infection and preterm birth. sequelae of preterm birth perinatalmortality neurologichandicap (75%)...
TRANSCRIPT
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
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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?