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Placental Vascular Pathology Findings and Pathways to
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Rachel L. Kelly

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Placental Vascular Pathology Findings and Pathways to Preterm Delivery

By

Rachel L. Kelly

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

MASTER OF SCIENCE
Epidemiology

2009

ABSTRACT
Placental Vascular Findings and Pathways to Preterm Delivery
By

Rachel L. Kelly

The authors examined the association between groups of placental vascular
findings and subtypes of preterm delivery in a subcohort (239 preterm, 814 term) of the
Pregnancy Outcomes and Community Health (POUCH) Study. Thirty-nine placental
vascular variables from microscopic examinations were grouped into 5 a priori
constructs: Matemal-vascular obstructive (MV-O), maternal-vascular disturbance of
integrity (MV-I), matemal-vascular developmental (MV-D), fetal-vascular obstructive
(FV-O), and fetal-vascular disturbance of integrity (F V-I). Scores were created by
adding the number of positive findings in each construct and the distribution of total
scores for each construct in term placentas was used to create cutpoints of ‘high’ (top
quartile) and ‘not high’ (bottom 3 quartiles). Concordance between pairs of constructs
was low (-0.0l to 0.17). In polytomous logistic regression models that included all 5
constructs and all maternal characteristics, the PTD risk for ‘high’ vascular score was
compared to that of ‘not high’. Strong associations between medically indicated PTD
(MI-PTD) at < 35 weeks and high scores for MV-O, MV-I, MV-D, and FV-I were found.
A second series of analyses placed all vascular constructs in a single model after
excluding Ml-PTD. These models showed significant interactions between MV-I, MV-
D, and FV-I. MV-O and FV-O were not related to spontaneous PTD. Our results suggest
that separating vascular constructs may be informative as we move forward to examine

biomarkers and upstream and downstream risk factors in greater depth.

To Ted—Your love and encouragement has brought me to where I am. Thank you.

iii

ACKNOWLEDGMENTS '

I would like to thank Claudia Holzman for her support, guidance and everlasting patience
during my tenure in the Epidemiology department. Her leadership has meant a

tremendous amount to me both personally and academically.

I would also like to thank the other members of my graduate committee. First, Dr.
Patricia Senagore for taking the time to teach me about an extraordinary field of medicine
and the extraordinary placenta. She has instilled in me the utmost respect for the practice
of pathology. Second, I would like to thank Dr. Hwan Chung for his patience and
insights during the analytic portion of this endeavor. Last, I would like to thank J ianling

Wang and Dr. MH Rahbar for their help with the data analysis.
I would also to thank the entire POUCH team. It has been a true pleasure working with
this wonderful group of people over the last 3 years. I appreciate all the help and

kindness during this process.

I would like to give a very special thanks to my wonderful husband for his support and

love. I could not have done any of this without you.

iv

TABLE OF CONTENTS

LITERATURE REVIEW ............................................................................ l
PLACENTAL VASCULAR PATHOLOGY FINDINGS AND PATHWAYS TO
PRETERM DELIVERY ............................................................................. 16
AIMS AND HYPOTHESES ....................................................................... 17
MATERIALS AND METHODS ................................................................. l8
ANALYTIC APPROACH ......................................................................... 22
RESULTS ............................................................................................. 24
DISCUSSION ........................................................................................ 26
CONCLUSIONS .................................................................................... 30
REFERENCES ....................................................................................... 45

LIST OF TABLES

Table 1. Studies using individual placental pathology findings ............................... 32
Table 2. Studies using grouped placental pathology findings ................................. 33

Table 3. Comparison of groupings of placental vascular pathology.................. ............34
Table 4. Studies testing intra/interrater reliability ................................................ 35

Table 5. Maternal characteristics and pregnancy outcome in the sub-cohort with
completed placental assessments (N =1053) ...................................................... 36

Table 6a. Spearman’s rank correlations (p values) between pathology-based vascular
construct scores ........................................................................................ 37

Table 6b. Kappa coefficients for co-occurrence of high pathology-based vascular
construct scores ...................................................................................... 37

Table 7. Maternal characteristics in relation to pathology-based vascular constructs
(weighted percentages, N=1053) ................................................................... 38

Table 8. Associations between vascular constructs and preterm delivery (N =1 053);
unadjusted odds ratios (95% CI) ............................................................... 39-41

Table 9. Associations between vascular constructs and medically-indicated PT D;
=890) ................................................................................................ 42

Table 10. Associations between vascular constructs and spontaneous PTD
(N =977) ................................................................................................. 43

vi

LIST OF FIGURES

Figure 1. Structure of the placenta ................................................................ 44

vii

LITERATURE REVIEW
Preterm delivery (PTD), defined by the World Health Organization as delivery

occurring before 37 completed weeks of pregnancy, is a major cause of poor maternal
and fetal outcomes. With an occurrence rate of 12—13% in the United States, PTD
accounts for up to 50% of neonatal mortality (1-4). Furthermore, it is consistently cited
as the leading cause of neonatal and African American infant deaths(1, 4). Since 1995,
the rate of infant mortality has decreased, most likely due to improvements in neonatal
care(4, S). In contrast, the rate of infant mortality and adverse outcomes attributed to
PTD has risen, which parallels an increase in very low birth weight deliveries during this

period (6).

Cognitive, educational, and developmental impairments, as well as intracranial
hemorrhage are consistently linked to very early PTD (<32 weeks gestation) (l , 5, 7).
More recently, mild and moderate PTD (34-36 weeks) have been related to lower
cognitive scores and increased risk for ADHD, as well as postneonatal death due to
infection, SIDS, and asphyxia when compared to infants delivered at term (5, 8). PTD
also accounts for one in five cases of children born with some form of mental
retardation(9). The serious ofien life-threatening morbidities and low birth weight of
preterm neonates put an economic strain on the health care system, since they require
costly neonatal intensive care unit services and frequent unscheduled acute care visits in

the first year of life(10).

Previous studies have shown a relation between low socioeconomic status and
PTD (1 1-14). Women living in disadvantaged areas are more likely to have a myriad of

health problems that complicate pregnancy, as well as increased rates of preterm birth

and infant mortality(l 1-14). These observations have persisted over time, even after
controlling for lack of access to health care (15). In addition to socioeconomic status,
race is also an important risk factor for PTD. African Americans have higher PTD rates
than whites, even after controlling for possible confounders such as differences in social
class and Medicaid status(6, 16-19). Furthermore, non-Hispanic blacks are nearly three
times more likely to deliver very preterm (<28 weeks) than white women (6). Hispanic
women, although underserved, have traditionally had rates similar to whites of PTD and
very low birth weight (V LBW)(4). However, Hispanic women have seen an increase in
both preterm delivery (11% since 1990) and VLBW (7.4% in 1990 to 8.5% in 2005) in

the last 20 years (4, 6).

Previous preterm delivery increases the risk of PTD in subsequent pregnancies
(20-23). This pattern is especially evident with each additional preterm delivery at less
than 35 weeks (21, 24). Subtype of PTD also appears to be an important factor in
determining recurrence. Women with histories of either spontaneous PTD or medically
indicated PTD are more likely to subsequently deliver in the sarne manner(20, 25). This
may reflect an ongoing maternal condition, placentation abnormality, or even increased

observation by physicians alerted to a patient’s complication history.

Recurrence rates are not consistent across social classes and racial groups, and are
higher in African Americans than in whites (24, 26). Possible explanations for this
finding suggest environmental factors, such as maternal stress and lack of maternal
support systems, and biological factors like bacterial vaginosis (27). As stated, previous

PTD is an important risk factor for PTD, yet it’s prognostic utility is unclear. A study of

15,000 women followed over two or more pregnancies showed that previous PTD could

predict only 10% of preterm births in this group (21).

Subtypes of PTD
PTD can be divided into multiple subtypes based on presentation at time of birth.

The most common subtypes are: 1) spontaneous labor beginning before rupture of
membranes (PTL); 2) premature rupture of membranes before the onset of labor
(PROM); and 3) medically-indicated PTD without rupture of membranes or spontaneous
labor (MI-PTD). Spontaneous preterm delivery, defined as labor beginning before 37
completed weeks of gestation with or without rupture of membranes, accounts for at least
two-thirds of preterm deliveries each year(28). PTL accounts for 40-45%, while PROM
accounts for 25-30% of PTD yearly(3). While PTL and PROM are separate clinical
scenarios, previous studies suggest that they may share common etiologies and often can
be grouped as spontaneous PTD(29, 30). Medically indicated PTD accounts for the rest
of PTD cases. This group is primarily comprised of pregnancies complicated with
preeclampsia, pregnancy-induced hypertension, poor fetal growth and evidence of fetal

distress or hypoxia (3]).

PTD can also be divided by gestational age. The majority of preterm deliveries
occur at 34-36 weeks gestation, comprising 60-70% of all PTD (3). The nearly 30%
increase in PTD in the last 25 years can be attributed to this group (28). PTD occurring
before 32 weeks gestation are frequently related to acute infection/inflammation and
bleeding (3, 32). Studies using very early PTD (<32 weeks) have shown a strong
correlation between acute inflammatory lesions in the placenta and PROM and PTL(20,

32-34). Placental lesions related to decidual hemosiderin (i.e. evidence of bleed), such as

uteroplacental vascular thrombosis, absence of physiologic spiral artery change, and
villous fibrosis, have also been linked to preterm delivery at less than 32 weeks(35). In
contrast, studies using a PTD cut-off of 37 weeks have shown stronger relationships
between spontaneous PTD and specific types of vascular placental pathology (lack of

physiologic change of spiral arteries and placental infarcts) (36-38).

Suspected Causes of PT D
The cause of the majority of deliveries before 37 weeks has not been established.

PTD is postulated to result from a variety of pathological processes that include ischemia,
inflammation/infection, short cervical length, uterine overdistention, and hormonal
disorders (2). There have been many studies examining the risk factors for PTD.
Despite the medical community’s best efforts to reduce the number of preterm births in
the United States, PTD rates continue to increase (3 9). Heretofore, clinical interventions
aimed at decreasing individual risk factors have been unsuccessful, primarily because

they do not address underlying pathologic processes (39).

The placenta has become a focus of investigation to help us better understand the
underlying mechanisms resulting in PTD. Two placental pathways to preterm delivery
have been identified, namely vascular and inflammatory (36, 40). Infection is implicated
in 25-40% of preterm births (41 , 42). Infection and acute inflammation lead to premature
rupture of membranes and spontaneous preterm labor, most likely by triggering an
inflammatory cascade(3). There are four pathways to intrauterine infection: ascending
from the lower genital tract; descending from the upper genital tract; hematogenous
spread through the placenta from maternal blood; and introduction during a procedure

such as amniocentesis (29). Infections originating in the genital tract are the most

common pathways to intrauterine infection (29) and are most consistently associated with

preterm labor and preterm PROM(29, 32, 42).

Much of the research has focused on infectious/ inflammatory causes of PTD,
although these causes account for less than half of all preterm births (43). An
infection/ inflammation pathway cannot adequately explain vascular complications
leading to PTD such as gestational hypertension, preeclampsia, IUGR, and overt
bleeding. Thus, vascular pathways to PROM and PTL have also been proposed. The
placenta is the ideal organ to explore vascular fimction during pregnancy on both the fetal
and maternal sides. Abnormal placentation, along with uteroplacental ischemia and
hemorrhage, comprise the major proposed mechanisms for the vascular pathway to PTD
(2, 3). Specifically, uteroplacental ischemia has been proposed as a possible mechanism
for PTL and PROM in the absence of infection and inflammation (2). A number of
studies that associate maternal vascular lesions with PROM and PTL, have found
abnormal maternal decidual blood vessels changes, including failure of transformation
and vasculopathy, to be much more common in these groups than in normal, term
deliveries (36-38). The role of fetal vascular lesions in the development of PTL and
PROM has not been established and little research has focused solely on the contribution

these findings have on delivery outcomes (2).

Placental Function

The placenta is essential for fetal development and pregnancy success. It is the
first fetal organ to develop, it mediates implantation into the uterus and supports fetal
development throughout pregnancy(44). Specifically, it regulates the exchange of

nutrients and electrolytes, such as amino acids, fatty acids, carbohydrates, and vitamins,

between maternal and fetal circulations (45). It also allows for extraction of oxygen from
and the elimination of carbon dioxide and carbon monoxide to the maternal circulation by
the fetus(44). It also stimulates both maternal blood cell and blood volume production

in order to facilitate increased delivery of oxygen to the fetus (44).

Second, the placenta is the source of hormones necessary for proper fetal
development. At the beginning of pregnancy, it produces chorionic gonadotropin (beta
hCG), a hormone that induces maternal recognition of the paternal elements of the fetus
(46). In mice, this hormone inhibits the development of sepsis (46). Progesterone is
produced beginning in the 4th month to help maintain the pregnancy. Estrogenic
hormones stimulate uterine growth and development of the mammary glands.
Somatomammotropin, a growth hormone-like substance, is made throughout pregnancy

to give the fetus priority on maternal blood glucose (45).

The placenta also creates a barrier between mother and fetus, allowing some
protection from maternal antibodies, bacteria, and viruses. During pregnancy, the
decidua sequesters numerous cells of the innate immune system in an attempt to protect
the fetus (46). Macrophages, white blood cells specializing in phagocytosis of necrotic
material and invading microorganisms, comprise 20-30% of decidual cells at the site of
implantation (47, 48). These cells persist through pregnancy, producing cytotoxic agents

that destroy invading pathogens(49).

Structure of the Placenta

The placenta is predominantly a fetal organ suffused by maternal blood. It has two
tissue components—matemal and fetal (Figure 2). The fetal-placental tissue consists of

a chorionic plate into which the umbilical cord “inserts,“ and branches into consecutively

smaller blood vessels that serve as stem villi from which numerous small terminal villi
project, forming the villous tree (45). The stem and terminal villi are suspended in the
maternal intervillous space, where they are bathed in maternal blood (45). Each villus is
a fetal vessel surrounded by a thin layer of mesoderm covered by two strata of
ectodermal cells derived by the trophoblast (cytotrophoblasts and syncytiotrophoblast)

(45).

The matemal-placental tissue consists of a thin layer of decidual tissue derived
from the endometrial lining of the uterus that is in continuity with the smooth muscle
wall until separation of the placenta at delivery (45). It represents a junctional zone,
where trophoblasts anchor the villous tree and invade to transform spiral arteries (45).
The maternal intervillous circulation is established when maternal uterine blood flows in
a fountain-like fashion through enlarged transformed decidual spiral arteries into the
placental intervillous space and returns via endometrial veins (45). This flow allows for

oxygen and nutrient transfer to the fetus across chorionic villi bathed in maternal blood.

Normal development of the Placenta

The placenta develops from the trophoblast, the cells of the outer wall of the
blastocyst and the embryo from the inner cell mass (45). Shortly after conception, the
outer trophoblastic cells proliferate to form an inner layer, called the cytotrophoblast, and
an outer layer, called the syncytiotrophoblast (45). These layers later will form the

chorionic plate and the chorionic villi at about the second month post-conception (45).

As the blastocyst implants into the uterine endometrium, it stimulates a reactive
change in the cells of the endometrial stroma. These stromal cells accumulate lipid and

nutrients, thicken, and form the decidua (45). During implantation, trophoblasts

infiltrate spiral artery walls, creating thin-walled large-diameter vessels with low
resistance (50). Transformation of these vessels allows large amounts of maternal blood
to reach the intervillous space and chorionic villi (50). By 18 weeks, 30% of the vessels
are invaded and successfully converted(51). In a normal pregnancy, more than 90% are
converted by 40 weeks(Sl). At about the same time, lacunae form within the trophoblast
shell and ultimately connect, forming the intervillous space into which maternal uterine

blood will circulate (45).

Abnormal Placental Development- Maternal Side

Placental abnormalities can reflect incomplete vascular development, or
obstruction to or disruption (loss of integrity) of blood flow. On the maternal side,
vascular lesions likely begin with abnormal remodeling of spiral arteries destined to
supply oxygen and other nutrients to the placenta and fetus. In normal development,
decidual and myometrial segments of the spiral arteries are infiltrated by trophoblasts,
and this process leads to thinned walls and wide-open lumens that result in decreased
peripheral vascular resistance. Additionally there is degeneration of muscular contractile
elements needed for vasoactive agents to cause constriction (3 7, 38, 50). In some cases
of abnormal development, trophoblastic invasion of the myometrium is incomplete or too
superficial, which leads to decreased vessel compliance and a diminished capacity of the
placenta to regulate blood flow to the fetus (3 8, 52). Initially this abnormal development
is identified microscopically as a persistence of smooth muscle in the walls of spiral
arteries of the decidua basalis (basal plate) (52). Much later, these vessel walls begin to
necrose (fibrinoid necrosis), and associated inflammatory and other changes are thought

to cause thrombotic or disruptive changes that prevent optimal uterine blood flow to the

intervillous space (obstructive lesions) (51, 53). These changes are similar to those seen
in atherosclerosis, since both are related to lipoprotein deposition and the accumulation of

foam cells (i.e. lipophilic macrophages) in the walls of the vessels (51).

Histologic placental changes that reflect obstructive lesions in the maternal
decidual vasculature of the placenta may result in decreased villous perfusion later in
gestation. Lesions associated with maternal under-perfusion/placental ischemia include
the diffuse formation of syncytial knots, excess deposition of perivillous fibrin, and
villous infarctions. Syncytial knots form when transient hypoxia causes the proliferation
of irregularly shaped capillaries in terminal villi, creating a knotted appearance on the
surface of the trophoblast (54). Syncytial knotting early in pregnancy (called budding) is
a normal process that serves to increase chorionic villi surface area (54, 55). Few of
these knots exhibit apoptotic nuclei and cytoplasmic degeneration consistent with normal
cell turnover during pregnancy(54, 55). However, extended periods of underperfusion or
reduced available oxygen in the villous space will stimulate capillary proliferation and

cell turnover, leading to increased numbers of syncytial knots later in pregnancy(54, 56).

The cause of excessive perivillous fibrin deposition during times of
underperfusion is unclear. However, increased deposition leads to altered maternal blood
flow into the intervillous space (56, 57). When alterations in maternal spiral artery blood
flow cause thrombus formation and complete occlusion of one or more maternal vessels,
the villous tree in the perfirsed area is at risk for infarction (56). Spiral arteries running
through the myometrium and decidua have no collateral microcirculation, so occlusion at

any part of these end-arteries is problematic (58). Since the villous tree “floats”

suspended in maternal intervillous blood, lack of local arterial flow will cause collapse of

the space and villous tissue with ischemic necrosis (5 8).

Disruption of blood flow (loss of integrity) within the maternal vasculature can
lead to hemorrhage. Bleeding can be acute or chronic, gross or microscopic, and occur
into the decidua or retroplacental space. Hemosiderin pigment in tissues (amnion,

chorion, or decidua) may represent evidence of a previous hemorrhage (56).

Abnormal Placental Development- Fetal Side

Normal development of the fetal vasculature is a complicated process involving
many maternal, fetal, and environmental factors such as adequate oxygen perfusion,
hormones, and growth factors (59). Obstruction of fetal-placental vessels has been
related to severe adverse fetal and neonatal outcomes such as preterm delivery, IUGR,
neonatal encephalopathy and neurologic impairments (60-62). These lesions are
commonly referred to as “fetal thrombotic vasculopathy” and include lesions such as
thrombosis of fetal disc or chorionic plate vessels, avascular villi, intimal fibrin cushions,
and karyorrhexis of the fetal vessel cells (63). Vasculopathy is thought to result from
vascular stasis, hypercoagulability, and tissue damage (64). Redline has shown that
chorionic plate and disc thrombosis leads to avascular villi and has also been related to
evidence of bleeding(61 , 64). Avascular villi are clusters or segments of terminal villi
that have become small and atrophic because of a prolonged period of thrombosis with
lack of fetal blood flow (63). Intimal fibrin cushions are focal areas of sub-intimal
fibroblast proliferation in fetal vessels walls that bulge into the lumen and contain
collections of fibrin material (63). Although the etiology of this lesion is not known, it is

similar to lesions that develop in the pulmonary vasculature secondary to pulmonary

10

hypertension (63). It has also been postulated to reflect insudation of plasma through
damaged endothelium resulting from increased transmural pressure of an upstream

compression (65).

Another group of important lesions are those that represent disruption/loss of fetal
vascular integrity such as subchorionic hemorrhage, intervillous thrombus, villous
stromal hemorrhage, and villous edema. Subchorionic hemorrhage and intervillous
thrombi are considered areas of fetal to maternal bleeding in the intervillous space, in
different locations(54). Both likely represent areas where fetal villous blood becomes
admixed (“laminated”) with maternal blood in the intervillous space (54, 65). The
hemorrhage is likely due to an extravasation from the villi into the maternal space from a
site of chorionic villous damage (54). Villous stromal hemorrhage is intravillous
hemorrhage that often accompanies sudden ischemia and hemodynamic shifts in
suspected preterm abruption(65). Villous edema was originally associated with
chorioarnnionitis and acute inflammation(66); it has since been linked to antenatal
hypoxia (67). The functional significance of villous edema is that it may limit blood flow
and gas exchange by compressing the intervillous space and increasing the distance that
oxygen must diffuse to reach fetal blood (53, 59, 66). As a group, these lesions may
represent placental evidence of more generalized circulatory disturbances similarly
affecting other body/organ tissues within the fetus, or matemal-placental vascular

disturbances that secondarily have damaged fetal vessels.

Although there is lack of consensus on what pathology findings are most
appropriate to include in each conceptual grouping outlined above, attempts have been

made to create an organizational tool to standardize recording and interpretation of

11

placental findings. Specifically, Raymond Redline, a leading pathologist in this field, has
created a conceptually driven collection of vascular pathology constructs using the same
5 groups discussed here. An abridged version of Dr. Redline’s placental pathology tool is

used in this study to categorize our 39 placental vascular findings.

Previous Studies of Placental Vascular Pathology and PT D

A number of approaches have been used to evaluate vascular placental pathology
in epidemiological studies of preterm delivery. One approach has been to evaluate
individual lesions. Table 1 compares four studies that focused on one lesion as an
indicator of a pathologic process occurring in the placenta. Three of the four studies
focus on maternal vascular findings and draw conclusions between abnormal

development and resulting placental hypoxia (37, 38, 68).

Although these studies illustrate the proposed pathophysiology to some degree,
they fail to provide a full explanation of the processes leading to PTD. Due to the
restricted scope of each study, there is insufficient information available to determine
whether the finding used is the most sensitive and specific indicators of a greater

placental pathological processes, or simply circumstantial, and therefore, irrelevant.

A much more common method used to study placental vascular pathology is to
employ clusters of lesions that have been grouped using empirical knowledge. Typically,
studies utilizing groupings of vascular lesions suggest that vascular pathology is related
to PTD(69), PTL (36, 37, 70), preterm PROM (36, 38), preeclampsia(71, 72), and
IUGR(33, 73, 74). More generally, previous studies have consistently reported a
relationship between PTD and ischemic injury and abnormal development of the

placental vasculature (36, 37, 69, 75). This has been extensively studied in preeclamptic

12

patients in addition to women presenting with premature rupture of membranes (37, 38,
71). Salafia, et al., have also shown that evidence of decidual disease (decidual
thrombosis, failure of physiologic change, fibrinoid necrosis of the decidual vessels) is
related more to medically indicated PTD than to spontaneous delivery(74). Most
recently, Ogunyemi, et al., showed that placental vasculopathy (placental infarcts, villous
fibrosis, vascular intimal hypertrophy, and fibrinoid necrosis) was significantly related to

medically indicated PT D and was negatively correlated to spontaneous PTD(76).

Table 2 highlights four studies using conceptually created groupings of placental
vascular lesions to evaluate the role of placental vascular pathology in preterm delivery.
All of these studies use histopathologic diagnoses such as maternal/decidual vasculopathy
and uteroplacental vascular changes as vascular pathology constructs (Table 3). Said
constructs contain many of the same placental vascular findings such as failure of
transformation of decidual vessels, syncytial knots, and fibrinoid necrosis. Each study

also contains unique findings, which makes comparison of results challenging.
General limitations of previous studies

Comparison of previous studies is difficult because: 1) there is little consistency
in placental vascular findings used to define maternal vascular outcomes such as
uteroplacental and decidual vasculopathy; 2) a variety of PTD outcomes and gestational
ages are used across studies, 3) study samples and reference groups are variable, and 4)
agreement of what constitutes a positive finding in a placenta is lacking. Where the
overlap of placental vascular findings is concerned, there is little consensus about what

individual pathology findings are necessary to include in empirically created groups.

13

Table 3 outlines the lesions employed in some studies using groups of vascular pathology
findings. The lack of consistency in defining such constructs as uteroplacental ischemia
and decidual vasculopathy makes it very challenging to compare the results of multiple
studies. In addition, as is illustrated in Table 4, the general lack of consistency in
findings has also contributed to low inter-rater reliability in studies that did not agree

upon a general definition of these groupings beforehand(77, 78).

As stated previously, a variety of PTD outcomes and gestational ages are used
across studies. This fact causes further inconsistency in the evaluation and comparison of
findings. Many studies have focused on very early preterm delivery (<32 completed
gestational weeks) when evaluating the placenta for vascular changes(20, 73, 75, 76). It
has been established that very early PTD is more often related to acute inflammation and
infection, whereas later PTD (34-36 weeks) seems to have a more chronic, vascular
etiology (20, 33, 34). Also, many studies of vascular pathology focus on preeclamptic
women, women requiring c-sections and women presenting in preterm labor; thus
limiting the generalizability of the results to more general PTD groupings such as

medically indicated or spontaneous preterm delivery (37, 38, 70-72, 77).

The fact that sample composition and reference groups are variable across studies
introduces further inconsistency. Many studies of placental vascular pathology are
conducted at university-based hospitals, leading to an oversampling of high-risk women
delivering after 37 weeks (33, 61, 75, 79). Furthermore, some studies do not even use
placentas from term women as controls (34, 75). These methods of comparison diminish
each study’s ability to establish meaningful relations between vascular pathology findings

and PTD groups.

14

Lastly, there is little consensus among study pathologists as to what constitutes a
positive histopathologic placental finding. Only four studies have addressed the problem
of lack of normalization in vascular placental pathology (40, 52, 64, 77, 78). Table 4
outlines the intrarater and interrater reliability of each study. Interrater reliability for
individual pathological findings tends to be good (> 0.50). However, when using
pathology constructs, such as maternal/decidual and fetal vasculopathy, the interrater
reliability becomes very poor (<0.30)(77, 78). Two studies used group consensus to
define these vague vascular constructs, resulting in improved agreement between
pathologists (40, 64). This suggests that the standardization of generally used vascular
groupings is needed to improve the reproducibility of pathology tools used to evaluate

both term and preterm placentas.

INTRODUCTION

Maternal vascular complications have been most consistently associated with
medically indicated preterm delivery (PTD), but they may also contribute to PTDs that
result from premature rupture of membranes (PROM) and spontaneous preterm labor
(PT L) (36-3 8, 72, 79). Studies of vascular pathways to PTD have considered clinical
signs/symptoms (31, 80), biomarkers (81-88), and placental pathology findings (20, 38,
72), all of which provide clues and unique challenges. Vascular related complications
such as preeclampsia, gestational hypertension, intrauterine growth restriction (IUGR),
and overt bleeding are defined by extreme signs/symptoms that have potentially multiple

causes, some distinct and some overlapping (31, 36-3 8, 89, 90). In addition, clinically

15

diagnosed vascular complications most likely under-represent vascular problems
associated with PTD, decreased fetal growth, and altered fetal development. Biomarkers
such as thrombin(83, 88), flt-l (85-87), VEG-F (81, 82) and PIGF (86, 87) have been
linked to multiple clinically defined vascular complications in pregnancy, which may

indicate common underlying etiologies or common sequelae following vascular damage.

Evaluation of placental vascular findings offers another avenue for uncovering
vascular pathways. Studies have repeatedly shown that placental evidence of decidual
vasculopathy or more basically, uteroplacental vascular lesions, is associated with
preeclampsia, gestational hypertension, and fetal intrauterine growth restriction (IUGR)
(72, 75, 91). Failed physiologic transformation of maternal spiral arteries and decidual
vascular artherosis were found to be more common in PROM and PTL than in normal,
term deliveries (38). But incorporating placental vascular findings into epidemiologic
studies is also fraught with challenges. There are no ‘gold’ standards demarcating
‘normal’ from ‘abnormal’ along the continuum of pathologic findings, and classification
schemes for the different pathologic findings have been quite variable. One approach
has been to focus on an individual placental vascular finding, such as failure of
physiologic transformation of spiral arteries, and relate it to PTD (37). Another has been
to group multiple placental findings to characterize globally-defined vascular
complications such as abnormal placentation, uteroplacental ischemia, and hemorrhage,
but across studies there are considerable inconsistencies in terminology, definitions, and
findings used (Table 3). Few studies have empirically evaluated placental vascular
findings to determine how often they co-occur (71 , 77) and one of these studies used both

term and preterm placentas (77). Finally, studies have primarily concentrated on

16

matemal-related vascular pathology in relation to PTD; so less is known about the
influence of fetal vascular findings, alone or in combination with maternal vascular

pathology (40, 61, 92).

The Pregnancy Outcomes and Community Health (POUCH) Study is a
prospective cohort study designed to examine the biological and psychosocial factors that
determine preterm delivery. Here, a subcohort of these women, including all preterm
women, all women with high MSAF P and a subset of term, normal MSAF P women,
were used to explore the relationship between vascular placental pathology and preterm
delivery. Microscopic vascular findings in term and preterm placentas of these women
were divided into five groups, each group representing a pathology-based latent
construct. The goals of these analyses were to: 1) examine the extent to which the
pathology-based constructs co-occur in the same placenta; 2) evaluate maternal
characteristics for each of the five pathology-based constructs; and 3) assess relations
between the pathology-based constructs and risk of spontaneous and/or medically

indicated PTD.

MATERIALS AND METHODS
Population and study design

The Pregnancy Outcomes and Community Health (POUCH) Study is a
prospective cohort study designed to examine pathways to preterm delivery in 3019
pregnant women (93). Between August 1998 and June 2004, pregnant women were

recruited fiom 52 clinics in five Michigan communities. Women were enrolled in the

17

15th - 27th week of pregnancy. Inclusion criteria included singleton pregnancy with no
known congenital anomaly, maternal age of 15 years or greater, prenatal screening of
maternal serum alpha-fetoprotein (MSAF P) at the 15th -22“d week of pregnancy, no pre-
pregnancy history of diabetes mellitus, and competency in English. Women were
recruited at the time of prenatal screening. All women with MSAF P levels greater than 2
MoM (multiples of the mean) were invited to participate (7% of the cohort) because this
biomarker had been linked to PTD previously(94) and was of particular interest in the
POUCH Study. Women with normal MSAF P levels were stratified by race/ethnicity and
sampled into the cohort. Nineteen of the 3,038 women enrolled were lost to follow-up,
resulting in a cohort of 3019 women. The study received institutional review board
approval at Michigan State University, Michigan Department of Community Health, and
nine community hospitals. Race/ethnicity specific comparisons of the study cohort with
birth certificate data from women delivering in the study communities showed that cohort
participants closely resembled community women on most maternal characteristics

measured.

At enrollment, study participants were interviewed and biologic samples were
obtained. For in-depth analyses, a sub-cohort (N =1 ,371) was created which included all
women who delivered preterm (<37 weeks gestation), all women who delivered at term
with elevated MSAF P (>2 MoM), and a sample of women who delivered at term with
normal MSAFP, with an over-sarnpling of African-American women from this latter
category. The sub-cohort sampling scheme was designed to maximize statistical power
for studying at-risk subgroups. All sub-cohort analyses use sampling weights to reflect

the sampling scheme, and therefore there is no bias introduced by over-sarnpling certain

18

subgroups. In the sub-cohort, prenatal and labor/delivery records were abstracted and
delivered placentas were examined by a study placental pathologist. Placentas were
retrieved for 88% (1,213 women) of the sub-cohort and this analysis includes the first

1,053 (239 preterm, 814 term) placentas assessed in the sub-cohort to-date.
Placental examination protocol

The POUCH Study placental examination protocol has been described elsewhere
(93). Briefly, placentas were formalin fixed and grossly examined by the study placental
pathologist. Five full thickness samples were taken from the disc: one at the cord
insertion, one in grossly normal central tissue, two more from central tissue and one from
marginal tissue. The latter three samples were from grossly abnormal tissue if present.
Four other samples were also taken: two umbilical cord samples and two extra-placental
membrane samples from a membrane roll. Tissue samples were paraffm-embedded,
sectioned and H&E stained for microscopic assessment. The study’s placental
pathologist was blinded to gestational age at delivery, all clinical data, and gross

examination findings during the microscopic examination.
Placental diagnostic coding tool

Placental microscopic findings were recorded in a computer-based data collection
instrument that was adapted from Carolyn Salafia. The instrument is primarily
descriptive, not diagnostic, and captures a large number of pathologic changes, their
location, frequency, extent, and proximity to one another. Maternal vascular findings
recorded in this instrument were organized using a scheme adapted from Raymond

Redline in his Placental Diagnostic Coding Tool. This adapted data summary tool was

19

used to categorize 39 findings into five conceptual groups, or pathology-based latent
constructs: 1) Maternal Vascular-Obstructive (MV-O) captures evidence of obstruction
as in major placental disc infarcts and decidual vessel atherosis; 2) Maternal Vascular-
Disturbance of Integrity (MV-I) includes findings associated with retroplacental
hemorrhage and bleeding in the decidua; 3) Maternal Vascular- Developmental (MV-D)
incorporates findings consistent with abnormal or incomplete trophoblast remodeling of
maternal spiral arteries; 4) Fetal Vascular-Obstructive (FV-O) represents findings related
to large and small fetal vessel obstruction; and 5) Fetal Vascular-Disturbance of Integrity
(F V-I) includes findings that suggest abnormalities of fetal villous blood flow such as
fetal to maternal hemorrhage. A complete list of findings included in each pathology-

based vascular construct appears in Table 8.
Pregnancy outcome

Gestational age at delivery was calculated from the date of the last menstrual
period (LMP). If the LMP estimate differed from an early ultrasound estimate by more
than two weeks ultrasound dates were given preference. PTD (<37 weeks’ gestation) was
subdivided into two commonly used clinical groupings: l) Spontaneous PTD, which
included women with spontaneous regular contractions that led to cervical changes (22
cm dilatation) or women with rupture of membranes prior to or at the onset of labor; and
2) Medically indicated PTD, which included women who delivered after induction of
labor or by Caesarian section before the onset of spontaneous regular contractions or
membrane rupture. Within the clinical subtypes, PTD was further divided according to
gestational week at delivery, i.e. <35 weeks and 35-36 weeks, because pregnancy

complications and clinical decisions to intervene vary as pregnancy progresses.

20

Maternal characteristics

Information on maternal education level, Medicaid insurance status, parity, pre-
pregnancy weight, height, and race/ethnicity were obtained through self-report at
enrollment. Pre-pregnancy body mass index (BMI) was calculated (weight in kilograms
divided by height in meters squared) and divided into three groups, normal (18.5-24.9
kg/mz), overweight (ZS-29.9 kg/mz) and obese (__>_30 kg/mz). Due to small numbers,
underweight women (N = 47) were excluded from analyses involving BMI and the 82
women who were not African-American or White were grouped with Whites

(White/other) who shared more similar risks of PTD.

ANALYTIC APPROACH
Development of the Pathology-based Vascular Construct Scores

Each of the 39 vascular findings had a continuous score representing the number
of samples per placenta in which the vascular pathology finding was present. Scores
ranged from 0 to 2 if relevant to the extra-placental membrane samples only, 0 to 5 if
relevant to the placental disc samples only, and 0 to 7 if relevant to the disc and the extra-
placental membrane samples. Data from women who delivered at term with normal
MSAF P levels were used to determine the typical frequency distribution (number of
positive samples per placenta) of each of the 39 vascular findings. The top quartile (or
approximately) was considered ‘high’ and accordingly a vascular finding was scored as
either ‘0’ (normal) or ‘1’ (high) for each placenta. The dichotomous vascular finding

scores were then summed to give a pathology-based construct score. For example, the

21

eight findings in the MV-O construct were added to create a construct-specific score
ranging from 0-8 for each placenta. Again data from women who delivered at term with
normal MSAFP were used to represent the typical frequency distributions of construct
scores. Due to clumping in the distributions, the most uniform cut-points for ‘high’ across
the constructs were the top 14‘11 -17th percentiles. One construct (FV-I) had to be cut at the
top 36th percentile. A dichotomous variable was created for each of the five pathology-

based vascular constructs; ‘high’ was at or above the cut-point and ‘normal’ was below.
Analyses Using Pathology-based Vascular Construct Scores

Correlations between pathology-based vascular construct scores were determined
in two ways. First, the score was modeled as a continuous variable and Spearman’s Rank
Correlation Coefficients were obtained using SAS Proc Corr (SAS Institute Inc., Cary,
NC). Second, the scores were modeled as a dichotomous variable (high and normal as

defined above) and co-occurrence was assessed using the Kappa statistic.

Each pathology-based vascular construct (modeled as high/normal) was evaluated
in relation to maternal characteristics (Chi-square test), and in relation to risk of PTD by
using a polytomous logistic regression model (SAS Surveylogistic) with a five level
outcome variable: term (referent), 35-36 weeks spontaneous PTD, 35-36 weeks
medically-indicated PTD, <35 weeks spontaneous PTD, and <35 weeks medically-
indicated PTD. In these analyses data were weighted to reflect over—sampling of preterm,
high MSAF P and African-American women into the sub-cohort. Because of the low to
moderate correlations between the pathology-based vascular constructs, all vascular

constructs were also included in a single polytomous logistic regression model to test

22

their associations with PTD after accounting for the presence of other constructs.
Significant (P< .05) construct interactions were observed for spontaneous PTD but not
medically indicated PTD. To clarify these interactions two separate polytomous
regression models were used: one excluded spontaneous PTD and had a three level
outcome of term (referent), < 35 weeks medically indicated PTD, 35-36 weeks medically
indicated PTD; the other excluded medically indicated PTD and had a three level
outcome of term (referent), < 35 weeks spontaneous PT D, and 35-36 weeks spontaneous
PTD. In a second version of these models, maternal characteristics related to PTD in
previous studies (race/ethnicity, parity, age, Medicaid insurance status, and BMI) were

added as potential confounders.

RESULTS

The first column in Table 5 shows the distributions of demographic and
pregnancy-related factors in this sub-cohort sample. The second column includes
sampling weights to show the distributions of these same maternal characteristics in the
POUCH Study cohort. Weighted and un-weighted distributions were similar except in the
characteristics used for sub-cohort sampling, i.e., race/ethnicity and pregnancy outcome.
In the sub-cohort sample approximately 28% were over 29 years of age, 51% had more
than 12 years of education, 38% were Afiican—American, 54% were insured by Medicaid,

and 22.7% delivered preterm.

Correlations between pathology-based vascular construct scores measured on a

continuous scale were generally weak to moderate in magnitude with Spearman’s Rank

23

Correlation Coefficients ranging from 0.03 to 0.30 (Table 6a). Co-occurrence of vascular
constructs was also tested using dichotomous variables (normal/ high) and a Kappa
statistic, which has a range of -l to 1 (complete concordance). The Kappa coefficients for

the vascular constructs were all low, -0.01 to 0.17 (Table 6b)

Maternal and fetal vascular obstructions, evidenced by a high MV-O or FV-O
score, were more common in primiparous women (Table 7). High MV-I and FV-O
scores, indicative of maternal bleeding and fetal vessel thrombosis, were observed more
often in whites/others than in African-Americans. A high MV-D score, consistent with
poor conversion of spiral arteries, was associated with being African-American, < 20
years of age, insured by Medicaid, overweight, and obese. When all maternal
characteristics were included in a single logistic regression model, a high MV-D score
continued to be more prevalent in African-American women (adjusted odds ratio-
AOR=2.1, 95% CI 1.3, 3.2), women <20 years of age (AOR=3.4, 95% CI 1.6, 7.2),
overweight women (AOR= 2.7, 95% CI 1.6, 4.6), and obese women (AOR= 3.3, 95% CI

2.0, 5.4).

High scores for MV-O, MV-I, MV-D, FV-O and F V-I were each associated with
medically indicated PTD at < 35 weeks with unadjusted ORs ranging from 2.3 to 4.8
(Table 8). MV-I and MV-D were also related to spontaneous PTD at <35 weeks
(unadjusted 0R3 2.0 and 2.1 respectively) and FVI was associated with spontaneous PTD
at 35-36 weeks (unadjusted OR=1.8). All pathology-based vascular constructs were
placed in a single model after excluding spontaneous PTDs. The AORs for medically
indicated PTD < 35 weeks were attenuated but remained statistically significant with the

exception of FV-O (Table 9). Following additional adjustment for maternal variables, i.e.,

24

parity, Medicaid status, race/ethnicity, age, and BM] there continued to be strong
associations between medically indicated PTD at < 35 weeks and high scores for MV-O
(OR= 3.5, 95% CI 1.6, 7.8), MV-I (OR= 2.5, 95% CI 1.1, 5.9), MV-D (OR= 3.7, 95% CI
1.6, 8.8), and F V-I (OR= 2.8, 95% CI 1.2, 6.5). There were no statistically significant
interactions (P<0.5) among the vascular constructs in this model and no significant

associations with medically indicated PTD at 3-36 weeks.

A second series of analyses placed all vascular constructs in a single model after
excluding medically indicated PTD. These models showed significant interactions
between MV-I, MV-D, and FV-I (Table 10). After adjusting for maternal characteristics,
the presence of a high score in any one of these three vascular constructs significantly
increased the risk of spontaneous PTD at 35-36 weeks with AORs ranging from 2.9 to
4.4. The presence of two or more high scores increased the risk of spontaneous PTD at <
35 weeks with AOR ranging from 4.0 to 7.5; only the combination of MV-I and MV-D
did not reach statistical significance. MV-O and FV-O were unrelated to spontaneous

PTD.

DISCUSSION

We found that a pathology-based system of grouping placental vascular findings
into constructs offers insights into preterm delivery pathways. Separate consideration of
the various vascular constructs was supported by three observations. First, the
correlations between the pathology-based vascular construct scores were weak to

moderate, suggesting co-occurrence of these latent processes is not common. Second,

25

there was considerable variation in the maternal characteristics associated with each of
the vascular constructs. And third, some but not all constructs were related to

spontaneous PTD.

The maternal vascular-developmental construct was most closely linked to
multiple maternal characteristics including high BMI, whereas the maternal vascular
obstructive construct was associated only with primiparity. While inadequate maternal
vessel remodeling can lead to placental obstructive lesions(52), our results suggest there
may be value in exploring upstream and downstream factors related to each of these
constructs. The higher prevalence of maternal vascular disturbance of integrity
(bleeding), and fetal vascular obstruction (thrombosis) in Whites/others compared with
that in African-Americans may reflect differential predispositions such as thrombophilias
(95). Some acute placental abruptions, which are most evident by clinical presentation
and/or gross pathology findings and may have a different epidemiology, are probably not

sufficiently captured in this construct defined only by microscopic placental findings.

From a clinical perspective, preeclampsia, fetal distress, poor fetal growth, and
placental abruption account for the majority of medically-indicated PTDs (31). It has
been unclear if all or only certain types of vascular pathology ‘drive the association with
medically indicated PTD’. By building models that included all five pathology-based
vascular constructs we were able to show that, with the exception of fetal vascular
obstructive, each construct increased the risk of medically indicated PTD at < 35 weeks.
The continued importance of the maternal vascular-developmental construct after
adjusting for maternal obstructive lesions (e. g. infarcts and atherosis) suggests that

developmental findings alone (abnormal or incomplete remodeling of maternal vessels)

26

may be sufficient to trigger maternal complications (high blood pressure) that result in

medically indicated PTD.

Other studies have reported an increased risk of spontaneous PTD in association
with placental findings such as uteroplacental vascular thrombosis, infarcts, absence of
physiologic spiral artery change, and villous fibrosis (36-38). We found that among three
of the five vascular constructs (MV-D, MV-I, and FV-I) there was an inverse ‘dose
response’ between the number of high construct scores and timing of spontaneous PTD, a
clear indication that vascular constructs are important to both late and early spontaneous
PTD. The reason for the presence of a three-way interaction in the spontaneous PTD
group only is unclear. This finding could reflect a number of different scenarios. First,
the placental injury resulting from the combination of two or more of these three groups
could result in clinical findings that only present after PROM or PTL have occurred.
Second, the severity of placental injury incurred from these three lesion groups could
result in sudden progression to preterm labor or rupture of membranes. However, the
underlying reason for this finding is ultimately unknown since 'we are still not able to
clearly understand the clinical and pathophysiological scenarios leading to spontaneous
and indicated PTD. The lack of association between maternal vascular-obstruction and
spontaneous PTD may be because in severe cases medically indicated PTD supersedes.
Fetal vessel obstruction was not linked to spontaneous or medically indicated PTD once
other vascular constructs were included in the models. The FV-O construct included the
largest number of items (findings). Future sensitivity analyses may help to pare down the

item list and strengthen the importance of this construct.

27

Comparisons across studies of PTD-related vascular placental pathology are made
difficult by: 1) the variability in definitions and groupings of pathology findings, and 2)
geographical and secular trends in medically indicated PTD, influenced both by
prevalence of indications and variation in medical practices. In addition, previous studies
have showed that inter-rater reliability for diagnosing histologic evidence of vascular-
related pathology is not high (40, 64, 77), perhaps because there is a lack of agreement as

to what constitutes a critical mass of findings for the designation of ‘positive’.

Strengths of the Study

Major strengths of this study include the sample, which was recruited fi'om
multiple community clinics and shown to be highly comparable to community women
delivering during this period. The pathologist was blinded to all clinical information,
which is not typical with referred placental examinations in perinatal medicine. We
examined the distributions of placental vascular findings and constructs in term placentas
as a means of determining what might be considered ‘normal.’ It is often the case that
studies of placental vascular pathology comparing subgroups of preterm (20, 73, 75, 76)
use high- risk term placentas as the reference group (79), or are conducted in teaching
hospitals where patient populations over-represent high-risk pregnancy conditions, even
among term deliveries. By using term women recruited from communities around
Michigan, we were able to illustrate what constitutes a normal threshold of placental
vascular change in pregnancies not complicated by preterm delivery or adverse birth

OUICOI'I‘ICS.

28

The placental evaluation tool in this study was one of the most detailed of those
used in vascular placental pathology research. Previous studies have suggested that
commonly used conceptual groupings (uteroplacental ischemia, maternal vasculopathy)
are vague and result in low agreement between pathologists in what constitutes a positive
finding (Table 3). Our tool identifies what individual findings represent each conceptual
grouping. This strongly suggests our results will be reproducible assuming the same
study protocol. In addition, we tested the correlations between conceptual groupings to
identify any collinearity. This suggests that each pathology grouping could potentially
represent a unique pathway to preterm delivery. Although not reported here, our
investigation employed factor analysis in our analysis to determine the patterns of
relationships between the placental pathology variables used. The factors created were
extremely similar to the empirical constructs used in this study. The results of this

analysis were reassuring in that it added validity to our five constructs.

Limitations of the Study

A limitation is that our approach required extensive effort to evaluate and score
each placenta. But our intent was not to supplant the hospital-based pathologists’
diagnostic process, which is less time consuming, encompasses pattern recognition,
makes use of clinical information, and allows for expert interpretation of placental
findings. Rather we view our approach as a research tool that can aid in uncovering
similarities and distinctions between the various vascular-related pathways that affect
pregnancy outcomes. In future analyses we plan to assess the importance of individual
placenta vascular findings within each vascular construct, and through sensitivity

analyses determine which if any can be excluded.

29

 

Another limitation to our approach is that we were unable to test either interrater
or intrarater reliability of our placental tool. Because it is extensive and time-consuming,
it could be difficult to reproduce. Future work will include testing the reliability of the

tool and determining if the tool can be collapsed to a more usable size.

CONCLUSION

Despite evidence that the vascular pathways leading to PTD have some
overlapping features (90), we have found with our results that separating vascular
constructs may be informative as we move forward to examine biomarkers and upstream
and downstream risk factors in greater depth. This approach is a more in depth look at
vascular pathology than has been previously attempted. It is unique in that it related

placental vascular pathology to both preterm delivery subtypes and gestational age.

This study provides new insights into the relationship between maternal and fetal
placental vascular changes and preterm delivery. More importantly, it provides evidence
that vascular findings on the fetal and maternal sides of the placenta are independently
related to PTD. Because these conceptual groupings have little overlap, we can conclude
that multiple vascular pathways exist to preterm delivery. Since some of these vascular
groupings have previously been related to a myriad of clinical circumstances, maternal
disorders and birth outcomes, there could also be some common vascular pathways to

PTD.

Future research should focus on clarifying the relations found here and identifying

possible biomarkers reflective of the underlying pathologic processes leading to PTD. A

30

larger cohort study could provide enough power to further divide birth outcomes and
gestational age in an attempt to clarify the relations found here. A larger study would
also make it possible to further investigate the importance of other risk factors (race, age,
SES, parity) in this association. Ultimately, conclusions developed here could help
decipher the complicated relationship between the placenta and preterm delivery, leading

to the early identification of those pathways leading to PTD.

31

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33

Table 3: Comparison of Groupings of Placental Vascular Pathology

Author Placental Vascular Pathology
Arias eta], 1993 (36) 1)Maternal vascular pathology: unaltered spiral arteries

containing recent or old organized thrombi, mural or occlusive,
presence of uneven accelerated maturation of the chorionic villi,
large numbers of multinucleated syncytial knots, and multiple
placental infarcts.

Salafia et al, 1995 (33) 1) Decidual vasculopathy: aberrant conversion of spiral arteries,
decidual vasculitis, and fibrinoid necrosis or atherosis

2) Uterine vascular insufficiency: villous infarcts, intervillous u.
thrombi, gross or microscopic evidence of abruption and villous 5‘
lesions . . .Gross evidence of abruption was frank retroplacental
clots with placental compression. Microscopically, abruption
was diagnosed if retroplacental hemorrhage and basal plate F
destruction was accompanied by villous necrosis, trophoblast F
basophilia and villous crowding. "

 

Beebe et al, 1996 (79) 1) Histopathologic ischemic changes: villous agglutination, i
shrinkage of villi, numerically increased syncytiotrophoblastic
knots, increased perivillous fibrin, infarcts, sclerotic or avascular
villi and fibrinoid material with abundant X cells.

2) Placental infarcts: ischemic villous necrosis, diffuse
fibrinoid material with abundant X cells and, sometimes, ghost-
like villi.

Ghidini et a1, 1997 (75) 1) Uteroplacental vascular and related villous lesions: unaltered
spiral arteries, fibrinoid necrosis and atheroma, abruptio
placentae, villous infarcts, terminal villous fibrosis, increased
syncytiotrophoblastic knotting, cytotrophoblast proliferation,
villous hypovascularity, villous thrombus, circulating fetal
nucleated erythrocytes.

Kim et a1, 2002 (38) 1) Aggregated vascular lesion: atherosis, fibrinoid necrosis of
the decidual vessels, decidual vessel thrombosis, and fetal
thrombotic vasculopathy (fibrin thrombi in chorionic or stem
vessels

Ogunyemi et al, 2003 (76) 1) Placental vascular pathology: placental infarction, placental
abruption, villous fibrosis and sclerosis, vascular intimal
hypertrophy and decidual fibrinoid necrosis.

2) Coagulation-related lesions: uteroplacental thrombosis,

hemorrhagic endovasculitis, intervillous thrombosis and
intervillous fibrin deposit

34

Table 4: Studies testing intra/interobserver reliability

 

 

 

 

 

 

placental findings used Intraobserver Interobserver
reliabilitx reliabilitx
Kramer, A. Chorioamnitis A. 0.51 A. 0.58
2006 B. Syncytial knots B. 0.38 B. NC
(77) C. Infarction C. 0.78 C. 0.79
D. Villitis D. 0.58 D. 0.28
E. Decidual Vasculopathy E. 0.62 E. -0.02
F. Fetal Vasculopathy F. -0.02 F. -0.02
Redline A. syncytial knots None A. 0.42
2004 B. intervillous fibrin B. 0.25
(40) C. villous hypoplasia C. 0.57
D. Acute atherosis D. 0.50
E. Mural hypertrophy E. 0.43
F. maternal underperfusion F. 0.54
Redline A. Avascular villi None A. 0.49
2004 B. Fetal thrombosis B. 0.34
(64) C. Intimal fibrin cushion- C. 0.47, 0.78
recent, remote
D. Fetal Vascular D. 0.63
obstruction
Grether A. Acute chorioamnionitis A. 0.66
1999 B. Chorionic Vasculitis B. 0.51
(78) C. syncytial knots C. 0.25
D. Maternal D. 0.23
vasculopathy
E. Chronic E. 0.51
chorioamnionitis

 

 

 

 

 

 

35

Table 5. Maternal characteristics and pregnancy outcome in the sub-cohort with completed

placental assessments (N= 1053)

 

 

Maternal Characteristics N % Weighted %1'
Maternal Age (years)

< 20 167 15.9 13.8

20 - < 30 592 56.2 56.5

>= 30 294 27.9 29.7
Maternal Education (years)

< 12 213 20.2 16.9

= 12 301 28.6 27.4

> 12 539 51.2 55.7
Race/Ethnicity

Non-Hispanic Whites 568 53.9 65.9

African Americans 403 38.3 24.6

Others 82 7.8 9.5
Medicaid Insured

Yes 567 53.9 48.0

No 485 46.1 52.0
Parity

No previous live birth 433 41.1 41.0

Previous live birth w/ PT D 59 5.6 4.4

Previous live birth w/o PTD 561 53.3 54.6
Week of Pregnancy at Enrollment

15- < 20 154 14.6 13.8

20- < 25 748 71.0 72.0

25- < 27 151 14.4 14.2
Pregnancy Outcome

Term 814 77.3 89.3

Spontaneous PTD 163 15.5 7.4

Medically-indicated PTD 76 7.2 3.3

'1‘ weighted for the sub-cohort sampling scheme; percentages reflect distribution in original

cohort.

36

1“)

 

Table 6a. Spearman's rank correlations (p value) between pathology-based vascular

 

 

construct scores*
MV-O MV-l MV-D FV-O FV-l
MV—O 1
MV-l 0.30 (<.0001) l
MV-D 0.04 (0.23) 0.08 (0.01) 1
FV-O 0.25 (<.0001) 0.12 (<.0001) 0.03 (0.39) 1
[NJ 0.07 (0.03) 0.19 (<.0001) 0.05 (0.09) 0.04 (0.25) 1

 

* continuous scores

Table 6b. Kappa coefficients for co-occurrence of high pathology-based vascular construct

 

 

scores*
MV-O MV-I MV-D FV—O FV-l
MV-O 1
MV-I 0. 17 1
MV-D 0.09 0.03 l
FV-O 0.18 0.08 0.07 1
FV-l -0.01 0.10 0.05 0.02 1

 

* dichotomous scores

37

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Table 9. Associations between vascular constructs and medically-indicated PTD (N= 89M)

 

Medically-indicated PTD, adjusted odds ratios (95%Cl)

** Model includes all five vascular

* Model includes all five vascular constructs, race, Medicaid, par “Y,

 

 

maternal age and BMI (pre-
pregnancy/at screening, continuous).

< 35* 35-36* < 35* * 35-36**
MV-O 3.5 (1.6, 7.7) 1.5 (0.7, 3.3) 3.5 (1.6, 7.8) 1.5 (0.7, 3.5)
MV-I 2.4 (1.0, 5.6) 0.8 (0.3, 2.0) 2.5 (1.1, 5.9) 0.9 (0.4, 2.3)
MV-D 3.6 (1.6, 8.2) 1.8 (0.8, 4.0) 3.7 (1.6, 8.8) 1.5 (0.6, 3.7)
FV-O 1.3 (0.5, 3.4) 0.9 (0.4, 2.1) 1.4 (0.5, 3.6) 0.9 (0.4, 2.0)
FV-l 2.8 (1.2, 6.5) 1.6 (0.8, 3.1) 2.8 (1.2, 6.5) 1.6 (0.8, 3.2)

 

1 Term and medically-indicated PTD only

42

 

 

 

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Appendix B: Figures

Figure 1: Structure of the Placenta

Decidua Basalis Chorion
(Maternal Portion (Fetal Portion of
of placenta) placenta)
l i

 

Chorionic ' _ I , I
villi f

 
 
  

Maternal a
venule , -
\

flmbilica! Cord

in” e“ ”1°” Umbilical

pac Arteries

Umbilical Vein

Maternal

arteriole CT

Fetal blood Ami“

vessel

10.

11.

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