Pathogenesis of Spontaneous Preterm Birth

39
Pathogenesis of Spontaneous
Preterm Birth
CATALIN S. BUHIMSCHI, MD
| JANE E. NORMAN, MD
Preterm Birth Syndrome: New

Phenotypic Classification
Preterm birth (PTB) occurs between fetal viability and 37 completed weeks of gestation.1 The definition of viability is controversial because of the increasing frequency of survival at
progressively lower gestational ages. Most countries define it as
a lower limit of 20 to 22 weeks, but this varies, preventing
straightforward comparison of reported rates of neonatal mortality and morbidity.2 A recent influential report has suggested
that a less arbitrary definition of PTB would include all births
(including live births, stillbirths, and pregnancy terminations)
occurring from 16 weeks 0 days to 38 weeks 6 days (i.e., 112 to
272 days).3 The rationale for the latter limit is that births
between 37 and 39 weeks are associated with greater short- and
long-term morbidity than those after 39 weeks,4 whereas the
rationale for the early limit is that the pathologies inducing
spontaneous abortion between 16 and 20 weeks are similar to
those inducing PTB at a later gestation. Where accurate recording of gestational age is not possiblefor example, in resourcepoor countriesa birth weight of 500 g has historically been
used to define the lower limit of viability. However, this approach
leads to inaccuracies, because viable neonates born after 24
weeks may be affected by intrauterine growth restriction
(IUGR), and some pre-viable infants may weigh more than
500 g.
Worldwide, approximately 1.1 million neonates die from
prematurity-related complications.5 Rates of PTB vary around
the world, with the United States having among the highest
incidences.6 In 2010, the PTB rate in the United States was
around 12.0%, representing a progressive decline over the past
4 years.7 Its decline from 2008 to 2010 was most noticeable
among infants born at 34 to 36 weeks (late preterm). However,
the percentage of infants born at less than 34 weeks also
dropped, from 3.56% to 3.50%. A reduction in PTB rates was
seen for most age, race, and ethnic groupings. By contrast, the
birth rate for infants having low birth weight (LBW; <2500 g)
was unchanged from 2008 to 2010, at 8.15%. Regretfully, the
percentage of newborns delivered at very low birth weight
(1500 g) declined only minimally, from 1.46% in 2008 to 1.45%
in 2010. This is significant, as very-low-birth-weight premature
newborns are at the highest risk for early death or disability.8
Traditional classification systems categorize PTBs as either
spontaneous or indicated. Spontaneous preterm labor can
occur either with intact membranes or with prelabor (premature) rupture of the fetal membranes (PROM). Indicated PTBs
can result from induction of preterm labor or from preterm

cesarean delivery for maternal or fetal indications (e.g., preeclampsia, IUGR).9 The Global Alliance to Prevent Prematurity
and Stillbirth (GAPPS) has recently proposed an alternative
classification system that is likely to be very influential.10 Under
this paradigm, PTB is categorized according to the clinical phenotype consisting of (1) one or more conditions of the mother,
placenta, or fetus; (2) the presence or absence of signs of parturition; and (3) the pathway to delivery (spontaneous or caregiver initiated) (Fig. 39-1). There is some overlap between the
GAPPS classification system and the traditional criteriafor
example, indicated preterm delivery in the previous system corresponds to caregiver-initiated parturition in the new system,
and it normally occurs in the absence of parturition. In this
chapter, we address PTB under the new classification system,
and we describe it according to the maternal, placental, and fetal
phenotype.10 Under the new classification system, PTB rates
include infants born between 37 + 0 and 38 + 6 weeks of pregnancy, and thus these rates are about 28% higher than previously. Unless otherwise indicated, it is assumed that for the
conditions described in this chapter, there is evidence of parturition, and the pathway to delivery is spontaneous. The mechanisms of disease responsible for indicated preterm deliveries
with caregiver-initiated parturition are discussed in other chapters. About 75% all PTBs have a spontaneous pathway to delivery: About 45% (23.2% to 64.1%) are from preterm labor with
intact membranes, and about 30% (7.1% to 51.2%) are from
preterm labor after PROM.11-14
Mechanisms of Spontaneous
Preterm Birth
THE COMMON PATHWAY
Term and preterm labor share common pathways, which include
increased uterine contractility, cervical ripening, and membrane rupture leading to fetal prematurity and damage.15
However, whereas term birth results from physiologic activation
of these common pathways, PTB results from a disease process
(or pathologic activation) (Fig. 39-2) that activates one or more
of the components of the common pathway via similar or alternative mechanisms.16,17
The common pathway of parturition includes anatomic, biochemical, immunologic, endocrinologic, and clinical changes.16
Although the anatomic and clinical events have been studied in
detail, the biochemical, immunologic, and endocrine events are
599
600
PART 4 Disorders at the Maternal-Fetal Interface
Significant Fetal Conditions

Significant Maternal Conditions
Extrauterine infection
Clinical chorioamnionitis
Maternal trauma
Worsening maternal disease
Uterine rupture
Preeclampsia/eclampsia
IUFD
IUGR
Abnormal FHR/BPP
Infection/fetal inflammatory
response syndrome
Fetal anomaly
Alloimmune fetal anemia
Polyhydramnios
Multiple fetuses
a) Twin-twin transfusion syndrome
b) Demise of fetus in multiple
pregnancy
Placental Pathologic Conditions

Histologic chorioamnionitis
Placental abruption
Placenta previa
Other placental abnormalities
SIGNS OF INITIATION OF PARTURITION

No evidence of Initiation of Parturition
Evidence of Initiation of Parturition

Cervical shortening
pPROM
Regular contractions
Cervical dilation
Bleeding
Unknown initiation
PATHWAY TO DELIVERY
Caregiver Initiated
Spontaneous
Clinically mandated
Clinically discretionary
Iatrogenic or no discernible reason
Pregnancy termination
No documented clinical indication
Regular contractions
Augmented
BIRTH >16 to <38+6 WEEKS

Figure 39-1 Phenotypic components of the preterm birth syndrome. BPP, biophysical profile; FHR, fetal heart rate; IUFD, intrauterine fetal
demise; IUGR, intrauterine growth restriction; PPROM, preterm premature rupture of membranes. (From Villar J, Papageorghiou AT, Knight HE,
et al: The preterm birth syndrome: a prototype phenotypic classification, Am J Obstet Gynecol 206:119123, 2012.)
Multiple
pregnancy
Infection
Intra-amniotic
inflammation
Fetal
allergy
Uterine overdistension
Uterine contractions
Cervical ripening
PPROM
Fetal damage
Nulliparity
Stress
Oxidative
stress
Utero-placental
ischemia
Environmental
toxins
Nutrition
Decidual
hemorrhage
Genetic
predisposition
Figure 39-2 Pathologic mechanisms in preterm birth. Proposed view of how multiple etiologies and pathogenic pathways converge to trigger
uterine contractility, cervical ripening, and preterm premature rupture of membranes (PPROM) in women with preterm birth. (From Buhimschi CS,
Schatz F, Krikun G, et al: Novel insights into molecular mechanisms of abruption induced preterm birth, Expert Rev Mol Med 12:e35, 2010.)
Pathogenesis of Spontaneous Preterm Birth
39
still incompletely understood. In the peripheral circulation, an

increase in unbound corticotropin-releasing hormone and, in
the uterus, increased nuclear factor kappa B (NF-B) activity
(associated with functional progesterone withdrawal, prostaglandin production, and leukocytic influx) are consistently
demonstrated in association with parturition.18 There is continuing debate about which (if any) of these events is the master
regulator that controls the timing of parturition, and which (if
any) is the sine qua non, without which parturition cannot
occur. Evidence for each of these processes is briefly reviewed
below.
Prostaglandins as Key Activators of the Common
Pathway of Parturition
Prostaglandins are viewed as crucial mediators for the onset
of labor,19-34 because they can induce myometrial contractility,19,23,32,34 promote proteolysis of cervical and fetal membrane
extracellular matrices to cause cervical ripening and fetal membrane rupture,21,22,26,27,31 and stimulate decidual/membrane activation.35 Evidence of a role for prostaglandins in the initiation
of human parturition includes the following: (1) Administration of prostaglandins induces termination of pregnancy30,36-46;
(2) indomethacin or aspirin therapy delays spontaneous onset
of parturition in animals47-50; (3) concentrations of prostaglandins in plasma and amniotic fluid increase during labor51-59; (4)
intra-amniotic injection of the prostaglandin precursor arachidonic acid induces abortion28; (5) expression of myometrial
prostaglandin receptors increases in labor60,61; and (6) labor is
associated with increased expression of prostaglandin endoperoxide synthase 2 (PTGS-2) messenger RNA and increased activity of this enzyme in the amnion (a rate-limiting step in the
production of prostaglandins). This increase in amniotic
PTGS-2 activity is accompanied by decreased expression of the
prostaglandin-metabolizing enzyme 15-hydroxyprostaglandin
dehydrogenase (PGDH) in the chorion. This would allow prostaglandins produced in the amnion to traverse the chorion and
NF-B
Inflammation
601
decidua to reach the myometrium, where they can stimulate

smooth muscle contractions.62 The increase in PTGS-2 activity
is induced by an increase in NF-B activity in both amnion63
and myometrim.64 The importance of NF-B in the induction
of PTB is further underscored by the demonstration that an
NF-B inhibitor can reduce lipopolysaccharide (LPS)-induced
PTB in a mouse model.65
NF-B and prostaglandins activate common pathways of
parturition by the following biochemical mechanisms: (1) Prostaglandins directly promote uterine contractions by increasing
sarcoplasmic and transmembrane calcium fluxes and through
increased transcription of oxytocin receptors, connexin-43
(gap junctions), and the prostaglandin E2 (PGE2) receptors EP1
through EP4 (although EP3 appears to be the predominant
receptor subtype66) and the PGF2 receptor FP67-70; (2) prostaglandins induce synthesis of matrix metalloproteinases (MMPs)
by fetal membranes and cells in the uterine cervix to promote
membrane rupture and cervical ripening71,72; (3) PGE2 and
PGF2 increase the ratio of expression of the progesterone
receptor (PR) isoforms PR-A and PR-B to induce functional
progesterone withdrawal73; and (4) NF-B activation induces
activation of a cassette of inflammatory genes, which may also
induce a functional progesterone withdrawal.64 Figure 39-3
describes the molecular mechanisms implicated in the common
pathway of parturition.
INFLAMMATION, STRESS, AND TERM AND
PRETERM PARTURITION
Inflammation is a highly orchestrated process designed to
ensure survival of the host.74 The inflammatory process has
a physiologic component intended to ensure maintenance of
homeostasis. Increasing evidence suggests that parturition at
term is such a process. Liggins first proposed that cervical ripening was an inflammatory event, and this hypothesis is supported by data showing a profound leukocytic (neutrophilic
PR-A/PR-B ratio
PG
+
Myometrium
Contractions
Ca2+
Oxytocin R
Connexin-43
PGE2 EP1
PGF2 FP
Fetal membranes
pPROM
+
+
MMPs
PG
Cervix
Dilation
Ripening
Figure 39-3 Prostaglandins as key activators of the common pathway of parturition. Ca2+, calcium; EP1, prostaglandin E1 receptor; FP, prostaglandin F receptor; MMPs, matrix metalloproteinases; NF-B, nuclear factor kappa B (a transcription factor); PR, progesterone receptor; PG,
prostaglandin; PGE2, prostaglandin E2; pGF2, prostaglandin F2; pPROM, preterm premature rupture of membranes, PR-A/PR-B, ratio of progesterone receptor type A to type B.
602
has been involved in the occurrence of maternal depression.84

Carriers of a polymorphism in the gene encoding for the 11HSD type-1 have a higher level of HPA activity and susceptibility to depression.85 Collectively, these and other data86 appear to
indicate a genetic predisposition toward maternal mood disorders and may implicate various placental polymorphisms in the
occurrence of maternal mood disorders linked to PTB.87
Calgranulin - C
Calgranulin - A
Severity of IAI
MR = 0
Preterm Birth Resulting from Intra-amniotic Infection

Preterm delivery is often associated with intra-amniotic infection. Infection may not be obvious (see Clinical Chorioamnionitis, later). That intrauterine infection may induce PTB is
suggested by at least three lines of evidence. First and most
compellingly, intrauterine infection or systemic administration
of microbial products (e.g., bacterial endotoxin) to pregnant
animals results in spontaneous preterm labor and birth.88-100
Second, subclinical intrauterine infections are consistently
associated with preterm labor and PTB in humans.101,102 Third,
pregnant women with intra-amniotic infection103-105 or intraamniotic inflammation (defined as an elevation of amniotic
fluid concentrations of proinflammatory cytokines,106,107
matrix-degrading enzymes,108 and a specific set of antimicrobial
peptides [e.g., defensins, calgranulins109] in the mid-trimester)
are at increased risk for spontaneous PTB later in that pregnancy (Fig. 39-4).110
Culture-based data suggest that a large number of intraamniotic infections are polymicrobial.110,111 Based on microbial
cultures alone, the most common microorganisms identified
in the fetal membranes and amniotic fluid of patients with
infection-associated PTB are Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella vaginalis, Streptococcus group B
(GBS), Bacteroides species, and Escherichia coli.110,112-114 Listeria
monocytogenes is a much rarer participant.115 However, it is
increasingly clear that culture techniques are extremely limited
as a diagnostic test for infection in the amniotic cavity and
elsewhere.116 Cultures underestimate the frequency with which
microbial pathogens are involved in the process. Metagenomics,
which uses genomics techniques to study communities of
100
no
MR = 1 - 2 minimal
MR = 3 - 4 severe
% undelivered patients
Defensin - 2
Defensin - 1
and macrophage) invasion into the cervix during normal parturition.75 Similar processes appear to operate in the myometrium,76 where labor is accompanied by increased expression of
cell adhesion molecules, chemotactic agents such as interleukin
(IL)-8, and proinflammatory cytokines,75,77 as well as by leukocyte activation in peripheral blood.78 Whether these events are
crucial to the initiation of labor or merely an epiphenomenon
remains uncertain. Although these events may be physiologic at
term, they can be activated pathologically before term, with
major damaging consequences. For example, proinflammatory
agents such as LPS and IL-1 can stimulate preterm labor in
animal models, and preterm labor in women is often accompanied by infection or inflammation, so a causal role for inflammation in the pathophysiology of preterm labor remains likely.
Complex biochemical and neurohormonal interactions
among maternal, fetal, and placental compartments are required
during normal term parturition in humans.79 In term labor,
these processes reflect the normal maturation of the fetal
hypothalamic-pituitary-adrenal-placental axis. A series of physiologic adaptive responses in each of these compartments can
also be triggered by stress subsequent to malnutrition, infection,
ischemia, vascular damage, and psychosocial factors.80 However,
the nature of the stimulus whereby stress induces premature
activation of the mechanisms involved in PTB remains unknown.
In early pregnancy, the villous trophoblast produces a variety
of growth factors, cytokines, neuropeptides, and
hormones. There is substantial evidence that the placenta
plays a central role in controlling the length of gestation and
the onset of parturition in humans.81 Placental histologic
changes consistent with infection and ischemia-induced fetal
stress are far more common in patients with spontaneous
preterm delivery than in controls with idiopathic preterm and
term birth.82,83 Maternal-fetal trafficking of numerous hormones is highly dependent on various enzymatic pathways. The
11-hydroxysteroid dehydrogenase (11-HSD) regulates placental transfer of cortisol, which is a glucocorticosteroid with a
key role in the activation of the hypothalamic-pituitary-adrenal
(HPA) axis. Interestingly, hyperactivity of the maternal HPA axis
75
50
25
0
0
20
40
60
80
100
120
Amniocentesis-to-delivery interval (days)
Figure 39-4 Intra-amniotic inflammation (IAI). Representative mass spectrometry profiles of the amniotic fluid based on the severity of inflammation (MR = 0 [no inflammation]; MR = 1 to 2 [minimal inflammation]; MR = 3 to 4 [severe inflammation]). The proteomic mass restricted
(MR) score is the result of the presence in the amniotic fluid of four protein biomarkers: neutrophil defensins 2 and 1, and calgranulins C and A.
Women with severe inflammation (3 to 4 biomarkers present in the amniotic fluid) had shorter amniocentesis-to-delivery intervals (i.e., were less
likely to carry the pregnancy to term) than women with MR = 0 (absent biomarkers) or MR = 1 to 2 (1 to 2 biomarkers present).
39
microbial organisms without the need to isolate and culture

them, has shown that many environmental and human microbial species cannot be cultured.117,118 Reasons for this include
the low prevalence of these organisms, their slow growth or
resistance to being cultured in conventional media, and their
specialized growth requirements.119 The cornerstone of
genomics-based detection methods are sequencing of fulllength or variable regions of the bacterial 16S ribosomal RNA
(16S-rRNA) gene.120 This gene is characterized by a high degree
of conservation and a clustering of the variable regions of the
16S-rRNA gene into discrete taxonomic units; the latter allows
an in-depth characterization of species richness and the diversity of complex microbial communities.121 Metagenomic studies
of amniotic fluid show that the bacterial diversity of the amniotic fluid microbiome is rich and is characterized by the presence of uncultivated and difficult-to-cultivate species, such as
Sneathia, Fusobacterium nucleatum, Bergeyella, Clostridiales,
Peptostreptococcus, and Bacteroides.122,123
Currently, the Human Microbiome Project is characterizing
the microbial communities found at several different sites on
the human body (see website commonfund.nih.gov/hmp).
Recent studies on the vaginal microbiome in women of
reproductive age have revealed the complexity of vaginal
flora, including major differences between ethnic groups.124
Mucus
plug
603
Comprehensive metagenomic studies of the amniotic fluid

microbiome in health and disease will surely emerge in the next
few years.
The mechanism by which microorganisms gain access to the
amniotic cavity is incompletely understood. Because most
intra-amniotic bacteria are genital tract microorganisms, and
the amniotic fluid is normally sterile, the current paradigm of
intrauterine infection implies that bacteria most often originate
from the lower genital tract and invade the pregnant uterus via
an ascending mechanism.125 Once the mechanical barrier and
the complex innate immune barrier of the cervix are bypassed
(Fig. 39-5), microorganisms infect the decidua and penetrate
the fetal membranes to invade the amniotic fluid.126,127 Finally,
microorganisms gain access to and infect the fetus.126 This biologically plausible conceptual framework is based on studies
that demonstrated that (1) microorganisms frequently implicated in intra-amniotic infection (e.g., GBS, Mycoplasma, E.
coli) are common constituents of the vaginal microbiome128 and
cohabitants of the amniochorionic space129; (2) the presence
of Ureaplasma and Mycoplasma in the amniochorion incites
polymorphonuclear tissue infiltration and a higher degree of
histologic chorioamnionitis in pregnancies complicated by
PTB130; (3) in vitro, GBS and E. coli have the capacity to attach
to the chorioamniotic membranes131; (4) in animal models of
Inside
Innate
immune
response
Cervix
Columnar epithelium
Nucleus
Dendritic
cell
Pathogen
(bacterial or fungal)
Neutrophil
PAMPs
TLR/DAMP receptor/
RAGE/PRR-TLR
NLR
IRAK
Necrotic cell
Macrophage
MyD88
NF-B
Chemokines
Cytokines
DAMPs
Defensins
Calprotectin, calgranulin
Viral DNA
Bacterial DNA
Outside
Figure 39-5 Mechanical and immune barriers of the cervix. The mucus plug is traditionally considered the cervixs mechanical barrier against
ascending infection. The data suggest that the mucus plug also carries innate immune properties, consisting of immune cells (dendritic cells, neutrophils, macrophages), and molecular components including pattern recognition receptors (PRR); Toll-like receptors (TLR); receptor for advanced
glycation end products (RAGE); nucleotide-binding, oligomerization domain (NOD)-like receptor (NLR); cytokines and chemokines; damageassociated molecular patterns (DAMPs); pathogen-associated molecular patterns (PAMPs); and antimicrobial peptides (defensins, calgranulins). The
microbe-specific molecules that are recognized by a given PRR (NOD, TLR) trigger an innate immune response via specific signaling pathways that
include tumor necrosis factor- (TNF-); myeloid differentiation primary response gene (88) protein (MyD88); and interleukin (IL)-1 receptor
associated kinases (IRAK).
604
infection-induced PTB, transcervical and choriodecidual inoculation of GBS is followed by transmigration of bacteria from
the choriodecidual space to the amniotic fluid cavity, a graded
amniotic-fluid leukocyte infiltration response, and levels of
proinflammatory cytokines (tumor necrosis factor- [TNF-],
IL-6, IL-1), prostaglandins (PGE2, PGF2), and uterine
activity.132,133
A secondary route of intra-amniotic infection is probably
hematogenous transplacental seeding of the fetus, with the
infectious organisms, in particular Haemophilus influenzae or
F. nucleatum, originating from other parts of the body including
the mouth.134,135 Iatrogenic infections during invasive procedures such as chorionic villous sampling, amniocentesis, and
cordocentesis are also possible.136 Retrograde microbial seeding
of the amniotic fluid through the fallopian tubes or colonization of the uterine endometrium before implantation has also
been proposed.126 Compelling evidence in support of these
pathways remains to be provided.
Emerging evidence suggests that microorganisms are
sensed by the innate components of the immune system,137
leading to a cascade of events that culminate in PTB. These
sensing components include soluble pattern-recognition receptors (PRRs), lectin, and C-reactive protein. The transmembrane
PRRs include scavenger receptors, C-type lectins, and Toll-like
receptors (TLRs). Intracellular PRRs include NOD1 and NOD2,
retinoic acidinduced gene type 1, and melanoma differentiationassociated protein 5, which mediate recognition of intracellular
pathogens (e.g., viruses).138 The best-studied PRRs are the
TLRs.137 Because of their strategic positioning at the maternalfetal interface (the decidua),139 fetal membranes, and myometrium,140 TLR4 and TLR2 are considered major mediators by
which the maternal and fetal reproductive tissues can respond
to infection. TLR4 is recognized as the membrane-bound receptor that triggers LPS signaling of gram-negative microbes.141 A
strain of mice bearing a spontaneous disabling mutation for
TLR4 is less likely than wild-type mice to have preterm delivery
after intrauterine inoculation of heat-killed bacteria or administration of LPS.98,142 TLR2 has been shown to be involved in
recognition of lipoproteins, peptidoglycan, and glycolipids of
gram-positive bacteria and Mycoplasmataceae.143 How TLRs
distinguish between commensal and pathogenic microorganisms in vaginal or other sites remains unknown.
Although the full spectrum of TLR-mediated responses
remains to be elucidated, it is known that, once engaged by
pathogen-associated molecular patterns (PAMPs), these bacterial sensors trigger a downstream molecular chain of events that
lead to synthesis and release of proinflammatory cytokines such
as TNF-; interferon-; cytokines IL-12, IL-6, IL-1; and many
others via an NF-Bmediated mechanism.144 Key chemokines
secreted after TLR activation include IL-8; monocyte chemoattractant proteins 1, 2, 3, and 4; macrophage inflammatory proteins 1 and 1; and RANTES (regulated on activation, normal
T cell expressed and secreted). Traditionally, it is believed that
activation of TLRs induces a T helper cell 1 (TH1) cytokine-type
response (i.e., IL-2, interferon-, lymphotoxins). However,
using genetically engineered animal models and a variety of in
vitro cell culture systems, Pulendran and colleagues showed that
TLR4 engagement can also trigger a TH2 cytokine reaction consistent with the release of IL-4, IL-5, IL-6, and the antiinflammatory cytokine IL-10, depending on bacterial type.145
The significance of this observation during human pregnancy
remains to be clarified, but these results underline the concept
that the balance among proinflammatory and anti-inflammatory

cytokine responses can dictate the intensity and possible resolution of an infectious process.
The biologic activity of the TLRs depends not only on the
presence of bacterial pathogenassociated molecular patterns
but on a palette of intracellular signaling adaptors (e.g., MyD88)
and co-receptor molecules (e.g., CD14) that associate with
TLRs in complex supramolecular arrangements.146 Equally
important is that TLR signaling can be elicited by endogenous
damage-associated molecular patterns (DAMPs).147 Like cytokines, DAMPs (i.e., high-mobility group box-1 [HMGB1, or
amphoterin], S100 proteins) are endogenous proinflammatory and pro-oxidative stress molecules. Acting through TLR2,
TLR4, and the receptor for advanced glycation end products
(RAGE), DAMPs recruit inflammatory cells, which in turn
amplify innate immune responses and enhance levels of cytokine activation.147 It was reported that the RAGE-DAMP system
is present in women with PTB and intra-amniotic infection.148
Activation of the RAGE-DAMP system correlates with the
degree of inflammation and oxidative stress damage in amnion
epithelial, decidual, and extravillous trophoblast cells (Fig.
39-6).149 PAMPs and DAMPs may continue to keep active the
processes that lead to fetal cellular damage.
Last, the roles of soluble receptor modulators (soluble TLR2,
soluble TNF receptor-1, soluble IL-6 receptor, soluble glycoprotein (gp)130, and soluble RAGE) in fine-tuning human TLRmediated signaling have just begun to be elucidated.150-153
Downstream of the TLR receptor, other molecules such as prokineticin amplify the inflammatory response,154 so that lentiviral knockout of the prokineticin receptor inhibits the ability of
the myometrium to produce proinflammatory cytokines in
response to LPS.155
Role of Proinflammatory Agents in Preterm Birth
Inflammation and its mediators (e.g., chemokines such as IL-8;
proinflammatory cytokines such as IL-1 and TNF-; and
others, such as platelet activating factor and prostaglandins) are
central to infection-induced PTB. IL-1 was the first cytokine
implicated in the onset of infection-associated PTB.156 Evidence
of the role of IL-1 in the pathogenesis of PTB includes the
following: (1) It is synthesized by human decidua in response
to bacterial products157; (2) it stimulates prostaglandin production by human amnion and decidua158; (3) IL-1 and IL-1
concentrations and IL-1-like bioactivity are increased in the
amniotic fluid of women with preterm labor and infection159;
(4) intravenous IL-1 stimulates uterine contractions160; and
(5) administration of IL-1 to pregnant animals induces preterm
labor and birth,161 and this effect can be blocked by the administration of its natural antagonist, the IL-1 receptor antagonist
(IL-1ra).162
Evidence supporting the role of TNF- in the mechanisms
of infection-associated PTB include the following: (1) TNF-
stimulates prostaglandin production by amnion, decidua, and
myometrium95; (2) human decidua can produce TNF- in
response to bacterial products163,164; (3) amniotic fluid TNF-
bioactivity and immunoreactive concentrations are elevated in
women with preterm labor and intra-amniotic infection165; (4)
in women with preterm PROM and intra-amniotic infection,
TNF- concentrations are higher in the presence of labor165; (5)
TNF- can stimulate the production of MMPs,166,167 which have
been implicated in membrane rupture168-170; (6) application of
TNF- to the cervix induces changes that resemble cervical
39
605
Systemic or
ascending infection
(PAMPs)
Inflammation
Cytokines, chemokines
Oxidative stress
Free radicals, ROS
FETAL CELLULAR DAMAGE
Figure 39-6 Working model for the potential role of the

RAGE-DAMP system leading to inflammation, oxidative
stress, and fetal damage. DAMPs, damage-associated
molecular patterns; HMGB1, high-mobility group box-1;
PAMPs, pathogen-associated molecular patterns; RAGE,
receptor for advanced glycation end products; ROS, reactive oxygen species; S100A8, calgranulin A; S100A12, calgranulin C.
Release of damage-associated
molecular patterns (DAMPs)
HMGB1, S100 proteins (S100A12, S100A8) etc.
ripening171; (7) TNF- can induce preterm parturition when

administered systemically to pregnant animals172,173; and (8)
TNF- and IL-1 enhance IL-8 expression by decidual cells,
and this chemokine is strongly expressed by term decidual cells
in the presence of chorioamnionitis.174
Other cytokines and chemokines (IL-6,175-180 IL-10,160,181,182
IL-16,183 IL-18,184 colony-stimulating factors,185-187 macrophage
migration inhibitory factor,188 IL-8,187,189-193 monocyte chemotactic protein-1,194 epithelial cellderived neutrophil-activating
peptide-78,195 and RANTES196) have also been implicated in
infection-induced PTB. The redundancy of the cytokine
network implicated in parturition is such that blockade of a
single cytokine is unlikely to be sufficient to prevent PTB in the
setting of infection. For example, preterm labor after exposure
to infection can occur in knockout mice for the IL-1 type I
receptor, suggesting that IL-1 is sufficient, but not necessary, for
the onset of parturition in the context of intra-amniotic infection or inflammation.197 However, blockade of multiple signaling pathways (e.g., IL-1 and TNF-) in a double-knockout
mouse model decreased the rate of PTBs after the administration of microorganisms.173
In the setting of intra-amniotic infection, a large array of
cytokines (e.g., IL-6, IL-8, IL-1, granulocyte-macrophage
colony-stimulating factor) are found in the amniotic fluid. The
sources of amniotic fluid cytokines probably include decidua,
fetal membranes, and the fetus. However, independent of the
source, amniotic fluid IL-6 and many other cytokines induce
recruitment of fetal neutrophils.198 Cytokines also induce
degranulation of neutrophilic granulocytes with release of
MMP-1 (collagenase). With the exception of TLR3, human leukocytes express the mRNAs of TLR1 through TLR10.199 Expression of TLR2 is higher in circulating leukocytes obtained from
women in labor than from pregnant women not in labor.78
Trauma, abruption or
intra-amniotic bleeding
(DAMPs)
RAGE activation
Thus, neutrophil secretion of cytokines and chemokines probably follows their recognition of a large repertoire of bacterial
PAMPs and cellular DAMPs. Taken together, these observations
highlight the maternal and fetal involvement in the process of
intra-amniotic inflammation and the role of mother and fetus
in amplification of the inflammatory status of the amniotic
fluid and tissue damage in a forward loop fashion.200
Increasing evidence points to a role for complement in
inflammation-induced PTB. Increased cervical deposition of
the split complement product C3 was noted in mouse models
of preterm labor induced both by LPS and by progesterone
withdrawal.201 Although work in this area is in its infancy, there
is evidence that complement activation is restricted to preterm
labor and is absent from physiologic parturition at term.202,203
Whether these inflammatory agents truly operate independently from intrauterine infection (i.e., sterile inflammation) or
whether intrauterine infection mediates all of these effects is
unclear, and reexamination using modern techniques to identify intrauterine infection is required (see Preterm Birth Resulting from Intra-amniotic Infection, earlier).
In addition to the proinflammatory events just described, a
wide variety of anti-inflammatory mediators are now known to
operate in the pregnant uterus. The most widely known of these
is the anti-inflammatory cytokine IL-10, which is thought to be
important for the maintenance of pregnancy.204-206 Its concentrations are increased in intra-amniotic inflammation,207 suggesting that IL-10 may play a role in damping the inflammatory
response208-213 and may have therapeutic value.214-219 IL-10
knockout mice are more sensitive to LPS-induced preterm labor
than wild-type micea defect that is ameliorated by external
IL-10 administration.220 In wild-type animals, exogenous IL-10
also attenuates the preterm labor phenotype. For example, in a
nonhuman primate model of intrauterine infection, pregnant
606
rhesus monkeys were allocated to one of three interventional

groups: (1) intra-amniotic IL-1 infusion with maternal dexamethasone intravenously; (2) intra-amniotic IL-1 and IL-10;
or (3) intra-amniotic IL-1 administered alone. Dexamethasone and IL-10 treatment significantly reduced IL-1-induced
uterine contractility. The amniotic fluid concentrations of
TNF- and leukocyte counts were also decreased by IL-10 treatment.160 In addition to these beneficial effects on inhibition of
contractility and inflammation, administration of IL-10 in
animal models of infection has also been associated with
improved pregnancy outcome.214,221
Another major group of anti-inflammatory molecules, the
lipoxins,222 are also expressed in the reproductive tract.223 Lipoxins are part of a group of pro-resolution molecules that appear
to actively terminate the inflammatory process, promoting neutrophil engulfment and inhibiting proinflammatory cytokine
expression. Although their role in infection-induced PTB has
not been elucidated, they circulate in increasing concentrations
as pregnancy advances, their receptor is present in the myometrium of pregnant women, and they attenuate the myometriums proinflammatory cytokine response to LPS.223 Thus, they
also show promise as therapeutic agents for infection-induced
preterm labor.
In summary, there is increasing interest in the use of antiinflammatory strategieseither for upregulating endogenously
produced molecules or for external application of antiinflammatory agents to treat preterm labor.224 These issues will
be discussed further in the chapter on treatment of preterm
labor.
Bacterial Species and the Intensity of Intra-amniotic
Inflammatory Responses
Once present in the amniotic fluid, microorganisms can stimulate the production of proinflammatory cytokines through activation of fetal membrane TLR receptors.225 Several
microorganisms (e.g., Ureaplasma, Mycoplasma) are traditionally considered to have low virulence.113,226 Studies describing
the presence of Ureaplasma parvum and M. hominis in the
amniotic fluid of second-trimester asymptomatic women are in
support of this concept.103 Menon and coworkers demonstrated
in vitro that in comparison with gram-positive and other gramnegative bacteria, Ureaplasma has a lower proinflammatory
effect on fetal membranes.225 However, isolation of Ureaplasma
and Mycoplasma in the amniotic fluid has been consistently
associated with a wide range of adverse outcomes, such as early
abortion, stillbirth, prematurity, and neonatal morbidity and
mortality.227 Although an intense intra-amniotic inflammatory
response is often encountered at the time of clinical onset of
PTB, these studies prove association, not causation.228 Evidence
that these so called silent microorganisms are capable of triggering an inflammatory response in vivo that can induce PTB
was recently provided by Novy and coworkers.229 They inoculated U. urealyticum and M. hominis into the amniotic fluid of
rhesus monkeys, which resulted in an increase in a myometrial
contractile activity that was preceded by an intense proinflammatory cytokine response and prostaglandin synthesis.229
Invasion of the amniotic fluid with gram-positive anaerobes,
E. coli, and GBS results in intra-amniotic inflammation and
fetal sepsis.114 However, intra-amniotic inflammation can also
occur in the absence of positive amniotic-fluid culture results.110
As previously mentioned, uncultivated or difficult-tocultivate bacteria may play an important role. The extent of
intra-amniotic inflammatory response triggered by such bacteria, separately or as a group, remains to be determined.
STRETCH AND PARTURITION
Myometrial Stretch and Term and Preterm Birth
During human pregnancy, significant physical and biochemical
adaptive transformations of the myometrium are required to
aid the development and growth of the fetus. These transformations facilitate conversion of the uterus into a thin-walled
muscular organ and maintain myometrial quiescence.230 Mathematical models derived from studies aimed to understand
myocardial contractility indicate that wall stress (applied force
per unit of cross-sectional area) is directly proportional to
intracavitary pressure and radius of the curve, but inversely
proportional to the thickness of the muscular wall.231 The relevance of this model for the pregnant uterus is that the thickness of the myometrium and intra-amniotic pressure both
influence uterine wall stress.232
Intra-amniotic pressure remains low through human gestation.233 A low pressure is achieved through various electrophysiologic (e.g., by decreased number of gap junctions)234 and
biomolecular (e.g., by hormonal signals that stimulate macrophage migration, by release of cytokines, by activation of
inflammatory transcription factors) processes that maintain a
state of uterine quiescence in the setting of progressive myometrial stretch.235 The mechanisms that signal conversion of the
myometrium from a quiescent to a highly contractile state are
unknown. However, it is reasonable to propose that several of
these mechanisms are mechanically activated.235
A large body of clinical data implicates excessive myometrial
stretch in the genesis of PTB. For example, a high amniotic fluid
index (AFI 25 cm) is associated with a significantly increased
incidence of PTB.236 Polyhydramnios and multiple gestations
are the most relevant examples.236,237 There has been increased
interest in identifying the molecular mechanisms responsible
for the onset of uterine contractility.238 Progesterone receptor
transcriptional activity has been proposed as critical for the
preservation of myometrial relaxation.238 This inhibitory effect
seems to be mediated by repressing the expression of genes that
encode contraction-associated proteins.238,239 Two such genes
are connexin-43 and oxytocin receptor. The connexin-43 gene
encodes a protein with critical roles in synchronizing myometrial contractile activity,234 and oxytocin receptor gene controls
responsiveness of myometrial cells to oxytocin.240 Mechanical
stretch, however, upregulates expression of connexin-43, an
effect that is inhibited by progesterone.241 In vitro data demonstrated that the upregulation of the expression of oxytocinreceptor mRNA that occurs as a result of myometrial stretching
is controlled via DNA binding to various transcription factors,
including activator protein-1 (AP-1) and CCAAT/enhancer
binding protein (C/EBP)-.242 Interestingly, the transcription
factor NF-B did not increase the promoter activity of the
oxytocin receptor gene.242 That mechanical stimulation of the
uterine wall promotes expression of oxytocin receptor mRNA,
and that this effect is favored by progesterone withdrawal, was
confirmed in vivo.243
Myometrial elongation stimulates the expression of a variety
of cytokines and chemokines (e.g., CCL2, CXCL8, CXCL1,
CCL2) with a characteristic proinflammatory profile for
preterm labor tissues.244,245 In various experimental models, the
primary mediator of myometrial stretch-induced inflammation
39
appears to be NF-B.244 These experiments provide support for

the concept that uterine distention carries an inflammatory
component. Other mechanisms that can lead to activation of
myometrial contractility subsequent to excessive mechanical
stretch are (1) increases in the transcription factor AP-1; (2)
activation of mitogen-activated protein kinase (MAPK)-dependent and cyclooxygenase (COX)-2-mediated prostaglandin
synthesis246,247; (3) downregulation in the expression of stretchdependent K+ (SDK) channels248; (4) changes in the expression
of transient receptor potential canonical (TRPC) proteins with
a role in store-operated calcium entry in human myometrial
smooth muscle cells249; and (5) upregulation in the expression
pattern of gastrin-releasing peptide, a molecule with agonistic
contractile properties.250
Fetal Membrane Stretch and Term and Preterm Birth
Fetal membranes carry important protective and biochemical
functions. In physiologic pregnancy, the fetal membranes
undergo progressive mechanical stretch, allowing their accommodation to the growing uterus.251 The human fetal membranes are complex tissues composed of highly specialized
epithelial and mesenchymal cells embedded in an extracellular
matrix composed primarily of collagen and proteoglycans.252
Interstitial types I and III collagens predominate and represent
the main structural components that maintain the mechanical
integrity of the membranes.252 Collagen can be stretched but it
is not elastic, whereas other structural components (e.g., elastin)
of the extracellular matrix are both stretchable and elastic.
By comparing the surface area of the fetal membranes with
that of the uterine cavity, Parry-Jones and Priya demonstrated
that after 28 weeks of gestation, the intact fetal membranes are
under tension and in a state of active stretch.253 A significant
decrease in the elasticity of membranes that ruptured before
labor was observed independent of gestational age. In a study
conducted by Millar and coworkers, the investigators confirmed
marked differences in elasticity between individual membranes
and a diminished ability of the membranes that rupture before
term to stretch.254
Traditionally, rupture of the fetal membranes was viewed as
a mechanical event.255 However, although this might hold true
for specific clinical cases, maintenance of the tensile strength of
fetal membranes appears to involve a highly coordinated balance
between synthesis and degradation of various components of
the extracellular matrix.256 It has been proposed that changes in
the membranes, including decreased collagen content, altered
collagen structure, and increased collagenolytic and proinflammatory activity, are associated with preterm PROM and PTB.253
In vitro, stretching of the fetal membranes induces collagenase
activity.257 Thus, it is possible that, in vivo, a loaded state of the
fetal membranes might facilitate their susceptibility to enzymatic degradation. Mechanical stimulation of the amnion cells
results in increased expression of COX-2 and PGE2 production,
suggesting a feed-forward loop under which stimulation of
uterine contractions magnifies the degree of stretching to the
point of rupture and preterm delivery.258 Because this phenomenon is mediated through members of the AP-1 family of transcription factors (i.e., Fos and Jun) and NF-B, involvement of
various inflammatory pathways has also been also proposed.
Synthesis and expression of the proinflammatory cytokines
IL-8 and IL-1 are increased after exposure of the whole membranes and amnion cells to mechanical stretch.257-259 Interestingly, expression of IL-8 was upregulated in both amnion
607
Rapid increases in myometrial stretch due to polyhydramnios,

multifetal gestations or uterine anatomic abnormalities
Myometrium
PG, oxytocin
receptors,
IL-8
Integrin-MAPK
signaling
MMPs
IL-8
Amniochorion
PG
IL-8
PG
Cervix
Contractions
ECM degradation
PTL !/" PPROM

Figure 39-7 Proposed mechanisms by which stretch can induce
preterm labor. ECM, extracellular matrix; IL-8, interleukin-8; MAPK,
mitogen-activated protein kinase; MMPs, matrix metalloproteinases;
PG, prostaglandins; PPROM, preterm premature rupture of membranes;
PTL, preterm labor.
and chorion, but not in decidua.259 Studies using an in vitro

cell culture model for fetal membrane distention demonstrated upregulation of proinflammatory genes, including
those for IL-8 and pre-B-cell colony-enhancing factor (visfatin).260 Stretching of the fetal membrane in vitro results in
overexpression of various genes, specifically those for IL-8,
interleukin-enhancer binding factor 2, huntingtin-interacting
protein 2, and interferon-stimulated gene encoding a 54-kDa
transcript.261
These molecular mechanisms, schematically represented in
Figure 39-7, highlight that myometrial and excessive mechanical stretch of the fetal membranes could lead to PTB through
integration of multiple cellular and extracellular signaling pathways. Each of these mechanisms can be linked to various phenotypic components of the PTB syndrome: polyhydramnios,
multiple fetuses, and twin-twin transfusion syndrome.
ACTIVATION OF THE MATERNAL-FETAL HPA AXIS
IN TERM AND PRETERM BIRTH
Considerable and well-deserved attention has been paid to glucocorticoid physiology during human pregnancy. Substantial
research data indicate the existence of a positive feedback loop
involving glucocorticoids, proinflammatory cytokines, prostaglandins, surfactant protein-A, and 11-HSD type-1 in human
fetal membranes in women who are going to have a preterm
delivery.262 There is evidence to support the hypothesis that this
mechanism is active in human preterm parturition in the
setting of infection-induced histologic chorioamnionitis.263
Additionally, in the model of preterm parturition, stress may be
involved in the production of abundant biologically active glucocorticoids and prostaglandins, which might promote accelerated fetal maturation and initiation of parturition.262
A schematic representation of the physiology of the fetal
hypothalamic-pituitary-adrenal-placental axis in pregnancy is
presented in Figure 39-8. Corticotropin-releasing hormone
(CRH; a 41-amino-acid peptide) appears to be the mediator of
stress-associated preterm deliveries.264 The glucocorticosteroid
608
Stress
(")
Hypothalamus
CRH
(")
Placenta,
decidua, and
amniochorion
Pituitary
ACTH
Adrenal gland
Cortisol
Figure 39-8 The fetal hypothalamic-pituitary-adrenal-placental
axis in pregnancy. ACTH, adrenocorticotropic hormone; CRH,
corticotropin-releasing hormone.
hormone cortisol displays an inhibitory effect on the hypothalamic CRH production.264 On the other hand, cortisol stimulates the placental production of CRH.264 A positive, feed-forward
system of CRH is a unique biologic feature of the placenta,
causing progressive increases in placental CRH production as
pregnancy advances to term. The effect of CRH seems to be
broad, based on its expression by various placental, chorionic,
amniotic, and decidual cells.265 In uncomplicated pregnancies,
maternal plasma free CRH levels rise exponentially during the
second half of pregnancy and peak during labor.81 The exponential rise in maternal plasma CRH concentration is associated
with a concomitant fall in levels of CRH binding protein,
leading to a rapid increase in maternal circulating levels of
bioavailable CRH. This suggests that CRH may act directly as a
trigger for parturition in humans. The CRH concentration
across the gestation curve in women with subsequent PTB runs
parallel but to the left of the CRH curve for term pregnancy.266
Despite these findings, it is unclear whether precocious elevation of maternal plasma CRH levels is an epiphenomenon or
a trigger for preterm delivery mechanisms.267 Because CRH
maternal plasma concentrations are elevated in both term and
preterm parturition, it appears that CRH is part of a common
pathway of labor.
Several effector mechanisms have been proposed as being
involved in activation of the common pathway of labor by CRH.
First, the output of PGF2 and PGE2 production and synthesis
is stimulated by CRH in amniotic, chorionic, decidual, and
placental cells.268,269 Cortisol synthesized in response to CRH
can increase amnion COX-2 expression while inhibiting chorionic PGDH expression.270-272 The net result would be an increase
in the bioavailability of prostaglandins. Prenatal stress increases
not only prostaglandin levels but also that of maternal circulating inflammatory markers (e.g., IL-6, IL-8, TNF-) that are
associated with prematurity.273 The link between stress hormones and various inflammatory signaling pathways in pregnancies complicated by infection and histologic chorioamnionitis
has been demonstrated.274 Torricelli and associates showed that
expression of the mRNAs of CRH and its receptor CRH-R1 was

higher in pregnancies complicated by preterm PROM and
chorioamnionitis.274 In their experimental setup, endotoxin
increased trophoblast CRH, urocortin-2, and CRH-R1 mRNA
expression in a dosage-dependent manner. Moreover, prostaglandins increase cervical expression of IL-8, which recruits and
activates neutrophils, releasing additional MMPs and collagenases, which can promote cervical extracellular matrix disorganization and weakening of the fetal membranes.71 The secretion
of IL-8 and MMP-1 was significantly higher, and MMP-3 secretion was lower, in preterm cervical fibroblasts. In summary,
cervical ripening seems to have an inflammatory component,
with CRH possibly contributing to its initiation. However,
preterm and term cervical fibroblasts might have different phenotypes based on different secretion patterns of IL-8, MMP-1,
and MMP-3.71
Progesterone is a hormone with key roles in human parturition. Data published by several groups suggest that CRH directly
modulates the endocrine function of placental trophoblasts,
including production of progesterone275 and estrogens.276
Keeping in mind the common pathway to parturition, it is
plausible that CRH-induced PGE2, and PGF2 increase the
expression of the PR-A isoform and decrease that of the PR-B
isoform in myometrium, cervix, and decidua.73,277,278 Because
PR-A antagonizes many of the classic PR-mediated genomic
effects of PR-B, prostaglandins appear to induce a functional
progesterone withdrawal. Decidual cells, and not amnion and
chorion cells, seem to be the direct target of progesterone during
human pregnancy.279 This assertion is supported by Merlino
and colleagues, who reported that in contrast to the intense
nuclear PR mRNA and protein expression observed in decidual
cells, PR expression is barely detectable in amnion and
chorion.279
Experimental data also suggest that a functional increase in
myometrial CRH signaling may lead to activation of myometrial contractility and labor. A direct CRH signaling effect is
possible based on the observation that both CRH-R1 and
CRH-R2 are expressed in pregnant upper- and lower-segment
human myometrium.280 Placing these observations in the
context of labor is difficult because the protein level of CRH-R1
in the upper contractile segment was significantly downregulated in pregnancy, with a further decrease at the onset of labor.
No significant changes in CRH-R2 expression were observed in
either upper- or lower-segment myometrium. There is evidence
for a myometrial relaxing effect of CRH, favoring uterine quiescence.281 Therefore, the role of CRH in controlling activation
of myometrial contractility, both term and preterm, continues
to be an enigma.
Fetal Control of the Onset of Parturition
Using matched maternal and fetal pairs samples, Lockwood and
coworkers evaluated activation of the maternal-fetal HPA axis
in patients undergoing cordocentesis during the second half of
gestation.282 The authors noted that in physiologic pregnancy,
placenta-derived maternal serum CRH values correlated better
with fetal (r = 0.40) but only modestly with maternal (r = 0.28)
cortisol levels. Based on these findings, it is possible that
placental-derived CRH stimulates the release of fetal pituitary
adrenocorticotropin to enhance fetal adrenal cortisol production, which further stimulates placental CRH release. At term,
cortisol released into the amniotic fluid can directly stimulate
fetal membrane prostaglandin production by increasing
39
amniotic COX-2 expression and inhibiting the chorionic

prostaglandin-metabolizing enzyme PGDH.271,283 This suggests
that a local amniotic-fluid positive feedback loop exists to tie
fetal HPA axis maturation to parturition.
Compelling data indicate that the fetus actively participates
in controlling the timing of labor via production of adrenal
hormonal precursors.284 This argument is supported by the evidence that at term, before the onset of labor, the weight and
volume of the fetal adrenal gland equals that of the adult.285 An
important role of the fetus in stress-induced PTB has been
proposed.286-288 By using volume analysisvirtual organ
computer-aided analysis (VOCAL)of three-dimensional
(3D) ultrasonographic images, Turan and colleagues demonstrated that a birth-weight-corrected fetal adrenal gland volume
of greater than 422 mm3/kg was a significant predictor of
PTB.289 Development of the fetal adrenal zone of the fetal
adrenal gland after 28 to 30 weeks gestation creates the context
of a stress-induced activation of the placental-fetal HPA axis
and enhancement of placental estrogen production. This is
because a unique adaptation evolved in primates: placental
expression of CRH.290 Placental CRH stimulates the fetal adrenal
zone, an adrenal structure unique to primates, to produce dehydroepiandrosterone sulfate (DHEAS), which is converted to
estrogen by the placenta. In addition, CRH can directly augment
fetal adrenal DHEAS synthesis.291 Remarkably, fetuses exposed
to intra-amniotic inflammation also have higher adrenal gland
volumes and lower cortisol-to-DHEAS ratios.292 Placental sulfatases facilitate conversion of fetal adrenal gland DHEAS to
estradiol, estrone, and estriol. These estrogens increase myometrial expression of contraction-associated proteins such as oxytocin receptor and connexin-43.293,294 Because reductions in
PR-B expression lead to increased expression of the estrogen
receptor- (ER-), placental estrogen production would act
synergistically to prostaglandin-induced increases in myometrial ER- expression.295
PROGESTERONE WITHDRAWAL AND PARTURITION
The role of progesterone in the timing of the onset of human
parturition has long puzzled reproductive biologists.
Progesteroneliterally, in favor of carrying [a baby]is
secreted initially by the corpus luteum and then by the placenta
in large amounts during pregnancy. It maintains uterine quiescence by inhibiting myometrial contractions.296 In many species,
including most mammals, the onset of parturition is triggered
(in part) by an increase in circulating estrogen and a decrease
in circulating progesterone levels.297 Although there is no acute
change in progesterone levels at the time of parturition,298 the
importance of progesterone in human pregnancy is shown by
the efficacy of the antiprogesterone mifepristone as an abortioninducing agent in early pregnancy299 and its actions in inducing
labor in later pregnancy300 (although its side-effect profile is
such that it should be used only in the scenario of intrauterine
fetal death). Additionally, progesterone administration reduces
the rate of spontaneous PTB by around 50% in women at high
risk because of a history of a previous PTB and in those who
are at risk because of a short cervix.301
Although progesterone levels do not change as human labor
starts, increasing evidence suggests that labor is associated with
a functional progesterone withdrawal (see Mesiano and coworkers for a review302). Briefly, although circulating progesterone
levels do not change, parturition is associated with changes in
609
the relative proportions of the nuclear PR-A and PR-B, through

which progesterone is thought to exert the bulk of its actions.
PR-A is thought to act as an endogenous repressor of PR-B, with
an increase in the ratio of myometrial PR-A to PR-B, which
decreases the response of the uterus to the relaxant effect of
progesterone. The role of other progesterone receptors such as
PR-C and PR cofactors and repressors is still debated,303 and
work continues into downstream mediators such as the miR-200
family and its targets, zinc finger E-box binding homeobox
proteins ZEB1 and ZEB2.239 Regardless, progesterone and
NF-B (see later) seem to exert a mutually repressive effect on
each others actions, generating a feed-forward loop when one
starts to predominate.63,304
GENE-ENVIRONMENT INTERACTION
A gene-environment interaction is said to be present when the
risk for a disease (occurrence or severity) among individuals
exposed to both the genotype and environmental triggers is
either more severe or less severe than that predicted from the
presence of either the genotype or the environmental exposure
alone.305,306 There is evidence for a gene-environment interaction in infection-related PTB.307 In a case-control study, patients
who had a spontaneous preterm delivery (>37 weeks) were
compared with controls delivered after 37 weeks. The environmental exposure was bacterial vaginosis diagnosed by symptomatic vaginal discharge, a positive whiff test, and clue cells on
a wet preparation. The genotype of interest was TNF- allele
2.308 The authors found that patients with both bacterial vaginosis and the TNF- allele 2 had an odds ratio (OR) of 6.1
(95% confidence interval [CI], 1.9 to 21) for spontaneous PTB,
and that this OR was higher than for patients with either bacterial vaginosis or carriage of the TNF- allele alone, suggesting
that a gene-environment interaction predisposes to PTB.307,309
A schematic representation of the principal molecular and
biochemical mechanisms responsible for the main pathways of
preterm parturition is presented in Figure 39-9.
Stretch
Inflammation
Integrins
IL-1
TNF-
Abruption
Thrombin
Stress
CRH
Estrogen
MMPs
IL-6 and 8
COX2
PGDH
PR-B
PTL or pPROM
Figure 39-9 Principal biochemical mechanisms responsible for the

main pathways of preterm parturition. COX-2, cyclooxygenase-2;
CRH, corticotropin-releasing hormone; IL, interleukin; MMPs, matrix
metalloproteinases; PGDH, prostaglandin dehydrogenase; pPROM,
preterm premature rupture of membranes; PR-B, progesterone receptor type B; PTL, preterm labor; TNF-, tumor necrosis factor-.
610
Spontaneous Preterm Parturition

as a Syndrome
It is increasingly clear that preterm labor is not a single disease,
but a syndrome with multiple causes. The classification system
used in this chapter is the system proposed by a project funded
by the Global Alliance to Prevent Prematurity and Stillbirth.10
Because the etiology of preterm labor is often not known, this
system has deliberately avoided classification based on cause
and has chosen a system based on phenotype. The phenotypes
are based on the following: (1) significant maternal conditions
(e.g., extrauterine infection, clinical chorioamnionitis, maternal
trauma, worsening maternal disease, uterine rupture,
preeclampsia/eclampsia), significant fetal conditions (e.g., fetal
demise, IUGR, abnormal fetal heart rate or biophysical profile,
infection or fetal inflammatory response syndrome, fetal
anomaly, alloimmune fetal anemia, polyhydramnios, multiple
fetuses), and pathologic placental conditions (e.g., histologic
chorioamnionitis, placental abruption, placenta previa); (2) the
presence or absence of signs of initiation of parturition; and (3)
whether the pathway to delivery is caregiver initiated or spontaneous. The aim is to provide a classification system to use in
both population surveillance and research, so that when specific
types of PTBs are discussed, studied, or compared across populations or over time, categories have consistent definitions that
are widely understood and accepted.10 Such an aim is laudable,
and this is the classification system followed here, but before it
is widely adopted and used, a paradigm shift will have to occur
in many clinicians approach to and understanding of PTB
(see Fig. 39-1).
MYOMETRIAL CONTRACTILITY
Myometrial contractions are a hallmark of parturition, both at
term and before term. The biochemistry of myometrial contractility has been extensively reviewed.310,311 Contraction of
individual myocytes is achieved by increasing intracellular
calcium levels, which ultimately promotes phosphorylation of
myosin, and hence increased actin-myosin cross-links and
contraction. During labor, the individual myocytes contract
together as a functional syncytium. This increased coordination
is induced by gap junction formation, which increases cell-tocell communication. Gap junctions develop in myometrium
before labor and disappear after delivery.234,312-315 Expression of
gap junction protein, connexin-43, in human myometrium is
similar in both term and preterm labor.241,316-319 These findings
suggest that the appearance of gap junctions and increased
expression of connexin-43 (contraction-associated proteins318,320,321) are part of the underlying series of molecular and
cellular events responsible for the switch from contractures to
contractions before the onset of parturition. Estrogen, progesterone, and prostaglandins have all been implicated in the regulation of gap junction formation, and they influence connexin-43
expression.67,322,323
Lye and colleagues324 proposed that the myometrium undergoes sequential phenotypic remodeling during pregnancy.
Their studies were undertaken in rodents but have implications
for humans. Three distinct stages of rat gestational myometrial
development were recognized:
1. Proliferative, in which the number of myocytes increased,
as demonstrated by greater levels of cell nuclear antigen
labeling and protein expression in early pregnancy. This
phenotype coincided with a higher myometrial expression of antiapoptotic proteins (BCL2 and BCL2L1 [formerly BCL-xL]).
2. Synthetic, in which the myometrial cells underwent
hypertrophy, as demonstrated by a higher protein-toDNA ratio in the second half of pregnancy. This stage
coincided with a higher secretion of extracellular matrix
proteins from the myocytes, in particular collagen I and
collagen III, as well as a high concentration of caldesmon
(a marker of synthetic phenotype).
3. Contractile, which occurred at the end of pregnancy and
coincided with low myometrial expression of interstitial
matrix proteins and high expression of components of
the basement membrane (laminin and collagen IV).
In humans, restrictions on tissue access mean that comparisons are largely limited to those between pregnant women
delivered in labor at term and women delivered before the onset
of labor. Gene microarray studies suggest that various cellular
processes, including inflammation, transcriptional regulation,
and intracellular signaling, are upregulated in laboring compared with nonlaboring myometrium, with these processes
overlapping but being slightly different from those occurring
in the cervix and fetal membranes.325,326 Notwithstanding
the important contribution that arrays made to understanding of myometrial physiology, it is increasingly recognized
that computerized modeling has much to contribute to the
understanding of uterine contractions. A model would integrate state-of-the-art knowledge in cardiac electrophysiology,
biochemistry/gene expression, and anatomy, and it would
provide an in silico arena for testing of novel therapies. This
approach, already well advanced in cardiac pathophysiology,327
is at a much earlier stage for pregnant uterine physiology.328
CERVICAL ADAPTATION AND REMODELING
DURING HUMAN PREGNANCY
Traditionally, it was held that the closed cervix holds the fetus
inside the uterus, and that progressively more forceful myometrial contractions lead to cervical effacement and dilation.329
However, 2D and 3D ultrasound evaluation of the cervix established that during human gestation, cervical shortening and
decreases in cervical volume often occur at an asymptomatic
stage, before the onset of uterine contractions.330,331
As noted, it was recently proposed that classification of the
preterm parturition syndrome based on phenotype, rather than
on clinical signs or symptoms, may facilitate a better understanding of the etiology of PTB.10 From this perspective, a short
or a dilated cervix may be the first clinical manifestation of a
parturition process triggered as a result of decidual activation332
or uterine contractility.330 The complexity of the issue is emphasized by the observation that in the Preterm Prediction Study,
a short cervix (2.0, 2.5, 3.0 cm), as seen by sonography, had
a low sensitivity but a high specificity for prediction of PTB
before 35 weeks.330,333 A cervical length of 2.5 cm or less at 22
to 24 6 7 weeks was associated with spontaneous PTB in only
18% and 27% of women prior to 35 and 37 weeks, respectively.
This suggests that the majority of women with a short cervix
by sonography will not deliver prematurely. On the basis of
these observations, Iams and colleagues proposed that a short
cervical length may represent a spontaneous preterm parturition phenotype characterized by asymptomatic shortening of
the cervix, but not decidual and myometrial activation.330
39
Understanding the process of cervical functional adaptation

to pregnancy has become critical for a better comprehension of
the mechanisms responsible for initiation of human parturition, cervical insufficiency, and spontaneous preterm labor.
Today, it is recognized that cervical biology undergoes major
enzymatic and biomechanical transformations that differ from
those of the myometrium.334,335 Thus, although anatomically
part of the uterus, the cervix should be viewed as a separate,
complex, and heterogeneous organ.336
For most of a normal human gestation, the cervix remains
closed and firm. The current working model of parturition
indicates that the cervix must undergo a multistep adaptive
process: (1) softening (chronic, slow, progressive); (2) ripening
(precedes labor); (3) effacement and dilation (acute, occurs
within hours); and (4) repair (occurs after delivery for several
weeks).336,337 Each of these phases involves distinct biochemical,
biomechanical, and molecular events, which could be phenotype
dependent. This assertion is supported by studies conducted in
animals with various genetic backgrounds (high-regenerative
repair versus low-regenerative high-fibrotic repair).338
The cervix is a composite viscoelastic material consisting of
elastic (collagen and elastin) and viscous macromolecular components (sulfated glycosaminoglycans and proteoglycans).339
The ratios of constitutive elements of the cervix vary by the
region of the cervix they occupy.340,341 During each phase of the
adaptive process, the complex interaction between connective
tissue, extracellular matrix (collagen, elastin, macromolecular
proteoglycans), smooth muscle, and fibroblasts dictates the
mechanical behavior of the uterine cervix.342
Collagen makes up almost 90% of the cervix343 and is believed
to be the most critical element responsible for maintenance of
tissue structural integrity.339,344 Major cervical collagens are
types I and III.345 Interestingly, interstitial collagens types I and
III also predominate and maintain the mechanical integrity of
the amnion.252 This observation implies that various factors
(e.g., inflammation) may modify the biology of the cervical and
fetal membrane tissues in parallel. Collagen is actively synthesized during pregnancy, and it is remodeled by the interplay of
neutrophils, fibroblasts, and various enzymatic pathways.346-348
The role of MMPs in cervical ripening remains incompletely
understood.337 A possible role of MMPs in the process of adaptation and collagen remodeling was supported by data showing
that in pregnant rabbits the antiprogesterone onapristone (ZK
98.299) augmented the cervical mRNA expression levels of
MMP-3 (or stromelysin-1).349 In addition, studies conducted in
rodents revealed that systemically administered PGE2 elevated
the cervical tissue levels of MMP-2 and MMP-9.350 This effect
was predominantly seen at term, not before term. However, the
role of collagenases during the process of cervical ripening
has been challenged.351 Incubation of the cervical tissue with
MMP-1 altered neither the stiffness nor the extensibility of the
rat cervix. Biomechanical experimentation revealed that the
changes in physical properties of the rat cervix during physiologic ripening are similar to those induced by PGE2 and antiprogestin, and they consist of increased extensibility, compliance,
and strength. They cannot be attributed to increased collagenase activity, which decreases tissue compliance and strength.351
Studies conducted in healthy pregnant women suggest that the
functional relevance of MMPs is probably minimal.352,353 This
assertion is based on the observation that cervicovaginal MMP-9
did not change with spontaneous labor or rupture of membranes at term and did not predict success of labor induction.352
611
The net enzymatic activity of MMPs, if there is any, is

modulated by their interaction with tissue inhibitors of MMP
(TIMPs) and various cytokines.354 Peptidyl lysine oxidase,
copper, and vitamins C and E are also important regulators of
collagen metabolism, directly involved in its synthesis and
degradation.355,356
Animal studies have generated a large body of knowledge
about processes involved in pregnancy-related changes to the
cervix.337 From this research we have learned that before cervical
ripening, the collagen is dense, organized, rigid, and not extensible.339 Collagens 3D structure, which limits access of degrading collagenases and permits cross-linking between fibrils,
might play a role. By the end of the first trimester, collagen
becomes less tightly packed.337 As a result, the cervix becomes
softer but retains its tensile strength. Cross-links between collagen molecules are essential for providing strength. Several
investigators have focused their attention on decorin (dermatan
sulfate proteoglycan), which seems to be implicated in the
process of collagen reorganization and cross-linking.357,358
Animal studies revealed that an increase in the decorin-to-collagen ratio was associated with disorganization and rearrangement of collagen fibrils, followed by a marked decrease in
mechanical strength.359
Orientation of the collagen fibrils is not the only element
involved in regulating the preparative process of the cervix for
labor. For example, a decline in the collagen type I mRNA
expression was observed in human gestation, suggesting that a
decreased synthesis of this collagen could be involved in the
process of uterine cervical ripening.360 This finding was in
agreement with light-induced autofluorescence measurements
of the human cervix.361 By using this noninvasive technology,
Maul and coworkers provided evidence that a gradual decrease
in cervical collagen concentration occurs with advancing
gestation.361
Other elements of the extracellular matrix, such as proteoglycans, elastin, and its hydration status, reliant on negatively
charged glycosaminoglycans and levels of vascular endothelial
growth factor (VEGF), are also considered important determinants of cervical biomechanics.362,363 Glycosaminoglycans such
as hyaluronic acid are distributed widely throughout connective
tissues, including the uterine cervix.364 These molecules have a
high affinity for water and therefore may control tissue hydration, which is an essential element of cervical ripening.365 A
decrease in collagen content was repeatedly proposed as one of
the mechanisms responsible for cervical ripening.339 The high
affinity of the glycosaminoglycans for water may artificially
decrease the cervical collagen concentration. This premise is
supported by studies that refute changes in collagen content of
the cervix across gestation.342
Hyaluronidase is an intrinsic enzyme that catalyzes the
hydrolysis of hyaluronic acid, effectively creating low-molecularweight hyaluronic acid molecules.364 This catalyzing action
lowers the viscosity of the hyaluronic acid, thus increasing tissue
permeability to water. Hyaluronidase modifies the tensile viscoelastic properties of the rat cervix, but its role in human cervical
remodeling remains to be determined.366 Elastin may have a role
in cervical dilation and tissue compliance to stretch. This conclusion is mostly supported by histologic data demonstrating
fragmentation of the elastin fibers in women with an incompetent cervix.367
Relaxin is a two-chain peptide hormone that serves an
important role in cervical growth and remodeling associated
612
with pregnancy.368,369 Specifically, relaxin-deficient mice display

difficult parturition, an event also observed in relaxin leucinerich repeat containing G proteincoupled receptors (LGR)
knockout mice.369 In humans, relaxin may manifest its effect via
an increase in collagenase activity and increased glycosaminoglycan synthesis.368 Other collagen accessory proteins such as
thrombospondin-2, tenascin-C and lysil-hydroxylase, with an
important role in collagen cross-linking, seem to be also
involved.370,371
Significant gestational changes also occur in the cellular
compartment of the cervix.341 Human studies demonstrated
that apoptosis of stromal cells may be involved in cervical
remodeling.372 A higher number of apoptotic nuclei were seen
in laboring than in nonlaboring cervix, suggesting an increased
rate of apoptosis as pregnancy progresses to term. Based on
animal studies, it was proposed that relaxin, estrogens, and
progesterone are important regulators of apoptosis.373 Interestingly, all of these three hormones promoted cell proliferation
and repressed apoptosis by unknown mechanisms. Availability
of co-regulatory proteins (nuclear receptor co-repressor transcriptional factor) at different stages of pregnancy, or the local
ratios of various hormones may contribute to the process.374
Apoptosis is followed by infiltration of macrophages and neutrophils that add to disorganization and dispersion of the collagen and elastin fibers.343 The increase in decorin expression
and the resulting collagen disorganization promote the influx
of water, enhancing the ability of the cervix to dilate during
labor.344
At the end of pregnancy, changes in the mechanical behavior
of the cervical tissue are the result of various biochemical transformations.375 What remains incompletely understood is the
nature of the signals responsible for coordination of the process
of cervical ripening, softening, and dilation. Chief candidate
regulatory molecules are hormones (e.g., prostaglandins, progesterone), cytokines, and decorin.376 Prostaglandins induce a
marked increase in the decorin-to-collagen ratio,377 which in
turn may provoke collagen disorganization and rearrangement
of its 3D conformation. In various studies, prostaglandininduced cervical ripening was characterized by extracellular
matrix transformations similar to physiologic ripening such
as diminished collagen concentration, increased synthesis of
hydrophilic proteoglycans, and increased collagen solubility.378
The mechanisms are extremely complex and may involve augmentation of glycosaminoglycan synthesis by IL-1, and the
neutrophil chemoattractant IL-8.71 IL-8 is also thought to initiate cervical ripening by promoting neutrophil chemotaxis to
and activation in cervical stroma.71 Interestingly, prostaglandins
had no effect on hyaluronic acid synthesis, so tissue hydration
most probably entails other mechanisms. Additional factors
involved may include relationships among prostaglandins and
the receptors for estrogen (EP4), androgens, and progesterone
(PR-A, PR-B).379
The important role of progesterone for maintenance of cervical competency has long been postulated.380 Today, the attention is even more focused on progesterone because of the results
of randomized clinical trials that pointed to its potential role in
prevention of premature birth.381,382 In an animal model, Stys
and colleagues demonstrated that progesterone has different
effects in the myometrium and in the cervix, supporting the
hypothesis that it prevents term and PTB by acting on both
myometrium and cervix.383 In humans, the contribution of progesterone to the process of cervical remodeling is supported by
the clinical data demonstrating that administration of the antiprogesterone RU486 increases the likelihood of a favorable
cervix.300 However, RU486 alone is not sufficient to induce
labor, implying that factors involved in controlling the activation of myometrial contractility play a decisive role. Understanding the molecular mechanism by which progesterone
maintains a state of cervical competency proved to be a challenge.384 It has been postulated that alterations in the expression
of PR isoforms and changes in the metabolism of estrogen and
progesterone are associated with cervical changes in human
parturition.337,385 Data generated using mice deficient in steroid
5-reductase type-1, an enzyme with an essential role in
cervical progesterone catabolism, indicate that at least part
of progesterones effect on cervical remodeling is controlled by
this enzyme.386 It has been also proposed that in the cervix,
progesterone is an important regulator of hyaluronic acid
and MMP metabolism, and it affects the intensity of an inflammatory response after activation of various inflammatory
pathways.201,387,388
The laboring cervix is histologically characterized by an
abundance of neutrophils and macrophages, and by an outpouring of proinflammatory cytokines.389,390 Young and collaborators reported that in the human cervix, IL-6, IL-8, and
TNF- were localized to leukocytes, glandular and surface epithelium, and stromal cells.391 Although these data might argue
that the cervical biology is heavily dependent on various inflammatory processes, especially at term, it is important to recognize
that during ripening, the influx of monocytes into the cervix
depends on the loss of progesterone function.392 Furthermore,
the timing of inflammatory cell migration and activation in
the pregnant cervix of mice deficient in 5-reductase type-1
(Srd5a1/) suggests a role for the inflammatory cells and activation of downstream signaling pathways of various cytokines,
in postpartum remodeling rather than in the cervical ripening
phase.393 As animal and human labor begins and the cervix
dilates, there is increased activity of inflammatory mediators
such as IL-1 and IL-8 that can activate various NF-Bdependent signaling pathways.394,395 Expression of proinflammatory
cytokines stimulates synthesis and activation of collagenases,
elastases, MMPs, and possibly nitric oxide synthases.396 The
increase in IL-6 stimulates prostaglandin and leukotriene production, potentially causing dilation of cervical vessels and promoting extravasation of various inflammatory cells.176 Proteases
released by degranulating neutrophils encounter an already
destabilized collagenous fiber network. In this context, collagen
disorganization can be further augmented by collagenases, even
in the absence of a significant change in their level of expression.
If true, the process should be strictly time limited, because the
sustained action of proteases may cause severe tissue damage.
Differential expression of nitric oxide synthase in the uterus and
cervix during pregnancy has been described.334 Nitric oxide
production is upregulated in the cervix during labor, an effect
that is opposite from that in the myometrium (i.e., anticontractile).335 This increase is accompanied by softening of the
cervix, and blockade of nitric oxide reduces cervical distensibility.335 The mechanism of nitric oxideinduced cervical ripening
during pregnancy may be mediated in part by increased
PGF2,397 but not by cytokine synthesis.398
What can be concluded from the large body of published
research is that cervical adaptation to pregnancy cannot be the
result of a single factor, and that various pathways should be
involved simultaneously. Indeed, various genes, with roles in
39
cell adhesion, regulation of extracellular matrix, and inflammation, were found to be differentially expressed in the ripened
cervix.326,399 Current data reveal that cervical shortening at term
was associated with downregulation of bone morphogenetic
protein-7, claudin-1, 6 integrin, and endometrial progesteroneinduced protein mRNA. The clinical significance of these discoveries remains to be determined.400
CERVICAL ADAPTATION AND REMODELING
DURING PRETERM BIRTH
Cervical adaptation and remodeling is a complex process.
However, a relevant question is whether cervical ripening and
dilation at term and preterm are driven by the same molecular
mechanisms. A study by Akins and colleagues demonstrated
that collagen morphology in premature cervical remodeling is
different from that in physiologic term ripening.401
Because the processes of term and preterm cervical ripening
and dilation have been associated with various inflammatory
events, inflammation was consistently presented as the final
common pathway of parturition.326 This hypothesis was supported by data that demonstrated that in the absence of infection, IL-8, IL-6, and monocyte chemotactic protein-1 (MCP-1)
were significantly elevated in human term and preterm cervical
tissues.402 As shown, asymptomatic women with intra-amniotic
infection or inflammation had higher degrees of cervical shortening and dilation.110,403-405 Thus, it is reasonable to assume that
in some clinical circumstances, a short or a dilated cervix favors
microbial invasion of the gestational sac via an ascending mechanism.125 In such cases, processes involved in premature cervical
shortening and dilation might represent the first event leading
toward premature birth. However, the reverse is possiblethat
is, intra-amniotic infection may induce an outpouring of
inflammatory mediators that in turn might persuade ripening
and opening of the cervix.
The clinical implication is that presence in the cervicovaginal
fluid of specific biomarkers may reflect activation of signaling
pathways involved in premature ripening, cervical dilation, and
premature birth. Additional nuances concerning the involved
molecular networks have been described with the recent
advances in genomic and proteomic technology.406,407 Comprehensive survey of the cervicovaginal fluid proteome showed
that calgranulin-A, calgranulin-B, azurocidin, insulin-like
growth factorbinding protein-1, and defensins were found
upregulated in the cervicovaginal fluids of women at risk for
PTB.406,407 Most of these biomarkers are part of the innate
immunity defense mechanism of the cervix and are constitutively expressed in the cervical mucus.407 Their differential
expression408 may mediate the process of leukocyte infiltration,
shown previously to be involved in cervical remodeling.390
To understand the process of cervical ripening and dilation
in the setting of intra-amniotic infection-induced PTB, several
investigators have used animal models of intrauterine infection.
With respect to the profile of cervical inflammatory infiltrate,
Holt and coworkers suggested that there might be differences
between various mechanisms involved in triggering PTB.409 The
monocyte population dominated the progesterone withdrawal
mechanism, whereas neutrophils governed the process of
endotoxin-induced PTB. A comparison of the genes differentially expressed in the cervix of animals in which PTB was
induced by mifepristone or endotoxin showed that genes
involved in immunity and inflammation were upregulated in
613
the cervix of inflammation-induced PTB.410 On the other hand,

term labor was not associated with a differential expression of
immune pathways. Genes responsible for the expression of
various cytokines (TNF-, IL-6, IL-1) and MMPs (MMP-2,
MMP-9) were upregulated in the cervix of animals with intrauterine infection.410 Notably, expression of cytokines was not
increased in term cervices but was amplified in the postpartum
period. These findings argue that, in the postpartum period,
cytokines may play an important cervical reparative role or may
confer immune protection.
Premature cervical ripening is a feature of patients with multiple gestations, and is rarely seen in diethylstilbestrol-exposed
women.411,412 IL-8,413,414 MMPs,31,348 prostaglandins,71,337,415 and
nitric oxide335 have been implicated in the control of cervical
ripening. These mediators may be synthesized in response to
amniochorion stretch and may exercise part of their biologic
effects in parturition by degradation of the cervical extracellular
matrix.
It has been suggested that cervical insufficiency is characterized by a muscular cervix, with low collagen and high smooth
muscle content.416 However, cervical insufficiency does not
appear to be associated with a constitutionally low collagen
content or collagen of inferior mechanical quality. Therefore,
the hypothesis that a muscular cervix with an abundance of
smooth muscle cells contributes to the development of cervical
insufficiency is not supported by the present studies aimed to
address this problem.
Collectively, the data presented here support the view that
PTB is not an accelerated form of physiologic cervical
ripening.
DECIDUAL ACTIVATION AND BLEEDING
Decidual activation refers to a complex set of pathophysiologic
events that lead to separation of the fetal amniochorionic membranes from the decidua, bleeding, spontaneous rupture of the
membranes, activation of myometrial contractility, and expulsion of the placenta. The relative contributions of the decidual
activation and bleeding process to PTB vary.
During gestation, the chorioamniotic membranes gradually
fuse with the decidua. Before delivery, biochemical and molecular occur that allow separation and expulsion of the fetal membranes. Fibronectins have multiple binding sites to permit
cell binding and interaction with cytoskeletal organization
to effect cell migration, adhesion, and decidual cell differentiation.417-419 Elastase-induced release and degradation of the glycosylated cellular fibronectin (i.e., fetal fibronectin) diminishes
the binding ability of this glycoprotein for components of
the extracellular matrix, thereby facilitating separation of the
fetal membranes from the decidua.420 Detection of fetal fibronectin into cervical and vaginal secretions before preterm
parturition421-423 is one of the most clinically useful biomarkers
of PTB.424-426
Placental abruption can be viewed as a binary event in which
molecular signals involved in decidual bleeding arise as a consequence of either inflammation or aberrant coagulation
(Fig. 39-10). Although relatively distinct from other causes
of prematurity, it is believed that many of the molecular
events responsible for decidual activation and abruption are
inflammatory. The acute lesions of chorioamnionitis and
funisitis (e.g., hematoma, fibrin deposition, compressed villi,
hemosiderin-laden histiocytes) are frequently associated with
614
Reduced or intermittent
uteroplacental blood flow
1st trimester
Angiogenesis
Hypoxia
FR / ROS
Decidual cell
VEGF
Decidual endothelial
cell dysfunction
sFlt1
Decidual TF expression
Inflammation
Thrombin
Inflammation
Abruption induced PTB

Figure 39-10 Binary theory of decidual bleeding and inflammation in pathogenesis of placental abruptioninduced preterm birth (PTB). A
reduced or intermittent uteroplacental blood flow causes focal decidual hypoxia and free radicals (FR) and reactive oxygen species (ROS) (through
reperfusion injury). Hypoxia induces the expression of decidual vascular endothelium growth factor (VEGF). This angiogenic factor acts directly on
decidual endothelial cells to enhance permeability and degrade the vascular wall through matrix metalloproteinase (MMP)-2 generation. This leads
to hemorrhage and aberrant endothelial expression of tissue factor (TF), generating additional thrombin that further induces TF expression and
uteroplacental thromboses, which exacerbate reduced blood flow. Free radicals and ROS induce endothelial cell injury, which allows perivascular
leakage of coagulation factors, including factor VIIa, which then comes in contact with TF, activating the extrinsic coagulation pathway. The resulting
thrombin further induces TF expression as well as expression of inflammatory cytokines, leading to inflammation in the absence of a microbial attack.
sFlt1, soluble fms-like tyrosine kinase-1.
histologic abruption.427 Histologic evaluation of the vasculopathy attending decidual hemorrhage provides evidence that the
nature of the damaging process is frequently chronic.83,428,429
The most frequent histopathologic lesions suggestive of chronic
decidual bleeding are chronic deciduitis and villitis, infarct
and necrosis, spiral vessels with absence of physiologic transformation and increased numbers of circulating nucleated
erythrocytes, vascular thrombosis, and villous fibrosis and
hypovascularity.428
Maintenance of appropriate hemostasis in human decidua is
central to normal human implantation and placental development.430 Survival of the embryo and development of the fetus
requires that extravillous trophoblasts gain access to the maternal circulation by penetrating the uterine spiral arteries without
causing hemorrhage.431 This process is gradual and well coordinated. Disarray of the highly controlled and synchronized
molecular mechanisms at the maternal-fetal interface increases
the risk for hemorrhage, leading to abortion, abruption, and
stillbirth. The key histologic finding in placental abruption is
hemorrhage in the decidua basalis.432 This hemorrhage is
believed to result from pathologic processes damaging the vascular endothelium.433
Incorporating the pathophysiology of abruption in the
framework of inflammation or bleeding alone is difficult. This
is because the molecular signals involved in decidual bleeding
are potentially triggered by both pathologic inflammation and
aberrant coagulation.15,434 Interestingly analysis of the expressed
decidual transcripts and proteins suggests that each spontaneous, infection-induced, and abruption-associated preterm
delivery is defined by distinct transcriptional profiles.435 Studies

demonstrating that inflammatory reactions (dependent or
independent of infection) can activate the coagulation pathways
emphasize the important role of inflammation in decidual
bleeing.429 Cytokines (e.g., IL-1, IL-6) act on decidual vascular
surfaces and increase the expression of leukocyte interactive
proteins such as P-selectin, E-selectin, vascular cell adhesion
molecule, and intercellular adhesion molecule-1.436-438 This phenomenon may lead to decidual neutrophil infiltration, vascular
damage, access of coagulation factors (factor VII) to the perivascular adventitial tissue factor, and generation of thrombin.439
Rosen and colleagues proposed that when the process of decidual thrombin activation overwhelms the physiologic anticoagulant and fibrinolytic response, the abruption process becomes
systemic, as assessed by circulating maternal plasma thrombinantithrombin complexes.440 Furthermore, this phenomenon
was mechanistically linked to adverse pregnancy outcomes,
such as preterm PROM.441
Decidua is a rich source of tissue factor, the primary initiator
of coagulation.439 The role of decidual cellexpressed tissue
factor in preservation of uterine hemostasis and its involvement
in the abruption process has been summarized in several excellent reviews.439,442 Taylor and colleagues demonstrated in an
animal (dog) model of LPS-induced sepsis that infusion of low
concentrations of thrombin was protective against death.443
Thus, it is possible for low levels of thrombin generated in the
early inflammatory phase of an abruption process to be beneficial. This may explain the high frequency of histopathologic
lesions suggestive of chronic decidual bleeding in the absence
39
of clinical manifestations of the disease.428,429 Various processes

that lead to vascular disruption and the interaction of circulating factor VIIa with decidual cell membranebound tissue
factor generate thrombin, explaining the strong association
between abruption and disseminated intravascular coagulation.444 The mechanisms responsible for the stimulation of
myometrial contractions in the presence of intrauterine hemorrhage and the specific role played by the thrombin have been
defined.445-447 Elovitz and coworkers demonstrated that intrauterine inoculation of whole blood stimulated rat myometrial
contractility.445 Furthermore, fresh whole blood stimulated
myometrial contractility in vitro, and this effect was partially
blunted by hirudin, a thrombin inhibitor.445 In vitro, thrombin
induced cytosolic calcium concentration oscillations that were
similar to those produced by oxytocin.445 These studies confirmed that membrane receptor-Gq protein and proteaseactivated receptor-1 (PAR1) coupling events play an important
role in modulating thrombin stimulation of myometrial smooth
muscle.445,447
Thrombin may exert pleiotropic effects on decidual cells.
Genomic studies have provided a better understanding of the
process of endometrial decidualization.448 Among the genes
responsible for the normal phenotypic and morphologic
remodeling processes of the human decidua, the homeobox
(HOX) gene family appears to be critical.449 In vitro, thrombin
decreased gene expression of HOXA9, HOXA10, and HOXA11.
Furthermore, thrombin decreased HOXA10 mRNA and protein
levels. IL-1, a cytokine with important regulatory roles in prostaglandin production,450 mimicked the effect of thrombin on
HOXA10 gene expression. These observations provide proof of
the concept that two recognized mediators of decidual inflammation and PTB, thrombin and IL-1, may operate by reducing
the expression of HOXA10 gene.
The inflammatory events that follow abruption can occur
dependent on or independent of progesterone.451,452 Coincident
with activation of the coagulation cascade, decidual injury
causes release of cytokines.453 Cytokines act in an autocrine or
paracrine manner to elicit and increase the synthesis of MMPs454
and VEGF.451 It has been proposed that TNF-, IL-1, IL-6,
IL-8, and IL-11 are involved.453 Other cytokines, such as
granulocyte-macrophage colonystimulating factor (GM-CSF),
monocyte chemoattractant protein-1 (CCL2), and colonystimulating factor-1 (CSF1), may be implicated in the regulatory process of decidual activation and bleeding.438,455
Progesterone appears to create both a hemostatic and an
antiproteolytic milieu in the decidua. Using a primary cell
culture experimental setup, Schatz and colleagues demonstrated
that first-trimester decidua expresses tissue factor and plasminogen activator inhibitor-1 (PAI-1), which is considered a
fast inhibitor of the primary fibrinolytic agent tissue plasminogen activator (tPA).456 There is experimental evidence that progestins are exercising a similar effect in cultured term decidual
cells.457 The molecular mechanisms through which progestins
promote decidual hemostasis via enhanced expression of tissue
factor, the primary initiator of hemostasis, and PAI-1, the
primary antifibrinolytic compound, involve epidermal growth
factor receptor (EGFR) and induction of transcription factors
Sp-1 and Sp-3.458
In addition to controlling the decidual hemostasis, progestins inhibit the proteolytic activity of collagenase MMP-1
and MMP-3.459,460 Because antiprogestins (e.g., RU486) reverse
the progestin-inhibited expression of MMPs, an attractive
615
hypothesis is that progesterone withdrawal may induce an

increase in the decidual expression of MMP-1 and MMP-3,
which would promote extracellular matrix and fibrillar collagen
degradation, preceding bleeding, premature separation of the
placenta, and preterm PROM.
Taken together, the results of these studies may explain at
least partially the potential role of progesterone in preventing
decidual activation and bleeding, by inhibiting the general
proteolytic and inflammatory activity at the maternal-fetal
interface. The mechanism by which progesterone function is
balanced in the setting of high maternal circulatory levels is
unknown. Abruption-associated PTB is accompanied by
reduced immunostaining for PR, and thrombin inhibits PR
protein and mRNA expression in cultured term decidual cells.460a
Epidemiologic studies suggest that for some women, the
recurrence risk for placental abruption is higher than the
general background risk, and that thromboembolic events
occur more commonly among female relatives of women with
placental abruption.461-463 However, genetic studies involving
candidate genes dispute this association.464,465 Zdoukopoulos
and Zintzaras tried to identify the most frequent gene polymorphisms associated with placental abruption.466 A positive association was identified for Arg506Gln (OR = 3.4; 95% CI, 1.4 to
8.3) and G20210A (OR = 6.7; 95% CI, 3.2 to 13.0) polymorphisms. The positive correlation between placental abruption
and prothrombin gene mutation (G20210A) was confirmed in
nulliparous women (OR = 12.1; 95% CI, 2.4 to 60.4).467 On the
other hand, a study conducted by the Maternal-Fetal Medicine
Units Network argues against this association, suggesting that
the practice of screening women without a history of thrombosis or adverse pregnancy outcomes for the G20210A prothrombin gene mutation polymorphism is not necessary.468
PRETERM PREMATURE RUPTURE OF MEMBRANES
Preterm PROM (pPROM) is one of the leading risk factors for
PTB. The amniochorion has a unique biology characterized by
distinctive molecular, enzymatic, and biomechanical transformations.235 Multiple pPROM risk factors have been identified.11,469 Whatever the cause, the final common pathway must
be weakness of the amniochorion membrane that allows
rupture. Clinicians and scientists have traditionally attributed
rupture of the membranes to mechanical stress, particularly
that associated with uterine contractions. The molecular mechanisms that could trigger pPROM after excessive mechanical
stretch were presented earlier.
Fetal membranes are pluristratified structures whose composition ensures their cohesion, elasticity, and mechanical
strength. The strength of the fetal membranes is derived from
both synthesis- and protease-induced degradation of the components of the extracellular matrix. The mechanisms responsible for degradation of the extracellular matrix are tightly
regulated by several MMPs (MMP-1, 2, 3, and 9) and TIMP-1
and TIMP-2.11 A marked decidual infiltrate of neutrophils,
which are a rich source of the extracellular matrixdegrading
proteases elastase and MMPs, are associated with abruptioninduced pPROM.428,429 This phenomenon occurs in the presence or in the absence of infection. Predominant activities for
MMP-1,470 MMP-8,471 and MMP-9,472 and a low concentration
of TIMP-1 and TIMP-2,473 have been demonstrated in the
amniotic fluid of women with pPROM. This implies that
at least part of the MMPs bioavailability at the site of
616
amniochorion injury and rupture is the result of activation and

degranulation of fetal neutrophils.198,474 In addition to collagen,
gelatinases cleave fibronectin and proteoglycans, facilitating
detachment of fetal membranes from the lower uterine segment,
disruption of the extracellular matrix, and rupture.11,475
Activation of MMPs and other proteases may occur dependent on or independent of inflammation and infection.472 The
existence of a focal defective area, rather than generally weakened fetal membranes, has been proposed.476 This theory is
based on the observation that an excessive matrix remodeling
process occurs in the region of fetal membranes overlying the
internal os of the cervix.477,478 Histologic examination of the
restricted zone of extreme altered morphology reveals marked
swelling and disruption of the fibrillar collagen network in the
compact, fibroblast, and spongy layers of the fetal membranes.478
Observations by Bell and colleagues suggest that changes in the
zone of altered morphology are more extensive in the setting of
pPROM.479 A significant decrease in the amount of collagen
type I, III, or V has been reported in the zone of altered morphology, and studies conducted by Lappas and associates demonstrate that remodeling of the extracellular matrix in the
supracervical area is probably related to activation of MAPK/
AP-1, and NF-B-dependent signaling pathways.480,481 Enhanced
expression of tenascin, an extracellular matrix protein expressed
during tissue remodeling and wound healing, may also be
involved.479,482 Identification of tenascin in the fetal membranes
signifies the presence of injury and a wound healinglike
response that may precede pPROM. Studies conducted by
George and colleagues suggest that apoptosis is accelerated in
the chorion of pPROM women, and that this phenomenon is
of higher intensity in the setting of chorioamnionitis.483
Although the precise mechanism responsible for programmed cell death in the fetal membranes is unknown, it is
conceivable that cytokines play a role.484 Kumar and coworkers
showed that TNF- and IL-1 incubated amniochorion exhibited a dosage-dependent decrease in the mechanical force
required to reach the breaking point of the tissue.485 Both
TNF- and IL-1 stimulated the production of immunoreactive MMP-9 and a decrease in TIMP-3, suggesting collagen
remodeling and apoptosis in fetal membranes exposed to
increased cytokine levels. The observation that -lipoic acid
inhibits cytokine-induced fetal membrane weakening suggests
that this mechanism is NF-B mediated.486 Fortunato and
Menon showed that IL-1 increased caspase 2, 3, 8, and 9 activities, whereas IL-6-treated membranes did not exhibit a significant change.484 However, the role of IL-6 and its alternative
trans-signaling pathway remains to be determined, especially
when the levels of this cytokine and that of soluble gp130 molecule were found to be significantly decreased in women with
pPROM and intra-amniotic infection compared with women
with intra-amniotic infection and intact membranes.153 A possible explanation for the low cytokine levels in the amniotic
fluid of women with pPROM could be fetuin-mediated aggregation of amniotic fluid cytokines and proteins into calcifying
nanoparticles that may play an important pathophysiologic
role in rupture of the amniochorion (increasing necrosis and
apoptosis).487
The observed reduced antioxidant glutathione peroxidase
and superoxide dismutase enzyme activity in the supracervical
area of the fetal membranes implies that local oxidative stress
is an important factor predisposing to pPROM.488 Compelling
evidence suggests that MMP activity in the human fetal
membranes is reduction-oxidation (redox) regulated.489 By

using an in vitro amniochorion explant model, it was shown
that MMP-9 activity was directly increased by superoxide anion,
a byproduct of macrophages and neutrophils that are abundantly present in both amniochorion and decidua of pregnancies complicated by infection and decidual hemorrhage.
N-Acetylcysteine decreased the amniochorionic MMP-9 activity, suggesting that this glutathione precursor may have therapeutic value.489
Vaginal bleeding is a well-recognized risk factor for PTB.
Women who are experiencing vaginal bleeding during the first
trimester have an increased risk for PTB (adjusted relative risk
[RR] = 2; 95% CI, 1.6 to 2.5).490 Moreover, the risk for pPROM
is increased if vaginal bleeding persists more than one trimester
during gestation (OR = 7.4; 95% CI, 2.2 to 25.6).491 Much interest has been shown about understanding the relationship
between decidual bleeding, activation of MMPs, and pPROM.
It was hypothesized that in abruption thrombin generated from
decidual cellexpressed tissue factor can indirectly promote
pPROM via enhanced expressed MMP-1 and stromelysin-1
(MMP-3).441,492 Furthermore, in vitro, thrombin enhances the
expression of MMP-9 in fetal membranes at term.493 Along with
data confirming that the maternal coagulation system is activated in women with ruptured membranes,441 the results of
these experiments support the premise that thrombin is central
to the pathophysiology of pPROM. Kumar and colleagues
demonstrated that thrombin and TRAP (specific agonist for
thrombin receptor PAR1) weaken the fetal membranes in a
dosage-dependent manner.494 Thrombin appears to exercise this
effect in a direct fashion, whereas cytokines such as TNF- and
IL-1 require the presence of choriodecidua.494 Interestingly,
thrombin, but not TNF- and IL-1, exhibited protein MMP-9
and decreased TIMP-3 production in isolated amniochorion
cells. Because thrombin-induced decreases in biomechanical
strength of the amniochorion are reversed by -lipoic acid, it
is probable that PKB/Akt, NF-B, or nuclear factorerythroid
2related factor 2 (Nrf2) signal transduction pathways, or more
than one of these, are directly involved.494,495
Phenotypic Components of the Preterm

Birth Syndrome
MATERNAL CONDITIONS
Extrauterine Infection
Given the very close link between intrauterine infection and
preterm labor (reviewed later), it is not surprising that there is
also a strong association between maternal extrauterine infection and PTB.
Globally, maternal infections with human immunodeficiency virus (HIV) and malaria are important contributors to
PTB. In a large population-based study, women infected with
HIV were more likely than uninfected women to give birth
before term.496 In this study, antiretroviral treatment of HIV
reduced rates of adverse outcomes, including PTB, but the specific antiretroviral agents used were not reported. Although this
study did not differentiate between spontaneous and caregiverinitiated PTB, others have shown that both are increased in
women infected with HIV.497 Accumulating evidence now suggests that the use of modern highly active antiretroviral therapy
(HAART, which involves multiple drugs and clearly reduces
39
vertical transmission of HIV) is itself a risk factor for spontaneous and caregiver-induced PTB, even after adjustment for
confounders.498 The mechanisms of the increase in preterm
labor associated with HIV infection and with HAART are
unknown.
Malarial infection increases the risk for both stillbirth and
PTB,499 probably by a combination of mechanisms including
placental dysfunction, anemia, and maternal sepsis. In endemic
areas, intermittent presumptive treatment for malaria is recommended during pregnancy to reduce perinatal mortality and
low birth weight,500 although the evidence that such a strategy
also prevents prematurity is weak.
More localized maternal extrauterine infections, whether
symptomatic or asymptomatic, also increase the risk for preterm
labor. The link between asymptomatic bacteriuria and PTB is
well established.501 Women hospitalized with appendicitis are
also more likely to give birth before term.502 These links also
appear to hold true for emerging infectionsfor example, the
risk for spontaneous preterm labor is some two to three times
higher in women infected with the H1N1 influenza virus, with
a significant increase in the risk for stillbirth and perinatal
mortality compared with uninfected women.503 The pathophysiology linking extrauterine infection to preterm labor is uncertain. For some infections, such as periodontitis, a mechanism
by which mouth microorganisms induce bacteremia and hence
reach the uterine has been postulated, 504 although evidence to
support this claim is weak.
Clinical Chorioamnionitis
Larsen and coworkers provided one of the first pieces of evidence that intrauterine infection is an important trigger for
PTB.505 There is now compelling microbiologic evidence to
suggest that intrauterine infection may contribute to about 25%
of PTBs, with bacterial involvement as high as 80% for early
gestation, declining to about 10% toward term (ascertainment
of intrauterine infection notwithstanding).200,506,507
Clinically, intrauterine infection can manifest with obvious
signs of maternal and or fetal infection (maternal fever, tachycardia, uterine tenderness, leukocytosis, and foul odor of the
amniotic fluid). Multiple studies confirmed the non-overlapping
nature of histologic and clinical chorioamnionitis.200,508,509 Clinical chorioamnionitis occurs in just 20% of pregnancies
complicated by intra-amniotic inflammation and histologic
chorioamnionitis. Because previous studies had associated
short- and long-term follow-up characteristics to distinct placental lesions,510-513 the results of histologic examination of the
placenta (as performed by a perinatal pathologist) was used as
an intermediate-outcome variable when evaluating performance of new diagnostic tests.514 Recognition of clinical chorioamnionitis is also a challenge in the setting of maternal
systemic inflammatory conditions unrelated to obstetric causes
(e.g., pyelonephritis, appendicitis, pneumonia).
In the newly proposed classification system, clinical chorioamnionitis is defined as clinically suspected intrauterine infection, manifest by maternal fever and rupture of the membranes
plus two features from maternal tachycardia, uterine tenderness, purulent amniotic fluid, fetal tachycardia and maternal
leukocytosis.10 It is acknowledged that this somewhat strict
definition would not include many women presenting in spontaneous preterm labor and subsequently found, on careful
testing, to have microorganisms in the uterine cavity. However,
for the purposes of this chapter, we will describe all the links
617
between intrauterine infection and inflammation (whether

clinically apparent or not) and preterm labor under this heading
of clinical chorioamnionitis (because of the consistency in
pathophysiology), while acknowledging that subclinical infection or inflammation may not strictly fulfill the recently proposed clinical phenotype of clinical chorioamnionitis.
Maternal Trauma and Uterine Rupture
Although major maternal trauma is uncommon during pregnancy, it is associated with an increased risk for immediate or
delayed PTB. Population-based studies suggest that the rate of
trauma sufficient to require hospitalization is around 2 to 3.5
per 1000 pregnancies.515,516 In some women, the trauma is so
severe that immediate PTB occurs either as a result of maternal
injury, or as a result of fetal or maternal death, or to facilitate
maternal resuscitation, although the absolute risk for immediate delivery is small. Women with major injuries who survive,
and women with minor trauma, have about double the odds of
either spontaneous preterm labor or placental abruption during
the remainder of the pregnancy.515-517
Other forms of maternal trauma that make important contributions to PTB include treatment for preinvasive cervical
carcinoma518 (see Cervical Disorders, later) and previous cesarean delivery, which leads to an increased risk for stillbirth in the
subsequent pregnancy after around 34 weeks gestation (hazard
ratio, about 2) compared with those with a previous vaginal
delivery.519 Although previous cesarean delivery is a common
antecedent of uterine rupture during labor, it is possible for
uterine rupture to occur de novo. Regardless of the setting of
the uterine rupture, PTB is commonly associated.520
Worsening Maternal Disease, Including Preeclampsia
The final maternal phenotypic components of the PTB syndrome include worsening maternal disease, preeclampsia, and
eclampsia. These conditions are risk factors for caregiverinitiated pathways to PTB (typical OR = 3 to 5),14 although a
recent population-based study demonstrated that maternal diabetes and preeclampsia were also associated with increased odds
of spontaneous preterm labor.14
Maternal Stress and Anxiety
A large number of epidemiologic studies confirmed that maternal psychosocial stress is, worldwide, an independent factor
for PTB.521-525 Although there is no universally accepted definition of stress, it is generally the result of an interaction between
a person and the environment in which there is a divergence
between environmental demand and the individuals psychological, social, and biologic resources. From this perspective,
the nature and timing of the stressful events may vary from a
heavy workload to anxiety and depression.526,527 Populationbased research conducted with pregnant women of different
sociodemographic backgrounds and races showed that periconception stress and anxiety are independently associated with
increased rates of spontaneous PTB.528,529 Stress during pregnancy also has adverse consequences, with the risk for PTB
apparently being higher when the stress exposure occurs during
the second half of gestation (months 5 to 6) (OR = 1.24; 99%
CI, 1.08 to 1.42).524 Because of the large heterogeneity of study
designs, populations, and the associated behavioral risk factors,
the magnitude of the effect is often difficult to determine.
However, the general consensus is that the overall impact
is modest.529,530
618
Data derived from registry-linked births have noted slightly

higher odds of PTB in women with post-traumatic stress disorder, with an OR that varies from 2.5 (95% CI, 1.05 to 5.84)531
to 2.3 (95% CI, 0.82 to 6.38).532 Exposure to specific severe
disaster events and the intensity of the disaster experience are
considered predictors of poor pregnancy outcomes.532 Antenatal depressive symptoms affect approximately 18% of pregnant
women.533 What can be concluded from the large body of literature is that during pregnancy, women with depression are at
increased risk for PTB.534 The extent of the effect varies depending on the method of ascertainment of depression, socioeconomic status, and race.535 For example, depression among
African-American women is associated with an adjusted OR for
PTB of 1.96 (95% CI, 1.04 to 3.72).536 Absence of similar findings in Hispanic and non-Hispanic white populations suggests
ethnic disparity in the effect of stress in the United States.
The clinical relevance of the impact of various maternal
stressors on the occurrence of PTB is multidimensional. First,
comorbidity of depression and anxiety creates the context for
the worst pregnancy outcome.537 Second, women with significant psychosocial stress factors and psychiatric conditions
(depression, anxiety, bipolar disease) are frequently prescribed
medications that may affect the growth and development of the
fetus.538 However, data on the use of antidepressant medication
during pregnancy is reassuring overalltreatment can be recommended in view of the risks associated with absence of
treatment.539-541 In a large study, exposure to selective serotonin
reuptake inhibitors (SSRIs) during the first trimester was not
associated with increased risk for congenital malformations in
general (OR = 1.22; 95% CI, 0.81 to 1.84) or increased risk for
PTB (OR = 1.21; 95% CI, 0.87 to 1.69). Others have shown a
modest impact on PTB. Yonkers and colleagues542 found that
use of an SSRI, both with (OR = 2.1; 95% CI, 1.0 to 4.6) and
without (OR = 1.6; 95% CI, 1.0 to 2.5) a major depressive
episode, was associated with PTB. A major depressive episode
without SSRI use (OR = 1.2; 95% CI, 0.68 to 2.1) had no
clear effect on PTB risk. Use of SSRIs in pregnancy was
associated with increases in spontaneous but not medically
indicated PTB.542 Third, early recognition of maternal stress and
Maternal
stress
Activation of fetal HPA axis
implementation of behavioral interventions reduces the occurrence of PTB (OR = 0.42; 95% CI, 0.19 to 0.93).543 Fourth, fetal
exposure to maternal stress may have sustained programming
effects on the HPA axis responsiveness and sympathetic nervous
system functionality later in life, which seems to be sex (male)
dependent.544
Complex biochemical and neurohormonal interactions
between maternal, fetal, and placental compartments are
required during normal and premature human parturition.79 A
series of physiologic adaptive responses in each of these compartments can be triggered by stress subsequent to malnutrition, infection, ischemia, vascular damage, and psychosocial
factors.80 However, the nature of the stimulus whereby stress
induces premature activation of the mechanisms involved in
PTB remains unknown. The pathways by which stress can
induce preterm labor are represented in Figure 39-11. There is
substantial evidence that the placenta plays a central role in
controlling the length of gestation and the onset of parturition
in humans.81 Thus, placental histologic changes consistent with
infection- and ischemia-induced fetal stress are far more
common in patients with spontaneous PTB than in idiopathic
preterm and term birth controls.82,83 Maternal-fetal trafficking
of numerous hormones is highly dependent on various enzymatic pathways. For example, 11-HSD regulates placental
transfer of cortisol, which is a glucocorticosteroid with a key
role in activation of the HPA axis. Interestingly, hyperactivity
of the maternal HPA axis has been involved in the occurrence
of maternal depression.84 Carriers of a polymorphism in the
gene encoding for 11-HSD type-1 have a higher level of HPA
activity and susceptibility to depression.85 Collectively, these
and other data86 appear to indicate a genetic predisposition
toward maternal mood disorders and may implicate various
placental polymorphisms in the occurrence of maternal mood
disorders linked to PTB.87
Cervical Disorders
Cervical insufficiency can produce a wide spectrum of diseases,545
including recurrent pregnancy loss in the mid-trimester and spontaneous PTB later in gestation. The latter often appears with
Placental
insufficiency
ACTH
Cortisol
Placenta, membranes,
and decidua
Fetal
adrenal
zone
(!) CRH
Placental
sulfatases
CRH
E1-E3
!
PG
Cervical change
DHEA/16-OH DHEA
Myometrial (PR-A/B, and ER-!)

enhances c-jun causing
increase in CAPs, FP, EP1, EP3
Preterm PROM
Contractions
Figure 39-11 Proposed pathways by which stress

can induce preterm labor. ACTH, adrenocorticotropic hormone; CAPs, contraction-associated proteins; CRH, corticotropin-releasing hormone; DHEA,
dehydroepiandrosterone; E1-E3, estrone, estradiol,
and estriol; EP1 and EP3, prostaglandin E receptors
types 1 and 3; ER-, estrogen receptor-; FP, prostaglandin F receptor; HPA, hypothalamic-pituitaryadrenal; PG, prostaglandins; PR, prostaglandin
receptor; PROM, premature rupture of membranes.
39
bulging membranes in the absence of significant uterine contractility or rupture of the membrane, as well as with precipitous labor
at term. Cervical insufficiency may be the result of a congenital
disorder (e.g., hypoplastic cervix or diethylstilbestrol exposure in
utero), surgical trauma (e.g., conization resulting in substantial loss
of connective tissue), or traumatic damage of the structural integrity of the cervix (e.g., by repeated cervical dilation).546
Most cases of cervical insufficiency reflect not primary cervical disease leading to premature remodeling but other pathologic processes such as infection, which has been reported in
50% of patients presenting with acute cervical insufficiency,547
or recurrent decidual hemorrhage. The reader is referred to a
detailed review of this condition and the role of cervical cerclage
in the prevention of PTB.548
Increasing evidence implicates treatment for pre-invasive
cervical carcinoma as a risk factor for PTB. Treatments associated with an increased risk for PTB include cold knife conization (RR = 2.59; 95% CI, 1.80 to 3.72) and large loop excision
(RR = 1.70; 95% CI, 1.24 to 2.35).549 There is a greater effect on
delivery before 30 weeks, with cold knife conization associated
with an RR of 5.33 (95% CI, 1.63 to 17.40).550 Cold knife conization is also associated with an increase in perinatal mortality.550
These data are important because the large number of women
treated means that treatment for pre-invasive cervical disease
could become a major contributor to rates of PTB.
The mechanisms by which treatment for pre-invasive disease
increases the risk for prematurity are unclear.551 One hypothesis
is simply that mechanical disruption of the cervix weakens the
cervix. In support of this hypothesis, there is evidence that the
depth of the excision correlates with the risk for prematurity,
with an estimated 6% increase in risk for each additional 1 mm
of tissue excised (OR = 1.06; 95% CI, 1.03 to 1.09).552 More recent
data suggest that cervical pre-invasive disease and spontaneous
preterm labor may share common risk factors but are not directly
linked. These common risk factors may include human papilloma viruses and other microbial infections in the cervix, or
defects in the immune response.551,553 For example, in a study of
more than 170,000 women, the increased risk for PTB applied
to both women undergoing colposcopy only and women undergoing a single excisional treatment, with both having an increased
risk compared with women with normal Pap smears.554 A metaanalysis suggested that, when all the relevant studies were combined, an increased risk for PTB remains for women having
excisional (but not ablative) treatment, compared with an
untreated comparison group, although the relative risk is less
than when an external comparison group (presumably not subjected to the same common risk factors) is used.518
FETAL CONDITIONS
Intrauterine Fetal Demise
A variety of definitions and gestational age cutoff levels are used
for reporting stillbirth.555 The ages range from 20 to 28 weeks,
and birth weights range from 350 to 1000 g.555 The World
Health Organization defines stillbirth as death before expulsion
or extraction from the mother of a product of conception,
independent of gestational age, showing no signs of life as indicated by the absence of breathing, heartbeat, pulsation of the
umbilical cord, or movements of voluntary muscles. The U.S.
fetal mortality rate declined for the past few decades, reaching
an all-time low level of approximately 6 per 1000 live births.556
619
A steady decline in fetal mortality at 28 weeks of gestation or

more has paralleled the increase in late PTBs. It is reasonable to
propose that better screening for syphilis, anemia, diabetes,
IUGR, preeclampsia, and PTB, and the development of rigorous
clinical protocols for evaluation of fetal heart rate, contributed
to the observed reduced rate of stillbirth, at the expense of
caregiver-initiated PTB. However, despite implementation of
various clinical strategies, fetal deaths at 20 to 27 weeks of gestation did not decline, thereby implying increased vulnerability
of the fetus at this gestational age.
Among the major risk factors for stillbirth worldwide are
uteroplacental vascular insufficiency, abruption, smoking,
maternal medical conditions (e.g., lupus, chronic hypertension,
antiphospholipid syndrome, thyroid disease, cholestasis, thrombophilia), African-American race, maternal nutritional deficiencies, obesity, congenital and aneuploidy preeclampsia,
infections (e.g., parvovirus, cytomegalovirus, syphilis, malaria,
Listeria monocytogenes), chorioamnionitis, multiple gestations,
and umbilical cord complications.557 Many of these are wellrecognized risk factors for either spontaneous or caregiverinitiated PTB (with the latter resulting from nonreassuring fetal
status in utero or a gestational age at which the risk for stillbirth
outweighs the risk for prematurity-related complications).558
The existence of various common factors that underlie both
stillbirth and PTB is supported by large epidemiologic studies.
Gordon and coworkers found that the risk for stillbirth in a
subsequent pregnancy was significantly increased if the initial
pregnancy was complicated by delivery of a small-forgestational-age (SGA) preterm neonate (7/1000 live births).559
These findings are consistent with the work of Surkan and colleagues, who found a similar association between PTB and stillbirth (19/1000 live births).560 These concepts are incorporated
in the PTB classification system proposed by the Global Alliance
on Prematurity and Stillbirth, which suggested that PTBs should
be classified using a single system, regardless of whether the
infant is alive or dead at birth.10
A reasonable hypothesis is that the health of the placenta is
a common denominator in the two conditions.561 The following
evidence supports this concept: (1) In animal models of LPSinduced PTB, cytotoxic natural killer cells infiltrate the placenta
and are associated with placental cell death, a phenomenon
similar to that observed in inflammation-induced fetal
demise562,563; (2) medical conditions associated with stillbirth
(e.g., severe thrombophilia) and spontaneous PTB share a
common constellation of placental histologic features (e.g.,
thrombosis, infarction, perivillous fibrin deposition, inflammation)428,564-566; (3) failure to modify spiral arteries resulting from
defective endovascular trophoblast invasion is associated with
stillbirth567; and (4) pregnancy loss rate is significantly higher
in patients with confined placental mosaicism than in the cytogenetically normal cohort.568 As whole exomic and genomic
sequencing becomes readily available, a common set of genes
that perturb the normal physiology of the placenta and uterus
in pregnancies complicated by stillbirth and PTB may be found.
Maternal stress521-524 and socioeconomic status569 have been
linked to PTB as well as stillbirth. Therefore, residual confounding related to social factors linked to stillbirth may be important
determinants of the PTB syndrome phenotype.
Intrauterine Growth Restriction
Diagnosis and management of IUGR is one of the most common
and challenging problems in modern obstetrics. Confusion in
620
terminology and lack of uniform diagnostic criteria play an

important role. For example, the terms SGA and IUGR are frequently used interchangeably, but some suggest that SGA is more
appropriate for the newborn570 and that IUGR should refer to the
fetus.571 The American College of Obstetricians and Gynecologists favors a sonographic estimated fetal weight of less than the
10th percentile for IUGR.572 There is evidence demonstrating that
most of the adverse perinatal outcomes are primarily confined to
infants below the fifth or third percentile at birth.573
The underlying etiology of IUGR is important and frequently assists with determination of the timing of delivery.
Overall fetal growth and development in utero is highly dependent on maternal, fetal, or placental factors, and perturbations
occurring in any of these compartments can lead to IUGR. A
detailed list of various maternal, fetal, and placental conditions
linked to IUGR is presented in Chapter 47. However, the risk
factors for IUGR, stillbirth, and PTB overlap.
The relationship between IUGR and prematurity is complex.
Traditionally, the etiology of IUGR is unknown in approximately 60% of cases.574 In such cases, gestational age may play
a considerable role because major complications of prematurity
wane considerably after 34 weeks of gestation.575 Therefore,
after 34 weeks of gestation, a caregiver-initiated premature
delivery of the idiopathic IUGR fetus is indicated to avoid stillbirth.575 In other clinical situations (e.g., preeclampsia) maternal status is the primary indication for premature delivery of
an IUGR fetus. However, several lines of epidemiologic evidence suggest a link between spontaneous PTB and fetal growth
restriction.559,560,576
Placental association with IUGR is unique because it can be
the primary cause (e.g., in the case of mosaicism) of fetal growth
restriction.577 However, placental mosaicism does not appear to
be associated with an increased risk for spontaneous PTB.568
IUGR is often related to placental abnormalities, including
partial abruptions, previa, infarcts, and hematomas. Salafia and
colleagues described histologic changes of the placenta in pregnancies complicated by IUGR.578 Placental lesions were infarction, chronic villitis, hemorrhagic endovasculitis, and placental
vascular thromboses. One or more of these lesions were present
in 55% of IUGR cases. The spectrum of placental lesions was
not uniform across cases. These observations suggest that in
some cases of IUGR, decidual hemorrhage is the primary mechanism of disease, whereas in others, inflammation is responsible
for commencement of myometrial contractility or pPROM. In
some other IUGR cases, chronic villitis and hemorrhagic endovasculitis tend to occur together, implying that the two pathways can also act in parallel.578-580
Abnormal Fetal Heart Rate or Biophysical Profile
A number of methods for assessing fetal well-being, including
the nonstress test (NST) and the biophysical profile (BPP), are
routinely used to assess fetal behavioral response to intrauterine
stress.581,582 Maturation and maintenance of the structural and
functional integrity of the fetal autonomic nervous system is
responsible for the changes in fetal heart and biophysical activity (movements, breathing, tonus) observed in utero at various
gestational ages.583 Approximately 80% of normally developed
fetuses at 28 to 32 weeks demonstrate BPP test scores and fetal
heart rate reactivity appreciated as normal (using the criteria of
8/8 or 8/10, and 10-beat, respectively).584,585
Many studies assessed the relationship between prematurity,
NST, and BPP.586-593 The purpose of this large body of research
was to assess whether appropriate clinical decisions (i.e., continuation of pregnancy or caregiver-initiated PTB) can be made
on the basis of these two tests to avoid neurologic morbidity
and stillbirth in preterm infants delivered in the setting of IUGR
or intrauterine infection. Although the original studies were
encouraging,594 the overall consensus was that neither the NST
nor the BPP had good sensitivity for predicting poor neurodevelopment (e.g., cerebral palsy) or infectious complications
(e.g., neonatal sepsis).589,592,595 Steroids that are universally recommended to avoid prematurity-related complications might
add to the complexity of the clinical decision process because
they can alter both fetal heart rate596 and BPP scores.597 Therefore, other tests such as umbilical artery and venous Doppler
velocimetry were proposed to be incorporated in the clinical
algorithms to indicate the appropriate time of delivery for
fetuses at risk.598
The fetus relies on the placenta to ensure adequate oxygen
and nutritional transfer from the mother.599 However, in the
context of an acutely or chronically impaired oxygen transfer
or placental inflammatory dysfunction, abnormal BPP scores
and fetal heart rate monitoring patterns may become the first
clinical manifestation of such an intrauterine process.600,601 This
paradigm is supported by the histopathologic evidence that
abnormal fetal heart rates and BPP scores are more frequently
present in association with thrombotic vasculopathy, villous
endothelial necrosis, placental infarcts, acute umbilical cord
vasculitis (funisitis), and histologic chorioamnionitis.589,593,602
Thus, an abnormal fetal heart rate or BPP is not the cause but
rather a symptom of an underlying etiology leading to spontaneous PTB or caregiver-initiated prematurity.
Infection and the Fetal Inflammatory
Response Syndrome
Infection and the inflammatory response syndrome are defined
as a fetal phenotype leading to preterm labor in the new classification system.10 Although there is extensive overlap between
these conditions and clinical chorioamnionitis, increasing evidence suggests that the fetal inflammatory response syndrome
(FIRS), which is almost always associated with fetal infection,
is a distinct entity.
FIRS was initially described in pregnancies complicated by
preterm labor and pPROM.176,396 It was defined as a fetal plasma
concentration of IL-6 greater than 11 pg/mL.396 There are close
parallels with the adult systemic inflammatory response syndrome, with similar peripheral blood leukocyte transcriptomic
responses.603 Fetuses with elevated plasma IL-6 concentrations
have higher rates of severe neonatal morbidity and a shorter
cordocentesis-to-delivery interval than those with IL-6 concentrations lower than 11 pg/mL.176,335,397,398 The histopathologic
landmarks of FIRS are funisitis and chorionic vasculitis.399 The
disorder can also be diagnosed by measurement of C-reactive
protein concentrations in umbilical cord blood.326 Fetuses with
FIRS have more systemic derangements, including hematologic
abnormalities (neutrophilia), and a higher median nucleated red
blood cell count, than those without elevated IL-6.400 In addition,
they have biochemical evidence of fetal stress, as manifested by
a fetal plasma ratio of cortisol to DHEAS,401 congenital fetal
dermatitis,402 fetal cardiac dysfunction,110 involution of the
thymus,403 and abnormalities of the fetal lung125,371,373,398,404-407
and brain.31,71,83,408-433,335 FIRS was initially described in the
context of fetal infection, and it is more common in infants
with demonstrable microorganisms (such as Mycoplasma and
39
Ureaplasma) in their cord blood.510 However, FIRS can be triggered by other fetal stressors such as hypoxemia.604
Fetal Anomaly
About 2% to 3% of all pregnancies are complicated by a fetal
anomaly.605,606 The incidence of fetal anomalies in monozygotic
twins, compared with those in singletons or dizygotic twins, is
increased by 5% to 6%.607 Overall, the antenatal detection rate
of fetal structural anomalies is approximately 45%, with a range
of 15% to 85%.608 Recognition of fetal structural anomalies
varies based on severity or whether the antenatal screening is
performed on a low- or a high-risk population.608 Approximately 18% of fetal structural anomalies are associated with
chromosomal aneuploidy, but in about 50% of the cases, no
cause is identified.609 Congenital heart defects are the most
common nonchromosomal anomalies (6.5/1000 births), followed by limb defects (3.8/1000 births), anomalies of the
urinary system (3.1/1000 births), and nervous system defects
(2.3/1000 births).610
Most fetal anomalies carry no risk in utero. However,
approximately 2% of cases of fetal anomalies, and 25% to 28%
of fetuses with aneuploidy, end as stillbirth.611,612 To avoid death
in utero, antenatal testing is often recommended for fetuses
with anomalies or chromosomal abnormalities appreciated as
nonlethal. This approach significantly increases the chance of
caregiver-initiated prematurity to facilitate immediate direct
care of the newborn.609
Fetal surgery consists of in utero treatment of various congenital malformations. Implementation of various forms of in
utero fetal surgical reparative techniques (e.g., meningomyelocele, spina bifida, congenital diaphragmatic hernia) is associated
with potential benefits that must be weighed against the
increased likelihood of maternal and fetal complications, such
as induced PTB, pPROM, infection, and placental abruption.613-615
An increased risk for spontaneous PTB was reported in pregnancies complicated by multiple anomalies,616 gastroschisis,617
and twin pregnancies with one anomalous fetus.618 The underlying etiology remains unknown, but anomalies associated with
polyhydramnios remain at highest risk. In such cases, excessive
myometrial stretch may play a role.236,237
Polyhydramnios
During human gestation, amniotic fluid is of great importance.
In the gestational sac, it protects the fetus from trauma and
favors fetal musculoskeletal and lung development. As noted in
Chapter 3, the complex nature of the amniotic fluid dynamics
reflects contributions from maternal and multiple fetal systems
(cutaneous, renal, respiratory, digestive, placental, fetal membrane).619 Volume-regulatory mechanisms that are involved
during the second half of pregnancy in controlling the amount
of amniotic fluid are fetal (urine, lung, swallowing) and amniochorion absorption dependent.
Polyhydramnios, or excess amniotic fluid, complicates
approximately 1% to 2% of pregnancies and has been associated with a variety of adverse pregnancy outcomes, including
PTB.620 Traditionally, polyhydramnios was diagnosed when the
AFI of the deepest pool was greater than 8 cm, or when the sum
of the AFIs of four quadrants was greater than 24 cm.621 Maternal, fetal, and placental conditions associated with polyhydramnios include maternal diabetes mellitus622 and insipidus,623
rhesus iso-immunization,624 congenital and chromosomal
abnormalities,625 multiple gestation,626 and placental tumors.627
621
However, 50% to 60% of polyhydramnios cases are classified

as idiopathic.628 In such situations, reduction of the physiologic amniotic fluid turnover may result from aberrant expression of members of the transmembrane channel family of
aquaporins.629
Perturbation of the amniotic fluid flow resulting from fetal
conditions can lead to volume abnormalities such as polyhydramnios. Irregular swallowing (from obstruction, or neurologic)630,631 and gastrointestinal tract anomalies (tracheoesophageal
fistula, congenital diaphragmatic hernia)632,633 may yield hydramnios in anomalous fetuses. In such clinical scenarios, it is reasonable to propose that excessive myometrial and fetal membrane
stretch leads to premature activation of uterine contractility, cervical ripening, and dilation. However, clinical studies estimate
that PTB occurs in 18.5% of cases with mild (AFI, 25 to 30 cm),
21.8% with moderate (AFI, 30.1 to 35 cm), and 14.3% with
severe (AFI > 35.1 cm) polyhydramnios.620 Fetuses with congenital malformations and those of diabetic mothers have a significantly higher incidence of PTB than fetuses with unexplained
polyhydramnios. Thus, the underlying cause of polyhydramnios,
rather than the relative excess of amniotic fluid, may determine
the occurrence of PTB.620
Multiple Pregnancies
Premature birth in multiple pregnancies is seven times greater
than in singletons.634 The gestational age at delivery decreases
with increasing numbers of fetuses. The average gestational age
of delivery with twins is 35 weeks, compared with 30 weeks for
quadruplets.635 Overall, 52.2% of multiple births deliver before
37 weeks and 10.7% before 32 weeks.636 These observations
implicate extreme mechanical stretching in the pathophysiology of multiple pregnancyrelated PTB.
Sfakianaki and coworkers explored whether the higher uterine
volume of multiple gestation could lead to a thinner uterine wall
and increased myometrial wall stress, and therefore perhaps
explain the tendency for twin gestations to deliver earlier than
singletons.637 However, there was no significant ultrasonographic
change in the myometrial thickness of the uterine body across
pregnancy in women who deliver twins term or preterm, even
though there is a substantial increase in the uterine volume in the
multiple pregnancies. However, thinning of the lower uterine
segment occurred earlier in twin pregnancies destined to deliver
before term. Based on these findings, it was proposed that the
uterus of the women who deliver preterm twins have a natural
limitation of adaptation to the increased length, volume, or
weight, and that this limit may be reached at an earlier point in
gestation than with twins delivering at term.
Structural and functional differences in the myometrium in
twin versus singleton pregnancies might be anticipated, as the
myometrium in a multiple pregnancy is exposed to a greater
degree of stretch. However, studies comparing myometrium of
singleton and multiple pregnancies found no difference in the
expression of G-protein (Gs, which mediates cyclic AMP synthesis and relaxation), gap junction proteins (connexin-43,
connexin-26), and prostaglandins (EP1, EP3, and EP4).638 Turton
and coworkers reported preliminary data that oxytocin augments contractions to a greater extent in myometrium from
twin pregnancies than myometrium from singletons in vitro.639
Further studies are required to determine whether this effect is
stretch dependent.
There is much heterogeneity among patients with multiple
gestations. In some, infection plays a central role.640-642 In others,
622
cervical shortening and dilation, coupled with acute inflammatory lesions of the placenta, may cause stress and decidual
hemorrhage-induced PTB.643,644 Assisted reproductive technology, which is responsible for approximately 15% to 20% of
multiple births,645 demonstrates increased rates of perinatal
complicationspreterm delivery as well as maternal complications, such as preeclampsia, gestational diabetes, placenta
previa, and placental abruption.646 It is not possible to separate
risks related to assisted reproductive technology from those
caused by underlying reproductive pathology, or from the
medical condition requiring delivery. These separate mechanisms of disease may operate alone or in conjunction with
uterine overdistention to activate the components of the
common pathway.647
PLACENTAL PATHOLOGIC CONDITIONS
Histologic Chorioamnionitis
A large body of research points toward the choriodecidua as a
major site of inflammatory processes linked to PTB.139,514,648,649
In the setting of silent chorioamnionitis, inflammatory cytokines and chemokines, released as a result of engagement of
TLRs, lead to recruitment of inflammatory cells such as macrophages, dendritic cells, and neutrophils, with the final purpose
of killing the invading pathogens and halting their spread into
the amniotic fluid and to the fetus.438,648 The leukocytes invading
the chorion and amnion are maternal in origin.650 The process
of inflammatory cell migration into the decidual and fetal
membrane tissue is tightly controlled and involves chemotactic
factors (chemokines) and cell adhesion molecules (e.g., selectins, integrins). The resultant microenvironment is rich in
inflammatory mediators that induce tissue damage and result
in cytokine and chemokine translocation in the amniotic fluid.
Nitric oxide, vascular endothelium growth factor, and angiopoietins seem to be involved in the process of cytokine transfer
across fetal membranes.648,651
The inflammatory events occurring in the choriodecidua
and fetal membranes are important because they could lead to
premature activation of myometrial contractility and PTB
through synthesis and release of free radicals, prostaglandins,
and metalloprotease.489,652,653 Based on these observations, it
is reasonable to assume that the development of a maternal
inflammatory response (deciduitis) has some diagnostic potential, even if the process at the time of evaluation is subclinical.
Examination of the placenta has been the first step in pathologically classifying the wide range of clinical phenotypes linked
to PTB (e.g., infection, abruption, hypoxia) and poor neurodevelopmental outcome of the neonate. A significant focus has
been on antenatal inflammatory processes.654-656 The proximity
of the placenta to the fetus, and their common embryologic
origin have facilitated a significant number of studies that
linked placental inflammatory lesions to short- and long-term
neonatal outcomes such as cerebral palsy.657 The major drawback is that pathologic examination of the placenta is possible
only after birth. As a result, histologic biomarkers are irrelevant
during the antenatal period, because they do not allow initiation of therapies meant to prevent either PTB or adverse
neonatal outcomes. Their overall usefulness is for postnatal
counseling and research purposes.
Pathologic examination of the placenta has a further limitation: the relatively large subjectivity in interpretation of
histologic findings. First, the inflammatory lesions responsible

for similar outcomes are characterized by a high degree of heterogeneity and poor to moderate intraoperator and interoperator variability.658 Second, the intricacy and redundancy of
biologic processes responsible for cellular and tissue injury
might lead to identical pathologic footprints in the context of
distinctive triggers. Third, a mild degree of histologic chorioamnionitis may occur after normal labor at term, without
pathologic consequences for the newborn.656,659
Placental Abruption
Placental abruption represents hemorrhage into the decidua
basalis, with complete or partial separation of the placenta from
its implantation site.432 The incidence of placental abruption
varies from 0.5% to 2%, based on the clinical definition and the
criteria applied to characterize its intensity.427,660 The peak rate
of abruption is at 24 to 27 weeks of gestation,661 with an occurrence of PTB as high as 40% (RR = 3.9; 95% CI, 3.5 to 4.4). The
high rate of abruption-related perinatal mortality, calculated to
be approximately 119 in 1000 births, is heavily confounded by
prematurity.662 In addition, the abruption-derived prematurity
may have long-term consequences for the surviving infants
(e.g., hypoxic ischemic encephalopathy, intraventricular hemorrhage, bronchopulmonary dysplasia, cerebral palsy).
The classic clinical presentation of abruption manifests as
vaginal bleeding, uterine contractions, or abnormal fetal heart
rate, or a combination of these. A challenging situation is a
concealed abruption, when bleeding is not clinically observable.
In this situation, a diagnosis of placental abruption can be
established on the basis of fresh macroscopic or histologic
examination of the placenta.428 The converging point between
abruption and intra-amniotic infection is histologic chorioamnionitis. The acute lesions of histologic chorioamnionitis are
frequently associated with evidence of abruption (hematoma,
fibrin deposition, compressed villi, hemosiderin-laden histiocytes).427 The key histologic finding in placental abruption is
hemorrhage in the decidua basalis,432 which is thought to result
from pathologic processes damaging the vascular endothelium
at the maternal-fetal interface.433 Important to understanding
the relationship between placental abruption and PTB is that
decidual hemorrhage is a risk factor for preterm contractions
and pPROM.663 This could be the consequence of bleedinginduced neutrophil infiltration, activation of MMPs, and prostaglandin synthesis.664 A comprehensive description of the
molecular mechanisms and pathways governing the process of
placental abruptioninduced PTB was presented earlier.
Placenta Previa
A diagnosis of placenta previa is established when the placenta
is inserted into the lower uterine segment and partially or
entirely covers the cervix.665 Placenta previa complicates about
0.3% to 0.8% of pregnancies and is one of the most frequent
causes of painless bleeding during the second half of gestation.665,666 Risk factors for placenta previa include a history of
prior cesarean delivery, uterine surgery, termination of pregnancy, smoking, advanced maternal age, multiparity, drug
abuse, and multiple gestations.665 Antepartum bleeding is a
strong predictive risk factor for PTB. In such clinical scenarios,
over 50% of the women are delivered before term.667 The
median gestational age of the first episode of bleeding is approximately 30 weeks, with a median interval of 20 days between the
first bleeding episode and delivery.667
39
The pathophysiology of bleeding in placenta previa includes

tearing of the placental attachment over the lower uterine
segment or the internal os of the cervix. Bleeding is augmented
by the inability of the myometrial fibers of the lower uterine
segment to contract and thereby close the bleeding vessels.
A variety of regulatory molecules play functional roles in controlling the process of trophoblast invasion during implantation and placentation.668-670 These include vasoactive and cell
surface proteins, proteases, cytokines, chemokines, and growth
factors.670 The underlying cause of the excessive myometrial
penetration that characterizes placenta accreta, increta, or percreta accompanying placenta previa remains largely unknown.665
Excessive trophoblast invasion can trigger profound vaginal or
intraperitoneal bleeding. Recent data suggest that a lower systemic level of free VEGF and a switch of the interstitial extravillous trophoblasts to a metastable cell phenotype characterize
placenta previa with excessive myometrial invasion and bleeding.671 The local hemostatic milieu of the human decidua plays
an important role in generating uterine contractions and amplification of bleeding through mechanisms that are similar to
those involved in placental abruption.
Other Placental Abnormalities
Umbilical cord abnormalities, such as single umbilical artery,
varices and aneurysms, thrombosis of umbilical vessels, hematoma, abnormal insertion of the blood vessels, and excessive
coiling, knots, and entanglement of the cords, in monoamniotic
twin pregnancies can be associated with abnormal fetal growth,
development, and behavior that can contribute to premature
delivery.672-676 Placental pathologic conditions previously associated with PTB include gestational trophoblastic diseases,
623
vascular tumors (chorangioma, teratoma), accessory lobes, and

vasa previa.677-679 The vast majority of the literature describing
these umbilical cord and placental abnormalities is descriptive.
Many cord and placental abnormalities occur in association
with complex congenital anomalies, chromosomal aneuploidy,
IUGR, hydrops, histologic chorioamnionitis, or abruption, or
as complications of multifetal gestation. On the basis of existing
knowledge, it is difficult to determine if pathophysiologic events
characteristic for each abnormality are independently responsible for triggering PTB, or if premature delivery is the result of
several overlapping factors.
Summary
Preterm labor, pPROM, and cervical insufficiency are syndromes caused by various pathologic processes leading to
decidual activation, increased myometrial contractility, cervical
remodeling, and membrane rupture. The clinical presentation
depends on the nature and timing of the insults affecting the
various components of the uterine common pathway of parturition. The revised classification system for PTB depends largely
on clinical phenotype. Although it requires a paradigm shift to
think of preterm parturition as a syndrome, it should facilitate
a more accurate comparison of causes of PTB in various populations and with regard to trends over time. The revised classification system has important implications for understanding
the biology of preterm parturition, as well as its diagnosis, treatment, and prevention.
The complete reference
www.expertconsult.com.
list
is
available
online
at
39
623.e1
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Pathogenesis of Spontaneous Preterm Birth

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39

Preterm Birth Syndrome: New

can result from induction of preterm labor or from preterm

PART 4 Disorders at the Maternal-Fetal Interface

Significant Fetal Conditions

Placental Pathologic Conditions

SIGNS OF INITIATION OF PARTURITION

Evidence of Initiation of Parturition

BIRTH >16 to <38+6 WEEKS