Chapter 28 PROM

Chapter 28
Pathogenesis of Spontaneous
Preterm Labor
Roberto Romero, MD, and Charles J. Lockwood, MD
Preterm deliveries are those occurring between fetal viability and 37

completed weeks of gestation (menstrual age).1 Delivery of a previable
fetus represents a spontaneous abortion rather than a preterm birth.
The precise definition of viability, however, is a subject of debate
because of the increased frequency of survival at very low gestational
ages. Some neonates can survive if born around 24 weeks of gestation,
but none at 20 weeks; therefore, we propose that preterm birth be
defined as one that occurs between 24 and 36 6/7 weeks of gestation.
This definition may need to be revised if future technologic advances
allow substantial survival at less than 24 weeks of gestation.
A birth weight of 500 g has historically been used to define the
lower limit of viability. However, this approach is limited because
viable neonates born after 24 weeks may be affected by intrauterine
growth restriction (IUGR) and have birth weights of less than 500 g.
Conversely, some previable infants may weigh more than 500 g. The
threshold of 500 g is valuable if there is uncertainty about gestational
age. An accurate definition of preterm birth has implications for the
calculation of vital statistics and comparisons of the rates of preterm
delivery among different countries and populations, an issue that is
often overlooked.
Preterm births can be spontaneous or indicated. Spontaneous
preterm labor can occur with either intact membranes or prelabor
(premature) rupture of the fetal membranes (PROM). Indicated
preterm births are those that result from induced preterm labor or
preterm cesarean delivery for maternal or fetal indications, usually
because of preeclampsia or IUGR or both. The mechanisms of disease
responsible for these two conditions are discussed in other chapters of
this text (see Chapter 5).
Of all preterm deliveries, some 25% (reported range, 18.7% to
35.2%) are indicated, and the remainder are spontaneous45%
(23.2% to 64.1%) from preterm labor with intact membranes and 30%
(7.1% to 51.2%) from preterm labor after PROM.2,3 The rate of
preterm delivery in the United States has climbed 14% since 1990; this
has been attributed to an increased frequency of indicated preterm
birth in singleton gestations, an increased number of multiple gestations, and an increased number of older parturients.4
Overview of the Mechanisms

of Labor
The Common Pathway
The traditional view, which has dominated the study of preterm parturition, is that term and preterm labor are the same processes, albeit
occurring at different gestational ages. Indeed, they do share a common
pathway, which includes increased uterine contractility, cervical ripening, and membrane rupture.5 It has been proposed that the fundamental difference between term and preterm labor is that the former results
from physiologic activation of this common pathway, whereas
preterm labor results from a disease process (pathologic activation)
that extemporaneously activates one or more of the components of the
common pathway.6
The common pathway of parturition is defined as the anatomic,
biochemical, immunologic, endocrinologic, and clinical events that
occur in the mother and fetus in both term and preterm labor.6 Much
clinical emphasis has been placed on the uterine components of the
pathway (myometrial contractility, cervical ripening, and membrane
rupture) (Fig. 28-1). However, there are systemic changes, such as an
increase in the plasma concentration of corticotropin-releasing
hormone (CRH) and in the caloric metabolic expenditures, that are
also part of the common pathway.7-10
Activation of the uterine components of the common pathway of
parturition may be synchronous or asynchronous. Synchronous activation results in clinical spontaneous preterm labor. Asynchronous
activation results in a different phenotype. For example, predominant
activation of the membranes leads to preterm PROM, that of the cervix
to cervical insufficiency, and that of myometrium to preterm uterine
contractions without cervical change or rupture of membranes (Fig.
28-2).
Spontaneous preterm labor with intact membranes, preterm
PROM, and cervical insufficiency can be considered syndromes caused
522
CHAPTER 28
Pathogenesis of Spontaneous Preterm Labor
Preterm
PROM
Membrane
Activation
Uterine
Contractility
Cervical
Dilatation
FIGURE 28-1 Uterine components of the common pathway of

parturition (preterm and term). (From Romero R, Gomez R, Mazor
M, et al: The preterm labor syndrome. In Elder MG, Romero R,
Lamont RF (eds). Preterm Labor. New York: Churchill Livingstone,
1997, pp 29-49.)
by multiple etiologies with specific pathogenic pathways. This chapter

reviews the pathophysiology of the common pathway of parturition
and examines the pathologic mechanisms responsible for its
activation.
Myometrial Contractility
Although myometrial contractility occurs throughout pregnancy,
labor is characterized by a dramatic change in the pattern of uterine
contractility, which evolves from contractures to contractions.6
Nathanielsz and Honnebier11 and Hsu and colleagues12 defined contractures as epochs of myometrial activity lasting several minutes, associated with a modest increase in intrauterine pressure and fragmented
bursts of electrical activity in the electromyogram. In contrast, contractions are epochs of myometrial activity of short duration associated
with dramatic increases in intrauterine pressure and electromyographic activity. The switch from a predominant contracture pattern
to a predominant contraction pattern occurs physiologically during
normal labor13 or can be induced by pathologic events such as food
withdrawal, infection, or intra-abdominal surgery.14-16
Increased cell-to-cell communication is thought to be responsible
for the effectiveness of myometrial contractility during labor. Gap
junctions develop in the myometrium just prior to labor and disappear
shortly after delivery.17-21 Gap junction formation and the expression
of the gap junction protein, connexin-43, in human myometrium is
similar in both term and preterm labor.22-26 These findings suggest that
the appearance of gap junctions and increased expression of connexin43 may be 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 been implicated in the regulation of gap junction formation,
and they also influence the expression of connexin-43.27-29 Lye and
others have referred to a set of distinct proteins, called contractionassociated proteins, that are characteristic of this phase of parturition
(see Chapter 5).24,30,31
Lye and colleagues32 also proposed that the myometrium undergoes
sequential phenotypic remodeling during pregnancy. Their studies
Preterm
Contractions
Cervical
Insufficiency
FIGURE 28-2 Clinical manifestations of preterm activation of the

common pathway of parturition. Clinical manifestations depend on
whether there is synchronous or asynchronous recruitment of the
pathway. Cervical insufficiency is the presenting phenotype if
activation of the cervix occurs in isolation. Prelabor rupture of
membranes (PROM) occurs if decidual/membrane activation is the
predominant pathway activated. Isolated activation of the
myometrium results in preterm uterine contractions. Synchronous
activation of the myometrium and the cervix results in the clinical
presentation generally recognized as preterm labor with intact
membranes. (From Romero R, Gomez R, Mazor M, et al: The
preterm labor syndrome. In Elder MG, Romero R, Lamont RF (eds).
Preterm Labor. New York: Churchill Livingstone, 1997, pp 29-49.)
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 proliferation 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/DNA ratio in the second half of
pregnancy. This stage coincided with a higher secretion of extracellular matrix (ECM) 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).
-Actin was expressed in the myometrium in early pregnancy, whereas
-actin was highly expressed by myometrium with a contractile phenotype. The switch from a proliferative to a synthetic phenotype
appeared to be regulated by caspase 3, and a decrease in progesterone
was responsible for the switch from the synthetic to the contractile
phenotype.32 This view is consistent with the proposal of Csapo about
the importance of progesterone in the regulation of myometrial contractility at the onset of parturition.33 Microarray experiments of myometrium in labor indicate an overexpression of genes involved in
CHAPTER 28
control of inflammation (Romero et al., unpublished observations)
This is consistent with other studies which used subtraction hybridization to identify genes differentially expressed during labor. Interleukin
8 (IL-8) and superoxide dismutase have been found to be differentially
regulated.34
Cervical Remodeling
The changes in the cervix include: (1) softening, (2) ripening, (3) dilatation, and, after delivery, (4) repair.35 Sonographic studies have demonstrated that shortening of the cervix occurs before the dramatic
increase in uterine contractility that characterizes term and preterm
labor. Hence, the regulation of cervical remodeling has become important in the understanding of cervical insufficiency and spontaneous
preterm labor.
The molecular and cellular bases for cervical remodeling during
pregnancy and parturition are largely dependent on the regulation of
extracellular matrix components.35-41 Softening of the cervix begins in
early pregnancy. The tensile strength of the softened cervix appears to
be maintained by an increase in collagen synthesis and growth of the
cervix. Cervical ripening is characterized by a decreased concentration
of collagen and the dispersion of collagen fibrils. The latter has been
attributed to glycosaminoglycans, such as decorin and hyaluronan,
which promote hydration of cervical tissue and dispersion of the collagen fibers.36 Dilation of the cervix is an inflammatory phenomenon
in which there is an influx of macrophages and neutrophils and matrix
degradation.42-44 Chemokines such as IL-845-49 and S100A950,51 attract
inflammatory cells, which, in turn, release proinflammatory cytokines,
including IL-152,53 and tumor necrosis factor- (TNF-),35-54 that can
activate the nuclear factor (NF)-B signaling pathway. NF-B can
block progesterone receptor-mediated actions.55 Progesterone has been
implicated in the regulation of cervical remodeling because (1) administration of antiprogestins to women in the mid-trimester and at term
induces cervical ripening;35,56-60 and (2) the administration of progesterone-receptor antagonists such as mifepristone (RU-486) or onapristone (ZK 98299) to pregnant guinea pigs,61,62 old-world monkeys,63 and
Tupaia belangeri induces cervical ripening.35 Cervical responsiveness to
antiprogestins increases with advancing gestational age,35 and the
effects of antiprogestins in the cervix are not always accompanied by
changes in myometrial activity.35 Indeed, Stys and associates64 demonstrated a dissociation between the effects of progesterone in the myometrium and those in the cervix. A frequent observation, in animals62,63
as well as in humans,65 is that antiprogestins induce cervical ripening
but not labor. Indeed, labor may be delayed by days or weeks, or it may
not begin at all after cervical ripening has been accomplished in
humans.35 Collectively, these findings suggest that the cervix is a major
site of progesterone action. This realization is important, because
much of the emphasis in previous years has been on the effect of progesterone on the myometrium. Yet, recent randomized clinical trials
suggest that progesterone may be helpful in preventing preterm birth
in women with a short cervix.66-69
523
allow separation and postpartum expulsion of the membranes. Fibronectins are a family of important extracellular matrix proteins. The
available evidence suggests that degradation of a heavily glycosylated
form of cellular fibronectin (i.e., fetal fibronectin) which is present at
the chorionic-decidual interface leads to its release into cervical and
vaginal secretions immediately before term and preterm parturition.70-73
Beyond proteolytic degradation of the decidual and amniochorionic
extracellular matrix by matrix-degrading enzymes, PROM is also associated with amnion epithelial apoptosis and localized inflammation.74
Therefore, these processes belong to the common terminal pathway of
parturition.
Enzymatic activity of matrix metalloproteinases (MMPs) and other
proteases has been implicated in the process of rupture of membranes
and parturition with intact membranes (with and without infection).75-77
Histologic studies of membranes in women with term PROM indicate that membranes that rupture prematurely have a decreased
number of collagen fibers, disruption of the normal wavy patterns of
these fibers, and deposition of amorphous materials among them.78
Similar changes have been observed in the membranes apposed to the
cervix in women undergoing elective cesarean delivery at term with
intact membranes. The implication is that, although spontaneous
rupture of membranes normally occurs at the end of the first stage of
labor, the process responsible for this phenomenon begins before the
onset of labor.
Histologic studies of the site of rupture have demonstrated a zone
of altered morphology (ZAM).79,80 A significant decrease in the amount
of collagen type I, III, or V and an increased expression of tenascin
have been reported in the ZAM. Tenascin is an extracellular matrix
characteristically expressed during tissue remodeling and wound
healing. Its identification in the membranes thus signifies the presence
of injury and a wound healinglike response. Observations by Bell and
colleagues81,82 suggested that changes in the ZAM are more extensive
in the setting of preterm PROM. These morphologic and biochemical
observations are consistent with the results of biophysical studies suggesting that rupture of membranes results from the application of
acute or chronic stress on localized areas of the membranes that are
weaker.
The precise mechanism of decidual/membrane activation remains
to be elucidated. As noted, roles for extracellular matrixdegrading
enzymes such as the MMPs and apoptosis have been proposed. Several
studies have demonstrated increased availability of MMP-1 (interstitial collagenase),83 MMP-8 (neutrophil collagenase),84 MMP-9
(gelatinase-B),85 and neutrophil elastase86 in the amniotic fluid of
women with preterm PROM, compared with women in preterm labor
with intact membranes. Plasmin has also been implicated in this
process,73 because this enzyme can degrade type III collagen, fibronectin, and laminin.87 Other MMPs are likely to be involved, but systematic studies have not been conducted to date.88-90 A role for tissue
inhibitors of MMPs (TIMPs) has also been postulated.91
Decidual/Membrane Activation
Prostaglandins as Key Activators of

the Common Pathway of Parturition
We use the term decidual/membrane activation to refer to a complex

set of anatomic and biochemical events that lead to separation of the
lower pole of the fetal amniochorionic membranes from the decidua
of the lower uterine segment and, eventually, to spontaneous rupture
of the membranes and delivery of the placenta.
During pregnancy, the chorioamnionic membranes fuse with the
decidua. In preparation for delivery, biochemical events take place to
A central question in the understanding of parturition is whether the

signals responsible for activation of the common pathway are similar
in term and preterm labor. Prostaglandins have been considered the
key mediators for the onset of labor,92-107 because they can induce
myometrial contractility,92,96,105,107 changes in extracellular matrix
metabolism associated with cervical ripening,94,95,99,100,104 and decidual/
membrane activation.5
524
CHAPTER 28
Descriptive evidence traditionally invoked to support a role for

prostaglandins in the initiation of human labor includes the following:
(1) administration of prostaglandins can induce early or late termination of pregnancy (abortion or labor)103,108-118; (2) treatment with indomethacin or aspirin can delay spontaneous onset of parturition in
animals119-122; (3) concentrations of prostaglandins in plasma and
amniotic fluid increase during labor123-130; (4) intra-amniotic injection
of arachidonic acid, the precursor of prostaglandins, induces abortion101; (5) amniotic fluid concentrations of prostaglandins increase
before the onset of spontaneous labor at term in humans and nonhuman primates131; (6) expression of myometrial prostaglandin receptors
increases in labor132,133; and (7) labor is associated with increased
cyclooxygenase-2 (COX-2) expression of messenger RNA (mRNA)
and increased activity of this enzyme in amnion (a rate-limiting step
in the production of prostaglandins). This increase in amnionic COX2 activity is accompanied by decreased expression of the prostaglandin-metabolizing enzyme, 15-hydroxy-prostaglandin dehydrogenase
(PGDH) in the chorion. This would allow prostaglandins produced in
the amnion to traverse the chorion and reach the myometrium, where
they can stimulate smooth muscle contractions.134
The biochemical mechanisms by which prostaglandins activate the
common pathway of parturition are the following: (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 receptors EP1 through EP4 and FP27,135,136; (2) prostaglandins induce
synthesis of MMPs by fetal membranes and cells within the uterine
cervix (as noted, MMPs have been implicated in the mechanisms of
membrane rupture and also in cervical ripening)137,138; and (3) prostaglandin E2 (PGE2) and PGF2 increase the ratio of expression of
the progesterone receptor (PR) isoforms, PR-A/PR-B.139 This may
induce a functional progesterone withdrawal. Figure 28-3 describes
the molecular mechanisms implicated in the common pathway of
parturition.
PG
PR-A/PR-B,
ER-
Spontaneous Preterm
Parturition as a Syndrome
The current taxonomy of disease in obstetrics is based on the clinical
presentation of the mother and not on the mechanisms of disease
responsible for the clinical presentation. Neither the term preterm
labor with intact membranes nor preterm prelabor rupture of membranes conveys information about the pathologic process that has led
to untimely delivery. This situation is not unique to preterm parturition: it is also the case in preeclampsia, small for gestational age (SGA),
fetal death, and other obstetric syndromes.
Generally, the diagnostic labels used in clinical obstetrics simply
reflect a collection of symptoms and signs (e.g., abdominal pain due
to uterine contractions, leakage of fluid) without information about
the mechanisms of disease. The lack of recognition of this is responsible for the failure of any single diagnostic test or treatment to detect,
cure, or prevent preterm delivery. To emphasize that preterm labor has
multiple causes, we have used the word syndrome, which is defined
as a combination of symptoms or signs that form a distinct clinical
picture but can be generated by multiple etiologies. The features of the
great obstetric syndromes have been described elsewhere.140
We also make a distinction between preterm labor as a multifactorial disorder versus a syndrome. We are unaware of any disease in
medicine that is unifactorial. For example, even sickle cell anemia,
which is caused by the mutation of a single nucleotide, produces a wide
range of clinical manifestations, and environmental factors such as
infection or hypoxia can influence the phenotype caused by a single
discrete genotype. The term multifactorial is often used in genetics
to refer to common complex disorders in which the genetic predisposition is attributed to several genes and can be altered by environmental
factors. Each of the causes of preterm parturition syndrome fits this
definition of multifactorial. For example, in the case of infection,
microorganisms can be considered an environmental factor, but the
intensity and nature of the host inflammatory response is under
genetic control. Thus, gene-environment interactions contribute to the
phenotype of infection associated preterm parturition. The same is the
case for vascular disease or hemorrhage, stress, and so on. The causes
of preterm parturition syndrome are presented in Figure 28-4. The
mechanisms of disease for each cause are in the following sections. The
molecular signaling pathways implicated in four of these mechanisms
are displayed in Figure 28-5.
FP and EP1, 3 PG receptors in fundus

Oxytocin receptor,
connexin-43, COX-2
MMPs
and IL-8
Ca
Cervical change
Preterm PROM
Contractions
FIGURE 28-3 Molecular mechanisms implicated in the common

pathway of parturition. COX-2, cyclooxygenase-2; EP1, PTGER1,
prostaglandin E receptor type 1; ER-, estrogen receptor-; FP,
PTGFR, prostaglandin F receptor; IL-8, interleukin 8; MMPs, matrix
metalloproteinases; PG, prostaglandins; PR, prostaglandin receptor;
PROM, premature rupture of membranes.
The Spontaneous Preterm

Parturition Syndromes
Infection and Inflammation
Infection is a frequent and important mechanism of disease in preterm
delivery. Indeed, it is the only pathologic process for which an unequivocal causal link with preterm parturition has been established. Evidence for causality includes the following: (1) intrauterine infection or
systemic administration of microbial products (bacterial endotoxin) to
pregnant animals results in spontaneous preterm labor and birth141-153;
(2) extrauterine maternal infections (malaria,154,155 pyelonephritis,156-160
pneumonia,161-163 and periodontal disease164-169) are associated with
preterm delivery; (3) subclinical intrauterine infections are consistently associated with preterm labor and preterm birth170; (4) pregnant
CHAPTER 28
525
Cervical
disease
Uterine
overdistention
Abnormal
allograft reaction
III
Uterine
Ischemia +
hemorrhage
Allergic
phenomena
Infection
Endocrine
disorder
FIGURE 28-4 The preterm parturition syndrome. Multiple

pathologic processes can lead to activation of the common pathway
of parturition. (Modified from Romero R, Espinoza J, Mazor M,
Chaiworapongsa T: The preterm parturition syndrome. In Critchely H,
Bennett P, Thornton S (eds): Preterm Birth. London: RCOG Press,
2004, pp 28-60.)
Stretch
Inflammation
Integrins
IL-1
TNF-
Abruption
Thrombin
COX2
PGDH
PR-B
Stress
CRH
Estrogen
MMPs
IL-6 and 8
PTL or PPROM
FIGURE 28-5 Principal biochemical mechanisms responsible for
the main pathways of preterm parturition. COX2, cyclooxygenase2; CRH, corticotropin-releasing hormone; IL-1, interleukin-1; 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-.
women with intra-amniotic infection171-173 or inflammation (defined

as an elevation of amniotic fluid concentrations of proinflammatory
cytokines174,175 and matrix-degrading enzymes176 in the mid-trimester)
are at risk for subsequent spontaneous preterm birth; (5) antibiotic
treatment of ascending intrauterine infections can prevent preterm
parturition in experimental models of chorioamnionitis149,177; and (6)
treatment of asymptomatic bacteriuria prevents preterm birth.178,179
Because the amniotic cavity is sterile for bacteria in 99% of cases,
detection of microorganisms in the amniotic cavity with either cultivation techniques or molecular microbiologic techniques defines microbial invasion of the amniotic cavity. Microorganisms or their products
IV
II
FIGURE 28-6 The pathway of ascending intrauterine

infection. Stage I refers to a change in microbial flora in the vagina
and/or cervix. In Stage II, microorganisms are located between the
amnion and chorion. Stage III represents intra-amniotic infection, and
Stage IV is fetal invasion. The most common sites for microbial
attack are the skin and the fetal respiratory tract. (Reproduced with
permission from Romero R, Mazor M: Infection and preterm labor.
Clin Obstet Gynecol 31:553-584, 1988.)
can elicit an inflammatory response within the amniotic cavity: intraamniotic inflammation. Inflammation of the chorioamniotic membranes, or histologic chorioamnionitis, can exist without clinical signs
of infection (clinical chorioamnionitis). The stages of ascending intrauterine infection are displayed in Figure 28-6.
Microbiologic studies using cultivation techniques suggest that
infection may account for 25% to 40% of all preterm births.180,181
Microbial invasion of the amniotic cavity (MIAC) is present in 12.8%180
of women with preterm labor with intact membranes, in 32% of those
with preterm PROM,180 and in 51% of patients with acute cervical
insufficiency.182,183 Patients with MIAC are more likely to deliver
preterm neonates, have spontaneous rupture of membranes, and
develop clinical chorioamnionitis than those with sterile amniotic
fluid.184 The most common organisms found in the amniotic fluid are
genital mycoplasmas.185,186 It is believed that ascending infection is the
most common source of microbial invasion of the amniotic cavity,
although transplacental infections may also occur. The lower the gestational age at which a patient presents with preterm labor and preterm
PROM, the higher the frequency of MIAC.187,188 Moreover, many of
these infections appear to be chronic in nature, because they have been
detected in women having mid-trimester amniocentesis for genetic
indications.171-173 Bacterial products such as endotoxin have also been
detected in the amniotic cavity of women with preterm labor and
preterm PROM.189,190 Endotoxin has powerful proinflammatory effects
in maternal and fetal tissues.191-193
526
CHAPTER 28
Microorganisms are sensed by the innate components of the

immune system,194 which include (1) the soluble pattern recognition
receptors (PRRs), lectin, and C-reactive protein; (2) transmembrane
PRRs, which include scavenger receptors, C-type lectins, and Toll-like
receptors (TLRs); and (3) intracellular PRRs, including Nod1 and
Nod2, retinoic-induced gene type 1, and melanoma differentiation
associated protein 5, which mediate recognition of intracellular pathogens (e.g., viruses).195 The best-studied PRRs are the TLRs.194 Ligation
of TLR results in activation of NF-B, which, in turn, leads to the
production of cytokines, chemokines, and antimicrobial peptides.194
Because TLRs are crucial for the recognition of microorganisms, it
could be anticipated that defective signaling through this pathway
would impair bacteria-induced preterm labor. Consistent with this
thesis, a strain of mice bearing a spontaneous mutation for TLR-4 was
less likely to deliver preterm after intrauterine inoculation of heatkilled bacteria or administration of lipopolysaccharide than wild-type
mice.151,196 In pregnant women, TLR-2 and TLR-4 are expressed in the
amniotic epithelium197 as well as in decidua.198 Moreover, spontaneous
labor that occurs at term or preterm and is complicated by histologic
evidence of chorioamnionitis, regardless of the membrane status
(intact or ruptured), is associated with increased mRNA expression of
TLR-2 and TLR-4 in the chorioamniotic membranes.197 These observations suggest that the innate immune system plays a role in
parturition.
The Role of Proinflammatory Cytokines
PG
etr
om
My
ua
cid
De
Am
n
Ch ion
orio
n
Am
nio
tic
flui
ium
Inflammation and its mediators, chemokines such as IL-8, the proinflammatory cytokines (IL-1, TNF-), and other mediators (e.g.,
platelet activating factor, prostaglandins) are central to preterm parturition induced by infection. IL-1 was the first cytokine implicated in
the onset of preterm labor associated with infection.199 Evidence in
support of this concept includes the following: (1) IL-1 is produced by
human decidua in response to bacterial products200; (2) IL-1 and IL1 stimulate prostaglandin production by human amnion and
decidua201; (3) IL-1 and IL-1 concentrations and IL-1like bioactiv-
ity are increased in the amniotic fluid of women with preterm labor
and infection202; (4) intravenous IL-1 stimulates uterine contractions203; and (5) administration of IL-1 to pregnant animals induces
preterm labor and delivery,204 and this effect can be blocked by the
administration of its natural antagonist, the IL-1 receptor antagonist
(IL-1ra).205
Evidence supporting the role of TNF- in the mechanisms of
preterm parturition is similar and includes the following: (1) TNF-
stimulates prostaglandin production by amnion, decidua, and myometrium148; (2) human decidua can produce TNF- in response to bacterial products206,207; (3) amniotic fluid TNF- bioactivity and
immunoreactive concentrations are elevated in women with preterm
labor and intra-amniotic infection208; (4) in women with preterm
PROM and intra-amniotic infection, TNF- concentrations are higher
in the presence of labor208; (5) TNF- can stimulate the production of
MMPs,209,210 which have been implicated in membrane rupture85,211,212;
(6) TNF- application to the cervix induces changes that resemble
cervical ripening213; (7) TNF- can induce preterm parturition when
administered systemically to pregnant animals214,215; 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.216 Figure 28-7 displays the mechanisms involved in
preterm parturition in the setting of infection.
Other cytokines and chemokines (IL-6,187,217-221 IL-10,203,222,223 IL224
16, IL-18,225 colony-stimulating factors,226-228 macrophage migration
inhibitory factor,229 IL-8,228,230-234 monocyte chemotactic protein-1,235
epithelial cellderived neutrophil-activating peptide-78,236 and, regulated on activation, normal T-cell expressed and secreted (RANTES)237)
have also been implicated in infection-induced preterm delivery. The
redundancy of the cytokine network implicated in parturition is such
that blockade of a single cytokine is insufficient to prevent preterm
delivery in the context 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/inflam-
PG
TNF
IL-1
PG
PAF
TNF
FIGURE 28-7 Cellular and
biochemical mechanisms
involved in initiation of preterm
labor in cases of intrauterine
infection. IL-1, interleukin-1; TNF,
tumor necrosis factor/cachectin;
PG, prostaglandins; PAF, platelet
activating factor. (Reproduced with
permission from Romero R, Mazor
M: Infection and preterm labor.
Clin Obstet Gynecol 31:553-584,
1988.)
IL-1
Deciduitis
CHAPTER 28
mation.238 However, blockade of both signaling pathways (i.e., for IL-1
and TNF-) in a double-knockout mice model was associated with
a decreased rate of preterm birth after the administration of
microorganisms.215
Anti-inflammatory Cytokines and

Preterm Labor
IL-10 is thought to be a key cytokine for the maintenance of pregnancy.239-241 Its concentrations are increased in intra-amniotic inflammation,242 suggesting that IL-10 may play a role in dampening the
inflammatory response243-248 and may have therapeutic value.249-254 In a
nonhuman primate model of intrauterine infection, pregnant rhesus
monkeys (n = 13) were allocated to one of three interventional groups:
(1) intra-amniotic IL-1 infusion with maternal dexamethasone intravenously (n = 4); (2) intra-amniotic IL-1 + IL-10 (n = 5); or (3)
intra-amniotic IL-1 administered alone (n = 5). Dexamethasone and
IL-10 treatment significantly reduced IL-1induced uterine contractility (P < .05). The amniotic fluid concentrations of TNF- and leukocyte counts were also decreased by IL-10 treatment (P < .05).203
Furthermore, the administration of IL-10 in animal models of infection has been associated with improved pregnancy outcome.249,255
Fetal Involvement in Intrauterine Infection

Carroll and Nicolaides256 found fetal bacteremia in 33% of fetuses with
positive amniotic fluid cultures and in 4% of those with negative
amniotic fluid cultures in the context of preterm PROM. Therefore,
subclinical fetal infection is far more common than traditionally recognized. Recently, Goldenberg and colleagues257 reported that 23% of
neonates born between 23 and 32 weeks of gestation had positive
umbilical blood cultures for genital mycoplasmas.
Inflammation and Fetal Injury: The Fetal

Inflammatory Response Syndrome
The fetal inflammatory response syndrome (FIRS) was initially
described in pregnancies complicated by preterm labor and preterm
PROM.258,259 It was defined as a fetal plasma concentration of IL-6
greater than 11 pg/mL.258 Fetuses with an elevated plasma IL-6 concentration had a higher rate of severe neonatal morbidity and a shorter
cordocentesis-to-delivery interval than those with an IL-6 concentration lower than 11 pg/mL.259 These original findings were subsequently
confirmed.259-262 The histopathologic landmarks of FIRS are funisitis
and chorionic vasculitis.263 The disorder can also be diagnosed by
measurement of C-reactive protein concentrations in umbilical cord
blood.264 Fetuses with FIRS have more systemic involvement, including
hematologic abnormalities (neutrophilia), and a higher median nucleated red blood cell count than those without elevated IL-6.265 In addition, they have evidence of fetal stress, as determined by the fetal
plasma ratio of cortisol to dehydroepiandrosterone sulfate (DHEAS),266
congenital fetal dermatitis,267 fetal cardiac dysfunction,268 involution of
the thymus,269 and abnormalities of the fetal lung230,232,262,270-274 and
brain.275-304
Among patients with preterm PROM, elevated fetal plasma IL-6 is
associated with the impending onset of preterm labor, regardless of the
inflammatory state of the amniotic fluid (Fig. 28-8).258 This suggests
that the human fetus plays a role in initiating the onset of labor.
However, maternal-fetal cooperation must occur for parturition to be
completed. Fetal inflammation has been linked to the onset of labor
in association with ascending intrauterine infection. However, systemic
fetal inflammation may occur in the absence of labor if the inflammatory process does not involve the chorioamniotic membranes and
decidua. Such instances may take place in the context of hema-
527
togenous viral infections or other disease processes (e.g., rhesus

alloimmunization).305
Gene-Environment Interaction
A gene-environment interaction is said to be present when the risk of
a disease (occurrence or severity) among individuals exposed to both
the genotype and an environmental factor is either more severe or less
severe than that which is predicted from the presence of either the
genotype or the environmental exposure alone.306,307 Evidence in
support of a gene-environment interaction in infection-related premature labor was reported by Macones and coworkers308 in a case-control
study in which cases were defined as patients who had a spontaneous
preterm delivery (<37 weeks) and controls as women who delivered
after 37 weeks. The environmental exposure was clinically diagnosed
bacterial vaginosis (symptomatic vaginal discharge, a positive whiff
test, and clue cells on a wet preparation). The genotype of interest was
TNF- allele 2, given that carriage of this genotype had been demonstrated by the authors to be associated with spontaneous preterm birth
in previous studies.309 The key observation was that patients with both
bacterial vaginosis and the TNF- allele 2 had an odds ratio of 6.1
(95% confidence interval [CI], 1.9 to 21) for spontaneous preterm
delivery and that this odds ratio was higher than for patients with
either bacterial vaginosis or carriage of the TNF- allele alone, suggesting that a gene-environment interaction predisposes to preterm
birth.308,310 Similar interactions may determine the susceptibility to
intrauterine infection, microbial invasion of the fetus, and the likelihood of fetal injury.
Uteroplacental Vascular Disease and

Decidual Hemorrhage
Vaginal bleeding in the first or second trimester is a risk factor for
preterm birth. Bleeding in the first trimester alone is associated with
an adjusted risk ratio of 2 (95% CI, 1.6 to 2.5) for preterm delivery.311
If vaginal bleeding is present in more than one trimester, the odds ratio
for preterm PROM is 7.4 (95% CI, 2.2 to 25.6).312 Therefore, a disorder
of uterine hemostasis that manifests clinically as bleeding places the
patient at risk for preterm birth. The location of bleeding could be the
decidua, specifically the interface between decidual parietalis and
chorion or between the basal plate of the placenta and the decidua.
The latter, when large enough, is known as abruptio placenta. The
typical patient with vaginal bleeding who delivers preterm is a privately
insured, white, older, parous, and college-educated patient.313
The evidence in support of spiral artery vasculopathy and decidual
hemorrhage as a mechanism of disease in spontaneous preterm delivery is the following: (1) abruptio placenta, a lesion of uteroplacental
vascular origin is more frequent in women who deliver preterm with
intact membranes314,315 or with PROM than in those who deliver at
term316-318; (2) the frequency of SGA infants is increased in women who
deliver after preterm labor with intact membranes and preterm
PROM319-324 (SGA has generally been attributed to a problem with the
uterine vascular supply line, and this could account for both IUGR and
abruption-associated preterm parturition); (3) vascular lesions in
decidual vessels attached to the placenta have been reported in 34% of
women with preterm labor and intact membranes and in 35% of those
with PROM, but only in 12% of control patients (term gestations
without complications) (such vascular lesions are associated with a
mean odds ratio of 3.8 for preterm labor with intact membranes and
4 for PROM)315; (4) women with preterm labor and intact membranes
and those with preterm PROM have a higher percentage of failure of
physiologic transformation in the myometrial segment of the spiral
528
CHAPTER 28
Procedure-to-delivery interval
(median, range, days)
AF IL-6 7.9 ng/mL

FP IL-6 11 pg/mL
14
5
(0.2 33.6)
II
AF IL-6 >7.9 ng/mL

FP IL-6 11 pg/mL
7
(1.5 32)
III
AF IL-6 >7.9 ng/mL

FP IL-6 >11 pg/mL
1.2
(0.25 2)
IV
AF IL-6 7.9 ng/mL

FP IL-6 >11 pg/mL
0.75
(0.13 1)
FIGURE 28-8 Classification and procedure-to-delivery intervals of patients according to amniotic fluid
(AF) and fetal plasma (FP) concentrations of interleukin-6 (IL-6). In the FP, the white color indicates a low
concentration of IL-6, and the dark red color represents a high concentration. Likewise, the white color in the
AF compartment indicates a low concentration of IL-6, and the gray color indicates a high concentration.
(Reproduced with permission from Romero R, Gomez R, Ghezzi F, et al: A fetal systemic inflammatory
response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol 179:186-193,
1998.)
arteries than women who deliver at term325,326; (5) decidual hemosiderin deposition and retrochorionic hematoma formation is present in
37.5% of patients who deliver preterm after PROM (between 22 and
32 weeks of gestation) than in those who deliver at term (0.8%)327
(patients with preterm deliveries with intact membranes had decidual
hemosiderin in 36% of cases); and (6) patients presenting with preterm
labor and intact membranes who go on to have a preterm delivery are
more likely to have an abnormal uterine artery velocimetry than
patients with an episode of preterm labor who deliver at term.328-330
The mechanisms by which uteroplacental ischemia, decidual hemorrhage, or both may activate the common pathway of parturition
include the generation of thrombin. Evidence in support of this mechanism has been summarized elsewhere331 and includes the following:
(1) because decidua is a rich source of tissue factor, the primary initiator of coagulation, hemorrhage into the decidua would generate substantial quantities of thrombin, explaining the strong association
between abruption and disseminated intravascular coagulation332; (2)
intrauterine administration of whole blood to pregnant rats stimulates
myometrial contractility,333 but administration of heparinized blood
does not (heparin blocks the generation of thrombin)333; (3) fresh
whole blood stimulates myometrial contractility in vitro, and this
effect is partially blunted by incubation with hirudin, a thrombin
inhibitor333; (4) thrombin stimulates myometrial contractility in a
dose-dependent manner333; (5) thrombin stimulates the production of
MMP-1,334 urokinase-type plasminogen activator (uPA), and tissuetype plasminogen activator (tPA) by decidualized endometrial stromal
cells in culture335 (MMP-1 can digest collagen directly, whereas uPA

and tPA catalyze the transformation of plasminogen into plasmin,
which in turn can degrade type III collagen and fibronectin,336 important components of the extracellular matrix of the chorioamniotic
membranes and decidua337); (6) thrombin/antithrombin (TAT) complexes, a marker of in vivo generation of thrombin, are increased in
the plasma338 and amniotic fluid339 of patients with preterm labor and
preterm PROM; (7) an elevation of plasma TAT complex concentration in the second trimester is associated with subsequent preterm
PROM340; and (8) the presence of retroplacental hematoma detected
by ultrasound examination in the first trimester is associated with
adverse pregnancy outcomes, including preterm delivery and fetal
growth restriction.341
Additional evidence providing biologic plausibility for a role of
thrombin is that the production of MMP-3 mRNA and protein by term
decidual cells is normally inhibited by progestins. However, thrombin
reverses this inhibition by interacting with the protease-activated
receptor type 1 (PAR-1).342 This is important, because MMP-3 can
degrade extracellular matrix located in the decidua and fetal membranes, but it can also activate MMP-1 and MMP-9, which can degrade,
respectively, fibrillar collagen and gelatin. Thrombin also binds to PARs
and increases expression of MMP-1 mRNA and proteins by decidual
cells.334
Histologic examination of placentas with abruption frequently
show evidence of inflammation.343,344 Neutrophils in the decidua colocalize with areas of fibrin deposition, suggesting a link between inflam-
CHAPTER 28
529
Decidual Hemorrhage
IXa Vllla
IX
Tissue
Factor
VII or VIIa
Thrombin
Prothrombin
Xa Va
Thrombin
Fibrinogen
PARs
Fibrin
FIGURE 28-9 Tissue factor generates thrombin. The decidua is a

rich source of tissue factor, the primary initiator of clotting. Disruption
of spiral arteries and/or arterioles permits factor X or IX to be
activated by the action of factor VII when complexed with tissue
factor. Factor IXa combines with its cofactor VIIa to generate factor
Xa indirectly. In either case, Xa binds to its cofactor to convert
prothrombin to thrombin, which cleaves fibrinogen to fibrin.
mation and thrombin generation. Thrombin increases IL-8 mRNA and

protein expression by decidual cells. IL-8 is a potent neutrophil chemokine that is capable of attracting neutrophils to the areas of bleeding.344 Inasmuch as neutrophils are a rich source of MMP-8, MMP-9,
elastase,345 and reactive oxygen radicals,346-348 these products can contribute to extracellular matrix degradation in the decidual/membrane
interface and to membrane rupture.
IL-11 has been demonstrated in the decidua of patients with abruption and preterm PROM. Thrombin induces IL-11 production (mRNA
and protein) by decidual cells,349 and IL-11 can induce PGE2 production.349 Therefore, this cytokine provides a link between thrombin
generation, inflammation, activation of PARs, and the common
pathway of parturition. Figures 28-9 and 28-10 describe the molecular
mechanisms implicated in hemorrhage- or vascular-induced preterm
labor.
Maternal and Fetal Stress

Maternal stress of exogenous or endogenous origin is modestly associated with an increased risk for preterm delivery.350-354 The nature and
timing of the stressful stimuli can range from a heavy workload to
anxiety and depression.355,356 African-American women with elevated
scores for depression have an adjusted odds ratio for preterm delivery
of 1.96 (95% CI, 1.04 to 3.72).357 The absence of similar findings in
Hispanic and non-Hispanic white populations suggests an ethnic disparity in the effect of stress in the United States.
The stressful insult could occur in the pre-conceptional period or
during pregnancy. Starvation before pregnancy leads to spontaneous
preterm delivery in sheep.358 The precise mechanism whereby stress
induces parturition is not known. However, a role for CRH has been
proposed. This hormone was originally identified in the hypothalamus
but is expressed by the placenta.359 The maternal plasma CRH concentrations increase during the second half of pregnancy and peak during
labor, whereas serum concentrations of the CRH binding protein
decline during the third trimester.360,361
Smith and colleagues360,361 demonstrated that the trajectory of CRH
serum concentration changes identify women destined for preterm,
term, and post-term delivery. The mechanisms regulating the serum
concentration and trajectory of CRH have been described as a placental clock. Because CRH maternal plasma concentrations are elevated in both term and preterm parturition, it would appear that CRH
is part of the common pathway of labor.
Myometrium
Decidua
amniochorion
Contractions
MMPs and IL-8
PTL / PPROM

FIGURE 28-10 Mechanisms implicated in abruption-associated
preterm labor and delivery. IL-8, interleukin 8; MMPs, matrix
metalloproteinases; PARs, protease-activated receptors; PTL, preterm
labor; PPROM, preterm premature rupture of membranes.
The mechanisms through which CRH activates the common

pathway of parturition include the following: (1) increased production
of PGE2 by amnion, chorion, and placental cells, but not by decidual
cells362-364; (2) increased production of PGF2 by amnion, decidua, and
placental cells, but not by chorion362-364; (3) increased expression of
MMP-9 by chorion and amnion365; (4) stimulation of the release of
adrenocorticotropin (ACTH) from the pituitary gland to drive fetal
cortisol production366 (this establishes a feed-forward cycle, because
cortisol stimulates production of CRH by the placenta and fetal membranes)359; (5) induction of the synthesis of fetal DHEAS by the fetal
adrenal zone367-369 (DHEAS serves as a source for estrogens,367 which
in turn enhance the expression of the oxytocin receptor, COX-2, prostaglandin receptors, and connexin-43)370-377; (6) cortisol produced in
response to CRH can increase amnion COX-2 expression while inhibiting chorionic PGDH expression378-381 (resulting in a net bioavailability of prostaglandins); and (7) CRH inhibits progesterone production
by the placenta.382 Figures 28-11 and 28-12 illustrate the molecular
mechanisms for stress-associated preterm labor.
As noted, CRH has been implicated in the mechanisms of spontaneous parturition at term. Therefore, this specific pathway may operate
in normal term labor as well as in preterm labor. In the former case,
placental CRH expression reflects maturation of the fetal hypothalamic-pituitary-adrenal axis; in the latter, it reflects physiologically
stressful events occurring at later gestational ages. It may be surmised
that some cases of preterm labor occurring close to term resort to the
physiologic mechanisms used in term labor after fetal maturation has
been accelerated by stressful stimuli.
Uterine Overdistention
Patients with mllerian duct abnormalities,383 polyhydramnios,384,385 or
multiple gestations386 are at increased risk for spontaneous preterm
labor and delivery. The frequency of preterm delivery in multifetal
gestations is 17%, and the mean gestational age at delivery decreases
as a function of the number of fetuses: 35.3 weeks for twins, 32.2 weeks
for triplets, and 29.9 weeks for quadruplets.4 Myometrial stretch has
been implicated as a key mechanism driving these preterm deliveries.
530
CHAPTER 28
However, the importance of stretch as a mechanism of activation of

the common pathway of parturition is not restricted to the myometrium. Indeed, stretch may play a role in cervical remodeling and
membrane rupture.387
How does stretch activate the common pathway of parturition?
Intra-amniotic pressure remains relatively constant during gestation,
despite the continued growth of the fetus, placenta, and uterus.388,389
This stability of pressure has been attributed to progressive myometrial
relaxation caused by the effects of progesterone390 and nitric oxide.391
Stretch, however, can induce increased myometrial contractility,392
prostaglandin release,393 expression of connexin-43,26 and increased
oxytocin receptors in pregnant and nonpregnant human myometrium.394 The gene expression of these stretch-induced contractionassociated proteins (CAPs) during pregnancy is inhibited by
progesterone.26
Stress
()
Hypothalamus
CRH
()
Placenta,
decidua and
amniochorion
Pituitary
ACTH

Adrenal gland
Cortisol
FIGURE 28-11 The fetal hypophysis-pituitary-adrenal-placental
axis in pregnancy. ACTH, corticotropin; CRH, corticotropin-releasing
hormone.
Mechanical stress in smooth muscle induces activation of integrin

receptors395 and stretch-activated calcium channels,396,397 phosphorylation of platelet-derived growth factor receptor,398 and activation of G
proteins.398,399 Mechanical force, once sensed, leads to activation of
protein kinase C and mitogen activated protein kinases, increased gene
expression of FOS (c-fos) and JUN (c-jun), and enhanced binding
activity of transcription factor AP-1, which drives transcription of
multiple parturition-associated genes.24,400-404 Other effects of physical
forces relevant to myometrium include increased expression of COX-2,
superoxide dismutase, and nitric oxide synthase. The precise nature of
the sensing mechanisms of pressure/tension in the myometrium is yet
to be determined.
Stretch can also affect the chorioamniotic membranes, which are
distended by 40% at 25 to 29 weeks, 60% at 30 to 34 weeks, and 70%
at term.405 Stretching of the membranes in vitro induces histologic
changes characterized by elongation of the amnion cells and increased
production of collagenase activity and IL-8,406,407 and stretching of
amnion cells in culture results in increased production of PGE2.408
Studies using an in vitro cell culture model for fetal membrane distention revealed upregulation of proinflammatory genes, including IL-8
and preB-cell colony-enhancing factor (visfatin).409 Distention of
fetal membrane in vitro results in overexpression of four genes, namely
IL-8, interleukin enhancer binding factor 2 (ILF2), huntingtininteracting protein 2, and an interferon-stimulated gene encoding a
54-kDa protein.410 Collectively, these observations suggest that mechanical forces associated with uterine overdistention may result in activation of mechanisms leading to membrane rupture.
Premature cervical ripening is also a feature of patients with multiple gestations, as well as those with certain mllerian duct anomalies
(e.g., incompetent cervix in diethylstilbestrol [DES]-exposed daughters). IL-8,45,411,412 MMP-1,104 prostaglandins,137,413,414 and nitric oxide415
have been implicated in the control of cervical ripening. Inasmuch as
these mediators are produced in response to membrane stretch, they
may exert part of their biologic effects in parturition by stimulating
extracellular matrix degradation of the cervix.
Figure 28-13 describes the mechanisms by which stretch may activate the common pathway of parturition. It is possible, however, that
patients with multiple gestations represent a heterogeneous group.
Maternal
stress
Activation of fetal HPA axis
Placental
insufficiency
ACTH
Cortisol
Placenta, membranes
and decidua
Fetal
adrenal
zone
DHEA/16-OH DHEA
() CRH
Placental
sulfatases
CRH
FIGURE 28-12 Proposed pathways by which
stress can induce preterm labor. ACTH,
corticotropin; 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, hypophysis-pituitaryadrenal; PG, prostaglandins; PR, prostaglandin
receptor; PROM, premature rupture of membranes.
E1-E3

PG
Cervical change
Myometrial (PR-A/B, and ER-)

enhances c-jun causing
increase in CAPs, FP, EP1, EP3
Preterm PROM
Contractions
CHAPTER 28
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 28-13 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; PTL, preterm labor; PPROM,
preterm premature rupture of membranes.
Some such patients have preterm labor associated with infection.416-418

Others have abnormalities of trophoblast invasion leading to vascular
pathology, with or without fetal growth disorders, causing stress or
decidual hemorrhagemediated preterm deliveries. These separate
mechanisms of disease may operate alone or in conjunction with
uterine overdistention to activate the components of the common
pathway.
Allergic Phenomena
Another potential mechanism of disease in preterm labor is an immunologically mediated phenomenon induced by an allergic mechanism.
We have previously proposed that an allergic-like immune response
(type I hypersensitivity) may be associated with preterm labor.419 The
term allergy refers to disorders caused by the response of the immune
system to an otherwise innocuous antigen.420 This allergen crosslinks immunoglobulin E (IgE) bound to high-affinity receptors on
uterine mast cells, causing degranulation of these cells. The products
of degranulation initiate inflammation.421
Evidence in support of the possibility that an allergic-like phenomenon may operate in preterm labor includes the following: (1) the
human fetus is exposed to common allergens such as house-dust mite,
which has been detected in amniotic fluid in the mid-trimester of
pregnancy and in umbilical cord blood422; (2) allergen-specific reactivity has been shown in umbilical cord blood at birth and as early as 23
weeks of gestation423; (3) pregnancy is traditionally regarded as a T
helper 2 (TH2) state that favors the production of IgE; (4) the human
uterus contains mast cells, the effector cells of allergy424; (5) products
of mast cell degranulation (i.e., histamine and prostaglandins) may
induce myometrial contractility425,426; (6) pharmacologic degranulation
of mast cells induces myometrial and cervical contractility427,428; (7)
incubation of myometrial strips from sensitized and nonsensitized
animals with an anti-IgE antibody increases myometrial contractility428; (8) human myometrial strips obtained from women known to
be allergic to ragweed demonstrate increased myometrial contractility
when challenged in vitro by the allergen, and, moreover, the sensitivity
of the myometrial strips of nonallergic women can be transferred
passively by preincubation of the strips with human serum (Robert
Garfield, University of Texas, Galveston, personal communication); (9)
531
nonpregnant guinea pigs sensitized with ovalbumin and then challenged with this antigen demonstrate increased uterine tone428; (10)
traditional descriptions of animals dying of anaphylactic shock have
demonstrated enhanced uterine contractility when autopsy was performed immediately after death; (11) severe latex allergy in a pregnant
woman after vaginal examination with a latex glove was followed by
regular uterine contractions429; (12) human decidua contains immune
cells capable of identifying local foreign antigens, including macrophages, B cells, T cells,430,431 and dendritic cells432; and (13) we have
identified a subgroup of patients with preterm labor who have eosinophils in the amniotic fluid as the predominant white blood cell419
(under normal circumstances, white blood cells are not present in
amniotic fluid; the presence of eosinophils therefore suggests an abnormal immune response, and perhaps they are the markers of an allergiclike response in preterm labor). The antigen eliciting an abnormal
immunologic response remains to be identified. Recent evidence suggests that administration of ovalbumin to sensitized pregnant guinea
pigs can induce preterm labor and delivery and that this phenomenon
can be prevented with treatment with either cromolyn sodium or
antihistaminics.433
Cervical Disorders
Cervical insufficiency is traditionally considered a cause of midtrimester abortion. However, accumulating evidence suggests that
it can produce a wide spectrum of disease,434 including the wellrecognized recurrent pregnancy loss in the mid-trimester, some forms
of preterm labor (presenting with bulging membranes in the absence
of significant uterine contractility or rupture of membrane), and probably precipitous labor at term. Cervical disease may be the result of a
congenital disorder (i.e., hypoplastic cervix or DES exposure in utero),
surgical trauma (i.e., conization resulting in substantial loss of connective tissue) or traumatic damage of the structural integrity of the cervix
(i.e., repeated cervical dilation).435
Cervical insufficiency in the mid-trimester can be considered an
example of asynchronous activation of the mechanisms that induce
cervical remodeling. Indeed, it is likely that 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,183 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 preterm birth.436
Hormonal Disorders: Suspension of

Progesterone Action
Progesterone has been considered central to pregnancy maintenance.437
Progesterone promotes myometrial quiescence, downregulates gap
junction formation, inhibits cervical ripening, and decreases the production of chemokines (i.e., IL-8) by the chorioamniotic membranes,
which is thought to impede decidual/membrane activation.65,438-440 Progesterone is considered important for pregnancy maintenance in
humans, because inhibition of progesterone action can result in parturition. Administration of progesterone receptor antagonists (i.e., mifepristone or onapristone) to pregnant women, nonhuman primates,441
and guinea pigs65 can induce labor or cervical change or both.437 Therefore, a suspension of progesterone action is believed to be important
for the onset of parturition in humans.
In many species, a progesterone withdrawal (a drop in serum
progesterone concentration) occurs before spontaneous labor.442
532
CHAPTER 28
However, in humans, nonhuman primates, and guinea pigs, a progesterone withdrawal has not been demonstrated (see Young443 for
a description of the comparative physiology of parturition in
mammals).
The mechanism by which, in humans, progesterone action is suspended in the setting of sustained high circulating concentrations of
progesterone has eluded discovery. Six potential mechanisms have
been posited to explain this paradox: (1) reduced bioavailability of
progesterone by binding to a high-affinity protein444,445; (2) increased
cortisol concentration in late pregnancy, which may compete with
progesterone for binding to the glucocorticoid receptor446; (3) conversion of progesterone to an inactive form within the target cell before
it interacts with its receptor447,448; (4) quantitative and qualitative
changes in progesterone receptor isoforms (PR-A, PR-B, PR-C)449-452;
(5) changes in progesterone receptor coregulators453; and (6) a functional progesterone withdrawal through NF-B.454-456
Progesterones actions are mediated by multiprotein complexes,
including progesterone receptors, modifying factors (co-regulators
and adaptors), and effector proteins (RNA-polymerase, chromatinremodeling proteins, and RNA-processing factors). In addition, nongenomic mechanisms have recently been proposed.453
There is evidence supporting the view that a functional progesterone withdrawal occurs locally in intrauterine tissues during human
parturition in both term and preterm gestation.453,457-463 The changes
in the ratio of estrogen and progesterone activity could activate the
three tissue components of the common pathway of parturition,
including myometrium, cervix, and decidual-amniochorionic membranes directly or indirectly through prostaglandin or oxytocin and its
receptor systems.437,450,451,453,457-469 However, the signal eliciting the onset
of these hormonal functional changes in human parturition remains
to be determined.
The interest in progestins to prevent preterm delivery has been
rekindled by several randomized clinical trials, suggesting that progestins may prevent preterm delivery.470 The initial trials were conducted
in women with a previous preterm delivery and used either vaginal
progesterone471 or 17-hydroxyprogesterone caproate.67 Subsequently,
vaginal progesterone was reported to reduce the rate of preterm birth
by 40% in women with a short cervix (15 mm).68 A post hoc analysis
of another trial was supportive of this concept.66,472 The precise mechanisms by which exogenous progestins reduce the rate of preterm birth
are unknown. It is possible that exogenous progesterone inhibits cervical remodeling in the mid-trimester of pregnancy through the mechanisms outlined earlier in this chapter.
Summary
It is becoming increasingly evident that preterm labor, preterm
PROM, and cervical insufficiency are syndromes caused by multiple
pathologic processes leading to increased myometrial contractility,
cervical remodeling, and/or membrane activation. The clinical presentation depends on the nature and timing of the insults affecting
the various components of the uterine common pathway of parturition. This view has important implications for understanding the
biology of preterm parturition, as well as its diagnosis, treatment, and
prevention.
Acknowledgment
This work was funded in part by the Intramural Program of the
Eunice Kennedy Shriver National Institute of Child Health and
Human Development (NICHD) of the National Institutes of Health

(NIH).
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CHAPTER 28
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Chapter 28

Preterm deliveries are those occurring between fetal viability and 37

Overview of the Mechanisms

Pathogenesis of Spontaneous Preterm Labor

FIGURE 28-1 Uterine components of the common pathway of

by multiple etiologies with specific pathogenic pathways. This chapter

FIGURE 28-2 Clinical manifestations of preterm activation of the

were undertaken in rodents but have implications for humans.

Pathogenesis of Spontaneous Preterm Labor

Prostaglandins as Key Activators of

We use the term decidual/membrane activation to refer to a complex

A central question in the understanding of parturition is whether the

Pathogenesis of Spontaneous Preterm Labor

Descriptive evidence traditionally invoked to support a role for

FP and EP1, 3 PG receptors in fundus

FIGURE 28-3 Molecular mechanisms implicated in the common

The Spontaneous Preterm

Pathogenesis of Spontaneous Preterm Labor

FIGURE 28-4 The preterm parturition syndrome. Multiple

women with intra-amniotic infection171-173 or inflammation (defined

FIGURE 28-6 The pathway of ascending intrauterine

Pathogenesis of Spontaneous Preterm Labor

Microorganisms are sensed by the innate components of the

The Role of Proinflammatory Cytokines

Anti-inflammatory Cytokines and

Fetal Involvement in Intrauterine Infection

Inflammation and Fetal Injury: The Fetal

Pathogenesis of Spontaneous Preterm Labor

togenous viral infections or other disease processes (e.g., rhesus

Uteroplacental Vascular Disease and

Pathogenesis of Spontaneous Preterm Labor

AF IL-6 7.9 ng/mL

AF IL-6 >7.9 ng/mL

AF IL-6 >7.9 ng/mL

AF IL-6 7.9 ng/mL

cells in culture335 (MMP-1 can digest collagen directly, whereas uPA

Pathogenesis of Spontaneous Preterm Labor

FIGURE 28-9 Tissue factor generates thrombin. The decidua is a

mation and thrombin generation. Thrombin increases IL-8 mRNA and

Maternal and Fetal Stress

MMPs and IL-8

PTL / PPROM

The mechanisms through which CRH activates the common

Pathogenesis of Spontaneous Preterm Labor

However, the importance of stretch as a mechanism of activation of

Mechanical stress in smooth muscle induces activation of integrin

Activation of fetal HPA axis

Myometrial (PR-A/B, and ER-)

PTL / PPROM

Some such patients have preterm labor associated with infection.416-418

Pathogenesis of Spontaneous Preterm Labor

Hormonal Disorders: Suspension of

Pathogenesis of Spontaneous Preterm Labor

Human Development (NICHD) of the National Institutes of Health

Pathogenesis of Spontaneous Preterm Labor

44. Liggins G: Cervical ripening as an inflammatory reaction. In Ellwood D,

Pathogenesis of Spontaneous Preterm Labor

67. Meis PJ, Klebanoff M, Thom E, et al: Prevention of recurrent preterm

88. Fortunato SJ, Menon R: Screening of novel matrix metalloproteinases