pregnancy, parturition and late foetal development

Question 1

what is embryo-foetal growth like in the first trimester?

Answer 1

Embryo-fetal growth during the first trimester is relatively limited

Early embryro nutrition is histiotrophic (derivation of nutrients from the breakdown of surroundnig tissues)

reliant on uterine gland secretions and breakdown of endometrial tissues

Question 2

how does embryo-foetal growth change in the second trimester?

Answer 2

Switch to haemotrophic support at start of 2nd trimester. (derives nutrients from the maternal blood)

Achieved in humans through a haemochorial-type placenta where maternal blood directly contacts the fetal membranes. (chorion)

happens around the 12th week

it increases the rate of foetal growth

Question 3

how does the syncitiotrophoblast help contribute to embryo-foetal growth?

Answer 3

in the first trimester

it invades the endometrium, and breaks down the tissue
nutrients can then be derived from the breakdown products

there are also secretions from the uterine glands
and breakdown of capillaries, so syncitiotrophoblast is exposed to maternal blood

Question 4

what is the amnion?

Answer 4

derivative of the epiblast, but unlike the rest of the epiblast it wont go on to form part of the foetus

instead it is the first of the key foetal membranes
(inner foetal membrane)

it forms the amniotic cavity.
over time this will expand to form the amniotic sac, that surrounds and cushions the foetus

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 5

what is the chorion?

Answer 5

the second of the key foetal membranes
(outer foetal membrane)

outer membrane that surrounds the whole conceptus unit

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 6

what is the connecting stalk?

Answer 6

Links developing embryo unit to the chorion

Question 7

what are trophoblast lacunae?

Answer 7

Large spaces filled with maternal blood formed by breakdown of maternal capillaries and uterine glands
Become intervillous spaces aka maternal blood spaces

Question 8

what are the foetal membranes?

Answer 8

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

1. amnion
2. chorion
3. allantois

Expansion of the amniotic sac by fluid accumulation forces the amnion into contact with the chorion, which fuse, forming the amniotic sac
Amniotic sac: 2 layers; amnion on the inside, chorion on the outside

Question 9

what is the 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

what are the primary chorionic villi?

Answer 10

Primary chorionic villi:
Cytotrophoblast forms
finger-like projections through syncitiotrophoblast layer Into maternal endometrium

extensions of the chorion

(cytotrophoblast - produces cells that contribute to the syncitiontrophoblast)

will form part of the maternal-foetal interface

Question 11

what is the purpose of chorionic villi?

Answer 11

Provide substantial surface area for exchange

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

Question 12

wha tare the three stages of chorionic villi development?

Answer 12

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.

allows close contact between foetal and maternal blood

Question 13

what is the microstructure of a terminal villus?

Answer 13

blood vessels from the foetus, coated in trophoblast, project up into the villi

the surrounding space they sit in is the lacunae, so are full of maternal blood

Convoluted knot of vessels and vessel dilation
Slows blood flow enabling exchange between maternal and fetal blood
Whole structure coated with trophoblast

Early pregnancy: 150-200µm diameter, approx. 10µm trophoblast thickness between capillaries and maternal blood.

Late pregnancy: villi thin to 40µm, vessels move within villi to leave only 1-2µm trophoblast separation from maternal blood.

Question 14

what is the maternal blood supply to the endometrium like?

Answer 14

Uterine artery branches give rise to a network of arcuate arteries. (outside myometrium)

Radial arteries branch from arcuate arteries, and branch further to form basal arteries. (in myometrium towards endometrium)

Basal arteries form spiral arteries during menstrual cycle endometrial thickening. if no implantation, the spiral arteries regress and the endometrium is shed
(in endometrium)

Question 15

what is spiral artery remodelling?

Answer 15

Spiral arteries provide the maternal blood supply to the endometrium during implantation and foetal development

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, forming a new endothelial layer
EVT cells replace the maternal endothelium

Conversion: turns the spiral artery into a low pressure, high capacity conduit for maternal blood flow.
this is really important

basically as the villi trophoblast cells invade down into the spiral arteries, it widens them out and makes them lower pressure and higher capacity

Question 16

what is an overview of the placental structure?

Answer 16

look at diagram in notes

like a big creepy cheshire cat smile

maternal artery on bottom ( with maternal vein wound round it )

lacunae above, these are supplied and filled with blood from the maternal spiral arteries

chorionic villi above, invading the lacunae

foetal artery and vein at the top

and theres a bit kinda like the cupids bow that is the umbilical cord, containing the foetal artery and vein

Question 17

what nutrients are exchanged across the placenta?

Answer 17

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.
important for development of the skeleton

Amino acids: reduced maternal urea excretion and active transport of amino acids to fetus

Question 18

what changes occur in the mother due to maternal-foetal oxygen exchange?

Answer 18

Maternal cardiac output increases 30% during first trimester (stroke vol & rate)

Maternal peripheral resistance decreases up to 30%

Maternal blood volume increases to 40% (near term (20-30% erythrocytes, 30-60% plasma)

Pulmonary ventilation increases 40%

Question 19

what changes occur in the placenta and foetus due to maternal-foetal oxygen exchange?

Answer 19

Placenta consumes 40-60% glucose and O2 supplied

But although fetal O2 tension is low, O2 content and saturation are similar to maternal blood.

Embryonic and fetal hemoglobins: greater affinity for O2 than maternal hemoglobin.

Question 20

how does the circulatory system mature?

Answer 20

Placenta acts as site of gas exchange for fetus

Ventricles act in parallel rather than series

vascular shunts bypass pulmonary & hepatic circulation -> close at birth

Organ maturation is co-ordinated by fetal cortico-steroids.

Question 21

how does the respiratory system mature?

Answer 21

Primitive air sacs form in lungs around 20 weeks, vascularization from 28 weeks

Surfactant production begins around week 20, upregulated towards term

Fetus spends 1-4h/day making rapid respiratory movements during REM sleep

Organ maturation is co-ordinated by fetal cortico-steroids.

Question 22

how does the gastro intestinal system mature?

Answer 22

Endocrine pancreas functional from start of 2T, insulin from mid-2T

Liver glycogen progressively deposited – accelerates towards term

Large amounts of amniotic fluid swallowed –debris and bile acids form meconium (the first stool

Organ maturation is co-ordinated by fetal cortico-steroids.

Question 23

how does the nervous system mature?

Answer 23

Fetal movements begin late 1T, detectable by mother from ~14 weeks

Stress responses from 18 weeks, thalamus-cortex connections form by 24 weeks

Fetus does not show conscious wakefulness – mostly in slow-wave or REM sleep

Organ maturation is co-ordinated by fetal cortico-steroids.

Question 24

what is labour?

Answer 24

Safe expulsion of the fetus at the correct time

Expulsion of the placenta and fetal membranes

Resolution/healing to permit future reproductive events

Labour has the characteristics of a pro-inflammatory reaction:
Immune cell infiltration

Inflammatory cytokine and prostaglandin secretion

Question 25

what are the phases of pregnancy in terms of parturition?

Answer 25

1: quiescent phase
prelude to parturition
contractile -unresponsiveness, cervical softening

2: activation
preparation for labour -
uterine preparedness for labour, cervical ripening

3: stimulation
process of labour -
uterine contraction, cervical dilation, foetal and placenta expulsion
(three stages of labour)

4: involution
parturient recovery -
uterine incolution, cervical repair, breast feeding

Question 26

what are the three stages of labour?

Answer 26

First Stage:
Contractions start,
Cervix dilation

Latent Phase-
Slow dilation of the cervix to 2-3cm
Active Phase-
Rapid dilation of the cervix to 10cm

Second stage:
Delivery of the fetus

Commences at full dilation of the cervix (10cm)
Maximal myometrial contractions

Third stage:
Delivery of the placenta

Explusion of placenta and fetal membranes
Post-partum repair

Question 27

what is remodelling of the cervix?

Answer 27

Cervix has a critical role in retaining the fetus in the uterus.

High connective tissue content:
Provides rigidity
Stretch resistant

Bundles of collagen fibres embedded in a proteo-glycan matrix

Changes to collagen bundle structure underlie softening, but mechanism unclear.

Question 28

what are the stages of cervix remodelling?

Answer 28

1. Softening – begins in first trimester
   Measurable changes in compliance but retains cervical competence
2. Ripening – weeks and days before birth
   Monocyte infiltration and IL-6 and IL-8 secretion
   Hylaluron deposition
3. Dilation – increased elasticity
   Increased hyaluronidase expression -> HA breakdown
   MMPs decrease collagen content
4. Post-partum repair
   Recovery of tissue integrity and competency

Question 29

what is the role of corticotrophin releasing hormone in the initiation of labour?

Answer 29

Current thinking: fetus determines timing of parturition through changes in fetal HPA axis

CRH levels rise exponentially towards the end of pregnancy

Decline in CRH binding protein levels, so CRH bioavailability increases

Question 30

what are the functions pf Corticotrophin releasing hormone in labour?

Answer 30

promotes fetal ACTH and cortisol release

Increasing cortisol drives placental production of CRH -> Positive feedback!

stimulates DHEAS production by the fetal adrenal cortex -> substrate for estrogen production

Question 31

what are oestrogen and progesterone like during labour?

Answer 31

High progesterone through pregnancy maintains uterine relaxation

Serum estrogen:progesterone ratio may shift in favour of estrogen – this is unclear

levels of oestrogen and progesterone increase during pregnancy

As term approaches, switch from PR-A isoforms (activating) to PR-B and PR-C (repressive) isoforms expressed in the uterus -> functional prog. withdrawal

Rise in Estrogen Receptor Alpha expression

Uterus becomes ‘blinded’ to progesterone action and sensitized to estrogen action

Control of these changes unclear but likely leads to local changes in E:P ratio in uterine tissues.

Question 32

what happens to oxytocin in labour?

Answer 32

Nonapeptide (9aa) hormone synthesized mainly in the utero-placental tissues and pituitary:
Uterine oxytocin production increases sharply at onset of labour

Expression increase is driven by increase in estrogen levels.

Release promoted by stretch receptors -> Ferguson reflex

Signals through G-coupled oxytocin receptor (OTR / OXTR)

Pre-labour: progesterone inhibits OXTR expression -> uterus relaxed
Rise in estrogen promotes

large increase in uterine OXTR expression

Question 33

what is the role of oxytocin?

Answer 33

Increases connectivity of myocytes in myometrium (syncytium)

Destabilise membrane potentials to lower threshold for contraction

Enhances liberation of intracellular Ca2+ ion stores

Question 34

what is the role of prostaglandins in labour?

Answer 34

Primary PGs synthesized during labour are PGE2, PGF2alpha and PGI2.

Rising estrogen levels drive prostaglandin action in the uterus in two ways:

1. Rising estrogen activates phospholipase A2 enzyme, generating more arachidonic acid for PG synthesis
2. Estrogen stimulation of oxytocin receptor expression promotes PG release.

PGE2 – cervix re-modelling
Promotes leukocyte infiltration into the cervix, IL-8 release and collagen bundle re-modelling

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 segnment.
important for inbetween contractions

Other factors: peptide hormone relaxin and nitric oxide (NO) implicated in cervix re-modelling

Question 35

what is an integrated hypothesis for the regulation of labour?

Answer 35

big diagram, look at notes

involves CRH from foetus pituitary, then positive feedback from CRH from placenta

DHEAS increase

oestrogen increase

oxytocin increase

prostaglandins

(progesterone inhibits all of these not during labour)

Question 36

what are myometrial contractions?

Answer 36

Myometrial muscle cells form a syncytium (extensive gap junctions)

Contractions start from the fundus, spread down upper segment

Muscle contractions are brachystatic –fibres do not return to full length on relaxation

This causes lower segment and cervix to be pulled up forming birth canal

Question 37

what is foetal expulsion?

Answer 37

Head engages with pelvic space 34-38wks

Pressure on fetus causes chin to press against chest (flexion)

Fetus rotates (belly to mother’s spine)
Head expelled first after cervix dilates

Shoulders delivered sequentially (upper first) followed by torso.

Question 38

what is placental expulsion and repair?

Answer 38

final phase

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 -> villi collapse

Hematoma formation between decidua and placenta

Contractions expel placenta and fetal tissues

Uterus remains contracted after delivery to facilitate uterine vessel thrombosis.

Uterine involution and cervix repair restore non-pregnant state:
Shielding uterus from commensural bacteria

Restore endometrial cyclicity in response to hormones