Parturition

Question 1

What is parturition?

Answer 1

• 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.

Question 2

What is pre-term birth?

Answer 2

• 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

Question 3

What are the causes of pre-term birth?

Answer 3

• 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

Question 4

What are the events of parturition?

Answer 4

• Ripening and dilatation of the cervix
• Myometrial contractions
• Rupture of fetal membranes
• Delivery of infant
• Delivery of placenta

Question 5

What is the definition of labour

Answer 5

Regular, painful contractions resulting in cervical dilatation.

Question 6

What is the first stage of labour?

Answer 6

• Onset of regular contractions
• Cervical softening, dilation and effacement
• Average 12 hours in nulliparous women, and

Question 7

What is the second stage of labour?

Answer 7

• 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

Question 8

What is the third stage of labour?

Answer 8

• 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

Question 9

What mediates cervical ripening and softening?

Answer 9

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

Question 10

How does cervical dilatation occur?

Answer 10

• Induced by myometrial contractions
• Push babys head down onto cervix
• Pressure on softening cervix causes it to dilate

Question 11

How does myometrial contractility change during pregnancy?

Answer 11

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

Question 12

How do spontaneous action potentials stimulate contraction?

Answer 12

1. 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
2. APs stimulate increase in cellular Ca2+
   • Change in potential difference causes an opening in voltage gated calcium channels
3. Ca2+ influx stimulates contraction
4. Action potential triggers calcium influx into the cell
5. Calcium binds to calmodulin
6. This activates MLC kinase
7. MLC kinase phosphorylates the myosin light chain → this causes the myosin head domain to bind the filamentous actin
8. ATP hydrolysis generates a force for the myosin to ‘walk’ along the actin filament, causing contraction
9. The contraction is released by dephosphorylation of the myosin by MLC phosphatase
10. The myosin and actin deassociate, and the cell relaxes

Question 13

What are the uterotones?

Answer 13

→ 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

Question 14

What is the role of cellular communication in parturition?

Answer 14

• 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

Question 15

How does stretch trigger parturition?

Answer 15

• Increases in intrauterine volume activate stretch-responsive genes in the myometrium
• Stimulates inflammation
• Multiple babies trigger it more – preterm labour risk

Question 16

How does inflammation lead to parturition?

Answer 16

• 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

Question 17

How do maternal hormones trigger parturition?

Answer 17

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

Question 18

How do fetal/placental hormones trigger parturition?

Answer 18

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.

Question 19

How can we induce labour clinically?

Answer 19

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

Question 20

How can we prevent pre-term labour clinically?

Answer 20

• Tocolytics stop preterm labour
• Nifedipine → Ca2+ channel blocker
• Atosiban → oxytocin receptor antagonist
• Indomethacin → COX inhibitor
• Progesterone treatment during pregnancy in high risk women