Post on 26-Jun-2015
transcript
Steven Offenbacher DDS, PhD, MMScJames D Beck, PhD
Center for Oral and Systemic DiseaseComprehensive Center for Inflammatory
DisordersUniversity of North Carolina at Chapel Hill
2001 Frances Glenn Mayson Symposium
“Pre-term Labor: Is the Fetus Trying to Tell Us Something November, 2001
What are the major pregnancy complications?
Preterm : <37 wks completed gestational age
Low birth weight <2500g
PPROM : Preterm premature rupture of membranes
PTL : Preterm labor Preeclampsia : Pregnancy
induced hypertension and proteinuria
Key Terms (outcomes)Partus & Neonate
Obstetric
Why is this important?
About 10% all births are preterm low birth weight
Preterm birth accounts for two-thirds of all infant mortality
Each gram of fetal weight under 2500g costs 75$ in neonatal unit expenses
USA NICU costs in excess of 5.5 billion dollars a year as consequence of preterm births
Preterm Births
Infant Health Issues Improvements in perinatal
care have dramatically improved survival rates of premature births
This has resulted in improvement in neonatal mortality
BUT There has been no decrease in the rate of preterm births.
Actual costs and number of low birth weight survivors with disabilitites has increased.
Low-birthweight live births(Percent of live births less than 2,500g in US during
selected years according to maternal race)
0
2
4
6
8
10
12
14
1970 1980 1990 1994 1998
All racesWhiteBlack
Infant Health Issues
Since 1981, percent born (survivors) < 37 weeks has increased 17%
Significant disparities by race and ethnicity
Preterm infants are–7x more likely to die prior to 1st birthday – at increased risk for: neuro-developmental, respiratory
disorders, learning disabilities, delayed development, cerebral palsy
KNOWN RISK FACTORS
Tobacco, drug or alcohol usage. Previous preterm delivery Concurrent genitourinary tract infection: Bacterial vaginosis, chorioamnionitits, STDs
MAJOR
KNOWN RISK FACTORS
Maternal age, weight, stature, cervical length
Nulliparous Stress – physical & social, familial
support, SES Familial history Level of prenatal care
MINOR
25-50% of preterm births occurin absence of significant risk factors
Cervicaldilation
Fetus
Amnion
Cervix
Vagina
Fetus
AmnionAmnion
Vaginal Infection[BV, bacterial vaginosis]
Uterine contraction
Pathogenesis of bacterial vaginosis induced
prematurity
?Fetus
AmnionAmnion
UterusPlacenta & Membranes
IL-1, TNF, PGE2
M
PGE2, IL-1b, TNFa, IL-6,
MMPs
Lymphocytes
Monocytes
Gram- Flora
Leukocyte
Wall
Epithelial Ulceration
Bacterial Invasion,Bacteremia
Periodontitis: Intra-Oral toExtra-Oral Pathway
Biochemical Mediators of Prematurity
ILIL-1
PGEPGE22
IL-1IL-1
TNF
TNF
LPS Can induce uterine contraction, cervical dilation, labor or abortion, placenta damage, inhibit fetal growth, mediate preterm delivery, low birth weight and neonatal morbidity.IL-6IL-6
ILIL-6
Biochemical mediators and indicators of fetal stress
Fetal antibody to bacteria : e.g. Rubella IgM
sICAM: soluble Intracellular adhesion molecule, a marker of vascular (endothelial) stress
Fetal CRP (C-reactive protein), acute phase response
Prospective Study of Pregnant Mothers
MaternalPeriodontitis
•Models that adjust for obstetric risk factors: e.g. Demographic, smoking, SES, infection, parity•Clinical periodontal disease as exposure for abnormal pregnancy outcome
Risk
Prematurity(gestational age <37 weeks)
Low Birth Weight(<2500g)
Impaired Fetal Growth(low weight for getational age)
Prospective Study of Pregnant Mothers
Prematurity
Low Birth Weight
Impaired Fetal Growth
MaternalPeriodontitis
Biological Mechanisms
Microbial InfectionMaternal Antibody
Fetal Exposure
PregnancyOutcome
OCAP- Oral Conditions and Pregnancy- NIDCR
funded
Preliminary Analyses• Prospective study of pregnant women to
determine contribution of periodontal disease to pregnancy complications.
• Exclusions included HIV, drug abuse, diabetes, hypertension, STD
• Currently enrolled over 1200 subjects, expected total of about 1500.
• Data presented reflect 814 deliveries
19
Flow Chart of Oral Conditions and Pregnancy Study (OCAP)University of North Carolina Chapel Hill and Duke University Medical Center
Presentation at Prenatal Clinic Refuse
Ineligible
EligibleWomen < 26 weeks
gestation
Refer for dental cleaning at UNC School of Dentistry
Obtain samples at initial prenatal or enrollment visit
Consent
Monitor for PTL, PROM, bacterial vaginosis and other infections
Obtain samples during immediate postpartum period
OCAP Measurements
OB Risk profile: Demographic, obstetric, medical, behavioral & socioeconomic parameters
Maternal Blood
Antepartum
IgG & IgM to Periodontal & Vaginal Organisms
Inflammatory MediatorsIL-1, TNFa, CRP, sICAM, IL-6, total 8-iso PGF2a
Interleukin SNPs
Vaginal & Cervical Vaginal and Periodontal Organisms
Inflammatory MediatorsIL-8, IL-1, TNFa, IL-6
Periodontal PlaqueGingival Crevicular FluidPeriodontal Exam
OCAP Measurements
OB Risk profile: Patient interview, chart abstraction
Repeat: Maternal Blood
Postpartum
Periodontal Plaque Gingival Crevicular Fluid Periodontal examFetal cord bloodNeonatal data
IgM to Periodontal Organisms (and vaginal)
Inflammatory MediatorsIL-1, TNFa, CRP, sICAM, IL-6, total 8-iso PGF2a
OCAP Pregnancy Outcomes
1. Prematurity (Gestational Age <37 weeks). Excluding elective abortion
2. Birth weight (<2500g)3. Weight for gestational age (small for
gestational age, growth restriction)
Weight
Gestational Age (weeks)37 3938 40
Prematurity
2500gGrowth Restriction
(lowest 10%)
OCAP Baseline characteristics and exposures
Term Preterm TotalSubjects
624 (76.9%) 188(23.1%) 812
275 (67.6%) 132 (32.4%)a 407 (50.1%)
311 (86.2%) 50 (13.9%) 361 (44.5%)
38 (86.4%) 6 (13.6%) 45 (5.4%)
27.6 + 6.63 25.8 + 6.07b
186 (29.8%) 56 (29.8%) 242 (29.8%)
98 (15.7%) 38 (20.2%) 136 (16.8%)
142 (22.8%) 50 (26.6%) 192 (23.7%)
Race Black
White
Other
Age (mean+SD)
Married
Smoke
WIC food stamps
P values
a)<0.0001
b) 0.0017
OCAP Baseline characteristics and exposures
Term Preterm TotalSubjects
624 (76.9%) 188(23.1%) 812
275 (67.6%) 132 (32.4%)a 407 (50.1%)
311 (86.2%) 50 (13.9%) 361 (44.5%)
38 (86.4%) 6 (13.6%) 45 (5.4%)
27.6 + 6.63 25.8 + 6.07b
186 (29.8%) 56 (29.8%) 242 (29.8%)
98 (15.7%) 38 (20.2%) 136 (16.8%)
142 (22.8%) 50 (26.6%) 192 (23.7%)
Race Black
White
Other
Age (mean+SD)
Married
Smoke
WIC food stamps
P values
a)<0.0001
b) 0.0017
OCAP Baseline characteristics and exposuresTerm Preterm Total
Subjects 624 (76.9%) 188(23.1%) 81289 (14.3%) 56 (29.8%)a 145 (17.9%)259 (41.5%) 80 (42.6%) 339 (41.8%)33 (5.3%) 14 (7.5%) 47 (5.8%)4 (0.6%) 12 (6.4%)a 16 (2.0%)
163 (26.1%) 38 (18.9%) 201 (24.8%)434 (69.6%) 132 (70.2%) 566 (69.7%)27 (4.3%) 18 (9.6%)c 45 (5.5%)180(33.1%) 75 (47.2%)d 255 (36.3%)
Previous PretermFirst Time BirthBV TreatmentChorioamnionitisPeriodontal StatusHealthMildMod-severeIncidence/Progression
P values
a)<0.0001
b) 0.0017
c) 0.013
d) 0.0012
OCAP Baseline characteristics and exposuresTerm Preterm Total
Subjects 624 (76.9%) 188(23.1%) 81289 (14.3%) 56 (29.8%)a 145 (17.9%)259 (41.5%) 80 (42.6%) 339 (41.8%)33 (5.3%) 14 (7.5%) 47 (5.8%)4 (0.6%) 12 (6.4%)a 16 (2.0%)
163 (26.1%) 38 (18.9%) 201 (24.8%)434 (69.6%) 132 (70.2%) 566 (69.7%)27 (4.3%) 18 (9.6%)c 45 (5.5%)180(33.1%) 75 (47.2%)d 255 (36.3%)
Previous PretermFirst Time BirthBV TreatmentChorioamnionitisPeriodontal StatusHealthMildMod-severeIncidence/Progression
P values
a)<0.0001
b) 0.0017
c) 0.013
d) 0.0012
Health= no PD>3mm or CAL>2mmHealth= no PD>3mm or CAL>2mm
Mod-severe= 4+ sites 5+mm PD and 2+mm C ALMod-severe= 4+ sites 5+mm PD and 2+mm C AL
Incidence/Progression = 4+ sites with PD Incidence/Progression = 4+ sites with PD increase 2+mmincrease 2+mm
Figure 1A. Adjusted distribution of maternal antepartum periodontal status by GA at delivery among 812 pregnant women
Gestational Age (weeks)
% of
Mothers
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
<28 <32 <35 <37 term
Mod-SevereMildHealth
a)p=0.06b)p=0.01c)p=0.006d)p=0.002
ab
cd
Figure 1A. Adjusted distribution of maternal antepartum periodontal status by GA at delivery among 812 pregnant women
Gestational Age (weeks)
% of
Mothers
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
<28 <32 <35 <37 term
Mod-SevereMildHealth
a)p=0.06b)p=0.01c)p=0.006d)p=0.002
ab
cd
Maternal Periodontitis and Gestational Age
Adjusted for race, smoking, food stamps, marital status, previous
preterm birth, first time birth,
bacterial vaginosis,
chorioamnionitis,
Maternal Periodontitis and Birth Weight
Figure 1B. Adjusted distribution of maternal antepartum periodontal status by BW at delivery among 812 pregnant women
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Mod-SevereMild
Health
Birth weight (grams)
% of
Mothers
>2500<1000 <1500 <2000 <2500
a)p=0.06b)p=0.004c)p=0.007d)p=0.0004
ab
cd
Figure 1B. Adjusted distribution of maternal antepartum periodontal status by BW at delivery among 812 pregnant women
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Mod-SevereMild
Health
Birth weight (grams)
% of
Mothers
>2500<1000 <1500 <2000 <2500
a)p=0.06b)p=0.004c)p=0.007d)p=0.0004
ab
cd
Adjusted for race, smoking, food stamps,
marital status, previous preterm
birth, first time birth, bacterial
vaginosis, chorioamnionitis
,
Distribution of time to premature delivery among 767 births based upon maternal antepartum periodontal status
Gestational Age (weeks)
% Pregnant
40
50
60
70
80
90
100
110
26 27 28 29 30 31 32 33 34 35 36 37 38
HealthMildMod-Severe
Health = absence of any PD>3mm and no sites with AL>2mm
Mod-Severe = 5mm PD and 2mm AL at 4 or more sites
Adjusted* Prevalence of Gestational Age at Delivery by Antepartum Maternal Periodontal
Disease Status
0%10%20%30%40%50%60%70%80%90%
100%
Health Mild Mod/Severe
< 2828 to <3535 to <37Term
% ofBirths
Maternal Antepartum Periodontal Status
* Maternal age, race, smoking, marital status, food stamps, bacterial vaginosis, and chorioamnionitis. Health = absence of any PD>3mm and no sites with
CAL>2mmMod-Severe = 5+mm PD and 2+mm CAL at 4 or more sites
Adjusted* Prevalence of Birth Weight at Delivery by Antepartum Maternal
Periodontal Disease Status
% ofBirths
Maternal Antepartum Periodontal Status
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
<1000
1000-1999
2000-2499
>2500
* Maternal age, race, smoking, marital status, food stamps, bacterial vaginosis , and chorioamnionitis.
Health Mild Mod/Severe
500
1000
1500
2000
2500
3000
3500
4000
<28 28 to <32 32 to <35 35 to<37 Term
No Incidence/Progression
Incidence/ Progression
Gestational Age in Weeks
Mean BirthWeight(grams)
a
a) p=0.01b) p=0.007c) p=0.09d) p=0.03e) p=0.12 _
b
c
d
e
Effects of maternal periodontal disease incidence/ progression * during pregnancy
on mean birth weight by gestational age adjusting for maternal race, sex of baby and
parity* 4+ sites with 2+mm PD increase
Table 2A. Logistic Regression Model* for Prematurity of GA<37 weeks (total n=672, n=148 for GA<37 )
0.98-2.191.47Incid/ProgrPeriodontal Disease
1.34-6.873.03Moderate-Severe Periodontal Disease
1.32-4.772.51BV & Chorioamnionitis
1.02-2.601.63First time birth
1.54-4.392.60Previous Preterm
0.70-2.001.18Smoking
1.75-4.552.82Race (African American)
0.83-2.211.35Mild Periodontal Disease
*Also adjusted for age, food stamps and marital status
OddsRatio 95% CI
Table 2B. Logistic Regression Model* for Prematurity of GA<35 weeks (total n=672, n=64 for GA<35)
1.40-4.912.62Incid/ProgrPeriodontal Disease
2.20-28.57.92Moderate-Severe Periodontal Disease
2.52-12.95.71BV & Chorioamnionitis
1.99-10.34.51First time birth
2.63-15.76.43Previous Preterm
0.45-2.441.05Smoking
2.65-13.35.95Race (African American)
1.05-6.272.56Mild Periodontal Disease
*Also adjusted for age, food stamps and marital status
OddsRatio 95% CI
Table 3. Logistic Regression Model* for Low Birth Weight of <2500 g (total n=664, n=96 for BW<2500g)
1.37-3.62.22Incid/ProgrPeriodontal Disease
1.54-11.54.20Moderate-Severe Periodontal Disease
1.45-6.052.96BV & Chorioamnionitis
1.63-5.63.03First time birth
2.35-8.854.56Previous Preterm
0.60-2.121.12Smoking
1.97-6.713.64Race (African American)
1.04-3.892.0Mild Periodontal Disease
*Also adjusted for age, food stamps and marital status
OddsRatio 95% CI
Table 4. Logistic Regression Model for Fetal Growth Restriction(lower 10th percentile of weight for gestational age, adjusting for maternal race, parity and baby sex)
0.95-4.091.97Smoking
2.09-17.26.00Moderate-Severe Periodontal Disease
0.41-2.240.96Ethanol
0.52-4.601.54Drugs
0.90-1.000.95Age
0.79-2.851.50Food Stamps
0..72-3.921.68Mild Periodontal Disease
OddsRatio 95% CI
Table 4. Logistic Regression Model for Fetal Growth Restriction(lower 10th percentile of weight for gestational age, adjusting for maternal race, parity and baby sex)
0.95-4.091.97Smoking
2.09-17.26.00Moderate-Severe Periodontal Disease
0.41-2.240.96Ethanol
0.52-4.601.54Drugs
0.90-1.000.95Age
0.79-2.851.50Food Stamps
0..72-3.921.68Mild Periodontal Disease
OddsRatio 95% CI
Perinatal MortalityHealth: 1.97%Mild: 3.16%
Mod-severe: 16.3%34/ 967, (p<0.0001)
Table 3. Effects of maternal periodontal disease progression during pregnancy on risk for FGR** (total n=680, n=39 for FGR )
1.72-7.243.52Incid/ Progrof Periodontal Disease
0.27-3.610.99BV & Chorioamnionitis
0.86-3.881.83Previous Preterm
1.37-5.932.85Smoking
0.88-1.000.94Age
*Also adjusted for food stamps and marital status**Using Berkowitz FGR lower 10th percentile weights for GA based upon parity, baby sex and race
OddsRatio 95% CI
Antepartum maternal periodontal disease status and progression on birth weight for
all births of GA<37 weeks
Prospective Study of Pregnant Mothers
Prematurity
Low Birth Weight
Impaired Fetal Growth
MaternalPeriodontitis
Biological Mechanisms
Microbial InfectionMaternal Antibody
Fetal Exposure
PregnancyOutcome
YES P.g. placental infection
NO P.g. placentalinfection
Runted fetusNormal weight fetus
MWFetal
Memb.Placenta
Liver
Positive control
Fetal Memb.
PlacentaSpleen
1,500 bp
400 bp
1,000 bp
Fetus #63-L3 Fetus #63-R2P.g. PCR signal in pregnant mouse with 2 small/5 normal fetus
P. gingivalisB. forsythusT. denticola
E. corrodensC. gingivalisC. sputigenaC. ochraceaA. actino. a
S. mitisS. oralis
S. sanguis
S. gordoniiS. intermedius
V. parvulaA. odontolyticus
P. intermediaP. nigrescens
P. microsF. nucleatum
F. periodonticum
E. nodatumS. constellatus
C. showae
C. rectusC. gracilis
S. noxia
A. actino. b
Socransky et al. 1998Socransky et al. 1998
**
********
**
********
****
**
**
****
P.g.
P.n.
P.i.
B.f.
C.r
.
A.a
.
E.c
.F
.n.
T.d.
P.m
.
C.o
.V
.p.
S,s.
S.o.
S.s.
A.v
.
Plaquesamples
Pooledbacterial
standards106
105
Maternal PlaqueMaternal Plaque
Plaque lanes
Maternalserum
Maternalserum
Human IgG(200-50ng/ml)
Pro
tein
A
Maternal IgG P.g
. P.n
.P.i.
B.f
.
C.r
.
A.a
. E.c
.F.n
. P.
m.C.o
.V.p
.S.s
.
T.d
. E.n
. S.i.
S.o
.M.c
.P.b
.
B.v
.G
.v.Vaginal Oral
FetalIgM
FetalIgM
Human IgM(200-50ng/ml)
P.g
. P.n
.P.i.
B.f
.
C.r
.
A.a
. E.c
.F.n
. P.
m.C.o
.V.p
.S.s
.
T.d
. E.n
. S.i.
S.o
.M.c
.P.b
.
B.v
.G
.v.Vaginal Oral
Pro
tein
A
FetalIgM
FetalIgM
Human IgM(200-50ng/ml)
P.g
. P.n
.P.i.
B.f
.
C.r
.
A.a
. E.c
.F.n
. P.
m.C.o
.V.p
.S.s
.
T.d
. E.n
. S.i.
S.o
.M.c
.P.b
.
B.v
.G
.v.Vaginal Oral
Pro
tein
A
Prevalence of Orange and Red Organisms in Maternal Plaque From 337 Term and 106 Preterm
Deliveries
Organism
C. rectusF. nucleatumP. microsP. nigrescensP. intermedia
P. gingivalisB. forsythusT. denticola
Term Preterm
18.1 12.347.5 40.649.3 45.329.1 27.435.3 30.2
7.42 4.72 8.90 7.5516.0 14.2
Orange
Red
Prevalence Orange>Red MicrobesPrevalence of O&R for Term ~
Preterm
(n=337) (n=106)
Maternal Plaque
0
20
40
60
0 1 2 3 4 5
# Orange Cluster Organisms Present
% Distribution of
Red Cluster
(1+ Positive)
Frequency Distribution of Red Microbial Cluster Organisms as Function of Orange
Cluster Organisms within Maternal Plaque
DNA Microbial Macroarray “Checkerboard”
Red cluster organism detection is enhanced by or “requires”
Orange cluster organisms
0
10
20
30
40
0 1 2 3 4 5
# Orange Cluster Organism IgG Positive
% Distribution of
Red Cluster
Positive IgG
Frequency Distribution of Maternal IgG Antibody Responses to Red Microbial Cluster Organisms as
Function of Orange Cluster IgG Responses Maternal IgG (n=390)
Red seropositity is enhanced by or “requires” Orange
seropositivity
Prevalence of Orange and Red Organism Positive IgG in Maternal Sera from 289 Term and 101
Preterm Deliveries
Organism
C. rectusF. nucleatumP. microsP. nigrescensP. intermedia
P. gingivalisB. forsythusT. denticola
Term Preterm
58.1 43.620.4 9.966.4 53.574.7 62.471.3 52.5
40.1 28.721.8 8.939.5 22.8
Orange
Red
Prevalence of positive maternal IgG responses for O&R Organisms among preterm has a non-significant trend to be generally less than that
of full term
(n=289) (n=101)
Maternal IgG (n=390)
Prevalence of Orange and Red Fetal IgM responses among 271 Term and 80 Preterm
Neonates
Organism
C. rectusF. nucleatumP. microsP. nigrescensP. intermedia
P. gingivalisB. forsythusT. denticola
Term Preterm
6.3 20.0 2.2 7.5 1.1 8.8 1.5 6.3 1.1 8.8
16.2 16.310.7 20.0 8.1 17.5
Orange
Red
(n=271) (n=80)
Fetal IgM (n=351)
P=0.0002
P=0.02
NS
0.018
0.0003
NS
P=0.03
P=0.015
Prevalence of Fetal IgM seropositive responses to Orange and Red Cluster
organisms is signficantly higher among preterm newborns
0
20
40
60
80
0 1 2 3 4 5# Orange Cluster Organism IgM Positive
% Distribution of
Red Cluster
Positive IgM
Frequency Distribution of Fetal IgM Responses to Red Microbial Cluster
Organisms as Function of Fetal Orange Cluster IgM Responses
Fetal Red cluster IgM response appears in absence of Orange
cluster organisms, [Orange IgM requires Red IgM response]
Rate of Prematurity as related to Maternal and Fetal Seropositivity to
Orange and Red Cluster Microbes (n=287)
Maternal IgGRed Cluster
Seroreactivity
Fetal IgMOrange ClusterSeroreactivity
++ -
-A-C, P=0.03B-C, P<0.0001D-C, P=0.0002
53.3% 20.9%
17.5%
32.8%
33.3% 16.2%
66.7% 27.3%
A B
C D
Column test: P<0.0001, OR=4.3, (2.11-8.90)Row test: P=0.0003, OR=2.37, (1.48-3.79)
Combined: OR=10.3
Incident Periodontal Disease Progression (% mothers with 4+ sites, 2+mm PD increase) as related to
Maternal and Fetal Seropositivity to Orange and Red Cluster Microbes (n=287)
Maternal IgGRed Cluster
Seroreactivity
Fetal IgMOrange Cluster
Seroreactivity
+
+ -
-
30.8 % 31.0 %
61.1 % 28.0 %
A B
C D
B-C, OR=3.5, P=0.015
Maternal Periodontal Disease
GA<37 weeksFetal Orange Complex IgM Response
AB
Prevalent, OR=2.44,
95% CI = 1.18, 5.04
Seropositive, OR= 5.0
95% CI = 2.22,11.3 C
Incident Progression, OR=2. 34,
95% CI = 1.001, 5.4
Models of Interrelationships among Maternal Periodontal Disease, Fetal Exposure to Oral Pathogens and Prematurity
Postpartum Maternal Periodontal Disease (4+ sites with PD> 5mm) and Mean Fetal
Cord Serum CRP by Gestational Age (n=186)
0
0.5
1
1.5
2
2.5
3
3.5
Term <37
No Periodontal Disease
Periodontal Disease
Gestational Age in Weeks
Mean Fetal CRP(ug/mL)
Fetal IgM C. rectus and Mean Fetal Cord Serum CRP by Gestational Age
(n=186)
0
1
2
3
4
5
6
Term <37
No CR IgM CR IgM
Gestational Age in Weeks
Mean Fetal CRP(ug/mL)
Patterns of Maternal Colonization, maternal IgG , fetal IgM and
prematurityMaternal Infection
Maternal Antibody
Patterns of Maternal Colonization, maternal IgG , fetal IgM and
prematurityMaternal Infection
Maternal Antibody
Patterns of Maternal Colonization, maternal IgG , fetal IgM and
prematurity
Maternal Infection
Maternal Antibody
No protective Red Complex IgG
Fetal Exposure
Fetal IgM to Red
Complex
Patterns of Maternal Colonization, maternal IgG , fetal IgM and
prematurity
Maternal Infection
Maternal AntibodyNo protective Red Complex
IgG
Fetal IgM to Red & Orange
Complexes
Increased Fetal
CRP
Fetal ExposureRed and Orange
Abnormal Pregnancy Outcome
Maternal Periodontal Disease
Progression ?
Conclusions1. Results suggest that antepartum
periodontal disease as well as incidence/ progression of periodontal disease is a significant independent risk factor for prematurity, low birth weight and fetal growth impairment.
2. Orange & Red complex organisms are similar at post-partum in preterm and full-term mothers.
3. Fetal IgM response to Red complex organisms occurs in absence of orange IgM, indicating early or initial exposure to maternal organims of the red complex
Conclusions
4. Maternal antibody to Red complex appears to “prevent” fetal exposure to maternal oral microbes.
5. Fetal IgM seropositive responses coupled with seronegative maternal red complex IgG confers greatest risk for prematurity OR=10.3.
New findings: University of Alabama Study of Prematurity (Jeffcoat &
Hauth)
0 1 2 3 4 5 6 7 8
Full term
GA<37 wks
GA<35 wks
GA<32 wks
Odds Ratio*
Bar 2Bar 1
*Adjusted for smoking, parity, age and race[p<0.05, as compared to no periodontal disease, full term deliveries]
Mild-moderateSevere
N=1313,Examined 21-24 wks
New findings :Nestor Lopez (Santiago, Chile)
Effects of Periodontal Therapy on rate of prematurity
850 pregnant women <20 weeks 390 women with periodontal disease ( 1
or more sites with PD>4mm and >3mm attachment loss).
Random assignment to 2 groups; periodontal scaling & root planing vs delayed treatment (post-partum).
Attrition low:24 and 15, respectively
Nestor Lopez (Santiago, Chile)
Risk Factor Distribution Untreated
28 (4.5)
1.2 (0.9)
23.7
4.3
13.5
Treated
27 (4.3)
1.4 (1.1)
24
7.4
13.8
Age
Parity
%Primiparous
% previous preterm
%previous miscarriage
P Value
0.04
0.13
0.43
0.21
0.92
Nestor Lopez (Santiago, Chile)
Risk Factor Distribution (%) Untreated
25.7
18.4
16.6
25.1
Treated
23.4
14.9
14.4
17
Smokers
UTI
Antibiotic Tx
Vaginosis
P Value
0.60
0.37
0.56
0.06
Nestor Lopez (Santiago, Chile)
Results: Untreated
3344(598)
10.1%(n=19)
Treated
3501 (429)
1.8%(n=3)
Mean birthweight
Incident GA<37*
P Value
0.0047
0.001
*Univariate RR =5.49, 95%CI= 1.65-18.22
Nestor Lopez (Santiago, Chile)
Results: (logistic regression) Odds Ratio
4.70
3.98
3.70
3.42
95% CI
1.29-17.1
1.11-14.2
1.46-9.38
1.16-10.0
No periodontal Tx
Previous GA<37
Low # Prenatal visits
Mother underweight
P Value
0.018
0.033
0.005
0.024
Variable
Also controlled for age, parity, smoking, vaginosis, first prenatal visit
Nestor Lopez (Santiago, Chile)
Conclusion:
Early studies by Lopez,
as well as those reported by Papapanou,
suggest that periodontal therapy
during pregnancy may reduce
the risk of prematurity.
Clinical Implications of OCAP Findings
Antepartum mild or moderate-severe periodontal disease and increases in PD during pregnancy appear to increase the risk for fetal exposure and pregnancy problems.
The magnitude of periodontal disease impact is significant with Odds ratios 2-10 depending on baseline status and worsening of condition during pregnancy
Evidence of fetal exposure to periodontal pathogens raises bacteremia risk questions
Maternal antibody appears to be protective
Prevention would appear to be prudent clinical management strategy
Implications for Health Care
Association may not be causal in nature. The potential benefits of treatment have
not yet been established. Periodontitis is both preventable and
treatable. Periodontal health is necessary for
overall health and periodontal disease may be as deleterious to pregnant mother as smoking, or alcohol consumption.
We need to educate the public, our patients and health care professionals to promote the need for good oral health as an important part of a healthy lifestyle.
OCAP Team UNC Epidemiologists
Susi Lieff (Ecol) Rosemary McKaig (Ecol) Pierre Beukins (SPH) Gary Slade (Ecol)
UNC Clinical Researchers Heather Jared (Hyg) Tracy Kachold (Hyg) Marsha Black (Tech) Sally Timlin (Nurse) Karen Dorman (Nurse) Sacha Singh (Perio)
UNC Clinical Scientists Ken Moise (MFM) Kim Boggess (MFM) Bob Strauss (MFM) Carl Bose (Ped) Phoebus Madianos
(perio) John Gilmore (Psych) Janet Southerland (Ecol)
Duke Clinical Scientists Phil Heine (MFM) Amy Murtha (MFM) Rick Auten (Ped) Ricki Goldstein (Ped)
OCAP Team UNC Lab Scientists
Catherine Champagne Estelle Riche
UNC Lab Technicians Frances Smith Russ Levy Sandra Elmore Jeremy Eissens Jermaine Fuller Christine Downey
UNC Computer Specialists Kevin Moss Morris Worley
UNC Students & Fellows Mark Suttle Dongming Lin Alvin Yeo Julie Hofheimer
UNC Administrative Gail Plaisance
Colleagues Epidemiologists
Sam Arbes Jim Beck Paul Eke John Elter Susi Lieff Rosemary McKaig Jim Pankow Gary Slade
Basic Scientists Catherine Champagne Sara Geva Sid Kalachandra Estelle Riché Chitpol Siddhivarn
Clinical Scientists Kim Boggess Elisa Ghezzi Alison Lohman Phoebus Madianos Sally Mauriello Steve Offenbacher David Paquette Rocio Quinonez Janet Southerland Ray Williams
Behavioral Scientists Julie Hofheimer
Clinical Research Peggy Allen Marsha Black Heather Jared Tracy Kachold Sue Riggsbee Barbara Oliver Betsi Petway
Research Students Nadine Brodala Waka Kadoma Dongming Lin Nora Rooney Diane Sitki Mark Suttle
Valuable Assistants Administration
Gail Plaisance
Computer Specialists Kevin Moss Morris Worley
Laboratory Christine Downey Jeremy Eissens Kendra Floyd Jermaine Fuller Russ Levy Frances Smith
Collaborators UNC Epidemiology
Gerardo Heiss Jim Pankow HA Tyroler
UNC Cardiology Wayne Cascio Efthymios
Deliargyris Alan Hinderliter Sid Smith
UNC Ob/Gyn Kim Boggess Karen Dorman Bob Strauss Steve Wells
UNC Psychiatry John Gilmore
UNC Biostatistics Woody Chambless David Couper Gary Koch
UNC Pediatrics Carl Bose Diane Marshall
Duke Ob/Gyn Elizabeth
Livingston Amy Murtha
Duke Pediatrics Rick Auten
AcknowledgementsNIH & NIDCR Grants :
DE R01HD26652, DE08289, DE012435 Contracts from NHLBI R01 DE 11551, P60 DE 13079
Dental Organizations : AAP, ADA
Corporate sponsors : Procter and Gamble, Block Drug,
Colgate, Orapharma, Interleukin Genetics, Sunstar, Merck, Glaxo-Wellcome, Phillips
Steven
Offenbacher &
James BeckSteven
Offenbacher &
James Beck