Labour and Delivery (21.02.2020) Flashcards
Miscarriage
(<23 weeks of gestation)
~350,000 p.a., within 13 weeks, ~7,000 late miscarriages
Term delivery
Term: 37-41 weeks of gestation
~700,000 infants p.a.
~525,000 labour (~75%)
~175,000 elective Caesarean section (~25%)
Pre-term delvery
~80,000 infants p.a.
~45,000 preterm labour
~35,000 preterm emergency Caesarean section
- when labour starts it is very difficult to stop it - if the mother goes into labour early there is not much you can do
- medical reasons for the mother to deliver early
- medical reasons for the baby to be delivered early
Labour - what are the 2 things that happen?
- fundally dominant contraactions
- cervical ripening (firm in order to hold baby for long -> soft and flexible) and effacement
The process of labour
Independent of gestational age:
- Cervical ripening and effacement (increasing)
- Co-ordinated myometrial contractions (increasing)
- Rupture of fetal membranes
- Delivery of infant
- Delivery of placenta
- Contraction of uterus
Labour duration
12-48 h
there are some small contractions in the latent stage in pregancy (about 8 weeks before giving birth)
Phases of labour
1: many hours, contractions, cervical changes
2: 2 hours, baby delivered
3: 30 minutes, placenta delivered
labour is quicker after the second time.
Initiation of labour
Term
- Not really sure!!
- Estrogens; low progesterone?; CRH?; oxytocin?
Preterm
- Intrauterine infection
- Intrauterine bleeding
- Multiple pregnancy
- Stress (maternal)
- Others
Cervical ripening and effacement
- Change from rigid to flexible structure
- Remodelling (loss) of extracellular matrix
- Recruitment of leukocytes (neutrophils)
- Inflammatory process
- Prostaglandin E2, interleukin-8
- Local (paracrine) change in IL-8
Co-ordinated myometrial contractions
- Fundal dominance
- Increased co-ordination of contractions
- Increased power of contractions
- Key mediators
- Prostaglandin F2a (E2) levels increased from fetal membranes
- Oxytocin receptor increased
- Contraction associated proteins
Rupture of fetal membranes
- biochemically a part of labour
Loss of strength due to changes in amnion basement component
Inflammatory changes, leukocyte recruitment
Modest in normal labour, exacerbated in preterm labour
Increased levels and activity of MMPs
Inflammatory process in fetal membranes
Summary of tissues, structures and processes in labour
Cervix
Prostaglandin E2, interleukin-8, MMPs
Myometrium
Prostaglandin F2a (E2) levels increased from fetal membranes
Oxytocin receptor increased
Contraction associated proteins
Fetal membranes
Inflammatory process in fetal membranes
PGs, interleukins, MMPs
NFKB
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What is an important factor in labour?
NFKB
- Almost all pro-labour genes have NFkB binding domains in their promoters
- Modification of NFkB sites in promoter sequences leads to loss of expression in cells or in expression vectors
Inflammation and labour
- Inflammatory changes are strongly linked with labour
- Activators of inflammation are readily linked with preterm labour (eg intrauterine infection)
- What about term labour?
- CRH rises close to labour and delivery
- COX 2 rises before delivery
PAF
= platelet activating factor
- Part of lung surfactant
- Surfactant proteins and complexes
- Produced by maturing lung, before birth
- Levels in amniotic fluid increase near term
- Fetal signal of maturity
Initiation of term labour
- CRH and PAF can up-regulate inflammatory pathways in fetal membranes
- Candidate initiators of term human labour (you would have to do antibody testing in a woman in labour to test this, which would have ethical issues)
What may predispose to labour?
- Anything that increases CRH may predispose to labour (stress, multiple infants)
- Anything that increases muscle contraction may predispose to labour (excess stretch of uterus)
- Anything that activates inflammatory cascades may predispose to labour
- The above apply to preterm labour (intrauterine infection, bleeding, twins)
Progesterone and human pregnancy
- Progesterone is NEEDED to sustain pregnancy
- Progesterone receptor blockade: pregnancy loss
- Progesterone levels remain very high until after delivery of the placenta (unlike sheep)
- Effect of progesterone lost in normal term labour
- progesterone binds to NFKB and stops it working
- stops myometrial contraction etc.
- at the end of pregnancy there is an increase in NFKB and a downregulation of progesterone receptors.
Summary of labour
- Labour strongly resembles an inflammatory response in fetal membranes and cervix
- The main active tissues are myometrium and cervix
- The key regulator seems to be NFkB
- Term and preterm labour differ mainly in the initiating factors
- Maternal progesterone levels remain high during labour – ‘functional progesterone withdrawal
Delivery at different gestational age timimgs
Term
- 37-41 weeks
Post-term
-42 weeks or more
Pre-term
- 22-37 weeks
Extremely preterm
- 22-28 weeks
Very preterm
- 28-32 weeks
Moderate to late preterm
- 32-36 weeks
Miscarriage
- Less than 22 weeks (non viable infant delivered).
Early miscarriage
- First trimester
Late miscarriage
- Second trimester less than 22 weeks.
Definition of human labour
The expulsion of the foetus and the placenta from the uterus
Three stages of labour
- first stage: beginning with the onset of uterine contractions through the period of dilation of the os uteri;
- second stage, the period of expulsive effort, beginning with complete dilation of the cervix and ending with expulsion of the infant;
- third stage or placental stage, the period beginning at the expulsion of the infant and ending with the completed expulsion of the placenta and membranes.
Why can labour last for a long time?
The uterus and cervix, which are the main tissues involved in labour, have to undergo a substantial change in structure and functions as they transition from what is needed for pregnancy (in which state they have been for 9 months) to what is needed for the delivery of the infant.
What are the main events of human labour?
- Cervical ripening and effacement
- Co-ordinated myometrial contractions, Preceded by “Braxton Hicks contractions” or ‘contractures’
- Rupture of fetal membranes
- Delivery of infant
- Delivery of placenta
- Contraction of uterus to limit maternal blood loss
What happens during the 1st stage of labour?
- The clinical definition of labour includes both the changes in the cervix, and in the myometrium, which are integral to the first stage of labour
- Rupture of the fetal membranes also normally occurs during the first stage.
- This stage of labour is usually the longest lasting for ~8 hours – this is likely to be longest in a woman having her first baby, and shorter in subsequent pregnancies.
- Note that this stage is very variable, with both shorter and longer times being quite common.
What happens during the 2nd stage of labour?
- Delivery of the infant is the second stage of labour
- this usually last about 30 minutes, but again can be longer in a first pregnancy and shorter in following pregnancies.
What happens during the 3rd stage of labour?
- delivery of the placenta
- should occur within 30 minutes of delivery of the infant.
- Delivery of the placenta is associated with very powerful contractions of the uterus, leading to a rapid decrease in overall size – this is referred to as involution.
- Once the placenta has been delivered, this involution of the uterus is very important, as this is the primary process through which blood flow through the spiral arteries is stopped.
- This process is linked to increased maternal levels of oxytocin – if it does not occur spontaneously, an injection of oxytocin (or similar muscle contracting agent) can be given to accelerate the process.
Involution
- very powerful contractions of the uterus after the delivery of the placenta
- rapid decrease in overall size of the uterus
- to stop blood flow through the spiral arteries and a r
Cervical ripening and dilatiation
- requires extensive remodelling of the extracellular matrix of the cervix, a process that can take many hours.
- This process is also accelerated by the increasing pressure of the fetal head on the cervix, caused by the increasing strength and decreasing gaps between myometrial contractions.
Mechanisms of labour - structures involved
Cervix
Prostaglandin E2, interleukin-8, Matrix metalloproteinases (MMPs)
Myometrium
Prostaglandin F2α (E2) levels increased from fetal membranes
Oxytocin receptor increased
Contraction associated proteins increased
Fetal membranes
- Inflammatory process in fetal membranes
- Prostaglandins, interleukins, MMPs
- These changes may generally be described as ‘inflammatory’, as they involve molecules that are present during inflammatory processes anywhere in the human body.
It seems that similar mechanisms are involved in labour at all gestational ages, so the changes summarised above will be present during preterm labour at 28 weeks, and during term labour at 40 weeks of gestational age.
Initiation of labor
- not fully understood
- integrate both the hormonal and inflammatory factors that have been implicated in the initiation of normal term human labour
Term
- Not really sure!!!
- Estrogens; low progesterone?; CRH?; oxytocin?
Preterm
- Intrauterine infection
- Intrauterine bleeding
- Multiple pregnancy
- Stress (maternal)
- Others
What fraction of human pregancies are delivered at term?
90%
= 37-41 w
Maternal risks
- if mother is in poor health in pregnancy (e.g. due to socio-economic factors such a poor nutrition), then the additional strain on her system caused by pregnancy may have considerable impact.
- Pre-eclampsia affects the maternal vascular system, which can pose risks to the health of the mother.
- Overall the main risk to the mother is the process of labour itself, particularly the necessity for uterine involution after delivery of the placenta. Due to the remodelling of the spiral arteries (see Session 3), they cannot vasoconstrict in the normal way to decrease blood flow, and hence blood loss into the uterine lumen. The powerful uterine contractions of involution effectively close the spiral arteries, and limit blood loss. It has been estimated that 1%-3% of women died from complications of pregnancy during pre-medical centuries – and this refers to each pregnancy, so with large numbers of serial conceptions, overall maternal death rates could be high (10 pregnancies, with a 2% risk of peripartum in each = 20% maternal death rate).
- Preterm labour and delivery does not pose any additional risk to the mother; the smaller size of the infant in preterm deliveries may lead to less affect on maternal tissues.
fetal risks
- Delivery at term normally has few specific risks for the infant, but delivery at gestations less than 32 weeks are much more likely to cause infant morbidities or mortality.
- Data from one study serves to emphasise the main points: Survival increased rapidly with increasing GA so that by 26 completed weeks of pregnancy, nearly 80% of babies left hospital alive. The great majority of these infants had major morbidities (87%), so that their quality of life, and life expectancy will be severely affected. Ongoing medical support may well be needed.
- In addition to the risks of early delivery, linked to incomplete development of lungs, brain, digestive or immune systems, it seems that the fetal brain is particularly sensitive to inflammatory mediators. As labour is an inflammatory process, and one clear cause of preterm labour is intrauterine infection, the incidence and severity of brain damage is particularly high in these extremely preterm infants.
Causes of early delivery
Many of these extremely preterm labour cases are linked to intrauterine infection, or other uterine complications such as bleeding, but not all causes have been identified.
From when is the conceptus referred to as a human?
After 8 w of development, the conceptus is referred to as a fetus (being recognisable as human), and the later stages of pregnancy are concerned mostly with growth and elaboration of the structures that develop during the first two months.
What is the main difference in terms of mechanism of term and pre-term labour?
Term and preterm labour differ mainly in the initiating factors
What is the key regulator in labour?
NFKB (=pro inflammatory TF)
Feed onward mechanism, this might be why is is difficult to stop labour
contractions in labour
- fundally dominant contractions
What are some causes of pre-term labour?
Intrauterine infection Intrauterine bleeding Multiple pregnancy Stress (maternal) Others
Mechanisms: Cervical ripening and effaacement
- Change from rigid to flexible structure
- Remodelling (loss) of extracellular matrix
- Recruitment of leukocytes (neutrophils)
- Inflammatory process
- PGE2, IL-8
- Local (paracrine) change in IL-8
Mechanism: Co-ordinated myometrial contractions
- Fundal dominance
- Increased co-ordination of contractions
- Increased power of contractions
- Key mediators
- Prostaglandin F2a (E2) levels increased from fetal membranes
- Oxytocin receptor increased
- Contraction associated proteins
Mechanism: Rupture of fetal membranes
Loss of strength due to changes in amnion basement component
Inflammatory changes, leukocyte recruitment
Modest in normal labour, exacerbated in preterm labour
Increased levels and activity of MMPs
Inflammatory process in fetal membranes
Overwiev of labour signalling
- Many initiators -> NFKB -> Many genes, mostly ‘inflammatory’: COX-2 (prostaglandins - PGs), IL-8, IL-1b, MMPs, Oxytocin receptor, PG receptors; contraction-associated proteins
- Almost all pro-labour genes have NFkB binding domains in their promoters
- Modification of NFkB sites in promoter sequences leads to loss of expression in cells or in expression vectors
Platelet activating factor
- Part of lung surfactant
- Surfactant proteins and complexes
- Produced by maturing lung, before birth
- Levels in amniotic fluid increase near term
- Fetal signal of maturity
How do CRH and PAF act on labour?
- CRH and PAF can up-regulate inflammatory pathways in fetal membranes (e.g. PG, IL)
- Candidate initiators of term human labour
4 things that can predispose to labour
- Anything that increases CRH may predispose to labour (stress, multiple infants)
- Anything that increases muscle contraction may predispose to labour (excess stretch of uterus)
- Anything that activates inflammatory cascades may predispose to labour
- The above apply to preterm labour (intrauterine infection, bleeding, twins)
Progesterone in human pregnancy
- Progesterone is NEEDED to sustain pregnancy
- Progesterone receptor blockade: pregnancy loss
- Progesterone levels remain very high until after delivery of the placenta (unlike sheep)
- Effect of progesterone lost in normal term labour
interaction between NFkB and PR
- mutually negative
- both repress one another
Progesterone receptor
- PR-B mediates the main effects of progesterone via gene expression
- PR-A is less able to mediate these effects
- Ratio of PR-A : PR-B increases at term
- Loss or change in PR may lead to ‘functional progesterone withdrawal’
