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Physiological & Biochemical Process regulating Parturition. Physiological process in human pregnancy that result in initiation of parturition & onset of labor : poorly defined Retreat from pregnancy maintenance & uterotonin induction of parturition hypotheses

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physiological biochemical process regulating parturition
Physiological & Biochemical Process regulating Parturition
  • Physiological process in human pregnancy that result in initiation of parturition & onset of labor : poorly defined
  • Retreat from pregnancy maintenance & uterotonin induction of parturition hypotheses
  • Mature human fetus : source of initial signal for commencement parturitional process
  • One or more uterotonins: initiation of human parturition ( myometrial R. elevation)
anatomical physiological consideration of myometrium
Anatomical & physiological consideration of myometrium
  • Characteristics – advantage in efficiency of uterine

contractions & delivery of fetus

① degree of shortening of smooth m cells with

contraction

: magnitude greater than in striated m cells

② forces can be exerted in smooth m cells in

any direction

③ not organized in same manner as skeletal m

- thick & thin filaments in long, random bundles

→ greater shortening & force-generating capacity

④ multidirectional force generation

regulation of myometrial contraction relaxation4
Regulation of myometrial contraction & Relaxation
  • Interaction of myosin & actin  activation of adenosine triphosphatase ATP hydrolysis force generation (by enzymatic phosphorylation of MLC)
  • Ca bind to calmodulin  activate myosin light chain kinase increase in intracellular Ca2+ (transient)
  • Contraction prolonged inhibition of myosin phosphatase activity by Rho kinase
  • Uterine activity regulation of contraction –associated protein (CAP) : include channels associaeted with smooth m excitation & contraction , gap junction component, uterotonic stimulatory or inhibitory R
slide5

1] Myometrial Gap junctions

  • Cellular signals transferred between cells through intercellular junctional channels
  • Communication is extabilished between myometrial cells by gap junctions that facilitate passage of electrical or ionic coupling current as well as metabolite coupling
    • Consist of two protein ”hemi-channels “ termed connexons hexameric assemblage of type of protein called connexin
    • Conduit for exchange of small molecule
    • Gap junctions optimal No : electrical synchrony in myometrium , coordination of contraction (  greater force during labor)
slide6

2] Cell surface R as regulator of

myometrium

  • Estrogen & progesteron R, variety of cell surface R that can directly regulate contractile state of cell
  • Most of heptahelical R in myometrium
    • Activation of adenylycyclase
    • G-protein-medicated activation of phospholipase C

 [Ca2+]) ↑& myometial cell contraction ↑

  • In high concentration: from maternal blood (endocrine), contiguous tissues or adjacent cells (paracrine) or direct synthesis in myometrial smooth m cell (autocrine) [Fig 6-16]
slide8

2] Cell surface R as regulator of

myometrium

  • Myometrial response to H. can change during course of pregnancy
  • Imposition of quiescence (activation of adenylyl cyclase) or facilitation of contraction ( activation of phospholipase C & increased [Ca+])
a fail safe system that maintains ut quiescence
A Fail-Safe system that maintains Ut quiescence
  • Multiple process act independently & cooperatively to estabilish ut quiescence
  • To sustain Ut quiescence of phase 0 : biomolecular systems ( neural, endocrine, paracrine, and autocrine )
a fail safe system that maintains ut quiescence10
A Fail-Safe system that maintains Ut quiescence
  • Phase 0 of parturition & its quiescent state factor
  • Actions of estrogen & progesterone via intracellular R
  • Myometrial cell plasma membrane R –mediated increase in cAMP
  • Generation of cGMP
  • Other systems, including modifications in myometrial cell ion channels
progesterone estrogen contributions to phase 0 of parturition
Progesterone & Estrogen contributions to Phase 0 of parturition
  • Maintains Phase 0 of human parturition
  • Removal of Progesterone ( Progesterone withdrawal) : progression of phase 0 into phase 1 of parturition
  • Progesteron action:
    • Successful maintenance of preg
    • Biomolecular evidence or role of other agents not defined
    • Maintain Phase 0 of human parturition
  • Estrogen action :
    • Promote progesteron responsiveness  Ut quiescence
    • In responsive tissues, Estrogen R. induces Progesteron R synthesis
steroid h regulation of myometrial cell to cell communication
Steroid H Regulation of myometrial Cell-to-Cell communication
  • Progesteron
  • Decrease expression of contraction associated proteins
  • CAP grouping : smooth m excitation contraction, gap junction components uterotonic stimulatory R
  • Inhibit expression of gap junctional protein connexin 43
  • Progesterone antagonist: premature development of gap junction preterm labor & delivery
  • Connexin 43 mRNA in human myometrial tissue increase before labor between 37 ~40 wks.
  • Gap junction in myometrium increase
  • But expression of connexin 43 protein not increase during gestation or at labor  ? in intracellular regulator of actual gap junction assembly at time of labor
heptahelical r that promote myometrial relaxation
Heptahelical R that promote myometrial relaxation
  • Multiple process act independently & cooperatively to estabilish ut quiescence
  • Associated with Gas-mediated activation of adenyly cyclase & increased level of cAMP in myometrium
  • Part of fail-safe system to maintain Ut quiescence of phase 0 of parturition
b adrenoreceptors
B-adrenoreceptors
  • B-adrenoreceptors mediate Gas- stimulated increase in adenylyl cyclase  increased level of cAMP

 myometrial cell relaxation

  • Exact role of catecholamines in maintaining ut quiescence : ill defined
luteinizing h lh chorionic gonadotropin hcg
Luteinizing H (LH) & chorionic gonadotropin(hCG)
  • LH & hCG R in myometrium during preg greater before than during labor
  • Chorionic gonadotropin(hCG) activate adenylyl cyclase by plasma memb R Gas-linked system
  •  decrease in contraction frequency & force & tissue-specific myometrial cell gap junctions
relaxin
Relaxin
  • Peptide H member of insulin like growth factor family of proteins, A & B chain
  • Secretion from corpus luteum
  • Greates & peak at 1ng/ml 8wks ~12wks.
  • Thereafter decline to lower lever until term
  • Activation of adenylyl cyclase & promotes myometrial realxation, effect cervical softening
corticotropin releasing h crh
Corticotropin–Releasing H(CRH)
  • Myltiple isoforms their affinity & coupling modified late in preg
  • Sythesized in PL,amnion,decidua,myometrium
  • Increase final 6~8wks of preg
  • Signal through cAMP or Calcium
  • Relaxation or contraction of myometrial cell depending on R isoform present
  • CRH role of uterorelaxant during phase 0 & uterotonin in phases 1 & 2 of parturition
parathyroid h related protein pth rp
Parathyroid H–related protein (PTH-rP)
  • Initiate Gas-medated activation of adenylyl cyclase
  • Expressd in myometrium,amnion,decidua & trophoblast
  • PTH-rP expression in smooth m icreased by m stretch
  • Function : not established,serve to maximize ut blood flow durng myometrial contraction by vasorelaxant action
  • Facilitate maintenance of Ut tranquility
prostaglandins
Prostaglandins
  • Interact with family of 8 different heptahelical R
  • PG : uterotonins,prostanoid sometimes can act as smooth m relaxant
  • Individual prostanoid : diverse effect
prostaglandins22
Prostaglandins
  • By action of phospholipase A2 or C
  • Arachidonic acid act as substrate of type 1 & type 2 PG synthase (PGHS-1 & -2) called COX –1 & –2
  • Both convert Arachidonic acid to unstable endoperoxide PG G2 and then to PGH2target of many NSAIDs & act as tocolytics to prevent preterm labor
  • PGH2 convert to active PG (PGE2,PGF2 & PGI2)
  • PGDH Expression :regulate in Ut rapidly incactivate PG metabolites
prostaglandins23
Prostaglandins
  • PG family of R classifed according to specificity of binding of given R to particular PG
  • DP(PGD2) & IP (prostacyclin or PGI2) : increase intracellular cAMP
  • FP R (PGF2a) : increase intracellular Ca
  • EP2 & EP4 (PGE2): activate cAMP production
  • PGE2 PGI2 : maintain Ut quiescence by increasing cAMP signaling
  • PGE2,PGD2,PGI2 : relaxation of vascular smooth m & vasodilation
prostaglandins24
Prostaglandins
  • Either generation of specific PG or relative expression of various PG R  determine responses of human myometrium
  • Change with gestation (32~35 wks vs 39~40wks .)
  • Regional change in upper & lower ut segment
  • Prostanoid : myometrial relaxation at one stage of preg & regional myometrial contraction after initiation of parturition (in fundus)
atrial brain natriuretic peptides cyclic guanosine monophosphate cgmp
Atrial & Brain natriuretic peptides & cyclic guanosine monophosphate(cGMP)
  • Guanylyl cyclase activation increase intracellular level of cGMP promote smooth m relaxation
  • ANP & BNP stimulate intracellular level of cGMP↑
  • BNP secreated by amnion,ANP expressed in PL
  • Soluble form Guanylyl cyclase activated by nitric oxide penetrate pl membrane to enter cell
  • NO react with iron in Guanylyl cyclase enzyme stimulate to produce cGMP act myometrial relaxation
accelerated uterotonin degradation phase 0 of parturition
Accelerated Uterotonin degradation & Phase 0 of parturition
  • To stimulate myometrial cell refractoriness, Activity of enzyme↑: degrade or inactivate endogenoulsy produced uterotonins
  • Uterotonins (degredative enz) PG(PGDH), endothelin (enkephalinase), oxytocin (oxytocinase), histamine (diamine oxidase), catecholamines(catechol O-methlytransferase), angiotensin-II (angiotensinase), PAF(PAF –acetylhydrolase)
  • These enzyme increase by Progesteron action & decrease late in gestation
fail safe system for ut activation
Fail-safe system for Ut activation
  • Phase 1 of parturition: morphological & functional change in myometrium & Cx that prepare Ut for labor
  • Development of uterotonin sensitivity, improved intercellular communicability via gap junctions
  • Alteration incapacity of myometrial cell to regulate concentration of cytoplasmic Ca2+
  • The process leading to enhance uterine responsiveness  activation (by Chalis & associates (2000))
  • As fuctional contractile capacity of myometrium & Cx ripened, phase1 merge into phase 2
  • Alteration in timing of these process cause preterm & delayed labor
classical progesteron withdrawal not cause human parturition
Classical Progesteron withdrawal not cause human parturition
  • In many species, plasma progesterone level decrease
  •  Activation of Ut in preparation for labor
  • Associated with increase in estrogen level in several species
  • In primate, plasma progesteron level not decrease before labor, only after delivery of PL decline
  • Nonetheless, morphological & fuctional modification that prepare Ut for labor occur in timely manner in human
classical progesteron withdrawal not cause human parturition31
Classical Progesteron withdrawal not cause human parturition
  • In species, Progesteron withdrawal can be blocked by administering Progesteron to mother
  • Conflicting reports whether or not Progesteron delay timely onset of parturition or prevent preterm labor
  • Majority of studies Progesteron cannot prevent preterm labor not appear to extend labor in control group
  • Progesteron metabolite, 17-hydroxy progesteron (less potent than Progesteron ):minimally decreased incidence of preterm labor in high –risk group
  •  additional research need
progesteron r antagonist human parturition
Progesteron R Antagonist & human parturition
  • RU 486, mifepristone: less effective in inducing abortion or labor in later preg , effective in ripening Cx & increase myometrium sensitivity to uterotonins

(Chwalisz & Garfield,1994)

  • Decreased circulating progesterone by inhibitioning enzyme 3B-hydroxysteroid degydrogenase induced labor
  • Inhibition of progesterone action: important for activation phase of parturition
  • But there is : ‘hidden’ or unique form of fuctional progesteron withdrawal that end ut quiescence
fuctional progesteron withdrawal in human parturition
Fuctional Progesteron withdrawal in human parturition
  • Unique mechanisms to inhibit progesterone action in human
  • Late gestational decrease in activity of progesteron R expression that cause fuctional withdrawal
  • Changes in relative expression of progesterone R or of its two isoforms
    • shift in relative ratio of PR-A to PR-B(active isoform) within myometrium
  • Activity of Progesteron R for gene transcription in late gestation
    • coactivator ↓
    • co-repressor ↑
oxytocin r
Oxytocin R
  • Oxytocin R : increase in myometrium during phase 1 of parturition
  • Progesterone & estradiol :primary regulator of Oxytocin R expression
  • Estradiol increase in myometrial Oxytocin R
  • Progesterone increase in myometrial Oxytocin R degradation

 inhibit oxytocin R activation at cell surface

 maintain Ut quiescence through inhibition of myometrial oxytocin response

fetal contributions to initiation of parturition
Fetal contributions to initiation of parturition
  • After growth & maturation of vital organs, fetus provide initial signal that set parturitional process
  • Via fetal brain, pituitary gl. adrenal gl. Fetal blood to placenta
  • Unlikely initial signal for phase 1 of parturition is uterotonin
  • But Ut first must be prepared for labor before uterotonin optimally effective
role of ut strecth in parturition
Role of Ut strecth in parturition
  • In association with fetal growth, significant increase in myometrial tensile stress & amnionic fluid pressure
  • Studies in rat models, strecth was required for normal induction of specific contraction-associated pretein(CAPs)
  • Stretch expression of gap junction protein↑,connexin 43 & oxytocin R
  • Twin preg & hydramnios(Uterine stretch occur): at much greater risk of preterm labor
role of ut strecth in parturition37
Role of Ut strecth in parturition
  • Cell signaling systems used by stretch to regulate myometrial cell: mechanotransduction
    • Activation of cell surface R or ion channels
    • signaling through extracellular matrix
    • through release of autocrine molecule that act directly on myometrial cell
fetal endocrine cascades leading to parturition
Fetal endocrine Cascades Leading to parturition
  • Placental-Pituitary –adrenal axis role in timing of human parturition
  • Activation of human fetal hypothalamic-Pituitary –adrenal axis :critical component of normal parturition
  • Steroid product of fetal adrenal gl : effect on placenta & memb : promote

myometrium quiescent ---> contractile state

  • Key component: CRH (corticotropin-releasing H)
action of crh on fetal adrenal gland
Action of CRH on fetal adrenal Gland
  • Weigh same & similar size in adult
  • Daily production of steroid 100~200 mg/day
  • Steroidogenic fuction different from adult
    • Fetal cortisol level increase during last wks of gestation
  • Increased DHEA-S production  increase in maternal estrogens (estriol)
  • Increase in adrenal activity in contrast fetal adrenocorticotropic H (ACTH) do not increase until stress of actual labor
    • ACTH levels do not increase during last gestation
    • Growth and differentiation of fetal adrenal gland influenced by factors secreted by placenta
    • Fetal zone of adrenal gland : rapid involution immediately after birth when placenta derived factors no longer available
action of crh on fetal adrenal gland40
Action of CRH on fetal adrenal Gland
  • CRH of placental origin : one of critical component that facilitate fetal adrenal hypertrophy & increase steroidogenesis late in gestation.
  • Ability of CRH to regulate adrenal gland & of adrenal to regulate placental production of CRH feed-forward endocrine cascade late in gestation
placental crh production
Placental CRH production
  • Unlike hypothalamic CRH, cortisol stimulate placental CRH feed-forward endocrine cascade until separation of fetus from placenta at delivery
  • Rise in CRH as well as fetal adrenal steroidogenesis in late gestation
  • Maternal plasma CRH low in first trimester, rising from midgestation to term
  • In last 12 wks, CRH level rise exponentially, peaking during labor then falling after delivery
  • Amnionic fluid levels of CRH increase in late gestation
placental crh production43
Placental CRH production
  • Late pregnancy: CRH-BP level in both maternal plasma & Amnionic fluid decline
  • CRH level increasing
  •  bioavailable CRH level increasing
  • Various Complications, CRH concentration in fetal plasma & amnionic fluid,maternal plasma increasing over normal gestation
  • PL source for stress-associated increase in CRH  fetal adrenal cortisol synthesis
  • Supranormal level of umbilical cord blood cortisol: occurred in stressed neonates
potential roles of crh in timing of parturition
Potential Roles of CRH in timing of parturition
  • Roles of PL CRH in regulation of parturition

1.Enhance fetal cortisol production((+) feedback on PL produce more CRH)

    • Modulate myometrial contractility

2.Cortisol affect myometrium indirectly by stimulating membranes to increase PG synthesis

3.CRH stimulate featal adrenal C19-steroid synthesis, increased substrate for PL aromatization

    • Elevation in estrogens shift estrogen-to-progesterone ratio  promote expression of contractile protein in myometrium
fetal anomalies delayed parturtion
Fetal anomalies & delayed parturtion
  • Hypoestrogenism : prolonged gestation
  • Fetal anencephaly, adrenal hypoplasia, placental sulfatase deficiency
  • Fetal anencephaly : prolong human gestation (anomalous brain-pituitary-adrenal fuction)
  • Fetal adrenal gland hypoplasia :onset of labor delayed
  • Fetal adrenal gland important for timely onset of parturtion
fail safe system for success of phase 2 of parturition
Fail-safe system for Success of phase 2 of Parturition
  • Phase 2 of Parturition :Ut contraction that bring progressive cervical dilatation & delivery
  • Formation of uterotonins most likely cause of initiation of labor
    • Oxytocin,PG,serotonin,histamine,PAF, angiotensin II
  • Activate Gzi or Gaq-mediated processes  increase myometrial cell [Ca2+]
  • Stimulate smooth m contraction through such G-protein coupling
oxytocin phase 2 of parturition
Oxytocin & Phase 2 of Parturition
  • During phase 1 of Parturition :50-fold or more increase in No of myometrial Oxytocin R
  • Uterine contractile responsiveness to Oxytocin increase
  • Nanopeptide synthesized in magnocellular neurons of supraoptic & paraventricular neurons
  • Oxytocin proH transport Carrier protein (neurophysin), along axons to neural lobe of post pituitary gl in membrane bound vesicles for storage and later release
  • Oxytocin proH converted enzymatically to oxytocin during transport
  • Oxytocin not cause initiation of parturition but one of several participants in effectiveness of active labor
  • Oxytocin act by way of heptahelical R, activate phospholipase
role of oxytocin in phase 2 phase 3 of parturition
Role of Oxytocin in Phase 2 & Phase 3 of Parturition
  • Striking increase in No of Oxytocin R in myometrial & decidual tissues near end of gestation
  • Oxytocin act on decidual tissue to promote PG release
  • Oxytocin synthesized directly in decidual & extraembryonic fetal tissues & in placenta
  • Evidence in support of important role for Oxytocin during 2nd stage labor & puerperium
  • Oxytocin level increase
    • (1) during 2nd stage labor (end of phase 2 of parturition)
    • (2) In early postpartum period
    • (3) Breast feeding (phase 3 of parturition)
role of oxytocin in phase 2 phase 3 of parturition50
Role of Oxytocin in Phase 2 & Phase 3 of Parturition
  • This timming of increased Oxytocin release : role for Oxytocin at end of labor & during puerperium
  • After completion of Ut phase 2,persistent contraction =>prevent postpartum hemorrhage
  • Oxytocin infusion in women promote increased level of mRNA in myometrium of genes that encode proteins essential for Ut involution
  • Oxytocin action at end of labor & during phase 3 of parturition : Ut involution
pg phase2 of parturition
PG&Phase2 of Parturition
  • PGF2a PGE2 : involved in Phase 2 of Parturition, process of labor
  • 1.Level of PG in amnionic fluid, maternal plasma & maternal urine increased during labor(Keirse,1979)
  • 2.Tx of PG :cause abortion or labor at all stage gestation (Novy & Liggins,1980)
  • 3.PGH synthase type 2(PGHS-2) inhibitor delay time of onset of spontaneous labor & sometimes arrest preterm labor
  • 4.PG Tx of myometrial smooth m in vitro cause contraction
  • PG: effectiveness of myometrial contractions of active labor once labor is initiated
ut events regulating pg production
Ut events regulating PG production
  • Result of an inflammatory response that signal event leading to active labor
  • Lowermost pole of fetal membranes structurally modified in formation of forebag of amnionic sac
  • Before labor, fetal membranes cotiguous with & attached to ut decidua vera :thin & poorly developed
  • As lower pole of amnionic sac pulled away from wall of Ut, fragment of decidua parietalis torn away but remain attached rather firmly to outer surface of chorion laeve
slide53
Fig 6-20] Sagittal view of exposed forebag & attached decidual fragment after Cx dilatation during labor
ut events regulating pg production54
Ut events regulating PG production
  • As Cx opend,forebag presents through Cx in upper vagina
  • Surface area of exposed forebag increases as cervical dilatation progresses during phase 2 of parturition
  • Traumatized, devascularized decidual tissue fragmnets that torn away from Ut : form irregular lining on outer surface of forebag, present in vagina
  • Forebag tissues bathed continoulsy by vaginal fluid, contain large number&variety ofmicroorganism,bacterial toxins in large amount & PG & cytokines
ut events regulating pg production55
Ut events regulating PG production
  • Taruma to decidual tissues in formation of forebag
  • Devascularization of decidual fragments that pulled away from Ut
  • Action of vaginal fluid, inflammatory response in decidual fragment of forebag
  • During labor, level of cytokine in forebag much greater than in upper compartment of amnionic sac
  • Cytokine produced in forebag : enhance level of PG prouduce by amnion
  •  higer level of PG in forebag
fig 6 22 pg recoverd from vaginal fluid before during labor pge 2 pgf 2 a pgfm
Fig 6-22]PG recoverd from vaginal fluid before & during labor PGE2,PGF2a .PGFM

PG synthesized in forebag tissues, released into vagina

ut events regulating pg production58
Ut events regulating PG production
  • Inflammatory mediators facilitate cervical dilatation & alteration to lower uterine segment
  • Cytokine & chemokine
    • further extracellular matrix degradation
    • increase level of hyaluronic acid
    • cause influx of leukocyte into area
  • Cytokine & PG degrade extracellular matrix  weakening fetal membrane

 rapid change in Cx

platelet acitvating factor paf
Platelet-Acitvating Factor(PAF)
  • Heptahelical family of transmembrane R & act to increase myometrial cell calcium promte Ut contraction
  • When cervical dilatation  exposure of traumatized forebag tissues to vaginal fluids  inflammatory process

 PAF produced in leukocytes

  • PAF –acetylhydrolase present and possesses high specific activity in macrophage (in large number of decidua)
  • Myometrium may be protected from PAF action by PAF –acetylhydrolase
endothelin 1
Endothelin-1
  • Endothelin A R in smooth m cell increase in intracellular calcium by linkage to both Gaq- G ai- subunit of G proteins
  • Endothelin-1 produced in myometrium
  • Endothelin-1 also synthesized in amnion
  • Transported to myometrium without degradation
angiotensinii
AngiotensinII
  • AT2: nonpregnant women
  • AT1: pregnant women
  • During pregnancy,vascular smooth m ,express AT2R is refractory to pressor effect of angiotensin II
  • In myometrium near term,angiotensin II another component of uterotonin system,acting to promote increased myometrial cell calcium
crh hcg pth rp
CRH,hCG,PTH-rP
  • Switch from cAMP formation to increased myometrial cell calcium
  • Oxytocin : attenuate CRH-stimulated accumulation of cAMP in myometrial tissue
  • CRH : augment contraction –inducing potency of oxytocin
  • CRH : increase myometrial contractile force in response to PGF2a
contribution of intrauterine tissues to parturition
Contribution of intrauterine tissues to parturition
  • Membrane, decidua important tissue shell around fetus that serves as physical immunological metabolic shield that protect against untimely initiation of parturition
  • Late in gestation fetal membrane change & act to prepare for labor
amnion
Amnion
  • Tensile strength of membranes, resistance to tearing and rupture
  • Resistant to penetration by leukocytes, microorganism, neoplastic cell from maternal compartment
  • Selective filter to prevent fetal particulate-bound lung and skin secretions from reaching maternal compartment
  • Maternal tissues protected from constituents in amnionic fluid that adversely affect decidual or myometrial function
amnion65
Amnion
  • Several bioactive peptides & PG which cause myometrial relaxation or contraction, are synthesized in amnion
  • Increase in amnion PG biosynthetic capability late in gestation
  • Amnion increase its activity for phospholipase A2 & PGHS-2 late in gestation
chorion laeve
Chorion laeve
  • Protective tissue, providing immunological acceptance
  • Enriched with enzyme inactivate uterotonin such as PG dehydrogenase,oxytocinase
  • During most of gestation, PG produced by amnion  release into amnionic fluid or metabolized by adjacent chorion
  • Exact role of fetal membrane derived peptide or PG in initiation of parturition : under debate
  • Important for process of labor & in involution (phase 2 & 3)
decidua parietalis
Decidua parietalis
  • Central question : Whether decidual activation preced or follow onset of labor
  • Process of decidual activation :localized to exposed decidual fragment lining forebag
  • Trauma,hypoxia, exposure of forebag decidua to endotoxin lipopolysaccharide,microorganism,IL-1B in vaginal fluid provoke inflammatory reaction

 series of cytokine increase production utertonins (principally PG) or act directly in myometrium to cause contraction

regulation of phase 2 of parturition summary
Regulation of phase 2 of parturition:Summary
  • Multiple process contribute to success of phase 2(active labor)
  • Variety of myometrial heptahelical R :promote Ut quiescence
  • But another group inhibit cAMP formation or activate phospholipase C or A2 or both
  • Source of regulatory ligand for teses R varies from endocrine H such as oxytocin to locally produced PG
physiology biochemistry of preterm labor
Physiology & Biochemistry of preterm labor
  • Conditions lead to preterm delivery
  • Complications of pregnancy that jeopardize fetal health& sometimes maternal heath mandate preterm delivery : 25%
  • Preterm premature rupture of fetal membranes (PPROM) ,followed by preterm delivery: 25%
  • Spontaneous preterm labor with intact fetal membrane : 50%
  • Cx of preg threaten fetal health
    • Maternal HTN, severe DM,failure of fetal growth, multiple preg, abrutio placenta
preterm premature rupture of fetal membranes pprom
Preterm premature rupture of fetal membranes (PPROM)
  • Spontaneous rupture of fetal membranes that occur before 37 wks complete weeks before onset of labor
  • Major predisposing cause : intrauterine infection.
  • Pathogenesis of PPROM : increased apoptosis of cellular components of fetal membrane as well as elevation in specific proteases in membrane & amnionic fluid
  • Much of tensile strength of fetal membranes provided by extracellular matrix within amnion
  • Interstitial amnionic collagen(type I, III) produced in mesenchymal cell : structual component most important for its strength
preterm premature rupture of fetal membranes pprom72
Preterm premature rupture of fetal membranes (PPROM)
  • 1.Degradation of collagen
  • Matrix metalloproteinase (MMP) family of proteinase: normal tissue remodeling & particularly degradation of collagen
  • MMP-2,MMP-3,MMP-9 members found in higher concentraion in amnionic fluid in PPROM
  • Activity of MMP regulated by tissue inhibitor of matrix metalloproteinase(TIMP)
  • In lower concentraion in amnionic fluid in PPROM
  • Elevation of MMP at time when protease inhibitor expression drop
  •  Alter tensile strength of amnion
  •  Increase incidence of PPROM
preterm premature rupture of fetal membranes pprom73
Preterm premature rupture of fetal membranes (PPROM)
  • 2.Higher degree of cell death
  • Markers of apoptosis increased in membrane with PPROM compared with normal term membranes
  • Activation of collagen breakdown & cell deathweakening amnion
  • Survey of 18 independent studies (1979~2000) of 1462 women with PPROM (+) culture of amnionic fluid in PPROM : 1/3
preterm premature rupture of fetal membranes pprom74
Preterm premature rupture of fetal membranes (PPROM)
  • Studies performed to address prophylatic antimicrobial Tx to prevent PPROM
  • Evidence early Tx of some asymptomatic lower genital tract infection, active periodontal inflammation reduce incidence of PPROM & preterm birth (conflicting study)
  • Current research being focused on certain mediators of this process that accumulate in amnionic fluid & may provide early markers for women at risk for PPROM
spontaneous preterm labor
Spontaneous preterm labor
  • More common cause
    • multifetal pregnancy
    • bleeding
    • intrauterine infection
    • placental infarction
    • premature cervical dilatation
    • cervical incompetence
    • uterine fundal abnormalities
    • fetal anomalies
  • Maternal illness ( nonobstetrical infection)
    • Autoimmune disease
    • Gestational hypertension
spontaneous preterm labor76
Spontaneous preterm labor
  • Actual process of preterm labor final step : result from premature uterine activation that initiate weeks before onset of labor
  • Result from premature initiation of phase 1 of parturition
  • (Cervical ripening & myometrial activation)
  • Major cause of spontaneous preterm labor : uterine distention, maternal-fertal stress, infection
uterine distention
Uterine distention
  • Ut stretch play important role in normal process of myometrial activation in prepartion for labor
  • Multifetal gestation or hydramnios.
  • Early uteirne distention initiate expression of contraction-associated protein(CAP) in myometrium
  • CAP gene influenced by strecth, coding for gap junction protein(such as connexin 43) for oxytocin R & for PG synthase
  • Excessive uterine strecth :premature loss of myometrial quiescence
uterine distention78
Uterine distention
  • Exhibit early activation of placental-fetal endocrine cascade
  • Early rise in maternal CRH & estrogen level, further enhance expression of myometrial of myometrial CAP genes
  • Cervical length : important risk factor in multifetal pregnancies
  • Uterine stretch & endocrine activity in multifetal gestation initiate sequence of event  shift in timming of uterine activation, including premature cervical ripening
maternal fetal stress
Maternal-fetal stress
  • Complexities of measuring stress and other moderating psychosocial factor that lead to stress contribute to difficulty of defining its exact role in preterm birth
  • Studies showing correlation between maternal psychological stress & placental-adrenal endocrine axis potential mechanism for stress-induced preterm birth
maternal fetal stress80
Maternal-fetal stress
  • Last trimester marked by rising maternal serum level of placental-derived CRH
  •  increase adult and fetal adrenal steroid hormone production, including initiation of fetal cortisol biosynthesis
  • Maternal & fetal cortisol further increase placental CRH secretion, develop feed-forward endocrine cascade
  • CRH stimulate fetal adrenal DHEA-S biosynthesis, increase maternal circulating estrogens (estriol)
  • Premature rise in cortisol & estrogen cause early loss of uterine quiescence
maternal fetal stress81
Maternal-fetal stress
  • Preterm labor is associated with early rise in maternal circulating CRH (Holzman,2001)
  • Level of CRH in term & preterm women :similar
  • However women destined for preterm labor : rise in CRH that occurs 2 to 6 weeks earlier (McLean & coworker,1995)
maternal fetal stress82
Maternal-fetal stress
  • Several studies :early rise of serum estriol in women preterm labor (Heine co-workers,2000)
  • Premature rise in estrogen alter myometrial quiescence
  • Associated with maternal fetal biological stress response
  • Several studies: CRH or estriol level activated in preterm birth due to infection & multifetal pregnancies (Gravett & collegue,2000)
  • Thus, activation of this axis activation of phase I of parturition
  • Further study will be needed to define exact biochemical role of CRH, estrogens & cortisol in preterm labor
infection preterm labor
Infection & preterm labor
  • Administration to animal of bacteria or bacterial endotoxin cause abortion or perterm delivery ,which is accompanied by decidual hemorrhage and necrosis
  • 40% of preterm labor caused by intrauterine infection
  • Incidence of (+) culture of amnionic fluid during preterm labor 10~40% (Average13%)
  • Morel likely to develope chorioamnionitis & PPROM than women with negative culture
  • More neonate complication
  • The earlier onset of perterm labor ,the greater likelihood of documented amnionic fluid infection
infection preterm labor84
Infection & preterm labor
  • Associate Chorioamnionitis with preterm labor (Chellam & Rushton,1985;Goldenberg & associates,2002)
    • Microbe invade maternal tissue only, not amnionic fluid
    • Endotoxin stimulate amnionic cell to secrete cytokine that enter amnionic fluid
    • Explain association between amnionic fluid cytokines and preterm labor, microbe not detectable in amnionic fluid
infection preterm labor85
Infection & preterm labor
  • Infection-mediated preterm delivery preventable by antimicrobial Tx
  • However debate on effectiveness of antimicrobial prophylaxis
  • Effectiveness of antimicrobial prophylaxis to prevent spontaneous preterm birth, recommneded in only a few situation to prevent spontaneous preterm delivery
sources for intrauterine infection
Sources for intrauterine infection
  • transplacental transfer of maternal systemic infection
  • Retrograde flow of infection from peritoneal cavity via fallopian tube
  • Ascending infection with bacteria form vagina & Cx
  • Lower pole of fetal membrane-decudual junction embraces orifice of cervical canal , which anatomically patent to vagina  Passageway for microorganisms to enter intrauterine tissue
sources for intrauterine infection87
Sources for intrauterine infection
  • Categorize intrauterine infection into four stage (Goncalves & co-workers ,20002)
  • stage I: microbial invasion that include bacterial vaginosis
  • stage II: Decidual infection
  • stage III: Amnionic infection
  • stage IV : Fetal systemic infection
  • Progression of these stages increase effect on preterm birth & neonatal morbidity
sources for intrauterine infection88
Sources for intrauterine infection
  • Pathogenesis of infection- induced preterm labor (fig 6-23)
  • Microorganism originating in vagina or cervix, after ascending, colonize decidua and possibly fetal membranes.  then may enter amnionic sac
  • Lipopolysaccharide or other toxin elaborated by these bacteria induce cytokine production in cell within decidua ,membrane, or fetus itself
  • Lipopolysaccharide & cytokine increase : provoked PG release from fetal membrane, decidua
  • Rise in cytokines & PG influence both cervical ripening & loss of myometrial quiescence with resultant myometrial stimulation (Challis,2002;Keelan,2003)
microbes associated with preterm birth
Microbes associated with preterm birth
  • Gardnerella vaginalis, Fusobacterium, Mycoplasma hominis Ureaplasma urealyticum, are detected more commonly in amnionic fluid of preterm labor
  • Further studies needed to better define intrauterine site of infection most influence timing of delivery, why some pregnant women appear more susceptible to microbe
intrauterine inflammatory response to infection
Intrauterine inflammatory response to infection
  • Initial inflammatory response elicited by bacterial toxin in mediated by specific R on mononuclear phagocytes, decidual cells, trophoblast
  • Toll-like R :present in placenta on trophoblast cell as well as fixed & invading leukocytes
  • Influence of ligand such as bacterial lipopolysaccharide, R increase local release of chemokine, cytokines, PG as part of inflammatory response
intrauterine inflammatory response to infection92
Intrauterine inflammatory response to infection
  • Lipopolysaccharide stimulation IL-1 : promote increase synthesis of other cytokines( TNF-A,IL-6, IL-8)
    • Proliferation, activation, migration of leukocyte
    • Modification in extracellular matrix protein
    • Mitogenic & cytotoxic effect ,including fever & acute phase response
  • IL-1:promote PG formation in many tissues, including myometrium,decidua, amnion
  • Appear to be cascade of event once inflammatory response in initiated that can result in preterm labor
origin of cytokines in intrauterine infection
Origin of cytokines in intrauterine infection
  • Transfer of cytokine from decidua across membranes into amnionic fluid severely limited
  • Thus, cytokine produced in maternal decidua & myometrium have effect on that side , whereas cytokine produced in membrane or in cell within amnionic fluid not tranferred to maternal tissue
  • In most cases of inflmmation resulting from infection, resident and invading leukocyte produce bulk of cytokine
  • Leukocyte (neutrophil,macrophage,T lymphocyte) infiltrate Cx, lower Ut segment , fundus at time of labor
  • Invading Leukocyte major source if cytokine at time of labor
origin of cytokines in intrauterine infection94
Origin of cytokines in intrauterine infection
  • In term laboring Ut, both invading leukocyte & certain parenchymal cell produce cytokine
  • Primary source of myometrial cytokines, including, IL-1, IL-6, IL-8, TNF-a (in decidua both stromal cell & invading leukocytes, in Cx: glandular & surface epithelial cell)
  • IL-8 critical cytokine in cervical ripening, produced in both epithelial & stromal cell of Cx
origin of cytokines in intrauterine infection95
Origin of cytokines in intrauterine infection
  • Cytokine in Amnionic fluid & their association with preterm labor has been well documented
  • But exact cellular origin not well defined
  • Amnionic fluid IL-1 probably not arise from amnion tissue, fetal urine,or fetal lung secretion, but most likely secreted by mononuclear phagocyte or neutrophils activated & recruited into amnionic fluid
  • IL-1 in amnionic fluid likely generated in situ from newly recruited cell
  • Amount of amnionic fluid IL-1 would be determined by number of leukocyte recruited, their activational status, or effect of amnionic fluid constituent on their rate of IL-1 secretion
origin of cytokines in intrauterine infection96
Origin of cytokines in intrauterine infection
  • Leukcocyte infiltration regulated by fetal membrane synthesis of specific chemokines
  • In term labor, increased amnionic fluid concentration of potent chemoattractant and monocyte-macropage activatior, monocyte chemotactic protein-1(MCP-1)
  • Level of MCP-1 : much higher in forebag compared with upper compartment
  • In preterm labor significantly higher than in normal term amnionic fluid
  • MCP-1 may be the factor that initiate fetal leukocyte infiltration of placenta & membrane
  • MCP-1may act as marker of intra-amnionic infection & inflammation
summary of infection preterm labor
Summary of infection & preterm labor
  • Intrauterine infection cause significant number of cases idiopathic spontaneous preterm labor
  • Variety of site for intrauterine infection & similarities between inflammatory response of preterm & term labor  difficult to determine proportion of pregnancies that end prematurely due to infection
  • Mechanistically, infection induced preterm labor as process causing early initiation of phase 1 of parturition
summary of infection preterm labor98
Summary of infection & preterm labor
  • Initial exposure to bacterial endotoxin leading to production of cytokines
  • In Cx, theses cytokine cause of infiltration of leukocyte & ripening
  • Activation of proteases in Cx

 promote Cx dilatation & weaken fetal membranes

 PPROM

summary of infection preterm labor99
Summary of infection & preterm labor
  • Transfer of bacteria or cytokine into fetal circulation

 premature activation of CRH & placental–adrenal endocrine cascade

 loss of myometrial quiescence

  • Continued leukocyte infiltration, proinflammatory cytokine further increase PG within maternal decidua & myometrium  act as uterotonin

 preterm labor