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Original Contribution
Histologic Chorioamnionitis and Preterm Delivery
Received for publication October 24, 2006; accepted for publication March 21, 2007.
chorioamnionitis; continental population groups; infection; inammation; neutrophils; placenta; premature birth;
term birth
Abbreviations: CI, condence interval; HCA, histologic chorioamnionitis; OR, odds ratio.
The link between infection and preterm delivery disparities is supported through a series of related observations.
Race/ethnic disparity is greatest for earlier preterm delivery
(e.g., <35 weeks) (14), and these early deliveries are more
often accompanied by premature rupture of membranes and/
or evidence of infection (2126). Bacterial vaginosis, a polymicrobial overgrowth associated with preterm delivery (27),
is more prevalent in disadvantaged (28, 29) and AfricanAmerican women (30, 31).
The placenta is a key tissue for understanding infection
and/or inflammation pathways leading to preterm delivery,
but the strength of association between histologic chorioamnionitis (HCA) and preterm delivery has been inconsistent.
Correspondence to Dr. Claudia B. Holzman, B601 West Fee Hall, East Lansing, MI 48824 (e-mail: holzman@msu.edu).
786
Am J Epidemiol 2007;166:786794
Inconsistent ndings linking placental histologic chorioamnionitis (HCA) and preterm delivery may result from
variations in HCA denition, population studied, and exclusion criteria. This analysis from the 19982004 Pregnancy Outcomes and Community Health Study (ve Michigan communities) includes the rst 1,053 subcohort
women (239 preterm, 814 term) with completed placental assessments. Multiple HCA denitions were constructed
by 1) varying polymorphonuclear leukocytes/high-powered eld thresholds and placenta components included and
2) using polymorphonuclear leukocyte characteristics to assign low/high maternal, fetal inammation stage and
grade. In African Americans, HCA was associated with preterm delivery before 35 weeks. The effect size was
modest for polymorphonuclear leukocytes/high-powered eld thresholds of greater than 10 and greater than 30
(odds ratios (ORs) 0.8 and 2.0); larger for greater than 100 (OR 3.2, 95% condence interval (CI): 1.4, 7.1);
strengthened after excluding medically indicated preterm deliveries (OR 4.9, 95% CI: 2.0, 11.8); and strongest
for high maternal/high fetal HCA (OR 5.6, 95% CI: 1.4, 22.1). These latter HCA criteria also produced the largest
effect size in Whites/others (OR 2.7, 95% CI: 0.3, 26.9). Among preterm deliveries before 35 weeks excluding
those medically indicated, 12% of Whites/others and 55% of African Americans had high maternal HCA. The
authors conclude that HCA denition, exclusion criteria, and race/ethnicity inuence the HCA-preterm delivery
association and that HCA contributes to preterm delivery-related ethnic disparity.
Michigan State University, Michigan Department of Community Health, and nine community hospitals. Women were
invited to participate at the time of prenatal screening. The
study included all interested women with unexplained maternal serum alpha-fetoprotein levels greater than two multiples of the median (7 percent of cohort) and a stratified
sample (ethnic-specific strata) of women with normal maternal serum alpha-fetoprotein levels. Of the 3,038 women
enrolled, 19 were lost to follow-up, leaving a cohort of
3,019. At enrollment, cohort women were interviewed and
had biologic samples collected and stored.
In a subcohort (n 1,371), assays were performed on
stored biologic samples, prenatal and labor and delivery records were abstracted, and delivered placentas were examined by a study placental pathologist. The subcohort
included all women who delivered preterm (<37 weeks),
all women with elevated maternal serum alpha-fetoprotein
(>2 multiples of the median) and term deliveries, and a sample of women with normal maternal serum alpha-fetoprotein
levels and term deliveries (i.e., 72 percent of African-American
and 23 percent of White/other women in this category). The
sampling scheme was designed to optimize available resources and maximize statistical power for studying at-risk subgroups (i.e., African Americans and women with high
maternal serum alpha-fetoprotein). Placentas were retrieved
for 1,213 (88 percent) subcohort women, and this analysis
included the first 1,053 (239 preterm, 814 term) with completed placenta assessments.
Placenta examination protocol
Placentas were formalin fixed and received gross examination using standard protocols. Nine tissue samples were
embedded in paraffin blocks for microscopic assessment:
two extraplacental membrane (membrane roll) samples;
two umbilical cord samples (one proximal and one distal
to disc insertion); and five full-thickness disc samples, one
at the cord insertion, one in central tissue that appeared
normal on gross examination, two from central tissue, and
one at the margin, these latter three representative of grossly
visible abnormalities if present. Microscopic findings were
recorded in a descriptive, computer-based instrument adapted from a prototype by Dr. Caroline Salafia. The microscopic description included details, such as the highest
number of cells/high-powered field for each leukocyte type
in each placenta tissue compartment (e.g., intervillous space,
subchorion, chorion and amnion of plate and extraplacental
membranes, chorionic vessels, and umbilical cord). While
performing microscopic examinations, the study pathologist
was blinded to gestational age at delivery, all clinical data,
and gross examination findings.
Denitions of histologic chorioamnionitis
787
Pregnancy outcome
Prevalence of HCA and its association with preterm delivery was calculated using SAS Survey Freq and Survey
Logistic procedures, respectively (54). Weights were applied to reflect oversampling of high maternal serum alpha-
3536
weeks
(n 161)
37 weeks
(n 814)
No.
%y
No.
%y
No.
%y
<20
14
18
22
14
131
16
2029
43
55
92
57
457
56
30
21
27
47
29
226
28
16
10
89
11
22
14
75
25
32
47
29
228
28
>12
40
51
76
47
422
52
Race/ethnicity
Whites
41
53
107
66
420
52
African Americans
28
36
40
25
335
41
11
14
59
Yes
41
53
85
53
441
54
No
37
47
75
47
373
46
No previous livebirth
39
50
60
37
334
41
30
39
82
51
449
55
11
19
12
31
1519
18
23
29
18
107
13
2024
54
69
107
66
587
72
2527
25
16
120
15
Others
Medicaid insurance
Parity/preterm delivery
history
DISCUSSION
12
789
FIGURE 1. Prevalence of histologic chorioamnionitis (HCA) by race/ethnicity and gestational week at delivery, Pregnancy Outcomes and
Community Health (POUCH) Study, 19982004. AD compare different criteria used to dene HCA: A and C, polymorphonuclear leukocytes
evaluated in plate, cord, and extraplacental membranes in Whites/others and African Americans, respectively; B and D, polymorphonuclear
leukocytes evaluated in extraplacental membranes only in Whites/others and African Americans, respectively. Prevalences are weighted to
account for the subcohort sampling design. HCA was considered present if the highest number of polymorphonuclear leukocytes/high-powered
eld (PMNL/hpf) observed in any tissue component was equal to or greater than the dened cutoff (threshold). The lowest threshold was greater
than zero PMNL/hpf and an inammatory pattern.
791
TABLE 2. Variation in denition of histologic chorioamnionitis and its association with preterm delivery at 3536 weeks and at less
than 35 weeks, Pregnancy Outcomes and Community Health Study,* 19982004
Preterm delivery at 3536 weeksz
Threshold
polymorphonuclear
leukocytes/high-powered
eld for histologic
chorioamnionitisy
Cord plate
extraplacental
membrane
Extraplacental
membrane
Extraplacental
membrane
Cord plate
extraplacental
membrane
95%
condence
interval
Extraplacental
membrane
95%
condence
interval
Odds
ratio
95%
condence
interval
Odds
ratio
95%
condence
interval
Odds
ratio
95%
condence
interval
Odds
ratio
95%
condence
interval
Odds
ratio
>0
0.4
0.3, 0.6
0.4
0.3, 0.7
0.1
0.1, 0.3
0.2
0.1, 0.5
0.2
0.1, 0.4
0.4
0.2, 1.0
>10
0.4
0.3, 0.6
0.5
0.3, 0.8
0.2
0.1, 0.3
0.3
0.1, 0.7
0.3
0.1, 0.6
0.4
0.1, 1.2
>30
0.5
0.3, 0.9
0.6
0.3, 1.2
0.2
0.1, 0.6
0.2
0.1, 1.0
0.3
0.1, 1.1
0.5
0.1, 2.0
>100
0.7
0.3, 1.7
0.5
0.1, 1.6
0.5
0.1, 2.3
0.8
0.2, 3.5
1.1
0.2, 4.8
1.6
0.4, 7.1
>0
0.3
0.1, 0.6
0.4
0.2, 0.9
0.3
0.1, 0.6
1.0
0.4, 2.1
0.6
0.2, 1.7
2.0
0.7, 5.2
>10
0.5
0.2, 0.9
0.6
0.3, 1.3
0.8
0.3, 1.7
2.0
0.9, 4.3
2.5
0.6, 4.0
4.0
1.5, 10.2
Odds
ratio
Whites/others
African Americans
0.5
0.2, 1.1
0.7
0.3, 1.6
1.5
0.7, 3.3
1.3
0.6, 3.0
2.5
1.0, 6.0
2.0
0.8, 4.6
>100
0.9
0.3, 2.2
1.3
0.5, 3.2
3.2
1.4, 7.1
2.9
1.2, 7.0
4.9
2.0, 11.8
4.1
1.6, 10.4
>30
Maternal inammation
HCAz severity
Whites/others
No HCA (referent)
Low stage/low grade
Low stage/high grade
High stage/low grade
High stage/high grade
Total
African Americans
No HCA (referent)
Low stage/low grade
Low stage/high grade
High stage/low grade
High stage/high grade
Total
Fetal inammation
No. of
preterm
deliveries
No. of
term
deliveries
Odds
ratio
70
26
7
2
10
115
183
213
52
6
25
479
0.4
0.3
1.2
1.0
0.2,
0.1,
0.2,
0.4,
14
11
5
1
17
48
94
146
40
7
48
335
0.5
0.7
0.9
2.2
0.2,
0.2,
0.1,
1.0,
Maternal-fetal combination
HCA severity
No. of
preterm
deliveries
No. of
term
deliveries
Odds
ratio
0.6
0.8
6.4
2.4
No HCA (referent)
Low stage/low grade
Low stage/high grade
High stage/low grade
High stage/high grade
Total
70
34
5
1
5
115
183
231
30
19
16
479
0.4
0.3
0.2
0.8
0.3,
0.1,
0.02,
0.3,
1.1
2.3
8.2
5.0
No HCA (referent)
Low stage/low grade
Low stage/high grade
High stage/low grade
High stage/high grade
Total
14
17
2
2
13
48
94
159
27
22
33
335
0.7
0.6
0.7
2.0
0.3,
0.1,
0.1,
0.9,
95%
condence
interval
HCA severity
No. of
preterm
deliveries
No. of
term
deliveries
Odds
ratio
0.7
1.0
1.2
2.6
No HCA (referent)
Low maternal/low fetal
Low maternal/high fetal
High maternal/low fetal
High maternal/high fetal
Total
70
32
1
8
4
115
183
255
10
25
6
479
0.4
0.3
0.9
1.9
0.2,
0.04,
0.4,
0.4,
0.6
2.4
2.2
8.1
1.4
2.7
3.2
4.9
No HCA (referent)
Low maternal/low fetal
Low maternal/high fetal
High maternal/low fetal
High maternal/high fetal
Total
14
14
2
7
11
48
94
172
14
36
19
335
0.5
0.7
1.4
3.2
0.2,
0.1,
0.5,
1.2,
1.1
3.6
3.9
8.3
95%
condence
interval
95%
condence
interval
TABLE 4. Associations between maternal and fetal inammatory responses and preterm delivery (<35 weeks), excluding medically indicated preterm delivery, Pregnancy
Outcomes and Community Health Study,* 19982004y
Maternal inammation
HCAz severity
No. of
term
deliveries
95%
condence
interval
Odds
ratio
15
8
0
1
2
26
183
213
52
6
25
479
0.5
0
2.7
1.2
0.2, 1.3
5
3
2
1
11
22
94
146
40
7
48
335
0.3
1.0
2.7
4.6
0.1,
0.2,
0.3,
1.4,
0.3, 26.9
0.2, 5.7
1.6
5.7
28.7
15.0
Maternal-fetal combination
HCA severity
No. of
preterm
deliveries
No. of
term
deliveries
95%
condence
interval
Odds
ratio
No HCA (referent)
Low stage/low grade
Low stage/high grade
High stage/low grade
High stage/high grade
Total
15
9
0
1
1
26
183
231
30
19
16
479
0.5
0
0.7
0.9
0.2, 1.3
No HCA (referent)
Low stage/low grade
Low stage/high grade
High stage/low grade
High stage/high grade
Total
5
6
2
2
7
22
94
159
27
22
33
335
0.7
1.6
2.0
3.7
0.2,
0.3,
0.3,
1.0,
0.1, 6.3
0.1, 7.9
2.5
9.6
11.6
13.4
HCA severity
No. of
preterm
deliveries
No. of
term
deliveries
Odds
ratio
No HCA (referent)
Low maternal/low fetal
Low maternal/high fetal
High maternal/low fetal
High maternal/high fetal
Total
15
8
0
2
1
26
17,283
255
10
25
6
479
0.4
0
1.2
2.7
0.2, 1.0
No HCA (referent)
Low maternal/low fetal
Low maternal/high fetal
High maternal/low fetal
High maternal/high fetal
Total
5
4
1
6
6
22
94
172
14
36
19
335
0.4
1.4
3.6
5.6
0.1,
0.1,
1.0,
1.4,
Am J Epidemiol 2007;166:786794
Whites/others
No HCA (referent)
Low stage/low grade
Low stage/high grade
High stage/low grade
High stage/high grade
Total
African Americans
No HCA (referent)
Low stage/low grade
Low stage/high grade
High stage/low grade
High stage/high grade
Total
Fetal inammation
No. of
preterm
deliveries
95%
condence
interval
0.2, 5.7
0.3, 26.9
1.7
13.5
13.4
22.1
TABLE 3. Associations between maternal and fetal inammatory responses and preterm delivery (<37 weeks), excluding medically indicated preterm delivery, Pregnancy
Outcomes and Community Health Study,* 19982004y
ACKNOWLEDGMENTS
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Am J Epidemiol 2007;166:786794