INFECTION AND PRETERM BIRTHINFECTION AND PRETERM BIRTH

Sequelae of Preterm BirthSequelae of Preterm BirthSequelae of Preterm BirthSequelae of Preterm Birth

Term Births

Preterm Birth

Perinatal Perinatal MortalityMortality

NeurologicNeurologicHandicapHandicap

(75%)(75%)

(50%)(50%)

(10%)(10%)

Incidence of Preterm Birth in The U.S.A.Incidence of Preterm Birth in The U.S.A.

1981-19941981-1994

0

1

2

3

4

5

6

7

8

9

10

11

12

1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994

Year

% P

rete

rm

Time Trends in Low Birth Weight (<1,500 g) Time Trends in Low Birth Weight (<1,500 g) by Race/Ethnicity - United States, 1970-1990by Race/Ethnicity - United States, 1970-1990

0

0.5

1

1.5

2

2.5

3

3.5

All races White Black NativeAmerican

Hispanic

Per

cen

tag

e o

f li

ve b

irth

s

1970

1975

1980

1985

1990

UAB Infants with Birthweights UAB Infants with Birthweights 1000 Grams1000 Grams

Mean BWMean BW SurvivalSurvival

19751975 900 gms900 gms 17%17%

19801980 860 gms860 gms 48%48%

19851985 820 gms820 gms 56%56%

19901990 804 gms804 gms 74%74%

Distribution of Neonatal MortalityDistribution of Neonatal Mortality

BWT (gms) BWT (gms) DistributionDistribution

<1000<100060%60%

1000-2500 1000-2500 20%20%

>2500>250020%*20%*

*Majority associated with congenital anomalies*Majority associated with congenital anomalies

Approximate Prevalence of Cerebral Palsy per 1,000 Births Approximate Prevalence of Cerebral Palsy per 1,000 Births by Birth Weight and Gestational Ageby Birth Weight and Gestational Age

Approximate Prevalence of Cerebral Palsy per 1,000 Births Approximate Prevalence of Cerebral Palsy per 1,000 Births by Birth Weight and Gestational Ageby Birth Weight and Gestational Age

LBW-PORTLBW-PORT

0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000

Birth Weight (g) / Gestational Age (wks)

0

10

20

30

40

50

Pre

vale

nce

of

Cer

ebra

l Pal

sy

per

1,0

00 L

ive

Bir

ths

Term

230

240

250

23 27 32 36

Survival Rate for Extremely Small Infants (<800g)Survival Rate for Extremely Small Infants (<800g)in Relation to Mid-Year of Birthin Relation to Mid-Year of Birth

0

20

40

60

80

1975 1980 1985 1990Mid-Year of Birth

Su

rviv

ors

per

Liv

ebir

th, %

Lorenz, 1998Lorenz, 1998

Prevalence of Disability Among Extremely Small Prevalence of Disability Among Extremely Small Survivors (<800g) in Relation to Mid-Year of BirthSurvivors (<800g) in Relation to Mid-Year of Birth

Mid-Year of Birth

0

10

20

30

40

50

60

70

1975 1980 1985 1990

Dis

able

d I

nfa

nts

per

Su

rviv

or, %

Lorenz, 1998Lorenz, 1998

Percentage of Extremely Small (<800g) Livebirths Surviving Percentage of Extremely Small (<800g) Livebirths Surviving with at Least One Disability in with at Least One Disability in Relation to Mid-Year of BirthRelation to Mid-Year of Birth

1990Mid-Year of Birth

0

5

10

15

20

1975 1980 1985

Dis

able

d I

nfa

nts

per

Liv

ebir

th, %

Lorenz, 1998Lorenz, 1998

Cerebral Palsy in <1000gm infantsCerebral Palsy in <1000gm infants

SurvivorsSurvivorswith Anywith Any

Disability**Disability**(n)(n)

3232

12801280

25602560

Survivors Survivors with CP*with CP*

(n)(n)

1616

640640

12801280

SurvivorsSurvivors(n)(n)

200200

8,0008,000

16,00016,000

Survival Survival (%)(%)

11

4040

8080

<1000g <1000g birthsbirths

(n)(n)

20,00020,000

20,00020,000

20,00020,000

YearYear

19601960

19851985

19971997

*Assuming an 8% incidence in survivors consistently over time.*Assuming an 8% incidence in survivors consistently over time.**Assuming a 16% incidence in survivors consistently over time.**Assuming a 16% incidence in survivors consistently over time.

Etiology of Preterm BirthEtiology of Preterm Birth

50%50%

30%30%

20%20%

SpontaneousSpontaneousPreterm LaborPreterm Labor

Preterm Birth Preterm Birth for Maternal or for Maternal or Fetal Fetal IndicationsIndications

Premature Rupture Premature Rupture of Membranesof Membranes

REVIEW OF INTERVENTIONS TO REVIEW OF INTERVENTIONS TO PREVENT PRETERM BIRTHPREVENT PRETERM BIRTH

REVIEW OF INTERVENTIONS TO REVIEW OF INTERVENTIONS TO PREVENT PRETERM BIRTHPREVENT PRETERM BIRTH

Prenatal carePrenatal care Risk screeningRisk screening Nutrition counselingNutrition counseling Caloric supplementationCaloric supplementation Protein supplementationProtein supplementation Iron supplementationIron supplementation Most labor inhibiting Most labor inhibiting

agentsagents

Drug, alcohol and Drug, alcohol and tobacco cessation tobacco cessation programsprograms

Bed restBed rest HydrationHydration Home uterine Home uterine

activity monitoringactivity monitoring

Commonly used interventions which have not been Commonly used interventions which have not been shown to reduce preterm birth include:shown to reduce preterm birth include:

INFECTION AND PRETERM BIRTHINFECTION AND PRETERM BIRTH

SURGICAL PATHOLOGY REPORTSURGICAL PATHOLOGY REPORTSURGICAL PATHOLOGY REPORTSURGICAL PATHOLOGY REPORT

Clinical HistoryClinical History

34 year old white female with an intrauterine 34 year old white female with an intrauterine pregnancy at 25 and 3/7th weeks.pregnancy at 25 and 3/7th weeks.

Microscopic DescriptionMicroscopic Description

Sections of the free fetal membranes show Sections of the free fetal membranes show severe, necrotizing chorioamnionitis. Both severe, necrotizing chorioamnionitis. Both umbilical arteries as well as the umbilical umbilical arteries as well as the umbilical vein exhibit funisitis.vein exhibit funisitis.

Infection and LaborInfection and LaborIn 1927, Harris and Brown reported culturing women undergoing C-In 1927, Harris and Brown reported culturing women undergoing C-section with intact membranes.section with intact membranes.

STATUSSTATUS RESULTS (# POSITIVE)RESULTS (# POSITIVE)No laborNo labor 0/210/21

Labor <5 hoursLabor <5 hours 0/50/5

Labor >5 hoursLabor >5 hours 6/7 (4/6 anaerobic)6/7 (4/6 anaerobic)

They concluded that organisms could reach the amniotic fluid with They concluded that organisms could reach the amniotic fluid with intact membranes and that fever was not a reliable sign of infection in intact membranes and that fever was not a reliable sign of infection in labor. labor.

Infection in the female reproductive tract can Infection in the female reproductive tract can cause premature rupture of the membranes and cause premature rupture of the membranes and induce premature labor…. The membranes in induce premature labor…. The membranes in allall premature cases in this series show evidence of premature cases in this series show evidence of infection…. In most instances this reaction is infection…. In most instances this reaction is severe.severe.

Knox, Am J Obstet Gynecol 1950Knox, Am J Obstet Gynecol 1950

Infection and PrematurityInfection and Prematurity

Elder treated 279 non-bacteriuric women with a 6-Elder treated 279 non-bacteriuric women with a 6-week course of 1gm tetracycline daily or a placebo week course of 1gm tetracycline daily or a placebo beginning at <32 weeks gestation.beginning at <32 weeks gestation.

Tetracycline treated women had fewer preterm Tetracycline treated women had fewer preterm births. births.

Elder, 1971Elder, 1971

Infection and Preterm LaborInfection and Preterm LaborIn 1977 Bobitt and Ledger performed amniocenteses on 10 women in In 1977 Bobitt and Ledger performed amniocenteses on 10 women in preterm labor with intact membranes.preterm labor with intact membranes.

7 had colony counts >1000 per ml with anaerobic organisms 7 had colony counts >1000 per ml with anaerobic organisms predominating.predominating.

““It appears that bacteria can penetrate the fetal It appears that bacteria can penetrate the fetal membranes and contaminate the amniotic fluid” membranes and contaminate the amniotic fluid”

““In patients in premature labor, the role of unrecognized In patients in premature labor, the role of unrecognized

amnionitis should be reevaluated.” amnionitis should be reevaluated.”

Bobitt & Ledger, 1977Bobitt & Ledger, 1977J Reprod MedJ Reprod Med

Intrauterine InfectionIntrauterine Infection

Clinical chorioamnionitisClinical chorioamnionitis Sub-clinical chorioamnionitisSub-clinical chorioamnionitis

– Organisms in amniotic fluid Organisms in amniotic fluid and membranesand membranes

– Organisms only in membranesOrganisms only in membranes

Of women with positive Of women with positive

chorioamnion cultures, chorioamnion cultures,

only 50% also have only 50% also have

positive amniotic fluid positive amniotic fluid

cultures.cultures.

INFECTION AND PREMATURITYINFECTION AND PREMATURITYINFECTION AND PREMATURITYINFECTION AND PREMATURITY

Only 8% of women with histologic Only 8% of women with histologic chorioamnionitis have clinical signs (fever chorioamnionitis have clinical signs (fever and uterine tenderness) prior to delivery.and uterine tenderness) prior to delivery.

Gusick 1985Gusick 1985

ChorioamnionitisChorioamnionitis

Histologic studies suggest a clear progression of Histologic studies suggest a clear progression of granulocyte infiltration:granulocyte infiltration:

Maternal GranulocytesMaternal Granulocytes

Decidua Decidua Chorion Chorion Amnion Amnion Amniotic fluid Amniotic fluid

Umbilical CordUmbilical Cord

Umbilical vessels Umbilical vessels Wharton’s Jelly Wharton’s Jelly Amniotic fluid Amniotic fluid

Granulocytes in AF likely represent both a maternal and Granulocytes in AF likely represent both a maternal and fetal response.fetal response.

FunisitisFunisitis Prior to 1970, funisitis was thought to Prior to 1970, funisitis was thought to

represent a sign of asphyxiarepresent a sign of asphyxia

In 1970, Cassady showed that funisitis was In 1970, Cassady showed that funisitis was associated with intrauterine infection - not associated with intrauterine infection - not asphyxiaasphyxia

The only proven intrauterine and fetal The only proven intrauterine and fetal infection occurring in the absence of infection occurring in the absence of funisitis was Group B strepfunisitis was Group B strep

Overbach and Cassady, Pediatrics 1970

ChorioamnionitisChorioamnionitis

Funisitis is present in about half the Funisitis is present in about half the cases of histologic chorioamnionitis cases of histologic chorioamnionitis and is almost never seen alone.and is almost never seen alone.

This suggests that the etiologic This suggests that the etiologic infection almost always starts in the infection almost always starts in the chorioamnion.chorioamnion.

Intrauterine Infection and Intrauterine Infection and

Preterm LaborPreterm Labor

Relationship to Gestational AgeRelationship to Gestational Age

0

10

20

30

40

50

60

70

80

90

100

21-24 25-28 29-32 33-36 37-40 41-44Weeks Gestation

Prevalence at Delivery of Histologic Chorioamnionitis at Different Stages of Gestation

Russell, P.Am J Diag Gyn Obst. 1979;1:127

Per

cen

t

Incidence of Chorioamnionitis in Incidence of Chorioamnionitis in Preterm Delivery PatientsPreterm Delivery Patients

0

20

40

60

80

100

21-24 25-28 29-32 33-36 > 37

6/9

11/19 17/33

27/120295/1526

% w

ith

Ch

or i

oam

nio

ni t

is

Gestational Age (weeks)

Mueller-Heubach 1990

Histological ChorioamnionitisHistological Chorioamnionitis

0

20

40

60

80

100

<1000 1000-1999 2000-2499

%

Birthweight (g)

Chellam, 1985

Patients in Labor with Intact MembranesPatients in Labor with Intact Membranes

0

20

40

60

80

100

23-24 25-26 27-28 29-30 31-32 33-34

Other Bacteria Ureaplasma Only

% P

osi

tive

Am

nio

tic

Flu

id

Cu

ltu

res

Gestational Age (weeks)

Watts, Ob/Gyn 79:351, 1992

20/105 (19%) + Cultures

0

20

40

60

80

100Spontaneous

Indicated

Chorioamnion Colonization Indicated vs. Spontaneous Delivery

<1000 1000-1499 1500-2499 2500 Birthweight (grams)

% PositiveCultures

20 24 28 32 36 38 40 42

Etiology of Spontaneous PTBEtiology of Spontaneous PTB

InfectionInfectionOtherOther

PathologiesPathologiesNoNo

PathologyPathology

Gestational AgeGestational Age

Etiology of Spontaneous Preterm BirthEtiology of Spontaneous Preterm Birth

Single potentSingle potent

risk factorrisk factor

(Infection and (Infection and placental abruption)placental abruption)

Multiple weaker risk Multiple weaker risk factors acting factors acting through usual through usual

hormonal pathwayshormonal pathways

20 weeks20 weeks 36 36 weeksweeks

Mediating FactorsMediating Factors cervical strengthcervical strength uterine contractilityuterine contractility host defenses host defenses

Histologic ChorioamnionitisHistologic ChorioamnionitisEvidence of chronicityEvidence of chronicity

1. Ureaplasma diagnosed by amniocentesis 1. Ureaplasma diagnosed by amniocentesis (PCR or culture) at 15-20 wks (PCR or culture) at 15-20 wks delivery delivery with HCA at 24-28 wks.with HCA at 24-28 wks.

2. 2. IL-6 in amniotic fluid at 15-20 wks IL-6 in amniotic fluid at 15-20 wks delivery with HCA at <32 to 34 wks.delivery with HCA at <32 to 34 wks.

3. FFN (a marker for membrane disruption) in 3. FFN (a marker for membrane disruption) in vagina or cervix at 13-24 wks - associated vagina or cervix at 13-24 wks - associated with HCA at 29-31 wks.with HCA at 29-31 wks.

Recurrent Preterm BirthRecurrent Preterm Birth

Women with recurrent spontaneous Women with recurrent spontaneous preterm births <32 weeks are more likely preterm births <32 weeks are more likely to have histologic chorioamnionitis than to have histologic chorioamnionitis than other women giving birth at similar other women giving birth at similar gestational ages.gestational ages.

Salafia, SMAM 2001Salafia, SMAM 2001

Bacteria Associated Bacteria Associated with Prematuritywith Prematurity

UreaplasmaUreaplasma

MycoplasmaMycoplasma

GardnerellaGardnerella

MobiluncusMobiluncus

PeptostreptococcusPeptostreptococcus

BacteroidesBacteroides

Low Virulence

Choriodecidual bacterial colonization(endotoxins and exotoxins)

Fetal tissueresponse

Fetus

Increased corticotropin-releasing

hormone

Increased adrenalcortisol production

Myometrialcontractions

Chorioamnion weakening and rupture

Preterm Delivery

Increasedprostaglandins

Decreased chorionicprostaglandin

dehydrogenase

Chorioamnionand placenta

Maternal response

Decidua

Increased cytokinesand chemokines

Neutrophilinfiltration

Increased metalloproteases

Cervicalripening

Bacterial VaginosisBacterial Vaginosisandand

Preterm BirthPreterm Birth

Normal vaginal secretionsNormal vaginal secretions Bacterial vaginosisBacterial vaginosis

BV and PrematurityBV and Prematurity

The odds ratio for preterm birth in The odds ratio for preterm birth in

association with BV in nearly every study association with BV in nearly every study

ranges from 1.5 to 3.0ranges from 1.5 to 3.0

BV and Preterm BirthBV and Preterm Birth

Women with BV type organisms such as Women with BV type organisms such as gardnerella, bacteroides and mycoplasma gardnerella, bacteroides and mycoplasma in the vagina early in pregnancy were in the vagina early in pregnancy were significantly more likely to have these significantly more likely to have these organisms in the amniotic fluid at the time organisms in the amniotic fluid at the time of delivery.of delivery.

VIP Study VIP Study Krohn, 1996Krohn, 1996

BACTERIAL VAGINOSIS

Korn et al., in non-pregnant women, showed Korn et al., in non-pregnant women, showed that BV was associated with plasma cell that BV was associated with plasma cell endometritis as well as with endometrial endometritis as well as with endometrial colonization by a number of organisms colonization by a number of organisms which are present in excessive numbers in which are present in excessive numbers in women with BV.women with BV.

Association of BV with Association of BV with Plasma Cell EndometritisPlasma Cell Endometritis

0

10

20

30

40

50

60

70

80

90

100

Metritis (%)

Positive Negative

Korn et al., Obstet Gynecol 1995;85:387-90

Bacterial Vaginosis

VIP Study, Am J Obstet Gynecol, 1996VIP Study, Am J Obstet Gynecol, 1996

GENITAL INFECTIONS IN PREGNANT WOMEN GENITAL INFECTIONS IN PREGNANT WOMEN BY RACEBY RACE

0

5

10

15

20

25

30

35

40

45

50

%

WhiteBlack

Chlamydia Gonorrhea Trichomonas Group B Mycoplasma Bacterial Strep vaginosis

Nearly 50% of the excess preterm Nearly 50% of the excess preterm births and mortality in black versus births and mortality in black versus

white infants is explained by the white infants is explained by the increase in vaginal and intrauterine increase in vaginal and intrauterine

infections in black womeninfections in black women

Fetal FibronectinFetal FibronectinFetal FibronectinFetal Fibronectin

A basement membrane proteinA basement membrane protein Produced primarily by fetal tissue, Produced primarily by fetal tissue,

the placenta and membranes.the placenta and membranes. It may help to adhere the placenta It may help to adhere the placenta

and membranes to the decidua.and membranes to the decidua.

FETAL FIBRONECTINFETAL FIBRONECTINFETAL FIBRONECTINFETAL FIBRONECTIN

A marker for upper genital tract A marker for upper genital tract basement membrane disruptionbasement membrane disruption

IIII

II

III

IV

INFECTION AND PRETERM BIRTHINFECTION AND PRETERM BIRTH

FFN AND PRETERM BIRTHFFN AND PRETERM BIRTHFFN AND PRETERM BIRTHFFN AND PRETERM BIRTH

Delivery (weeks)Delivery (weeks) OROR

<28<28 6060

<30<30 4242

<32<32 2323

<35<35 1111

<37<37 55

+Goldenberg AJOG 1995+Goldenberg AJOG 1995

ASSOCIATION OF FFN AND INFECTIONASSOCIATION OF FFN AND INFECTIONASSOCIATION OF FFN AND INFECTIONASSOCIATION OF FFN AND INFECTION

1. FFN is twice as common in women with BV1. FFN is twice as common in women with BV

2. FFN was 16-20 fold more common in women 2. FFN was 16-20 fold more common in women who developed clinical chorioamnionitiswho developed clinical chorioamnionitis

3. All women with FFN has histologic 3. All women with FFN has histologic chorioamnionitischorioamnionitis

4. FFN was 6 fold more common in women 4. FFN was 6 fold more common in women whose infants developed sepsiswhose infants developed sepsis

TIMINGTIMINGTIMINGTIMING

EventEvent Gestational AgeGestational Age(Weeks ± SD)(Weeks ± SD)

Screening for FFNScreening for FFN 23.9 ± .0623.9 ± .06

Clinical ChorioamnionitisClinical Chorioamnionitis 30.6 ± 4.130.6 ± 4.1

SPECULATIONSPECULATIONSPECULATIONSPECULATION

At 24 weeks, FFN in the vagina or At 24 weeks, FFN in the vagina or cervix is a marker for an cervix is a marker for an asymptomatic upper genital tract asymptomatic upper genital tract infection which later manifests itself infection which later manifests itself as spontaneous preterm labor or as spontaneous preterm labor or PROM frequently in conjunction with a PROM frequently in conjunction with a perinatal infection.perinatal infection.

Is pregnancy an antibiotic-Is pregnancy an antibiotic-

deficient state?deficient state?

Antibiotics in LaborAntibiotics in Labor

andand

Preterm BirthPreterm Birth

Antibiotics in Women with Preterm Antibiotics in Women with Preterm Labor and Intact MembranesLabor and Intact Membranes

Delayed Delayed Improved Infant Improved Infant

StudyStudy AntibioticAntibiotic N N DeliveryDelivery OutcomeOutcome

MacGregor, 1986MacGregor, 1986 ErythromycinErythromycin 1717 YesYes No No

Morales, 1988Morales, 1988 Erythromycin, AmpicillinErythromycin, Ampicillin 150150 YesYes No No

Winkler, 1988Winkler, 1988 Erythromycin Erythromycin 1919 YesYes - -

Newton, 1989Newton, 1989 Erythromycin / AmpicillinErythromycin / Ampicillin 9595 No No No No

MacGregor, 1991MacGregor, 1991 ClindamycinClindamycin 103103 YesYes No No

McCaul, 1992McCaul, 1992 AmpicillinAmpicillin 4040 No No No No

Romero, 1993Romero, 1993 Ampicillin / Amoxicillin / Ampicillin / Amoxicillin /

ErythromycinErythromycin 275275 No No No No

Cox, 1995Cox, 1995 Ampicillin / AmoxicillinAmpicillin / Amoxicillin 7878 No No No No

Gordon, 1995Gordon, 1995 CeftizoximineCeftizoximine 117117 No No No No

Antibiotics in Women with Preterm Antibiotics in Women with Preterm Labor and Intact MembranesLabor and Intact Membranes

Meta-analysis of existing RCTsMeta-analysis of existing RCTs

These results do not support the These results do not support the routine use of antibiotics in women in routine use of antibiotics in women in preterm laborpreterm labor

Egarter et al, 1996Egarter et al, 1996

Antibiotics and Preterm BirthAntibiotics and Preterm BirthLabor with Intact MembranesLabor with Intact Membranes

Study GroupStudy Group Placebo GroupPlacebo GroupOutcomeOutcome n=43n=43 n=38n=38

BWT (x) (g)BWT (x) (g) 23182318 20932093 Days to Days to delivery (median)delivery (median) 15 15 2.5* 2.5*

Delivery <7 days (%)Delivery <7 days (%) 37%37% 63%*63%*

NEC (%)NEC (%) 0%0% 13%*13%*

*p<.05*p<.05††greater prolongation occurred in <30 week pregnanciesgreater prolongation occurred in <30 week pregnancies

Metronidazole and Ampicillin for 6 days at ~30 weeks in a RCTMetronidazole and Ampicillin for 6 days at ~30 weeks in a RCT

Norman et al (South Africa), Br J Obstet Gynaecol, 1994Norman et al (South Africa), Br J Obstet Gynaecol, 1994

Antibiotics and Preterm Birth Antibiotics and Preterm Birth Labor with Intact MembranesLabor with Intact Membranes

AntibioticsAntibiotics PlaceboPlaceboOutcomeOutcome (n=59)(n=59) (n=51) (n=51) P valueP value

Days to delivery (x)Days to delivery (x) 4848 2727 .01.01GA at delivery (wks) (x)GA at delivery (wks) (x) 3737 3434 .01.01Birth <37 weeks (%)Birth <37 weeks (%) 42%42% 65%65% .01.01BWT (g) (x)BWT (g) (x) 26622662 2370 2370 .08.08NICU Admission (%)NICU Admission (%) 40%40% 63%63% .03.03Neonatal sepsis (%)Neonatal sepsis (%) 10%10% 22%22% .18.18

Ampicillin and Metronidazole for 8 days at ~30 weeks in a RCT

Svare et al (Denmark), Br J Ob Gyn 1997Svare et al (Denmark), Br J Ob Gyn 1997

Antibiotics in Women with Preterm Antibiotics in Women with Preterm Labor and Intact MembranesLabor and Intact Membranes

The most promising studies used The most promising studies used metronidazole.metronidazole.

the organisms found in upper tract the organisms found in upper tract infection associated with early preterm infection associated with early preterm labor are likely to be more responsive to labor are likely to be more responsive to this antibiotic.this antibiotic.

Additional RCTs to test the efficacy of Additional RCTs to test the efficacy of metronidazole to reduce early preterm birth metronidazole to reduce early preterm birth in laboring women are indicated.in laboring women are indicated.

Antibiotics Prior to Antibiotics Prior to

LaborLabor

and Preterm Birthand Preterm Birth

A Randomized Trial of Cefamet-Pivoxil A Randomized Trial of Cefamet-Pivoxil in High Risk Pregnant Women in Nairobiin High Risk Pregnant Women in Nairobi

NumberNumber

EGA at RxEGA at Rx

BirthweightBirthweight

LBW (<2500g)LBW (<2500g)

PP EndometritisPP Endometritis

AntibioticsAntibiotics

160160

~ 30 wks~ 30 wks

29272927

18.7%18.7%

17.3%17.3%

PlaceboPlacebo

160160

~ 30 wks~ 30 wks

27722772

32.8%32.8%

31.6%31.6%

Gichangi, Am J ObGyn, 1997

PP

.04.04

.01.01

.03.03

Rakai Study of Mass STD Treatment Rakai Study of Mass STD Treatment During PregnancyDuring Pregnancy

OutcomeOutcome

Neonatal DeathNeonatal Death

Preterm deliveryPreterm delivery

T. vagT. vag

B.V.B.V.

Maternal NG/CTMaternal NG/CT

Infant NG/CTInfant NG/CT

R.R.R.R.

0.800.80

0.730.73

0.280.28

0.380.38

0.420.42

0.380.38

95% C.I.95% C.I.

0.69-0.940.69-0.94

0.54-0.990.54-0.99

0.17-0.460.17-0.46

0.21-0.680.21-0.68

0.25-0.700.25-0.70

0.21-0.680.21-0.68*There was no difference in maternal HIV acquisition or in MCT of HIV or in stillbirths, spontaneous Ab or maternal death.

BV AND PRETERM BIRTHBV AND PRETERM BIRTH

WHAT ARE WE TREATING?WHAT ARE WE TREATING?

BV and PrematurityBV and Prematurity

Randomized trial of metronidazole in 80 Randomized trial of metronidazole in 80

women with BV and a previous PTBwomen with BV and a previous PTB

Rx = 18%Rx = 18% Placebo = 39%Placebo = 39%

p = <.05p = <.05

Morales 1994Morales 1994

BV and PrematurityBV and Prematurity

Randomized trial of metronidazole and Randomized trial of metronidazole and

erythromycin in women with BV and at erythromycin in women with BV and at

high risk for PTBhigh risk for PTB

Rx = 23%Rx = 23% Placebo = 37%Placebo = 37%

p = <.001p = <.001

Hauth 1994Hauth 1994

BV

During pregnancy at 14-26 weeks, During pregnancy at 14-26 weeks,

intravaginal 2% Clindamycin cream intravaginal 2% Clindamycin cream

cured BV (86%), but had no effect on cured BV (86%), but had no effect on

the rate of preterm delivery - the rate of preterm delivery -

15% vs. 13.5% for placebo.15% vs. 13.5% for placebo.

OR 1.1 (0.7-1.7).OR 1.1 (0.7-1.7).

IndonesiaIndonesia Joesoef SER 1995 Joesoef SER 1995

BV Treatment and BV Treatment and Spontaneous Preterm BirthSpontaneous Preterm Birth

MetronidazoleMetronidazole PlaceboPlacebo OROR

BV PositiveBV Positive 11/242 (4.5%)11/242 (4.5%) 15/238 (6.3%)15/238 (6.3%) 0.71 (0.3-1.7)0.71 (0.3-1.7)

BV Positive BV Positive and Prior PTBand Prior PTB 1/17 (5.9%)1/17 (5.9%) 6/17 (35.3%)6/17 (35.3%) 0.11 (0.0-1.2)0.11 (0.0-1.2)

BV Positive and BV Positive and Negative and Negative and Prior PTBPrior PTB 2/22 (9.1%)2/22 (9.1%) 10/24 (42%)10/24 (42%) 0.14 (0.0-0.8)0.14 (0.0-0.8)

McDonald, 1997McDonald, 1997Br J Obstet GynaecolBr J Obstet Gynaecol

BV and Preterm BirthBV and Preterm Birth

Treating asymptomatic predominantly low-Treating asymptomatic predominantly low-

risk women with BV with two doses of 2 gm risk women with BV with two doses of 2 gm

of metronidazole 48 hours apart, on two of metronidazole 48 hours apart, on two

occasions did not reduce preterm birthoccasions did not reduce preterm birth

A randomized trial of antibiotics A randomized trial of antibiotics

in 700 women positive for fFN in 700 women positive for fFN

showed no benefit in reducing showed no benefit in reducing

spontaneous preterm birth.spontaneous preterm birth.

Metronidazole to Prevent Preterm Metronidazole to Prevent Preterm

Birth Among Asymptomatic Birth Among Asymptomatic

Pregnant Women with Pregnant Women with

Trichomonas VaginalisTrichomonas Vaginalis

NICHD MFMU NetworkNICHD MFMU Network

Preterm Birth - Antibiotic TreatmentPreterm Birth - Antibiotic Treatment

Old literature: oral tetracycline during Old literature: oral tetracycline during pregnancy reduced SPBpregnancy reduced SPB

Treatment of BV in high risk women with oral Treatment of BV in high risk women with oral metro. and erythro. has reduced SPBmetro. and erythro. has reduced SPB

Topical treatment of BV has not reduced SPBTopical treatment of BV has not reduced SPB In women in SPL, penicillin-type antibiotics In women in SPL, penicillin-type antibiotics

have not generally reduced SPBhave not generally reduced SPB Treatment of women in SPL with metro. and Treatment of women in SPL with metro. and

amp. has reduced SPBamp. has reduced SPB

PREMATURITYPREMATURITY

““The treatment of premature labor The treatment of premature labor is identical with that already is identical with that already described for term labor and described for term labor and does not require further mention.”does not require further mention.”

Williams 1908Williams 1908

IIII

II

IIIIII

IVIV

Markers for InfectionMarkers for Infection

•Amniotic FluidAmniotic Fluid•Plasma/SerumPlasma/Serum•Vaginal FluidVaginal Fluid•Cervical FluidCervical Fluid•UrineUrine• SalivaSaliva

Markers of Intrauterine Infection in Markers of Intrauterine Infection in Asymptomatic Women in Routine Asymptomatic Women in Routine

Prenatal CarePrenatal Care

Amniotic FluidAmniotic Fluid

High interleukin-6High interleukin-6

Cervix or VaginaCervix or Vagina

Bacterial vaginosisBacterial vaginosis

High interleukin-6High interleukin-6

High ferritinHigh ferritin

High fetal fibronectinHigh fetal fibronectin

High High -FP-FP

High HCGHigh HCG

High ProlactinHigh Prolactin

High CICPHigh CICP

SerumSerum

High GCSFHigh GCSF

High ferritin High ferritin

Markers of Intrauterine Markers of Intrauterine Infection in Pregnant WomenInfection in Pregnant Women

Women Presenting in LaborWomen Presenting in LaborAmniotic FluidAmniotic FluidBacteriaBacteria

Low glucoseLow glucose

High wt-cell countHigh wt-cell count

High GCSFHigh GCSF

High IL-1High IL-1

High IL-6High IL-6

Cervix or VaginaCervix or VaginaBacterial vaginosisBacterial vaginosis

High GCSFHigh GCSF

High TNF-High TNF-High IL-1High IL-1

High IL-6High IL-6

High IL-8High IL-8

High fetal fibronectinHigh fetal fibronectin

SerumSerumHigh GCSFHigh GCSF

High IL-6High IL-6

High TNF-High TNF-High C-reactive High C-reactive

proteinprotein

Research QuestionsResearch Questions

When do bacteria invade the uterus?When do bacteria invade the uterus?

What is the infection status of the uterus What is the infection status of the uterus prior to conception? prior to conception?

What Mechanical and molecular What Mechanical and molecular mechanisms are associated with uterine mechanisms are associated with uterine invasion? invasion?

What are the protective mechanisms?What are the protective mechanisms?

Why is the rate of genital tract Why is the rate of genital tract infection so high in black women?infection so high in black women?

Lack of access to treatment?Lack of access to treatment?

Douching or other behaviors?Douching or other behaviors?

Immunological differences?Immunological differences?

Greater risk of exposure?Greater risk of exposure?

What strategies work to reduce these What strategies work to reduce these differences?differences?

And what role does genetics play?And what role does genetics play?

None?None?Differences in immune response?Differences in immune response?Differences in chorioamnion membrane Differences in chorioamnion membrane

strength or ability to repair (keloids)?strength or ability to repair (keloids)?Differences in uterine muscle contractility?Differences in uterine muscle contractility?

Research QuestionsResearch Questions

Which markers best predict current Which markers best predict current intrauterine infection?intrauterine infection?

Which interventions (i.e., antibiotics, Which interventions (i.e., antibiotics, anti-inflammatory agents) will reduce anti-inflammatory agents) will reduce preterm birth and neonatal damage preterm birth and neonatal damage associated with intrauterine infection?associated with intrauterine infection?