Pregnancy, Parturition and Late Fetal Development

Question 1

How does early fetal development occur?

Answer 1

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.

Question 2

How does embryo development switch from histiotrophic to haemotrophic?

Answer 2

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.

Question 3

What are the origins of the placenta?

Answer 3

Amnion is a derivative of the epiblast but unlike rest of it, does not go on to form a part of the foetus. Is the first of the foetal membranes and goes on to form the amniotic cavity which will eventually form amniotic sac, cushioning and supporting foetus.

Question 4

What parts form the origins of the placenta?

Answer 4

Connecting stalk - Links developing embryo unit to the chorion
Trophoblastic lacunae - Large spaces filled with maternal blood formed by breakdown of maternal capillaries and uterine glands. Become intervillous spaces aka maternal blood spaces.
Amnion

Question 5

What are fetal membranes?

Answer 5

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

Question 6

What is the amnion?

Answer 6

Inner fetal membrane. 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 7

What is the chorion?

Answer 7

Outer fetal membrane. 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 8

What is the allantois?

Answer 8

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 9

What is the amniotic sac?

Answer 9

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 10

What is the primary chorionic villi?

Answer 10

Cytotrophoblast forms finger-like projections through

syncitiotrophoblast layer into maternal endometrium.

Question 11

What is the role of the chorionic villi?

Answer 11

Provide substantial surface area for exchange. Finger-like extensions of the chorionic cytotrophoblast, which then undergo branching.

Question 12

What are the 3 phases of chorionic villi development?

Answer 12

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.

Question 13

Describe terminal villi microstructure

Answer 13

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

Question 14

How does terminal villi microstructure change through pregnancy?

Answer 14

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 15

Describe maternal blood supply to the endometrium

Answer 15

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.

Question 16

How do spiral arteries remodel?

Answer 16

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.

Question 17

How are different nutrients 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.
Amino acids: reduced maternal urea excretion and active transport of amino acids to fetus

Question 18

What maternal changes occur in terms of 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%.

CORP 30 BP 40

Question 19

What placenta and fetal changes occur in terms of 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 in late fetal development?

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.

Question 21

How does the respiratory system mature in late fetal development?

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 practicing breathing reflex and to strengthen diaphragm.

Question 22

How does the GI system mature in late fetal development?

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.

Question 23

How does the nervous system mature in late fetal development?

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.

Question 24

What are the aims of 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

Question 25

What are the characteristics of labour?

Answer 25

Labour has the characteristics of a pro-inflammatory reaction:
Immune cell infiltration
Inflammatory cytokine and prostaglandin secretion

Question 26

What are the 3 stages of labour?

Answer 26

First Stage: Contractions start, Cervix dilation
Contains 2 stages. Latent stage is when slow dilation of cervix occurs up to 2-3cm. Active stage is rapid dilation from there of the cervix to 10cm.
Second stage: Delivery of 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

Describe the cervix

Answer 27

Cervix has a critical role in retaining the fetus in the uterus.
High connective tissue content: Provides rigidity and stretch resistant
Bundles of collagen fibres embedded in a proteo-glycan matrix
Changes to collagen bundle structure underlie softening, but mechanism unclear.

Question 28

How is the cervix remodelled during pregnancy?

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 occurs. Hylaluron deposition.
3. Dilation - increased elasticity. Increased hyaluronidase expression -> HA breakdown. MMPs (matrix metalloproteinases) decrease collagen content.
4. Post-partum repair - Recovery of tissue integrity and competency.

Question 29

What is a theory about the timing of parturition?

Answer 29

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. This 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 30

How do oestrogen and progesterone levels change at labour?

Answer 30

High progesterone through pregnancy maintains uterine relaxation. As term approaches, switch from PR-A isoforms (activating) to PR-B and PR-C (repressive) isoforms expressed in the uterus leading to functional prog. withdrawal. Rise in Estrogen Receptor Alpha expression. Therefore, uterus becomes ‘blinded’ to progesterone action and sensitized to estrogen action.

Question 31

How does oxytocin change around labour?

Answer 31

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.

Question 32

How does oxytocin signal?

Answer 32

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 are the functions of oxytocin?

Answer 33

1. Increases connectivity of myocytes in myometrium (syncytium)
2. Destabilise membrane potentials to lower threshold for contraction
3. Enhances liberation of intracellular Ca2+ ion stores

Question 34

How does oestrogen influence prostaglandin release?

Answer 34

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

Question 35

What prostaglandins are released during labour?

Answer 35

PGE2, PGF2alpha and PGI2.
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 segment.

Question 36

What other factors are released during labour?

Answer 36

Peptide hormone relaxin and nitric oxide (NO) implicated in cervix re-modelling.

Question 37

What is the integrated hypothesis for the regulation of labour?

Answer 37

Cortisol axis leads to DHEAS formation and estrogen increased. Estrogen induces oxytocin formation and oxytocin receptors on uterus (progesterone inhibits this). Oxytocin made from fetus and mother’s posterior pituitary stimulates uterus to contract and placenta to make prostaglandins. Prostaglandins cause more vigorous contraction of the uterus which via positive feedback causes release of more oestrogen and prostaglandins.