Prevention and Treatment of Preterm Labour.

Question 1

Preterm labour?

Answer 1

Birth of a baby between 24 and 37 weeks.
1:13 live births (6% single and 53% multiple)
1 % deliver <30 weeks but accounts for 80% of neonatal morbidity/mortality.
Many babies survive due to increase neonatal care BUT survival is associated with disability.
Labour that oftens leads to sponatneous preterm birth (SPTB) ~60% all preterm births.

Question 2

Causes of preterm labour?

Answer 2

Multiple ateiologies.

Spontaneous PTL
Preterm rupture of membranes.

Question 3

Influencing factors of PTL?

Answer 3

Clinical/subclinical infection.
Cervical weakness/shortening.
Decidual haemorrhage/abruption.
Multiple foetuses
Bacterial vaginosis.
Maternal age.
Genetics.
Prenatal BMI and diet.
Environment.
Social and psychological stress.

Question 4

Triggers of early activation of normal labour process…

Answer 4

Placental/vascular problems.
Inflammation, infection.
Maternal stress.
Hormonal signals/uterine stretch.

Question 5

Maternal stress?

Answer 5

Maternal cortisol influences fetal HPA.

Question 6

Impact of decidual/placental haemorrhage.

Answer 6

Bypasses mechanisms - causes production of thrombin which induces uterine contractions

Question 7

Impact of multiple foetuses.

Answer 7

2 x HPA.

Uterine distension.

Question 8

Mechanical stretch?

Answer 8

Required for induction of oxytocin receptor mRNA in labour.

Induces COX2 and IL8.

Question 9

Infection and inflammation?

Answer 9

Functional withdrawal of P4.
Increase COX2, IL-1B, MMPs and decrease PGDH.

Linked with bacterial vaginosis
Subclinical infection
Women in PTL, increase in cytokines - increase PGs and MMPs (matrix metalloproteases).

Question 10

Activation of maternal/fetal HPA axis?

Answer 10

Maternal stress
Premature activation of physiological processes.
CRH/ACTH/cortisol
Adrenal androgens
Placental steroids.

Question 11

Inflammation/infection?

Answer 11

Intra-amniotic, cerival/decidual, systemic

= cytokines, fetal imflammatory response syndrome.

Question 12

Ischemia, decidual haemorrhage.

Answer 12

Placental abruption.

Thrombin.

Question 13

Uterine distension?

Answer 13

Multiple foetuses.
Structural anomaly.
Polyhydramnios - excess amniotic fluid.

= Gap junctions, contraction associated proteins.

Question 14

How do these aforementioned triggers cause preterm labour?

Answer 14

Act on decidua, fetal membranes, cervic and myometrium…
…MMPs, cervical ripening, rupture of membrances, PGs, uterotonins and uterine contractions

= preterm labour.

Question 15

Treatment aims?

Answer 15

1) Stop uterine contractions
2) Reverse cervical shortening/ripening
3) Prevent initiation of PTL

Question 16

Treatment approaches?

Answer 16

1) Smooth muscle relaxants
2) inhibition of contractile pathways
3) Treat infection
4) Stop bleeding/response to bleeding
5) Inhibit inflammation related events (COX2, PGR)
6) Increase progesterone.

Question 17

Current treatments?

Answer 17

Tocolytics.

Oxytocin receptor antagonists - atosiban.
B2 receptor agonists - salbutamol
Ca++ channel inhibitors - nifedipine.

and magnesium sulphate.

Future - K+ channel activators (Retigabine - treats epilepsy)? PDE inhibitors?

NO and COX2 inhibitors = no good!

Question 18

How do we predict SPTB?

Answer 18

Previous history!

Cervix/vagina - fetal fibronectin, cervical length
Amniotic fluid - IL6/8
Serum
Saliva - oestriol, progesterone.

Question 19

Prevention - prophylaxis?

Answer 19

1) Treat infection - antibiotics
2) Inhibit inflammation related events - COX2/PGR inhibitors
3) Prevent progesteron withdrawal - natural/synthetic supplements.
4) Maintain active cAMP system - inhibit PDE activity.

Question 20

Do COX2 inhibitor works to prevent SPTB?

Answer 20

NO! They make people deliver earlier!!

Question 21

Progesterone in PTL?

Answer 21

1) Functional progesterone withdrawal
2) MPA pevents PTL in animals (inc progesterone)
3) Progesterone antag induces delievery in animals and women.
4) Progesterone thought to be anti-inflammatory.

Question 22

Summary?

Answer 22

PTL/SPTB - global problem
Consequences - social, emotional and economical
Current prophylaxis and preventative treatments are not proven.
Need more understanding of mechanisms of pathophysiological events.