Labour Flashcards
What is happening when the woman is pregnant and what happens when labour begins in the myometrium, cervix and membranes?
- During the antenatal (pre-labour) period, these are the three aspects to think about (the myometrium, the cervix and the membranes).
- The myometrium is the smooth muscle of the uterus. During the antenatal period, the myometrium must not contract until it is time to give birth (remains quiescent). Otherwise, there will be a problem; if the uterus contracts too soon, it is called pre-term labour. If it remains quiescent for a very long time, it is called post-term labour (post-maturity). This is also associated with problems. Labour must happen at the appropriate time. This is called term. The median duration of human pregnancy is 40 weeks. This is a period and there is variation on either side. The period between 37 and 42 weeks completed weeks is called term. Anything before this is called pre-term and everything happening after is called post-term. This is the duration in which most labours are meant to happen. If labour happens in this period of time, it is physiological (considered normal). This is the definition of the word term.
- As opposed to this antenatal period, intrapartum is when things have to change for labour to begin. The myometrium needs to contract. The cervix yields to uterine contractions, allowing the baby to be delivered. Changes must occur in the cervix to facilitate it in opening up. The cervix is opened up by these contractions of the uterus. The membranes should be broken; it is very uncommon for the membranes to be intact when the baby is born, because the processes of labour are enhanced by breaking the membranes.
- Historically, breaking the waters was the most effective way of starting labour. Breaking the waters when a woman was not in labour would then induce it. It still is the most effective way of inducing labour, but it is irreversible (clock starts ticking). This causes problems, e.g. prolonged breakage of waters, baby not coming out. Although it does remain the most effective method of inducing labour, it is not the most often used as there are more controlled (reversible) methods.
- If the myometrium contracts and relaxes, the baby will never be born. If the uterus contracts and pushes the baby, the baby would be sucked back in when it relaxes because the volume has to remain constant (unlike air or gas when the volume can be changed with pressure). There must be a permanent shortening of the muscle fibre length – this is known as RETRACTION (NOT relaxation). When the myometrium contracts, it shortens and when it relaxes, it does not come back to its original length (it retracts). There is a gradual pushing the baby down and it stays down without going back because there is a permanent shortening of the myometrium; it is contraction and retraction.
- The cervix is the neck of the womb
- The membranes surround the baby. The baby is in a bag of water which is enclosed by membranes (amniotic sac). They are intact in the antenatal period and ruptured in the intrapartum period,
- When labour begins, changes must occur = intrapartum. Myometrium must contract, the cervix yields open (passively). It is a result of contractions of the uterus.
How does the uterus contract?
- If the myometrium contracts and relaxes, the baby will never be born. These must be a permanent shortening of the myometrium. This is known as RETRACTION.
- There is this coupling of actin and myosin, which leads to binding together and bending of the head so the muscle fibre length decreases. This is all dependent on the presence of intracellular calcium. Calcium channels are present and intracellular calcium is required.
1) At position 1, the myosin head is at rest. Each myosin molecule has a long tail region with a globular head region. The tail adheres to the tails of other myosin to form the thick filament.
2) ATP at the myosin head gets hydrolysed by ATPase which powers the priming of the myosin head. This form ADP and P. The hydrolysis of ATP converts myosin to a high energy form which binds to actin.
3) Myosin is able to bind to actin on the myosin binding sites. Forms a cross-bridge and pulls the thin filament towards the centre of the sarcomere.
4) A power stroke occurs and ADP is released, Myosin undergoes a conformational change, Actin moves towards the sarcomere
5) ATP then comes along again and binds to the myosin head causing detachment of myosin from actin. The cross-bridge is then broken.
6) ATP hydrolysis then takes place and the myosin head binds on the next actin binding site - This calcium has to then be taken back for the muscles to relax. This is also an energy-dependent process. It is all dependent on calcium.
How do the vertical and horizontal muscle layers of the uterus contribute to pushing the baby out?
- When the uterus is contracting in labour, there is progressive effacement of the cervix.
- The cervix normally looks like a tube; it has a length (cervical canal) with an internal and external opening (the internal and external os). Nearer labour, there is no more length of the cervix (this is what happens to the neck of the moon). The internal opening cannot be differentiated from the external opening. The percentage decrease in the length of the cervix is called effacement. This often happens before labour even begins. This is under the control of several hormones. Once the cervix becomes very thin, it starts to open up in response to contractions of the uterus. If the uterus contracts equally from all sides, the baby will never be born. There has to be a gradient of contractions. The top of the uterus must contract harder and stronger for a longer period of time in order for the baby to be pushed down. It also must start contracting first before the rest of the uterus contracts. It is called a triple descending gradient (wave-like contraction which starts at the fundus). Contractions start from the top and then go down, so the baby is pushed down. If the reverse happened, the baby would then be pushed up (if the lower part of the uterus starts to contract first and stronger, then the baby will not cut come out).
- PROGRESSIVE EFFACEMENT OF CERVIX
What factors are important in the quiescent phase?
1) Progesterone
2) PGI2 (Prostacyclin - a variation of prostaglandins)
3) Relaxin (relaxes the uterus)
4) Parathyroid hormone-related peptide (PTHrP)
5) Calcitonin gene-related peptide, vaso-active
intestinal peptide
6) Nitric oxide (NO) = Smooth muscle relaxant, e.g. a potent vasodilator in blood vessels. Used when there is narrowing of blood vessels in the heart which often leads to angina pectoris. NO is not used directly; medicines which produce NO (nitric oxide donors) are used. Short-acting, so not used for high blood pressure (need a long-term solution).
- All these lead to increased intracellular (cAMP)or
(cGMP) which inhibit the release of intracellular
calcium for myometrial contractility
- All of these substances inhibit the release of intracellular calcium which downregulates contractile properties of the myometrium. It maintains the myometrium in a relaxed phase.
- All of these hormones are responsible for keeping the uterus in a quiescent phase. Therefore, the levels of all of these must be high during pregnancy. When it is time to begin labour, they must either increase or the levels of counteracting factors must increase. Otherwise, the uterus will not contract.
What factors are important in the activation phase?
1) Rise in estrogen and CRH
2) Mechanical stretch
3) up-regulation of a panel of genes required for
contractions: Connexin 43, prostaglandin and
oxytocin receptors (OTRs)
- The quiescent phase is the antepartum period (the long period between conception and labour). The duration of pregnancy is around 40 weeks since the last menstrual period.
- 40 weeks duration = menstrual age
- Gestational age = menstrual age. However, conception does not happen on the day of menstruation; it happens sometime later. This is not possible to pinpoint, so all calculations and terminology refers to menstrual age (first day of the last menstrual period). This is technically an overestimation by a couple of weeks.
- When it is time to go into labour, there is an activation (preparatory) phase; the environment has to be right. For the environment to be right, several things have to happen. Firstly, there is a rise in oestrogen and CRH.
- One theory is that when there is enough stretch in the uterus, it is time to give birth. One concept that supports this is that when there is too much stretch in the uterus, labour tends to come early, e.g. twins (median gestational age = 37 weeks, triplets (median gestational age = 35 weeks), quadruplets (median gestational age = 31 weeks). As the number of foetuses increase, the average age decreases. More stretch (too much water) = earlier labour.
- Genes controlling synthesis of prostaglandins (stimulants of the uterus) and oxytocin receptors are upregulated for labour to begin. Oxytocin is a hormone secreted by the pituitary that stimulates contractions of the uterus.
What factors are important in the stimulation phase?
1) Prostaglandins
2) Oxytocin
3) CRH
4) Increased synthesis of cytokines
- When the process of preparation has been completed, actual labour begins.
- Oxytocin is a hormone produced by the posterior pituitary which acts on the uterus.
- Lastly, there is the stimulation phase. When the process of preparation has been completed, this is when actual labour begins. PGs form the final common pathway in labour. Prostaglandins are used for starting the labour process and are involved in initiation of labour (PGs are increased in labour). Oxytocin stimulates the uterus. CRH is also involved. There are several varieties of cytokines, but many cytokines are proinflammatory substances; labour is in many ways a pro-inflammatory process. Many processes in labour are very similar to inflammation; when clinicians are trying to make a diagnosis of infection related to labour, it is difficult because all of the inflammatory markers are increased when a woman is in labour. Considering all the signs will result in overdiagnoses, while discounting signs because they are increased in labour would lead to underdiagnoses.
What factors are important in the initiation of labour?
1) Functional Progesterone withdrawal
2) Increased Estrogen bio-availability
3) CRH and neuro-endocrine mediators
4) Increased responsiveness of the myometrium
to prostaglandins and oxytocin
- An important factor in the initiation of labour is functional progesterone withdrawal. Progesterone levels increase as pregnancy advances and then plateau (remain constant). When a woman begins labour, progesterone levels do not change. This is why it is called functional progesterone withdrawal. There is also increased oestrogen bio-availability. Oestrogen and progesterone are competing hormones that antagonise each other (counteracting actions).
- Not only is oxytocin secreted, but the responsiveness to oxytocin is also increased. There is an increase in the concentration of oxytocin receptors, thereby increasing the sensitivity.
How is labour initiated?
- Exact mechanisms uncertain but believed to involve:
1. Progesterone = Progesterone is involved in keeping the uterus quiescent, so must be involved in initiating labour.
2. Oestrogen = Oestrogen is involved because it antagonises progesterone.
3. Oxytocin = Oxytocin is involved because it is used to start contractions (can be administered to improve contractions).
4. Relaxin
5. Corticotrophin-releasing hormone / fetal cortisol
6. Nitric oxide = NO keeps the uterus in quiescent phase.
7. Prostaglandins = PGs can be used as medication to initiate labour.
8. Inflammatory cytokines = labour is very similar to natural inflammation - Understanding of human physiology, particularly labour and pregnancy, is largely based on animal experiments, particularly sheep (foetal weight is similar, same number of babies born at a time etc). The approximate weight of a lamb is approximately 2.5 kg for a similar to humans. There are differences between human and sheep physiology, but they are still very similar. It was found that infusing sheep with corticosteroids initiates labour, but the same does not happen in humans. This experiment led to a different scientific breakthrough; it was found that administering corticosteroids to humans tends to prevent babies from developing respiratory distress syndrome due to prematurity. It turned out to be a treatment for reducing prematurity-related problems in babies, but this was an incidental finding. Overall, though, it is currently not known how labour begins in humans.
What is the role of progesterone in pregnancy?
- One of the main hormones of pregnancy
- Produced by corpus luteum in early pregnancy
and the placenta later - Cholesterol is converted to Progesterone by
the action of P450scc and 3βHSD - Progesterone is derived from cortisol (required for cortisol synthesis)
- Decreases myometrial contractility = Co-ordinated uterine activity needed; gap junctions are required for an impulse to travel from one cell to another. When the contractions start, all muscles have to start contracting. Therefore, they must communicate via gap junctions.
- Inhibits myometrial gap junction formation
- Stimulates uterine NO synthetase
- Stimulates cAMP and sequesters intracellular calcium in the sarcoplasmic reticulum (SR) = Inhibits contractility.
- Down-regulates prostaglandin production,
development of calcium channels and oxytocin
receptors = Downregulates factors that stop the uterus from contracting - inhibits collagenolysis in the cervix by increasing tissue
inhibitor of matrix metalloproteinase-1 (TIMP-1) = - As well as becoming shorter, the cervix becomes softer. This is controlled by the actions of progesterone..
What are the inhibitory roles of progesterone in pregnancy?
- Prostaglandin synthesis
- CRF secretion
- Interleukin synthesis
- Oestrogen receptor expression
- Oxytocin receptors affinity
Ultimately contributes to the inhibition of uterine contractility.
What are the inhibitory roles of progesterone in pregnancy?
- Prostaglandin degradation
- PTH-rp synthesis
- CGRP secretion
- CGRP and AM receptors expression
Ultimately contributes to the inhibition of uterine contractility.
How are progesterone levels affected in pregnancy?
- In most species, progesterone levels fall pre-labour
- This does not occur in humans, however there is
upregulation of (pro-inflammatory) PR-A, and
suppression of (anti-inflammatory) PR-B receptor
activity, resulting in “functional” progesterone
withdrawal. There is upregulation of different varieties of progesterone receptors. The levels of progesterone remain the same, but the action is modified through receptor expression = functional progesterone withdrawal - Increased PR-A/PR-B ratio is linked with activation of
nuclear factor kappaB (NF-κB) in the myometrium - NF-κB increases expression of COX-2 and various pro-inflammatory cytokines (e.g. IL-8 and IL-1b), which
cause cervical ripening and up-regulate oxytocin
receptor expression in the myometrium - In summary, it is making the environment favourable for action of substances that will allow contraction of the uterus.
What is the role of oestrogen in pregnancy?
- Essential for uterine development & function
- The placenta is the primary source
- Placenta relies on DHEAS from the fetal &
maternal adrenal glands for the supply of
precursor for estrogen synthesis. This suggests, in some ways, that the foetus would be able to regulate the onset of labour, because it is a contributor to DHEAS supply to the placenta. Both mother and baby’s adrenal glands produce DHEAS. It reaches the placenta and a variety of oestrogenic compounds are produced. They are all related with similar functions. Used to be measured as a reflection of placental function (no longer used), since the placenta is the source. - Both estrogen and progesterone increase
towards term but the ratio of estrogen to
progesterone begins to favor estrogen. When oestrogen predominates, labour is more likely to win.
What are the oestrogen-induced myometrial changes?
- Increase in the number of PG and OCT (oxytocin)
receptors. Increased oxytocin responsiveness. - Up-regulation of the enzymes responsible for
muscle contractions (myosin light chain
kinase, calmodulin) - Increase in connexin-43 synthesis & gap
junction formation in the myometrium. All of these factors are necessary for labour to begin. - Induction of collagenase & elastase: Cervical
ripening. Effects on the cervix = breaks down the connective tissue in the cervix, making it softer and more pliable (less resistant to contractions). Leads to cervical dilatation.
What is the role of oxytocin in pregnancy?
- Synthesised in hypothalamus and released from posterior pituitary gland of mother, also produced by myometrium, decidua, placenta and membranes
- Myometrial sensitivity to oxytocin increases near to
term due to changes in density (up to 200-300 fold)
and affinity of oxytocin receptors - Receptor concentration greatest in the fundus and
minimal in the lower segment and cervix. If everything contracted, the baby would not come out. Practically, the cervix does not have much contractile tissue at all. It has to dilate and the muscle fibres in the cervical region have to stretch (lengthens) for the baby to come through. This is one of the reasons why if the placenta is low, the chances that a woman bleeds more are high, because that area does not contract very well (there are not many muscle fibres). - Oxytocin receptor upregulation is promoted by
oestrogen and mechanical stretch - Increased inositol 1,4,5-triphosphate and intracellular Ca
- It acts on several kinds of smooth muscles.
- The levels of oxytocin increase even after the mother has given birth. It allows the uterus to return to its normal state (nearly) and allows the release of breast milk. This oxytocin also helps the uterus to contract and prevent postpartum haemorrhage.
- There are smooth muscles in the breast. Nipple stimulation causes those muscles to contract and it leads to expression of milk for the baby. The effects are many-fold.
- Nipple stimulation is a recognised way of starting labour because it leads to oxytocin release.
- Labour can be started by stretch, nipple stimulation, breaking water
