Evidence Based Commentary

Evidence Based Commentary EBC Topic 2: 1 st Sept 2009 to 31 st Aug 2010 Faculty candidate number: ExM00643 Date completed: 26 th August 2010 Word Count: 1995 This Evidence Based Commentary is submitted as part of the requirements for the Examination for Membership of the Faculty of Sexual and Reproductive Healthcare of the Royal College of Obstetricians and Gynaecologists. 1

Summary of Key Issues Bacterial Vaginosis (BV) is the commonest cause of abnormal vaginal discharge in young women, characterised by overgrowth of anaerobic organisms including Gardnerella vaginalis, Mycoplasma hominis, Prevotella and Mobiluncus species, which replace normal lactobacilli leading to an increase in vaginal ph above 4.5. 1 Karen describes an offensive vaginal discharge, without pelvic pain or vulvovaginal soreness, characteristic of BV. BV may be more notable after intercourse 2, is not associated with itching or irritation 1, and is asymptomatic in 50% of infected women. 2 Details of the nature of the discharge, self medication, and a sexual history should be obtained. It is important to elicit whether Karen has any other concerns, or ideas about treatments. There is a large stigma surrounding sexual health 3, so it is important to be sensitive, and make her feel at ease. Karen s questions can be addressed by asking; 1. What is the evidence based medical management of BV? 2. What is the evidence for alternative treatments for BV? 3. What are the risk factors for BV? 4. How can a recurrence of BV be prevented? 5. Is there an association between BV and Intrauterine Device (IUD) use? Literature Review 1. Evidence based medical management of BV Current guidance for first line treatment is oral metronidazole 400mg to 500mg twice daily (bd) for 5-7 days. A single dose of 2g orally can be given if adherence to treatment is likely to be an issue. 1,4 A systematic review of 4 randomised controlled trials showed that 2

metronidazole bd for 7 days was associated with higher cure rates than a single dose of metronidazole (82% with 7 day regimen verses 62% single dose regimen, P<0.05). 2 Oral clindamycin 300mg bd for 7 days and oral tinidazole (single dose 2g) are alternatives. Oral clindamycin has been associated with pseudomembranous colitis. 1, 4 No significant difference in cure rate has been found between oral clindamycin and metronidazole. Both have been shown to be more effective than placebo in non pregnant women. 2 Intravaginal metronidazole gel (0.75%) once daily (od) for 5 days, or intravaginal clindamycin cream (2%) od for 5 7 days 1 can be used if the woman cannot tolerate oral metronidazole or if she prefers topical treatment. Both have been shown to be significantly superior to placebo, 2, 4, 5 however intravaginal clindamycin has been associated with mild to severe colitis and vaginal candidiasis. 2 No significant difference has been found between different intravaginal treatment regimes. 2 All treatments have a cure rate of 70-80% after 4 weeks. 1, 6 The Cochrane collaboration published a systematic review and meta-analysis of randomised controlled trials, looking at effectiveness of antimicrobial agents on BV in non-pregnant women. 24 trials involving 4422 participants were included. No significant difference was found between metronidazole and clindamycin irrespective of regimen. Topical clindamycin was associated with a lower rate of adverse effects than oral metronidazole, RR 0.08 (95% C.I 0.1 0.59) which is associated with metallic taste, nausea and vomiting. No significant difference was found between tinidazole and metronidazole; clindamycin ovule and clindamycin cream; vaginal lactobacilli tampon and placebo; clindamycin and sulphonamide creams; tinidazole with acid gel and clindamycin; or cefadroxil and metronidazole. 5 3

2. Evidence for alternative treatments for BV There are several over the counter products containing lactic acid, but insufficient evidence to make a recommendation for their use. Studies to date are generally small and poor quality. 4 Women may consider the use of probiotics to manage BV, 6 but there has been lack of evidence for their effectiveness. 1,4,6 The Cochrane collaboration published a review of randomised controlled trials studying the efficacy of probiotics in the treatment of BV. There was a statistically significant benefit of adding 30 days of oral probiotics to metronidazole, and adding lactobacillus to estriol vaginal tablets during menstruation (no adverse effects reported). 7 A further single centre randomised observer blind study found a significant benefit in adding topical lactobacillus after treatment with clindamycin. 8 No significant difference in cure rate was found between intravaginal probiotic capsules and metronidazole gel. There were significantly more side effects in the metronidazole group. No significant difference was found between a lactobacillus impregnated tampon and placebo, following use of a clindamycin ovule. 7 An additional systematic review including eight studies showed a significant relative risk reduction in BV after use of probiotics. Lactobacilli preparations were found to be well tolerated and caused minimal side effects. 9 3. Risk factors for BV Vaginal douching, use of IUD, low socioeconomic status, black ethnicity, new or multiple sexual partners and early age of intercourse appear to increase the risk of BV. 2,7,10 A systematic review and meta-analysis found a significant association between new or multiple male sexual partners and BV, RR 1.6 (95% C.I. 1.5 1.8), P<0.01. Condom use was shown to significantly protect from BV, RR 0.18 (95% C.I 0.8 0.9), p<0.01. There was some publication bias in this review against smaller studies. 11 4

A retrospective case-control study showed a significant increased risk of BV in IUD users (RR 2.3, P<0.01), those divorced, separated or widowed, unemployed, heavy drinkers, and those with a past pregnancy. Smoking was the strongest independent non-sexual risk factor for BV (OR 1.9, 95% C.I. 1.4 2.61), and this risk was directly proportional to number of cigarettes smoked. The small odds ratios in this study suggest that individual predictive values may be low. 12 There is insufficient evidence to say that BV is sexually transmitted, and there is no benefit in treating the male partner. 13 4. How can a recurrence of BV be prevented? The cure rate of BV is around 80-90% at one week. Recurrence rates are around 30% within three months. Recurrent BV is defined as three or more proven episodes in 12 months. 14 The use of hormonal contraception has been shown to reduce the recurrence of BV. 15 Women should be advised to avoid douching, shampoo, gels and antiseptics in the bath. Acidifying gel may reduce relapse at 1 month. 6 A small observational study reported that AcI- Jel used at the time of menstruation and after unprotected intercourse was associated with a reduction in relapse, and longer time to relapse, after a course of metronidazole or clindamycin for initial treatment. Aci-Jel has now been discontinued and replaced by Balance Activ. 14 Small studies of live yoghurt or Lactobacillus have not demonstrated benefit. 1 Six randomised controlled trials showed that treating the male partner did not reduce recurrence rates of BV. Indeed it may cause emotional harm by implying that BV is sexually transmitted. 2 A more recent retrospective case controlled study demonstrated that African American ethnicity and more than one sexual partner in the previous two years were strongly associated with recurrent BV (OR 42.7 and 5.34 respectively). No significant link was found between IUD use, condom use or hormonal contraception use and recurrent BV, however 5

the sample used in this study was small n=28 cases, 122 controls), there was poor participation rate, and the study was subject to recall bias. 16 5. Is there an association between BV and IUD use? A link has been found between BV and IUD use suggesting that the IUD may be a risk factor for BV. 2, 4,7,10 A cross sectional study involving 211 IUD users and 155 nonusers, found that women with the IUD were 2.78 times more likely to have BV (P<0.00). IUD users were more likely to complain of vaginal discharge, and have vaginal discharge on examination. The two groups did not differ significantly helping to eliminate confounding factors. 17 A prevalence survey tested 357 women using different forms of contraception for sexually transmitted infections (STIs) and BV. BV was significantly more common among IUD users (47.2%) than hormonal contraceptive (26.6%) or condom users (33.9%), p<0.05, and persisted after controlling for age, level of education, douching practices and current STIs. 18 An additional study (n= 1314), looked at contraceptive use and risk factors for BV including smoking and sexual behaviour. After adjusting for confounding factors women using an IUD had a positive association with BV (OR 2.98, P<0.0003). Oral contraception and condoms had a negative association with BV, odds ratios 0.43 (p, 0.004) and 0.56 (p<0.05) respectively. 19 6

Application of Evidence History A history of how long the discharge has been present and association to menstrual cycle or intercourse should be obtained. Karen has no red flag symptoms such as pelvic pain, dyspareunia or fever which may suggest pelvic inflammatory disease (PID). It is important to take a sexual history, asking about recent partners and sex of the partners. 3 BV is particularly prevalent among women who have sex with women 2, 11 Karen has had two similar episodes in the past; as these were undiagnosed we cannot confirm recurrent BV. We should ask if she has tried any over the counter treatments, and about washing practices. Examination Guidance suggests that patients who present with typical symptoms of BV can be treated without sampling. 1,6 If examination is required a chaperone should be offered according to GMC guidance. 3 I would examine Karen to check the IUD threads, and take a swab to confirm the diagnosis, in view of previous episodes. Investigations A high vaginal swab should be taken for BV, and Candida. If Karen is at risk of STI, this can be tested for Trichomonas Vaginalis, and an endocervical swab obtained for Gonorrhoea and Chlamydia. Vaginal ph testing would distinguish between BV (ph >4.5) and Candida (ph <4.5). Although not often now used Amsel s criteria can be used to diagnose BV. 1 Treatment Karen is not on any medication; after checking her allergy status I would offer her oral Metronidazole 400mg bd for 7 days or 2g stat dose, depending on preference and likelihood 7

of compliance. I would discuss the adverse effects of metronidazole and efficacy of both regimes. If she preferred topical treatment she could be offered topical metronidazole or clindamycin. Karen must be advised to avoid alcohol with metronidazole because of the possibility of a disulfiram like reaction. 1 To reduce risk of recurrence Karen can be informed of risk factors for BV including smoking and sexual practices. Karen should be advised to avoid douching, shampoo, gels and antiseptics in the bath. She may wish to try acidic gel, but evidence is weak. There is better, albeit not robust evidence for probiotics. It is good practice to provide written information, for example, a leaflet. Karen can be advised that BV is more common in IUD users; if BV becomes a recurrent problem her contraception can be reviewed. The risk of BV with an IUD needs to be balanced against the risk of unplanned pregnancy. It is imperative to find an acceptable contraceptive alternative before considering removal of the IUD. Hormonal contraception and condoms have been shown to reduce recurrence rates of BV. Follow up Karen should be advised to return for review should initial treatment fail to clear her symptoms, or if she has problems tolerating antibiotics. 8

Identification of knowledge gaps and suggestions for future research Most studies looking at medical treatment of BV have followed patients for one to two months only, so long term outcomes, adverse effects and recurrence have generally not been evaluated. 2 Studies looking at acidic vaginal gels are small and of poor quality. 4 Larger, well designed randomised controlled trials are needed to establish their efficacy. There is emerging evidence that probiotics may be useful in treating BV; a meta-analysis of large randomised controlled trials is needed. Studies looking at efficacy of probiotics on recurrence rates and secondary outcomes including obstetric complications 7, PID and endometritis are needed, as well as studies looking at adverse affects, optimal type, duration, and dosing of probiotic. 9 There is no evidence that treating the male partner is beneficial, 13 but several studies have linked BV with sexual behaviour. A large well designed study looking at whether treatment of the male partner is beneficial would be valuable. A link has been demonstrated between IUD use and BV, but studies are small and have poor control groups. Better designed studies to confirm or refute the hypothesis that IUDs are implicated in causing BV are needed before a recommendation for removal can be made. It would also be advantageous to study whether screening for BV prior to IUD insertion reduces rates of PID in IUD users. 18 9

References 1. Hay P. National Guideline for the Management of Bacterial Vaginosis. Clinical Effectiveness Group. British Association for Sexual Health and HIV 2006 [www.bashh.org/documents/62/62.pdf]. Accessed 22/05/2010. 2. Joesoef MR and Schmid G. Bacterial Vaginosis. BMJ Clinical Evidence 2007; 12: 1601. 3. Spence D and Melville C. Clinical Review: Vaginal Discharge. British Medical Journal 2007; 335: 1147-1151. 4. Clinical Knowledge Summaries. Bacterial Vaginosis. CKS March 2009 [www.cks.nhs.uk/bacterial_vaginosis]. Accessed 22/05/2010. 5. Oduyebo OO, Anorlu RI and Ogunsola FT. The effects of antimicrobial therapy on bacterial vaginosis in non-pregnant women (Review). The Cochrane Library 2009, Issue 3. 6. Faculty of Family Planning and Reproductive Health Care Clinical Effectiveness Unit. FFPRHC and BASHH Guidance: The management of women of reproductive age attending non genito-urinary settings complaining of vaginal discharge. Journal of Family Planning and Reproductive Healthcare 2006; 32(1): 33-42. 7. Senok AC, Verstraelen H, Temmerman M et al. Probiotics for the treatment of bacterial vaginosis (Review). The Cochrane Library 2009, Issue 4. 8. Petricevic L and Witt A. The role of Lactobacillus casei rhamnosus Lcr35 in restoring the normal vaginal flora after antibiotic treatment of bacterial vaginosis. BJOG 2008; 115(11): 1369 1374. 10

9. Abad CL and Safdar N. The Role of Lactobacillus Probiotics in the Treatment or Prevention of Urogenital Infections- A Systematic Review. Journal of Chemotherapy 2009; 21(3): 243 252. 10. Wilson J. Managing recurrent bacterial vaginosis. Sex Transm Infect 2004; 80: 8-11. 11. Fethers KA, Fairley CK, Hocking JS et al. Sexual risk factors and bacterial vaginosis: A Systematic Review and Meta Analysis. Clin Infect Dis 2008; 47(11): 1426-1435. 12. Smart S, Singal A and Mindel A. Social and sexual risk factors for bacterial vaginosis. Sex Transm Infect 2004; 80: 58 62. 13. Verstraelen H, Verhelst R, Vaneechoutte M et al. The epidemiology of bacterial vaginosis in relation to sexual behaviour. BMC Infectious Diseases. 2010; 10: 81. 14. Wilson JD, Shann SM, Brady SK et al. Recurrent bacterial vaginosis: the use of maintenance acidic vaginal gel following treatment. International Journal of STD & AIDS 2005; 16: 736-738. 15. Bradshaw CS, Morton AN, Hocking J et al. High recurrence rates of bacterial vaginosis over the course of 12 months after oral metronidazole therapy and factors associated with recurrence. JID 2006; 193: 1478-1486. 16. Klatt TE, Cole DC, Eastwood DC et al. Factors associated with Recurrent Bacterial Vaginosis. Journal of Reproductive Medicine 2010; 55: 55-61. 17. Hodoglugil SNN, Aslan D, Bertan M. Intrauterine device use and some issues related to sexually transmitted disease screening and occurrence. Contraception 2000; 61: 359-364. 11

18. Joesoef MR, Karundeng A, Runtupalit C et al. High rate of bacterial vaginosis among women with intrauterine devices in Manado, Indonesia. Contraception 2001; 64: 169-172. 19. Calzolari E, Masciangelo R, Milite V. Bacterial Vaginosis and Contraceptive Methods. International Journal of Gynaecology and Obstetrics 2000; 70: 341-346. 12