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INFECTION AND PRETERM BIRTH
Sequelae of Preterm Birth
(75%)
Perinatal
Mortality
(10%)
(50%)
Term Births
Preterm Birth
Neurologic
Handicap
Incidence of Preterm Birth in The U.S.A.
% Preterm
1981-1994
12
11
10
9
8
7
6
5
4
3
2
1
0
1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994
Year
Time Trends in Low Birth Weight (<1,500 g)
by Race/Ethnicity - United States, 1970-1990
3.5
1970
1975
1980
1985
1990
Percentage of live births
3
2.5
2
1.5
1
0.5
0
All races
White
Black
Native
American
Hispanic
UAB Infants with Birthweights 
1000 Grams
Mean BW
Survival
1975
900 gms
17%
1980
860 gms
48%
1985
820 gms
56%
1990
804 gms
74%
Distribution of Neonatal Mortality
BWT (gms)
Distribution
<1000
60%
1000-2500
20%
>2500
20%*
*Majority associated with congenital anomalies
Approximate Prevalence of Cerebral Palsy per 1,000 Births
by Birth Weight and Gestational Age
250
240
230
Prevalence of Cerebral Palsy
per 1,000 Live Births
50
40
30
20
10
0
0
500
23
1000
27
1500
2000
32
2500
3000
3500
36
4000
4500
5000
Term
Birth Weight (g) / Gestational Age (wks)
LBW-PORT
Survival Rate for Extremely Small Infants (<800g)
in Relation to Mid-Year of Birth
Survivors per Livebirth, %
80
60
40
20
0
1975
1980
1985
1990
Mid-Year of Birth
Lorenz, 1998
Prevalence of Disability Among Extremely Small
Survivors (<800g) in Relation to Mid-Year of Birth
Disabled Infants per Survivor, %
70
60
50
40
30
20
10
0
1975
1980
1985
1990
Mid-Year of Birth
Lorenz, 1998
Percentage of Extremely Small (<800g) Livebirths Surviving
with at Least One Disability in
Relation to Mid-Year of Birth
Disabled Infants per Livebirth, %
20
15
10
5
0
1975
1980
1985
Mid-Year of Birth
1990
Lorenz, 1998
Cerebral Palsy in <1000gm infants
Survivors
<1000g
Survivors with Any
births Survival Survivors with CP* Disability**
Year
(n)
(%)
(n)
(n)
(n)
1960 20,000
1
200
16
32
1985 20,000
40
8,000
640
1280
1997 20,000
80
16,000
1280
2560
*Assuming an 8% incidence in survivors consistently over time.
**Assuming a 16% incidence in survivors consistently over time.
Etiology of Preterm Birth
Spontaneous
Preterm Labor
20%
Preterm Birth
for Maternal or
Fetal
Indications
50%
30%
Premature Rupture
of Membranes
REVIEW OF INTERVENTIONS TO
PREVENT PRETERM BIRTH
Commonly used interventions which have not been
shown to reduce preterm birth include:
 Prenatal care
 Drug, alcohol and
tobacco cessation
 Risk screening
programs
 Nutrition counseling
 Bed rest
 Caloric supplementation
 Hydration
 Protein supplementation
 Home uterine
 Iron supplementation
activity monitoring
 Most labor inhibiting
agents
INFECTION AND PRETERM BIRTH
SURGICAL PATHOLOGY REPORT
Clinical History
34 year old white female with an intrauterine
pregnancy at 25 and 3/7th weeks.
Microscopic Description
Sections of the free fetal membranes show
severe, necrotizing chorioamnionitis. Both
umbilical arteries as well as the umbilical
vein exhibit funisitis.
Infection and Labor
In 1927, Harris and Brown reported culturing women undergoing Csection with intact membranes.
STATUS
No labor
Labor <5 hours
Labor >5 hours
RESULTS (# POSITIVE)
0/21
0/5
6/7 (4/6 anaerobic)
They concluded that organisms could reach the amniotic fluid with
intact membranes and that fever was not a reliable sign of infection in
labor.
Infection in the female reproductive tract can
cause premature rupture of the membranes and
induce premature labor…. The membranes in all
premature cases in this series show evidence of
infection…. In most instances this reaction is
severe.
Knox, Am J Obstet Gynecol 1950
Infection and Prematurity
Elder treated 279 non-bacteriuric women with a 6week course of 1gm tetracycline daily or a placebo
beginning at <32 weeks gestation.
Tetracycline treated women had fewer preterm births.
Elder, 1971
Infection and Preterm Labor
In 1977 Bobitt and Ledger performed amniocenteses on 10 women in
preterm labor with intact membranes.
7 had colony counts >1000 per ml with anaerobic organisms
predominating.
“It appears that bacteria can penetrate the fetal
membranes and contaminate the amniotic fluid”
“In patients in premature labor, the role of unrecognized
amnionitis should be reevaluated.”
Bobitt & Ledger, 1977
J Reprod Med
Intrauterine Infection


Clinical chorioamnionitis
Sub-clinical chorioamnionitis
– Organisms in amniotic fluid
and membranes
– Organisms only in
membranes
Of women with positive
chorioamnion cultures,
only 50% also have
positive amniotic fluid
cultures.
INFECTION AND PREMATURITY
Only 8% of women with histologic
chorioamnionitis have clinical signs (fever
and uterine tenderness) prior to delivery.
Gusick 1985
Chorioamnionitis
Histologic studies suggest a clear progression
of granulocyte infiltration:
Maternal Granulocytes
Decidua  Chorion  Amnion  Amniotic fluid
Umbilical Cord
Umbilical vessels  Wharton’s Jelly  Amniotic fluid
 Granulocytes in AF likely represent both a
maternal and fetal response.
Funisitis

Prior to 1970, funisitis was thought to
represent a sign of asphyxia

In 1970, Cassady showed that funisitis
was associated with intrauterine
infection - not asphyxia

The only proven intrauterine and fetal
infection occurring in the absence of
funisitis was Group B strep
Overbach and Cassady, Pediatrics 1970
Chorioamnionitis

Funisitis is present in about half the
cases of histologic chorioamnionitis
and is almost never seen alone.

This suggests that the etiologic
infection almost always starts in the
chorioamnion.
Intrauterine Infection and
Preterm Labor
Relationship to Gestational Age
Prevalence at Delivery of Histologic Chorioamnionitis at
Different Stages of Gestation
100
90
80
Percent
70
60
50
40
30
20
10
0
21-24
25-28
29-32
33-36
Weeks Gestation
37-40
41-44
Russell, P.
Am J Diag Gyn Obst. 1979;1:127
Incidence of Chorioamnionitis in
Preterm Delivery Patients
100
80
6/9
11/19
60
17/33
40
27/120
20
295/1526
0
21-24
25-28
29-32
33-36
> 37
Histological Chorioamnionitis
100
80
60
40
20
0
<1000
1000-1999
2000-2499
Patients in Labor with Intact Membranes
100
Watts, Ob/Gyn 79:351, 1992
20/105 (19%) + Cultures
80
60
Other Bacteria
40
Ureaplasma Only
20
0
23-24
25-26
27-28
29-30
31-32
33-34
Chorioamnion Colonization
Indicated vs. Spontaneous Delivery
100
Spontaneous
80
% Positive
Cultures
Indicated
60
40
20
0
<1000
1000-1499
1500-2499
Birthweight (grams)
 2500
Etiology of Spontaneous PTB
Infection
20
24
28
Other
Pathologies
32
36
Gestational Age
No
Pathology
38
40
42
Etiology of Spontaneous Preterm Birth
Single potent
risk factor
(Infection and
placental abruption)
Multiple weaker risk
factors acting
through usual
hormonal pathways
20 weeks
36 weeks
Mediating Factors
cervical strength
uterine contractility
host defenses
Histologic Chorioamnionitis
Evidence of chronicity
1. Ureaplasma diagnosed by
amniocentesis (PCR or culture) at 15-20
wks  delivery with HCA at 24-28 wks.
2.  IL-6 in amniotic fluid at 15-20 wks 
delivery with HCA at <32 to 34 wks.
3. FFN (a marker for membrane disruption)
in vagina or cervix at 13-24 wks associated with HCA at 29-31 wks.
Recurrent Preterm Birth
Women with recurrent spontaneous
preterm births <32 weeks are more likely
to have histologic chorioamnionitis than
other women giving birth at similar
gestational ages.
Salafia, SMAM 2001
Bacteria Associated
with Prematurity
Ureaplasma
Mycoplasma
Gardnerella
Mobiluncus
Peptostreptococcus
Bacteroides
Low
Virulence
Choriodecidual bacterial colonization
(endotoxins and exotoxins)
Fetal tissue
response
Maternal
response
Fetus
Chorioamnion
and placenta
Decidua
Increased
corticotropin-releasing
hormone
Decreased chorionic
prostaglandin
dehydrogenase
Increased cytokines
and chemokines
Increased adrenal
cortisol production
Increased
prostaglandins
Neutrophil
infiltration
Increased
metalloproteases
Myometrial
contractions
Chorioamnion weakening and
rupture
Preterm Delivery
Cervical
ripening
Bacterial Vaginosis
and
Preterm Birth
Normal vaginal secretions
Bacterial vaginosis
BV and Prematurity
The odds ratio for preterm birth in
association with BV in nearly every study
ranges from 1.5 to 3.0
BV and Preterm Birth
Women with BV type organisms such as
gardnerella, bacteroides and mycoplasma
in the vagina early in pregnancy were
significantly more likely to have these
organisms in the amniotic fluid at the time
of delivery.
VIP Study
Krohn, 1996
BACTERIAL VAGINOSIS
Korn et al., in non-pregnant women, showed
that BV was associated with plasma cell
endometritis as well as with endometrial
colonization by a number of organisms
which are present in excessive numbers in
women with BV.
Association of BV with
Plasma Cell Endometritis
100
90
80
70
60
50
40
30
20
10
0
GENITAL INFECTIONS IN PREGNANT WOMEN
BY RACE
50
45
White
Black
40
35
30
% 25
20
15
10
5
0
Chlamydia
Gonorrhea
Trichomonas
Group B
Strep
Mycoplasma
Bacterial
vaginosis
VIP Study, Am J Obstet Gynecol, 1996
Nearly 50% of the excess preterm
births and mortality in black versus
white infants is explained by the
increase in vaginal and intrauterine
infections in black women
Fetal Fibronectin



A basement membrane protein
Produced primarily by fetal tissue,
the placenta and membranes.
It may help to adhere the placenta
and membranes to the decidua.
FETAL FIBRONECTIN
A marker for upper genital tract
basement membrane disruption
INFECTION AND PRETERM BIRTH
III
IV
II
I
FFN AND PRETERM BIRTH
Delivery (weeks)
<28
<30
<32
<35
<37
+Goldenberg AJOG 1995
OR
60
42
23
11
5
ASSOCIATION OF FFN AND INFECTION
1. FFN is twice as common in women with BV
2. FFN was 16-20 fold more common in women
who developed clinical chorioamnionitis
3. All women with FFN has histologic
chorioamnionitis
4. FFN was 6 fold more common in women
whose infants developed sepsis
TIMING
Event
Gestational Age
(Weeks ± SD)
Screening for FFN
23.9 ± .06
Clinical Chorioamnionitis
30.6 ± 4.1
SPECULATION

At 24 weeks, FFN in the vagina or
cervix is a marker for an
asymptomatic upper genital tract
infection which later manifests itself
as spontaneous preterm labor or
PROM frequently in conjunction
with a perinatal infection.
Is pregnancy an antibiotic-
deficient state?
Antibiotics in Labor
and
Preterm Birth
Antibiotics in Women with Preterm
Labor and Intact Membranes
Study
Antibiotic
N
Delayed
Delivery
MacGregor, 1986
Erythromycin
17
Yes
No
Morales, 1988
Erythromycin, Ampicillin
150
Yes
No
Winkler, 1988
Erythromycin
19
Yes
-
Newton, 1989
Erythromycin / Ampicillin
95
No
No
MacGregor, 1991
Clindamycin
103
Yes
No
McCaul, 1992
Ampicillin
40
No
No
Romero, 1993
Ampicillin / Amoxicillin /
Erythromycin
275
No
No
78
No
No
117
No
No
Cox, 1995
Ampicillin / Amoxicillin
Gordon, 1995
Ceftizoximine
Improved Infant
Outcome
Antibiotics in Women with Preterm
Labor and Intact Membranes

Meta-analysis of existing RCTs

These results do not support the
routine use of antibiotics in women in
preterm labor
Egarter et al, 1996
Antibiotics and Preterm Birth
Labor with Intact Membranes
Metronidazole and Ampicillin for 6 days at ~30 weeks in a RCT
Outcome
BWT (x) (g)
delivery (median)
Delivery <7 days (%)
NEC (%)
Study Group
n=43
2318
15
37%
0%
Placebo Group
n=38
2093
2.5*
63%*
13%*
Days to
*p<.05
†greater prolongation occurred in <30 week pregnancies
Norman et al (South Africa), Br J Obstet Gynaecol, 1994
Antibiotics and Preterm Birth
Labor with Intact Membranes
Ampicillin and Metronidazole for 8 days at ~30 weeks in a RCT
Outcome
Days to delivery (x)
GA at delivery (wks) (x)
Birth <37 weeks (%)
BWT (g) (x)
NICU Admission (%)
Neonatal sepsis (%)
Antibiotics
(n=59)
Placebo
(n=51)
P value
48
37
42%
2662
40%
10%
27
34
65%
2370
63%
22%
.01
.01
.01
.08
.03
.18
Svare et al (Denmark), Br J Ob Gyn 1997
Antibiotics in Women with Preterm
Labor and Intact Membranes



The most promising studies used
metronidazole.
the organisms found in upper tract
infection associated with early preterm
labor are likely to be more responsive to
this antibiotic.
Additional RCTs to test the efficacy of
metronidazole to reduce early preterm
birth in laboring women are indicated.
Antibiotics Prior to
Labor
and Preterm Birth
A Randomized Trial of Cefamet-Pivoxil
in High Risk Pregnant Women in Nairobi
Antibiotics
Placebo
160
160
~ 30 wks
~ 30 wks
2927
2772
.04
LBW (<2500g)
18.7%
32.8%
.01
PP Endometritis
17.3%
31.6%
.03
Number
EGA at Rx
Birthweight
P
Gichangi, Am J ObGyn, 1997
Rakai Study of Mass STD Treatment
During Pregnancy
Outcome
R.R.
95% C.I.
Neonatal Death
0.80
0.69-0.94
Preterm delivery
0.73
0.54-0.99
T. vag
0.28
0.17-0.46
B.V.
0.38
0.21-0.68
Maternal NG/CT
0.42
0.25-0.70
Infant NG/CT
0.38
0.21-0.68
*There was no difference in maternal HIV acquisition or in MCT of HIV or in
stillbirths, spontaneous Ab or maternal death.
BV AND PRETERM BIRTH
WHAT ARE WE TREATING?
BV and Prematurity
Randomized trial of metronidazole in 80
women with BV and a previous PTB
Rx = 18% Placebo = 39%
p = <.05
Morales 1994
BV and Prematurity
Randomized trial of metronidazole and
erythromycin in women with BV and at
high risk for PTB
Rx = 23% Placebo = 37%
p = <.001
Hauth 1994
BV
During pregnancy at 14-26 weeks,
intravaginal 2% Clindamycin cream
cured BV (86%), but had no effect on
the rate of preterm delivery 15% vs. 13.5% for placebo.
OR 1.1 (0.7-1.7).
Indonesia
Joesoef SER 1995
BV Treatment and
Spontaneous Preterm Birth
Metronidazole
Placebo
11/242 (4.5%)
15/238 (6.3%)
0.71 (0.3-1.7)
BV Positive
and Prior PTB
1/17 (5.9%)
6/17 (35.3%)
0.11 (0.0-1.2)
BV Positive and
Negative and
Prior PTB
2/22 (9.1%)
10/24 (42%)
0.14 (0.0-0.8)
BV Positive
OR
McDonald, 1997
Br J Obstet Gynaecol
BV and Preterm Birth
Treating asymptomatic predominantly
low-risk women with BV with two
doses of 2 gm of metronidazole 48
hours apart, on two occasions did not
reduce preterm birth
A randomized trial of antibiotics
in 700 women positive for fFN
showed no benefit in reducing
spontaneous preterm birth.
Metronidazole to Prevent Preterm
Birth Among Asymptomatic
Pregnant Women with
Trichomonas Vaginalis
NICHD MFMU Network
Preterm Birth - Antibiotic Treatment

Old literature: oral tetracycline during
pregnancy reduced SPB

Treatment of BV in high risk women with oral
metro. and erythro. has reduced SPB

Topical treatment of BV has not reduced SPB

In women in SPL, penicillin-type antibiotics
have not generally reduced SPB

Treatment of women in SPL with metro. and
amp. has reduced SPB
PREMATURITY
“The treatment of premature labor
is identical with that already
described for term labor and
does not require further mention.”
Williams 1908
Markers for Infection
III
IV
II
I
•Amniotic Fluid
•Plasma/Serum
•Vaginal Fluid
•Cervical Fluid
•Urine
• Saliva
Markers of Intrauterine Infection in
Asymptomatic Women in Routine
Prenatal Care
Amniotic Fluid
High interleukin-6
Cervix or Vagina
Bacterial vaginosis
High interleukin-6
High ferritin
High fetal fibronectin
High -FP
High HCG
High Prolactin
High CICP
Serum
High GCSF
High ferritin
Markers of Intrauterine
Infection in Pregnant Women
Women Presenting in Labor
Amniotic Fluid
Cervix or Vagina
Serum
Bacteria
Low glucose
High wt-cell count
High GCSF
High IL-1
High IL-6
Bacterial vaginosis
High GCSF
High TNF-
High IL-1
High IL-6
High IL-8
High fetal fibronectin
High GCSF
High IL-6
High TNF-
High C-reactive
protein
Research Questions

When do bacteria invade the uterus?

What is the infection status of the uterus
prior to conception?

What Mechanical and molecular
mechanisms are associated with uterine
invasion?

What are the protective mechanisms?
Why is the rate of genital tract
infection so high in black women?
Lack of access to treatment?
Douching or other behaviors?
Immunological differences?
Greater risk of exposure?
What strategies work to reduce these
differences?
And what role does genetics play?
None?
Differences in immune response?
Differences in chorioamnion membrane
strength or ability to repair (keloids)?
Differences in uterine muscle contractility?
Research Questions

Which markers best predict current
intrauterine infection?

Which interventions (i.e., antibiotics,
anti-inflammatory agents) will
reduce preterm birth and neonatal
damage associated with intrauterine
infection?