Labour

Question 1

Recognise why the timing of labour is important.

Answer 1

Labour

• Miscarriage - <23 weeks’ gestation - ~350,000.
• Term – 37-41 weeks’ gestation - ~700,000.
  
  • ~525,000 by labour, ~175,000 by caesarean section.
• Pre-term – 23-37 weeks’ gestation - ~80,000.
  
  • ~40,000 preterm labour, ~35,000 by C-section.
• Labour is defined as – increasing fundally dominated contractions combined with increasing cervical ripening and effacement.

Labour involves:

• Baby is being pushed towards the cervix (with their head)
• Cervical ripening and effacement – INCREASING.
  
  • Change of tissue strucutre from firm to soft
• Co-ordinated myometrial contractions – INCREASING.
• Rupture of foetal membranes.
• Delivery of infant -> then delivery of placenta.
• Contraction of uterus.
• The stages up to term involve 3 trimesters and then the 3 phases with the baby delivered in P2 and placenta in P3.
• Labour lasts 12-48h and the phases get shorter.
  
  • First labor usually takes longer in the first labor

Initiation of labour

•Term

–Not really sure!!!

–Estrogens; low progesterone?; CRH?; oxytocin?

•Preterm

–Intrauterine infection

–Intrauterine bleeding

–Multiple pregnancy

–Stress (maternal)

–Others

Mothers need to contract to get rid of placenta because if not they will bleed to death

Question 2

Identify the main processes of labour.

Answer 2

Process:

Initiation:

Process:

Cervical ripening and effacement:

• Change from rigid -> flexible structure.
• Remodelling – loss of ECM.
• Recruitment – of leucocytes such as neutrophils.
• Inflammation – Prostaglandin E2, IL-8.

Co-ordinated myometrial contractions:

• A fundal dominance with increased power and coordination.
• Mediators – Prostaglandin F2a (E2) increased, oxytocin receptors increased, contraction proteins.

Rupture of foetal membranes – loss of strength due to changes in amnion BM.

• Inflammation and leucocyte recruitment (exacerbated in preterm), increased MMPs.

nFKB regulate all inflammatory mediators, and cytokines

Question 3

Recognise the key tissues involved in labour (cervix, myometrium and fetal membranes).

Question 4

Summarise the main biochemical processes of labour with respect to endocrine and inflammatory processes.

Question 5

Explain the main roles of NFκB, progesterone receptor and progesterone in human labour.

Answer 5

Labour – Summary:

• Cervix:
  
  • Prostaglandin E2, IL-8, MMPs.
• Myometrium:
  
  • Prostaglandin F2a (E2) levels increase, oxytocin receptor upregulation, contraction associated proteins.
• Foetal membranes:
  
  • PGs, ILs, MMPs, inflammatory processes.

NFKB is a pro-inflammatory transcription molecule.

• Closely related to – IL-1b, IL-6, COX2, cPLA2, IL-8.

NFKB has MANY initiators and it can then induce MANY effects (mostly inflammatory) through:

• COX-2, IL-8, IL-1b, MMPs, oxytocin receptors, PG receptors, contraction-associated proteins.

Evidence for this comes from:

1. Pro-labour genes have NFKB binding domains in promotor regions.
2. Modification of NFKB sites in the domains lead to loss of expression of the cells.

Causes?

• Inflammatory changes are strongly linked with labour
• Activators of inflammation are readily linked with preterm labour (eg intrauterine infection)

Key regulator of labour:

• NFKB is a pro-inflammatory transcription molecule.
  
  • Closely related to – IL-1b, IL-6, COX2, cPLA2, IL-8.
• NFKB has MANY initiators and it can then induce MANY effects (mostly inflammatory) through:
  
  • COX-2, IL-8, IL-1b, MMPs, oxytocin receptors, PG receptors, contraction-associated proteins.
  • Evidence for this comes from:
    
    1. Pro-labour genes have NFKB binding domains in promotor regions.
    2. Modification of NFKB sites in the domains lead to loss of expression of the cells.
• PGE2 is constitutively expressed BEFORE any changes can be witnessed that are conducive to labour.
  
  • Equally, some tissues could not be stimulated to express PGE2 as the levels are already high.

Stimulation to PGE2 reaches a maximum before labour so we can’t raise them even more

Question 6

Control of labour

Answer 6

CRH and PAF:

Control of labour comes about mainly via CRH and PAF (which then activate other molecules and ultimately MMPs, PGE2 and upregulation of oxytocin receptors).

1. PAF – Platelet Activating Factor.
2. CRH – Corticotrophin Releasing Hormone.

CRH – produced not only by the pituitary gland but by the human placenta:

• Levels rise at the end of pregnancy whilst CRH-binding-proteins drop towards end of pregnancy.
• High CRH also correlates with high COX2 molecule expression.

PAF:

• Part of lung surfactant that is produced by maturing lungs before birth.
• Levels in amniotic fluid increase near term (as PAF is part of surfactant that also increases).
• Thus, the levels of PAF are a signal of foetal maturity (may stimulate labour).

Both above can upregulate – cannot prove whether these are involved though as unethical.

• Expression of PGE2 and COX2.
• IL-1b (inflammatory mediator) levels.

Lungs are the last part to develop in a foetus as prior to that they are collapsed with excess surfactant

Corollaries of the above

1. Anything that increases CRH may predispose to labour (stress, multiple infants)
2. Anything that increases muscle contraction may predispose to labour (excess stretch of uterus)
3. Anything that activates inflammatory cascades may predispose to labour
4. The above apply to preterm labour (intrauterine infection, bleeding, twins)

Cortisol excelerates cortisol accelerates CRH production - activates labor

adrenal gland - steroid that mature the lungs

adrenal gland - precursor for oestrogens

Question 7

Progesterone

Answer 7

Progesterone

Progesterone is needed to SUSTAIN pregnancy – PR-blockade = pregnancy loss.

Progesterone levels remain very high until AFTER delivery of the placenta.

This means that the effects of progesterone must be LOST in normal term labour which means the PR receptor must be disrupted.

High levels of NFKB before term can BLOCK the PRs and thus reduce the effect of progesterone to sustain pregnancy so labour can begin (and NFKB is high towards term).

Progesterone receptor (PR):

PR-B – mediates main effects of progesterone.

PR-A – less able to mediate than PR-B.

Ratio of PR-A: PR-B increases towards term so progesterone has less of an effect.

Loss or change in PR may lead to a “functional progesterone withdrawal” which is physiologically normal towards term labour.

Progesterone can switch off MANY of the labour pathways.

__

In pregnancy, lots of progesterone in these tissues which has to bind to nfkb and block its action

At the end of pregnancy progesterone decreases and enables nfkb to induce labor