Vaginal Infections and Vaginal Infections and Preterm Birth -Preterm Birth -

An UpdateAn Update

J. Chris Carey, MDJ. Chris Carey, MD

Disponible en: Disponible en: http://www.ihs.gov/MedicalPrograms/MCH/M/documents/VIPPRES2.PPThttp://www.ihs.gov/MedicalPrograms/MCH/M/documents/VIPPRES2.PPT

•OverviewOverview• HistoryHistory• RationaleRationale• Asymptomatic Asymptomatic

bacteriuriabacteriuria• GonorrheaGonorrhea• SyphilisSyphilis• Genital Genital

MycoplasmasMycoplasmas

• Chlamydia Chlamydia trachomatistrachomatis

• Group B strepGroup B strep• Periodontal Periodontal

diseasedisease• Bacterial vaginosisBacterial vaginosis• Trichomonas Trichomonas

vaginalisvaginalis

RationaleRationale• Preterm birth is the leading cause Preterm birth is the leading cause

of neonatal morbidity and of neonatal morbidity and mortalitymortality

• Increasing body of evidence to Increasing body of evidence to indicate that infections are indicate that infections are associated with preterm birthassociated with preterm birth

Evidence linking Evidence linking infection with preterm infection with preterm

birthbirth• Histologic Chorioamnionitis is more Histologic Chorioamnionitis is more

common in preterm deliveriescommon in preterm deliveries• Postpartum endomyometritis (PPE) Postpartum endomyometritis (PPE)

is more common after preterm is more common after preterm deliveries deliveries

• Preterm delivery is more common Preterm delivery is more common in women with a variety of genital in women with a variety of genital infectionsinfections

% PPE by Gestational % PPE by Gestational AgeAge

VIP studyVIP studyVaginal Deliveries

05

10

1520

30 31 32 33 34 35 36 37 38 39 40 41 42 >42

Weeks

% P

PE

Risk factors for PPERisk factors for PPEFactorFactor Adjusted ORAdjusted OR 95% CI95% CI2 sex 2 sex partnerspartners

2.12.1 1.2-3.71.2-3.7

> 2 partners> 2 partners 1.61.6 0.7-3.90.7-3.9Pregnancy Pregnancy UTIUTI

1.81.8 1.0-3.41.0-3.4

Pressure Pressure cathcath

2.02.0 1.2-3.41.2-3.4

ROM > 12 hROM > 12 h 2.22.2 1.2-4.31.2-4.3

Gest Gest < < 34 w34 w 6.26.2 2.9-13.42.9-13.4

Mechanism for preterm Mechanism for preterm laborlabor

C ontractions

M ultip le organ system s

Fetal u rine Placental - cerv icalvaginal in fection

A ctivated decidual m acrophages

D ecidua

I ntra am n iotic prostagland in

C el l to cel l gap junctions

C a++ release

A ctin -m yosin

Shortened m yom etrial fi bers

PgE , m C SF, I L 1, T N F

Fibrob lasts, W B C s

I ncreased col lagenases

D ecreased col lagen

A ctive ripen ing

C erv ical eff acem ent

Asymptomatic Asymptomatic bacteriuriabacteriuria

• Occurs in 3 - 10 % of pregnant Occurs in 3 - 10 % of pregnant womenwomen

• First asymptomatic infection to be First asymptomatic infection to be linked to preterm birthlinked to preterm birth

Asymptomatic Asymptomatic bacteriuriabacteriuria

• Kass (NY State J Med 1962:62: Kass (NY State J Med 1962:62: 2815) showed2815) showed

• 24% preterm birth in untreated24% preterm birth in untreated• 10% in treated10% in treated• 10% in controls10% in controls

Asymptomatic Asymptomatic bacteriuriabacteriuria

Elder, AJOG 1971:111;441Elder, AJOG 1971:111;441TetracyclineTetracycline PlaceboPlacebo

Birthwt (oz)Birthwt (oz) 115.6115.6 110.8110.8TermTerm 137137 110110 % term% term 93.293.2 83.383.3PretermPreterm 88 2020 % preterm% preterm 5.45.4 15.215.2IUFDIUFD 22 11 % IUFD% IUFD 1.41.4 0.80.8AbortionAbortion 00 11

Asymptomatic Asymptomatic bacteriuriabacteriuria

• Screen all women at first visitScreen all women at first visit• Treatment reduces risk of Treatment reduces risk of

pyelonephritispyelonephritis

SyphilisSyphilis• Effects of untreated syphilis Effects of untreated syphilis

include stillbirth, preterm birth and include stillbirth, preterm birth and congenital anomaliescongenital anomalies

• Half of congenital syphilis occurs in Half of congenital syphilis occurs in women with no prenatal carewomen with no prenatal care

• Screen all pregnant women at first Screen all pregnant women at first visit – high risk in third trimestervisit – high risk in third trimester

GonorrheaGonorrhea• Occurs in 1 - 6 % of pregnant Occurs in 1 - 6 % of pregnant

womenwomen• Untreated gonorrhea associated Untreated gonorrhea associated

with preterm delivery and PPROMwith preterm delivery and PPROM• Treatment of gonorrhea reduces Treatment of gonorrhea reduces

risk risk

Genital MycoplasmasGenital Mycoplasmas• Ureaplasma urealyticumUreaplasma urealyticum

• Found in 50 - 90% of pregnant womenFound in 50 - 90% of pregnant women• Early studies indicated strong Early studies indicated strong

association with preterm birthassociation with preterm birth• Later studies fail to confirm Later studies fail to confirm

associationassociation

Ureaplasma treatment Ureaplasma treatment trial - VIPtrial - VIP

• 1181 women - 605 erythromycin, 1181 women - 605 erythromycin, 576 placebo576 placebo

• No difference in No difference in • mean birth weight mean birth weight • low birth weightlow birth weight• delivery < 37 weeksdelivery < 37 weeks• delivery < 32 weeksdelivery < 32 weeks

Genital MycoplasmasGenital Mycoplasmas• Mycoplasma hominisMycoplasma hominis

• Inconclusive results from studiesInconclusive results from studies• ¿ Association with BV ?¿ Association with BV ?

Chlamydia trachomatisChlamydia trachomatis• Early studies showed a strong Early studies showed a strong

association with preterm delivery association with preterm delivery and neonatal deathand neonatal death

• Later studies show an association Later studies show an association with preterm delivery and low birth with preterm delivery and low birth weightweight

• Treatment trials are inconclusiveTreatment trials are inconclusive

Chlamydia treatment Chlamydia treatment trial - VIPtrial - VIP

< 2500gm

PPROM PTL < 37 PTD < 37

Erythro 16/183(8.7%)

5/181(2.8%)

22/181(12.2%)

25/183(13.7%)

Placebo 22/183(12%)

7/179(3.9%)

23/179(12.9%)

29/184(15.8%)

Group B strepGroup B strep• Early studies showed association Early studies showed association

between early onset GBS sepsis and between early onset GBS sepsis and preterm birthpreterm birth

• Early studies also showed association Early studies also showed association between preterm birth and GBS between preterm birth and GBS carriagecarriage

• Large study showed weak associationLarge study showed weak association• Treatment trials showed no effect of Treatment trials showed no effect of

therapytherapy

Group B StrepGroup B Strep• VIP study resultsVIP study results

• GBS recovered from 21 % of 13,646 womenGBS recovered from 21 % of 13,646 women• Heavy colonization was associated with a Heavy colonization was associated with a

modest risk of preterm low birth weight modest risk of preterm low birth weight infant (RR 1.5, 95% CI 1.1-1.9 )infant (RR 1.5, 95% CI 1.1-1.9 )

• Light colonization showed no increase riskLight colonization showed no increase risk• Treatment with antibiotics active against Treatment with antibiotics active against

GBS reduced risk in heavily colonized GBS reduced risk in heavily colonized womenwomen

• Regan et al AJOG 1996;174:1354-60Regan et al AJOG 1996;174:1354-60

Group B Strep Group B Strep treatment trial - VIP treatment trial - VIP

Outcome Erythro-mycin

Placebo RR C.I

<2500 gm

8.6 % 6.1 % 1.4 0.9-2.2

< 37 wks 11.4% 12.3% 0.9 0.6-1.3

Group B StrepGroup B Strep• VIP studyVIP study

• Randomized clinical trial of Randomized clinical trial of erythromycin did not reduce the risk erythromycin did not reduce the risk of preterm birth in women colonized of preterm birth in women colonized with GBSwith GBS

Bacterial vaginosisBacterial vaginosis• Occurs in 20 – 30 % of Occurs in 20 – 30 % of

asymptomatic womenasymptomatic women• Approximately 1,000,000 cases/yr Approximately 1,000,000 cases/yr

in USA in pregnant womenin USA in pregnant women• Numerous studies show Numerous studies show

association with preterm birthassociation with preterm birth

Bacterial vaginosisBacterial vaginosis• Gravett, 1986 JAMAGravett, 1986 JAMA• N=534 pregnant women (102 with N=534 pregnant women (102 with

BV)BV)• BV associated withBV 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)

Bacterial vaginosisBacterial vaginosis• Kurki - Obstet Gynecol 1992Kurki - Obstet Gynecol 1992• N = 790 pregnant womenN = 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 withBV associated with• PTL RR 2.6PTL RR 2.6• PTB RR 6.9PTB RR 6.9• PPROM RR 7.3PPROM RR 7.3

Bacterial VaginosisBacterial Vaginosis• Hay – BMJ 1994Hay – BMJ 1994• N=783, screened at 9-24 weeksN=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

Bacterial vaginosisBacterial vaginosis• Total of 11 studies show increase Total of 11 studies show increase

in PTB with RR ranging from 2 - 4in PTB with RR ranging from 2 - 4

Bacterial vaginosisBacterial vaginosis• VIP data – Hillier NEJM 1995VIP data – Hillier NEJM 1995• N = 10,397 women without N = 10,397 women without

chlamydia, TV or GBSchlamydia, TV or GBS• BV in 1645BV in 1645

• PTD – rr 1.4PTD – rr 1.4• LBW – rr 1.5 LBW – rr 1.5

BV treatment trialsBV treatment trials• Clindamycin trialsClindamycin trials

• McGregor AJOG 1994McGregor AJOG 1994• Joesoef AJOG 1995Joesoef AJOG 1995

• Metronidazole trialsMetronidazole trials• Morales AJOG 1994Morales AJOG 1994• McDonald et al - Br J Obstet Gyn McDonald et al - Br J Obstet Gyn

1997;104:13911997;104:1391

BV treatment trial BV treatment trial Morales AJOG 1994Morales AJOG 1994

01020304050607080

PTB PROM PTL LBW

MetroPlacebo

Treatment of BVTreatment of BVHauth NEJM 1995Hauth NEJM 1995

• 263 high-risk women with BV263 high-risk women with BV• Randomized 2:1 metro + erythro Randomized 2:1 metro + erythro

or placeboor placebo• Incidence of PTDIncidence 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%

Treatment of BVTreatment of BVMcGregor AJOG 1994McGregor AJOG 1994

0

5

10

15

20

25

PTB PROM PTL LBW

Clindamycin CreamPlacebo

Treatment of BVTreatment of BVJoeseof, AJOG 1995Joeseof, AJOG 1995

02468

10121416

PTB < 37 PTB < 32 LBW

CVCPlacebo

Other clindamycin trialsOther clindamycin trialsAuthorAuthor NN RouteRoute ClindaClinda PlacebPlaceb

ooKurkinen-Kurkinen-RatyRaty 101101 VaginalVaginal 13.7%13.7% 6.0%6.0%KekkiKekki 375375 VaginalVaginal 5%5% 4%4%UgwumaduUgwumadu 494494 OralOral 5.3%5.3% 15.8%15.8%VermuelenVermuelen 168168 VaginalVaginal 23%23% 18%18%LamontLamont 409409 VaginalVaginal 4%4% 10%10%

McDonald BV trialMcDonald BV trial• 879 women with BV by Gram stain 879 women with BV by Gram stain

or culture for G Vaginalis at 19 or culture for G Vaginalis at 19 weeksweeks

• Oral metronidazole 400 mg BID for Oral metronidazole 400 mg BID for 2 days or placebo at 24 weeks and 2 days or placebo at 24 weeks and at 29 weeks if persistent at 29 weeks if persistent

McDonald BV trialMcDonald BV trialOutcome Metronidazole Placebo

Overalldelivery < 37

31/429 (7.2%) 32/428 (7.5%)

Spontaneousdelivery < 37

20/429 (4.7%) 24/428 (5.6%)

Mc Donald BV trialMc Donald BV trialSpontaneousPTD

Metronidazole Placebo

BV by gramn=480

11/242 (4.5%) 15/238 (6.3%)

Prior PTDn=46

2/22 (9.1%) 10/24 (41.7%)

Compliantwith priorPTD and BV

0/14 (0%) 6/17 (35.3%)

MFMU BV StudyMFMU BV StudyNEJM 2000NEJM 2000

• Purpose – To determine whether Purpose – To determine whether treatment of BV with metronidazole treatment of BV with metronidazole would prevent preterm birthwould prevent preterm birth

• Screened from 8-22 weeksScreened from 8-22 weeks• Treated with 2 grams metro on day Treated with 2 grams metro on day

1 and 3 from 13 – 24 weeks1 and 3 from 13 – 24 weeks• Treatment repeated late second Treatment repeated late second

trimestertrimester

MFMU BV study MFMU BV study MetroMetro PlacebPlaceb

ooRRRR 95% CI95% CI

nn 953953 966966< 37 w< 37 w 12.2%12.2% 12.5%12.5% 0.970.97 0.8-1.20.8-1.2PTLPTL 5.15.1 5.75.7 0.90.9 0.6-1.30.6-1.3PPROMPPROM 4.24.2 3.73.7 1.121.12 0.7-1.80.7-1.8LBWLBW 10.910.9 11.411.4 0.960.96 0.5-1.50.5-1.5

MFMU Trichomonas MFMU Trichomonas trialtrial

• Carriage of Carriage of T. vaginalisT. vaginalis increases increases risk of preterm birthrisk of preterm birth

• T. vaginalisT. vaginalis commonly found with commonly found with BVBV

• T. vaginalisT. vaginalis is common and often is common and often asymptomaticasymptomatic

PurposePurpose• To determine if To determine if

metronidazole treatment metronidazole treatment would prevent preterm would prevent preterm birth in asymptomatic birth in asymptomatic women who carried women who carried T. T. vaginalisvaginalis

ResultsResultsConsidered forculture

40,857

Ineligible 7,768Refused screen 1,711Test not done 221Cultures done 31,157TV positive 2,377

7.6%

ResultsResultsTV positive 2,377

Ineligible for trial 1,333

Refused consent 265

No show for visit 152

Randomized in error to BV trial 12

Randomized* *includes two TV negative patients

617

RandomizedRandomized• 297 patients randomized to 297 patients randomized to

placeboplacebo• 320 randomized to metronidazole320 randomized to metronidazole

• The study was stopped early by The study was stopped early by the Data Safety Monitoring Boardthe Data Safety Monitoring Board

Effectiveness of Effectiveness of therapytherapy

Persistence of TV At 24-29 weeks

Metronidazole 20/277 (7%)

Placebo 168/267 (63%)

ResultsResults

Metro Placebo RR 95%CI

Total PTD 19.0% 10.7% 1.78 1.19-2.66PTD-PTL 10.3% 3.5% 2.95 1.48-5.90PTD-PPROM 4.5% 4.2% 1.08 0.51-2.29<32 weeks 5.1% 3.8% 1.33 0.63-2.83< 2500 gm 16.4% 11.8% 1.38 0.92-2.07< 1500 gm 5.5% 3.8% 1.43 0.68-2.99

ResultsResults

Metro Placebo CI

PTD – BVpositive

26.1% 14.2% 1.84(1.07-3.18)

PTD – BVnegative

14.9% 8.7% 1.72(0.96-3.11)

IAI 7.8% 8.4% NS

PPE 4.2% 4.2% NS

What can we learn from What can we learn from the treatment trials of the treatment trials of

BV?BV?• Treatment of women with a prior Treatment of women with a prior

PTD with metronidazole and PTD with metronidazole and erythromycin may reduce the risk erythromycin may reduce the risk of subsequent PTD but does not of subsequent PTD but does not reduce the risk in women who do reduce the risk in women who do not have BVnot have BV

• Women with a prior PTD may be in Women with a prior PTD may be in some way different some way different

What should we do in What should we do in clinical practice?clinical practice?

• Screen and treat for gonorrhea, Screen and treat for gonorrhea, syphilis, asymptomatic bacteriuria, syphilis, asymptomatic bacteriuria, chlamydiachlamydia

• Screen women with a prior PTD for Screen women with a prior PTD for BV and treat with metronidazole and BV and treat with metronidazole and erythromycin?erythromycin?

• DO NOT treat BV with clindamycin DO NOT treat BV with clindamycin vaginal creamvaginal cream

• DO NOT treat asymptomatic trichDO NOT treat asymptomatic trich

ConclusionsConclusions• The more we learn, the less we know The more we learn, the less we know

about infections and preterm deliveryabout infections and preterm delivery• Antibiotic therapy in pregnancy may Antibiotic therapy in pregnancy may

be harmfulbe harmful• Treatment of infections in pregnancy Treatment of infections in pregnancy

should only be done if clear benefit should only be done if clear benefit has been shown from randomized has been shown from randomized trialstrials