Pathogenesis of Spontaneous

Preterm Birth
Buhimschi CS, Norman JE
Preterm Birth Syndrome: New Phenotypic
Classification
• Preterm birth (PTB) occurs between fetal viability and 37 completed
weeks of gestation
• Definition of viability is variable, most of countries define it as a lower
limit of 20-22 weeks
• Recent study suggested definition of PTB would includes all births
(including live births, stillbirths, and pregnancy termination)
occurring from 16 weeks 0 days to 38 weeks 6 days (112-272 days)
• Birth weight of 500 g, doesn’t represent of vaibiity
Preterm Birth Syndrome: New Phenotypic
Classification
• In 2010, PTB rate in US was around 12%
• Classification of PTB
• Spontaneous: can occur either with intact membrane or with premature
rupture of fetal membranes (PROM)
• Indicated: can result from induction of preterm labor or from preterm
caesarean delivery for maternal or fetal indication.
Preterm Birth Syndrome: New Phenotypic
Classification
• Classification of PTB from
Global Alliance to Prevent
Prematurity and Stillbirth
(GAPPS)
Mechanisms of Spontaneous Preterm Birth
(Common Pathway)
• Term and PTB share
common pathway
• Increased uterine
contractility, cervical
ripening and
membrane rupture
leading to fetal
prematurity and
damage
Mechanisms of Spontaneous Preterm Birth
(Common Pathway)
• Increase in unbound
corticotropin –releasing
hormone and increase
nuclear factor kappa
B(NF-κB) activity
(associated with
functional progesterone
withdrawal,
prostaglandin production,
and leukocytic influx) are
demonstrated in
association with
parturition
Prostaglandins as Key Activator of the
Common Pathway of Parturition
• Prostaglandins as crucial mediator :
• induce myometrial contractility
• promote proteolysis of cervical and fetal membrane extracellular matrices to cause
cervical ripening and fetal membrane rupture
• Stimulate decidual/membrane activation
• Evidence of a role prostaglandin in parturition:
• Administration of prostaglandin induces termination of pregnancy
• Indomethacin or aspirin therapy delays spontaneous onset of parturition
• Concentrations of prostaglandins in plasma and amniotic fluid increase during labor
• Intra-amniotic injection of prostaglandin precursor induces abortion
• Expression of myometrial prostaglandin receptors increase in labor
• Labor is associated with increased expression of prostaglandin endoperoxide
synthase 2 (PTGS-2) messenger RNA
Prostaglandins as Key Activator of the
Common Pathway of Parturition
• Prostaglandin directly promote uterine contractions by increasing
sarcoplasmic and transmembrane calcium fluxes and through increased
transcription of oxytocin receptor, connexin-43 (gap junctions), and
Prostaglandin E2 (PGE2) receptors.
• Prostaglandin induces synthesis of matrix metalloproteinases (MMPs) by
fetal membrane and cells in uterine cervix to promote membrane rupture
and cervical ripening
• PGE2 and PGF2α increase ratio expression of progesterone receptors (PR)
isoforms PR-A and PR-B to induce functional progesterone withdrawal
• NF-κB activation induces activation of inflammatory genes which may also
induces functional progesterone withdrawal
Inflammation, Stress, and Parturition
• Leukocytic (neutrophil and macrophage) invasion into cervix during
normal parturition
• Increased expression of cell adhesion molecules, chemotactic
agents such as interleukin (IL)-8 and pro inflammatory cytokines
• Normal maturation of fetal HPA-Placental axis induces parturition,
this condition due to stress subsequent to malnutrition, ischemia,
infection, vascular damage, and psychosocial factors
• The 11β-hydroxysteroid dehydrogenase (11β-HSD) regulates
placental transfer of cortisol, which is a glucocorticosteroid with a
key role in the activation of the hypothalamic-pituitary-adrenal
(HPA) axis
Preterm Birth Resulting from Intra-amniotic
Infection
• Intrauterine infection or systemic administration of microbial products to pregnant
women result in spontaneous preterm labor
• Subclinical intrauterine infection are consistently associated with preterm labor
and PTB in humans
• Pregnant women with intra-amniotic infection or intra-amniotic inflammation
(defined as an elevation of amniotic fluid concertation of proinflammatory
cytokines, matrix degrading enzymes, and specific set of antimicrobial peptide) are
increase risk for spontaneous PTB
• Most common microorganisms identified in the fetal membranes and amniotic fluid
of patients with infection-associated PTB are Ureaplasma urealyticum,
Mycoplasma hominis, Gardnerella vaginalis, Streptococcus group B (GBS),
Bacteroides species, and Escherichia coli
Preterm Birth Resulting from Intra-amniotic
Infection
• Most intra-amniotic bacteria are genital tract microorganisms, and the
amniotic fluid is normally sterile, the current paradigm of intrauterine
infection implies that bacteria most often originate from the lower
genital tract and invade the pregnant uterus via an ascending
mechanism
• Mechanical barrier and the complex innate immune barrier of the
cervix are bypassed, microorganisms infect the decidua and penetrate
the fetal membranes to invade the amniotic fluid
Preterm Birth Resulting from Intra-amniotic
Infection
Preterm Birth Resulting from Intra-amniotic
Infection
• Microorganisms frequently implicated in intra-amniotic infection (e.g., GBS,
Mycoplasma, E. coli) are common constituents of the vaginal microbiome and128

cohabitants of the amnio chorionic space

• The presence of Ureaplasma and Mycoplasma in the amniochorion incites
polymorphonuclear tissue infiltration and a higher degree of histologic
chorioamnionitis in pregnancies complicated by PTB
• In vitro, GBS and E. coli have the capacity to attach to the chorioamniotic membranes
• Transcervical and choriodecidual inoculation of GBS is followed by transmigration of
bacteria from the choriodecidual space to the amniotic fluid cavity, a graded amniotic-
fluid leukocyte infiltration response, and levels of proinflammatory cytokines (tumor
necrosis factor-α [TNF-α], IL-6, IL-1β), prostaglandins (PGE 2, PGF2α), and uterine
activity
 Preterm Birth Resulting from Intra-amniotic
Infection
• A secondary route of intra-amniotic infection is probably
hematogenous transplacental seeding of the fetus, with
the infectious organisms, in particular Haemophilus
influenzae or F. nucleatum, originating from other parts
of the body including the mouth
• Retrograde microbial seeding of the amniotic fluid
through the fallopian tubes or colonization of the uterine
endometrium before implantation has also been proposed
• Pathogen-associated molecular patterns (PAMPs) trigger
a downstream molecular chain of events that lead to
synthesis and release of proinflammatory cytokines such
as TNF-α; interferon-γ; cytokines IL-12, IL-6, IL-1β; and
many others via an NF-κB–mediated mechanism
Role of Proinflammatory Agents in Preterm
Birth
• Inflammation and its mediators (e.g., chemokines such as IL-8; proinflammatory
cytokines such as IL-1β and TNF-α; and others, such as platelet activating factor
and prostaglandins) are central to infection-induced PTB
• The role of IL-1β in the pathogenesis of:
• It is synthesized by human decidua in response to bacterial products 1

• It stimulates prostaglandin production by human amnion and decidua 1

• IL-1α and IL-1β concentrations and IL-1-like bioactivity are increased in the amniotic
fluid of women with preterm labor and infection
• Intravenous IL-1β stimulates uterine contractions
• Administration of IL-1 to pregnant animals induces preterm labor and birth, and this
161

effect can be blocked by the administration of its natural antagonist, the IL-1 receptor
antagonist (IL-1ra)
Role of Proinflammatory Agents in Preterm
Birth
• The role of TNF-α in the mechanisms of infection-associated PTB:
• TNF-α stimulates prostaglandin production by amnion, decidua, and myometrium 9

• Human decidua can produce TNF-α in response to bacterial products

• Amniotic fluid TNF-α bioactivity and immunoreactive concentrations are elevated in
women with preterm labor and intra-amniotic infection
• In women with preterm PROM and intra-amniotic infection, TNF-α concentrations are
higher in the presence of labor
16

• TNF-α can stimulate the production of MMPs, which have been implicated in membrane
166,167

rupture
• Application of TNF-α to the cervix induces changes that resemble cervical ripening 1

• TNF-α can induce preterm parturition when administered systemically to pregnant animals
• TNF-α and IL-1β enhance IL-8 expression by decidual cells, and this chemokine is strongly
expressed by term decidual cells in the presence of chorioamnionitis
Stretch and Parturition
• Progesterone receptor transcriptional activity has been proposed as
critical for the preservation of myometrial relaxation
• Mechanical stretch, however, upregulates expression of connexin-43,
an effect that is inhibited by progesterone
• The connexin-43 gene encodes a protein with critical roles in
synchronizing myometrial contractile activity
• Oxytocin receptor gene controls responsiveness of myometrial cells to
oxytocin
Stretch and Parturition
Activation of Maternal-Fetal HPA Axis in
Term and Preterm Birth
• Glucocorticoid hormone cortisol displays an inhibitory effect on the
hypothalamic CRH production
• Cortisol stimulates the placental production of CRH
• CRH feature of the placenta, causing progressive increases in placental
CRH production as pregnancy advances to term
• Exponential rise in maternal plasma CRH concentration is associated
with a concomitant fall in levels of CRH binding protein, leading to a
rapid increase in maternal circulating levels of bioavailable CRH
Activation of Maternal-Fetal HPA Axis in
Term and Preterm Birth
Mechanism of common pathway of labor by
CRH
• The output of PGF2α and PGE2 production and synthesis is
stimulated by CRH in amniotic, chorionic, decidual, and placental
cells
• Cortisol synthesized in response to CRH can increase amnion COX-2
expression while inhibiting chorionic PGDH expression
• CRH-induced PGE2, and PGF2α increase the expression of the PR-A
isoform and decrease that of the PR-B isoform in myometrium, cervix,
and decidua
• There is evidence for a myometrial relaxing effect of CRH, favoring
uterine quiescence
Mechanism of common pathway of labor by
CRH
• Placental-derived CRH stimulates the release of fetal pituitary adrenocorticotropin to enhance
fetal adrenal cortisol production, which further stimulates placental CRH release
• cortisol released into the amniotic fluid can directly stimulate fetal membrane prostaglandin
production by increasing amniotic COX-2 expression and inhibiting the chorionic
prostaglandin-metabolizing enzyme PGDH
• Placental CRH stimulates the fetal adrenal zone, an adrenal structure unique to primates, to
produce dehydroepiandrosterone sulfate (DHEAS), which is converted to estrogen by the
placenta
• Placental sulfatases facilitate conversion of fetal adrenal gland DHEAS to estradiol, estrone,
and estriol
• reductions in PR-B expression lead to increased expression of the estrogen receptor-β (ER-β),
placental estrogen production would act synergistically to prostaglandin-induced increases in
myometrial ER-β expression
Progesterone Withdrawal and Parturition
• Parturition is associated with changes in the relative proportions of the
nuclear PR-A and PR-B, through which progesterone is thought to
exert the bulk of its actions
• PR-A is thought to act as an endogenous repressor of PR-B, with an
increase in the ratio of myometrial PR-A to PR-B, which decreases the
response of the uterus to the relaxant effect of progesterone
Spontaneous Preterm Parturition as a
Syndrome
Phenotype of spontaneous preterm based on:
• Significant maternal conditions (e.g., extrauterine infection, clinical
chorioamnionitis, maternal trauma, worsening maternal disease, uterine
rupture, preeclampsia/eclampsia), significant fetal conditions (e.g.,
fetal demise, IUGR, abnormal fetal heart rate or biophysical profile,
infection or fetal inflammatory response syndrome, fetal anomaly,
alloimmune fetal anemia, polyhydramnios, multiple fetuses), and
pathologic placental conditions (e.g., histologic chorioamnionitis,
placental abruption, placenta previa);
• The presence or absence of signs of initiation of parturition
• Whether the pathway to delivery is caregiver initiated or spontaneous
Myometrial Contractility
• During labor, individual myocytes contract together as a functional
syncytium induced by gap junction formation, which increases cell-to-cell
communication
• Expression of gap junction protein, connexin-43, in human myometrium is
similar in both term and preterm labor
• Distinct stages of gestational myometrial development
• Proliferative, in which the number of myocytes increased, as demonstrated by greater levels of cell nuclear
antigen labeling and protein expression in early pregnancy
• Synthetic, in which the myometrial cells underwent hypertrophy, as demonstrated by a higher protein-to-DNA
ratio in the second half of pregnancy.
• Contractile, which occurred at the end of pregnancy and coincided with low myometrial expression of
interstitial matrix proteins and high expression of components of the basement membrane (laminin and
collagen IV).
Cervical Adaptation and Remodeling During
Preterm Birth
• IL-8, MMPs, prostaglandins, and nitric oxide have been implicated in
the control of cervical ripening
• These be synthesized in response to amniochorion stretch and may
exercise part of their biologic effects in parturition by degradation of
the cervical extracellular matrix
Decidual Activation and Bleeding
Preterm Premature Rupture of Membrane
• The mechanisms responsible for degradation of the extracellular
matrix are tightly regulated by several MMPs (MMP-1, 2, 3, and 9)
and TIMP-1 and TIMP-2
• decidual infiltrate of neutrophils, which are a rich source of the
extracellular matrix–degrading proteases elastase and MMPs, are
associated with abruption-induced pPROM
• Activation of MMPs and other proteases may occur dependent on or
independent of inflammation and infection
• Significant decrease in the amount of collagen type I, III, or V has
been reported in the zone of altered morphology
Phenotypic Components of the Preterm Birth
Syndrome
• Maternal Condition • Fetal Condition
• Extrauterine Infection • Intrauterine Fetal Demise
• Clinical Chorioamnionitis • Intrauterine Growth Restrictions
• Maternal Trauma and Uterine • Abnormal Fetal Heart Rate or Biophysical
Profile
Rupture • Infection and Fetal Inflammatory Response
• Worsening Maternal Disease, Syndrome
Including Preeclampsia • Fetal Anomaly
• Placental Pathologic
• Maternal Stress Condition
and Anxiety • Polyhydramnios
• Histologic Chorioamnionitis • Multiple Pregnancies
• Cervical Disorder
• Placenta Previa
• Placenta Abruption
Extrauterine Infection
• Maternal infections with human immunodeficiency virus (HIV) and
malaria are important contributors to PTB
• The mechanisms of the increase in preterm labor associated with HIV
infection and with HAART are unknown
• Malarial infection increases the risk for both stillbirth and PTB,
probably by a combination of mechanisms:
• placental dysfunction
• anemia,
• maternal sepsis
Clinical Chorioamnionitis
• Clinical chorioamnionitis is defined as “clinically suspected
intrauterine infection, manifest by maternal fever and rupture of the
membranes plus two features from maternal tachycardia, uterine
tenderness, purulent amniotic fluid, fetal tachycardia and maternal
leukocytosis
Maternal Trauma and Uterine Rupture
• Trauma is so severe that immediate PTB occurs either as a result of
maternal injury, or as a result of fetal or maternal death, or to facilitate
maternal resuscitation
• Important contributions to PTB include treatment for preinvasive
cervical carcinoma
• Previous cesarean delivery, which leads to an increased risk for
stillbirth in the subsequent pregnancy after around 34 weeks gestation
Maternal Stress and Anxiety
Cervical Disorder
• Cervical insufficiency may be the result of
• Congenital disorder : hypoplastic cervix or diethylstilbestrol exposure in utero
• Surgical trauma : conization resulting in substantial loss of connective tissue
• Traumatic damage of the structural integrity of the cervix : by repeated
cervical dilation)
Intrauterine Fetal Demise
• Major risk factors for stillbirth are:
• Uteroplacental vascular insufficiency
• Abruption
• Smoking
• Maternal medical conditions (e.g., lupus, chronic hypertension, antiphospholipid syndrome, thyroid
disease, cholestasis, thrombophilia
• African-American race
• Maternal nutritional deficiencies
• Obesity
• Congenital and aneuploidy
• Preeclampsia
• Infections (e.g., parvovirus, cytomegalovirus, syphilis, malaria, Listeria monocytogenes)
• Chorioamnionitis
• Multiple gestations,
• Umbilical cord complications
Intrauterine Growth Restrictions
• American College of Obstetricians and Gynecologists favors a
sonographic estimated fetal weight of less than the 10th percentile for
IUGR
• IUGR is often related to placental abnormalities, including partial
abruptions, previa, infarcts, and hematomas. Placental lesions were
infarction, chronic villitis, haemorrhagic endovasculitis, and placental
vascular thromboses
Infection and the Fetal Inflammatory
Response Syndrome
• FIRS was defined as a fetal plasma concentration of IL-6 greater than
11 pg/mL
• Fetal stress, as manifested by a fetal plasma ratio of cortisol to
DHEAS, congenital fetal dermatitis, fetal cardiac dysfunction,
involution of the thymus, and abnormalities of the fetal lung and brain
,
Reference
Buhimschi CS, Norman JE. Pathogenesis of Spontaneous Preterm Birth.
In: R.K. Creasy, R. Resnik, J.D. Iams, C.J. Lockwood, T.R. Moore, M.
Greene, editors. Creasy & Resnik's Maternal‐Fetal Medicine: Principles
and Practice, 7th ed. Philadelphia: Elsevier Saunders. 2014:599;623