Physiology of labour - at or before term Flashcards
What does expulsion of the fetus require?
Co-ordinated contractions of the myometrium to increase intrauterine pressure.
Cervical softening (ripening)
What does the myometrium consist of?
Bundles of non-striated muscle fibres, plus connective tissue, nerves, blood and lymph vessels
Why does the myometrial bulk increase during pregnancy?
Primarily due to estrogens
Also due to:
* Muscle cell hypertrophy (from 50 to 500 um)
* Hyperplasia
* Increasing glycogen deposition
How are the muscle cells arranged in the myometrium?
Circularly in the inner wall and longitudinally on the outer wall.
Why is such a structure important?
Contractions from both directions will exert force circumferentially and along the axis of the uterus.
How do the muscle cells of the myometrium behave as a syncytium?
Depolarisation in one cell rapidly moves to the next cell because of special gap junctions.
How do contractions occur in the myometrium?
Spontaneous depolarizing pacemaker potentials occur. If threshold is exceeded, an action potential occurs –> rise in intracellular (Ca2+)
What are three ways to alter myometrial contractility?
1) Change the pacemaker potentials
2) Alter the threshold
3) Alter calcium release
Which factors promote and demote mymometrial contraction?
Refer to black and white diagram in Chang’s notes.
What is the cervix composed of?
High content of connective tissue (collagen fibre bundles in proteoglycan matrix)
What is the key role of the cervix in pregnancy?
Resists stretch
What does cervical softening involve?
1) Decrease in collagen fibres
2) Increase in glycosaminoglycans
In humans:
* Increase in keratan sulphate (doesn’t bind collagen tightly)
* Decrease in dermatan sulphate (binds collagen tightly)
* Loosening of collagen bundles
Which factors cause cervical softening?
1) Increased metalloproteases in the cervix
2) Influx of inflammatory cells
3) Increased proinflammatory cytokines (IL2, IL8)
4) Increase in inducible nitric oxide synthase (iNOS) - (an enzyme that makes nitric oxide) –
causing an increase in NO – note that NO relaxes the myometrium. This allows the cervix to soften before contractions begin
What is the clinical use of prostaglandins?
Often used to induce labour or for late abortion.
* PGE2 and PGF2alpha intravaginally or intracervically
* Used for induction of labour and late abortion
* Prostaglandin inhibitors arrest premature cervical ripening
What is the neuroendocrine reflex?
The actual process of labour that commences once the myometrium and cervix are ready.
What are the steps of the neuroendocrine reflex?
Sensory nerves in vagina and cervix –> somatosensory pathway in spinal cord –> brainstem, medial forebrain bundle –> supraoptic and paraventricular nuclei –> oxytocin release from posterior pituitary –> uterine contraction and cervical softening (in interaction with E, P, PGs, NO)
What is oxytocin synthesised as part of?
Preprooxyphysin in the supraoptic and paraventricular nuclei in the hypothalamus
How does preprooxyphysin become oxytocin?
The leader sequence of this big molecule is removed and the remainder is transported in a secretory granule down the axons in the posterior pituitary. While being transported, the remainder is cleaved into oxytocin and neurophysin 1.
How does oxytocin increase uterine contractions?
1) Acting directly on uterine smooth muscle cells causing contraction
2) Stimulating formation of prostaglandins in the decidua. These PGs enhance the oxytocin-induced contractions.
How does oxytocin help with milk ejection?
Contracts the myoepithelial cells of the breast.
How do levels of oxytocin change?
Basal maternal plasma levels increase gradually by 3-4 fold during pregnancy.
Pulses increase in frequency, duration and amplitude in late pregnancy and during labour.
What is myometrial transformation?
The ‘awakening’ of the myometrium to a state of responsiveness to endogenous stimulants (oxytocin, prostaglandins) to produce labour contractions.
What does the myometrial transformation involve?
Increase in the expression of a group of genes encoding ‘contraction associated proteins’ (CAP)
* Ion channels (Na+, Ca2+)
* Agonist receptors (for oxytocin, PG)
* Gap junctions
What does a rise in the estrogen/progesterone ratio cause?
Increased synthesis of PGs:
* via release of phospholipase A2 from lysosomes
* estrogen labilizes lysosomes
* progesterone stabilises lysosomes
Increased number of oxytocin receptors
* estrogen increases oxytocin receptors
* progesterone decreases oxytocin receptors
Increased release of PGs
* via increased number of oxytocin receptors
* oxytocin stimulates PG release
Induction of iNOS activity –> produces nitrix oxide to soften the cervix
Facilitation of the neuroendocrine reflex underlying oxytocin synthesis and secretion
Increase in CAP genes associated with uterine transformation
What does a mechanical pathway involve?
After a rise in the O/P ration, stretching of the uterus contributes to myometrial activation.
Why is a mechanical pathway also important to transformation?
Endocrine changes are not sufficient
What did the study in unilateral pregnant rats show?
- No increase in CAP expression in non-preg horn
- Mechanical stretch using a polyvinyl tube induced CAP in non-preg horn
- Mechanical stretch not effective prior to the increased E/P ratio
What determines the timing of parturition?
In many species the fetus itself determines the timing of parturition via maturational changes in the fetal hypothalamic-pituitary-adrenal axis.
Why does ablation of the adrenal gland cause prolonged pregnancy in sheep?
Because ACTH (adrenocorticotrophic hormone) from the foetal pituitary stimulates production of cortisol in the adrenal gland which converts progesterone into oestrogen.
Why is the human placenta unable to change progesterone into oestrogen?
It does not contain enzyme 17alpha-hydroxylase
How could the initiating factor be CRH?
CRH and CRH-BP are synthesised in the placenta and secreted into both maternal and fetal circulations.
As maternal levels of CRH-BP are high, only modest increases in ACTH and cortisol result.
Maternal plasma levels of CRH increase exponentially with gestation.
During the last month of pregnancy, CRH-BP drops –> rise in free CRH.
How does CRH affect the fetus?
In the fetus:
* CRH stimulates the pituitary gland (increases ACTH) and exerts a direct action on the fetal zone of the adrenal cortex –> increasing DHEAS.
* This increases placental production of estrogen –> increasing E/P ratio.
How does CRH affect the uterus?
- Stimulation of CRH receptors:
- increased production of locally acting prostaglandins (especially PGE2 & PGF2alpha)
- potentiates the contractile response of smooth muscle to oxytocin (via a prostaglandin dependent mechanism)
- NOTE: the CRH receptor isoforms change towards term from those favouring relaxation to those favouring contraction.
What are uterine contractures?
During the pregnancy the uterus shows recurring contractile events of low amplitude (3-10mmHg) and low frequency (0.5-3/h) with a duration of 3-15 min.
What is the flow of cell-free fetal DNA being the trigger?
Term gestation –> placental maturation and senescence of palcental trophoblast cells –> increased cell-free fetal DNA in maternal plasma –> TLR9 activation –> innate immune response by the chorion, decidua, myometrium and cervix –> increased proinflammatory cytokines and chemokines –> increased uterine-activation protein expression by the chorion, decidua, myometrium and cervix –> cervical ripening, membrane rupture, phasic uterine contractions –> parturition
What are contractions?
High frequency, high amplitude and short duration tightening known as contractions.
What are the two functionally distinct segments of the uterus?
1) Upper uterine segment: muscular
2) Lower uterine segment: relatively thin and amuscular. Unifies with the vagina during labour to provide a relatively passive fibromuscular birth canal.
What marks the start and end of the first stage of pregnancy?
The onset of regular, painful contraction associated with dilation and shortening of the cervix. Ends with full dilation of the cervix.
What are key features of the first stage of pregnancy?
Subdivided into:
Latent phase (slow dilation until about 3cm)
Active phase (rapid dilation)
- Each muscle cell becomes thicker and shorter; each contraction is followed by relaxation in which initial length is not regained
- Fundal musculature becomes thicker and uterine volume decreases
- The lower uterine segment does not contract - becomes continuous with the vaginal wall (effacement)
- The retraction ring gradually moves upwards
What starts and ends the second stage of pregnancy?
Begins at full dilation of the cervix and ends at complete delivery of fetus.
What is the key feature of the second stage of pregnancy?
Uterine contractions (aided by abdominal wall contractions) push the fetus down and through the pelvis.
What marks the start and end of the third stage of pregnancy?
Begins at the end of fetal expulsion and ends at delivery of the placenta.
What are key features of the third stage of pregnancy?
- A few min after delivery of the fetus and clamping of the cord, the placenta becomes detached from wall.
- The placenta is completely expelled by uterine contractions often aided by the midwife or obstetrician.
- Active management of Stage 3 involves:
- Oxytocin or syntometrine (oxytocin + ergometrine)
- steady traction on the umbilical cord
How can you calculate the expected date of delivery?
- Most infants deliver 280 +- 14 days after the first day of the last normal menstrual period (266 days post conception)
- Add 7 days to the date of the LMP, count back 3 months and add 1 year
What are the main risk factors for premature labour?
1) Premature rupture of the membranes
2) Previous preterm labour or low birth weight
3) Uterine and cervical abnormalities
* Short cervix
* Cervical incompetence
* Repeated 2nd trimester abortions
3) Uterine overdistension
* Multiple pregnancy
* Polyhydramnios
4) Infection - could be responsible for up to 40% of cases of preterm labour
* Bacterial vaginosis in early pregnancy carries high risk
* Urinary tract infection
What are some other risk factors for premature labour?
- Bleeding e.g placental abruption, abnormal placentation
- In vitro fertilization (even after correction for multiple births)
- Fetal abnormality/birth defect/intrauterine fetal death
- Medically indicated
- maternal complications like severe hypertension
- endangered fetus e.g fetal growth restriction, fetal distress
What are the smaller risk factors for premature labour?
Extreme stress, work/standing more than 2h a day, age < 17 or >35, short conception cycle, reduced BMI, smoking, drug abuse, low SES, male fetus
How is pre-term labour managed?
- Corticosteroids (betamethasone)
- Antibiotics if membranes ruptured
- Magnesium sulphate (neuroprotection <30 weeks)
- Totolytic agents
- calcium channel blockers (nifedipine)
- beta-antagonists (salbutamol)
- prostaglandin synthase inhibitors (indomethacin)
- oxytocin antagonists (atosiban)
- Progesterone - high risk pregnancies
- vaginal
- injections (17alphaOH progesterone caproate)
