor M Munoz H Gomez R Galasso M Sherer D.M The preterm labor syndrome.Ann N Y Acad Sci. 1994; 734: 414-429Crossref PubMed Scopus (170) Google Scholar Another is that clinical trials have not focused on the population that can benefit from this intervention.58.Romero R Sibai B Caritis S Paul R Depp R Rosen M et al.Antibiotic treatment of preterm labor with intact membranes: a multicenter, randomized, double-blinded, placebo-controlled trial.Am J Obstet Gynecol. 1993; 169: 764-774Abstract Full Text PDF PubMed Google Scholar, 59.Mertz H.L Ernest J.M Antibiotics and preterm labor.Curr Womens Health Rep. 2001; 1: 20-26PubMed Google Scholar, 60.Stetzer B.P Mercer B.M Antibiotics and preterm labor.Clin Obstet Gynecol. 2000; 43: 809-817Crossref PubMed Scopus (10) Google ScholarScreening and treatment of bacterial vaginosis has been used to test whether antimicrobial agents can prevent preterm birth. The basic rationale is that bacterial vaginosis is associated with intra-amniotic infection5.Eschenbach D.A Bacterial vaginosis and anaerobes in obstetric-gynecologic infection.Clin Infect Dis. 1993; 16 Suppl 4: S282-S287Crossref PubMed Google Scholar, 9.Gibbs R.S Chorioamnionitis and bacterial vaginosis.Am J Obstet Gynecol. 1993; 169: 460-462Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 22.Martius J Eschenbach D.A The role of bacterial vaginosis as a cause of amniotic fluid infection, chorioamnionitis and prematurity—a review.Arch Gynecol Obstet. 1990; 247: 1-13Crossref PubMed Scopus (67) Google Scholar, 23.Silver H.M Sperling R.S St Clair P.J Gibbs R.S Evidence relating bacterial vaginosis to intraamniotic infection.Am J Obstet Gynecol. 1989; 161: 808-812Abstract Full Text PDF PubMed Google Scholar, 42.Hillier S.L Martius J Krohn M Kiviat N Holmes K.K Eschenbach D.A A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity.N Engl J Med. 1988; 319: 972-978Crossref PubMed Google Scholar and is a risk factor for preterm delivery.10.Hillier S.L Nugent R.P Eschenbach D.A Krohn M.A Gibbs R.S Martin D.H 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: 1737-1742Crossref PubMed Google Scholar, 15.Flynn C.A Helwig A.L Meurer L.N Bacterial vaginosis in pregnancy and the risk of prematurity: a meta-analysis.J Fam Pract. 1999; 48: 885-892PubMed Google Scholar, 17.Kimberlin D.F Andrews W.W Bacterial vaginosis: association with adverse pregnancy outcome.Semin Perinatol. 1998; 22: 242-250Abstract Full Text PDF PubMed Google Scholar, 19.Chaim W Mazor M Leiberman J.R The relationship between bacterial vaginosis and preterm birth: a review.Arch Gynecol Obstet. 1997; 259: 51-58Crossref PubMed Google Scholar, 61.Goldenberg R.L Iams J.D Mercer B.M Meis P.J Moawad A.H Copper R.L et al.The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network.Am J Public Health. 1998; 88: 233-238Crossref PubMed Google Scholar, 62.Hill G.B Preterm birth: associations with genital and possibly oral microflora.Ann Periodontol. 1998; 3: 222-232Crossref PubMed Google Scholar However, randomized clinical trials have yielded conflicting results.63.Morales W.J Schorr S Albritton J Effect of metronidazole in patients with preterm birth in preceding pregnancy and bacterial vaginosis: a placebo-controlled, double-blind study.Am J Obstet Gynecol. 1994; 171: 345-347Abstract Full Text PDF PubMed Google Scholar, 64.Hauth J.C Goldenberg R.L Andrews W.W DuBard M.B Copper R.L Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis.N Engl J Med. 1995; 333: 1732-1736Crossref PubMed Scopus (406) Google Scholar, 65.Carey J.C Klebanoff M.A Hauth J.C Hillier S.L Thom E.A Ernest J.M et al.Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.N Engl J Med. 2000; 342: 534-540Crossref PubMed Scopus (354) Google Scholar, 66.Paavonen J Mangioni C Martin M.A Wajszczuk C.P Vaginal clindamycin and oral metronidazole for bacterial vaginosis: a randomized trial.Obstet Gynecol. 2000; 96: 256-260Crossref PubMed Scopus (42) Google Scholar, 67.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: 643-648Crossref PubMed Google Scholar, 68.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: 983-988Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 69.McDonald H.M O'Loughlin J.A Vigneswaran R Jolley P.T Harvey J.A Bof A et al.Impact of metronidazole therapy on preterm birth in women with bacterial vaginosis flora (Gardnerella vaginalis): a randomised, placebo controlled trial.BJOG. 1997; 104: 1391-1397Crossref Google Scholar, 70.Lamont D.F Changes in vaginal flora after 2% clindamycin vaginal cream in women at high risk of preterm birth.BJOG. 2003; 110: 788-789Crossref PubMed Google Scholar, 71.Rosenstein I.J Morgan D.J Lamont R.F Sheehan M Dore C.J Hay P.E 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: 158-165PubMed Google Scholar The reader is referred to the original trials and systemic reviews for details of this controversy.72.Leitich H Brunbauer M Bodner-Adler B Kaider A Egarter C Husslein P Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis.Am J Obstet Gynecol. 2003; 188: 752-758Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 73.Brocklehurst P Hannah M McDonald H Interventions for treating bacterial vaginosis in pregnancy (Cochrane Review).Cochrane Database Syst Rev. 2002; Google Scholar, 74.Guise J.M Mahon S.M Aickin M Helfand M Peipert J.F Westhoff C Screening for bacterial vaginosis in pregnancy.Am J Prev Med. 2001; 20: 62-72Abstract Full Text Full Text PDF PubMed Google Scholar, 75.Klebanoff M.A Guise J.M Carey J.C Treatment recommendations for bacterial vaginosis in pregnant women.Clin Infect Dis. 2003; 36: 1630-1631Crossref PubMed Scopus (6) Google ScholarThe Centers for Disease Control, as well as some leaders in the field of Infectious Diseases in Obstetrics and Gynecology, have recommended that patients at high risk for preterm delivery (those with a previous history of a spontaneous preterm birth) may/should be screened and treated with metronidazole or clindamycin.72.Leitich H Brunbauer M Bodner-Adler B Kaider A Egarter C Husslein P Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis.Am J Obstet Gynecol. 2003; 188: 752-758Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 74.Guise J.M Mahon S.M Aickin M Helfand M Peipert J.F Westhoff C Screening for bacterial vaginosis in pregnancy.Am J Prev Med. 2001; 20: 62-72Abstract Full Text Full Text PDF PubMed Google Scholar, 76.US Preventive Services Task Force Screening for bacterial vaginosis in pregnancy. Recommendations and rationale.Am J Prev Med. 2001; 20: 59-61Abstract Full Text Full Text PDF PubMed Google Scholar, 77.Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention.MMWR Recomm Rep. 2002; 51: 1-78Google Scholar, 78.McDonald H Brocklehurst P Parsons J Vigneswaran R Antibiotics for treating bacterial vaginosis in pregnancy.Cochrane Database Syst Rev. 2003; : CD000262PubMed Google Scholar, 79.Koumans E.H Markowitz L.E Hogan V Indications for therapy and treatment recommendations for bacterial vaginosis in nonpregnant and pregnant women: a synthesis of data.Clin Infect Dis. 2002; 35: S152-S172Crossref PubMed Scopus (64) Google Scholar In low-risk patients, diagnosis and treatment is not recommended at this time.77.Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention.MMWR Recomm Rep. 2002; 51: 1-78Google Scholar3. Why the conflicting results of randomized clinical trials of bacterial vaginosis?The 3 main reasons invoked to explain the discrepancies72.Leitich H Brunbauer M Bodner-Adler B Kaider A Egarter C Husslein P Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis.Am J Obstet Gynecol. 2003; 188: 752-758Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 74.Guise J.M Mahon S.M Aickin M Helfand M Peipert J.F Westhoff C Screening for bacterial vaginosis in pregnancy.Am J Prev Med. 2001; 20: 62-72Abstract Full Text Full Text PDF PubMed Google Scholar, 76.US Preventive Services Task Force Screening for bacterial vaginosis in pregnancy. Recommendations and rationale.Am J Prev Med. 2001; 20: 59-61Abstract Full Text Full Text PDF PubMed Google Scholar, 77.Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention.MMWR Recomm Rep. 2002; 51: 1-78Google Scholar, 78.McDonald H Brocklehurst P Parsons J Vigneswaran R Antibiotics for treating bacterial vaginosis in pregnancy.Cochrane Database Syst Rev. 2003; : CD000262PubMed Google Scholar, 79.Koumans E.H Markowitz L.E Hogan V Indications for therapy and treatment recommendations for bacterial vaginosis in nonpregnant and pregnant women: a synthesis of data.Clin Infect Dis. 2002; 35: S152-S172Crossref PubMed Scopus (64) Google Scholar are: (1) gestational age at diagnosis/enrollment, (2) history of preterm birth, and (3) choice of antimicrobial agent (agent, route, and dose). First, some investigators have argued that detection and treatment of bacterial vaginosis/abnormal flora must begin early in pregnancy to accrue the benefits of preventing spontaneous abortion and preterm delivery.72.Leitich H Brunbauer M Bodner-Adler B Kaider A Egarter C Husslein P Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis.Am J Obstet Gynecol. 2003; 188: 752-758Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 74.Guise J.M Mahon S.M Aickin M Helfand M Peipert J.F Westhoff C Screening for bacterial vaginosis in pregnancy.Am J Prev Med. 2001; 20: 62-72Abstract Full Text Full Text PDF PubMed Google Scholar, 80.Lamont R.F Infection in the prediction and antibiotics in the prevention of spontaneous preterm labour and preterm birth.BJOG. 2003; 110 Suppl 20: 71-75Crossref PubMed Scopus (38) Google Scholar Second, the reduction in preterm birth in trials or subpopulations with a history of preterm birth may simply reflect the effectiveness of clinical history and a laboratory test (Gram stain) to identify the patient at risk for recurrent infection-related preterm birth.64.Hauth J.C Goldenberg R.L Andrews W.W DuBard M.B Copper R.L Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis.N Engl J Med. 1995; 333: 1732-1736Crossref PubMed Scopus (406) Google Scholar Third, the relative value of metronidazole and clindamycin has also been a subject of debate.65.Carey J.C Klebanoff M.A Hauth J.C Hillier S.L Thom E.A Ernest J.M et al.Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.N Engl J Med. 2000; 342: 534-540Crossref PubMed Scopus (354) Google Scholar, 66.Paavonen J Mangioni C Martin M.A Wajszczuk C.P Vaginal clindamycin and oral metronidazole for bacterial vaginosis: a randomized trial.Obstet Gynecol. 2000; 96: 256-260Crossref PubMed Scopus (42) Google Scholar, 67.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: 643-648Crossref PubMed Google Scholar, 68.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: 983-988Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 72.Leitich H Brunbauer M Bodner-Adler B Kaider A Egarter C Husslein P Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis.Am J Obstet Gynecol. 2003; 188: 752-758Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 74.Guise J.M Mahon S.M Aickin M Helfand M Peipert J.F Westhoff C Screening for bacterial vaginosis in pregnancy.Am J Prev Med. 2001; 20: 62-72Abstract Full Text Full Text PDF PubMed Google Scholar One additional possibility is that the current diagnostic criteria of bacterial vaginosis may not be the optimal method to identify the patient at risk for infection-associated preterm birth and, thus, one who may benefit from antimicrobial therapy during pregnancy. Bacterial vaginosis is diagnosed in up to 15% to 20% of pregnant women4.Eschenbach D.A Gravett M.G Chen K.C Hoyme U.B Holmes K.K Bacterial vaginosis during pregnancy: an association with prematurit