INFECTION AND PRETERM BIRTH

1
INFECTION AND PRETERM BIRTH
2
Sequelae of Preterm Birth
(75)
Perinatal Mortality
(10)
(50)
Neurologic Handicap
3
Incidence of Preterm Birth in The
U.S.A.1981-1994
4
Time Trends in Low Birth Weight (lt1,500 g) by
Race/Ethnicity - United States, 1970-1990
5
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

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Distribution of Neonatal Mortality

• BWT (gms) Distribution
• lt1000 60
• 1000-2500 20
• gt2500 20

Majority associated with congenital anomalies
7
Approximate Prevalence of Cerebral Palsy per
1,000 Births by Birth Weight and Gestational Age
250
240
230
50
40
30
Prevalence of Cerebral Palsy
per 1,000 Live Births
20
10
0
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
32
36
Term
23
27
Birth Weight (g) / Gestational Age (wks)
LBW-PORT
8
Survival Rate for Extremely Small Infants
(lt800g)in Relation to Mid-Year of Birth
80
60
40
Survivors per Livebirth,
20
0
1975
1980
1985
1990
Mid-Year of Birth
Lorenz, 1998
9
Prevalence of Disability Among Extremely Small
Survivors (lt800g) in Relation to Mid-Year of Birth
Mid-Year of Birth
Lorenz, 1998
10
Percentage of Extremely Small (lt800g) Livebirths
Surviving with at Least One Disability in
Relation to Mid-Year of Birth
Lorenz, 1998
11
Cerebral Palsy in lt1000gm infants
Survivors with Any Disability (n) 32 1280 2560
Survivors with CP (n) 16 640 1280
Survivors (n) 200 8,000 16,000
Survival () 1 40 80
lt1000g births (n) 20,000 20,000 20,000
Year 1960 1985 1997
Assuming an 8 incidence in survivors
consistently over time. Assuming a 16
incidence in survivors consistently over time.
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Etiology of Preterm Birth
Preterm Birth for Maternal or Fetal Indications
Spontaneous Preterm Labor
20
50
30
Premature Rupture of Membranes
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REVIEW OF INTERVENTIONS TO PREVENT PRETERM BIRTH
Commonly used interventions which have not been
shown to reduce preterm birth include

• Prenatal care
• Risk screening
• Nutrition counseling
• Caloric supplementation
• Protein supplementation
• Iron supplementation
• Most labor inhibiting agents

• Drug, alcohol and tobacco cessation programs
• Bed rest
• Hydration
• Home uterine activity monitoring

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INFECTION AND PRETERM BIRTH
15
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.

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Infection and Labor

• In 1927, Harris and Brown reported culturing
  women undergoing C-section with intact
  membranes.
• STATUS RESULTS ( POSITIVE) No labor 0/21
• Labor lt5 hours 0/5
• Labor gt5 hours 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.

17

• 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

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Infection and Prematurity

• Elder treated 279 non-bacteriuric women with a
  6-week course of 1gm tetracycline daily or a
  placebo beginning at lt32 weeks gestation.
• Tetracycline treated women had fewer preterm
  births.

Elder, 1971
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Infection and Preterm Labor

• In 1977 Bobitt and Ledger performed amniocenteses
  on 10 women in preterm labor with intact
  membranes.
• 7 had colony counts gt1000 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, 1977J Reprod Med
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Intrauterine Infection

• Clinical chorioamnionitis
• Sub-clinical chorioamnionitis
• Organisms in amniotic fluid and membranes
• Organisms only in membranes

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Of women with positive chorioamnion cultures,
only 50 also have positive amniotic fluid
cultures.
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INFECTION AND PREMATURITY

• Only 8 of women with histologic chorioamnionitis
  have clinical signs (fever and uterine
  tenderness) prior to delivery. Gusick 1985

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Chorioamnionitis

• Histologic studies suggest a clear progression of
  granulocyte infiltration
• Maternal Granulocytes
• Decidua ? Chorion ? Amnion ? Amniotic fluid
• Umbilical Cord
• Umbilical vessels ? Whartons Jelly ? Amniotic
  fluid
• ? Granulocytes in AF likely represent both a
  maternal and fetal response.

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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
25
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.

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Intrauterine Infection and Preterm Labor

• Relationship to Gestational Age

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Prevalence at Delivery of Histologic
Chorioamnionitis at Different Stages of Gestation

100
90
80
70
60
Percent
50
40
30
20
10
0
21-24
25-28
29-32
33-36
37-40
41-44
Weeks Gestation
Russell, P. Am J Diag Gyn Obst. 19791127
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Incidence of Chorioamnionitis in Preterm Delivery
Patients
with Chorioamnionitis
Gestational Age (weeks)
Mueller-Heubach 1990
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Histological Chorioamnionitis

Birthweight (g)
Chellam, 1985
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Patients in Labor with Intact Membranes
Watts, Ob/Gyn 79351, 1992 20/105 (19)
Cultures
Positive Amniotic Fluid Cultures
Gestational Age (weeks)
31
Chorioamnion Colonization Indicated vs.
Spontaneous Delivery

100
Spontaneous
80
Indicated
60
Positive
Cultures
40
20
0
lt1000
1000-1499
1500-2499
³ 2500






Birthweight (grams)
32
Etiology of Spontaneous PTB
OtherPathologies
NoPathology
Infection
Gestational Age
33
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
34
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 lt32 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.

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Recurrent Preterm Birth

• Women with recurrent spontaneous preterm births
  lt32 weeks are more likely to have histologic
  chorioamnionitis than other women giving birth at
  similar gestational ages.
• Salafia, SMAM 2001

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Bacteria Associated with Prematurity

• Ureaplasma
• Mycoplasma
• Gardnerella
• Mobiluncus
• Peptostreptococcus
• Bacteroides

Low Virulence
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Choriodecidual bacterial colonization (endotoxins
and exotoxins)
Fetal tissue response
Maternal response
Chorioamnion and placenta
Fetus
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
Cervical ripening
Preterm Delivery
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39
Bacterial VaginosisandPreterm Birth

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Normal vaginal secretions
Bacterial vaginosis
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BV and Prematurity

• The odds ratio for preterm birth in association
  with BV in nearly every study ranges from 1.5 to
  3.0

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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
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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.
44
Association of BV with Plasma Cell Endometritis
Metritis ()
Positive Negative
Bacterial Vaginosis
Korn et al., Obstet Gynecol 199585387-90
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GENITAL INFECTIONS IN PREGNANT WOMEN BY RACE
Chlamydia Gonorrhea Trichomonas Group B
Mycoplasma Bacterial Strep vaginosis
VIP Study, Am J Obstet Gynecol, 1996
46
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

47
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.

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FETAL FIBRONECTIN

• A marker for upper genital tract basement
  membrane disruption

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INFECTION AND PRETERM BIRTH
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FFN AND PRETERM BIRTH

• Delivery (weeks) OR
• lt28 60
• lt30 42
• lt32 23
• lt35 11
• lt37 5
• Goldenberg AJOG 1995

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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

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TIMING

• Event Gestational Age (Weeks SD)
• Screening for FFN 23.9 .06
• Clinical Chorioamnionitis 30.6 4.1

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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.

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Is pregnancy an antibiotic-deficient state?
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Antibiotics in LaborandPreterm Birth
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Antibiotics in Women with Preterm Labor and
Intact Membranes

• Delayed Improved Infant Study Antibiotic
  N Delivery Outcome
• 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
• Cox, 1995 Ampicillin / Amoxicillin 78 No
  No
• Gordon, 1995 Ceftizoximine 117 No No

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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
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Antibiotics and Preterm BirthLabor with Intact
Membranes
Metronidazole and Ampicillin for 6 days at 30
weeks in a RCT

• Study Group Placebo GroupOutcome n43 n38
  
• BWT (x) (g) 2318 2093 Days to delivery
  (median) 15 2.5
• Delivery lt7 days () 37 63
• NEC () 0 13 plt.05
• greater prolongation occurred in lt30 week
  pregnancies

Norman et al (South Africa), Br J Obstet
Gynaecol, 1994
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Antibiotics and Preterm Birth Labor with Intact
Membranes
Ampicillin and Metronidazole for 8 days at 30
weeks in a RCT

• Antibiotics Placebo
• Outcome (n59) (n51) P value
• Days to delivery (x) 48 27 .01
• GA at delivery (wks) (x) 37 34 .01
• Birth lt37 weeks () 42 65 .01
• BWT (g) (x) 2662 2370 .08
• NICU Admission () 40 63 .03
• Neonatal sepsis () 10 22 .18

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

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Antibiotics Prior to Laborand Preterm Birth
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A Randomized Trial of Cefamet-Pivoxil in High
Risk Pregnant Women in Nairobi
Number EGA at Rx Birthweight LBW (lt2500g) PP
Endometritis
Antibiotics 160 30 wks 2927 18.7 17.3
Placebo 160 30 wks 2772 32.8 31.6
P .04 .01 .03
Gichangi, Am J ObGyn, 1997
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Rakai Study of Mass STD Treatment During Pregnancy
Outcome Neonatal Death Preterm delivery T.
vag B.V. Maternal NG/CT Infant NG/CT
R.R. 0.80 0.73 0.28 0.38 0.42 0.38
95 C.I. 0.69-0.94 0.54-0.99 0.17-0.46 0.21-0.68 0
.25-0.70 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.
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BV AND PRETERM BIRTH
WHAT ARE WE TREATING?
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BV and Prematurity

• Randomized trial of metronidazole in 80 women
  with BV and a previous PTB
• Rx 18 Placebo 39 p lt.05

Morales 1994
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BV and Prematurity

• Randomized trial of metronidazole and
  erythromycin in women with BV and at high risk
  for PTB
• Rx 23 Placebo 37 p lt.001

Hauth 1994
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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
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BV Treatment and Spontaneous Preterm Birth

• Metronidazole Placebo OR
• BV Positive 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)

McDonald, 1997 Br J Obstet Gynaecol
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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

70

• A randomized trial of antibiotics in 700 women
  positive for fFN showed no benefit in reducing
  spontaneous preterm birth.

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Metronidazole to Prevent Preterm Birth Among
Asymptomatic Pregnant Women with Trichomonas
Vaginalis

• NICHD MFMU Network

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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

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PREMATURITY

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

Williams 1908
74

• Markers for Infection
• Amniotic Fluid
• Plasma/Serum
• Vaginal Fluid
• Cervical Fluid
• Urine
• Saliva

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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
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Markers of Intrauterine Infection in Pregnant
WomenWomen Presenting in Labor

• Amniotic Fluid
• Bacteria
• Low glucose
• High wt-cell count
• High GCSF
• High IL-1
• High IL-6

Cervix or Vagina Bacterial vaginosis High
GCSF High TNF-? High IL-1 High IL-6 High
IL-8 High fetal fibronectin
Serum High GCSF High IL-6 High TNF-? High
C-reactive protein
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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?

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• 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?

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• 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?

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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?

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