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4 Acute Abdomen-Induced Preterm Labor
metabolism associated with cervical ripening
[53, 54], and decidual/membrane activation.
Both COX-1 and COX-2 are present within the
pregnant uterus. The expression of COX-1
remains constant throughout gestation. However,
there is an exponential rise in COX-2 activity
throughout gestation in the fetal membranes,
chorion-decidua, and myometrium, with most of
the increase occurring before the onset of labor.
The fetal membranes are a major source of prostaglandin synthesis. Prostaglandin synthesis in
fetal membrane explants is suppressed by COX2- specic inhibitors but not by COX-1-specic
inhibitors. This demonstrates the importance of
COX-2in the production of intrauterine prostaglandins. This increase in amniotic COX-2 activity is accompanied by decreased expression of
the prostaglandin-metabolizing enzyme,
15-hydroxy-prostaglandin dehydrogenase
(PGDH), in the chorion. Progesterone promotes
PGDH expression through its effect on the progesterone receptor (PR) B. This would allow
prostaglandins produced in the amnion to traverse the chorion and reach the myometrium,
where they can stimulate smooth muscle contractions [55]. 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 uxes and through increased transcription
of oxytocin receptors, connexin-43 (gap junctions), and the prostaglandin receptors EP1
through EP4 and FP27 [56, 57], (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) [58, 59]; and (3) prostaglandin E2
(PGE2) and PGF2α increase the ratio of expression of the PR-A and PR-B isoforms [60].
Progesterone interaction with PR-B inhibits
myometrial ERα expression causing the myometrium to be refractory to estrogens. As gestation
progresses, the increase in myometrial PR-A
expression decreases PR-B activity and eliminates the PR-B-mediated inhibition of ERα
expression [61]. Changes in progesterone recep-
tor ratio induce a functional progesterone withdrawal because, unlike other mammalian species,
circulating progesterone levels do not decrease
during the onset of labor.
4.3 Etiopathogenesis ofPreterm
Spontaneous PTL can result from (1) maternal
conditions, (2) fetal conditions, and (3) placental
conditions. These conditions could be infective
or noninfective. Intra-amniotic infections (IAI)
are present in ~50% of all pregnancies that result
in PTB, and the earlier the gestational age at
delivery, the higher the frequency of IAI [62].
This chapter will concentrate on the inuence of
localized/diffuse peritonitis and abdominal
trauma on PTL.Localized/diffuse peritonitis synergistically increases the rate of PTL with other
factors. Risk factors for PPROM are generally
similar to those for spontaneous PTL with intact
membranes, although infections and tobacco
exposure are essential [63]. Oxidative stressinduced fetal membrane senescence contributes
to inammation [64]. In response to oxidative
stress-inducing risk factors, premature senescence activation and inammation can predispose to PTB and PPROM [65].
chemical pathway (see Sect. 4.3.4), employed by
each pathogenic pathway with specic genetic or
epidemiologic risk factors and unique biochemical triggers. Mechanical uterus stretching from
multifetal gestations and cervical insufciency is
outside this book’s scope.
4.3.1 Inammation
The amniotic cavity is sterile for bacteria in 99%
of cases. It contains antimicrobial properties—a
low number of WBC, lactoferrin, and other proteins implicated in fetal host defense mechanisms
[66]. With IAI, WBC rise in the amniotic cavity
[67]. The most abundant WBC in the amniotic
cavity are the neutrophils in both types of inammatory processes—initiated by either intra-
Labor
Spontaneous PTLs utilize a common bio-
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amniotic microorganisms or danger signals
derived from necrosis or cellular stress (i.e., sterile IAI) [67]. Single amniocentesis shows that
40% of intra-amniotic neutrophils are mostly
fetal, >30% predominantly maternal, and 20% a
mixture of fetal and maternal neutrophils [68].
Extreme PTL is present with predominantly
amniotic uid neutrophils of fetal or mixed origin
(71.5% and 66.7%, respectively). All women
with predominantly amniotic uid neutrophils of
maternal origin had a term or late PTL [68]. Fetal
neutrophils are predominant in the amniotic cavity of women with IAI or (sterile) inammation
with resultant PTL. Fetal neutrophils possibly
invade the amniotic cavity by migrating from the
fetal vasculature of a chorionic plate of the fetus
[69]. An amniotic uid containing predominantly
fetal neutrophils did not show maternal or fetal
inammatory responses in the placental tissues
[68]. Neutrophils migrate from the maternal vasculature into the amniotic uid of women with
IAI to participate in the host defense mechanisms
against pathogens invading the amniotic cavity
[68].
Infection is a frequent and essential cause of
PTL. Microorganisms can gain access to the
amniotic cavity by (Fig.4.1):
• ascending from the vagina and the cervix,
• by hematogenous dissemination through the
placenta,
• introduction at the time of invasive
procedures,
• by retrograde spread through the Fallopian
tubes,
• combined access.
Evidence for causality includes:
• intrauterine infection or systemic presence of
microbial products (bacterial endotoxin),
• extrauterine maternal infections (periodontal
disease [70], malaria, pyelonephritis, and
pneumonia),
• subclinical intrauterine infections (histologic
chorioamnionitis) [71],
• intra-amniotic infection or inammation
(dened as an elevation of amniotic uid con-
Fig. 4.1 Potential
routes of intrauterine
infection. (Reproduced
with permission from
[4])
Haematogeneously
through placenta
Retrograde from
abdominal cavity
Amniocentesis
Ascending from vagina
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centrations of pro-inammatory cytokines and
matrix-degrading enzymes in the midtrimester) [72],
• antibiotic treatment of ascending intrauterine
infections can prevent PTL in experimental
models of chorioamnionitis,
• treatment of asymptomatic bacteriuria prevents PTL.
The extent of bacterial colonization, route of
infection, and bacterial stimulatory capacity are
important in activating maternal and fetal proinammatory signaling cascades. Most studies
are based on genital tract infections causing
intrauterine infection, without large studies on
the pathophysiology and microbiology of
peritonitis- induced PTL.
Intrauterine inammation is associated with
approximately 25–40% of all PTLs [4, 73] and
79% of extreme PTB tested [74]. This is a conservative estimate due to the difculty of detecting chorioamnionitis using conventional culture
techniques [4]. Also, women with a PCR-positive
amniotic uid for U. urealyticum but a negative
culture have similar rates of PTL as women with
positive cultures for the same microorganism
[75]. Furthermore, since the rate of microbial
colonization of the chorioamnion is twice that
seen in the amniotic cavity, rates of intrauterine
infection based only on amniotic uid cultures
substantially underestimate the level of association [76].
4.3.1.1 Ascending Intrauterine
Infection
Ascending intrauterine infection has four stages
(Fig.4.2). Stage I involves changing the vaginal
and cervical microbial ora. Some forms of bacterial vaginosis may be an early manifestation of
stage I.Once microorganisms gain access to the
intrauterine cavity, they reside in the decidua
(Stage II). A localized inammatory reaction
leads to deciduitis. Microorganisms may then
reside in the chorion and amnion. The infection
may invade the fetal vessels (choriovasculitis/
choriodeciduitis) or proceed through the amnion
(amnionitis) into the amniotic cavity, leading to
the microbial invasion of the amniotic cavity or
4 Acute Abdomen-Induced Preterm Labor
Fig. 4.2 The pathway of ascending intrauterine infection.
Stage I refers to a change in the vagina or cervix microbial
ora. In Stage II, microorganisms are between the amnion
and chorion. Stage III represents intra-amniotic infection,
and Stage IV is a fetal invasion. (Reproduced with permis-
sion from [78] and modied)
an IAI (Stage III). Rupture of the membranes is
not a prerequisite for IAI because microorganisms can cross intact membranes [77]. Once in
the amniotic cavity, the bacteria may access the
fetus through different ports of entry (Stage IV).
Aspiration of the infected uid by the fetus may
lead to congenital pneumonia. Otitis and conjunctivitis may occur by the direct spread of
microorganisms from the infected amniotic uid.
Funisitis results from the spread of infection to
and through the umbilical cord. Seeding from
these sites to fetal circulation may result in fetal
bacteremia and sepsis.
IAI and FIRS are more severe in PTL than in
PPROM, despite less common IAI in PTL than in
PPROM in the most advanced stage of ascending
IAI(-)/FIRS(-) IAI(+)/FIRS(-) IAI(+)/FIRS(+)
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81
intrauterine infection—funisitis [79].
Inammation is not detected in any compartment
(i.e., amnion, chorionic plate, or umbilical cord)
except the choriodecidua in the IAI(−)/FIRS(−)
group with PTL, while present in all compartments in the IAI(−)/FIRS(−) group with
PPROM.Also, IAI(+)/FIRS(−) group has a signicantly higher frequency of inammation in
each compartment than the IAI(−)/FIRS(−)
group in PTL but not PPROM (Fig.4.3) [80].
Microbial invasion of the amniotic cavity or
chorioamnion may be caused by direct accessibility without substantial involvement of choriodecidua by cervicovaginal microorganisms
with ROM. PPROM would be more likely to
show neutrophils exiting from decidual postcapillary venules and migrating to amnion in
response to microorganisms that have already
entered the AF or chorioamnion than PTL even
PTL
before cytokine responses in AF become elevated [80].
Microbial invasion of the amniotic cavity
(MIAC) is present in 12.8% of women with PTL
[81] and 21–32% with PPROM [81, 82]. Most
(83%) are complicated by microbial-associated
IAI.Sterile IAI is responsible for a small proportion of pregnancies complicated by IAI (17–
33%). The majority of women with PPROM have
sterile inammation [82, 83]. Different gestational week ranges and IL-6 cut-off values for the
denition of IAI were used. The amniotic cavity
microbial invasion was detected in 51% of
patients with acute cervical insufciency. Patients
with MIAC are more likely to have PTL, spontaneous ROM, and clinical chorioamnionitis than
those with sterile amniotic uid. The most common organisms found in the amniotic uid are
genital mycoplasmas. It is believed that ascend-
IAI(-)/FIRS(-)
IAI(+)/FIRS(-)
IAI(+)/FIRS(+)
Orange color: Chorio-deciduitis
Red color: Amnionitis
Brown color: Funisitis
Purple color: Chorionic-plate inflammation
Orange color: Chorio-deciduitis
Red color: Amnionitis
Brown color: Funisitis
Purple color: Chorionic-plate inflammation
Preterm-PROM
25.0%
46.2%
23.1%
30.8%
7.7%
Fig. 4.3 A schematic representation of the histotopographic distribution of involved compartments,
according to the presence or absence of IAI or FIRS.The
colored area of each compartment (i.e., choriodecidua,
0%
0%
0%
65.6%
28.1%
25.0%
25.0%
69.7%
27.3%
36.4%
21.2%
100%
72.4%
65.5%
55.2%
100%
91.7%
87.5%
70.8%
amnion, umbilical cord, and chorionic plate) means the
proportion of cases with inammation. IAI intra-amniotic
infection, FIRS fetal systemic inammatory response.
(Reproduced with permission from [80])
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4 Acute Abdomen-Induced Preterm Labor
ing infection is the most common source of
microbial invasion of the amniotic cavity,
although transplacental infections may also
occur. The lower the gestational age at which a
patient presents with PTL and PPROM, the
higher the frequency of MIAC.Moreover, many
of these infections appeared to be chronic and
were detected in women having mid-trimester
amniocentesis for genetic indications. Bacterial
products such as endotoxin have also been
detected in the amniotic cavity of women with
PTL and PPROM.Endotoxin has powerful proinammatory effects in maternal and fetal tissues. While PPROM near term likely results
mainly from the physiologic processes, PPROM
remote from term has been associated with several pathologic processes, especially infection
and inammation, membrane stretch, and local
tissue hypoxia.
PPROM in ascending infection is due to bacterial proteases (collagenases and phospholipases) that cause membrane weakening.
Ascending bacterial colonization can also cause a
local inammatory response, including the production of cytokines, prostaglandins, and metalloproteases which cause membrane degradation
and weakening.
Microorganisms are detected by the innate
components of the immune system: (1) the soluble pattern recognition receptors (PRRs), lectin,
and CRP; (2) transmembrane PRRs, which
include scavenger receptors, C-type lectins, and
Toll-like receptors (TLRs); and (3) intracellular
PRRs, including Nod1 and Nod2, retinoicinduced gene type 1, and melanoma
differentiation- associated protein 5, which mediate recognition of intracellular pathogens (e.g.,
viruses). The best-studied PRRs are the TLRs.
Ligation of TLR results in the activation of
NF-κB, which, in turn, leads to the production of
cytokines, chemokines, and antimicrobial peptides. Because TLRs are crucial for recognizing
microorganisms, defective signaling through this
pathway could be anticipated to impair bacteriainduced PTL. Consistent with this, 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 adminis-
tration of lipopolysaccharide than wild-type
mice. In pregnant women, TLR-2 and TLR-4 are
expressed in the amniotic epithelium and decidua.
Moreover, spontaneous labor that occurs at term
or preterm and is complicated by histologic evidence of chorioamnionitis, regardless of the
membrane status (intact or ruptured), is associated with increased mRNA expression of TLR-2
and TLR-4 in the chorioamniotic membranes.
These observations suggest that the innate
immune system plays a role in parturition.
4.3.1.2 Hematogenous Spread
tothePlacenta
Few bacteria are capable of placental and fetal
infections (Brucella spp, C. bumetii, L. monocy-
togenes, M. tuberculosis, and T. pallidum), and
even for these, the maternal infection does not
result in placental or fetal infection [84]
Common distant infective focuses include
periodontal respiratory disease with several
hypothetical models for the contribution in PTL.
Direct pathway: periodontal bacteria or their
pathogenic products disseminate to the placenta,
initiating a distant infection or triggering a local
inammatory response that elevates inammatory cytokines and mediators. Indirect pathway:
inammatory cytokines and mediators produced
by gingiva in response to periodontal pathogens
enter the blood circulation and reach (1) the placenta and enhance the accumulation of larger
amounts of these mediators, (2) the liver, where
they stimulate a systemic inammatory response
by the production of acute-phase reactants. These
products gain access to blood circulation and
may enter the placenta exacerbating intrauterine
inammation. During pregnancy, elevated levels
of estrogens and progesterone increase vascular
permeability in the gingiva, and bacteria or their
products diffuse through the tissues more easily
[85].
Pro-inammatory cytokines in the maternal
circulation and transient bacteremia may induce
systemic inammation by stimulating the production of acute-phase reactants, such as CRP
and brinogen. Elevated levels of plasma CRP
could amplify the inammatory response at the
feto-placental interface through complement
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83
activation. Thus, elevated CRP could initiate
PTL or PPROM [86] and other obstetric
complications such as IUGR [87]. The difference between acute (PTL or PPROM) and
chronic obstetric complications (IUGR, LBW)
could depend on (1) the infective burden (diffuse
stercoral peritonitis or periodontal disease), (2)
different feto- maternal unit compartment
involvement, and (3) different inammation
pathway activation. Finally, this could result in
differences in maximal acute-phase reactant levels, increasing obstetric complication rates.
Also, several loci of infection could be present
simultaneously, stimulating inammation via the
hematogenous route (i.e., periodontal disease
and acute respiratory disease) or different routes,
for example, hematogenous and ascending route
(i.e., asymptomatic bacteriuria, acute respiratory
disease, and bacterial vaginosis). Combined
infections/inammations can result in higher
serum acute-phase reactant levels than a single
infective locus.
4.3.1.3 Intraperitoneal Infection
The extrauterine intraperitoneal infection reaches
the fetal circulation by placental transmission.
Concomitant IAI could be present. There are no
studies in this eld, and only hypotheses can be
drawn.
4.3.1.4 Molecular Basis ofInfection
Pro-inammatory Cytokines
Chemokines (IL-8), the pro-inammatory cytokines (IL-1α, TNF-α), and other mediators (e.g.,
platelet-activating factor, prostaglandins) are
central to infection-induced PTL.IL-1 is implicated in the onset of infection-induced PTL: (1)
IL-1 is produced by human decidua in response
to bacterial products; (2) IL-1α and IL-1β stimulate prostaglandin production by human
amnion and decidua; (3) IL-1α and IL-1β concentrations and IL-1–like bioactivity are
increased in the amniotic uid of women with
PTL and infection; (4) intravenous IL-1α stimulates uterine contractions; and (5) administration of IL-1 to pregnant animals induces PTL,
and this effect can be blocked by the administra-
tion of its natural antagonist, the IL-1 receptor
antagonist (IL-1ra).
The role of TNF-α in the mechanisms of PTL
is similar: (1) TNF-α stimulates prostaglandin
production by the amnion, decidua, and myometrium; (2) human decidua can produce TNF-α in
response to bacterial products; (3) amniotic uid
TNF-α bioactivity and immunoreactive concentrations are elevated in women with PTL and IAI;
(4) in women with PPROM and IAI, TNF- α concentrations are higher in the presence of labor; (5)
TNF-α can stimulate the production of MMPs,
implicated in membrane rupture; (6) TNF-α
application to the cervix induces changes that
resemble cervical ripening; (7) TNF-α can induce
PTL by inducing apoptosis via the Fas ligand and
stimulates the production of uterotonic agents
such as endothelin [88]; and (8) TNF-α and IL-1α
enhance IL-8 expression by decidual cells, and
this chemokine is strongly expressed by term
decidual cells in the presence of chorioamnionitis.
Other cytokines and chemokines (IL-6, IL-16,
IL-18, colony-stimulating factors, macrophage
migration inhibitory factor, monocyte chemotactic protein-1, epithelial cell-derived neutrophilactivating peptide, etc.) are implicated in the
complex host response to pathogenic insults and
infection-induced PTL. The redundancy of the
cytokine network implicated in parturition is such
that the blockade of a single cytokine is insufcient to prevent infection- induced PTL.However,
blockade of both IL-1 and TNF-α signaling pathways in mice was associated with a decreased rate
of PTL, partly because IL-1 and TNF mediate
some of their effects via COX-2 [89]. Even the
combined inhibition of IL-1 and TNF-α does not
entirely abolish susceptibility to bacterially
induced labor, suggesting that there are yet other
important factors.
Prostaglandins produced in the amnion are
inactivated by prostaglandin dehydrogenase
released by the chorionic tissue. This prevents
prostaglandins from reaching the myometrium to
cause uterine contractions [73]. Infection of the
chorion inhibits the activity of prostaglandin
dehydrogenase, thereby allowing prostaglandins
to reach the myometrium and cause premature
contractions [90].
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4 Acute Abdomen-Induced Preterm Labor
Anti-Inammatory Cytokines
IL-10 is a crucial cytokine for the maintenance of
pregnancy. With IAI, concentration increases,
suggesting that IL-10 dampens the inammatory
response and may have therapeutic value. In a
nonhuman primate model of IAI, dexamethasone
and IL-10 treatment signicantly reduced IL-1α-
induced uterine contractility. The amniotic uid
concentrations of TNF-α and leukocyte counts
were also decreased by IL-10 treatment.
Furthermore, the administration of IL-10in animal infection models has been associated with
improved pregnancy outcomes.
Cytokeratins
The early choriodecidual infection decreases cellular membrane integrity and tensile strength via
Fig. 4.4 The pathway
of ascending intrauterine
infection. (Reproduced
with permission from
[91] under the CC BY
4.0)
AF IL-6/-8
cytokines
a
dysfunction of cytokeratin networks.
Downregulation of cytokeratin expression and
perturbations in the amniotic epithelial cell intermediate lament network occur after Group B
Streptococcus choriodecidual infection, which
may contribute to PPROM (Fig.4.4).
4.3.2 Maternal andFetal Stress
The bombardment of Strassbourg in 1870 produced many abortions, probably through fright.
A similar observation was by Bouvocque with 92
uninjured women after a powder mill exploded in
Grenelle. On the contrary, the bombing of
Hiroshima did not affect the interruption of pregnancy. Moreover, abortions were no greater in
Early Choriodecidual Infection
cytokines in
amniotic
fluid
Group B
Streptococcus
in chorio-
decidual
interface
Group B Streptococcus
Weakened Fetal Membranes
After Choriodecidual Infection
b
AMNIONCHORION
neutrophil
decidua with
choriodecidual
amniotic fluid
epithelium
basement membrane
macrophages
basement membrane
decidua
catheter
Inflammation
MMP1
SRGN
CXCL2
IL-6
PECAM1
Apoptosis
MYC
CEBPD
BAX
CASP12
CASP1
SGPL1
CFLAR
TP53
Cytostructural
Integrity and
Support Genes
KRT5
KRT6A
KRT8
KRT14
KRT15
KRT17
KRT19
DSG2
DSG3
DSP
LAMB3
LAMA3
LAMC2
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85
London than before the bombings of World War
II.Increased intra-abdominal pressure (see Chap.
3) could be an important etiologic factor in explo-
sions rather than emotional disturbance [92].
The maternal stress of exogenous or endogenous origin is modestly associated with an
increased risk for PTL.The stressful insult could
occur in the pre-conceptional period or during
pregnancy. The precise mechanism is unknown;
however, it includes a CRH. The hormone was
originally identied in the hypothalamus, but is
expressed by the placenta. The maternal plasma
CRH concentrations increase during the second
half of pregnancy and peak during labor, whereas
serum concentrations of the CRH-binding protein decline during the third trimester. The trajectory of CRH serum concentration changes
identies women destined for preterm, term, and
post-term delivery. The mechanisms regulating
the serum concentration and trajectory of CRH
have been described as “a placental clock”. The
mechanisms through which CRH activates the
common pathway of parturition include: (1)
increased production of PGE2 by the amnion,
chorion, and placental cells, but not by decidual
cells; (2) increased production of PGF2α by the
amnion, decidua, and placental cells, but not by
chorion; (3) increased expression of MMP-9 by
chorion and amnion; (4) stimulation of the release
of adrenocorticotropin (ACTH) from the pituitary gland to drive fetal cortisol production (this
establishes a feed-forward cycle because cortisol
stimulates the production of CRH by the placenta
and fetal membranes); (5) induction of the synthesis of fetal DHEAS by the fetal adrenal zone
(the human placenta lacks the enzyme
17- hydroxylase, and it is not able to convert progesterone to estrogen as occurs in other mammals [93]. Fetal DHEAS is the primary substrate
converted by the placenta to estrogen, which in
turn enhances the expression of the oxytocin
receptor, COX-2, prostaglandin receptors, and
connexin-43); (6) cortisol in response to CRH
can increase amnion COX-2 expression while
inhibiting chorionic PGDH expression (resulting
in a net bioavailability of prostaglandins); and (7)
CRH inhibits progesterone production by the placenta. Figure4.5 illustrates the molecular mecha-
nisms for stress-associated PTL.As noted, CRH
has been implicated in the mechanisms of spontaneous parturition at term. Therefore, this specic pathway may operate in normal term labor
Fig. 4.5 Proposed
pathways by which stress
can induce preterm labor.
ACTH adrenocorticotropic
hormone, CRH corticotropin-releasing hormone,
DHEAS dehydroepiandrosterone sulfate, HPA
hypothalamic-pituitaryadrenal, PG prostaglandin,
COX-2 cyclo-oxygenase 2,
PGDH 15-hydroxyprosta-
glandin dehydrogenase.
(Reproduced with
permission from [94])
Maternal stress
Activation of maternal HPA axis
+
cox-2 in amnion
PGDH in chorion
+
Prostaglandins
Cortisol
Decidua
Placenta
Membranes
CRH
Contractions
+
Cervical
change
Fetal stress
(uteroplacental insufficiency)
Activation of fetal HPA axis
ACTH
Adrenal
+
Myometrial OTR, PGs, MLCK,
calmodulin, gap junctions
DHEAS
Placenta Membranes
Estrogen
Rupture of
membranes
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4 Acute Abdomen-Induced Preterm Labor
and PTL. In the former case, placental CRH
expression reects the maturation of the fetal
hypothalamic-pituitary-adrenal axis; in the latter,
it reects physiologically stressful events occurring at later gestational ages. It may be surmised
that some cases of PTL occurring close to term
resort to the physiologic mechanisms used in
term labor after stressful stimuli have accelerated
fetal maturation.
Although the concept that psychosocial stress
may contribute to PTL risk through its effects on
several stress-sensitive biologic processes implicated in parturition, tests of pathway (meditational) models did not conrm a causal
relationship. Cortisol production invivo is inuenced not only by the psychological state of the
individual, but also concurrently by a host of
other conditions, such as variations in the nutritional milieu, physical activity, infection/inammation, hypoxia, sleep, chronobiological state,
and, in the case of pregnancy, by the stage of gestation. Moreover, the effects of psychological
stress on cortisol production likely vary due to
other conditions (i.e., an interactional, conditional, or effect-modication model). Second, it
is unknown when perturbation within a particular
biologic system remains constrained within that
system. Adopting and implementing a systems
biology approach will be required to uncover the
complex interrelationships and pathways inherent invivo human models of complex multifactorial disorders such as PTL (Fig.4.6).
4.3.3 Decidual Hemorrhage
Decidual hemorrhage (placental abruption) originates in damaged spiral arteries or arterioles and
presents clinically as vaginal bleeding, or retroplacental or retrochorionic hematoma formation
noted on ultrasound (US). Decidual hemorrhage
secondary to placental abruption is histologically
noted in up to 60% of PTB [96]. The association
of abruption with increasing maternal age may
malnutrition
infection
epigenetic regulation
STRESS
vascular
genetic and
psychosocial
hypoxia
Fig. 4.6 Contribution of maternal stress and stress biology to preterm birth. No one-to-one correspondence exists
between psychosocial stress and stress-sensitive biology;
the nature, magnitude, and duration of the effects of
maternal psychosocial stress during pregnancy on any
given stress-sensitive biologic system are altered by the
context of other conditions/stressors, including nutrition,
CNS
endocrine
BIOLOGIC
SYSTEM(S)
immune
vascular
infection, and hypoxia. Similarly, the nature, magnitude,
and duration of the effects of a given stress-sensitive biologic system in pregnancy on maternal and fetal target
systems involved in parturition are altered by the secondary perturbations in other closely related biologic systems
and their feedback effects. (Reproduced with permission
from [95])
epigenetic regulation
PRETERM
BIRTH
genetic and
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87
reect an increase in myometrial artery sclerosis,
which increases from 11% of spiral arteries at
age 17–19years to 83% after age 39 [97].
Three principal mechanisms for the initiation
of placental abruption are:
• Decidual spiral arteries disruption,
• Infection-induced placental abruption,
• Trauma-induced placental abruption.
4.3.3.1 Decidual Spiral Arteries
Disruption
The decidua is a rich source of tissue factor, the
primary initiator of clotting through thrombin
generation [98]. Following the spiral arterial vascular disruption, the decidual tissue factor is
exposed to and can complex with plasma factor
VII to generate factor Xa that, in turn, converts
prothrombin to thrombin. Thrombin subserves
some hemostatic functions to produce a retroplacental or retromembranous thrombus. However,
in addition to its procoagulant properties, thrombin also enhances the expression of tissue-type
and urokinase-type plasminogen activators (uPA
and tPA), which directly degrade bronectin and
generate plasmin from plasminogen which
degrades laminin, collagen III, and bronectin,
crucial components of the decidua and fetal
membranes [99].
MMP-1 and MMP-3 protein expression is
enhanced by thrombin binding to its receptor,
protease-activated receptor type-1 (PAR-1) [100,
101]. Thrombin also enhances MMP-9 expres-
sion [102]. Abruption-associated PPROM is
accompanied by dense decidual neutrophil inltration without infection [103]. Neutrophils are a
rich source of elastase and MMP-9 [104], contributing to PPROM and cervical effacement.
These ndings suggest that a mechanism linking
abruption-associated PPROM to decidual
thrombin–PAR interactions triggers myometrial
contractions [105].
4.3.3.2 Infection-induced Placental
Abruption
In all abruptions, the proportion of intrauterine
infections is 6.7% and is threefold higher than
without intrauterine infection [106].
Histologically conrmed chorioamnionitis is
30% among women with placental abruption
[107] and is strongly associated with placental
abruption in both term and preterm pregnancies
[107]. With maternal intraperitoneal infection,
microorganisms may access the intervillous
space by hematogenous dissemination during
maternal bacteremia. From there, the infection
could spread to the villi and fetal circulation.
Histologic chorioamnionitis and funisitis are signicantly more common with acute, severe preterm placental abruption than in normal deliveries
[108]. Another route could be the retrograde
transport of bacteria through the Fallopian tubes,
causing chorioamnionitis. Direct bacterial colonization of the decidua in generalized peritonitis
with resultant tissue inammation may initiate
disruption of decidual lysosomes and tissue disruption, which results in placental abruption
[109].
Placental abruption or uteroplacental apoplexy (Couvelaire uterus) induced by acute pancreatitis is rare, mostly during the third trimester
[110, 111]. Placental abruption likely occurs in
the rst phase of AP, resulting from a systemic
inammatory response (Fig.4.7). Studies in animal models found markedly increased expression
of E-selectin in serum and placenta tissues 1 h
after induction of pancreatitis. The concentration
of E-selectin was signicantly related to the
degree of pancreatic and placenta injury [112].
Another mechanism of placental injury during
pancreatitis might be associated with activating
the mitogen-activated protein kinases pathway,
particularly c-Jun N-terminal kinase and p-38
[113].
Placental abruption is several-fold higher in
patients with acute appendicitis [114]. Placental
abruption after acute appendicitis occurs during
the third trimester [108, 115–117]. The association between the severity of acute appendicitis or
type of bacteria and placental abruption is
unknown because, in a single case, the bacteria
was described (E. coli), and culture specimens
from the neonate's nose, pharynx, and ear canals
were sterile [108].
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