labour Flashcards
What is the transition in myometrium, cervix and membranes in successful labour between antenatal and intrapartum
Myometrium goes from quiescent to contractile
Cervix becomes open from closed
membranes go from intact to ruptured
describe actin myosin interactions in uterine contractility
Thin actin filaments going horizontally across
Thick myosin filaments in between vertically
During contraction the Z discs come closer together
There are 4 phases in labour- quiescence, activation, stimulation and initiation of labour. Describe the quiescence phase
• Progesterone
• PGI2
• Relaxin
• Parathyroid hormone-related peptide(PTHrP)
• Calcitonin gene-related peptide, vaso-active
intestinal peptide
• Nitric oxide(NO)
All these lead to increased intracellular (cAMP)or
(cGMP) which inhibit the release of intracellular
calcium for myometrial contractility
Describe the activation phase
Rise in estrogen and CRH
• Mechanical stretch
• up-regulation of a panel of genes required for
contractions: Connexin 43, prostaglandin and
oxytocin receptors (OTRs)
Describe the stimulation phase
Prostaglandins
• Oxytocin
• CRH
• Increased synthesis of cytokines
Describe initiation of labour
Functional Progesterone withdrawal • Increased Estrogen bio-availability • CRH and neuro-endocrine mediators • Increased responsiveness of the myometrium to prostaglandins and oxytocin
Describe the role of progesterone in labour
Is one of the main hormones of pregnancy
• Produced by corpus luteum in early pregnancy
and the placenta later
• Cholesterol is converted to Progesterone by
the action of P450scc and 3βHSD
Decreases myometrial contractility
• Inhibits myometrial gap junction formation
• Stimulates uterine NO synthetase
• Stimulates cAMP and sequesters intracellular calcium
in the sarcoplasmic reticulum (SR)
• Down-regulates prostaglandin production,
development of calcium channels and oxytocin
receptors
• inhibits collagenolysis in the cervix by increasing tissue
inhibitor of matrix metalloproteinase-1 (TIMP-1)
What does stimulation and inhibition of progesterone cause
Stimulation: prostaglandin secretion PTH-rp synthesis CGRP secretion AM receptor expression
Inhibition: Prostaglandin synthesis CRF secretion interleukin synthesis oestrogen receptor expression oxytocin receptors affinity
Progesterone pathway affecting inflammatory factors
In most species, progesterone levels fall pre-labour
• This does not occur in humans, however there is
upregulation of (pro-inflammatory) PR-A, and
suppression of (anti-inflammatory) PR-B receptor
activity, resulting in “functional” progesterone
withdrawal
• Increased PR-A/PR-B ratio is linked with activation of
nuclear factor kappaB (NF-κB) in the myometrium
• NF-κB increases expression of COX-2 and various proinflammatory cytokines (e.g. IL-8 and IL-1b), which
cause cervical ripening and up-regulate oxytocin
receptor expression in the myometrium
What is the role of oestrogen in labour
Essential for uterine development & function
• The placenta is the primary source
• Placenta relies on DHEAS from the fetal &
maternal adrenal glands for the supply of
precursor for estrogen synthesis
• Both estrogen and progesterone increase
towards term but the ratio of estrogen to
progesterone begins to favor estrogen
DHEAS to oestrogen
Foetus releases DHEA-S (from adrenals of mother and foetus)
3BHSD, aromatase, and 17BHSD
causes conversion into
oestradiol, oestriol, estron
oestrogen induced myometrial changes
Increase in the number of PG and OCT
receptors
• Up-regulation of the enzymes responsible for
muscle contractions (myosin light chain
kinase, calmodulin)
• Increase in connexin-43 synthesis & gap
junction formation in the myometrium
• Induction of collagenase & elastase: Cervical
ripening
oestrogen increases:
gap junction formation, oxytocin responsiveness, PG synthesis and release. All work together to increase uterine contractility
collegenase and elastase induction
causing cervical dilatation
Describe oxytocin in labour
Synthesised in hypothalamus and released from
posterior pituitary gland of mother, also produced
by myometrium, decidua, placenta and membranes
• Myometrial sensitivity to oxytocin increases near to
term due to changes in density (up to 200-300 fold)
and affinity of oxytocin receptors
• Receptor concentration greatest in the fundus and
minimal in the lower segment and cervix
• Oxytocin receptor upregulation is promoted by
oestrogen and mechanical stretch
• Increases inositol 1,4,5-triphosphate and intracellular Ca
Effect of oxytocin on the myometrium and decidua
Effect of oxytocin on myometrium:
Intracellular Ca2+ increased
causes myosin phosphorylation
increases actin-myosin
effect of oxytocin on decidua
PGF2alpha synthesis and secretion
both cause uterine contractions
Role of relaxin in labour
Insulin-like hormone produced by placenta and
myometrium (corpus luteum in early pregnancy)
• Promotes myometrial quiescence in pregnancy
• Induces vasodilatation, skeletal muscle relaxation
and renal adaptation to pregnancy
• Increases cAMP, inhibits calcium release in
myocytes, decreases affinity of MLCK for
calmodulin and myosin and activates K channels,
thus hyperpolarising the muscle cell membrane
• Suppresses oxytocin release
• Enhances cervical ripening
Effect of inflammatory cytokines in labour
Play a major role in enhancement of uterine
contractility and cervical ripening
• Include IL-1, IL-6, IL-8, TNF-α, interferon and TGF-β
• All stimulate prostaglandin (PG) production in the
myometrium, placenta and fetal membranes
• IL-8 also induces neutrophil chemotaxis/activation
and production of matrix metalloproteinase (MMP)
• Inflammation outwith the uterus can also trigger
labour e.g. surgical procedures, appendicitis, UTI
Effect of nitric oxide in labour
Produced by decidua, membranes, fetoplacental
vascular endothelium and the syncytiotrophoblast
• Regulates vascular tone via release of prostacyclin
• Maintains myometrial quiescence
• Activates guanylate cyclase pathway, increases
cGMP, decreases intracellular Ca concentrations
• Levels elevated in myometrium (but not cervix)
during pregnancy and ê prior to onset of labour
• Cervical NO é at term, thus implicated in ripening
Effect of CRH and cortisol
Extra CRH is produced by placenta and myometrium
and levels increase 50–100 fold by late gestation
• CRH binding proteins fall towards term, increasing
free (active) levels of CRH
• CRH inhibits PGE2, increases cAMP and upregulates
NO synthase, promoting quiescence antenatally
• At term, however, CRH enhances the myometrial
contractile response to PGF2α, PGE2 and oxytocin
• CRH stimulates the fetal adrenal gland to produce
cortisol, which triggers conversion of progesterone
to oestrogen – also promotes fetal lung maturation
Effect of uro-cortins
Uro-cortins (Ucn,Ucn2,Ucn3) are structurally
similar to CRH and show similar biological effects
• Are synthesized and secreted by placenta and
fetal membranes
• Ucn levels remain relatively constant during
gestation and increase only after onset of
parturition
• Augment matrix metalloproteinase, ACTH and
prostaglandin secretion
• Act as pro-inflammatory agents
Effect of prostaglandins
Final common pathway in labour onset mechanisms
• Produced in decidua and fetal membranes
• Stimulatory PGs (PGF2α, thromboxane, PGE1, PGE2)
bind to the myocyte cell membrane, increase action
potential frequency and stimulate contraction
• PGE2 plays a central role in cervical ripening
• PGF2α increases intracellular calcium / contractility
• Inhibitory PGs (PGD2 and PGI2) repress contraction
• PG levels are low and receptors down-regulated
during pregnancy, and increase towards term
• Synthesis upregulated by NF-κB / COX-2 activation
Other factors affecting contractility and induction of labour
Epidermal growth factor – é PG levels, promotes
uterine contraction by increasing intracellular Ca
• Parathyroid hormone related peptide (PTHrP)
– has relaxant effect on myometrium (ê levels at
term), also relaxes blood vessels and plays a role
in placental calcium transport
• Magnesium – competes with calcium for
calmodulin binding, reduces MLCK
• Endothelin – enhances myometrial contractility by
increasing intracellular Ca / MLC phosphorylation,
modulates fetoplacental circulation
Other Factors
• Oestrogen to progesterone ratio
• Engagement and descent of fetal head
(placing pressure on cervix)
• Neuroendocrine effects of cervical stretch, leading
to increase oxytocine release (“Ferguson’s reflex”)
• Altered uterine wall tension (myometrial stretch)
• Parasympathetic to sympathetic balance
• Hyaluronic acid levels
• Cervical stimulation (sexual intercourse / “sweep”)
What are the major changes in the myometrium during initiation of labour
up Coupling
up Ion channels
up Receptors
down NO-system
up Conductivity
up Excitability
down Relaxation
Reinforcement
of contractions
What are the major changes in the cervix during initiation of labour
Increased Inflammatory
response
Increased Collagenase
Increased Ripening
all cause Dilatation in successful labour
What are the major changes in the membranes during initiation of labour
ECM
degradation
Reduced Tissue integrity
in successful there is rupture
What are the phases of labour
Quiescence- phase 0
activation- phase 1
stimulation- phase 2- delivery happens (postpartum)
involution- phase 3
uterine activity is down the whole time and on the graph it curves upwards at phase 2
Define labour
Regular painful contractions associated with cervical change (± spontaneous rupture of fetal membranes) • End result is delivery i.e. expulsion of the fetus(es), placenta and membranes) – also called “parturition”
First stage = onset to full cervical dilatation
(10cm)
• latent phase = 0–3cm
• active phase = from 4cm
• Second stage = full dilatation to delivery of the
foetus
• Third stage = delivery of foetus to delivery of
placenta
Describe preterm birth
Delivery prior to 37 completed weeks gestation
• Affects between 7 to 11% pregnancies worldwide
• Predictive tests perform poorly but may be used in
high risk groups – cervical length / fetal fibronectin
• Causative/associated factors Ø Infection Ø Inflammation Ø Maternal stress Ø Intrauterine haemorrhage Ø Uteroplacental insufficiency (e.g. pre-eclampsia and fetal growth restriction)
Summary
Labour is a complex physiologic process
involving fetal, placental, and maternal
signals.
• A variety of endocrine systems play a role in
the maintenance of uterine quiescence and
the onset of labour (increase in uterine
contractility and cervical ripening)
• There are many factors that can tip the
balance between quiescence & contractile
