|Year : 2015 | Volume
| Issue : 2 | Page : 64-68
Should Abnormal Vaginal Flora in 2 nd Trimester of Pregnancy be Treated to Prevent Preterm Labor
Gunjan Kumari, Anjali Tempe
Department of Obstetrics and Gynecology, Maulana Azad Medical College, New Delhi, India
|Date of Web Publication||1-Jun-2015|
Dr. Anjali Tempe
Department of Obstetrics and Gynecology, Maulana Azad Medical College, New Delhi - 110 002
Source of Support: None, Conflict of Interest: None
Screening and treatment of abnormal vaginal flora during pregnancy to prevent preterm labor is a matter of debate for practicing obstetrician and physician in a country where maternal health and its outcome is a big concern. The recent evidence suggests that infection may be implicated in a substantial proportion of cases of preterm delivery. Neonatal morbidity and mortality are primarily influenced by gestational age and less so by birth weight. Microbial flora normally present in the human vagina play a key role in preventing pathological organisms including those responsible for sexually transmitted diseases, yeast infections, bacterial vaginosis (BV), and urinary tract infection. The outcome gathered from various recent studies have been remarkably consistent and managed to support the hypothesis that antibiotic treatment before 20 weeks of gestation reduces the risk of preterm birth. It is concluded that screening for abnormal vaginal flora cannot be generalized, but it may be safely carried out in pregnant women who have a previous history of preterm labor. Antibiotics with lactobacillus treatment can eradicate abnormal vaginal flora in pregnancy, however, screening and treating all pregnant women with asymptomatic BV to prevent preterm birth and its consequences is not substantiated by evidence.
Keywords: Aerobic vaginitis, bacterial vaginosis, vaginal flora
|How to cite this article:|
Kumari G, Tempe A. Should Abnormal Vaginal Flora in 2 nd Trimester of Pregnancy be Treated to Prevent Preterm Labor. MAMC J Med Sci 2015;1:64-8
|How to cite this URL:|
Kumari G, Tempe A. Should Abnormal Vaginal Flora in 2 nd Trimester of Pregnancy be Treated to Prevent Preterm Labor. MAMC J Med Sci [serial online] 2015 [cited 2020 Sep 28];1:64-8. Available from: http://www.mamcjms.in/text.asp?2015/1/2/64/157912
| Introduction|| |
Preterm delivery defined as delivery before 37 completed weeks of gestation is a major problem in obstetrics. The management of preterm babies and their developmental handicaps concerns a major part of health care resources. Thus, any intervention to prevent preterm birth, if effective, would be of great value especially in under-resourced settings as ours.
The recent evidence suggests that infection may be implicated in a substantial proportion of patients with preterm delivery.  The most common pathway of intrauterine infection is ascending infection. The vaginal bacteria ascend and colonize the decidua and chorion, eventually proliferating and invading the amniotic fluid and fetus. Infection and ensuing inflammatory response stimulate the production of prostaglandins and cytokines leading to initiation of myometrial activation.
Vaginal infections, particularly bacterial vaginosis (BV) have consistently been shown in many longitudinal population studies to be associated with late miscarriage and preterm deliveries. It is characterized by a change from lactobacillus predominated vaginal flora to a mixed vaginal flora comprising of Gardnerella vaginalis, Mobiluncus species, Mycoplasma, Ureaplasma urealyticum, and other Gram-negative anaerobic bacteria.
This suggests that incorporating a simple screening and treatment program for subclinical vaginal infections into routine prenatal care early in 2 nd trimester can prevent a proportion of preterm births.
The microbial flora normally present in the human vagina play a key role in preventing pathological organisms including those responsible for sexually transmitted diseases, yeast infections, BV, and urinary tract infections.  Lactobacilli have been thought to be the predominant members of normal postpubertal vaginal microflora because of its ability to grow at a relatively low pH of < 4.5. Estrogens improve lactobacilli colonization by enhancing vaginal glycogen, which breaks down into glucose and acts as a substrate for the bacteria.
Bacteria such as Staphylococcus epidermidis, Ureaplasma, Group B Streptococcus, Group D Streptococcus, nonhemolytic Streptococcus (non A or B), Peptostreptococcus species, Gardnerella, Bacteroides fragilis, Mycoplasma, Escherichia More Details coli, Bifidobacterium, and Candida can be present as abnormal vaginal flora.  Lactobacilli play a critical role in maintaining the normal vaginal ecosystem by preventing overgrowth by pathogens and other opportunistic organisms by producing lactic acid, hydrogen peroxide (H 2 O 2 ), bacteriocins, and other antimicrobial substances.  BV (40-50%), vulvovaginal candidiasis (20-25%), trichomonas vaginitis (15-20%), aerobic vaginitis have been implicated among the common causes of vaginitis. The predominant organisms that cause BV are Mycoplasma hominis, G. vaginalis, and U. urealyticum. Mobiluncus, Bacteroides, and Peptostreptococcus have also been identified as other anaerobic flora associated with BV.
Evidence indicates that there is an association between the presence of subclinical chorioamnionitis and preterm delivery. The term subclinical infection is described as an infection without clinical signs and symptoms of disease, but endotoxins released by the microbes can stimulate amniotic cells to secrete cytokines and activate the pathway of parturition. , Intrauterine infection may occur early in pregnancy or even before pregnancy and remain asymptomatic and undetected for months until preterm labor or premature rupture of membranes occur.  The entry of lower genital tract bacteria into the decidua is associated with the recruitment of leucocytes that is followed by cytokine production. Specific receptors are present on mononuclear phagocytes, decidua cells, and trophoblasts which have been called "toll like receptors".  Under the influence of ligands such as bacterial lipopolysaccharides, these receptors increase the release of cytokines including interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor, chemokines in the amnion, chorion, decidua, and myometrium.  Furthermore, cytokines, endotoxins, and exotoxins stimulate prostaglandin synthesis and release, which causes cervical dilatation, uterine contractions, membrane exposure, and greater entry of microbes into the uterine cavity. Cytokines have also been found to stimulate the production of matrix metalloproteinases responsible for cervical ripening and degradation of the fetal membranes. Lower genital tract bacteria may also act locally producing enzymes such as sialidase or mucinase which may weaken protective cervical mucus and promote bacterial invasion of the upper genital tract.
However, it has been established now that serious complications may ensue if pregnant women with abnormal vaginal flora are not identified and treated.
Approximately 10-30% of pregnant women have BV. Major obstetric complications are: Preterm delivery, preterm premature rupture of membranes (PPROM), amniotic fluid infection, chorioamnion infection and postpartum endometritis.
The most advanced and serious stage of ascending intrauterine infection is a fetal infection. The overall mortality rate of neonates with congenital neonatal sepsis is between 25% and 90%. In fact, isolates from the amniotic fluid obtained before or during labor in preterm pregnant women with PPROM allow the earliest identification of the pathogenic bacteria. Conjunctivitis in newborns is an important entity. It is an indirect indicator of reproductive tract microbial carriage in their mothers.
It has been suggested that these organisms not only induce preterm labor, but their presence in the lung causes low-grade inflammatory response increasing the need for ventilation and hence increasing the degree of damage by the ventilator resulting in chronic lung disease later in life. In addition to this, surfactant deficiency due to prematurity also leads to hyaline membrane disease thereby increasing the need for ventilation.
| Diagnostic Methods for Bacterial Vaginosis|| |
The predominant changes are in the volume and odor of discharge. Malodorous vaginal discharge which is milky or homogenous, thin in viscosity, white or greyish in color and mild vulvar itching or burning are common symptoms of BV. The genital odor as perceived by the patient is described as that of rotting fish. The odor is more offensive after sexual intercourse or during menstruation because of alkalinization that elicits the odor by liberating amine products of anaerobic metabolism.
Some authors have reported that diagnosis of BV can be established by the presence of at least three of the following four criteria (Amsel criteria): ,
- Thin homogenous discharge that adheres to but can be easily wiped from the vaginal wall
- Vaginal pH more than 4.5
- Positive whiff test (amine odor test): Liberation of a fishy smell after adding KOH to the vaginal discharge
- Presence of clue cells in vaginal discharge constituting 20% or more of vaginal cells.
It can be determined by subjecting the vaginal discharge to pH sensitive paper strips. It is usually >4.5. Elevation of vaginal pH is the most sensitive, but least specific of diagnostic criteria for BV. Its value as a test of cure and in the prediction of recurrence is questionable.
Pheifer et al.  were the first to report the presence of characteristic odor with the addition of a few drops of 10% potassium hydroxide to the vaginal discharge. The anaerobic component of BV associated flora is usually responsible for diamine production. The methylamine is the cause of characteristic odor.
Clue cells are described as vaginal epithelial cells with an ill-defined outline that appear to be granular because of large number of G. vaginalis attached to their surfaces. Clue cells are detected when vaginal fluid mixed with normal saline is examined under the microscope. The detection of clue cells is the single most useful procedure for diagnosis of BV. The demonstration of clue cells, comprising more than 20% of total vaginal epithelial cells is a significant indicator for BV.  The sensitivity and specificity of clue cells in diagnosing BV is 81% and 99%, respectively. 
| Special Diagnostic Methods|| |
Gram stain of vaginal discharge reveals the characteristic picture. There is a predominance of bacteria mainly G. vaginalis and Mobiluncus species together with small Gram-negative rods, and Gram-positive cocci and absence of lactobacilli. Nugent et al. provided a method to standardize the Gram stain interpretation of BV [Table 1]. 
Gram-stain findings corresponding to a normal Nugent score is particularly useful to exclude BV, because it has a high negative predictive value, and is a cost effective test to perform and can be used in local health center. It is particularly useful for research purposes whereas Amsel's criteria are useful for clinical diagnosis. The sensitivity and specificity of Nugent's criteria as compared to Amsel's criteria are 83.3% and 92.1% respectively.
Clue cells and changes in bacterial flora can also be found in the papanicolaou smear. Clue cells on routine papanicolaou smear have a sensitivity of 90% and specificity of 98%.
Culture for Gardnerella vaginalis
Although there are different selective media available for its isolation, culture of this organism is not recommended routinely.
Proline aminopeptidase activity
It is a rapid diagnostic test to confirm BV which is based on the detection of proline aminopeptidase activity in vaginal secretions that is analyzed colorimetrically with microsomal leucine aminopeptidase as a standard enzyme. 
Gas liquid chromatography
It has 78% sensitivity and 81% specificity for the diagnosis of BV in women with clinical signs of disease. The vaginal fluid in pregnant women with BV has increased the quantity of succinic acid and decreased the quantity of lactic acid. An increased ratio of succinic acid to lactic acid is diagnostic for BV.
| Treatment of Abnormal Vaginal Flora|| |
It is now well known that abnormal genital tract flora is associated with the occurrence of preterm labor. It still remains controversial whether screening and treating asymptomatic pregnant women for abnormal vaginal flora is routinely warranted. Many trials have been conducted to show that treatment of these infections can prevent preterm birth and have shown mixed results. Earlier studies did not support routine screening and treatment of asymptomatic low-risk pregnant women for BV to prevent preterm labor. The routine screening is supported in pregnant women who were at risk for preterm labor (e.g., those who had a history of previous preterm delivery) and recent evidence suggests that treatment of BV in asymptomatic women early in pregnancy before 20 weeks of gestation may reduce the risk of preterm labor. ,
Initiating antibiotic therapy for the abnormal flora early in pregnancy is relevant and important, as restoring normal flora at a later stage does not decrease the incidence of preterm delivery. , The appropriate choice of antibiotics is crucial (should be active against BV) and should be used early in pregnancy. It is logical to use intravaginal antibiotics in the presence of large abnormal colonization and also, systemic use of antibiotics should be a consideration to eradicate those organisms that may have gained access to the decidua. Sometimes, combined use of systemic as well as local antibiotics may offer the best chance of benefit to the patient. However, no study till date has evaluated the combination of intravaginal and systemic antibiotics to eradicate abnormal genital tract flora for the prevention of preterm birth.  Mixed results have been obtained with the use of erythromycin for the treatment of vaginal and cervical infections with Ureaplasma or Mycoplasma.  Addition of metronidazole can be of benefit. The overall results suggest that in women with a previous preterm delivery and with BV diagnosed in the second trimester, treatment for 1-week or more with oral metronidazole, and perhaps along with erythromycin results in a significant reduction in the incidence of preterm delivery. ,, There was no significant reduction in preterm delivery when antibiotics were administered vaginally, when shorter courses of antibiotics or antibiotic regimens not including metronidazole were used, or when the women treated were at low risk (usually defined as not having had a prior preterm delivery). ,,, McDonald et al.  in 2000 conducted a review for Cochrane database to assess the effects of antibiotic treatment of BV in pregnancy. They reviewed 13 studies involving 5,300 women and concluded that detection and treatment of BV early in pregnancy may prevent a proportion of women with a history of preterm birth but did not support routine screening and treatment of all pregnant women for BV. Subsequent Cochrane database in 2003 and 2005 by the same authors on 4249 and 5300 pregnant women involving a larger number of trials reported similar results. , Five randomized controlled trials involving treatment with clindamycin conducted after Cochrane study have documented the benefit of screening and treatment of BV and other abnormal flora in reducing the incidence of preterm birth.
Ugwumadu et al.  in 2003 showed that screening for and treating asymptomatic abnormal vaginal flora and BV early in the second trimester reduces the rate of preterm birth in a general obstetric population. Lamont et al.  in 2003 showed that topical treatment with clindamycin vaginal cream early in the second trimester reduces the incidence of preterm birth despite the reservations regarding the topical treatment of BV that were expressed earlier. Kiss et al.  in 2004 analyzed and showed that treating asymptomatic vaginal infections by vaginal clindamycin early in second trimester reduces the rate of preterm birth. A recent study conducted by Larsson et al.  in 2006 also established the decrease in rate of preterm births (9.09% vs. 41.6%) with vaginal clindamycin in pregnant women with BV diagnosed between 10 and 14 weeks of gestational age, thereby concluding that early screening and treatment for BV is associated with significantly prolonged gestation and reduced cost of neonatal care in women with BV. Review by McDonald et al.  in 2007 for Cochrane database concluded that treatment of BV before 20 weeks of gestation may reduce the risk of preterm births. The recent review by Swadpanich et al.  in 2008 for Cochrane database also concluded the efficacy of treatment of BV in the prevention of preterm birth.
Novikona  in 2009 screened for lower genital tract infections BV, trichomoniasis, and candidiasis. The study concluded that preterm birth before 37 weeks of gestation was significantly decreased (3% vs. 5%) on treatment in early pregnancy. The most recent additions to the study regarding the prevention of preterm labor in BV is the use of probiotics, that is, Lactobacillus. The various studies by Reid et al. and Shalev showing the efficacy of treatment of BV by lactobacilli probiotics, indicate that the ecologic treatment of BV through the colonization of vagina by exogenous lactobacilli is an alternative worth trying to prevent preterm delivery. , Study by Krauss-Silva et al.  in 2010, is a randomized control trial of probiotics for prevention of spontaneous preterm delivery associated with intrauterine infections, the results are yet to be published.
The review by Brocklehurst et al.  in 2013 for Cochrane database concluded that antibiotic treatment can eradicate BV in pregnancy, but the overall risk of preterm birth was not significantly reduced. However, the two included studies in the same systemic analysis suggested that when the screening criteria included women with abnormal flora there was a 47% reduction in preterm birth.
| Conclusion|| |
Most studies in the recent years have been remarkably consistent and support the hypothesis that antibiotics along with probiotics treatment before 20 weeks gestation reduces the risk of preterm birth. It is concluded that screening for abnormal vaginal flora cannot be generalized, but it may be safely carried out in pregnant women who have a previous history of preterm labor. However, routine screening of asymptomatic pregnant women with low risk of preterm labor is not advocated as there is little evidence that it helps in prevention of preterm labor.
| References|| |
Taylor D, Kenyon S, Tarnow-Mordi W. Infection and preterm labour. Br J Obstet Gynaecol 1997;104:1338-40.
Donders GG, Bosmans E, Dekeersmaecker A, Vereecken A, Van Bulck B, Spitz B. Pathogenesis of abnormal vaginal bacterial flora. Am J Obstet Gynecol 2000;182:872-8.
Redondo-Lopez V, Cook RL, Sobel JD. Emerging role of lactobacilli in the control and maintenance of the vaginal bacterial microflora. Rev Infect Dis 1990;12:856-72.
Hillier SL. The vaginal microbial ecosystem and resistance to HIV. AIDS Res Hum Retroviruses 1998;14 Suppl 1:S17-21.
Romero R, Espinoza J, Chaiworapongsa T, Kalache K. Infection and prematurity and the role of preventive strategies. Semin Neonatol 2002;7:259-74.
Iams JD, Clapp DH, Contos DA, Whitehurst R, Ayers LW, O′Shaughnessy RW. Does extra-amniotic infection cause preterm labor? Gas-liquid chromatography studies of amniotic fluid in amnionitis, preterm labor, and normal controls. Obstet Gynecol 1987;70:365-8.
Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med 2000;342:1500-7.
Janssens S, Beyaert R. Role of Toll-like receptors in pathogen recognition. Clin Microbiol Rev 2003;16:637-46.
Pheifer TA, Forsyth PS, Durfee MA, Pollock HM, Holmes KK. Nonspecific vaginitis: Role of haemophilus vaginalis and treatment with metronidazole. N Engl J Med 1978;298:1429-34.
Amsel R, Totten PA, Spiegel CA, Chen KC, Eschenbach D, Holmes KK. Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiologic associations. Am J Med 1983;74:14-22.
Schaaf VM, Perez-Stable EJ, Borchardt K. The limited value of symptoms and signs in the diagnosis of vaginal infections. Arch Intern Med 1990;150:1929-33.
Cohen CR, Duerr A, Pruithithada N, Rugpao S, Hillier S, Garcia P, et al.
Bacterial vaginosis and HIV seroprevalence among female commercial sex workers in Chiang Mai, Thailand. AIDS 1995;9:1093-7.
Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol 1991;29:297-301.
Thomason JL, Gelbart SM, Wilcoski LM, Peterson AK, Jilly BJ, Hamilton PR. Proline aminopeptidase activity as a rapid diagnostic test to confirm bacterial vaginosis. Obstet Gynecol 1988;71:607-11.
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;361:983-8.
McDonald H, Brocklehurst P, Parsons J, Vigneswaran R. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2007;1:CD000262.
Seo K, McGregor JA, French JI. Preterm birth is associated with increased risk of maternal and neonatal infection. Obstet Gynecol 1992;79:75-80.
Lamont RF. Can antibiotics prevent preterm birth - The pro and con debate. BJOG 2005;112 Suppl 1:67-73.
Lamont RF, Duncan SL, Mandal D, Bassett P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol 2003;101:516-22.
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.
Morales WJ, 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;171:345-7.
McDonald HM, O′Loughlin JA, Vigneswaran R, Jolley PT, Harvey JA, Bof A, et al.
Impact of metronidazole therapy on preterm birth in women with bacterial vaginosis flora (Gardnerella vaginalis
): A randomised, placebo controlled trial. Br J Obstet Gynaecol 1997;104:1391-7.
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. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 2000;342:534-40.
Joesoef MR, Hillier SL, Wiknjosastro G, Sumampouw H, Linnan M, Norojono W, et al.
Intravaginal clindamycin treatment for bacterial vaginosis: Effects on preterm delivery and low birth weight. Am J Obstet Gynecol 1995;173:1527-31.
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 randomised placebo-controlled double-blind trial. Br J Obstet Gynaecol 1999;106:652-7.
McDonald H, Brocklehurst P, Parsons J, Vigneswaran R. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2000;1:CD000262.
McDonald H, Brocklehurst P, Parsons J, Vigneswaran R. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2003;1:CD000262.
McDonald H, Brocklehurst P, Parsons J, Vigneswaran R. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2005;1:CD000262.
Kiss H, Petricevic L, Husslein P. Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery. BMJ 2004;329:371.
Larsson PG, Fåhraeus L, Carlsson B, Jakobsson T, Forsum U; Premature study group of the Southeast Health Care Region of Sweden. Late miscarriage and preterm birth after treatment with clindamycin: A randomised consent design study according to Zelen. BJOG 2006;113:629-37.
Swadpanich U, Lumbiganon P, Prasertcharoensook W, Laopaiboon M. Antenatal lower genital tract infection screening and treatment programs for preventing preterm delivery. Cochrane Database Syst Rev 2008;2:CD006178.
Novikona N. Antenatal lower genital tract infection screening and treatment programmes for preventing preterm delivery, RHL. WHO Public Health Library; 2009.
Reid G, Jass J, Sebulsky MT, McCormick JK. Potential uses of probiotics in clinical practice. Clin Microbiol Rev 2003;16:658-72.
Shalev E. Ingestion of probiotics: Optional treatment of bacterial vaginosis in pregnancy. Isr Med Assoc J 2002;4:357-60.
Krauss-Silva L, Moreira ME, Alves MB, Rezende MR, Braga A, Camacho KG, et al.
Randomized controlled trial of probiotics for the prevention of spontaneous preterm delivery associated with intrauterine infection: Study protocol. Reprod Health 2010;7:14.
Brocklehurst P, Gordon A, Heatley E, Milan SJ. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2013;1:CD000262.