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American Journal of Epidemiology

The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health.
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Vol. 166, No. 7


DOI: 10.1093/aje/kwm168
Advance Access publication July 11, 2007

Original Contribution
Histologic Chorioamnionitis and Preterm Delivery

Claudia Holzman1, Ximin Lin1, Patricia Senagore2, and Hwan Chung1


1
2

Department of Epidemiology, Michigan State University, East Lansing, MI.


Department of Physiology, Michigan State University, East Lansing, MI.

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.

Preterm birth is a major cause of infant mortality and


morbidity (13) and is associated with long-term adverse
sequelae (e.g., cerebral palsy and sight, hearing, and learning problems) (47). The risk of preterm delivery is inversely related to indices of social class in most studies
(811), but the reasons for this remain unclear. In the United
States, African Americans have had consistently higher preterm delivery rates compared with those in Whites (1214),
even in studies attempting to adjust for social class inequalities through study design (1517) or by statistical modeling
with relevant covariates (1820). Undoing these social class
and race/ethnic disparities is an important goal and drives
many lines of inquiry into preterm delivery.

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).

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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.

Histologic Chorioamnionitis and Preterm Delivery

MATERIALS AND METHODS


Study population

The Pregnancy Outcomes and Community Health (or


POUCH) Study recruited pregnant women from August
1998 to June 2004 from 52 clinics in five Michigan communities. Women were enrolled in gestational weeks 15
through 27 (87 percent before week 25). Inclusion criteria
were singleton pregnancy with no known congenital anomaly, maternal age of 15 or more years, maternal serum alphafetoprotein screen in gestational weeks 1522, no prepregnancy diabetes mellitus, and proficiency in English. The
study received approval from institutional review boards at
Am J Epidemiol 2007;166:786794

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

HCA definitions were constructed to parallel those found


in the literature on HCA and preterm delivery. One set of
definitions incorporated variations in placental tissue components (i.e., cord, plate, and extraplacental membrane; extraplacental membrane only) and polymorphonuclear
leukocyte threshold (i.e., at least one high-powered field

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Some studies have examined only preterm placentas (26, 32,


33), and others have included preterm and term placentas
assessed for clinical indications (34, 35) with the potential
for selection bias. In studies comparing term and preterm
placentas, odds ratios for HCA have ranged from 0.8 to 5.9
(23, 34, 3643). This wide range may be due, in part, to
differences in maternal characteristics, excluded subgroups
(e.g., hypertensives, medically indicated deliveries), preterm
category (e.g., early vs. all preterm), and HCA definition.
Throughout the preterm delivery literature, HCA case
definitions have differed markedly. Most studies can be
grouped into one of two categories: those that have used
inflammatory cell thresholds (i.e., polymorphonuclear leukocytes/high-powered field) (24, 38, 4348) and those that
have incorporated a complex HCA grading and/or staging
approach (4951). Within the first category, HCA criteria
have varied with respect to 1) the tissue components included, for example, placental disc, extraplacental membranes, and cord (33, 42, 47, 52), disc only (24, 25, 38, 40,
53), or extraplacental membranes only (41, 43, 44, 48); 2)
threshold, for example, any inflammation (25, 33, 34, 42,
52, 53), greater than five polymorphonuclear leukocytes/
high-powered field (24, 38, 47), and greater than 10 polymorphonuclear leukocytes/high-powered field (43, 45, 46,
48); and 3) number of high-powered fields that must exceed
the threshold (43, 46, 48). In the second category, the detailed systems of staging/grading have also varied. Typically
these protocols document polymorphonuclear leukocyte location, density, and degeneration to estimate intensity and
progression (i.e., grade and stage) (4951) and, in some instances, to distinguish fetal from maternal inflammatory response (50). Differences across studies in HCA definition,
population, and exclusion criteria make it difficult to disentangle the influences of specific variations on study results.
In the community-based, prospective Pregnancy Outcomes and Community Health Study, delivered placentas
from a subset of women (subcohort) were assessed by a study
pathologist using a detailed descriptive rather than diagnostic approach. This protocol permitted construction of several
commonly used HCA definitions within a single sample to
determine how these definitions affect associations between
HCA and preterm delivery. In addition, it provided an
opportunity to examine modification of the HCA-preterm
delivery association by factors such as preterm subgroup,
exclusion criteria, and race/ethnicity.

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788 Holzman et al.

Pregnancy outcome

Gestational age at delivery was calculated by use of the


date of the last menstrual period or gestational age estimate
from ultrasound if the last menstrual period and ultrasound
estimate differed by more than 2 weeks. The last menstrual
period-based estimate was similar (within 2 weeks) to the
ultrasound-based estimate at less than or equal to 20 weeks
in 64 percent of the cohort and to the ultrasound-based estimate at 2125 weeks in an additional 12 percent of the cohort. Ultrasound-based estimates were used for 18 percent of
the cohort with absent or conflicting last menstrual periodbased estimates. In the remaining 6 percent, only the last
menstrual period-based estimates were available. Two abstractors, a physician and a study labor-and-delivery nurse,
independently reviewed subcohort prenatal and labor and
delivery records to identify medically indicated preterm deliveries. Disagreements were resolved through reexamination of medical records. Medically indicated preterm
delivery was defined as delivery before 37 weeks that begins
by induction or cesarean section in the absence of spontaneous labor (cervix dilated 2 cm and regular contractions) or
rupture of membrane as an initiating event.
Analytical approach

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-

fetoprotein into the cohort and the subcohort sampling


scheme. Odds of HCA in term deliveries were compared
with those in preterm deliveries at 3536 weeks and before
35 weeks by use of various HCA definitions in race/ethnicspecific models. Analyses were repeated after removing all
medically indicated preterm deliveries, a group delivered
early most often because of maternal vascular disease and
rarely HCA. These models were constructed to examine
variation in effect size for the association between HCA
and preterm delivery in relation to factors that are inconsistent across studies, that is, HCA definition, race/ethnicity,
gestational weeks of the preterm delivery, and inclusion/
exclusion of medically indicated preterm delivery.
For both maternal and fetal inflammatory responses,
stages 13 and grades 14 were dichotomized into low
(i.e., one or two) and high (i.e., three or more), and a fivelevel HCA severity variable was created: no HCA (referent); low grade/low stage; low grade/high stage; high grade/
low stage; and high grade/high stage. The two five-level
variables representing maternal and fetal inflammatory responses were each incorporated into separate models to assess their association with preterm delivery. In a final model,
maternal and fetal inflammatory responses were combined
into a single HCA severity variable. The cutpoints for dichotomizing low and high responses were based on associations with preterm delivery in the maternal-specific and
fetal-specific models. The maternal high inflammatory
response was stage 3 or higher and any grade, and low
was stage 1 or 2 and any grade. The fetal high inflammatory response was stage and grade 3 or higher, and
low was stage or grades 12. The new five-level variable
for maternal/fetal inflammation was as follows: no HCA
(referent); low maternal/low fetal; low maternal/high fetal;
high maternal/low fetal; and high maternal/high fetal.
RESULTS

The maternal characteristics of this subcohort sample are


presented in table 1 without sampling weights; therefore, the
overall prevalences and differences between term and preterm in this table do not reflect those in the entire cohort. In
this subcohort sample, 54 percent were insured by Medicaid,
38 percent were African Americans, and a small percentage
was other ethnic minorities. In the following analyses, sampling weights were used, and the other ethnic group was
combined with Whites because HCA prevalence in the
other group more closely paralleled that in Whites than
that in African Americans.
HCA prevalence in term deliveries ranged from 85 percent
down to 7 percent and in preterm delivery from 63 percent
down to 4 percent, depending on the polymorphonuclear
leukocytes/high-powered field threshold used to define
HCA (figure 1). Overall, the prevalence dramatically decreased as the threshold increased, and for most thresholds,
the HCA prevalence was lower when based on examination
of extraplacental membranes only versus examination of
all placental tissue compartments (figure 1). In term and preterm deliveries, the HCA prevalence was higher in African
Americans compared with that in Whites/others, and these
race/ethnic differences increased as the polymorphonuclear
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with a polymorphonuclear leukocyte inflammatory pattern;


>10 polymorphonuclear leukocytes; >30 polymorphonuclear leukocytes; and >100 polymorphonuclear leukocytes). A staging and grading system was adapted from
an approach described by Redline et al. (50). Maternal
stages 13 were assigned as follows: stage 1at least
one high-powered field with greater than 10 polymorphonuclear leukocytes in subchorionic fibrin but not in chorion or
amnion; stage 2polymorphonuclear leukocyte inflammatory pattern in chorionic plate or extraplacental membrane
chorion plus or minus amnion but no polymorphonuclear
leukocyte karyorrhexis or necrotizing inflammation; and
stage 3polymorphonuclear leukocyte inflammatory pattern in chorionic plate and/or extraplacental membrane chorion and amnion, plus karyorrhexis and/or necrotizing
inflammation. Fetal stages 13 were assigned as follows:
stage 1at least one high-powered field with a polymorphonuclear leukocyte inflammatory pattern in fetal chorionic
plate vessels but not in umbilical vessels; stage 2polymorphonuclear leukocyte inflammatory pattern in umbilical
vessels, confined to the vessel wall; and stage 3polymorphonuclear leukocyte inflammatory pattern in umbilical
vessels extending into Whartons jelly. Maternal grade and
fetal grade were based on maximum polymorphonuclear
leukocytes/high-powered field, that is, grade 1 (110
polymorphonuclear leukocytes), grade 2 (1130 polymorphonuclear leukocytes), grade 3 (31100 polymorphonuclear leukocytes), and grade 4 (>100 polymorphonuclear
leukocytes).

Histologic Chorioamnionitis and Preterm Delivery

TABLE 1. Maternal characteristics of the subcohort with


completed placenta assessments (n 1,053), Pregnancy
Outcomes and Community Health Study,* 19982004
Gestational week at delivery
<35 weeks
(n 78)

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

Maternal age (years)

Maternal education (years)


<12 (maternal age: <20)
<12 (maternal age: 20)

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

Previous livebirth without


preterm delivery

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

Previous livebirth with


preterm delivery
Week of pregnancy at
enrollment

* Referred to as the POUCH Study.


y These are raw percentages (not weighted) in the subcohort and
do not reect distributions within the entire cohort.

leukocytes/high-powered field threshold increased (figure 1).


When cord, plate, and extraplacental membrane were examined and a polymorphonuclear leukocytes/high-powered
field threshold of greater than 30 was used to define HCA,
the prevalence of HCA in African Americans versus Whites/
others was 37 percent versus 25 percent in term deliveries, 23
percent versus 14 percent in preterm deliveries at 3536
weeks, and 46 percent versus 6 percent in preterm deliveries
before 35 weeks.
In race/ethnic-specific logistic regression models, HCA
defined by any of the polymorphonuclear leukocytes/highpowered field thresholds was not associated with preterm
delivery at 3536 weeks (table 2). HCA was significantly
related to preterm delivery before 35 weeks but only in
Am J Epidemiol 2007;166:786794

African Americans, and only when the polymorphonuclear


leukocytes/high-powered field threshold for HCA was
greater than 100 (odds ratio (OR) 3.2, 95 percent confidence interval (CI): 1.4, 7.1). After removal of the medically
indicated preterm deliveries, this association was further
strengthened (OR 4.9, 95 percent CI: 2.0, 11.8), and even
HCA defined by lower thresholds (e.g., >30 polymorphonuclear leukocytes/high-powered field) appeared related to
preterm delivery before 35 weeks in African Americans
(table 2).
By use of a staging and grading system for maternal and
fetal inflammatory response (HCA) and excluding medically indicated preterm deliveries, the association between
high maternal/high fetal inflammatory response and preterm
delivery before 37 weeks was weak and statistically nonsignificant among Whites/others (OR 1.9, 95 percent CI:
0.4, 8.1) and, again, more pronounced in African Americans
(OR 3.2, 95 percent CI: 1.2, 8.3) (table 3). The same
analytical models were repeated but this time comparing
HCA in term with that in preterm deliveries before 35 weeks
(table 4). The odds ratio estimate for high maternal/high
fetal inflammatory response increased slightly in Whites/
others (OR 2.7, 95 percent CI: 0.3, 26.9), but the confidence interval was wider because of the smaller sample size
after excluding 35- to 36-week preterm deliveries. In African Americans, preterm delivery before 35 weeks was associated with high maternal/low fetal response (OR 3.6,
95 percent CI: 1.0, 13.4) and with high maternal/high fetal
response (OR 5.6, 95 percent CI: 1.4, 22.1).

DISCUSSION

In this study, the HCA-preterm delivery relation was


strongly influenced by HCA definition, inclusion/exclusion
of preterm delivery at 3536 weeks and medically indicated
preterm delivery, and the race/ethnic group studied. Surprisingly, there has been little discussion regarding variations in
HCA definition across studies. Within studies, kappas for
interrater reliability have ranged from 0.15 to 0.83, with less
agreement for mild HCA or severity of HCA and greater
agreement for the presence of any HCA (5557). However,
in most reliability studies, the HCA definition and protocol
were standardized. Across studies, two approaches for assessing HCA predominate, one using polymorphonuclear
leukocytes/high-powered field thresholds and the other using a complex staging and/or grading scheme, with each
approach having its own set of varied definitions. Blanc
(49) first proposed three stages based on maternal polymorphonuclear leukocyte movement from subchorion to chorion
to amnion overlying the placental plate. Later classification
schemes, for example, those reported by Salafia et al. (51)
and Redline et al. (50), incorporated location, density, and
characteristics of polymorphonuclear leukocyte infiltrates.
Applying the polymorphonuclear leukocytes/highpowered field approach with low thresholds (i.e., >0 or
>10 polymorphonuclear leukocytes/high-powered field) in
the cord, extraplacental membranes, plate, or subchorion, we
observed that 5476 percent of White/other term placentas
and 6485 percent of African-American term placentas met

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12

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790 Holzman et al.

these HCA criteria. Other studies examining term placentas


have reported HCA prevalences ranging from 4 percent to
79 percent (23, 34, 3643, 51). These findings underscore
the need to compare inflammatory cells/patterns in preterm
placentas with those in term placentas to arrive at meaningful relations between HCA and preterm delivery. Previous
studies have often focused solely on HCA in preterm placentas (21, 26, 33, 45, 52), and many studies have used a low
polymorphonuclear leukocytes/high-powered field threshold to define HCA (24, 38, 47), which would have an attenuating effect on the HCA-preterm delivery association. The
high prevalence of low intensity HCA in term placentas may
mark the beginning of a maternal response to microbial
ascent during labor. In addition, infection may precipitate
delivery at any point along the gestational continuum, and
a less fulminating inflammation may adequately trigger
delivery in late gestational tissues already primed. We observed high stage/high grade fetal inflammation in 3 percent
of White/other and 10 percent of African-American term
placentas, evidence that this problem is not confined to
preterm delivery and that ethnic disparities persist at term.
For each polymorphonuclear leukocytes/high-powered
field threshold in our analyses, assessment of cord, plate,

and extraplacental membranes tended to produce a higher


HCA prevalence than that found in extraplacental membranes alone. One explanation could be empirical; the more
tissue locations sampled, the greater the likelihood of finding
a locus with a high number of polymorphonuclear leukocytes/high-powered field. However, these results highlight
the challenges of comparing HCA results across studies that
include only extraplacental membranes (23, 41, 43, 48), only
disc (24, 25, 38, 40, 53), or both (26, 34, 36, 46).
In our HCA stage/grade analyses that excluded medically
indicated preterm deliveries, all but one placenta delivered
before 35 weeks with high fetal response also had high
maternal response. However, among term placentas with
high fetal response, a substantial proportion (10 of 16
White/others, 14 of 33 African American) had a low maternal response. This may reflect the ability of a more mature
fetus to mount a robust immune response earlier in the process of exposure to infection and possibly discordance
in maternal and fetal immune responsiveness.
We also observed a higher prevalence of HCA in African
Americans compared with that in Whites/others within
term, preterm delivery at 3536 weeks, and preterm delivery
before 35 weeks. In deliveries before 35 weeks that were not
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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.

Histologic Chorioamnionitis and Preterm Delivery

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

Preterm delivery at <35 weeksz


excluding medically indicated
preterm delivery

Preterm delivery at <35 weeksz


Cord plate
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

* Referred to as the POUCH Study.


y Histologic chorioamnionitis was considered present if the highest number of polymorphonuclear leukocytes/high-powered eld observed in
any tissue component was equal to or greater than the dened cutoff (threshold).
z Term deliveries are the referent group, and all odds ratios and 95% condence intervals incorporate cohort/subcohort sampling weights as
applicable; the column subtitles denote tissue components used to assess evidence of histologic chorioamnionitis.
Greater than zero polymorphonuclear leukocytes/high-powered eld and an inammatory pattern.

medically indicated, 12 percent of White/other placentas


and 55 percent of African-American placentas showed evidence of a high maternal inflammatory response. The largest
HCA odds ratio for very preterm delivery was 5.6 in African
Americans but only 2.7 and not statistically significant in
Whites/others. These results are in agreement with many
(21, 5860), but not all (40), previous studies showing that
HCA is a key element in race/ethnic disparity in early preterm delivery. The findings also suggest that the importance
of an HCA pathway to preterm delivery could vary considerably with the population studied. Often reports on HCA
and preterm delivery come from inner-city teaching hospitals with large proportions of minority populations and
urban poor (38, 59, 60).
Among the African-American deliveries in our study,
three factors increased the effect size of the association
between HCA and preterm delivery: 1) higher polymorphonuclear leukocytes/high-powered field threshold or more
advanced maternal and fetal inflammatory response; 2) restricting the outcome to preterm delivery before 35 weeks;
and 3) exclusion of medically indicated preterm delivery.
Thus, even studies with similar populations may be expected to produce different results if these factors are not
consistent. Our findings are in agreement with previous research showing that inflammation/infection plays a larger
role in the earliest preterm delivery (2126) and in preterm
delivery that begins with spontaneous labor or rupture of
membranes (21, 32, 33) as compared with medically indicated preterm delivery.
Am J Epidemiol 2007;166:786794

One study limitation was sample size. We had 26 White/


other and 22 African-American deliveries before 35 weeks
after excluding medically indicated preterm deliveries.
Based on the low prevalence of high maternal/fetal inflammatory response in the White/other placentas, one would
need at least 324 nonmedically indicated preterm deliveries
before 35 weeks in Whites/others to have 80 percent power
to detect an odds ratio of 2.0. We also had too few extreme
preterm deliveries, that is, before 33 weeks, to separately
examine this subgroup. The importance of HCA may be
more similar across race/ethnic groups in the before-33week deliveries compared with the marked race/ethnic disparities that we observed in the before-35-week deliveries.
Another limitation is one inherent in much of the literature
on HCA. We used the location of polymorphonuclear leukocytes to infer an inflammatory infiltrate and direction of
chemotaxis, and we had no additional immunohistologic
staining or RNA microarray evidence that these polymorphonuclear leukocytes were recruited as part of an inflammatory process.
Despite these limitations, this study also had multiple
strengths. The sample was socioeconomically diverse, and
participants were recruited from a large number of prenatal
clinics that serve urban, suburban, and rural women with
low- and high-risk pregnancies, thereby improving the generalizability of findings. During gross and histologic examinations, the pathologist was unaware of the gestational week
at delivery, pregnancy complications, delivery circumstances, and race/ethnicity associated with each placenta,

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>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

* Referred to as the POUCH Study.


y All odds ratios and 95% condence intervals incorporate cohort/subcohort sampling weights as applicable.
z HCA, histologic chorioamnionitis.

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,

* Referred to as the POUCH Study.


y All odds ratios and 95% condence intervals incorporate cohort/subcohort sampling weights as applicable.
z HCA, histologic chorioamnionitis.

Downloaded from http://aje.oxfordjournals.org/ by guest on November 20, 2014

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

792 Holzman et al.

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

Histologic Chorioamnionitis and Preterm Delivery

ACKNOWLEDGMENTS

This study was supported by funding from the following:


National Institute of Child Health and Human Development
and the National Institute of Nursing Research (grant R01
HD34543), March of Dimes Foundation (grants 20FY01-38
and 20-FY04-37), Thrasher Research Foundation (grant
02816-7), and Centers for Disease Control and Prevention
(grant U01 DP000143-01).
The authors would also like to thank the Prematurity
Study Group, project director Dr. Bertha Bullen, and
physician abstractors Dr. Joseph Marshall, Dr. Lynn Reuss,
and Dr. Judith Suess.
Conflict of interest: none declared.

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