L2 Foetal and Placental Physiology Flashcards
What does the placenta facilitate transfer of?
- Mother to fetus: Oxygen, nutrients, hormones
- Fetus to mother: carbon dioxide, wastes, hormones
What are the gross structures of the feto-placental unit?
- Umbilical cord joined to baby
- At fetal surface, amnion forms the outer layer
- Beneath this is the chorion which faces the mother (highly vascularised)
What does it mean that the human placenta is a haemochorial villous organ?
- Maternal blood comes into direct contact with placental trophoblast cells
Give 5 examples of pregnancy complications that can arise from disordered placental development:
- Pre-eclampsia
- Fetal growth restriction
- Recurrent miscarriage
- Preterm birth
- Still-birth
How does the placenta develop? (Prelacunar stage)
- Arises from trophoectoderm (outer layer of blastocyst)
- Polar trophoectoderm attaches to surface epithelium of uterine mucosa (endometrium) (5 dpf)
- At ~6-7 dpf, the TE fuses with endometrium to form a primary syncytium which quickly invades underlying endometrium (precursor to decidua)
How does the placenta develop? (Lacunar stage)
- At around 14 dpf, the blastocyst is completely embedded in the decidua and is covered by surface epithelium
- Fluid filled spaces called lacunae then form within the syncytial mass that enlarge and merge
- The syncytium also erodes into decidual glands, allowing secretions to bathe the syncytial mass
How does the placenta develop? (Villous stage)
- The trophoblast cells under the syncytium (aka cytotrophoblast) rapidly proliferate to form projections into the primary syncytium to form primary villi
- Villous tress form by further proliferations and branching -> lacunae become the intervillous spaces
- At around 17-18dpf, extraembryonic mesenchymal cells penetrate through the villous core -> secondary villi
- Fetal capillaries next appear within the core (tertiary villi)
- The villous tree continues to rapidly enlarge by progressive branching from the chorionic plate to form a system of villous trees
What is the maternal-fetal interface composed of?
- Invasive cytotrophoblasts which have undergone EMT to become extravillous trophoblasts (finger-like projections)
- Some are able to fuse with endothelium of spiral artery, opening into intravillous space to allow blood to flow in
- Some EVTs remain interstitial
Outline the key lineages that villous stem ell cytotrophoblasts can follow:
- Extravillous -> form cytotrophoblast cell columns and shell and utlimately remodel uterine arteries as endovascular trophoblast or become interstitial trophoblast (migrating into decidua and myomterium)
- Villous pathway -> become syncytiotrophoblasts, the primary site of placental transport, protective and endocrine functions
Bulletpoint the 4 major functions that trophoblast cells facilitate in the placenta:
- Gas exchange
- Transport and metabolism
- Protection
- Endocrine functions
How is the fetus supplied with oxygen at the maternal-fetal interface?
- Oxygen passes passively down pressure gradient between maternal blood in intervillous space and umbilical artery of the fetus (~10% net O2 transfer)
- Conversely, CO2 passes passively down PCO2 pressure gradient from fetus to mother
What is unusal about the terminology of the fetal circulatory system?
- Fetal umbilical artery is actually deoxygenated instead of pumping oxygenated blood from heart to body as in adult system
How does the placenta facilitate transport of carbohydrates? (2 examples)
- Since the fetus has a low capacity for gluconeogenesis, it relies on transfer of glucose from maternal blood via glucose transporters (GLUTs) which are present on both apical and basal surfaces of synctiotrophoblasts and villous endothelial cells
- The human placenta also produces a lot of lactate -> transported by placenta to fetus
How does the placenta facilitate transport of amino acids?
- Transported from mother to fetus through syncytiotrophoblast via active transport
- Various types of channel proteins e.g. sodium independent transporter of cationic amino acids
How does the placenta facilitate transport of lipids?
- Fatty acids and cholesterols are bound to plasma proteins to form lipoprotein complexes -> maternal surface of placenta contains lipoprotein lipase which releases free fatty acids from their complexes
- Transfer from mother to fetus occurs by simple diffusion through placenta then fatty acid binding proteins
How and why does the placenta deal with excess hepatobiliary products?
- Cholephilic compounds (bile acids, biliary pigments like bilirubin) are produced by fetal liver but are not effectively excreted so spill over into fetal circulation
- A small amount is then excreted by the fetal kidney into the amniotic fluid
- As such, it is important that they are secreted via the placenta -> some passively diffuse but majority are pumped by solute-carrier transporters like SLC21A9 and SLC22A9
- Fetal jaundice can occur when BPs like bilirubin build up in the blood
How is the fetus supplied with electrolytes and vitamins?
- Passive diffusion and active transport through placenta
- Electrolytes: Na+, Cl-
Which electrolytes must be actively transported to fetus?
- Na+ and Cl-: similar concentrations
- K+, Ca2+, phosphate: higher in fetal blood, require ion pumps
How does the placenta physically defend against pathogens? (2x features)
- Syncytiotrophoblast forms contunuous syncytial layer without cell-cell junction over chorionic villi, reducing microbial invasion
- Dense actin filament network under brush border apical surface -> able to protect against parasitic invasion (e.g. toxoplasma gondii)
Describe 4 placental secretory factors that defend the fetus against pathogens:
- Interferons (Type III) inhibit viral infections
- Pattern recognition receptors such as toll-like receptors sense bacteria and release antimicrobial peptides and cytokines
- Chemokines are secreted in response to infection, recruiting T cells (h, reg) -> immune response e.g. CCL22 in T.gondii exposure
- miRNAs: Placenal exosome-enclosed miRNAs attenuate viral replications by inducing autophagy
How does the maternal immune system support placental immune defense?
- Active transport of IgG antibodies into fetus (protective function)
- Neonatal Fc receptors for IgG facilitate this uptake
- Maternal humoral immunity starts at week 16, facilitated by placenta
How does the placenta protect against graft rejection of the fetus?
- Requires careful restriction and modulation of leukocytes at maternal-fetal interface
- e.g. Antiinflammatory cytokines like IL-10 and TGF-B abundant at the interface (causing differentiation of monocytes and T-cells) -> differentiated monocytes release IDO which hinders T cell activation and phagocytosis of apoptotic trophoblasts
- Syncytiotrophoblasts secrete exosomes containing TRAIL and Fas death ligand -> apoptosis of leukocytes
- KEY: No expression of HLA by STB cells -> not recognised as ‘non-self’
- Protection of targeting by NK cells by expression of HLA-G by placental EVTs (binds to dNK inhibitory receptors)
- Failure of this mechanism associated with pre-eclampsia, miscarriage, preterm birth
Why are endocrine functions especially important for communications between mother and fetus?
- Placenta has no nerves; blood-borne substances are the only way to communicate
- The placenta is acting as a major endocrine gland to maintain pregnancy and fetal growth
What major hormones does the placenta produce?
- hCG
- Progesterone
- Oestrogen (e.g. oestrone, oestradiol, oestriol)
- Placental lactogen
- Placental growth hormone
Where in the placenta is hCG produced? How does it influence corpus luteum and placental function?
- Produced by STB, peaking at around 8 weeks
- Corpus luteum: stimulates progesterone and oestrogen production
- Placenta: stimulates cytotrophoblastic cell fusion and differentiation of villous trophoblasts
When does the placenta take over steroid hormone production? What are the consequences…
- At 8 wks, placenta takes over progesterone and oestrogen production
- Primarily produced by synctiotrophoblast cells
- Progesterone inhibits uterine contraction and supresses LH release -> no ovulation
- Oestrogen acts as specialised growth hormone for mother’s reproductive organs
What is the function of human placental lactogen?
- hPL is a polypeptide hormone, primarily synthesises by STB -> appears in maternal circulation at 3 - 6 wks
- Regulates maternal lipid and carbohydrate metabolism and contributes to maternal insulin resistance in mid to late gestation -> increased maternal circulatory glucose level -> ensures adequate nutrition to fetus
What is the function of placental growth hormone?
- GH is a single chain peptide hormone synthesises by STB from 15 - 20 weeks
- Gradually replaces pituitary growth hormone -> regulates maternal blood glucose levels ensuring adequate nutrition to fetus
Outline the germinal stage of fetal development:
- Fertilisation (fallopian tube)
- Mitosis resumes 24hrs later -> division into morula
- Blastocyst 5dpf -> ICM, TE form
- Implantation 7dpf
Outline the embryonic phase of fetal development:
- 2nd week: ICM forms 2-layered embryonic disc and amniotic cavity
- Beginning of 3rd wk: embryonic disc differentiates into 3 layers (ectoderm, mesoderm, endoderm) -> gastrulation
What organs differentiate from the endoderm layer?
- Digestive system
- Liver
- Pancreas
- Inner layers of lungs
What organs/tissues differentiate from the mesoderm layer?
- Circulatory system
- Lung epithelium
- Skeletal system
- Muscular system
What organs/tissues differentiate from the ectoderm layer?
- Hair
- Nails
- Skin
- Nervous system
Features of the gastrula:
- Implanted into endometrium (with mucosa reformed over top) -> TE has formed chorion (placental precursor) establishing contact with maternal blood pool
- Amniotic cavity containing fluid contained within chorion -> fetus sits in middle, with 3 germ layers and yolk sac lined with endoderm at its centre, connected to chorion via allantois
Describe the key events of the fetal stage of fetal development:
- 9th week onwards
- Neural tube develops into brain and spinal chord, and neurons (and synapses begin to connect them up)
- During 3rd month, sex organs begin to differentiate
- Most body parts formed by 3rd month
- Organ development and maturation proceeds from this point
What is the role of insulin in fetal development?
- Growth
- Important both in normal and adverse nutritional conditions
What disorders can arise due to insulin dysfunction?
- Fetal hyperinsulinaemia (DM) -> macrosomia due to excessive fat deposition
- Low fetal insulin -> FGR
What is the role of thyroxine in normal fetal development?
- Required through late gestation for normal growth
Consequences of a lack of thyroxine during late gestation?
- Deficiency in skeletal and cerebral maturation -> cretinism
- Delays surfactant production in lungs (important for inflating lungs at birth)
What is the role of cortisol during fetal development? (consider 3 key organ maturation processes)
- Limited role in stimulating growth
- Stimulates surfactant release -> lung maturation
- Induces B receptors and glycogen deposition -> liver maturation, adequate glucose supply after delivery
- Villous proliferation in the gut, induces digestive enzymes
What key differences are there between fetal and mature circulatory system?
- Umbilical vein: oxygenated blood from placenta to fetus
- Umbilical artery (x2): deoxygenated blood to placenta
- 3 shunts are in place which bypass the normal routes for oxygenated blood
- Umbilical arteries wind around the large umbilical vein on the way down to the umbilical chord and ultimately placenta
- Shunt 1 connects the umbilical vein to rest of system
Where is fetal blood produced throughout development?
- In yolk sac from 4-18th day
- Haemopoiesis continues through first trimester in the yolk sac
- During the 5th week, haemopoiesis begins in the liver (secondarily in spleen)
- Bone marrow: RBC production from week 7/8
What are the key structural differences between fetal and adult haemoglobin?
- HbF: 2a, 2y chains
- HbA: 2a, 2B
- HbA2: 2a, 2d
How does the Hb composition of fetal blood change through gestation?
- 90% HbF from 10 to 28wk
- Switch to HbA starts at this point, reaching 80:20 by term, and 1% HbF by 6mths old
- Generally speaking, the overall Hb concentration is higher during gestation than in adults -> enhanced oxygen transfer across gestation
What is the functional difference between fetal and adult hemoglobin?
- HbF: Higher affinity for oxygen than HbA
- This is due to the presence of the gamma subunits on HbF -> 2,3-BPG is unable to bind (inhibits O2 binding in mother by strongly binding with B subunits)
What is a typical consequence of abnormal Hb production?
- Thalassaemia
How does the respiratory system develop?
- Epithelium develops from mesoderm and inner layers develop from endoderm
- By 20 weeks, pulmonary capillaries are fully developed, but alveoli develop after 24 weeks
- Fetal lung is filled with fluid which is produced early in gestation and is important for lung maturation
- Surfactants line alveoli and prevent their collapse -> continually produced from type 2 alveolar cells (10% of lung parenchyma)
- Adequate amniotic fluid volume is important for lung maturation
- Fetus will exhibit rhythmic breathing movements in utero (important for lung development and muscle training)
What happens in the lungs after birth?
- Drop in pressures and stimulation from external environment triggers first breath -> lungs expand and fluid clears
- Surfactants must be absorbed to allow alveoli to begin their function
- Cessation of surfactant production is stimulated by adrenaline
What is respiratory distress syndrome and how may it be prevented?
- Specific to premature babies, associated with surfactant deficiency
- May be complicated by hypocia, intraventricular haemorrhage and necrotizing entercolitis
- Incidence and severity can be reduced with steroids antenatally for mothers at risk of preterm birth
How and when does the gastrointestinal tract develop?
- Fetal alimentary tract begins to form at 3rd week
- Swallowing reflex develops in fully formed GI tract and matures gradually
- Peristalsis in intestine occurs from 2nd trimester
- Fetus is continually and increasingly swallowing amniotic fluid up to 20ml/hr to term -> necessary to maintain the right amount of fluid in the amniotic sac
- A failure of the swallowing mechanism (as in neurological abnormalities or gut obstruction) will result in polyhydramnios
How does the fetal liver differ from adults?
- Reduced ability to conjugate bilirubin due to lack of necessary enzymes (e.g. gluconoryl transferase)
- Bilirubin thus cannot excrete in the bile, and the placenta is instead responsible for this hepatobiliary excretion
- Glycogen store gradually builds up throughout gestation
When are certain components of the fetal immune system are produced?
- Lymphocytes appear from 8wk
- By middle of 2nd trimester, all phagocytic cells, T and B cells and complements are up and running
- Most IgG comes from mother
- Fetus makes a small amount of IgM and IgA (don’t cross placenta)
Describe the immunological defence system in the fetus:
- Amniotic fluid contains lysosomes and maternal IgG
- Placenta contains lymphoid cells, phagocytes and acts as a physical barrier
- Liver and bone marrow produce granulocytes
- Lymphocytes release interferons
What is the function of amniotic fluid?
- Protects fetus from mechanical injury -> cushioning effect
- Permits movements and prevents limb contracture
- Prevents adhesions between limb and amnion
- Permits fetal lung development
How does the amnion develop?
- Membrane is thin and translucent, surrounding feus (epithelium, basement membrane and stroma)
- Doesn’t have any vessels or nerves but does have lots of phospholipids and enzymes
- The choriodecidua layer is important in producing PG E2 and F2a to induce labour
- The fluid itself is initially secreted by the amnion but is later contributed by kidney and lung fluids and removed by swallowing
