10.4 - Pregnancy, Parturition and Late Foetal Development Flashcards
How much does the embryo grow in the first trimester?
- embryo-foetal growth during the first trimester is relatively limited
- this is because early embryo is reliant on histiotrophic nutrition
- it is reliant on uterine gland secretions (uterine milk) and breakdown of endometrial tissues and maternal capillaries (to derive nutrients from maternal blood)
- the syncitiotrophoblasts that invade the maternal endometrium do this breakdown to fuel embryo development
As we go from the first to second trimester, how does the growth rate of the embryo change?
- significant increase in rate of foetal growth
- embryo changes to haemotrophic support at start of second trimester (around 12wks gestation)
- this means the foetus starts to derive nutrients from maternal blood
- achieved in humans through a haemochorial-type placenta where maternal blood directly contacts the foetal membranes
What happens in the early implantation stage (1)? (Origins of the placenta)
- syncitiotrophoblasts are invading surrounding endometrium to breakdown cells to provide nutrients to support embryo
- uterine gland secretions
- maternal capillary breakdown to bathe embryo in maternal blood which gives nutrients too
- amnion - derivative of epiblast which is the first of the foetal membranes and forms amniotic cavity
- amniotic cavity expands to become amniotic sac which surrounds and cushions foetus in 2nd and 3rd trimesters
What happens in the next stage of development (2), a few days later?
- invasion of syncitiotrophoblasts has become more extensive
- amnion’s amniotic cells are secreting secretions into space in the middle which will start to expand
- yolk sac formed from hypoblast
- chorion is another key foetal membrane - outer membrane surrounding whole conceptus unit
- embryo unit develops connecting stalk
- formation of trophoblastic lacunae
What is the connecting stalk?
Links developing embryo unit to the chorion
What are trophoblastic lacunae?
- large spaces filled with maternal blood formed by breakdown of maternal capillaries and uterine glands
- later in development, become intervillous spaces aka maternal blood spaces
What are foetal membranes?
- extraembryonic tissues that form a tough but flexible sac encapsulating the foetus and forms the basis of the maternal-foetal interface
- amnion - inner foetal membrane
- chorion - outer foetal membrane
- allantois
Where does the amnion come from and what does it do?
- inner foetal membrane
- arises from the epiblast - but does not contribute to the foetal tissues
- forms a closed, avascular sac with the developing embryo at one end
- begins to secrete amniotic fluid from 5th week - forms a fluid-filled sac that encapsulates and protects the foetus
Where does the chorion come from and what does it do?
- outer foetal membrane
- formed from yolk sac derivatives and the trophoblast
- highly vascularised (unlike amnion)
- gives rise to chorionic villi - outgrowths of cytotrophoblast from the chorion that form the basis of the foetal side of the placenta
What does the expansion of the amniotic sac do?
- expansion of the amnion by amniotic fluid accumulation forces the amnion into contact with the chorion, which fuse to form the amniotic sac
- amniotic sac has two layers - amnion on inside, chorion on outside
What are the allantois and where do they come from?
- outgrowths of the yolk sac
- grows along the connecting stalk from embryo to chorion
- becomes coated in mesoderm and vascularises to form the umbilical cord
What happens in the next stage of development (3)?
- cytotrophoblast forms finger-like projections through syncitiotrophoblast layer into maternal endometrium
- these are the primary chorionic villi and are an important part of the maternal-foetal interface
What are the chorionic villi important for?
- provide substantial surface area for exchange
- finger-like projections of the chorionic cytotrophoblast that then undergo branching
What are the three phases of chorionic villi development?
- primary - outgrowth of the cytotrophoblast and branching of these extensions
- secondary - growth of the foetal mesoderm into the primary villi
- tertiary - growth of the umbilical artery and umbilical vein into the villus mesoderm, providing vasculature
Describe the blood network around each villus.
- there is a convoluted knot of vessels that are dilated around each villus
- this slows down the blood flow to enable exchange between maternal and foetal blood
- they are surrounded by maternal blood in lacunae = facilitates exchange
- whole structure coated with trophoblast
How does the villus change from early to late pregnancy?
- early pregnancy - 150-200um diameter, approx 10um trophoblast thickness between capillaries and maternal blood
- late pregnancy - villi thin to 40um, vessels move within villi to leave only 1-2um trophoblast separation from maternal blood - reduced diffusion distance between maternal and foetal circulation
Describe the maternal blood supply to the endometrium.
- uterine artery branches to give rise to a network of arcuate arteries –> radial arteries
- radial arteries branch from arcuate arteries, and branch further to form basal arteries
- basal arteries form spiral arteries during menstrual cycle endometrial thickening
What is spiral artery remodelling?
- spiral arteries provide the maternal blood supply to the endometrium
- extra-villus trophoblast (EVT) cells coating the villi invade down into the maternal spiral arteries, forming endovascular EVT
- endothelium and smooth muscle is broken down - EVT coats inside of spiral vessels
- conversion - turns the spiral artery into a non-spiral low pressure, high conduit for maternal blood flow to feed the maternal blood spaces
Describe the final placental structure.
- the maternal unit is on the bottom side with the maternal blood supply made up of spiral arteries
- the spiral arteries supply the intervillous spaces, some of which drains from the maternal vein system
- on foetal side, we get chorionic villi formation which invade the trophoblasts, become branched and vascularised
- foetal circulatory system invade into chorionic villi which provide large SA between maternal blood and foetal chorionic villi
How is oxygen exchanged across the placenta?
Diffusional gradient (high maternal O2 tension, low foetal O2 tension)
How is glucose exchanged across the placenta?
Facilitated diffusion by transporters on maternal side and foetal trophoblast cells
How is water exchanged across the placenta?
- placenta is main site of exchange
- some crosses amnion-chorion
- majority by diffusion, though some local hydrostatic gradients
How are electrolytes exchanged across the placenta?
- large traffic of sodium and other electrolytes across the placenta
- combination of diffusion and active energy-dependent co-transport
How is calcium exchanged across the placenta?
Actively transported against a concentration gradient by a magnesium ATPase calcium pump
How are amino acids exchanged across the placenta?
Reduced maternal urea excretion and active transport of amino acids that make up urea to foetus where they can be used
How does mother’s circulation change through pregnancy?
- maternal cardiac output increases 30% during first trimester (stroke volume and rate)
- maternal peripheral resistance decreases up to 30%
- maternal blood volume increases to 40% (near term - 20-30% increase in erythrocytes, 30-60% increase in plasma)
- pulmonary ventilation increases by 40%
What is the placenta/foetus’ O2 consumption like?
- placenta consumes 40-60% glucose and O2 supplied
- but although foetal O2 tension is low, O2 content and saturation are similar to maternal blood
- embryonic and foetal haemoglobins - greater affinity for O2 than maternal haemoglobin
When are organs developed in embryos?
- most organ systems are completed by end of 1st trimester
- through 2nd and 3rd trimesters the organ systems mature
How does the circulatory system develop?
- begins with a tube of mesoderm that pumps blood by around day 22 of embryo development
- by 2nd trimester, circulatory system is pretty much complete
How does the foetal circulatory system differ to a neonate’s?
- placenta acts as the site of gas exchange for foetus
- ventricles act in parallel rather than series around same circulatory loop
- vascular shunts bypass pulmonary and hepatic circulations to allow heart to drive oxygenated blood from placenta with greater efficiency –> close at birth
How does the respiratory system develop?
- lungs begin as a bud around the foregut which branches in first trimester
- branches develop further in 2nd trimester and we get primitive air sacs at 20 weeks
- surfactant production begins around week 20 and upregulated towards term
- vascularisation of lungs at 28 weeks
- foetus spends 1-4h a day making rapid respiratory movements during REM sleep (practise breathing reflex for when foetus born and strengthens diaphragm)
How does the gastrointestinal system develop?
- formed from endoderm and yolk sac
- functional pancreas from start of 2T, insulin from mid-2T
- liver develops from 23 days and through 2T&3T
- liver glycogen progressively deposited - accelerates towards term
- large amounts of amniotic fluid is swallowed by foetus - debris and bile acids form meconium (first stool)
How does the nervous system develop?
- foetal movements begin late 1T, detectable by mother from 14 weeks
- stress responses from 18 weeks, thalamus-cortex connections form by 24 weeks
- foetus does not show conscious wakefulness - mostly in slow-wave or REM sleep
What do we think is the cause for the final development of these organ systems closer to term?
- organ maturation is coordinated by foetal corticosteroids
- increase in foetal corticosteroids from around mid-gestation to end of term
What is labour?
- safe expulsion of the foetus at the correct time
- expulsion of the placenta and foetal membranes
- resolution/healing to permit future reproductive events
What type of reaction is labour and why?
- labour has the characteristics of a pro-inflammatory reaction
- immune cell infiltration
- inflammatory cytokine and prostaglandin secretion
What is phase 1 - quiescence - of labour?
- prelude to parturition (happens from late 3T onwards)
- contractile unresponsiveness
- cervical softening
What is phase 2 - activation - of labour?
- preparation for labour
- uterine preparedness for labour
- cervical ripening
What is phase 3 - stimulation - of labour?
- actual process of labour - characterised by the three stages of labour
- uterine contraction
- cervical dilation
- foetal and placenta expulsion
What is phase 4 - involution - of labour?
- parturient recovery
- uterine involution
- cervical repair
- breast feeding
What is the first stage of labour?
- contractions start
- cervical dilation
- latent phase - slow dilation of the cervix to 2-3cm
- active phase - rapid dilation of the cervix to 10cm
- extensive stage (14h), latent and active phase roughly same duration
What is the second stage of labour?
- delivery of foetus
- commences at full dilation of the cervix (10cm)
- maximal myometrial contractions
- relatively quick - 2h around
What is the third stage of labour?
- delivery of the placenta
- expulsion of placenta and foetal membranes
- post-partum repair
- relatively quick (1-2h)
How long do deliveries take for a woman’s first delivery and subsequent ones?
- first delivery: 8-18h
- subsequent deliveries: 5-12h
What role does the cervix have when the foetus is being delivered?
- cervix has critical role in retaining foetus in uterus
- due to high connective tissue content to keep cervix closed, rigid, stretch-resistant
- achieved through bundles of collagen fibres embedded in a proteoglycan matrix
- near the time of delivery, cervical remodelling occurs - changes to collagen bundle structure underlie softening, but mechanisms unclear
Softening - What is the first phase of cervical remodelling?
- begins in first trimester
- measurable changes in compliance but retains cervical competence to keep foetus in uterus
Ripening - What is the second phase of cervical remodelling?
- weeks and days before birth
- monocyte infiltration and IL-6 and IL-8 secretion
- hyaluronan deposition
Dilation - What is the third phase of cervical remodelling?
- increased elasticity
- increased hyaluronidase expression –> hyaluronan breakdown
- matrix metalloproteinases decrease collagen content and increase elasticity of tissue
Post-partum repair - What is the fourth stage of cervical remodelling?
Recovery of tissue integrity and competency - allows subsequent pregnancies
What do we think is the cause of initiation of labour?
- the foetus determines the timing of parturition through changes in the foetal HPA axis
- corticotrophin releasing hormone (CRH) levels rise exponentially towards the end of pregnancy
- decline in CRH-binding protein levels, so bioavailable CRH increases
What do we think these rising CRH levels do in labour?
- promotes foetal ACTH release from pituitary which acts on foetal adrenal cortex to release cortisol
- this increasing cortisol drives placental production of CRH - positive feedback
- this stimulates DHEAS production by foetal adrenal cortex - substrate for oestrogen production
What is the importance of high progesterone through pregnancy?
- made by placenta and maintains uterine relaxation
- maintains endometrium lining
How does the relationship between oestrogen and progesterone levels near labour change?
There may be a shift in serum oestrogen:progesterone ratio in favour of oestrogen
What happens to progesterone receptors closer to labour?
- as term approaches, there is a switch from progesterone receptor A (PR-A) isoforms (activating) to PR-B and PR-C isoforms (repressive) expressed in the uterus
- this causes functional progesterone withdrawal - where the level of progesterone is still high but type of receptor has changed so it cannot act properly anymore
What happens to oestrogen receptors closer to labour?
Rise in oestrogen receptor alpha expression
What do the changes in oestrogen and progesterone receptors at labour mean?
- uterus becomes ‘blinded’ (non-responsive) to progesterone action and sensitised to oestrogen action
- control of these changes is unclear but likely leads to local changes in oestrogen:progesterone ratio in uterine tissues
What is oxytocin?
A nonapeptide (9 amino acid) hormone synthesised mainly in the utero-placental tissues and pituitary
What happens to oxytocin levels closer to labour and why?
- uterine oxytocin production increases sharply at onset of labour
- expression increase is driven by increase in oestrogen levels
- release promoted by stretch receptors (Ferguson reflex) - as foetus bears down on cervix, stretch receptors send signals to hypothalamus which acts on posterior pituitary to release oxytocin to act on uterus and myometrium
What does oxytocin signal through?
- G-coupled oxytocin receptors (OTR/OXTR)
- pre-labour - high progesterone inhibits OXTR expression in uterus = uterus relaxed
- rise in oestrogen promotes large increase in uterine OXTR expression
What are the functions of oxytocin in pregnancy?
- increases connectivity of myocytes in myometrium - the myocytes form a syncytium and oxytocin promotes gap junction connections between myocytes
- destabilise membrane potentials to lower threshold for contraction
- enhances liberation of intracellular Ca2+ ion stores
What are the primary prostaglandins (PGs) synthesised during labour?
- PGE2 - cervix remodelling - promotes leukocyte infiltration into cervix, IL-8 release and collagen bundle remodelling
- PGF2alpha - myometrial contractions - destabilises membrane potentials and promotes connectivity of myocytes (with oxytocin)
- PGI2 - myometrium - promotes myometrial smooth muscle relaxation and relaxation of lower uterine segment
How do rising oestrogen levels drive prostaglandin action in the uterus?
- rising oestrogen activates phospholipase A2 enzyme, generating more arachidonic acid for PG synthesis
- oestrogen stimulation of oxytocin receptor promotes PG release
What other factors are involved in cervical remodelling?
- peptide hormone relaxin
- nitric oxide (NO)
What is the integrated hypothesis for regulation of labour?
- production of CRH by foetal pituitary which acts on foetal adrenal glands to produce cortisol
- cortisol transferred to placenta where it triggers production of more CRH - positive feedback
- CRH on foetal adrenal promotes DHEAS which is converted to oestrogen
- oestrogen acts on myometrium, promoting expression of OXTR = uterus becomes sensitive to pituitary production of maternal oxytocin = triggers contractions
- oestrogen also promotes local production of oxytocin which stimulates contraction and promotes PG production
- PGs important for mediating myometrial contractions and helping soften/ripen cervix so dilation can occur
- progesterone inhibits OXTR in non-labour state to stop premature contractions
How do myometrial contractions work?
- myometrial muscle cells form a syncytium (extensive gap junctions) - transmits contractions across muscle of upper segment of uterus
- contractions start from fundus (top) and spread down upper segment
- these contractions are brachystatic - fibres do not return to full length on relaxation
- these contractions act to pull up the lower segment and cervix to form birth canal
Describe how the baby emerges?
- head engages with pelvic space at 34-38 weeks
- as labour occurs, pressure on foetus from myometrial contractions causes chin to press against chest (flexion)
- foetus then rotates so the belly faces the mother’s spine
- head expelled first after cervix dilates
- shoulder delivered sequentially (upper first) followed by torso
Describe how the placenta is expulsed and repaired?
- rapid shrinkage of the uterus after foetal delivery causes area of contact of placenta with endometrium to shrink
- uterine shrinkage also causes folding of foetal membranes - peel off the endometrium
- clamping of the umbilical cord after birth stops foetal blood flow to placenta –> villi collapse
- haematoma forms between decidua and placenta
- contractions expel placenta and foetal tissue
What happens after placenta expulsion?
- uterus remains contracted after delivery to facilitate uterine vessel thrombosis
- uterine involution and cervix repair restore non-pregnant state - why is this important?
- to shield the uterus from commensural bacteria
- to restore endometrial cyclicity in response to reproductive hormones to allow uterus to accept another embryo if egg is fertilised
