Pregnancy, Parturition and Late Fetal Development Flashcards
What occurs during the first trimester of pregnancy?
Single cell zygote to highly complex embryo
Body plan established - each of the major organ systems are put in place
Although the actual growth during the first trimester is limited
Why is growth limited during the first trimester?
Partly become the embryo is dependent on histiotrophic nutrition in the first trimester
Histiotrophic nutrition - derivation of nutrients from the breakdown of surrounding (endometrial) tissues i.e. when the syncitiotrophoblast invading the maternal endometrium
As it invaded, it broke down the local tissues and used those products of tissue breakdown to fuel the development of the embryo
Where else does the syncitiotrophoblast get nutrients from? Other than the breakdown of endometrial tissue
It can also breakdown maternal capillaries so the syncitiotrophoblast bathes in maternal blood - from which is derives nutrients
And glands within the endometrium which supply uterine milk - also a source of nutrients for the developing embryo
What happens between first and second trimester?
First trimester = limited growth
Between first and second trimester - rapid increase in rate of growth
Can this sudden increase in rate of growth in the second trimester be supported by histiotrophic nutrition?
No
How is the increase in rate of growth supported?
Switch to haemotrophic support at the start of the second trimester
Starts to derive nutrients from maternal blood
Achieved through activation of haemochorial-type placenta around the 12th week of gestation, where maternal blood directly contacts the foetal membranes (AKA chorion)
What is the the first foetal membrane?
The amnion - derivative of epiblast
But unlike the rest of the epiblast, does not go on to form part of foetus
Forms the amniotic cavity that goes on to become the amniotic sac (closed and avascular) - surrounds and cushions the foetus during the second and third trimester
What causes the amniotic sac to expand?
Secretions from the amniotic sac spilling into the amniotic sac space - fluid accumulation = amniotic space expands until the amnion and chorion join to for the amniotic sac = more fluid = more amniotic sac expansion
What is the second key foetal membrane?
Chorion - outer membrane surrounding the whole conceptus unit
What is the connecting stalk?
Part of extra embryonic tissues which grows from the embryo and connects the conceptus with the chorion
How are trophoblastic lacunae formed and what are they?
Formation trophoblastic lacunae =
As the syncitiotrophoblast invades the endometrium and breaks down the maternal capillaries and glands
The lumens of the maternal capillaries and glands as a consequence of breakdown - creating a continuous space through which maternal blood can flow
These spaces are called lacunae - when these large spaces develop and are filled with blood, they become known as intervillous spaces (AKA maternal blood spaces)
So maternal blood flows through those spaces and contacts the syncitiotrophoblasts
What are the foetal membranes?
Predominantly the amnion and chorion
Extraembryonic tissues that do not contribute to the foetus ultimately, instead form a tough but flexible sac encapsulates the fetus and forms the basis of the maternal-fetal interface
What is the amnion?
Inner of the foetal membranes - arises from the epiblast but does not contribute to fetal tissues
Forms a closed avascular sac with the developing embryo at one end
What happens to the amnion cells at the 5th week of gestation?
Amnion cells start to secrete amniotic fluid - amniotic space increases
Forms fluid filled sac that encapsulates and protects the foetus
What is the chorion?
Outer foetal membrane
Derived from yolk sac and part of the trophoblast
Highly vascularised - unlike the amnion
Why is the chorion important in placental development?
Gives rise to the chorionic villi - outgrowths of cytotrophoblasts from the chorion that forms the basis of the fetal side of the placenta
What happens as the amniotic sac expands?
Forces amnion into contact with the chorion
Fusion of the amnion and chorion = formation of the amniotic sac
What is the third foetal membrane?
Allantois
Derived from yolk sac - outgrowth of the yolk sac
Grows along the connecting stalk from embryo to chorion
Becomes coated in mesoderm and vascularises to form the umbilical cord
Why is the allantois important?
Still unclear
Seems to contribute partly to the embryonic bladder - maybe important in the removal of toxins from the developing embryo
Important role in the development of the umbilical cord - provides circulatory link from the embryo to the fetal side of the placenta
What forms the umbilical cord?
Connecting stalk
Allantois
Additional mesoderm
What are cytotrophoblast cells?
Sits on the outside of the chorion
Trophectoderm divides into trophoblast - trophoblast divides into the outer syncitiotrophoblast layer and proliferative cytotrophoblast inner layer (divides to give rise to cells that contribute to the syncitiotrophoblast)
Outgrowths of the cytotrophoblast form finger-like projections through syncitiotrophoblast layer into maternal endometrium called primary chorionic villi - begins to form part of the maternal foetal interface
Important in the development of the placenta
What are the chorionic villi and why are they important?
Derived from outgrowths of cytotrophoblasts
Provide substantial surface area for exchange (gases and nutrients)
Finger-like extensions of the chorionic cytotrophoblast, which 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 fetal mesoderm into the chorionic primary villi
Tertiary = growth of the umbilical artery and umbilical vein into the villus mesoderm, providing vasculature
What is the microstructure of terminal chorionic villi?
Capillary cast (trophoblast cast) of the vasculature of one of the chorionic villi - blood vessels come up through into the villus
Villus normally coated in trophoblast - the space surrounding it (outside trophoblast) would be filled with maternal blood (lacunae)
Capillary network in the villus forms a convoluted knot of vessels and vessel dilation
What does the convoluted knot structure and dilation of vessels allow for?
Combination of both slows down the blood flow through the terminal villi structures - enabling exchange between maternal and fetal blood
How big are the villi in early pregnancy?
150-200µm diameter
With a think layer of trophoblast - approx. 10µm trophoblast thickness over the surface, between capillaries and maternal blood
How big are the villi in late pregnancy?
Villi thin to 40µm,
Blood vessels within these villi move within the villi to become closer to the maternal blood supply
So the layer of trophoblasts laying over the villi shrinks to become thinner = 1-2µm trophoblast separation from maternal blood
Diffusion distance reduced between maternal blood and fetal circulation
How does the maternal blood supply perfuse the endometrium?
Uterine artery travels up to fuse with the ovarian artery
Uterine artery branches give rise to a network of arcuate arteries - supplies the uterus
Radial arteries branch from arcuate arteries, which go thorugh the myometrium of the unterus into the endometrium
Radial arteries branch further to form basal arteries
Basal arteries form spirals known as spiral arteries - supplies endometrium lining of uterus
What happens to the spiral arteries during the menstrual cycle?
Basal arteries begin to spiralise as the menstrual cycle goes on
These spiral arteries grow out (i.e. continue to grow and spiralise as endometrium thickens) during the menstrual cycle - during process of endometrial development / thickening
If implantation does not occur - there is loss of the endometrium and regression of the spiral arteries
If implantation does occur, the spiral arteries are stabilised and provides maternal blood supply to the foetus
When does spiral artery remodelling occur?
What happens in spiral artery remodelling?
Extensive remodelling of spiral arteries occurs during implantation and placental development
As the spiral arteries develop, the trophoblast cells on the outside of the villi starts to invade the maternal spiral arteries
Outgrowth of trophoblast down into maternal spiral arteries
Known as extra-villus trophoblast cells
What forms the endovascular EVT?
Extra-villus trophoblast (EVT) cells coating the villi invade down into the maternal spiral arteries, forming endovascular EVT
What is the role of the endovascular EVT?
Important in replacing maternal endothelium of the spiral blood vessels
As the endovascular EVT grow down, they break down the maternal endothelium and maternal smooth muscle - causes the spiral arteries to de-spiralise
Forms a new endothelial layer where the foetal EVT cells now coat the inside of the vessel
This causes the arteries to go from spiral to non-spiral (straight channels)
What is the process of going from spiral to non-spiral arteries called?
Conversion
What is the purpose of conversion?
Turns the spiral artery from a highly convoluted, high pressure vessels
Into a low pressure, high capacity conduit for maternal blood flow - to feed the maternal blood spaces
What can issues with conversion cause?
Pre-eclampsia
Intra-uterine growth retardation
What is the structure of the placenta and how does it contribute to exchange between the maternal and foetal blood?
Maternal unit forms the side closest to the mother:
Blood supply gives rise to spiral arteries
Spiral arteries supply maternal blood spaces with blood
Some of that blood drains away via the venous system
From the foetal side:
Formation of chorionic villi - invasions of trophoblast that branch and become vascularised
Invasion of fetal circulatory system into chorionic villi that provide the large surface area for exchange between mother and fetus
How does nutrient exchange across the placenta occur? What does it depend on?
Diffusion - size and morphology
Facilitated diffusion - concentration gradients or transporter abundance
Active transport - nutrient metabolism
Nutrient exchange across the placenta is nutrient specific - i.e. type of exchange depends on the nutrient being exchanged
How is oxygen exchanged in the placenta?
Diffusional gradient (high maternal O2 tension, low fetal O2 tension) - leads to diffusion of O2 across the placenta
How is glucose exchanged in the placenta?
Facilitated diffusion by transporters on maternal side and on the fetal trophoblast cells
How and where is water exchanged?
Placenta = main site of exchange
Though some crosses amnion-chorion meeting pointd
Majority by diffusion, though some local hydrostatic gradients
How are electrolytes exchanged?
Large traffic of sodium and other electrolytes across the placenta – combination of diffusion and active energy-dependent co-transport
How is calcium exchanged?
Actively transported against a concentration gradient by magnesium ATPase calcium pump
Important for the development of the foetal skeleton
How are amino acids exchanged?
Reduced maternal urea excretion and the amino acids that make up the urea are more efficiently utilised by being transported actively across the placenta to the foetus
What are the changes observed in the mother’s cardiac system?
Maternal cardiac output increases 30% during first trimester (increase in stroke vol & rate)
Maternal peripheral resistance decreases up to 30% (about a 1/3)
Maternal blood volume increases by 40% (near term - 20-30% erythrocytes, 30-60% plasma)
What are the changes observed in the mother’s respiratory system?
Pulmonary ventilation increases 40%
How much glucose and oxygen does the placenta consume?
Placenta consumes 40-60% glucose and O2 supplied by maternal circulation
What are the features of fetal blood O2?
But although fetal O2 tension is low, O2 content and saturation are similar to maternal blood
This is achieved because during the embryonic and foetal stages of development, there are specific developmental haemoglobins that are used (different to maternal or adult Hb)
Embryonic and fetal hemoglobins = greater affinity for O2 than maternal hemoglobin = binds ot O2 at a higher capacity
What happens to the organ systems in the first trimester VS the second and third trimesters?
First trimester = establishing the different organ systems
Second and third trimester = maturation and growth of the organ systems
How did the circulatory system begin?
Tube of mesoderm that was pumping blood by day 22 of embryo development
By the beginning of the 2nd trimester - relatively complete circulatory system
What are some differences between the circulatory system of the foetus compared to a neonate (newborn)?
Placenta acts as site of gas exchange for fetus (compared to lung in a newborn)
Ventricles act in parallel rather than series
Vascular shunts bypass pulmonary and hepatic circulation to permit the heart to drive oxygenated blood from the placenta around the body with greater efficiency -> these vascular shunts close at birth to give the circulatory system we know in neonatals and adulthood
How did the respiratory system begin?
Lungs began as a bud around the foregut, and that went through a period of branching in the first trimester to give off different lung structures
What are the stages of maturation for the respiratory system?
Primitive air sacs form in lungs around 20 weeks, vascularisation from 28 weeks
Surfactant production begins around week 20, upregulated towards term
Fetus spends 1-4hr/day making rapid respiratory movements during REM sleep even though it is within the amniotic sac and the lungs are not actually the site of gas exchange
This is practice for the breathing reflex for once it leaves the uterus and also important in development of diaphragm
How did the GI system begin?
Gut tube forms in the early embryo from the endoderm with some contribution from the yolk sac
Liver cells form around 23 days of development
What are the stages of maturation for the GI system?
Second trimester (2T) = developing pancreas
Endocrine pancreas functional from start of 2T, insulin secreted from mid-2T
Liver glycogen progressively deposited – accelerates towards term
Large amounts of amniotic fluid inhaled and swallowed by foetus – this fluid contains a large amount of debris, and that together with bile acids and cells from the developing intestine form the meconium (first stool)
Meconium delivered just after birth
How did the nervous system begin?
x
What are the stages of maturation for the nervous system?
Fetal movements begin late 1T, detectable by mother from ~14 weeks (early in 2T)
Foetus can make responses to stress from 18 weeks, but thalamus-cortex connections form around 24 weeks onwards (so sensory inputs can only be processed from around mid-pregnancy onwards)
Fetus does not show conscious wakefulness – mostly in slow-wave or REM sleep
What initiates the madevelopmental changes and maturation process of the organ systems?
Orchestrated by increase in foetal corticosteroids towards the end of pregnancy
Exponnential increase in level of foetal corticosteroids in foetal blood
What are the aims of labour?
Safe expulsion of the fetus at the correct time
Expulsion of the placenta and fetal membranes - so uterus is empty for future reproductive events
Resolution/healing to permit future reproductive events
What are the characteristics of labour?
Labour has the characteristics of a pro-inflammatory reaction
Extensive immune cell infiltration into the tissues of the female reproductive tract
Extensive inflammatory cytokine and prostaglandin secretion - important in orchestrating the timing and sequence of events of labour
What are the 4 phases of parturition (giving birth) and what occurs at each phase?
Phase 1: Quiescence (prelude to parturition)
Uterus is quiet, no contractions yet (contractile unresponsiveness), but there are some changes in the cervix - cervical softening
Occurs from late first trimester onwards
Phase 2: Activation (preparation for labour)
Some activity of the uterus (uterine preparedness)
Further developments in the cervix (cervical ripening) - getting it ready to dilate to allow for delivery
Phase 3: Stimulation (processes of labour
Uterine contractions, cervical dilations, fetal and placental expulsion (achieved via the 3 stages of labour)
Phase 4: Involution (paturient recovery(
Restoration of uterus to original size - uterine involution, cervical repair, onset of lactation for breastfeeding
What are the 3 stages of labour (comes in phase 3 of parturition)?
- First stage = contractions start, cervix dilation
- Latent phase = slow dilation of the cervix to 2-3cm
- Active phase = rapid dilation of the cervix to 10 cm - Second stage = delivery of the foetus
- Commences at full dilation of the cervix (10cm)
Maximal myometrial contractions - Third stage = delivery of the placenta
- Expulsion of the placenta and foetal membranes
- Onset of post partum repair
What is the timings for labour?
Prolonged first stage - the latent (slow increase in dilation) and active (accelerated increase in dilation) phases are roughly equal in duration
Second and third - each takes around an hour or two
Between 8 and 18 hours for first delivery
Between 5 and 12 for subsequent
What is the role of the cervix?
Cervix has a critical role in retaining the fetus in the uterus
Why is remodelling the cervix important tolabour?
Cervical softening = allows for cervix to dilate = opens birth canal to let foetus through
What features of the cervix allow it to function to retain the foetus in the uterus?
High connective tissue content:
Provides rigidity and stretch resistance
This is achieved through bundles of collagen fibres within the cervical tissue embedded in a proteoglycan matrix
As time of delivery is approached, there are changes to collagen bundle structures - remodelling of collagen underlines cervical softening for dilation, but mechanism unclear
When does cervical softening begin?
Begins in first trimester
Measurable changes in compliance (in terms of stretch resistance) but retains cervical competence (i.e. cervix remains closed and capable of keeping the foetus inside the uterus)
When does cervical ripening occur?
As you get close to birth – weeks and days before birth
Characterised by extensive immune cell infiltration of the cervix
Monocyte infiltration and IL-6 and IL-8 secretion
Hylaluron deposition
When does cervical dilation occur?
What is cervical dilation?
Occurs with the onset of labour - opening up the cervix to allow the transit of the foetus
Dilation = increased elasticity
Characterised by increased hyaluronidase expression -> leads to HA breakdown
MMPs (MatrixMetalloProteinases) - breaks down collagen and so decreased collagen content = increased elasticity of tissue
When does post-partum repair begin?
What occurs during post-partum repair?
After the foetus is born
Recovery of tissue integrity and competency - ensures if the woman gets pregnant again, the cervix is capable of keeping the foetus within the uterus
What do we currently think are the triggers for the initiation of labour?
Fetus determines timing of delivery through changes in fetal HPA axis - so through increasing amounts of corticosteroids
CRH (corticotrophin releasing hormone) production and release rises exponentially towards the end of pregnancy
Decline in CRH-BP (corticotrophin releasing hormone binding protein) levels, so CRH bioavailability increases
What is the role of Corticotrophin-releasing hormone (CRH) in labour?
Increased level of CRH acts on foetal adrenal cortex = promotes fetal ACTH and cortisol release
Cortisol travels via foetal circulation to placenta
Increasing cortisol drives placental production of CRH -> Positive feedback loop (as placental CRH travels back to foetus to drive more foetal CRH production)
CRH also stimulates DHEAS production by the fetal adrenal cortex -> substrate for estrogen production by the placenta
What are levels of oestrogen and progesterone through pregnancy?
Oestrogen and progesterone conitnue to increase throughout the pregnancy
This high progesterone level is produced by the placenta, and is maintained through pregnancy to maintain uterine relaxation
What happens to the oestrogen:progesterone ratio around the time of birth?
Serum oestrogen:progesterone ratio may shift in favour of oestrogen and reduce the ratio overall
And this may be associated with the onset of labour – this is unclear in humans but is true in other mammals e.g. sheep
What are the changes in oestrogen and progesterone signalling as delivery approaches?
As term approaches, we start ot approach delivery = switch from PR-A (progesterone receptor A) isoforms (activating functions of progesterone) to PR-B and PR-C (repressive functions of progesterone) isoforms expressed in uterus
Leads to functional progesterone withdrawal - so although levels of progesterone remain high, the change in the type of receptor = uterus no longer reacts to progesterone
Rise in Oestrogen Receptor Alpha expression within the uterus = uterus sensitised to the action of oestrogen
So overall, although levels of progesterone and oestrogen stay high, it becomes blinded to the action of progesterone whilst being sensitised to the action of oestrogen
What is driving the change in the oestrogen:progesterone ratio?
Unknown what is driving this change
But locally, in the uterine tissues, oestrogen:progesterone ratio changes where oestrogen = high, progesterone = low
What is oxytocin and what promotes its release?
Nonapeptide (9aa) hormone synthesized mainly in the utero-placental tissues and pituitary
Change in oestrogen:progesterone ratio = production of oxytocin
What happens to uterine oxytocin during labour?
Uterine oxytocin production increases sharply at onset of labour - partly driven by oestrogen so increasing levels of oestrogen production by the placenta promotes local uterine production of oxytocin
Expression increase is driven by increase in oestrogen levels
But predominantly, oxytocin production comes from maternal pituitary - release promoted by stretch receptors as the foetus bares down on the cervix, stretching it -> Ferguson reflex (i.e. the neuroendocrine stretch reflex)
Stretch receptors send signals to hypothalamus, firing of hypothalamus onto posterior pituitary triggers release of oxytocin from posterior pituitary into maternal circulation where it acts back onto the uterus and myometrium
How does Oxytocin signal?
Signals through G-protein coupled receptor known as the oxytocin reception = OTR / OXTR
How do the levels of oxytocin receptors (OXR / OXTR) change from pre-labour to labour?
Pre-labour =
Through most of pregnancy = progesterone dominance
Progesterone inhibits OXTR expression in the myometrium of the uterus = uterus relaxed
Labour =
Rise in oestrogen promotes large increase in number of uterine OXTR expression
This sensitises the myometrium of the uterus to oxytocin
What are the functions of oxytocin?
Increases connectivity of myocytes in myometrium (myocytes form syncytium in the myometrium, allowing myometrium to act as a syncitium - fusion of the cells so there are no cell boundaries)
Destabilise membrane potentials to lower threshold for contraction
Promotes liberation of intracellular Ca2+ ion stores - which additionally aids contraction
What does oxytocin work in conjunction with?
Prostaglandins (PGs)
What are prostaglandins (PGs) and what are the 3 primary PGs synthesised during labour?
Key effectors of labour
Primary PGs synthesised during labour = PGE2, PGF2alpha and PGI2
How do rising oestrogen levels drive PG action in the uterus?
- Rising oestrogen activates phospholipase A2 enzyme, generating more arachidonic acid for PG synthesis
- Oestrogen stimulation of oxytocin receptor (OXTR) expression promotes PG release thorugh oxytocin signalling
What is the function of PGE2?
Cervix re-modelling
Promotes leukocyte infiltration into the cervix, IL-8 release, and ultimately resulting in collagen fibre rebundle-ing that allow the softening and ripening of the cervix
What is the function of PGF2 alpha?
Predominantly acting on the myometrium
Myometrial contractions
Alongside oxytocin, helps destabilise membrane potentials and promotes connectivity of myocytes
What is the function of PGI2 (pee-gee-eye-two)?
Acting on the myometrium
Promotes myometrial smooth muscle relaxation and particularly relaxation of lower uterine segment
Important that inbetween myometrial contractions there is some relaxation, because that relaxation allows the blood flow to return into the uterus and placenta to ensure blood flow to foetus
What are other factors important for cervix remodelling?
Peptide hormone relaxin - levels increase sharply towards end of pregnancy = important in cervix remodelling
And nitric oxide (NO) implicated in cervix re-modelling
What is the integrated hypothesis for the regulation of labour?
Foetal CRH production by foetal pituitary acts on foetal adrenal cortices
Foetal adrenals produce foetal cortisol
Foetal cortisol transfers to placenta to trigger further production of placental CRH
Placental CRH acts back as a positive feedback loop on the foetal CRH production, to ultimately promote more cortisol production
The CRH acting on the foetal adrenal also promotes production of DHEAS, which is converted to oestrogen in the placenta
Oestrogen acts on myometrium promoting the expression of the oxytocin receptor
Uterus becomes sensitive to the pituitary production of maternal oxytocin and that triggers contractions
Oestrogen also promotes local production of oxytocin, which acting via OXTR stimulates contractions and prostaglandin production
PGs (particularly PF2 alpha) mediate myometrial contractions and help to soften and ripen the cervix to ensure dilation can occur
What happens in the non-labouring state to stop premature contractions?
Progesterone inhibits the production of these oxytocin receptors that keeps the myometrium quiescent
Stops contractions occurring prematurely
How do the myometrial contractions work?
Driven by the top part of the uterus - known as the fundus; but delivery also many other parts of the uterus e.g. dilated cervix, lower segment of uterus = passive (does not contribute to contractions), upper segment of uterus = muscles driving contractions
Myometrial muscle cells form a syncytium (extensive gap junctions so contractions can transmit across muscle of upper segment)
Contractions start from the fundus, spread down upper segment
Muscle contractions are brachystatic –fibres do not return to full length on relaxation between contractions
So each consequent contraction opens the cervix and lower segment until complete dilation is achieved
This also causes lower segment and cervix to be pulled up - forming the birth canal
What happens to foetal positioning towards the end of term?
Head engages with pelvic space 34-38wks
Pressure on fetus from contractions causes chin to press against chest (flexion)
How is the foetus expelled as delivery progresses?
Fetus rotates (belly to mother’s spine)
Head expelled first after cervix dilates
Shoulders delivered sequentially (upper first) followed by torso
Rest of foetus can follow quickly once shoulders are out
What occurs to allow for placental expulsion?
Expulsion of placenta achieved by collapse of uterus after delivery
Rapid shrinkage of the uterus after fetal delivery causes area of contact of placenta with endometrium to shrink
Uterine shrinkage also causes folding of fetal membranes – peel off the endometrium
Clamping of the umbilical cord after birth stops fetal blood flow to placenta - leads to villi collapsing
Triggers haematoma formation between decidua and placenta
That, couples with ongoing uterine contractions expel the placenta and foetal tissues
How is the uterus repaired?
Uterus remains contracted after delivery to facilitate uterine vessel thrombosis and healing - prevent intrauterine bleeding
Eventually, restoration of the uterus and repair of the cervix - uterine involution and cervix repair to restore non-pregnant state
Important to stop commensal bacteria that live within the reproductive tract getting up in the uterus - shielding uterus from commensural bacteria
Restore endometrial cyclicity in response to reproductive hormones to ensure the uterus is ready for consequent implantations of embryos if another one comes in the next reproductive cycle
