The effect of treating bacterial vaginosis on preterm laborObjective: Multiple studies suggest that...

The effect of treating bacterial vaginosis on preterm labor

Christine C. Tebes1, Catherine Lynch1 and John Sinnott2

1Department of Obstetrics and Gynecology, and2Department of Infectious Diseases, University of South Florida, Tampa, FL

Objective: Multiple studies suggest that bacterial vaginosis (BV) causes preterm labor; yet its routine treatmentremains controversial. In order to help to elucidate this controversy, we performed a thorough review of studieswith levels of evidence ranging from I to II–II.Methods: We searched for all of the studies from the years 1994 to 2001 via Medline’s database, includingMD Consult and Ovid Mednet.Results: Several trials discovered a decrease in the incidence of preterm labor when BV was treated, but mostof those trials were performed on women with a history of preterm labor. However, the majority of trialsreviewed advise against treatment of a general low-risk obstetric population, as there was no significant decreasein preterm labor.Conclusions: Therefore, based on the above studies and the current guidelines of the Centers for DiseaseControl and Prevention (CDC), treating pregnant women in high-risk populations who are diagnosed with BVprovides the clinician with an opportunity to possibly prevent preterm labor in this population. In nulliparouswomen without a history of preterm birth, treatment is recommended if other risk factors are present (e.g.gonorrhea or chlamydia). However, in the general low-risk populations, routine screening is not indicated.

Key words: INFECTION; MOBILUNCUS; ANTIBIOTICS; VAGINITIS; PREMATURITY

Premature births remain a serious problem inthe USA, occurring in 11% of all pregnancies.Preterm birth, defined as delivery of an infantbefore 37 weeks’ gestation, is also the leadingcause of neonatal mortality and morbidity in thedeveloped world. In the USA alone, an excess of$4 billion1, or 57% of direct nursery costs2 can beattributed to the care of premature infants. Inaddition, infants who survive exhibit an increasedrisk of long-term morbidity, chronic lung disease,cerebral palsy, developmental delay, and visual andhearing impairment1,2.

Causes of preterm labor vary, but infection ishighly suspect. Up to 80% of early premature birthsare associated with an intrauterine infection priorto the rupture of membranes. Asymptomatic

bacteriuria, Neisseria gonorrhea, Chlamydia tracho-matis, Trichomonas vaginalis and bacterial vaginosis(BV) have all been associated with an increased riskof preterm birth3. The exception is vaginal yeastinfections4. Risk factors for preterm delivery arelisted in Table 1. Multiple studies suggest thatBV is a cause of preterm labor, yet its routinetreatment remains controversial5–8.

In conjunction with preterm delivery, BV inpregnant patients is associated with prematurerupture of membranes, infection of the amnionand chorion, histologic chorioamnionitis andinfection of amniotic fluid. Flynn et al.5 noted a60% increase in the risk of preterm delivery in thepresence of BV. Another study by Hillier et al.6

associated BV with risk of spontaneous preterm

Infect Dis Obstet Gynecol 2003;11:123–129

Correspondence to: John Sinnott, MD, Department of Infectious Diseases, University of South Florida, PO Box 1289, Tampa,FL 33601-1289, USA. Email: [email protected]

2003 The Parthenon Publishing Group 123

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birth by a factor of 1.5 to 3 in high-risk women,while other studies suggest that BV almost doublesthe risk of spontaneous preterm delivery7.

Although BV is present in almost 20% of preg-nant women, most cases remain asymptomatic,and not all women with the condition will deliverprematurely8. It is postulated that there exists a sub-group of high-risk women (e.g. those who havevaginal colonization with Mycoplasma hominis).African–American women may also exhibit200–300% more BV than white populations7,8.The exact conditions under which BV directlycorrelates with preterm labor are unknown5.

The purpose of this paper is to review therecent literature addressing the associationbetween BV and preterm birth4.

METHODS

In order to perform this review, we searched theMedline database, including MD Consult andOvid Mednet for the years 1994–2001. Some ofthe search terms included preterm labor, BV, treat-ment, metronidazole, clindamycin, and vaginitis.

RESULTS

Hauth et al. (Level I study in 1995) treatedpregnant women with a history of preterm birth

or weight < 50 kg and a positive diagnosis of BV7.Treatment consisted of metronidazole (250 mgthree times a day for 7 days) and erythromycin(333 mg three times a day for 14 days). The resultsof this 2:1 double-blind randomization trialrevealed a decreased incidence of preterm delivery(< 37 weeks) for the entire study population (oddsratio, OR, 0.48; 95% confidence interval, CI0.28–0.81), as well as for a subset of patients with aprevious preterm delivery (OR, 0.48; 95% CI,0.25–0.90). Women who were diagnosed with BVat the initial visit (24 weeks) and who receivedantibiotics rather than placebo presented withfewer preterm deliveries. Since this treatmentbenefit was only observed at initial examination,the overall results do not support mid-trimestertreatment with metronidazole and erythromycinin women at risk for preterm delivery withoutBV. There are no data to suggest that treatmentof low-risk pregnant women with BV decreasesthe rates of prematurity7.

Over a period of 3 years, Morales et al. (level Istudy in 1994) screened for BV in women between13 and 20 weeks with a singleton gestation anda history of preterm birth via a double-blindrandomized trial. The 80 women with a positivescreen received either metronidazole (250 mgthree times a day) or a placebo for 7 days. The studyshowed a significant decrease in delivery priorto 37 weeks among women taking metronidazole(18%) compared with those on placebo (39%)(p < 0.05). In the metronidazole group there weresignificantly fewer hospital admissions for pretermlabor, cases of premature rupture of membranes,and low birth weights9.

In 1995, McGregor et al. (level I study)performed a prospective, controlled treatment trialof 1260 subjects to study the effect of clinda-mycin on pregnant women with BV. Womenwho were treated with 300 mg of clindamycinorally twice daily for 7 days showed a reduction inpreterm birth (relative risk 0.5; 95% CI, 0.3–0.9),and the authors recommended that women at riskfor preterm birth with BV should be screened andtreated1.

In 1997, McDonald et al.10 conducted amulticenter, randomized, placebo-controlled trialof 879 women at 19 weeks’ gestation, but failedto demonstrate a reduced preterm birth rate

Bacterial vaginosis and preterm labor Tebes et al.

124 • INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY

History of preterm birthMultiple gestationBacterial vaginosisUrinary tract infectionCrack cocaine usageAbruptionSecond- and third-trimester vaginal bleedingMaternal age under 16 years or over 40 yearsAfrican–American raceHistory of uterine surgerySmokingStrenuous workPolyhydramnios and oligohydramniosCervical infectionsCervical incompetencePre-eclampsiaPremature preterm rupture of membranesDomestic violenceRetained intrauterine device

Table 1 Risk factors for preterm labor1,2



among pregnant women with BV or those with aheavy growth of Gardnerella vaginalis (level I). Theintention-to-treat analysis showed no differencebetween the treatment and placebo groups inoverall preterm birth (31/429 [7.2%] vs. 32/428[7.5%]) or spontaneous preterm birth rate (20/429[4.7%] vs. 24/428 [5.6%]). However, amongwomen with a previous preterm birth, thosetreated with oral metronidazole (400 mg twicedaily for 2 days at 24 weeks’ gestation, and again at29 weeks) demonstrated a marked reduction inspontaneous preterm birth rate (OR, 0.14; 95%CI, 0.01–0.84)10.

A meta-analysis from the Cochrane databasedetermined that preterm birth rates did not differsignificantly between treated and non-treatedpregnant patients with BV (OR, 0.78; 95%CI, 0.60–1.02), yet a subgroup of women with aprevious preterm birth demonstrated a significantdecrease in the incidence of preterm birth, with anodds ratio of 0.37 (95% CI, 0.23–0.60)3. Thismeta-analysis of 1504 women from a total of fivetrials using amoxicillin, clindamycin and metro-nidazole did not recommend screening and treat-ing all pregnant women for BV in order toprevent preterm birth.

Carey et al.11 recently conducted a randomized,double-blind clinical trial of the use of metro-nidazole to treat asymptomatic BV. Treatmentdid not reduce the frequency of delivery before37 weeks’ gestation (relative risk in the metro-nidazole group, 1.0; 95% CI, 0.8–1.2). Thisclinical trial differed from previous attemptsbecause it was larger (1953 subjects) and it studiedthe general obstetrical population, not just womenwith a history of preterm delivery. Treatmentinvolved a shorter course of metronidazole therapywith two 2 g doses during a 48-hour period, anda second treatment of the women between 24and 30 weeks’ gestation. These researchersrecommended the longer course of therapy toeradicate upper genital tract organisms11.

The results of this study supported those ofMcDonald et al.10 in that metronidazole did notreduce preterm delivery among the generalpopulation of pregnant women, nor did it reducehospital admissions for preterm labor or pretermpremature rupture of the membranes, postpartumendometritis, clinical intra-amniotic infections,

vaginal infections serious enough to require treat-ment, and treatment with tocolytic drugs. Theplacebo and metronidazole groups did not differwith regard to incidence of admissions to the neo-natal intensive-care unit, passage of meconium, orfetal death/neonatal death. This study foundthat routine screening of pregnant women forasymptomatic BV and treating the latter with ashort course of orally administered metronidazoledid not reduce the risk of preterm birth, despite itseffectiveness in eradicating BV. Studies do notsupport the use of metronidazole treatment inpregnant women with asymptomatic BV who areconsidered to be at either high or low risk forpreterm delivery11. Studies by McDonald et al.10,Morales et al.9 and Hauth et al.7 did find evidenceof a decreased incidence of recurrent pre-term delivery among women with a priorpreterm delivery treated with metronidazole ormetronidazole/erythromycin.

The findings of Joesoef et al.12 concur with thoseof Carey et al.11. This multicenter, double-blind,randomized, placebo-controlled trial failed todemonstrate a reduction in preterm delivery(level I, 1995) in 745 women between 14 and26 weeks’ gestation who were diagnosed with BV(via Gram stain score > 6) with 2% clindamycinvaginal cream or with a placebo cream for 7 days.Although 15% of the women treated withclindamycin had a preterm delivery, only 13.5% ofplacebo patients did (OR, 1.1; 95% CI, 0.7–1.7).The authors proposed that the increased frequencyof preterm delivery might be caused by a transientincrease in vaginal colonization by Escherichi coliand Enterococcus 1 month after therapy. Since E. coliis linked to an increased risk of preterm delivery,this may explain the value of 15%, comparedwith the 13.5% difference found in the study byJoesoef et al.12.

In 1994, McGregor et al.13 evaluated 271women between 16 and 27 weeks’ gestation in adouble-blind trial (level I). Women who werediagnosed with BV were treated with 2%clindamycin vaginal cream or placebo for 7 days.Although 2% clindamycin vaginal cream waseffective in treating BV during pregnancy(p = 0.001) it was not permanent, as the conditiongradually returned, and treatment did not reducethe risk of prematurity during the second trimester.


INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY • 125



Possible reasons cited include the inadequatepower of the study, the timing of treatment, andthe use of local vaginal treatment13.

In 2001, Kekki et al.14 performed a multicenter,randomized, double-blind, placebo-controlledtrial (level I) which showed that the treatment ofBV in early pregnancy with vaginal clindamycinfor 7 days did not decrease the rate of pretermdeliveries or peripartum infections. In 375 ran-domized subjects, preterm delivery occurred in5% of the clindamycin group and 4% of theplacebo group (OR, 1.3; 95% CI, 0.5–3.5). Theefficacy of intravaginal clindamycin can be as highas 90% in studies on non-pregnant women, and issimilar to that of oral metronidazole. The subjectsincluded a low-risk population of healthy womenwith singleton pregnancies and without a historyof preterm delivery14. The results are similar to theconclusion of McGregor et al.13 that topical treat-ment in early pregnancy reduced vaginal fluidmucinase and sialidase, but failed to reduce the rateof preterm births14.

A recent randomized controlled trial byKurkinen-Raty et al.15 assessed the efficacy ofvaginal clindamycin in reducing preterm birth(level I). Of the 1956 women without a history ofpreterm delivery who were screened at the firstantenatal visit (gestational week 12), 143 womentested positive for BV. After randomization andtreatment with clindamycin or placebo, thepreterm birth rate in the clindamycin group was13.7%, compared with 6.0% in the placebo group(OR, 2.5; 95% CI, 0.6–10). This study thereforesupports the evidence that vaginal clindamycintreatment of BV in the first trimester does notreduce the risk of preterm birth15.

In 1999, French et al.16 evaluated the associationbetween BV, first-trimester vaginal bleeding andpreterm labor in 1100 pregnant women who wereenrolled in a prospective observational study (levelII–II). It was determined that treatment of BV withclindamycin (300 mg orally twice daily for 7 days)significantly reduced the risks of preterm birthamong women without first-trimester bleeding(relative risk, 0.37; 95% CI, 0.16–0.88). Althoughthe overall population of women with both BVand first-trimester vaginal bleeding experiencedreductions in preterm birth, the finding was not

statistically significant (relative risk, 0.52; 95%CI, 0.18–1.55)16.

Several authors have proposed that the timingof the diagnosis and/or treatment is important ifpreterm labor is to be decreased. A level II–IIstudy by Meis et al.17 highlighted the effect oftiming of diagnosis on BV and the incidence ofpreterm labor. Women who tested negative at 24weeks but were positive when tested again at 28weeks had the highest likelihood of preterm birth(OR, 2.53; 95% CI, 1.32–4.85; p = 0.005)17.

Riduan et al.18 found the opposite to be true(level II–I trial). Women who tested positive forBV at 24 weeks and received antibiotics showed asignificantly decreased incidence of preterm birth(OR, 0.44; 95% CI, 0.11–1.91). The authorsfound that the presence of BV at 16 weeks wasmore predictive of preterm delivery than itspresence at 28 to 32 weeks18.

Table 2 provides a concise summary of thearticles reviewed above.

DISCUSSION

Preterm labor may be classified as either physio-logic or pathologic. Physiologic preterm labordescribes a normal initiating factor that occurs tooearly in pregnancy, while pathologic preterm laborresults from an abnormal initiating factor withtiming being a distinguishing factor. The earlier inpregnancy preterm labor occurs, the more likelyit is that a pathologic etiology exists. Priorto 16 weeks’ gestation, BV is related to pretermdelivery by a risk factor of 5 to 7.5. After 26 weeks’gestation, the risk factor drops to 1.4 to 1.919,20.

BV, an overgrowth of anaerobic species thatproduce protease, phospholipase A2 andcollagenases in the vagina21, is found in 800 000pregnant women each year11. There is disruptionof the vaginal ecosystem that results in increasedlevels of anaerobes. BV alters the vaginal flora bydecreasing the number of hydrogen-peroxide-producing Lactobacillus acidophilus organisms.Consequently, the levels of G. vaginalis, M.hominis, and Mobiluncus species increase ratherthan remaining in their normal state of suppres-sion. The metabolic by-products of these





organisms include amines, which increase thevaginal pH, and exfoliation of vaginal epithelialcells results22.

Although the exact mechanism is not known,studies have shown that BV can cause infection ofthe upper genital tract, which acts as a prematurebirth trigger6. BV and T. vaginalis are also asso-ciated with many microorganisms that producephospholipase A2 and C or phospholipase-likeactivity, and affected patients show increased levelsof sialidase, phospholipase A2, prostaglandin E2and interleukin–1(beta). The rise in levels ofthese enzymes may result in the decidual or fetalmembrane cell fatty acid tissue stores releasingarachidonic acid2, a precursor of the uterotonicprostaglandins.

Other explanations of an association betweenBV and preterm labor include activation offetal and/or maternal inflammatory responses orproteolytic enzymes. Elevated vaginal or cervicallevels of endotoxin, mucinase, sialidase and

interleukin-1(alpha) are found in women with BV,which suggests that the microorganisms producecytokines6. These cytokines and the release ofinterleukin-1(beta) and tumor necrosis factorinduce cyclooxygenase II, an enzyme that pro-duces prostaglandins involved in parturition.Proteolytic enzymes that may overcome maternalmucous membrane defenses and impair fetalmembrane strength and elasticity includecollagenases, immunoglobulin A proteases,elastases, mucinases and/or sialidases2.

Several studies have concluded that screeningand treating for BV is futile, and one of the largestclinical trials to date found no difference in thetreated low-risk pregnant population comparedwith the placebo11. However, since the clinicaldiagnosis of BV need not be symptomatic, screen-ing all pregnant women who have risk factors maybe unnecessary and not cost-effective21, whilethe most advantageous time to screen and theoptimum dosage of antibiotic is uncertain.



Author Year Study type Effect on preterm labor DrugLevel ofevidence

Hauth et al.7

Morales et al.9

McGregor et al.1

McDonald et al.10

Cochrane database3

Joesoef et al.12

Carey et al.11

McGregor et al.13

Kekki et al.14

Kurkinen-Raty et al.15

French et al.16

1995

19941995

1997

1991 to 2001

1995

2000

1994

2001

2000

1999

Double-blind

Placebo controlledProspective controlledtreatment trialRandomized, placebo,controlled

Meta-analysis ofcontrolled trials

Double-blind,randomized, placeboRandomized,double-blind

Randomized,double-blindDouble-blind, placebo

Randomized,controlledProspective,observational

Decreased in high-risk

Decreased in high-riskDecreased in women athigh riskDecreased only in subsetwith a history of pretermlaborNo decrease in generalpopulation, but a decreasein those at high riskNo decrease in low-riskpopulationAsymptomatic generalpopulation withoutdecreaseNo decrease in women at16 to 27 weeks' gestationNo decrease in low-riskpopulationNo significant decrease inlow-risk populationDecreased in low-riskpopulation, but notstatistically significant

Metronidazole/erythromycinMetronidazoleClindamycin

Metronidazole

Amoxicillin,metronidazoleand/or clindamycinMetronidazole

Metronidazole(short course)

Clindamycin

Clindamycin

Clindamycin

Clindamycin

Level I

Level ILevel I

Level I

Level I

Level I

Level I

Level I

Level I

Level I

Level II–II

Table 2 Studies that have evaluated the effect of treatment of bacterial vaginosis on the incidence of preterm labor



Although the The Cochrane Library’s review is anexcellent resource, our paper differs in that wehave investigated different aspects of this approach.We have included not only level I but also level IIstudies. Furthermore, we included two studiesthat investigated the effects of timing on the treat-ment of BV17,18. However, ultimately our conclu-sion is similar to that of the Cochrane review3.

To the clinicians who decide to screen forand treat BV, the most effective antibiotic appearsto be oral metronidazole, which can besafely administered during pregnancy. Vaginal

clindamycin therapy has shown slight butstatistically non-significant increases in pretermbirth rate for the reasons discussed previously23.

Analysis of the reviewed studies supports thecurrent guidelines of the Center for DiseaseControl. Treating pregnant women in high-riskpopulations who have been diagnosed with BVcan prevent preterm labor in these individuals.In nulliparous women without a history of pre-term birth, the recommendation is to treat ifother risk factors, such as gonorrhea or chlamydia,are present.

REFERENCES1. McGregor JA, French JI, Parker R, et al. Preven-

tion of premature birth by screening and treatmentfor common genital tract infections: results of aprospective controlled evaluation. Am J ObstetGynecol 1995;173:157–67

2. Andolsek KM, Kelton GM. Risk assessment. PrimCare 2000;27:71–103

3. Brocklehurst P, Hannah M, McDonald H. Inter-ventions for treating bacterial vaginosis inpregnancy. The Cochrane Library. Issue 4. Oxford:Update Software, 2001

4. Goldenberg RL, Rouse DJ. Prevention ofpremature birth. N Engl J Med 2001;339:313–20

5. Flynn CA, Helwig AL, Meurer LN. Bacterialvaginosis in pregnancy and the risk of prematurity:a meta-analysis. J Fam Pract 1999;48:885–92

6. Hillier SI, Nugent RP, Eschenbach DA, et al. Asso-ciation between bacterial vaginosis and pretermdelivery of a low-birth-weight infant. N Engl J Med1995;333:1737–42

7. Hauth JC, Goldenberg RL, Andrews WW, et al.Reduced incidence of preterm delivery withmetronidazole and erythromycin in womenwith bacterial vaginosis. N Engl J Med 1995;333:1732–6

8. Lamont RF. Antibiotics for the prevention ofpreterm birth. N Engl J Med 2000;342:581–3

9. Morales WJ, Schorr S, Albritton J. Effect ofmetronidazole in patients with preterm birth inpreceding pregnancy and bacterial vaginosis: aplacebo-controlled, double-blind study. Am JObstet Gynecol 1994;171:345–9

10. McDonald HM, O’Loughlin JA, Vigneswaran R,et al. Impact of metronidazole therapy on pre-term birth in women with bacterial vaginosisflora (Gardnerella vaginalis): a randomized, placebo

controlled trial. Br J Obstet Gynaecol 1997;104:1391–7

11. Carey JC, Klebanoff MA, Hauth JC, et al.Metronidazole to prevent preterm delivery inpregnant women with asymptomatic bacterialvaginosis. N Engl J Med 2000;342:534–40

12. Joesoef MR, Hillier SL, Wiknjosastro G, et al.Intravaginal clindamycin treatment for bacterialvaginosis: effects on preterm delivery and low birthweight. Am J Obstet Gynecol 1995;173:1527–31

13. McGregor JA, French JI, Jones W, et al. Bacterialvaginosis is associated with prematurity and vaginalfluid mucinase and sialidase: results of a controlledtrial of topical clindamycin cream. Am J ObstetGynecol 1994:170:1048–59

14. Kekki M, Kurki T, Pelkonen J, et al. Vaginalclindamycin in preventing preterm birth andperipartal infections in asymptomatic women withbacterial vaginosis: a randomized, controlled trial.Obstet Gynecol 2001;97:643–8

15. Kurkinen-Raty M, Vuopala S, Koskela M, et al.A randomized, controlled trial of vaginal clinda-mycin for early pregnancy bacterial vaginosis.Br J Obstet Gynaecol 2000;107:1427–32

16. French JI, McGregor JA, Draper D, et al. Gesta-tional bleeding, bacterial vaginosis and commonreproductive tract infections: risk for pretermbirth and benefit of treatment. Obstet Gynecol1999;93:715–24

17. Meis PJ, Goldenberg RL, Mercer B. The pretermprediction study: significance of vaginal infections.Am J Obstet Gynecol 1995;173:1231–5

18. Riduan JM, Hillier SL, Utomo B, et al. Bacterialvaginosis and prematurity in Indonesia: associationin early and late pregnancy. Am J Obstet Gynecol1993;169:175–8





19. Kurki T, Sivonen A, Renkonen OV, et al. Bacterialvaginosis in early pregnancy and pregnancy out-come. Obstet Gynecol 1992;80:173–7

20. Hay PE, Lamont RF, Taylor-Robinson D, et al.Abnormal bacterial colonization of the genital tractand subsequent preterm delivery and late mis-carriage. Br Med J 1994;308:295–8

21. McCoy M, Katz C, Vern L, et al. Bacterial vaginosisin pregnancy: an approach for the 1990s. ObstetGynecol Surv 1995;50:482–8

22. Egan ME, Lipsky MS. Diagnosis of vaginitis.Am Fam Physician 2000;62:1095–104

23. Burtin P, Taddio A, Ariburnu O, et al. Safetyof metronidazole in pregnancy: a meta-analysis.Am J Obstet Gynecol 1995;172:525–9

RECEIVED 11/06/02; ACCEPTED 05/02/03





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