# Presentation: 175668

## Vaginal Infections and Preterm Birth -An Update

- J. Chris Carey, MD

## Overview

- History
- Rationale
- Asymptomatic bacteriuria
- Gonorrhea
- Syphilis
- Genital Mycoplasmas

- Chlamydia trachomatis
- Group B strep
- Periodontal disease
- Bacterial vaginosis
- Trichomonas vaginalis

## Rationale

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

## Evidence linking infection with preterm birth

- Histologic Chorioamnionitis is more common in preterm deliveries
- Postpartum endomyometritis is more common after preterm deliveries
- Preterm delivery is more common in women with a variety of genital infections

## % PPE by Gestational AgeVIP study

## Risk factors for PPE

| Factor | Adjusted OR | 95% CI |
| --- | --- | --- |
| 2 sex partners | 2.1 | 1.2-3.7 |
| > 2 partners | 1.6 | 0.7-3.9 |
| Pregnancy UTI | 1.8 | 1.0-3.4 |
| Pressure cath | 2.0 | 1.2-3.4 |
| ROM > 12 h | 2.2 | 1.2-4.3 |
|  |  |  |
| Gest <34 w | 6.2 | 2.9-13.4 |

## Mechanism for preterm labor

## Asymptomatic bacteriuria

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

## Asymptomatic bacteriurea

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

## Asymptomatic bacteriureaElder, AJOG 1971:111;441

|  | Tetracycline | Placebo |
| --- | --- | --- |
| Birthwt (oz) | 115.6 | 110.8 |
| Term | 137 | 110 |
|   % term | 93.2 | 83.3 |
| Preterm | 8 | 20 |
|   % preterm | 5.4 | 15.2 |
| IUFD | 2 | 1 |
|     % IUFD | 1.4 | 0.8 |
| Abortion | 0 | 1 |

## Asymptomatic bacteriurea

- Screen all women at first visit
- Treatment reduces risk of pyelonephritis

## Syphilis

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

## Gonorrhea

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

## Genital Mycoplasmas

- Ureaplasma urealyticum
- Found in 50 - 90% of pregnant women
- Early studies indicated strong association with preterm birth
- Later studies fail to confirm association

## Ureaplasma treatment trial - VIP

- 1181 women - 605 erythromycin, 576 placebo
- No difference in
- mean birth weight
- low birth weight
- delivery < 37 weeks
- delivery < 32 weeks

## Genital Mycoplasmas

- Mycoplasma hominis
- Inconclusive results from studies
- ? association with BV

## Chlamydia trachomatis

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

## Chlamydia treatment trial - VIP

## Group B strep

- Early studies showed association between early onset GBS sepsis and preterm birth
- Early studies also showed association between preterm birth and GBS carriage
- Large study showed weak association
- Treatment trials showed no effect of therapy

## Group B Strep

- VIP study results
- 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 )
- Light colonization showed no increase risk
- Treatment with antibiotics active against GBS reduced risk in heavily colonized women
- Regan et al AJOG 1996;174:1354-60

**Group B Strep treatment trial - VIP **

## Group B Strep

- VIP study
- Randomized clinical trial of erythromycin did not reduce the risk of preterm birth in women colonized with GBS

## Bacterial vaginosis

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

## Bacterial vaginosis

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

## Bacterial vaginosis

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

## Bacterial Vaginosis

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

## Bacterial vaginosis

- Total of 11 studies show increase in PTB with RR ranging from 2 - 4

## Bacterial vaginosis

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

## BV treatment trials

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

## BV treatment trial Morales AJOG 1994

## Treatment of BVHauth NEJM 1995

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

## Treatment of BVMcGregor AJOG 1994

## Treatment of BVJoeseof, AJOG 1995

## Other clindamycin trials

| Author | N | Route | Clinda | Placebo |
| --- | --- | --- | --- | --- |
| Kurkinen-Raty | 101 | Vaginal | 13.7% | 6.0% |
| Kekki | 375 | Vaginal | 5% | 4% |
| Ugwumadu | 494 | Oral | 5.3% | 15.8% |
| Vermuelen | 168 | Vaginal | 23% | 18% |
| Lamont | 409 | Vaginal | 4% | 10% |
|  |  |  |  |  |

## McDonald BV trial

- 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

## McDonald BV trial

## Mc Donald BV trial

## MFMU BV StudyNEJM 2000

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

## MFMU BV study 

|  | Metro | Placebo | RR | 95% CI |
| --- | --- | --- | --- | --- |
| n | 953 | 966 |  |  |
| < 37 w | 12.2% | 12.5% | 0.97 | 0.8-1.2 |
| PTL | 5.1 | 5.7 | 0.9 | 0.6-1.3 |
| PPROM | 4.2 | 3.7 | 1.12 | 0.7-1.8 |
| LBW | 10.9 | 11.4 | 0.96 | 0.5-1.5 |

## MFMU Trichomonas trial

- Carriage of *T. vaginalis* increases risk of preterm birth
*T. vaginalis* commonly found with BV
*T. vaginalis* is common and often asymptomatic

## Purpose

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

## Results

## Results

## Randomized

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

## Effectiveness of therapy

## Results

## Results

## 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
- Women with a prior PTD may be in some way different

## What should we do in clinical practice?

- Screen and treat for gonorrhea, syphilis, asymptomatic bacteriuria, chlamydia
- 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 asymptomatic trich

## Conclusions

- The more we learn, the less we know about infections and preterm delivery
- 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