1. Vaginal Infections and Preterm Birth - An Update J. Chris Carey, MD Disponible en: http://www.ihs.gov/MedicalPrograms/MCH/M/documents/VIPPRES2.PPT

2. Overview Overview HistoryHistory RationaleRationale Asymptomatic bacteriuriaAsymptomatic bacteriuria GonorrheaGonorrhea SyphilisSyphilis Genital MycoplasmasGenital Mycoplasmas Chlamydia trachomatisChlamydia trachomatis Group B strepGroup B strep Periodontal diseasePeriodontal disease Bacterial vaginosisBacterial vaginosis Trichomonas vaginalisTrichomonas vaginalis

3. Rationale Preterm birth is the leading cause of neonatal morbidity and mortality Preterm birth is the leading cause of neonatal morbidity and mortality Increasing body of evidence to indicate that infections are associated with preterm birth Increasing body of evidence to indicate that infections are associated with preterm birth

4. Evidence linking infection with preterm birth Histologic Chorioamnionitis is more common in preterm deliveries Histologic Chorioamnionitis is more common in preterm deliveries Postpartum endomyometritis (PPE) is more common after preterm deliveries Postpartum endomyometritis (PPE) is more common after preterm deliveries Preterm delivery is more common in women with a variety of genital infections Preterm delivery is more common in women with a variety of genital infections

5. % PPE by Gestational Age VIP study

6. Risk factors for PPE Factor Adjusted OR 95% CI 2 sex partners 2.11.2-3.7 > 2 partners 1.60.7-3.9 Pregnancy UTI 1.81.0-3.4 Pressure cath 2.01.2-3.4 ROM > 12 h 2.21.2-4.3 Gest < 34 w 6.22.9-13.4

7. Mechanism for preterm labor

8. Asymptomatic bacteriuria Occurs in 3 - 10 % of pregnant women Occurs in 3 - 10 % of pregnant women First asymptomatic infection to be linked to preterm birth First asymptomatic infection to be linked to preterm birth

9. Asymptomatic bacteriuria Kass (NY State J Med 1962:62: 2815) showed Kass (NY State J Med 1962:62: 2815) showed 24% preterm birth in untreated 24% preterm birth in untreated 10% in treated 10% in treated 10% in controls 10% in controls

10. Asymptomatic bacteriuria Elder, AJOG 1971:111;441 TetracyclinePlacebo Birthwt (oz) 115.6110.8 Term137110 % term % term93.283.3 Preterm820 % preterm % preterm5.415.2 IUFD21 % IUFD % IUFD1.40.8 Abortion01

11. Asymptomatic bacteriuria Screen all women at first visit Screen all women at first visit Treatment reduces risk of pyelonephritis Treatment reduces risk of pyelonephritis

12. Syphilis Effects of untreated syphilis include stillbirth, preterm birth and congenital anomalies Effects of untreated syphilis include stillbirth, preterm birth and congenital anomalies Half of congenital syphilis occurs in women with no prenatal care Half of congenital syphilis occurs in women with no prenatal care Screen all pregnant women at first visit – high risk in third trimester Screen all pregnant women at first visit – high risk in third trimester

13. Gonorrhea Occurs in 1 - 6 % of pregnant women Occurs in 1 - 6 % of pregnant women Untreated gonorrhea associated with preterm delivery and PPROM Untreated gonorrhea associated with preterm delivery and PPROM Treatment of gonorrhea reduces risk Treatment of gonorrhea reduces risk

14. Genital Mycoplasmas Ureaplasma urealyticum Ureaplasma urealyticum Found in 50 - 90% of pregnant womenFound in 50 - 90% of pregnant women Early studies indicated strong association with preterm birthEarly studies indicated strong association with preterm birth Later studies fail to confirm associationLater studies fail to confirm association

15. Ureaplasma treatment trial - VIP 1181 women - 605 erythromycin, 576 placebo1181 women - 605 erythromycin, 576 placebo No difference inNo difference in mean birth weightmean birth weight low birth weightlow birth weight delivery < 37 weeksdelivery < 37 weeks delivery < 32 weeksdelivery < 32 weeks

16. Genital Mycoplasmas Mycoplasma hominisMycoplasma hominis Inconclusive results from studiesInconclusive results from studies ¿ Association with BV ?¿ Association with BV ?

17. Chlamydia trachomatis Early studies showed a strong association with preterm delivery and neonatal death Early studies showed a strong association with preterm delivery and neonatal death Later studies show an association with preterm delivery and low birth weight Later studies show an association with preterm delivery and low birth weight Treatment trials are inconclusive Treatment trials are inconclusive

18. Chlamydia treatment trial - VIP

19. Group B strep Early studies showed association between early onset GBS sepsis and preterm birth Early studies showed association between early onset GBS sepsis and preterm birth Early studies also showed association between preterm birth and GBS carriage Early studies also showed association between preterm birth and GBS carriage Large study showed weak association Large study showed weak association Treatment trials showed no effect of therapy Treatment trials showed no effect of therapy

20. Group B Strep VIP study results VIP study results GBS recovered from 21 % of 13,646 women GBS recovered from 21 % of 13,646 women Heavy colonization was associated with a modest risk of preterm low birth weight infant (RR 1.5, 95% CI 1.1-1.9 ) Heavy colonization was associated with a modest risk of preterm low birth weight infant (RR 1.5, 95% CI 1.1-1.9 ) Light colonization showed no increase risk Light colonization showed no increase risk Treatment with antibiotics active against GBS reduced risk in heavily colonized women Treatment with antibiotics active against GBS reduced risk in heavily colonized women Regan et al AJOG 1996;174:1354-60 Regan et al AJOG 1996;174:1354-60

21. Group B Strep treatment trial - VIP

22. Group B Strep VIP study VIP study Randomized clinical trial of erythromycin did not reduce the risk of preterm birth in women colonized with GBSRandomized clinical trial of erythromycin did not reduce the risk of preterm birth in women colonized with GBS

23. Bacterial vaginosis Occurs in 20 – 30 % of asymptomatic women Occurs in 20 – 30 % of asymptomatic women Approximately 1,000,000 cases/yr in USA in pregnant women Approximately 1,000,000 cases/yr in USA in pregnant women Numerous studies show association with preterm birth Numerous studies show association with preterm birth

24. Bacterial vaginosis Gravett, 1986 JAMA Gravett, 1986 JAMA N=534 pregnant women (102 with BV) N=534 pregnant women (102 with BV) BV associated with BV associated with PROM (RR= 2.4)PROM (RR= 2.4) Preterm labor (RR = 2.0)Preterm labor (RR = 2.0) IAI (RR = 2.7)IAI (RR = 2.7)

25. Bacterial vaginosis Kurki - Obstet Gynecol 1992 Kurki - Obstet Gynecol 1992 N = 790 pregnant women N = 790 pregnant women BV by culture 21.4%BV by culture 21.4% BV by Gram stain 21.1%BV by Gram stain 21.1% BV associated with BV associated with PTL RR 2.6PTL RR 2.6 PTB RR 6.9PTB RR 6.9 PPROM RR 7.3PPROM RR 7.3

26. Bacterial Vaginosis Hay – BMJ 1994 Hay – BMJ 1994 N=783, screened at 9-24 weeks N=783, screened at 9-24 weeks BV associated with BV associated with PTD – RR 2.8PTD – RR 2.8 Late miscarriage – 5.5Late miscarriage – 5.5

27. Bacterial vaginosis Total of 11 studies show increase in PTB with RR ranging from 2 - 4 Total of 11 studies show increase in PTB with RR ranging from 2 - 4

28. Bacterial vaginosis VIP data – Hillier NEJM 1995 VIP data – Hillier NEJM 1995 N = 10,397 women without chlamydia, TV or GBS N = 10,397 women without chlamydia, TV or GBS BV in 1645 BV in 1645 PTD – rr 1.4PTD – rr 1.4 LBW – rr 1.5LBW – rr 1.5

29. BV treatment trials Clindamycin trials Clindamycin trials McGregor AJOG 1994McGregor AJOG 1994 Joesoef AJOG 1995Joesoef AJOG 1995 Metronidazole trials Metronidazole trials Morales AJOG 1994Morales AJOG 1994 McDonald et al - Br J Obstet Gyn 1997;104:1391McDonald et al - Br J Obstet Gyn 1997;104:1391

30. BV treatment trial Morales AJOG 1994

31. Treatment of BV Hauth NEJM 1995 263 high-risk women with BV 263 high-risk women with BV Randomized 2:1 metro + erythro or placebo Randomized 2:1 metro + erythro or placebo Incidence of PTD Incidence of PTD < 37 w - 37% v 23%< 37 w - 37% v 23% < 34 w - 19% v 11%< 34 w - 19% v 11% < 32 w - 11% v 6%< 32 w - 11% v 6%

32. Treatment of BV McGregor AJOG 1994

33. Treatment of BV Joeseof, AJOG 1995

34. Other clindamycin trials AuthorNRouteClindaPlacebo Kurkinen- Raty 101Vaginal13.7%6.0% Kekki375Vaginal5%4% Ugwumadu494Oral5.3%15.8% Vermuelen168Vaginal23%18% Lamont409Vaginal4%10%

35. McDonald BV trial 879 women with BV by Gram stain or culture for G Vaginalis at 19 weeks 879 women with BV by Gram stain or culture for G Vaginalis at 19 weeks Oral metronidazole 400 mg BID for 2 days or placebo at 24 weeks and at 29 weeks if persistent Oral metronidazole 400 mg BID for 2 days or placebo at 24 weeks and at 29 weeks if persistent

36. McDonald BV trial

38. MFMU BV Study NEJM 2000 Purpose – To determine whether treatment of BV with metronidazole would prevent preterm birth Purpose – To determine whether treatment of BV with metronidazole would prevent preterm birth Screened from 8-22 weeks Screened from 8-22 weeks Treated with 2 grams metro on day 1 and 3 from 13 – 24 weeks Treated with 2 grams metro on day 1 and 3 from 13 – 24 weeks Treatment repeated late second trimester Treatment repeated late second trimester

39. MFMU BV study MetroPlaceboRR 95% CI n953966 < 37 w 12.2%12.5%0.970.8-1.2 PTL5.15.70.90.6-1.3 PPROM4.23.71.120.7-1.8 LBW10.911.40.960.5-1.5

40. MFMU Trichomonas trial Carriage of T. vaginalis increases risk of preterm birth Carriage of T. vaginalis increases risk of preterm birth T. vaginalis commonly found with BV T. vaginalis commonly found with BV T. vaginalis is common and often asymptomatic T. vaginalis is common and often asymptomatic

41. Purpose To determine if metronidazole treatment would prevent preterm birth in asymptomatic women who carried T. vaginalis To determine if metronidazole treatment would prevent preterm birth in asymptomatic women who carried T. vaginalis

42. Results

43. Results

44. Randomized 297 patients randomized to placebo 297 patients randomized to placebo 320 randomized to metronidazole 320 randomized to metronidazole The study was stopped early by the Data Safety Monitoring Board The study was stopped early by the Data Safety Monitoring Board

45. Effectiveness of therapy

46. Results

47. Results

48. What can we learn from the treatment trials of BV? Treatment of women with a prior PTD with metronidazole and erythromycin may reduce the risk of subsequent PTD but does not reduce the risk in women who do not have BV Treatment of women with a prior PTD with metronidazole and erythromycin may reduce the risk of subsequent PTD but does not reduce the risk in women who do not have BV Women with a prior PTD may be in some way different Women with a prior PTD may be in some way different

49. What should we do in clinical practice? Screen and treat for gonorrhea, syphilis, asymptomatic bacteriuria, chlamydia Screen and treat for gonorrhea, syphilis, asymptomatic bacteriuria, chlamydia Screen women with a prior PTD for BV and treat with metronidazole and erythromycin? Screen women with a prior PTD for BV and treat with metronidazole and erythromycin? DO NOT treat BV with clindamycin vaginal cream DO NOT treat BV with clindamycin vaginal cream DO NOT treat asymptomatic trich DO NOT treat asymptomatic trich

50. Conclusions The more we learn, the less we know about infections and preterm delivery The more we learn, the less we know about infections and preterm delivery Antibiotic therapy in pregnancy may be harmful Antibiotic therapy in pregnancy may be harmful Treatment of infections in pregnancy should only be done if clear benefit has been shown from randomized trials Treatment of infections in pregnancy should only be done if clear benefit has been shown from randomized trials