Parturition Flashcards
What is parturition?
- Delivery of infant – process of labour
- Signifies conclusion to a successful pregnancy
- Highly coordinated event
- Involves complex interactions between maternal and fetal tissues
- Ideally occurs between 37-42 weeks gestation.
What is pre-term birth?
• Delivery before 37 weeks → 24 weeks are limits of viability, only 50% survive.
• 8-12% births → incidence rising in UK and USA
• Biggest cause of neonatal mortality and morbidity
− responsible for 75% of neonatal death and majority ICU admission.
− Respieratory distress syndrome – lungs aren’t mature
• Outlook improves for each 7 days > 23 weeks in utero
What are the causes of pre-term birth?
- Iatrogenic → due to pregnancy complications – danger to mum or baby, eg) pre-eclampsia or FGR.
- Spontaneous preterm labour – in many causes cause unknown.
Potential causes for spontaneous PTL
• Infection – intrauterine infection (chorioamnionitis)
• Preterm rupture of fetal membranes
• Over-distension of the uterus → multiple pregnancies, excessive amount of amniotic fluid
• Abnormalities of the cervix eg) short cervix or cervical surgery
• Fetal abnormalities, eg) genetic problems
Other risk factors • Previous preterm birth • Extremes of maternal age • Periodontal disease – link with systemic infection • Black race (18% vs 11% Caucasians) • Smoking, drug abuse
What are the events of parturition?
- Ripening and dilatation of the cervix
- Myometrial contractions
- Rupture of fetal membranes
- Delivery of infant
- Delivery of placenta
What is the definition of labour
Regular, painful contractions resulting in cervical dilatation.
What is the first stage of labour?
- Onset of regular contractions
- Cervical softening, dilation and effacement
- Average 12 hours in nulliparous women, and
What is the second stage of labour?
- Full dilatation until delivery – 4 hours max, preferably 2
- Cervix fully effaced and dilated
- Begins as head enters birth canal
- Myometrial contractions now 2-3 minutes apart
- Mother feels abdominal pressure to push
- Baby is delivered
What is the third stage of labour?
- From delivery of baby until placenta is expelled and uterus is contracted
- Placenta detaches and delivers
- Uterus contracts to prevent excess bleeding from uterine arteries → main cause of death in LEDCS
What mediates cervical ripening and softening?
Leukocytes
• Infiltrate cervix
• Stimulate uterine cervical cells to induce a massive increase in collagenase and protease production
Matrix metalloproteases
• Breakdown collagen fibres
Prostaglandins → key mediator
• Pro-inflammatory
• Lipid metabolites
• Produced locally in sites of inflammation
• Induce a variety of actions:
− Constriction or dilation of smooth muscle cells
− Alter vascular tone and permeability so fluid enters tissue
− Regulate calcium movement
− Sensitise neurons to pain
− Induce fever
• Inhibited by NSAIDs
Prostaglandin synthesis:
• Phospholipids and DAG converted to arachidonic acid
• This is converted to PGH2 by COX enzymes (COX2 most important for inflammation and labour)
• PGH2 converted to prostaglandins by PG synthases
• → PGE2 (vasodilator) and PGF2 (constrictor) important for parturition
• NSAIDS inhibit COX enzymes
How does cervical dilatation occur?
- Induced by myometrial contractions
- Push babys head down onto cervix
- Pressure on softening cervix causes it to dilate
How does myometrial contractility change during pregnancy?
During pregnancy:
• Growth to enable expansion with fetal growth
− Stimulated by estrogen
− Smooth muscle cell hypertrophy (larger) and hyperplasia (more)
• Suppression of contractions
− Progesterone suppresses normal excitable behavior of smooth muscle cells
Before parturition:
• Preparation for contractile effects
− Suppressive action of progesterone removed
− Upregulation of contraction associated proteins (CAPS)
− Production of uterotones PGF2a and oxytocin
During parturition
− Myometrial stimulation and contractions
How do spontaneous action potentials stimulate contraction?
- Contractions are driven by spontaneous action potentials:
• Influx of sodium ions through voltage gated channels decreases the potential difference. Reaches a plateau until there is an efflux of sodium, and the potential returns to resting.
• These action potentials occur every 5 seconds - APs stimulate increase in cellular Ca2+
• Change in potential difference causes an opening in voltage gated calcium channels - Ca2+ influx stimulates contraction
- Action potential triggers calcium influx into the cell
- Calcium binds to calmodulin
- This activates MLC kinase
- MLC kinase phosphorylates the myosin light chain → this causes the myosin head domain to bind the filamentous actin
- ATP hydrolysis generates a force for the myosin to ‘walk’ along the actin filament, causing contraction
- The contraction is released by dephosphorylation of the myosin by MLC phosphatase
- The myosin and actin deassociate, and the cell relaxes
What are the uterotones?
→ An agent used to induce contraction or greater tonicity of the uterus
• Used to induce labour and reduce post-partum haemorrhage
Oxytocin
• Key uterotone for regulator and strong contractions during active stages of labour
• Secreted by posterior pituitary
− Under hypothalamic controle
− Pulsatile
− Increased pulsatility during labour
− Also synthesized by the uterus at term
• Acts via oxytocin receptors on myometrial cells
• Stimulates myometrial contractions by 3 ways
− Augments excitability of myometrial cells
− Increases frequency of action potentials
− Increases frequency and amplitude of contractions
• Women encouraged to breastfeed right way as this releases oxytocin and causes contractions to assist with uterine clotting and remodeling after delivery (also helps with mother-infant bonding).
Prostaglandin
• PGF2a
• Stimulates contractions
• Sitimulates action potentials and Ca2+ channels
• Produced by decidua and fetal membranes, and also by leukocytes
What is the role of cellular communication in parturition?
- Parturition is highly coordinated, so the smooth muscle cells must behave as a functional unit for synchronous contractions
- Mediated by gap junctions
Gap Junctions
• 6 connexins form a connexon
• 2 connexons from neighbouring cells form a gap junction
Gap junctions in the myometrium
• Increase in late pregnancy in preparation for labour
• Are important parts of the CAPs
• At least 20 mammalian connexins identified
• Cx40, 43 and 45 are in the myometrium → Cx 43 is increased late in pregnancy
• Facilitate synchronous contractions of the smooth muscle
How does stretch trigger parturition?
- Increases in intrauterine volume activate stretch-responsive genes in the myometrium
- Stimulates inflammation
- Multiple babies trigger it more – preterm labour risk
How does inflammation lead to parturition?
• Inflammatory reactions:
− Leukocytes infiltrate cervic, decidua and myometrium (mainly macrophages)
− Increased production of IL-1 in amniotic fluid
− Activate NFkB – master regulator of inflammation
• Activated NfkB increases expression of:
− COX-2
− PGF2a receptor
Connexin 43
− Oxytocin receptor
How do maternal hormones trigger parturition?
Progesterone
During Pregnancy → Maintenance of Uterine Quiescence
• May be indirect, by inhibiting activation of inflammatory response pathways and expression of contractile genes → prevents NFkB (by upregulating the inhibitor IkB) and COX-2 activation
• Inhibits expression of CCL-2 chemokine which recruits macrophages
At Term:
In most species:
• Progesterone levels fall at term (increased expression of progesterone metabolizing enzymes) removing suppressive effect on myometrial contractions
• Progesterone withdrawal:
− Upregulates COX-2 → increased prostaglandin production
− Increases oxytocin pulsatility
− Stimulates leukocyte recruitment
But there is no systemic progesterone withdrawal in humans
Is there a functional withdrawal?
• Blocking progesterone induced delivery
− Mifepristone induced terminations → used for terminations and pregnancy induction if a baby has died in utero.
− Increased cervical ripening
− Increased sensitivity to labour induction by oxytocin and prostaglandins
• Evidence for ‘functional’ withdrawal at term:
− changes in responsiveness of myometrium to P
− Altered balance of PR subtypes:
− PRB = active form in myometrium, PRA = inhibitory to PRB
− Increased PRA:PRB ratio at term 10 fold
− PR-C also exits – truncated form that may sequester progesterone away from PR-B – increased in term-women.
− Increased production of NFkB → NFkB inhibits PR activity
So P withdrawal may be important in humans, but
Estrogen
• Increase in E production leading up to delivery
• Increased ERa in myometrium at term → occurs simultaneously to reduced PRB
• Switch from progesterone to estrogen dominance at etrm
• Estrogen involved in activation of myometrium:
− Stimulates gap junctions
− Increased oxytocin production and oxytocin receptors
− Increased prostaglandin synthesis
How do fetal/placental hormones trigger parturition?
What triggers estrogen increase?
• Signals from the fetus and placenta
Fetal Stress Axis
• Fetal HPA axis suppressed during pregnancy
• Shortly before birth, the HPA axis matures
• Cortisol and DHEA are made by the adrenal gland
• Axis is important for maturing lungs → cortisol stops cells proliferating, making them mature instead
Does the placenta activate the HPA axis?
- Placenta produces a lot of factors normally only made in neurons → synthesies CRH
- CRH acts on the pituitary to release ACTH
- ACTH acts on adrenal to release cortisol and DHEA
• There are increased CRH levels at term – may trigger fetal HPA
• Suggests there may be a ‘placental clock’ dictating time of delivery
− Mclean et al, 1995
• Study of 485 women
• Demonstrated that placental secretion of CRH is a marker of the placental clock process, which determines length of gestation and timing of parturition
• Measurement of CRH as early as 16-20 weeks gestation idenfities groups of women destined to experience normal term, pre-term or post-term delivery → suggests the placental clock process is established early in pregnancy
• Directly challenges the concept that parturition is determined solely by events later in pregnancy
• Increase in CRH with advancing pregnancy associated with concomitant fall in CRH binding protein, leading to a rapid increase in CRH that coincides with onset of parturition.
What are the consequences of fetal HPA activation?
Cortisol
• Normall anti-inflammatory, but in the uterus it is pro-inflammatory
• Upregulates COX-2
• Increases PGF2a and PGE2
DHEA
• Substrate for estrogen production by placenta
- Axis is important for maturing lungs → cortisol stops cells proliferating, making them mature instead
- CRH rise precedes induction of lung surfactant protein synthesis
- Therefore, CRH may contribute to initiation of labour by enhancing cortisol and DHEA production, and stimulating lung maturation → in this regard, lung maturation may be a fetal signal for induction of labour.
Fetal Lung Surfactant
• Synthesis initiated during 3rd trimester
• Function to reduce alveolar suface tension, and also as immune defense
• Been observed that pulmonary surfactant isolated from amniotic fluid stimulated synthesis of prostaglandins
• SP-A is secreted into the amniotic fluid in large amounts near term and may act as a signal for induction of labour
• Synthesis of SP-A only initiated after 80% gestation is complete
• Mice injected with SP-A delivered prematurely
• → Postulate that in increase in SP-A provides a hormonal stimulus for activation of inflammatory signals that increase myometrial contractility.
• Signals that fetal lungs are ready for transition from aqueous to aerobic environment.
How can we induce labour clinically?
Cervical Ripening
Prostin (PGE2)
• Gel on cervix
• Ripens and dilates cervix within 24 hours
• Quicker in multiparous women – because cervix never completely returns to pre-pregnancy state
• Artificial membrane rupture when cervix partially dilated triggers massive inflammatory response
Usually this is enough to trigger labour
Stimulation of contractions
• Syntocinon – synthetic oxytocin
− Stimulates contractions
− Given following induction of labour or to augment dysfunctional labour
• PGF2a
− Important uterotone, but not given in labour
− Too potent, gives massive contraction
− Used instead after delivery if post-partum haemorrhage
How can we prevent pre-term labour clinically?
- Tocolytics stop preterm labour
- Nifedipine → Ca2+ channel blocker
- Atosiban → oxytocin receptor antagonist
- Indomethacin → COX inhibitor
- Progesterone treatment during pregnancy in high risk women
