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
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 spontaneous—45%
(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 gesta-
tions, and an increased number of older parturients.4
Overview of the Mechanisms
The Common Pathway
The traditional view, which has dominated the study of preterm par-
turition, 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 ripen-
ing, and membrane rupture.5
It has been proposed that the fundamen-
tal 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
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
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 acti-
vation 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.
Spontaneous preterm labor with intact membranes, preterm
PROM, and cervical insufﬁciency can be considered syndromes caused
Pathogenesis of Spontaneous
Roberto Romero, MD, and Charles J. Lockwood, MD
522 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
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
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
tractures as epochs of myometrial activity lasting several minutes, asso-
ciated with a modest increase in intrauterine pressure and fragmented
bursts of electrical activity in the electromyogram. In contrast, contrac-
tions are epochs of myometrial activity of short duration associated
with dramatic increases in intrauterine pressure and electromyo-
graphic activity. The switch from a predominant contracture pattern
to a predominant contraction pattern occurs physiologically during
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 connexin-
43 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
others have referred to a set of distinct proteins, called contraction-
associated 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
were undertaken in rodents but have implications for humans.
Three distinct stages of rat gestational myometrial development were
1. Proliferative, in which the number of myocytes increased, as dem-
onstrated 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 extracel-
lular matrix (ECM) proteins from the myocytes, in particular col-
lagen 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
and collagen IV).
α-Actin was expressed in the myometrium in early pregnancy, whereas
γ-actin was highly expressed by myometrium with a contractile phe-
notype. 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
This view is consistent with the proposal of Csapo about
the importance of progesterone in the regulation of myometrial con-
tractility at the onset of parturition.33
Microarray experiments of myo-
metrium in labor indicate an overexpression of genes involved in
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.)
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.)
523CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
control of inﬂammation (Romero et al., unpublished observations)
This is consistent with other studies which used subtraction hybridiza-
tion to identify genes differentially expressed during labor. Interleukin
8 (IL-8) and superoxide dismutase have been found to be differentially
The changes in the cervix include: (1) softening, (2) ripening, (3) dila-
tation, and, after delivery, (4) repair.35
Sonographic studies have dem-
onstrated 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 impor-
tant in the understanding of cervical insufﬁciency and spontaneous
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 col-
Dilation of the cervix is an inﬂammatory phenomenon
in which there is an inﬂux of macrophages and neutrophils and matrix
Chemokines such as IL-845-49
inﬂammatory cells, which, in turn, release proinﬂammatory cytokines,
and tumor necrosis factor-α (TNF-α),35-54
activate the nuclear factor (NF)-κB signaling pathway. NF-κB can
block progesterone receptor-mediated actions.55
Progesterone has been
implicated in the regulation of cervical remodeling because (1) admin-
istration of antiprogestins to women in the mid-trimester and at term
induces cervical ripening;35,56-60
and (2) the administration of proges-
terone-receptor antagonists such as mifepristone (RU-486) or onapris-
tone (ZK 98299) to pregnant guinea pigs,61,62
Tupaia belangeri induces cervical ripening.35
Cervical responsiveness to
antiprogestins increases with advancing gestational age,35
effects of antiprogestins in the cervix are not always accompanied by
changes in myometrial activity.35
Indeed, Stys and associates64
strated a dissociation between the effects of progesterone in the myo-
metrium 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
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 pro-
gesterone 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
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
allow separation and postpartum expulsion of the membranes. Fibro-
nectins 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 asso-
ciated with amnion epithelial apoptosis and localized inﬂammation.74
Therefore, these processes belong to the common terminal pathway of
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 indi-
cate 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 healing–like response. Observations by Bell and
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 sug-
gesting that rupture of membranes results from the application of
acute or chronic stress on localized areas of the membranes that are
The precise mechanism of decidual/membrane activation remains
to be elucidated. As noted, roles for extracellular matrix–degrading
enzymes such as the MMPs and apoptosis have been proposed. Several
studies have demonstrated increased availability of MMP-1 (inter-
MMP-8 (neutrophil collagenase),84
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
because this enzyme can degrade type III collagen, ﬁbronec-
tin, and laminin.87
Other MMPs are likely to be involved, but syste-
matic studies have not been conducted to date.88-90
A role for tissue
inhibitors of MMPs (TIMPs) has also been postulated.91
Prostaglandins as Key Activators of
the Common Pathway of Parturition
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
changes in extracellular matrix
metabolism associated with cervical ripening,94,95,99,100,104
524 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
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 termina-
tion of pregnancy (abortion or labor)103,108-118
; (2) treatment with indo-
methacin or aspirin can delay spontaneous onset of parturition in
; (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 abor-
; (5) amniotic ﬂuid concentrations of prostaglandins increase
before the onset of spontaneous labor at term in humans and nonhu-
; (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 COX-
2 activity is accompanied by decreased expression of the prostaglan-
din-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 prostaglan-
din 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) prosta-
glandin E2 (PGE2) and PGF2α increase the ratio of expression of
the progesterone receptor (PR) isoforms, PR-A/PR-B.139
induce a functional progesterone withdrawal. Figure 28-3 describes
the molecular mechanisms implicated in the common pathway of
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 mem-
branes” conveys information about the pathologic process that has led
to untimely delivery. This situation is not unique to preterm parturi-
tion: 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 respon-
sible 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 multifacto-
rial 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 predisposi-
tion 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.
The Spontaneous Preterm
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 unequiv-
ocal causal link with preterm parturition has been established. Evi-
dence 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
and periodontal disease164-169
) are associated with
preterm delivery; (3) subclinical intrauterine infections are consis-
tently associated with preterm labor and preterm birth170
; (4) pregnant
Cervical change Preterm PROM Contractions
FP and EP1, 3 PG receptors in fundus
FIGURE 28-3 Molecular mechanisms implicated in the common
pathway of parturition. COX-2, cyclooxygenase-2; EP1, PTGER1,
prostaglandin E receptor type 1; ER-α, estrogen receptor-α; FP,
PTGFR, prostaglandin F receptor; IL-8, interleukin 8; MMPs, matrix
metalloproteinases; PG, prostaglandins; PR, prostaglandin receptor;
PROM, premature rupture of membranes.
525CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
women with intra-amniotic infection171-173
or inﬂammation (deﬁned
as an elevation of amniotic ﬂuid concentrations of proinﬂammatory
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 cultiva-
tion techniques or molecular microbiologic techniques deﬁnes micro-
bial invasion of the amniotic cavity. Microorganisms or their products
can elicit an inﬂammatory response within the amniotic cavity: intra-
amniotic inﬂammation. Inﬂammation of the chorioamniotic mem-
branes, or histologic chorioamnionitis, can exist without clinical signs
of infection (clinical chorioamnionitis). The stages of ascending intra-
uterine 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
Patients with MIAC are more likely to deliver
preterm neonates, have spontaneous rupture of membranes, and
develop clinical chorioamnionitis than those with sterile amniotic
The most common organisms found in the amniotic ﬂuid are
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 ges-
tational 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
Bacterial products such as endotoxin have also been
detected in the amniotic cavity of women with preterm labor and
Endotoxin has powerful proinﬂammatory effects
in maternal and fetal tissues.191-193
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.)
PTL or PPROM
IL-6 and 8
FIGURE 28-5 Principal biochemical mechanisms responsible for
the main pathways of preterm parturition. COX2, cyclooxygenase-
2; CRH, corticotropin-releasing hormone; IL-1β, interleukin-1β; MMPs,
matrix metalloproteinases; PGDH, prostaglandin dehydrogenase;
PPROM, preterm premature rupture of membranes; PR-B,
progesterone receptor type B; PTL, preterm labor; TNF-α, tumor
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.)
526 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
Microorganisms are “sensed” by the innate components of the
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 patho-
gens (e.g., viruses).195
The best-studied PRRs are the TLRs.194
of TLR results in activation of NF-κB, 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 heat-
killed bacteria or administration of lipopolysaccharide than wild-type
In pregnant women, TLR-2 and TLR-4 are expressed in the
as well as in decidua.198
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
tions suggest that the innate immune system plays a role in
The Role of Proinﬂammatory Cytokines
Inﬂammation and its mediators, chemokines such as IL-8, the proin-
ﬂammatory cytokines (IL-1β, TNF-α), and other mediators (e.g.,
platelet activating factor, prostaglandins) are central to preterm partu-
rition induced by infection. IL-1 was the ﬁrst cytokine implicated in
the onset of preterm labor associated with infection.199
support of this concept includes the following: (1) IL-1 is produced by
human decidua in response to bacterial products200
; (2) IL-1α and IL-
1β stimulate prostaglandin production by human amnion and
; (3) IL-1α and IL-1β concentrations and IL-1–like bioactiv-
ity are increased in the amniotic ﬂuid of women with preterm labor
; (4) intravenous IL-1β stimulates uterine contrac-
; 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
Evidence supporting the role of TNF-α in the mechanisms of
preterm parturition is similar and includes the following: (1) TNF-α
stimulates prostaglandin production by amnion, decidua, and myome-
; (2) human decidua can produce TNF-α in response to bacte-
; (3) amniotic ﬂuid TNF-α 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-α concentrations are higher
in the presence of labor208
; (5) TNF-α can stimulate the production of
which have been implicated in membrane rupture85,211,212
(6) TNF-α application to the cervix induces changes that resemble
; (7) TNF-α can induce preterm parturition when
administered systemically to pregnant animals214,215
; and (8) TNF-α
and IL-1β enhance IL-8 expression by decidual cells, and this chemo-
kine is strongly expressed by term decidual cells in the presence of
Figure 28-7 displays the mechanisms involved in
preterm parturition in the setting of infection.
Other cytokines and chemokines (IL-6,187,217-221
monocyte chemotactic protein-1,235
epithelial cell–derived neutrophil-activating peptide-78,236
lated 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-
FIGURE 28-7 Cellular and
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,
527CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
However, blockade of both signaling pathways (i.e., for IL-1
and TNF-α) in a double-knockout mice model was associated with
a decreased rate of preterm birth after the administration of
Anti-inﬂammatory Cytokines and
IL-10 is thought to be a key cytokine for the maintenance of preg-
Its concentrations are increased in intra-amniotic inﬂam-
suggesting that IL-10 may play a role in dampening the
and may have therapeutic value.249-254
nonhuman primate model of intrauterine infection, pregnant rhesus
monkeys (n = 13) were allocated to one of three interventional groups:
(1) intra-amniotic IL-1β infusion with maternal dexamethasone intra-
venously (n = 4); (2) intra-amniotic IL-1β + IL-10 (n = 5); or (3)
intra-amniotic IL-1β administered alone (n = 5). Dexamethasone and
IL-10 treatment signiﬁcantly reduced IL-1β–induced uterine contrac-
tility (P < .05). The amniotic ﬂuid concentrations of TNF-α and leu-
kocyte counts were also decreased by IL-10 treatment (P < .05).203
Furthermore, the administration of IL-10 in animal models of infec-
tion 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 rec-
ognized. 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
It was deﬁned as a fetal plasma concentration of IL-6
greater than 11 pg/mL.258
Fetuses with an elevated plasma IL-6 concen-
tration had a higher rate of severe neonatal morbidity and a shorter
cordocentesis-to-delivery interval than those with an IL-6 concentra-
tion lower than 11 pg/mL.259
These original ﬁndings were subsequently
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
Fetuses with FIRS have more systemic involvement, including
hematologic abnormalities (neutrophilia), and a higher median nucle-
ated red blood cell count than those without elevated IL-6.265
tion, 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
and abnormalities of the fetal lung230,232,262,270-274
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
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 inﬂamma-
tory process does not involve the chorioamniotic membranes and
decidua. Such instances may take place in the context of hema-
togenous viral infections or other disease processes (e.g., rhesus
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
support of a gene-environment interaction in infection-related prema-
ture 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-α allele 2, given that carriage of this genotype had been demon-
strated 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-α 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-α allele alone, sug-
gesting that a gene-environment interaction predisposes to preterm
Similar interactions may determine the susceptibility to
intrauterine infection, microbial invasion of the fetus, and the likeli-
hood of fetal injury.
Uteroplacental Vascular Disease and
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 deliv-
ery is the following: (1) abruptio placenta, a lesion of uteroplacental
vascular origin is more frequent in women who deliver preterm with
or with PROM than in those who deliver at
; (2) the frequency of SGA infants is increased in women who
deliver after preterm labor with intact membranes and preterm
(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 Pathogenesis of Spontaneous Preterm Labor
arteries than women who deliver at term325,326
; (5) decidual hemosid-
erin 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 hem-
orrhage, or both may activate the common pathway of parturition
include the generation of thrombin. Evidence in support of this mech-
anism has been summarized elsewhere331
and includes the following:
(1) because decidua is a rich source of tissue factor, the primary initia-
tor of coagulation, hemorrhage into the decidua would generate sub-
stantial quantities of thrombin, explaining the strong association
between abruption and disseminated intravascular coagulation332
intrauterine administration of whole blood to pregnant rats stimulates
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
; (4) thrombin stimulates myometrial contractility in a
; (5) thrombin stimulates the production of
urokinase-type plasminogen activator (uPA), and tissue-
type 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
tant components of the extracellular matrix of the chorioamniotic
membranes and decidua337
); (6) thrombin/antithrombin (TAT) com-
plexes, a marker of in vivo generation of thrombin, are increased in
and amniotic ﬂuid339
of patients with preterm labor and
preterm PROM; (7) an elevation of plasma TAT complex concentra-
tion in the second trimester is associated with subsequent preterm
; 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
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 mem-
branes, 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
Histologic examination of placentas with abruption frequently
show evidence of inﬂammation.343,344
Neutrophils in the decidua colo-
calize with areas of ﬁbrin deposition, suggesting a link between inﬂam-
n Procedure-to-delivery interval
(median, range, days)
AF IL-6 ≤7.9 ng/mL
FP IL-6 ≤11 pg/mL
AF IL-6 >7.9 ng/mL
FP IL-6 ≤11 pg/mL
AF IL-6 >7.9 ng/mL
FP IL-6 >11 pg/mL
AF IL-6 ≤7.9 ng/mL
FP IL-6 >11 pg/mL
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,
529CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
mation and thrombin generation. Thrombin increases IL-8 mRNA and
protein expression by decidual cells. IL-8 is a potent neutrophil che-
mokine that is capable of attracting neutrophils to the areas of bleed-
Inasmuch as neutrophils are a rich source of MMP-8, MMP-9,
and reactive oxygen radicals,346-348
these products can con-
tribute to extracellular matrix degradation in the decidual/membrane
interface and to membrane rupture.
IL-11 has been demonstrated in the decidua of patients with abrup-
tion and preterm PROM. Thrombin induces IL-11 production (mRNA
and protein) by decidual cells,349
and IL-11 can induce PGE2 produc-
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
Maternal and Fetal Stress
Maternal stress of exogenous or endogenous origin is modestly associ-
ated 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 dis-
parity 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 concen-
trations 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 pla-
cental clock.” Because CRH maternal plasma concentrations are ele-
vated in both term and preterm parturition, it would appear that CRH
is part of the common pathway of labor.
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
; (2) increased production of PGF2α 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
(this establishes a feed-forward cycle, because
cortisol stimulates production of CRH by the placenta and fetal mem-
; (5) induction of the synthesis of fetal DHEAS by the fetal
(DHEAS serves as a source for estrogens,367
in turn enhance the expression of the oxytocin receptor, COX-2, pros-
taglandin receptors, and connexin-43)370-377
; (6) cortisol produced in
response to CRH can increase amnion COX-2 expression while inhib-
iting chorionic PGDH expression378-381
(resulting in a net bioavailabil-
ity 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 sponta-
neous 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 hypotha-
lamic-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.
Patients with müllerian duct abnormalities,383
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.
Xa ؉ VaX
IXa ؉ Vllla
؉ VII or VIIa
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.
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.
530 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
However, the importance of stretch as a mechanism of activation of
the common pathway of parturition is not restricted to the myome-
trium. Indeed, stretch may play a role in cervical remodeling and
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
expression of connexin-43,26
oxytocin receptors in pregnant and nonpregnant human myome-
The gene expression of these stretch-induced contraction-
associated proteins (CAPs) during pregnancy is inhibited by
Mechanical stress in smooth muscle induces activation of integrin
and stretch-activated calcium channels,396,397
tion of platelet-derived growth factor receptor,398
and activation of G
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%
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 disten-
tion revealed upregulation of proinﬂammatory genes, including IL-8
and pre–B-cell colony-enhancing factor (visfatin).409
fetal membrane in vitro results in overexpression of four genes, namely
IL-8, interleukin enhancer binding factor 2 (ILF2), huntingtin-
interacting protein 2, and an interferon-stimulated gene encoding a
ical forces associated with uterine overdistention may result in activa-
tion of mechanisms leading to membrane rupture.
Premature cervical ripening is also a feature of patients with mul-
tiple gestations, as well as those with certain müllerian duct anomalies
(e.g., incompetent cervix in diethylstilbestrol [DES]-exposed daugh-
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 acti-
vate the common pathway of parturition. It is possible, however, that
patients with multiple gestations represent a heterogeneous group.
Activation of fetal HPA axis Placental
Cervical change Preterm PROM Contractions
Myometrial (PR-A/B, and ER-␣)
enhances c-jun causing
increase in CAPs, FP, EP1, EP3
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-α, estrogen receptor-α; FP,
prostaglandin F receptor; HPA, hypophysis-pituitary-
adrenal; PG, prostaglandins; PR, prostaglandin
receptor; PROM, premature rupture of membranes.
FIGURE 28-11 The fetal hypophysis-pituitary-adrenal-placental
axis in pregnancy. ACTH, corticotropin; CRH, corticotropin-releasing
531CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
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 hemorrhage–mediated preterm deliveries. These separate
mechanisms of disease may operate alone or in conjunction with
uterine overdistention to activate the components of the common
Another potential mechanism of disease in preterm labor is an immu-
nologically 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
term “allergy” refers to disorders caused by the response of the immune
system to an otherwise innocuous antigen.420
This “allergen” cross-
links 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 phenom-
enon 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 reactiv-
ity 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
incubation of myometrial strips from sensitized and nonsensitized
animals with an anti-IgE antibody increases myometrial contractil-
; (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)
nonpregnant guinea pigs sensitized with ovalbumin and then chal-
lenged with this antigen demonstrate increased uterine tone428
traditional descriptions of animals dying of anaphylactic shock have
demonstrated enhanced uterine contractility when autopsy was per-
formed 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 macro-
phages, B cells, T cells,430,431
and dendritic cells432
; and (13) we have
identiﬁed a subgroup of patients with preterm labor who have eosino-
phils 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 abnor-
mal immune response, and perhaps they are the markers of an allergic-
like response in preterm labor). The antigen eliciting an abnormal
immunologic response remains to be identiﬁed. Recent evidence sug-
gests 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
Cervical insufﬁciency is traditionally considered a cause of mid-
trimester abortion. However, accumulating evidence suggests that
it can produce a wide spectrum of disease,434
including the well-
recognized 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 prob-
ably 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 connec-
tive 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
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 has been considered central to pregnancy maintenance.437
Progesterone promotes myometrial quiescence, downregulates gap
junction formation, inhibits cervical ripening, and decreases the pro-
duction of chemokines (i.e., IL-8) by the chorioamniotic membranes,
which is thought to impede decidual/membrane activation.65,438-440
gesterone is considered important for pregnancy maintenance in
humans, because inhibition of progesterone action can result in partu-
rition. Administration of progesterone receptor antagonists (i.e., mife-
pristone or onapristone) to pregnant women, nonhuman primates,441
and guinea pigs65
can induce labor or cervical change or both.437
fore, 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
Rapid increases in myometrial stretch due to polyhydramnios,
multifetal gestations or uterine anatomic abnormalities
IL-8 IL-8 PG
PTL ؉/؊ PPROM
Contractions ECM degradation
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.
532 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
However, in humans, nonhuman primates, and guinea pigs, a pro-
gesterone withdrawal has not been demonstrated (see Young443
a description of the comparative physiology of parturition in
The mechanism by which, in humans, progesterone action is sus-
pended 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) conver-
sion 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 func-
tional progesterone withdrawal through NF-κB.454-456
Progesterone’s actions are mediated by multiprotein complexes,
including progesterone receptors, modifying factors (co-regulators
and adaptors), and effector proteins (RNA-polymerase, chromatin-
remodeling proteins, and RNA-processing factors). In addition, non-
genomic mechanisms have recently been proposed.453
There is evidence supporting the view that a “functional progester-
one withdrawal” occurs locally in intrauterine tissues during human
parturition in both term and preterm gestation.453,457-463
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 mem-
branes directly or indirectly through prostaglandin or oxytocin and its
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 proges-
tins may prevent preterm delivery.470
The initial trials were conducted
in women with a previous preterm delivery and used either vaginal
or 17α-hydroxyprogesterone caproate.67
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 mecha-
nisms by which exogenous progestins reduce the rate of preterm birth
are unknown. It is possible that exogenous progesterone inhibits cervi-
cal remodeling in the mid-trimester of pregnancy through the mecha-
nisms outlined earlier in this chapter.
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 pre-
sentation depends on the nature and timing of the insults affecting
the various components of the uterine common pathway of parturi-
tion. This view has important implications for understanding the
biology of preterm parturition, as well as its diagnosis, treatment, and
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
1. Mazaki-Tovi S, Romero R, Kusanovic JP, et al: Recurrent preterm birth.
Semin Perinatol 31:142-158, 2007.
2. Parry S, Strauss JF III: Premature rupture of the fetal membranes. N Engl
J Med 338:663-670, 1998.
3. Moutquin JM: Classiﬁcation and heterogeneity of preterm birth. BJOG
110(Suppl 20):30-33, 2003.
4. Martin JA, Hamilton BE, Sutton PD, et al: Births: Final data for 2002. Natl
Vital Stat Rep 52:1-113, 2003.
5. Romero R, Mazor M, Munoz H, et al: The preterm labor syndrome. Ann
N Y Acad Sci 734:414-429, 1994.
6. 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.
7. Genazzani AR, Petraglia F, Facchinetti F, et al: Lack of beta-endorphin
plasma level rise in oxytocin-induced labor. Gynecol Obstet Invest 19:130-
8. Ohrlander S, Gennser G, Eneroth P: Plasma cortisol levels in human fetus
during parturition. Obstet Gynecol 48:381-387, 1976.
9. Petraglia F, Giardino L, Coukos G, et al: Corticotropin-releasing factor and
parturition: Plasma and amniotic ﬂuid levels and placental binding sites.
Obstet Gynecol 75:784-789, 1990.
10. Randall NJ, Bond K, Macaulay J, et al: Measuring fetal and maternal tem-
perature differentials: A probe for clinical use during labour. J Biomed Eng
11. Nathanielsz P, Honnebier M: Myometrial function. In Drife J, Calder A
(eds): Prostaglandins and the Uterus. London: Springer-Verlag, 1992, p
12. Hsu HW, Figueroa JP, Honnebier MB, et al: Power spectrum analysis of
myometrial electromyogram and intrauterine pressure changes in the
pregnant rhesus monkey in late gestation. Am J Obstet Gynecol 161:467-
13. Taylor NF, Martin MC, Nathanielsz PW, et al: The fetus determines circa-
dian oscillation of myometrial electromyographic activity in the pregnant
rhesus monkey. Am J Obstet Gynecol 146:557-567, 1983.
14. Binienda Z, Rosen ED, Kelleman A, et al: Maintaining fetal normoglyce-
mia prevents the increase in myometrial activity and uterine 13,14-
dihydro-15-keto-prostaglandin F2 alpha production during food
withdrawal in late pregnancy in the ewe. Endocrinology 127:3047-3051,
15. Nathanielsz P, Poore E, Brodie A, et al: Update on molecular events of
myometrial activity during pregnancy. In Nathanielsz P, Parer J (eds):
Research in Perinatal Medicine. Ithaca, NY: Perinatology, 1987, p 111.
16. Romero R, Avila C, Sepulveda W, et al: The role of systemic and intrauter-
ine infection in preterm labor. In Fuchs A, Fuchs F, Stubbleﬁeld P (eds):
17. Cole WC, Garﬁeld RE, Kirkaldy JS: Gap junctions and direct intercellular
communication between rat uterine smooth muscle cells. Am J Physiol
18. Garﬁeld RE, Sims S, Daniel EE: Gap junctions: Their presence and
necessity in myometrium during parturition. Science 198:958-960,
19. Garﬁeld RE, Sims SM, Kannan MS, et al: Possible role of gap junctions in
activation of myometrium during parturition. Am J Physiol 235:C168-
20. Garﬁeld RE, Hayashi RH: Appearance of gap junctions in the myome-
trium of women during labor. Am J Obstet Gynecol 140:254-260,
21. Garﬁeld RE, Puri CP, Csapo AI: Endocrine, structural, and functional
changes in the uterus during premature labor. Am J Obstet Gynecol
533CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
22. Balducci J, Risek B, Gilula NB, et al: Gap junction formation in human
myometrium: A key to preterm labor? Am J Obstet Gynecol 168:1609-
23. Chow L, Lye SJ: Expression of the gap junction protein connexin-43 is
increased in the human myometrium toward term and with the onset of
labor. Am J Obstet Gynecol 170:788-795, 1994.
24. Lefebvre DL, Piersanti M, Bai XH, et al: Myometrial transcriptional regu-
lation of the gap junction gene, connexin-43. Reprod Fertil Dev 7:603-611,
25. Orsino A, Taylor CV, Lye SJ: Connexin-26 and connexin-43 are differen-
tially expressed and regulated in the rat myometrium throughout late
pregnancy and with the onset of labor. Endocrinology 137:1545-1553,
26. Ou CW, Orsino A, Lye SJ: Expression of connexin-43 and connexin-26 in
the rat myometrium during pregnancy and labor is differentially regulated
by mechanical and hormonal signals. Endocrinology 138:5398-5407,
27. Cook JL, Zaragoza DB, Sung DH, et al: Expression of myometrial activa-
tion and stimulation genes in a mouse model of preterm labor: Myome-
trial activation, stimulation, and preterm labor. Endocrinology
28. Lye SJ, Nicholson BJ, Mascarenhas M, et al: Increased expression of con-
nexin-43 in the rat myometrium during labor is associated with an
increase in the plasma estrogen:progesterone ratio. Endocrinology
29. Petrocelli T, Lye SJ: Regulation of transcripts encoding the myometrial gap
junction protein, connexin-43, by estrogen and progesterone. Endocrinol-
ogy 133:284-290, 1993.
30. Lye SJ: The initiation and inhibition of labour: Towards a molecular
understanding. Semin Reprod Endocrinol 12:284-294, 1994.
31. Lye SJ, Mitchell J, Nashman N, et al: Role of mechanical signals in
the onset of term and preterm labor. Front Horm Res 27:165-178,
32. Lye S, Tsui P, Dorogin A, et al: Myometrial programmning: A new concept
underlying the mainteinance of pregnancy and the initiation of labor. In
VIIth International Conference on the Extracelullar Matrix of the Female
Reproductive Tract and Simpson Symposia, Centre for Reproductive
Biology, University of Edinburgh, 2004.
33. Csapo AI: The “see-saw” theory of parturition. Ciba Found Symp (47):159-
34. Chan EC, Fraser S, Yin S, et al: Human myometrial genes are differentially
expressed in labor: A suppression subtractive hybridization study. J Clin
Endocrinol Metab 87:2435-2441, 2002.
35. Word RA, Li XH, Hnat M, et al: Dynamics of cervical remodeling during
pregnancy and parturition: Mechanisms and current concepts. Semin
Reprod Med 25:69-79, 2007.
36. Winkler M, Rath W: Changes in the cervical extracellular matrix during
pregnancy and parturition. J Perinat Med 27:45-60, 1999.
37. Ludmir J, Sehdev HM: Anatomy and physiology of the uterine cervix. Clin
Obstet Gynecol 43:433-439, 2000.
38. Westergren-Thorsson G, Norman M, Bjornsson S, et al: Differential
expressions of mRNA for proteoglycans, collagens and transforming
growth factor-beta in the human cervix during pregnancy and involution.
Biochim Biophys Acta 1406:203-213, 1998.
39. Leppert PC: Anatomy and physiology of cervical ripening. Clin Obstet
Gynecol 38:267-279, 1995.
40. Straach KJ, Shelton JM, Richardson JA, et al: Regulation of hyaluronan
expression during cervical ripening. Glycobiology 15:55-65, 2005.
41. Obara M, Hirano H, Ogawa M, et al: Changes in molecular weight of
hyaluronan and hyaluronidase activity in uterine cervical mucus in cervi-
cal ripening. Acta Obstet Gynecol Scand 80:492-496, 2001.
42. Sakamoto Y, Moran P, Bulmer JN, et al: Macrophages and not granulo-
cytes are involved in cervical ripening. J Reprod Immunol 66:161-173,
43. Hassan SS, Romero R, Haddad R, et al: The transcriptome of the uterine
cervix before and after spontaneous term parturition. Am J Obstet Gynecol
44. Liggins G: Cervical ripening as an inﬂammatory reaction. In Ellwood D,
Anderson A (eds): The Cervix in Pregnancy and Labour: Clinical and
Biochemical Investigations. Edinburgh: Churchill Livingstone, 1981.
45. Sennstrom MK, Brauner A, Lu Y, et al: Interleukin-8 is a mediator of the
ﬁnal cervical ripening in humans. Eur J Obstet Gynecol Reprod Biol 74:89-
46. Sakamoto Y, Moran P, Searle RF, et al: Interleukin-8 is involved in cervical
dilatation but not in prelabour cervical ripening. Clin Exp Immunol
47. Maradny EE, Kanayama N, Halim A, et al: Effects of neutrophil chemo-
tactic factors on cervical ripening. Clin Exp Obstet Gynecol 22:76-85,
48. Osmers RG, Blaser J, Kuhn W, et al: Interleukin-8 synthesis and the onset
of labor. Obstet Gynecol 86:223-229, 1995.
49. Tornblom SA, Klimaviciute A, Bystrom B, et al: Non-infected preterm
parturition is related to increased concentrations of IL-6, IL-8 and MCP-1
in human cervix. Reprod Biol Endocrinol 3:39, 2005.
50. Roth J, Vogl T, Sorg C, et al: Phagocyte-speciﬁc S100 proteins: A novel
group of proinﬂammatory molecules. Trends Immunol 24:155-158,
before and during parturition. Biol Reprod 72:707-719, 2005.
52. Ito A, Hiro D, Ojima Y, et al: Spontaneous production of interleukin-1-like
factors from pregnant rabbit uterine cervix. Am J Obstet Gynecol 159:261-
53. Ito A, Leppert PC, Mori Y: Human recombinant interleukin-1 alpha
increases elastase-like enzyme in human uterine cervical ﬁbroblasts.
Gynecol Obstet Invest 30:239-241, 1990.
54. Kelly RW: Inﬂammatory mediators and cervical ripening. J Reprod
Immunol 57:217-224, 2002.
receptor interactions as a functional basis of anti-inﬂammatory action of
steroids in reproductive organs. Mol Hum Reprod 2:433-438, 1996.
56. Chwalisz K, Shi Shao O, Neff G, et al: The effect of antigestagen ZK 98,
199 on the uterine cervix. Acta Endocrinol 283:113, 1987.
57. Elliott CL, Brennand JE, Calder AA: The effects of mifepristone on cervical
ripening and labor induction in primigravidae. Obstet Gynecol 92:804-
58. Giacalone PL, Daures JP, Faure JM, et al: The effects of mifepristone on
uterine sensitivity to oxytocin and on fetal heart rate patterns. Eur J Obstet
Gynecol Reprod Biol 97:30-34, 2001.
59. Norman J: Antiprogesterones. Br J Hosp Med 45:372-375, 1991.
60. Stenlund PM, Ekman G, Aedo AR, et al: Induction of labor with mifepris-
tone: A randomized, double-blind study versus placebo. Acta Obstet
Gynecol Scand 78:793-798, 1999.
61. Chwalisz K, Shao-Qing S, Garﬁeld RE, et al: Cervical ripening in guinea-
pigs after a local application of nitric oxide. Hum Reprod 12:2093-2101,
62. Hegele-Hartung C, Chwalisz K, Beier HM, et al: Ripening of the uterine
cervix of the guinea-pig after treatment with the progesterone antagonist
onapristone (ZK 98.299): An electron microscopic study. Hum Reprod
63. Wolf JP, Sinosich M, Anderson TL, et al: Progesterone antagonist (RU 486)
for cervical dilation, labor induction, and delivery in monkeys: Effective-
ness in combination with oxytocin. Am J Obstet Gynecol 160:45-47,
64. Stys SJ, Clewell WH, Meschia G: Changes in cervical compliance at par-
turition independent of uterine activity. Am J Obstet Gynecol 130:414-
65. Chwalisz K: The use of progesterone antagonists for cervical ripening and
as an adjunct to labour and delivery. Hum Reprod (9 Suppl 1):131-161,
66. DeFranco EA, O’Brien JM, Adair CD, et al: Vaginal progesterone is associ-
ated with a decrease in risk for early preterm birth and improved neonatal
outcome in women with a short cervix: A secondary analysis from a
randomized, double-blind, placebo-controlled trial. Ultrasound Obstet
Gynecol 30:697-705, 2007.
534 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
67. Meis PJ, Klebanoff M, Thom E, et al: Prevention of recurrent preterm
delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med
68. Fonseca EB, Celik E, Parra M, et al: Progesterone and the risk of preterm
birth among women with a short cervix. N Engl J Med 357:462-469,
69. Facchinetti F, Paganelli S, Comitini G, et al: Cervical length changes during
preterm cervical ripening: Effects of 17-alpha-hydroxyprogesterone cap-
roate. Am J Obstet Gynecol 196:453-454, 2007.
70. Lockwood CJ, Senyei AE, Dische MR, et al: Fetal ﬁbronectin in cervical
and vaginal secretions as a predictor of preterm delivery. N Engl J Med
71. Iams JD, Casal D, McGregor JA, et al: Fetal ﬁbronectin improves the accu-
racy of diagnosis of preterm labor. Am J Obstet Gynecol 173:141-145,
72. Nageotte MP, Casal D, Senyei AE: Fetal ﬁbronectin in patients at increased
risk for premature birth. Am J Obstet Gynecol 170:20-25, 1994.
73. Oshiro B, Edwin S, Silver R: Human ﬁbronectin and human tenascin
production in human amnion cells. J Soc Gynecol Invest 3:351A, 1996.
74. Bell SC, Meade EA: Fetal membrane rupture. In Critchley H, Bennett P,
Thornton S (eds): Preterm Birth. London: RCOG Press, 2004, pp
75. King L, MacDonald P, Casey ML: Regulation of tissue inhibitor of metal-
loproteinase-1 (TIMP-1) in human amnion. J Soc Gynecol Invest 3:232A,
76. Romero R, Gomez R, Helming R, et al: Amniotic ﬂuid elastase and secre-
tory leukocyte protease natural inhibitor during labor, rupture of mem-
branes and intrauterine infection. 41st Annual Meeting of the Society for
Gynecologic Investigation, Chicago, 1994. Abstract O183, p 183.
77. Vadillo-Ortega F, Hernandez A, Gonzalez-Avila G, et al: Increased matrix
metalloproteinase activity and reduced tissue inhibitor of metalloprotein-
ases-1 levels in amniotic ﬂuids from pregnancies complicated by
premature rupture of membranes. Am J Obstet Gynecol 174:1371-1376,
78. Skinner SJ, Liggins GC: Glycosaminoglycans and collagen in human
amnion from pregnancies with and without premature rupture of the
membranes. J Dev Physiol 3:111-121, 1981.
79. Malak TM, Bell SC: Structural characteristics of term human fetal mem-
branes: A novel zone of extreme morphological alteration within the
rupture site. BJOG 101:375-386, 1994.
80. McLaren J, Malak TM, Bell SC: Structural characteristics of term human
fetal membranes prior to labour: Identiﬁcation of an area of altered mor-
phology overlying the cervix. Hum Reprod 14:237-241, 1999.
81. Bell SC, Pringle JH, Taylor DJ, et al: Alternatively spliced tenascin-C
mRNA isoforms in human fetal membranes. Mol Hum Reprod 5:1066-
82. Malak TM, Mulholland G, Bell SC: Morphometric characteristics of the
decidua, cytotrophoblast, and connective tissue of the prelabor ruptured
fetal membranes. Ann N Y Acad Sci 734:430-432, 1994.
83. Maymon E, Romero R, Pacora P, et al: Evidence for the participation
of interstitial collagenase (matrix metalloproteinase 1) in preterm
premature rupture of membranes. Am J Obstet Gynecol 183:914-920,
84. Maymon E, Romero R, Pacora P, et al: Human neutrophil collagenase
(matrix metalloproteinase 8) in parturition, premature rupture of the
membranes, and intrauterine infection. Am J Obstet Gynecol 183:94-99,
85. Athayde N, Edwin SS, Romero R, et al: A role for matrix metalloprotein-
ase-9 in spontaneous rupture of the fetal membranes. Am J Obstet
Gynecol 79:1248-1253, 1998.
86. Helmig BR, Romero R, Espinoza J, et al: Neutrophil elastase and secretory
leukocyte protease inhibitor in prelabor rupture of membranes, parturi-
tion and intra-amniotic infection. J Matern Fetal Neonatal Med 12:237-
87. Everts V, van der ZE, Creemers L, Beertsen W: Phagocytosis and intracel-
lular digestion of collagen, its role in turnover and remodelling. Histo-
chem J 28:229-245, 1996.
88. Fortunato SJ, Menon R: Screening of novel matrix metalloproteinases
(MMPs) in human fetal membranes. J Assist Reprod Genet 19:483-486,
89. Reboul P, Pelletier JP, Tardif G, et al: The new collagenase, collagenase-3,
is expressed and synthesized by human chondrocytes but not by synovio-
cytes: A role in osteoarthritis. J Clin Invest 97:2011-2019, 1996.
90. Velasco G, Pendas AM, Fueyo A, et al: Cloning and characterization
of human MMP-23, a new matrix metalloproteinase predominantly
expressed in reproductive tissues and lacking conserved domains in other
family members. J Biol Chem 274:4570-4576, 1999.
91. Maymon E, Romero R, Pacora P, et al: A role for the 72 kDa gelatinase
(MMP-2) and its inhibitor (TIMP-2) in human parturition, premature
rupture of membranes and intraamniotic infection. J Perinat Med 29:308-
92. Bennett PR, Elder MG, Myatt L: The effects of lipoxygenase metabolites
of arachidonic acid on human myometrial contractility. Prostaglandins
93. Bleasdale JE, Johnston JM: Prostaglandins and human parturition: regula-
tion of arachidonic acid mobilization. Rev Perinat Med 5:151, 1985.
94. Calder A: Pharmacological management of the unripe cervix in the
human. In Naftolin F, Stubbleﬁeld P (eds): Dilatation of the Uterine
Cervix. New York: Raven Press, 1980, p 317.
95. Calder AA, Greer IA: Pharmacological modulation of cervical compliance
in the ﬁrst and second trimesters of pregnancy. Semin Perinatol 15:162-
96. Carraher R, Hahn DW, Ritchie DM, et al: Involvement of lipoxygenase
products in myometrial contractions. Prostaglandins 26:23-32, 1983.
97. Challis JRG: Endocrine control of parturition. Physiol Rev 59:863, 1979.
98. Challis JR, Olson D: Parturition. In Knobil E, Neill J (eds): The Physiology
of Reproduction. New York: Raven Press, 1988, p 2177.
99. Ellwood DA, Mitchell MD, Anderson AB, et al: The in vitro production of
prostanoids by the human cervix during pregnancy: Preliminary observa-
tions. BJOG 87:210-214, 1980.
100. Greer I: Cervical ripening. In Drife J, Calder A (eds): Prostaglandins and
the Uterus. London: Springer-Verlag, 1992, p 191.
101. MacDonald PC, Schultz FM, Duenhoelter JH, et al: Initiation of human
parturition. I: Mechanism of action of arachidonic acid. Obstet Gynecol
102. Mitchell MD: The mechanism(s) of human parturition. J Dev Physiol
103. Novy MJ, Liggins GC: Role of prostaglandins, prostacyclin, and throm-
boxanes in the physiologic control of the uterus and in parturition. Semin
Perinatol 4:45-66, 1980.
104. Rajabi M, Solomon S, Poole AR: Hormonal regulation of interstitial col-
lagenase in the uterine cervix of the pregnant guinea pig. Endocrinology
105. Ritchie DM, Hahn DW, McGuire JL: Smooth muscle contraction as a
model to study the mediator role of endogenous lipoxygenase products
of arachidonic acid. Life Sci 34:509-513, 1984.
106. Thorburn GD, Challis JR: Endocrine control of parturition. Physiol Rev
107. Wiqvist N, Lindblom B, Wikland M, et al: Prostaglandins and uterine
contractility. Acta Obstet Gynecol Scand Suppl 113:23-29, 1983.
108. Ekman G, Forman A, Marsal K, et al: Intravaginal versus intracervical
application of prostaglandin E2 in viscous gel for cervical priming and
induction of labor at term in patients with an unfavorable cervical state.
Am J Obstet Gynecol 147:657-661, 1983.
109. Embrey MP: Induction of abortion by prostaglandins E1 and E2. BMJ
110. Gordon-Wright AP, Elder MG: Prostaglandin E2 tablets used intravagi-
nally for the induction of labour. BJOG 86:32-36, 1979.
111. Husslein P: Use of prostaglandins for induction of labor. Semin Perinatol
112. Husslein P: Prostaglandins for induction of labour. In Drife J, Calder A
(eds): Prostaglandins and the Uterus. London: Springer-Verlag, 1992.
113. Karim SM, Filshie GM: Therapeutic abortion using prostaglandin F2alpha.
Lancet 1:157-159, 1970.
535CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
114. Macer J, Buchanan D, Yonekura ML: Induction of labor with prostaglan-
din E2 vaginal suppositories. Obstet Gynecol 63:664-668, 1984.
115. MacKenzie IZ: Prostaglandins and midtrimester abortion. In Drife J,
Calder A (eds): Prostaglandins and the Uterus. London: Springer-Verlag,
1992, p 119.
116. World Health Organization Task Force: Repeated vaginal administration
of 15-methyl pgf2 alpha for termination of pregnancy in the 13th to 20th
week of gestation. Contraception 16:175, 1977.
117. World Health Organization Task Force: Comparison of intra-amniotic
prostaglandin f2 alpha and hypertonic saline for second trimester abor-
tion. BMJ 1:1373, 1976.
118. World Health Organization Task Force: Termination of second trimester
pregnancy by intramuscular injection of 16-phenoxy-w-17, 18, 19, 20-
tetranor PGE methyl sulfanilamide. Int J Gynaecol Obstet 16:175,
119. Giri SN, Stabenfeldt GH, Moseley TA, et al: Role of eicosanoids in abortion
and its prevention by treatment with ﬂunixin meglumine in cows during
the ﬁrst trimester of pregnancy. Zentralbl Veterinarmed A 38:445-459,
120. Harper MJ, Skarnes RC: Inhibition of abortion and fetal death produced
by endotoxin or prostaglandin F2alpha. Prostaglandins 2:295-309, 1972.
121. Keirse MJ: Eicosanoids in human pregnancy and parturition. In Mitchell
M (ed): Eicosanoids in Reproduction. Boca Raton, FL: CRC Press, 1990,
122. Skarnes RC, Harper MJ: Relationship between endotoxin-induced abor-
tion and the synthesis of prostaglandin F. Prostaglandins 1:191-203,
123. Keirse MJ: Endogenous prostaglandins in human parturition. In Keirse
MA, Gravenhorst J (eds): Human Parturition. The Hague, Netherlands:
Nijhoff Publishers, 1979, p 101.
124. Romero R, Emamian M, Quintero R, et al: Amniotic ﬂuid prostaglandin
levels and intra-amniotic infections. Lancet 1:1380, 1986.
125. Romero R, Emamian M, Wan M, et al: Increased concentrations of
arachidonic acid lipoxygenase metabolites in amniotic ﬂuid during par-
turition. Obstet Gynecol 70:849-851, 1987.
126. Romero R, Emamian M, Wan M, et al: Prostaglandin concentrations in
amniotic ﬂuid of women with intra-amniotic infection and preterm labor.
Am J Obstet Gynecol 157:1461-1467, 1987.
127. Romero R, Wu YK, Mazor M, et al: Amniotic ﬂuid prostaglandin E2 in
preterm labor. Prostaglandins Leukot Essent Fatty Acids 34:141-145,
128. Romero R, Wu YK, Mazor M, et al: Increased amniotic ﬂuid leukotriene
C4 concentration in term human parturition. Am J Obstet Gynecol
129. Romero R, Wu YK, Sirtori M, et al: Amniotic ﬂuid concentrations of
prostaglandin F2 alpha, 13,14-dihydro-15-keto-prostaglandin F2 alpha
(PGFM) and 11-deoxy-13,14-dihydro-15-keto-11, 16-cyclo-prostaglan-
din E2 (PGEM-LL) in preterm labor. Prostaglandins 37:149-161, 1989.
130. Sellers SM, Mitchell MD, Anderson AB, et al: The relation between the
release of prostaglandins at amniotomy and the subsequent onset of
labour. BJOG 88:1211-1216, 1981.
131. Romero R, Baumann P, Gonzalez R, et al: Amniotic ﬂuid prostanoid con-
centrations increase early during the course of spontaneous labor at term.
Am J Obstet Gynecol 171:1613-1620, 1994.
132. Brodt-Eppley J, Myatt L: Prostaglandin receptors in lower segment myo-
metrium during gestation and labor. Obstet Gynecol 93:89-93, 1999.
133. Matsumoto T, Sagawa N, Yoshida M, et al: The prostaglandin E2 and F2
alpha receptor genes are expressed in human myometrium and are down-
regulated during pregnancy. Biochem Biophys Res Commun 238:838-841,
134. Mohan AR, Loudon JA, Bennett PR: Molecular and biochemical mecha-
nisms of preterm labour. Semin Fetal Neonatal Med 9:437-444, 2004.
135. Myatt L, Lye SJ: Expression, localization and function of prostaglandin
receptors in myometrium. Prostaglandins Leukot Essent Fatty Acids
136. Olson DM: The role of prostaglandins in the initiation of parturition. Best
Pract Res Clin Obstet Gynaecol 17:717-730, 2003.
137. Denison FC, Calder AA, Kelly RW: The action of prostaglandin E2 on
the human cervix: Stimulation of interleukin 8 and inhibition of
secretory leukocyte protease inhibitor. Am J Obstet Gynecol 180:614-620,
138. Yoshida M, Sagawa N, Itoh H, et al: Prostaglandin F(2alpha), cytokines
and cyclic mechanical stretch augment matrix metalloproteinase-1 secre-
tion from cultured human uterine cervical ﬁbroblast cells. Mol Hum
Reprod 8:681-687, 2002.
139. Madsen G, Zakar T, Ku CY, et al: Prostaglandins differentially modulate
progesterone receptor-A and -B expression in human myometrial cells:
Evidence for prostaglandin-induced functional progesterone withdrawal.
J Clin Endocrinol Metab 89:1010-1013, 2004.
140. Romero R, Espinoza J, Mazor M, et al: The preterm parturition syndrome.
In Critchely H, Bennett P, Thornton S (eds): Preterm Birth. London:
RCOG Press, 2004, pp 28-60.
141. Elovitz MA, Mrinalini C: Animal models of preterm birth. Trends Endo-
crinol.Metab 15:479-487, 2004.
142. Fidel PL Jr, Romero R, Wolf N, et al: Systemic and local cytokine proﬁles
in endotoxin-induced preterm parturition in mice. Am J Obstet Gynecol
143. Gravett MG, Witkin SS, Haluska GJ, et al: An experimental model for
intraamniotic infection and preterm labor in rhesus monkeys. Am J
Obstet Gynecol 171:1660-1667, 1994.
144. Hirsch E, Saotome I, Hirsh D: A model of intrauterine infection and
preterm delivery in mice. Am J Obstet Gynecol 172:1598-1603, 1995.
145. Kullander S: Fever and parturition: An experimental study in rabbits. Acta
Obstet Gynecol Scand Suppl 66:77-85, 1977.
146. McDufﬁe RS Jr, Sherman MP, Gibbs RS: Amniotic ﬂuid tumor
necrosis factor-alpha and interleukin-1 in a rabbit model of bacterially
induced preterm pregnancy loss. Am J Obstet Gynecol 167:1583-1588,
147. McKay DG, Wong TC: The effect of bacterial endotoxin on the placenta
of the rat. Am J Pathol 42:357-377, 1963.
148. Romero R, Mazor M, Wu YK, et al: Infection in the pathogenesis of
preterm labor. Semin Perinatol 12:262-279, 1988.
149. Romero R, Munoz H, Gomez R, et al: Antibiotic therapy reduces the rate
of infection-induced preterm delivery and perinatal mortality. Am J
Obstet Gynecol 170:390, 1994.
150. Takeda Y, Tsuchiya I: Studies on the pathological changes caused by the
injection of the Shwartzman ﬁltrate and the endotoxin into pregnant
rabbits. Jap J Exp Med 21:9-16, 1953.
151. Wang H, Hirsch E: Bacterially-induced preterm labor and regulation of
prostaglandin-metabolizing enzyme expression in mice: The role of toll-
like receptor 4. Biol Reprod 69:1957-1963, 2003.
152. Zahl PA, Bjerknes C: Induction of decidua-placental hemorrhage in mice
by the endotoxins of certain gram-negative bacteria. Proc Soc Exp Biol
Med 54:329-332, 1943.
153. Gibbs RS, McDufﬁe RS Jr, Kunze M, et al: Experimental intrauterine infec-
tion with Prevotella bivia in New Zealand White rabbits. Am J Obstet
Gynecol 190:1082-1086, 2004.
154. Gilles HM, Lawson JB, Sibelas M, et al: Malaria, anaemia and pregnancy.
Ann Trop Med Parasitol 63:245-263, 1969.
155. Herd N, Jordan T: An investigtion of malaria during pregnancy in Zim-
babwe. Afr J Med 27:62, 1981.
156. Hibbard L, Thrupp L, Summeril S, et al: Treatment of pyelonephritis in
pregnancy. Am J Obstet Gynecol 98:609-615, 1967.
157. Patrick MJ: Inﬂuence of maternal renal infection on the foetus and infant.
Arch Dis Child 42:208-213, 1967.
158. Wren BG: Subclinical renal infection and prematurity. Med J Aust 2:596-
159. Cunningham FG, Morris GB, Mickal A: Acute pyelonephritis of preg-
nancy: A clinical review. Obstet Gynecol 42:112-117, 1973.
160. Kaul AK, Khan S, Martens MG, et al: Experimental gestational pyelone-
phritis induces preterm births and low birth weights in C3H/HeJ mice.
Infect Immun 67:5958-5966, 1999.
161. Benedetti TJ, Valle R, Ledger WJ: Antepartum pneumonia in pregnancy.
Am J Obstet Gynecol 144:413-417, 1982.
536 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor
162. Madinger NE, Greenspoon JS, Ellrodt AG: Pneumonia during pregnancy:
Has modern technology improved maternal and fetal outcome? Am J
Obstet Gynecol 161:657-662, 1989.
163. Munn MB, Groome LJ, Atterbury JL, et al: Pneumonia as a complication
of pregnancy. J Matern Fetal Med 8:151-154, 1999.
164. Goepfert AR, Jeffcoat MK, Andrews WW, et al: Periodontal disease and
upper genital tract inﬂammation in early spontaneous preterm birth.
Obstet Gynecol 104:777-783, 2004.
165. Jarjoura K, Devine PC, Perez-Delboy A, et al: Markers of periodontal
infection and preterm birth. Am J Obstet Gynecol 192:513-519, 2005.
166. Jeffcoat MK, Geurs NC, Reddy MS, et al: Current evidence regarding
periodontal disease as a risk factor in preterm birth. Ann Periodontol
167. Offenbacher S, Boggess KA, Murtha AP, et al: Progressive periodontal
disease and risk of very preterm delivery. Obstet Gynecol 107:29-36,
168. Xiong X, Buekens P, Fraser WD, et al: Periodontal disease and adverse
pregnancy outcomes: A systematic review. BJOG 113:135-143, 2006.
169. Offenbacher S: Maternal periodontal infections, prematurity, and growth
restriction. Clin Obstet Gynecol 47:808-821, 2004.
170. Gomez R, Ghezzi F, Romero R, et al: Premature labor and intra-amniotic
infection: Clinical aspects and role of the cytokines in diagnosis and
pathophysiology. Clin Perinatol 22:281-342, 1995.
171. Cassell GH, Davis RO, Waites KB, et al: Isolation of Mycoplasma hominis
and Ureaplasma urealyticum from amniotic ﬂuid at 16-20 weeks of gesta-
tion: Potential effect on outcome of pregnancy. Sex Transm Dis 10:294-
172. Gray DJ, Robinson HB, Malone J, et al: Adverse outcome in pregnancy
following amniotic ﬂuid isolation of Ureaplasma urealyticum. Prenat
Diagn 12:111-117, 1992.
173. Horowitz S, Mazor M, Romero R, et al: Infection of the amniotic cavity
with Ureaplasma urealyticum in the midtrimester of pregnancy. J Reprod
Med 40:375-379, 1995.
174. Romero R, Munoz H, Gomez R, et al: Two thirds of spontaneous abor-
tion/fetal deaths after genetic amniocentesis are the result of a pre-existing
sub-clinical inﬂammatory process of the amniotic cavity. Am J Obstet
Gynecol 172:S261, 1995.
175. Wenstrom KD, Andrews WW, Hauth JC, et al: Elevated second-trimester
amniotic ﬂuid interleukin-6 levels predict preterm delivery. Am J Obstet
Gynecol 178:546-550, 1998.
176. Yoon BH, Oh SY, Romero R, et al: An elevated amniotic ﬂuid matrix
metalloproteinase-8 level at the time of mid-trimester genetic amniocen-
tesis is a risk factor for spontaneous preterm delivery. Am J Obstet Gynecol
177. Fidel P, Ghezzi F, Romero R, et al: The effect of antibiotic therapy on
intrauterine infection-induced preterm parturition in rabbits. J Matern
Fetal Neonatal Med 14:57-64, 2003.
178. Romero R, Oyarzun E, Mazor M, et al: Meta-analysis of the relationship
between asymptomatic bacteriuria and preterm delivery/low birth weight.
Obstet Gynecol 73:576-582, 1989.
179. Smaill F: Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane
Database Syst Rev (2);CD000490, 2001.
180. Goncalves LF, Chaiworapongsa T, Romero R: Intrauterine infection and
prematurity. Ment Retard Dev Disabil Res Rev 8:3-13, 2002.
181. Romero R, Salaﬁa CM, Athanassiadis AP, et al: The relationship between
acute inﬂammatory lesions of the preterm placenta and amniotic ﬂuid
microbiology. Am J Obstet Gynecol 166:1382-1388, 1992.
182. Mays JK, Figueroa R, Shah J, et al: Amniocentesis for selection before
rescue cerclage. Obstet Gynecol 95:652-655, 2000.
183. Romero R, Gonzalez R, Sepulveda W, et al: Infection and labor: VIII.
Microbial invasion of the amniotic cavity in patients with suspected cervi-
cal incompetence: Prevalence and clinical signiﬁcance. Am J Obstet
Gynecol 167:1086-1091, 1992.
184. Romero R, Espinoza J, Chaiworapongsa T, et al: Infection and prematurity
and the role of preventive strategies. Semin Neonatol 7:259-274, 2002.
185. Romero R, Sirtori M, Oyarzun E, et al: Infection and labor: V. Prevalence,
microbiology, and clinical signiﬁcance of intraamniotic infection in
women with preterm labor and intact membranes. Am J Obstet Gynecol
186. Romero R, Mazor M, Morrotti R, et al: Infection and labor: VII. Microbial
invasion of the amniotic cavity in spontaneous rupture of membranes at
term. Am J Obstet Gynecol 166:129-133, 1992.
187. Andrews WW, Hauth JC, Goldenberg RL, et al: Amniotic ﬂuid interleukin-
6: Correlation with upper genital tract microbial colonization and gesta-
tional age in women delivered after spontaneous labor versus indicated
delivery. Am J Obstet Gynecol 173:606-612, 1995.
188. Watts DH, Krohn MA, Hillier SL, Eschenbach DA: The association
of occult amniotic ﬂuid infection with gestational age and neonatal
outcome among women in preterm labor. Obstet Gynecol 79:351-357,
189. Romero R, Kadar N, Hobbins JC, et al: Infection and labor: The detection
of endotoxin in amniotic ﬂuid. Am J Obstet Gynecol 157:815-819, 1987.
190. Romero R, Roslansky P, Oyarzun E, et al: Labor and infection: II. Bacterial
endotoxin in amniotic ﬂuid and its relationship to the onset of preterm
labor. Am J Obstet Gynecol 158:1044-1049, 1988.
191. Grigsby PL, Hirst JJ, Scheerlinck JP, et al: Fetal responses to maternal and
intra-amniotic lipopolysaccharide administration in sheep. Biol Reprod
192. Jobe AH, Newnham JP, Willet KE, et al: Effects of antenatal endotoxin and
glucocorticoids on the lungs of preterm lambs. Am J Obstet Gynecol
193. Jobe AH, Newnham JP, Willet KE, et al: Endotoxin-induced lung matura-
tion in preterm lambs is not mediated by cortisol. Am J Respir Crit Care
Med 162:1656-1661, 2000.
194. Janeway C, Travers P, Walport M, et al: Innate immunity. In Janeway C,
Travers P, Walport M, Schlomchik M (eds): Immunobiology. New York:
Garland Science Publishing, 2005, pp 37-102.
195. Hargreaves DC, Medzhitov R: Innate sensors of microbial infection. J Clin
Immunol 25:503-510, 2005.
196. Elovitz MA, Wang Z, Chien EK, et al: A new model for inﬂammation-
induced preterm birth: The role of platelet-activating factor and toll-like
receptor-4. Am J Pathol 163:2103-2111, 2003.
197. Kim YM, Romero R, Chaiworapongsa T, et al: Toll-like receptor-2 and -4
in the chorioamniotic membranes in spontaneous labor at term and in
preterm parturition that are associated with chorioamnionitis. Am J
Obstet Gynecol 191:1346-1355, 2004.
198. Krikun G, Lockwood CJ, Abrahams VM, et al: Expression of toll-like
receptors in the human decidua. Histol Histopathol 22:847-854, 2007.
199. Romero R, Durum SK, Dinarello CA, et al: Interleukin-1: A signal for the
initiation of labor in chorioamnionitis. 33rd Annual Meeting for the
Society for Gynecologic Investigation, Toronto, Ontario, 1986.
200. Romero R, Wu YK, Brody DT, et al: Human decidua: A source of inter-
leukin-1. Obstet Gynecol 73:31-34, 1989.
201. Romero R, Durum S, Dinarello CA, et al: Interleukin-1 stimulates
prostaglandin biosynthesis by human amnion. Prostaglandins 37:13-22,
202. Romero R, Brody DT, Oyarzun E, et al: Infection and labor: III.
Interleukin-1: A signal for the onset of parturition. Am J Obstet Gynecol
203. Sadowsky DW, Novy MJ, Witkin SS, et al: Dexamethasone or interleukin-
10 blocks interleukin-1beta-induced uterine contractions in pregnant
rhesus monkeys. Am J Obstet Gynecol 188:252-263, 2003.
204. Romero R, Mazor M, Tartakovsky B: Systemic administration of interleu-
kin-1 induces preterm parturition in mice. Am J Obstet Gynecol 165:969-
205. Romero R, Tartakovsky B: The natural interleukin-1 receptor antagonist
prevents interleukin-1-induced preterm delivery in mice. Am J Obstet
Gynecol 167:1041-1045, 1992.
206. Casey ML, Cox SM, Beutler B, et al: Cachectin/tumor necrosis factor-alpha
formation in human decidua: Potential role of cytokines in infection-
induced preterm labor. J Clin Invest 83:430-436, 1989.
207. Romero R, Mazor M, Manogue K, et al: Human decidua: A source of
cachectin-tumor necrosis factor. Eur J Obstet Gynecol Reprod Biol 41:123-