Pregnancy, Parturition and Late Fetal Development.

Question 1

LO:

Answer 1

• Embryo development: Summarise the key developmental events occurring in embryo in the first trimester.
• Pregnancy physiology: Summarise the key changes in maternal physiology across the course of pregnancy.
• Fetal development: Summarise the key developmental events occurring in the fetus in the second and third trimesters
• Parturition: Summarise the major events of parturition and the mechanisms regulating this process

Question 2

Session Plan: Pregnancy, parturition and late fetal development

Answer 2

Question 3

Fetal growth acceleration occurs with changes in support

Answer 3

• Embryo-fetal growth during the first trimester is relatively limited
• Early embryro nutrition is histiotrophic
• Reliant on uterine gland secretions and breakdown of endometrial tissues
• Switch to haemotrophic support at start of 2nd trimester.
• Achieved in humans through a haemochorial-type placenta where maternal blood directly contacts the fetal membranes.

Notes from lecturer:

So although, we go from a relatively simple single celled zygote to a highly complex embryo. By the end of the first trimester, with the body plan established and each of the major organ systems in place, the actual amount of growth that occurs in the embryo over that first trimester is relatively limited.

That’s partly because the embryo is dependent on histiotrophic nutrition in the first trimester. And histiotrophic nutrition is the derivation of nutrients from the breakdown of surrounding tissues. You remember in the last guided online learning session, we saw the synctiotrophoblast invading the maternal endometrium. And as it invaded, it broke down the local tissues and used those products of tissue breakdown to fuel the development of the embryo. Along with those tissue breakdown products, there’s also some breakdown of the maternal capillaries. So syncitiotrophoblast can be bathed in a bit of maternal blood from which it can derive nutrients. And there are also glands within the endometrium which supply something known as uterine milk, which is also a source of nutrients for the developing embryo.

But you can see from this graph here that as we proceed from the first trimester and into the second trimester, there’s a significant increase in the rate of foetal growth and that increase in foetal growth cannot be maintained or supported by histiotrophic nutrition. We therefore see a switch from histiotrophic support to haemotrophic support at the start of the second trimester. That is to say, in haemotrophic support the foetus will start to derive its nutrients from the maternal blood.

There are lots of different types of placenta across mammals, reptiles and birds, but in humans we have what we call a haemochorial type placenta. That is to say, the maternal blood is directly in contact with the chorion or one of the foetal membranes. And it’s the activation of this haemochorial type placenta around the 12th week of gestation, which allows the switch from histiotrophic to haemotrophic support and the resulting uptick in foetal growth.

Question 4

Origins of the placenta: early implantation stage

Answer 4

So if we want to think about how the placenta develops, we need to wind right back to that early implantation stage. And of course, this is when that histiotrophic nutrition is occurring. The syncitiotrophoblast shown here in Grey is invading the surrounding endometrium breaking down the cells here and using the breakdown products from that tissue to support the development of the embryo here.

There’s also secretions from the uterine glands and the breakdown of the maternal capillaries results in this syncitiotrophoblast being exposed to maternal blood from which it can also derive some nutrients.

An important structure to note here is the amnion, which we met in the last guided online learning session but didn’t really talk very much about. The amnion is a derivative of the epiblast. But unlike the rest of the epiblast, it’s not going to go on and form part of the foetus. Instead, the amnion is the first of the foetal membranes and it forms this structure here. The amniotic cavity. The amniotic cavity is going to expand and will eventually become part of the amniotic sac, which surrounds and cushions the foetus for its development through the second and third trimesters.

Question 5

Origins of the placenta

Answer 5

If we move on a few days in development, we can see that the invasion of the synctiotrophoblast, has become much more extensive. Here we’ve got the amnion and you can see that this amniotic sac here is starting to form secretions from the amniotic cells into this space here will cause it to start to expand. We’ve got the embryo disk here. And you’ll recall the yolk sac was going to form from the hypo blast of the embryo here.

So the amnion is the first of the key foetal membranes. The second is the chorion and the chorion is this outer membrane here. Surrounding the whole conceptus unit. There are two other things to note at this point in development.

The first is that the embryo unit has started to develop something called the connecting stalk, and the connecting stalk is a part of extra embryonic tissue which grows from the embryo and connects the conceptus with the chorion. CCC

The second developmental point to note is the formation of the trophoblastic lacunae. As the syncitiotrophoblast invades the endometrium, it breaks down the maternal capillaries and the maternal glands. The lumens of these maternal capillaries and uterine glands start to fuse.

As a consequence of breakdown and create a continuous space through which the maternal blood can flow.We call these species lacunae as they develop. They’ll become filled with maternal blood. And later in development, they become known as intervillus spaces.And they are also known as maternal blood spaces because the maternal blood will be flowing through these gaps and contacting with the syncitiotrophoblast

Question 6

Fetal membranes – the fetal-maternal interface

Answer 6

Fetal membranes: extraembryonic tissues that form a tough but flexible sac encapsulates the fetus and forms the basis of the maternal-fetal interface.

So let’s think a little bit about the foetal membranes, the foetal membranes and predominantly the amnion and the chorion here are extra embryonic tissue so they don’t contribute to the foetus ultimately, but they form a tough but flexible sac that will encapsulate the foetus and will form the basis of the maternal foetal interface through later development.

We’ve already met the amnion. So the amnion is the inner of the foetal membranes, which arises from the epiblast, and it’s going to form this closed avascular sac with the developing embryo at one end of this stack. And from around the fifth week of gestation, the amnion cells start to secrete this amniotic fluid that causes the amniotic sac to increase. And ultimately, this forms a fluid filled sac that will encapsulate and protect the foetus.

We met the chorion in the last slide and the chorion is the outer foetal membrane, so the chorion is ultimately derived from the yolk sac and part of the trophoblast. And it’s highly vascularised. So it has a blood supply. Unlike the amnion, the chorion plays a really important part in placental development because it’s going to give rise to the Chorionic Villi. These are outgrowths of cytotrophoblast as we’ll see in the next few slides. They are outgrowths of the cytoptrophoblast from the chorion, that will form the basis of the foetal side of the placenta.

As the amniotic sac expands through fluid accumulation, this is going to force the amnion into contact with the chorion. So you can imagine the amnion and the chorion are like two balloons. And if we put the amnion one balloon inside the chorion on the second balloon and inflate the inner balloon, eventually that balloon will come into contact with the outer balloon. And that’s essentially what happens during the development of the amniotic sac. The amnion, the inner foetal membrane expands through this accumulation of amniotic fluid that pushes out the amnion towards the chorion on the outer foetal membrane. And eventually the two of them come into contact. And when they come into contact, they fuse. And ultimately, that forms the amniotic sac with the amnion on the inside and the chorion on the outside.

There’s a third structure to be aware of at this point. Another one of the foetal membranes, which is the allantois. The allantois is also derived from the yolk sac. We don’t really know quite what its role is in development. It seems to contribute partly to the embryonic bladder. So it might be important with the removal of toxins from the development in developing embryo. But we do know it plays an important role in the development of the umbilical cord as the allentois grows out from the yolk sac. It grows along the connecting stalk, which links the embryo to the chorion. And as it does so, it starts to become coated in mesoderm. And so this combination of the connecting stalk, the allantois and the additional mesoderm together forms the umbilical cord. The mesoderm that grows over the allantois will become vascularised. And then that provides the circulatory link of the embryo to the foetal side of the placenta.

Question 7

Amnion (inner fetal membrane)

Answer 7

• Arises from the epiblast (but does not contribute to the fetal 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 fetus

Question 8

Chorion (outer fetal membrane)

Answer 8

• Formed from yolk sac derivatives and the trophoblast
• Highly vascularized
• Gives rise to chorionic villi – outgrowths of cytotrophoblast from the chorion that form the basis of the fetal side of the placenta

Question 9

Allantois

Answer 9

• Outgrowth of the yolk sac
• Grows along the connecting stalk from embryo to chorion
• Becomes coated in mesoderm and vascularizes to form the umbilical cord.

Question 10

Origins of the placenta: chorionic villus formation

Answer 10

So here again, we’ve got our developing embryo. Here we have the chorion in orange. And on the outside here, you can see these purple cells here. So these purple cells are cytotrophoblast cells. You’ll remember that the trophectoderm gives rise to the trophoblast. And it’s that trophoblast which divides into the syncitiotrophoblast and the proliferative cytotrophoblast, which is a dividing cell population which gives rise to cells which contribute to the syncitiotrophoblast.

Well, around this stage of development, the cytotrophoblast also adopts another role, and it becomes quite important in the development of the placenta, as well as continuing to provide cells that will form the syncitiotrophoblast. We get outgrowths of the cytotrophoblast, which now sits on the outside the chorion. We get outgrowths of the cytotrophoblasts, these finger like outgrowths you can see here, which we know as primary chorionic villi. These are outgrowths of the cytotrophoblast that push through the Synctiotrophoblast and will start to form part of the maternal foetal interface. So we see outgrowth of these structures pushing into the syncitiotrophoblast as shown by the arrows here.

Question 11

Chorionic villi

Answer 11

Provide substantial surface area for exchange

Finger-like extensions of the chorionic cytotrophoblast, which then undergo branching

Three phases of chorionic villi development:

• Primary: outgrowth of the cytotrophoblast and branching of these extensions
• Secondary: growth of the fetal mesoderm into the primary villi
• Tertiary: growth of the umbilical artery and umbilical vein into the villus mesoderm, providing vasculature.

Notes from lecturer:

So what are the chorionic villi? Well, the chorionic villi, which are derived from the cytotrophoblast, are really important for providing a substantial surface area for the exchange of gases and nutrients. And as we saw in the last slide, that these finger like extensions of the cytotrophoblast, which overlays the chorion and they grow out into the syncitriotrophoblast and then start to undergo branching. And there are three phases of chorionic villus development. The first, as we saw in the last slide, is primary chorionic villus development. That’s the outgrowth of those cytotrophoblast fingers and the subsequent branching of those extensions.

The second phase of chorionic villus development is the growth of the foetal mesoderm into the chorionic primary villi.

And then lastly, there is a growth of the umbilical artery and the umbilical vein into that mesoderm within the villi, which provides vasculature. And we can see that on the figures here in the right.

So here we’ve got the embryo, we’ve got the amnion and the chorion. And you can see here that we started to get these little fingers of cytotrophoblast growing into the endometrium here. As they do so, they get invaded by mesoderm and then subsequently blood vessels. And this allows a close contact between the fetal blood here and these maternal blood spaces here, which are being fed by the spiral arteries and ultimately by the uterine vein. So we have maternal blood coming in here into these maternal blood spaces. We have the growth of the Chorionic Villi into these spaces. And you can see they’re coated here in trophoblast in grey with the blood vessels here in purple. And so this allows the creation of a large surface area interface of the foetal tissue with the maternal blood, which permits nutrient and gaseous exchange.

Question 12

Terminal villus microstructure

Answer 12

If we look at one of those villi, in more detail here, we have a capillary cast of the vasculature of one of those Chorionic Villi. So here we’ve got the blood vessels coming up through into the villus. And this would normally be coated in trophoblast. This space here would all be filled with maternal blood. This would be the maternal blood space or the lacunae. And you can see that the capillary network within these villi forms are relatively convoluted knot of vessels. And in some places they’re quite dilated. And it’s this combination of convolution of the vessels and the dilation of the vessels that slows down the blood flow through these terminal villus structures and then allows exchange to occur between the maternal and foetal blood.

It’s important to remember this is just a capillary cast. So we’re just looking at the blood vessel network here. Normally, this whole villus structure would be coated with a layer of trophoblast. Early on in pregnancy, these villi are 150 to 200 micrometers in diameter with quite a thick layer of trophoblast =Up to 10 micrometers over the surface. But as we proceed through pregnancy, the blood vessels within these villi move within the villi to become much closer to the maternal blood supply and the layer of trophoblast that overlays the villus essentially shrinks to only one to two micrometers so that the distance required for diffusion to occur from the maternal blood into the foetal circulation here becomes much reduced.

Question 13

Maternal blood supply to the endometrium

Answer 13

• Uterine artery branches give rise to a network of arcuate arteries.
• Radial arteries branch from arcuate arteries, and branch further to form basal arteries.
• Basal arteries form spiral arteries during menstrual cycle endometrial thickening.

Remember as U ARBS (ie U tree artery)

Notes from lecturer:

So what about the maternal blood supply to the endometrium?

Well, here we have the uterine artery, which will ultimately fuse with the ovarian artery at the top here. And there are various branches off the uterine artery that supply the uterus. The first of these branches is the accurate artery. And in turn, the arcuate artery has the radial branches, which goes through the myometrium of the uterus and into the endometrium. So these are the radial arteries here. The radial arteries give rise to the basal arteries and the basal arteries form these spiral structures known as spiral arteries, which grow out during the process of endometrial development.

So as we move through the menstrual cycle, we go from having these basal arteries here, which are terminal. These will progressively go grow and spiralise producing these spiral arteries. And if implantation doesn’t occur, we get loss of the endometrium and regression of these spiral arteries. If implantation does occur, these spiral arteries are stabilised and provide the maternal blood supply to the foetus.

Question 14

Spiral artery re-modelling

Answer 14

• 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 vessels
• Conversion: turns the spiral artery into a low pressure, high capacity conduit for maternal blood flow.

Notes from lecturer:

There’s extensive remodelling of the spiral arteries during implantation and placental development. We have here a cross section through one of the villi, this is a tertiary chorionic villus. So we have the blood vessels here growing up. They they would be coming out of the screen towards you. And this is a cross section through one of those villi. You can see the coating of trophoblast on the outside here. And as the spiral arteries develop the trophoblast cells on the outside of these villi start to invade the maternal spiral arteries.

So we get outgrowth of the trophoblast and these trophoblast cells grow down into the maternal spiral arteries. These cells that go down into the spiral arteries are known as extra-villus, trophoblast, as in they’re on the outside, the extravillus trophoblast, outside the villus. And the tropoblast cells that grow down into the spiral arteries are known as endovascular extra villus trophoblast.

The role of the endovascular extra villus trophoblast is essentially to replace the maternal endothelium of these blood vessels. So as these endovascular EVT cells grow down into the spiral arteries, they break down the maternal endothelium of these vessels and also the underlying smooth muscle and form a new endothelial layer which is formed by these foetal EVT cells. This is really important during placental development, and it’s a process called conversion, because as you can see here, as these trophy blast cells grow down, they start to de-spiralie the capillaries opening them up into relatively straight channels. The effect of this is to turn these spiral arteries from being highly convoluted, high pressure vessels into lower pressure, high capacity conduits which can feed those maternal blood spaces, which would be up here.

And obviously, these villi are sitting within this maternal blood space and therefore can draw nutrients from the blood that’s being supplied. We call this process of transition from spiral arteries to non spiral arteries, a process called conversion. And this process of conversion is really important. And it may underlie some conditions such as pre-eclampsia or into uterine growth retardation.

Question 15

Placental structure - overview

Answer 15

This brings us then to an overview of the placenta. First of all, we have the maternal unit, this site. So we have the maternal blood supply giving rise to these spiral arteries and these spiral arteries will supply these into villus spaces or these maternal blood spaces with blood. And some of that then drains away through the venous system here.

From the foetal side, we get the formation of these chorionic villi, so these invasions of trophoblast, which then branch and become vascularised, and it’s the invasion then of the foetal circulatory system into these Chorionic Villi which provides this large surface area for exchange between the maternal blood and the foetal chorionic villi

Question 16

Nutrient exchange across the placenta

Answer 16

• Oxygen: diffusional gradient (high maternal O2 tension, low fetal O2 tension)
• Glucose: facilitated diffusion by transporters on maternal side and fetal trophoblast cells.
• Water: placenta main site of exchange, though some crosses amnion-chorion. Majority by diffusion, though some local hydrostatic gradients.
• Electrolytes: large traffic of sodium and other electrolytes across the placenta – combination of diffusion and active energy-dependent co-transport.
• Calcium: actively transported against a concentration gradient by magnesium ATPase calcium pump.
• Amino acids: reduced maternal urea excretion and active transport of amino acids to fetus

Notes from the lecturer:

So how does that exchange occur? Well, nutrient exchange across the placenta is very much nutrient specific, and there’s a range of different ways that nutrients and gases can cross the placenta. That can be simple diffusion. We can have facilitated fusion through the formation of concentration gradients or controlled by the abundance of transporter proteins on the cell membranes. Or we can get active or energy dependent transport either by blood flow or transiting nutrients over with energy dependent co transporters.

In terms of oxygen getting across the placenta, we know there’s a diffusion or gradient, so high oxygen tension in the maternal blood and low oxygen tension in the foetal blood, which leads to diffusion of oxygen across the placenta.

The transit of glucose occurs by facilitated diffusion by transporters on the maternal side and onto the foetal trophoblast cells.

And in terms of getting water into the foetus, we know that the placenta is the main site of exchange, although there is some contact and water transmission where the amnion and chorion meet in areas around the amniotic sac that are not part of the placenta. The majority of water transit occurs by diffusion, although there is some local hydrostatic gradient.

Most of the electrolyte traffic and there is a large traffic of sodium and other ions across the placenta occurs through a combination of diffusion and active energy dependent co transport. And the latter of those is particularly true of calcium, which is obviously important for development of the foetal skeleton.

And calcium is actively transported against a concentration gradient across the placenta by the magnesium ATPase Calcium pump.

And lastly, in terms of amino acid transport, as pregnancy progresses, there is reduced excretion of urea by the mother. And those amino acids that make up the urea much more efficiently utilised and they’re transported across the placenta actively to the foetus.

Question 17

Maternal-fetal oxygen exchange

Answer 17

Just lastly, if we think a little bit about maternal and foetal oxygen exchange, we see some quite dynamic physiological changes in the maternal and the foetal circulatory systems.

During the first trimester, we see that maternal cardiac output increases by about 30 percent, both as a consequence of increased stroke volume and stroke rate, peripheral resistance within the maternal circulation decreases by about a third.

And as we progressed through pregnancy, we see an increase in maternal blood volume as well, such that by the time we’re getting to the point of birth, there’s been an increase of around 40 percent in maternal blood volume. And that’s partly achieved by an increase in erythrocytes and an increase in plasma volume. There’s also an increase of around 40 percent in the parliamentary ventilation of the mother.

On the foetal side, the placenta is a highly, highly metabolic structure in its own right. And as a consequence, the placenta itself utilises around 40 to 60 percent of the glucose and the oxygen which is supplied by the maternal circulation. But although the foetal oxygen tension itself, the oxygen tension in the fixed circulation is low.

If we look at O2 content or saturation, we can see those levels are actually similar to what’s occurring in the maternal blood. And we know that process is achieved because in the embryonic and foetal stages of development, there are specific developmental haemoglobins that are used which are different to those present in the adult. And those embryonic and foetal haemoglobins have a greater affinity for oxygen than those maternal or adult haemoglobin. And therefore can bind O2 at a higher affinity.

Question 18

Session review: 1. Fetal growth and placentation

Answer 18

• Increased fetal growth occurs coincident with switch from histiotrophic to haemotrophic support.
• Invasion of chorionic cytotrophoblast, and associated fetal blood vessels forms chorionic villi – surface for exchange
• Spiral artery re-modelling reduces maternal vessel pressure and increases capacity.
• Mechanisms of transport across the placenta are nutrient-specific.

Notes from lecturer:

So that brings us to the end of this first part of this guided online learning. We’ve looked at how increased foetal growth occurs. Coincident with the switch from histiotrophic to haemotrophic support.

We’ve looked at how the invasion of the chorioniccytrophoblast forms the chorionic villi, coupled with invasion of the mesoderm and blood vessels into these villi to form a foetal surface nutrient exchange.

We’ve looked at how spiral artery remodelling can reduce the pressure of the maternal vessels and increased capacity to ensure there’s a continuous and extensive blood flow to those maternal blood spaces. And lastly, we’ve looked briefly at nutrient specific processes of transport across the placenta.

Question 19

Part 2: Later fetal development, labour and parturition

Session plan

Answer 19

Question 20

Organ maturation in late fetal development

Answer 20

You’ll recall from the early embryo development guided online learning that most of the organ systems were complete by the end of the first trimester, and that the second and third trimesters are characterised by maturation of those organ systems.

If we think about the circulatory system, we began with the tube of mesoderm that was pumping blood by around day 22 of embryo development. By the time we go into the second trimester, we’ve got a relatively complete circulatory system. But obviously with some differences to what will occur in the neonate, perhaps the most important of those is that the placenta is acting as the site of gas exchange for the foetus here rather than the lungs. And the ventricles of the heart are pumping in parallel rather than series. So they’re driving blood together around the same circulatory loop. That’s achieved by the presence of some vascular shunts which allow the circulatory system to bypass the pulmonary and hepatic circulation, and permit the heart to drive oxygenated blood from the placenta around the body with greater efficiency, particularly to the head, to ensure that those tissues are, well, oxygenated and have the nutrients and gas supply they need for successful development. Those vascular shunts subsequently close at birth to give us the circulatory system we know in the neonatal and the adult.

The lung began as a bud around the foregut and that went through a period of branching in the first trimester to give us the lung structures, those develop further through the second trimester. So we start to see the air sacs forming around 20 weeks of development and then the lungs become vascularised from around 28 weeks. We see the production of surfactant from around a week, 20. And that’s upregulated sharply towards term. And interestingly, the foetus spends between an hour and four hours a day making rapid respiratory movements during periods of rapid eye movement sleep, even though it’s within the amniotic sac and therefore within the amniotic fluid, and the lungs aren’t actually the site of gas exchange. We think these rapid respiratory movements are probably practised by the foetus for the breathing reflex once it leaves the uterus, and that they might also be important for the development of the diaphragm.

We get the gut tube in the early embryo development, guided online learning, forming from the endoderm with some contribution of the yolk sac. By the time we’ve got into the second trimester, we start to have a developing pancreas, which is functional from the start of the second trimester, secretes insulin from around mid-pregnancy. The liver is present from relatively early on in embryo development. We can see liver cells from around 23 days of development, and certainly through the second and third trimesters that organ progressively develops and we see significant deposition of glycogen, particularly towards the time of delivery. The foetus is within the amniotic sac and inhales and swallows large amounts of amniotic fluid in its period in utero. That amniotic fluid contains a large amount of debris and that together with bile acids and also cells coming off from the inside of the developing intestine, form the first stool known as meconium, which is delivered just after birth.

We could spend an entire lecture talking about the nervous system, but just some key developmental milestones here. The foetus starts to make determined movements from around the late first trimester, and they’re detectable by the mother from early in the second trimester. We know the foetus can make responses to stress from around 18 weeks. But the connections between the thalamus and the cortex are really only there from around 24 weeks onwards. So sensory inputs can probably only be processed from around mid pregnancy onwards. And importantly, the foetus doesn’t really show any evidence of conscious wakefulness while it’s in the womb. Instead, it’s spending most of its time in either slow wave or rapid eye movement sleep.

Question 21

Organ maturation is co-ordinated by…

Answer 21

…fetal cortico-steroids.

We think these developmental changes are orchestrated by an increase in foetal corticosteroids. Towards the end of pregnancy. So you can see in the graph here that the blue line from around mid gestation here up to around term sees an exponential increase in the level of corticosteroids in the foetal blood. Changes in surfactant production, shown here in green, and the deposition of liver glycogen both occur exponentially in parallel with this increase in corticosteroids. And so we think it’s the corticosteroids increasing the foetus, which is orchestrating the final maturation of each of these organ processes, getting the foetus ready for survival outside of the womb.

Question 22

Labour

Answer 22

So once we’ve got those organ systems in place, then we’re ready to deliver the foetus. And the process of labour really is all about the safe expulsion of the foetus, ideally, at the correct time. We need to evacuate the uterus of the placenta and the foetal membranes to ensure it’s empty for future reproductive events. And also, the uterus has gone through extensive tissue remodelling and also distension. And so we need to go through a period of resolution and healing to ensure that the uterus is suitable for carrying another baby in future.

Labour has the characteristics of being a pro inflammatory reaction. And so what we see during the process of labour is extensive immune cell infiltration into the tissues of the female reproductive tract. And coupled with that extensive production of inflammatory cytokines and prostaglandins, which we think are important in orchestrating the timing and sequence of the events of labour.

We can break labour down into a series of phases. (QuASI)

1. The first phase is in the kind of early parts of pregnancy, which is quiescence, where essentially the uterus is quiet. It’s not contracting, but we are starting to see some changes in the cervix. And so this will happen from the late first trimester onwards.
2. Phase two is activation, we start to see some activity of the uterus and particularly further developments in the cervix that are getting ready, they’re getting the cervix ready to dilate to allow delivery.
3. In phase three, we have active uterine contractions and cervical dilation. So the opening of the cervix to allow the foetus to pass through it. And this third phase is characterised by the three stages of labour, which we’ll look at next.
4. And then lastly, phase four is known as involution, which is the restoration of the uterus to its original size, repair of the cervix and also then the onset of lactation.

Question 23

The three stages of labour

Answer 23

These three stages of labour are all occurring in that third phase of labour. We have three stages of labour within that third phase.

The first stage of labour, we start to see the contractions beginning and the onset of cervical dilation. And the first stage can then be broken down into a latent phase and an active phase in the latent phase of the first stage. We see slow dilation of the cervix to around three centimetres and then as we move into the active phase, that cervical dilation occurs much more rapidly. So we get dilation of the cervix to its maximum size of 10 centimetres in diameter.

Once we reach that maximal cervical dilation, the second stage occurs. And the second stage is largely characterised by delivery of the foetus, accompanied by intense and frequent myometrial contractions.

And the third stage of labour is the delivery of the placenta, the expulsion of the placenta and the foetal membranes, and then allowing the onset of postpartum or after birth repair.

And the timing of those events are outlined in the graph here on the right. So we can see this first stage is particularly extensive. Much more so than the second and third stages. And the first stage is largely broken up into the latent phase and the active phase here, both of which are roughly equal duration. But you can see there’s this slow increase in cervical dilation in the latent phase and then an accelerated dilation up to 10 centimetres diameter through the active phase. Once we hit that maximal cervical dilation, the second stage of labour can occur, which is foetal descent and delivery. And that’s a relatively quick only being an hour or two, usually in duration. And then finally, once the foetus has been born, that’s followed by delivery of the placenta, which takes another hour to two hours. So overall, for a woman in her first delivery, the whole process takes somewhere usually between eight and 18 hours. But for subsequent deliveries, probably a bit shorter than that, between five and 12 hours.

Question 24

Re-modelling of the cervix

Answer 24

So remodelling of the cervix is critical to Labour occurring because we need to soften the cervix to allow it to dilate, to open the birth canal and let the foetus through. During pregnancy, the cervix has a critical role in retaining the foetus within the uterus. And it does that by having a very high connective tissue content, which keeps the cervix closed and rigid and stretched resistant. And that rigidity and stretch resistance is achieved through bundling of collagen fibres within the cervical tissue. And those collagen fibres are then embedded within a proteo-glycan matrix. As we approach the time of delivery, those collagen bundles change. So the structure of those collagen bundles changes. And it’s the remodelling of this collagen which underlines the softening of the cervix, which will allow it to dilate. But the exact control of that process is unclear. We know cervical remodelling goes through a series of phases.

SOFTENING->RIPENING->DILATION->REPAIR

So the first is cervical softening, which begins in the first trimester. And here we start to see changes in compliance of the cervix in terms of which stretch resistance. But importantly, we retain cervical competence. So the cervix remains closed and capable of keeping the foetus inside the uterus. As we get close to birth, we start to see cervical ripening. And this occurs in the weeks and days before birth. And this ripening is characterised by extensive immune cell infiltration of the cervix. And you can see on the right here the infiltration of macrophages. So this is before labour begins and after labour begins. And the same with neutrophils here. So it’s these immune cells that here are stained in brown.

With the onset of labour comes cervical dilation, so we’re going to need to open up the cervix to allow the transit of the foetus. And that’s characterised by increased hyaluronidase expression, which breaks down hyaluronan (aka Hyaluronic acid), which had been deposited in the ripening stage. And also the influx of these immune cells leads to the production of large amounts of matrix metalloproteinases, which can break down collagen and allow increased elasticity of the tissue.

And finally, after the foetus has been born, we’re going to need to go through this process of postpartum repair, which is characterised by a recovery of tissue integrity and competency to ensure that if the woman gets pregnant again, the cervix is capable of keeping the foetus within the uterus. And also then again, going through these processes of remodelling when labour comes around again.

Question 25

Corticotrophin-releasing hormone (CRH) and the initiation of labour

Answer 25

The endocrine regulation of labour is quite unclear in humans. We think we have it fairly well mapped out in some other mammals, but within humans, there is still quite a lot of uncertainty about what the triggers for the initiation of labour are. So in the next few slides, we're going to explore what the current thinking is on the endocrine regulation of labour. We think, in the same way that the corticosteroid increase in late pregnancy and the foetus is important in regulating organ maturation. We think the foetus may also determine the timing of its delivery through increasing amounts of corticosteroids. So what we see is that as we approach term, so we're around 30 days out before delivery, we start to see an exponential increase in the production of corticotrophin releasing hormone by the foetus. And also there's a concomitant decrease in the levels of binding proteins of CRH, which means the amount of bioavailable CRH is increasing as well. We think this increased level of CRH acts on the foetal adrenal cortex and promotes cortisol release by the foetus. Most of that cortisol then goes to the placenta. And when the cortisol arrives at the placenta, that drives placental production of corticotrophin releasing hormone as well. So we have production of CRH by the foetal pituitary acting on the foetal adrenal to produce cortisol that cortisol transits through the foetal circulation to the placenta, where it triggers the production of placental CRH. And obviously that placental CRH then returns to the foetus and drives the positive feedback loop of more cortisol production. We also think that CRH is stimulating the production of DHEAS production by the foetal adrenal cortex. And this DHEAS production is then used as a substrate to allow greater oestrogen production by the placenta.

Question 26

Estrogen and progesterone at labour

Answer 26

So what about oestrogen and progesterone during labour? Well, you can see from the graph here that the levels of progesterone and oestrogen increased steadily through pregnancy, and this high level of progesterone is being produced by the placenta. It's important for the maintenance of pregnancy and it's very, very important for maintaining uterine relaxation until we're ready to go through labour. We know in some mammals such as sheep, there is a clear shift in the progesterone to oestrogen ratio in the circulation around the time of birth. And that discernable shift in progesterone to oestrogen may be associated with the onset of labour. That's less clear in humans. But you can see from the graph here that there may indeed be a shift in the ratio. What we think is happening potentially, if that shift is happening, is that there's a shift in favour of oestrogen and so INCREASING overall oestrogen progesterone ratio. But what we do know is that there are some important changes in oestrogen and progesterone signalling within the uterus. As term approaches, as we start to approach delivery, there's a switch from progesterone receptor A isoforms, which allow the activating functions of progesterone to be transmitted to B and C isoforms of the progesterone receptor, which are more repressive. So we think what's happening with this shift in receptor subtypes or receptor isoforms, is that we get what we call functional progesterone withdrawal. So although the levels of progesterone remain high, the change in the types of receptor essentially blinds the uterus to the action of progesterone. In parallel with that, we see a rise in oestrogen receptor expression within the uterine tissues. And so the overall effect of this is that although the levels of progesterone and oestrogen stay high, the uterus becomes blinded to progesterone action, but sensitised to the action of oestrogen. And although we don't really understand what's driving these changes, we think the ultimate consequence of it is that within the uterus there is probably a local shift in the oestrogen to progesterone ratio within the uterine tissues. And that's going to be important for some of the downstream processes of labour that will look at in the subsequent slides.

Question 27

Oxytocin

Answer 27

One of the most important outputs of that change in oestrogen to progesterone ratio, is probably the production of oxytocin. So oxytocin is a peptide hormone that's synthesised predominantly in the pituitary, but also to some extent in the utero-placental tissues. And we see the production of oxytocin increasing sharply around the time of labour. We think partly that increase is driven by oestrogen, so the increasing levels of oestrogen produced by the placenta probably promote local uterine production of oxytocin. But predominantly, the production of oxytocin comes from the maternal pituitary, and that's prompted by stretch receptors. So as the foetus starts to bear down on the cervix, stretch receptors in the cervix and in the vagina, signal up to the hypothalamus, and the firing of the hypothalamus onto the posterior pituitary, triggers release of oxytocin from the posterior pituitary into the maternal circulation where it can act back onto the uterus and particularly on the myometrium. And this neuroendocrine stretch reflex is known as the Ferguson reflex (think Fergurson's owner from new girl thinks he's pregnant). Oxytocin signals through a G-protein Coupled receptor known as the oxytocin receptor. And that's either written as OXTR or OTR and through most of pregnancy, when we've got progesterone dominance, the high levels of progesterone inhibit the production of the oxytocin receptor in the uterus. So there's very little oxytocin receptor around in the myometrium of the pre labour uterus, and that allows the uterus to remain in a relaxed state, so no contractions. But as we get this rise in oestrogen approaching the end of pregnancy, that oestrogen increase promotes a large increase in the number of oxytocin receptors in the uterus. So as the uterus becomes sensitive to oestrogen, that oestrogen in turn promotes the production of oxytocin receptors, which then sensitises the uterus, and in particular the myometrium, to oxytocin. So what's oxytocin doing in pregnancy? Well, it has a really important function in increasing how connected the myocytes in the myometrium are. So essentially the myocytes in the myometrium form a syncytium, there's extensive gap junction connections and oxytocin promotes the formation of those gap junctions. So the myometrium can act as a syncytium. And it's also important for destabilising membrane potentials within those muscle cells. So the threshold for contraction is lowered, and it promotes the liberation of intracellular calcium within those muscle cells as well, in addition, aiding contraction.

Question 28

Prostaglandins: key effectors of labour

Answer 28

Oxytocin seems to work in conjunction with prostaglandins, which themselves are key effectors of labour. PGE_2, PGF₂alpha and PGI₂ are the predominant prostaglandins that are synthesised during labour. And they're driven again by these rising oestrogen levels. So the increase in oestrogen as we approach term activates phospholipase A2, and so that generates more arachidonic acid that can be used for prostaglandin synthesis. And also the oestrogen stimulation of this promotion of oxytocin receptor expression by oestrogen also allows some prostaglandin release through oxytocin signalling. If we think about the individual roles of these prostaglandins, we think PGE₂ is probably most important in remodelling the cervix. So PGE₂ is promoting leukocyte or infiltration into the cervix, Interleukin 8 release and ultimately resulting in the re-modelling of these collegen fibres that allow the softening of the cervix and the ripening of the cervix. PGF₂Alpha, we think is predominantly acting on the myometrium. So with oxytocin, it helps destabilise the membrane potentials and also helps promote this connectivity of the myocytes. And PGI₂ is also probably acting on the myometrium, and we think it probably promotes relaxation of the smooth muscle and particularly relaxation of the lower uterine segment. We think this is probably important because it's important that inbetween myometrial contractions, there is some relaxation, because that relaxation allows the blood flow to return into the uterus and into the placenta, to ensure that there is blood flow to the foetus. But we don't know if prostaglandins are really the whole story. There is some evidence that a peptide hormone whose levels increased sharply towards the end of pregnancy, known as relaxin, might be important in orchestrating remodelling of the cervix. And there may also be some role for nitric oxide.

Question 29

An integrated hypothesis for the regulation of labour

Answer 29

So we can start to put together an integrated hypothesis for the regulation of labour. So we have here a foetus, and it's the production of CRH by the foetal pituitary, which acts on the foetal adrenal to produce cortisol. That cortisol gets transferred to the placenta where it triggers the production of more CRH. And that's CRH acts back as a positive feedback loop to promote more cortisol production and so on. The CRH acting on the foetal adrenal also promotes production of DHEAS, which in the placenta is converted to oestrogen. That oestrogen then acts on the myometrium, promoting the expression of the oxytocin receptor. So the uterus becomes sensitive to pituitary production of maternal oxytocin and that triggers contractions. We know that oestrogen also promotes the local production of oxytocin, and that oxytocin, acting through those oxytocin receptors, stimulates contractions and also promotes prostaglandin production. Those prostaglandins, particularly F2alpha are also important for mediating those myometrial contractions and also helping to soften and ripen the cervix to ensure that dilation can occur. And in the non labouring state, it's the action of progesterone to inhibit these oxytocin receptors, inhibit the production of these oxytocin receptors, that keeps the myometrium quiescent and stops contractions occurring prematurely.

Question 30

Myometrial contractions and fetal expulsion

Answer 30

So how do those myometrial contractions work? Well, it's all driven by this part of the uterus at the top here, known as the fundus, but we also recognise that there are different functional compartments within the uterus during labour. So we have the cervix down at the bottom here, which is going to dilate. We have the lower segment of the uterus shown here in the darker shading, which is passive. And what we mean by that is it doesn't contribute to the contractions. And it's this upper segment of the uterus, which is going to be the muscle which contracts to drive those contractions. So this whole upper segment, the muscle cells within this form, this syncytium and we've got these extensive gap junctions so we can transmit contractions across this muscle of the upper segment. And so what happens is the contractions begin from the fundus at the top. So this part will contract initially, followed by this part, followed by this part. And the whole effect of this is to pull up the cervix and the lower segment, creating one large open birth canal. So you can see the dilation of the cervix here and the lower segment has been pulled up and apart, creating this large space for the foetus to transit out of. This is achieved because the contractions are brachystatic That is to say that after each contraction, we don't get complete relaxation of the muscle fibres, so they retain some shortening. And so each contraction progressively opens the cervix and the lower segment, until the point at which we reach complete dilation. Once the birth canal has been formed and the cervix is dilated, delivery can occur. So the foetus's head starts to engage with the cervix in the final weeks of pregnancy. And as the onset of labour occurs, pressure on the hindquarters of the foetus from the myometrial contractions up here, and pressure of the head on the cervix, causes this flexion of the head to bow forward and the foetus's chin to be pressed against the chest. As delivery progresses, the foetus rotates such that the belly of the foetus will face the mother spine. We start to get delivery of the head immediately after the cervix has dilated. And then once the head is out, we see sequential delivery of the shoulders. So the top shoulder is delivered first. You can see the lower shoulder still retained here within the birth canal. And once both of those shoulders are out, the rest of the foetus can follow quite quickly.

Question 31

Final Phase: placental expulsion and repair

Answer 31

Once we delivered the foetus, the final phase is placental expulsion and repair. The expulsion of the foetus is essentially achieved by the collapse of the uterus after delivery. So once the foetus, which has obviously been taking up a lot of space, has left the uterus, the uterus shrinks down. And one of the consequences of that is that the area of contact of the placenta with the endometrium starts to shrink. At the same time, that uterine shrinkage causes the foetal membranes, which were originally quite stretched, to essentially gather up and fold. And the consequence of that is that we get peeling off of the foetal membranes from the endometrium. The clamping of the umbilical cord after the baby's born stops foetal blood flow back to the placenta. And the consequence of that is that those villi that we met in the first part of the guided online learning, collapse, and this starts to trigger haematoma formation between the decidua and the placenta. And that coupled with myometrial contractions, ongoing uterine contractions expel the placenta and the foetal tissues. Once the placenta has been delivered, the uterus remains in a contracted state to facilitate the thrombosis and the healing of those uterine vessels, and prevent intrauterine bleeding. And eventually what will start to happen is that we'll get restoration of the uterus and repair of the cervix to restore the nonpregnant state. That's important to stop the commensal bacteria that live within the reproductive tract getting up into the uterus. But also, we want to restore endometrial cyclicity in response to reproductive hormones, to ensure that the uterus is ready to allow implantation of another embryo, if another one comes in the next reproductive cycle.

Question 32

Session review part 1 and part 2:

Answer 32

Functional progesterone withdrawal and sensitisation to oestrogen of the uterus allows the production of oxytocin receptors and those oxytocin receptors can then allow the binding of oxytocin from the maternal pituitary. And it's that binding of oxytocin, which is going to trigger myometrial contractions. And then in conjunction with utero-cervical prostaglandins, oxytocin and prostaglandins together play key roles in the local regulation of labour.