10.1 - Disorders of pregnancy & parturition Flashcards
1
Q
How much does the embryo grow in the first trimester?
A
Embryo-foetal growth during the first trimester is relatively limited
2
Q
Why is embryo-foetal growth in the first trimester limited?
A
- low foetal demand on placenta
- early embryo is reliant on histiotrophic nutrition (feeding of tissues)
- = reliant on uterine gland secretions and breakdown of endometrial tissues and maternal capillaries (to derive nutrients from maternal blood)
- done by syncitiotrophoblasts that invade the maternal endometrium
3
Q
As we go from first to second trimester, how does the growth rate of the embryo change?
A
There is significant increase in rate of foetal growth
4
Q
What kind of nutritional support does the embryo change to during the second trimester, and why?
A
- switch to haemotrophic support at start of 2nd trimester (histiotrophic can no longer support) = foetus derives nutrients from maternal blood
- foetal demands on placenta increase with pregnancy
- achieved in humans through a haemochorial-type placenta where maternal blood directly contacts foetal membranes (chorionic villi)
5
Q
How do the chorionic villi change throughout pregnancy, and why?
A
Branching of chorionic villi increases with progression through pregnancy to increase area for exchange, due to increasing foetal demands
6
Q
Describe what happens in the early implantation stage (origins of the placenta).
A
- syncitiotrophoblasts invade surrounding maternal endometrium to break down cells to provide nutrients to support embryo
- uterine gland secretions
- maternal capillary breakdown to bathe embryo in maternal blood (nutrients)
- amnion - derivative of epiblast which is the first of the foetal membranes and forms amniotic cavity
- amniotic cavity expands to become amniotic sac which surrounds and cushions foetus in 2nd and 3rd trimesters
7
Q
What are foetal membranes? (recap)
A
Extraembryonic tissues that form a tough but flexible sac encapsulating the foetus and forms the basis of the maternal-foetal interface
8
Q
Where does the amnion (inner foetal membrane) come from and what does it do? (recap)
A
- arises from the epiblast (doesn’t contribute to foetal tissues)
- forms a closed, avascular sac with the developing embryo at one end
- begins to secrete amniotic fluid from week 5- forms a fluid filled sac that encapsulates and protects the foetus
9
Q
Where does the chorion (outer foetal membrane) come from and what does it do? (recap)
A
- formed from yolk sac derivates and the trophoblast
- highly vascularised
- gives rise to chorionic villi- outgrowths of cytotrophoblast from the chorion that form the basis of the foetal side of the placenta
10
Q
What does the expansion of the amniotic cavity do (recap)?
A
- expansion of the amniotic cavity by fluid accumulation forces the amnion into contact with the chorion, which fuse to form the amniotic sac
- amniotic sac has 2 layers - amnion on the inside and chorion on the outside
11
Q
What are allantois and where do they come from (recap)?
A
- outgrowths of the yolk sac
- grows along the connecting stalk from the embryo to chorion
- becomes coated in mesoderm and vascularised to form the umbilical cord
12
Q
Describe an overview of placental structure.
A
- chorionic villi (invade trophoblasts, branched and vascularised) enter lacunae (maternal blood spaces) = bathed in maternal blood
- draw in oxygen and nutrients
- excrete waste products
- maternal blood spaces are supplied by spiral arteries that are remodelled to increase capacity and reduce resistance
13
Q
What are chorionic villi?
A
Finger-like extensions of the chorionic cytotrophoblast, which then undergo branching
14
Q
What are the chorionic villi important for?
A
Provide substantial surface area for exchange of gases and nutrients
15
Q
What are the three phases of chorionic villi development?
A
- primary - outgrowth of the cytotrophoblast and branching of these extensions
- secondary - growth of the foetal mesoderm into the primary villi
- tertiary - growth of the umbilical artery and vein into the villus mesoderm, providing vasculature
16
Q
Describe the blood network around each villus.
A
- convoluted knot of vessels that are dilated around each villus
- slows blood flow to enable exchange between maternal and foetal blood
- surrounded by maternal blood in the lacunae
- whole structure coated with trophoblast
17
Q
How do the chorionic villi change from early to late pregnancy?
A
- early pregnancy: 150-200um in diameter, 10um trophoblast thickness between capillaries and maternal blood
- late pregnancy: villi thin to 40um in diameter, vessels move within villi to leave only 1-2um trophoblast separation from maternal blood (decrease diffusion distance)
18
Q
Describe the maternal blood supply to the endometrium (recap).
A
Uterine artery –> arcuate arteries –> radial arteries –> basal arteries –> spiral arteries (during menstrual cycle endometrial thickening)
19
Q
What do spiral arteries do?
A
Spiral arteries provide the maternal blood supply to the endometrium
20
Q
Describe the process of spiral artery remodelling.
A
- extra-villus trophoblast (EVT) cells originally coating the villi invade down into the maternal spiral arteries, forming endovascular EVTs
- as they invade, they break down the endothelium and smooth muscle and replace them = EVT coats the inside of the spiral artery vessel
21
Q
What is the process of spiral artery remodelling called and what is the end result?
A
Conversion - turns the spiral artery into a low pressure, high capacity conduit for maternal blood flow (to feed the maternal blood spaces)
22
Q
How does spiral artery remodelling occur at a cellular level?
A
- EVT invasion activates endothelial cells and triggers them to release chemokines, recruiting immune cells
- immune cells invade spiral artery walls and begin to disrupt vessel walls - endothelium and smooth muscle broken down
- EVT cells break down normal vessel wall extracellular matrix and replace them with a new matrix known as fibrinoid
23
Q
What happens if there is failed conversion (spiral artery remodelling)?
A
Smooth muscle remains, immune cells become embedded in vessel wall, and vessels occluded by RBCs
24
Q
What are the consequences of failed spiral artery remodelling?
A
- unconverted spiral arteries are vulnerable to pathological change including intimal hyperplasia and atherosis
- this can lead to perturbed flow and local hypoxia, free radical damage and inefficient delivery of substrates into the intervillous space
- retained smooth muscle may allow residual contractile capacity –> perturb blood delivery to intravillous space
- atherosis can also occur in basal (non-spiral) arteries that would not normally be targeted by trophpblast
25
How do we diagnose pre-eclampsia? (4)
- new onset hypertension (in previously normotensive woman)
- BP >/= 140 mmHg systolic and/or >/= 90 mmHg diastolic
- occurring after 20 weeks gestation
- oedema common but not discriminatory for PE
- headache (in around 40% of severe PE)
- abdominal pain (in around 15% of severe PE)
26
What else happens in severe cases of pre-eclampsia? (3)
- visual disturbances
- breathlessness
- risk of eclampsia (seizures)
27
What happens to foetal movement and amniotic fluid volume in pre-eclampsia?
Reduced foetal movement and/or amniotic fluid volume (by ultrasound) in 30% of cases
28
What are the two subtypes of pre-eclampsia?
- early onset (<34 weeks)
- late onset (>34 weeks)
29
What is early onset pre-eclampsia associated with? (3)
- associated with foetal and maternal symptoms
- changes in placental structure
- reduced placental perfusion
30
What is late onset pre-eclampsia associated with? (4)
- more common (80-90% cases)
- mostly maternal symptoms
- foetus generally OK
- less overt/no placental changes
31
What risks do pre-eclampsia pose to the mother? (4)
- damage to kidneys, liver, brain and other organ systems
- possible progression to eclampsia (seizures, loss of consciousness)
- HELLP syndrome: Haemolysis, Elevated Liver enzymes, Low Platelets
- placental abruption (separation of the placenta from the endometrium)
32
What risks do pre-eclampsia pose to the foetus? (3)
- pre-term delivery
- reduced foetal growth (inter-uterine growth restriction IUGR/FGR)
- foetal death (500k/year worldwide)
33
What risk does pre-eclampsia pose to the placenta?
Placental abruption - separation of placenta from endometrium
34
What happens normally in placental development in terms of maternal spiral arteries?
- EVT invasion of maternal spiral arteries (endothelial and SM breakdown) through decidua and into myometrium
- EVT become endothelial EVT
- spiral arteries become high capacity
35
What happens abnormally in placental development in pre-eclampsia, terms of maternal spiral arteries? (Especially early onset PE)
- spiral remodelling (conversion) does not fully occur
- EVT invasion of maternal spiral arteries is limited to decidual/endometrial layer (not into myometrium)
- spiral arteries are not extensively remodelled
- placental perfusion is restricted
- placental ischaemia occurs, chorionic villi cannot draw out nutrients it needs
36
What is PLGF (placental growth factor)?
- VEGF related
- pro-angiogenic factor released in large amounts by the placenta
37
What is Flt1 (soluble VEGFR1)?
- soluble receptor for VEGF-like factors, which bind soluble angiogenic factors to limit their bioavailability
- sort of like a sponge to mop up factors - can bind PLGF and VEGF and take them out of circulation, stopping it binding receptors on endothelial cells = anti-angiogenic
38
What is PLGF and Flt1 like in healthy placenta?
- releases PLGF and VEGF into the maternal circulation (and little Flt1)
- these growth factors bind receptors on the endothelial surface to promote vasodilation, anti-coagulation and 'healthy' maternal endothelial cells
39
What is PLGF and Flt1 like in pre-eclampsia placenta?
- PE: excess production of Flt-1 by distressed placenta leads to reduction of available pro-angiogenic factors in maternal circulation, resulting in endothelial dysfunction
- releases sFlt1, which acts as a sponge - mops up PLGF and VEGF preventing them binding to the endothelial cell receptors
- in the absence of these signals, the endothelial cells become dysfunctional
- vasoconstriction & pro-coagulants --> hypertension
40
What are extracellular vesicles (EVs)?
- EVs are tiny (nanometer scale) lipid bilayer laminated vesicles released by almost all cell types
- contain diverse cargos, including mRNAs, proteins and microRNAs (miRNAs that block protein translation), and can influence cell behaviour (locally and at distance)
- different cell types give out different EVs
41
What are the roles of extracellular vesicles (EVs)? (2)
- cell signalling: autocrine, paracrine, endocrine
- homeostasis
42
What changes do you see in extracellular vesicles (EVs) in pre-eclampsia?
- overall increase in EVs in the maternal circulation
- increase in endothelial-derived EVs (indicative of maternal circulation defects)
- decrease in placenta-derived EVs
43
What is the possible mechanism of pre-eclampsia using concept of extracellular vesicles (EVs)?
- placental ischaemia (from incomplete spiral artery remodelling) induces trophoblast cell apoptosis and EV release
- these enter the maternal circulation
- act on endothelial cells to induce dysfunction, inflammation and hypercoagulation
- collectively these may contribute to pre-eclampsia
44
What have studies shown about extracellular vesicles (EVs) and pre-eclampsia? (2)
- EVs from severely pre-eclamptic patients inhibit vasorelaxation of mouse aorta explants vs normotensive EVs
- EVs inhibit production of nitric oxide synthase (eNOS) by human endothelial cells (vasodilator)
45
What type of eclampsia are theories about incomplete spiral artery remodelling & extracellular vesicles more relevant to?
Early onset PE
46
What causes later onset pre-eclampsia?
- although >80% PE cases are late onset, the underlying mechanisms are poorly understood
- in late onset PE there is little/no evidence of reduced spiral artery conversion
- placental perfusion is normal (possibly increased?)
- current theory - existing maternal genetic predisposition to cardiovascular disease, which manifests during the 'stress-test' of pregnancy (as pregnancy is stressful so can cause hypertension etc)
47
What is the development/stages of pre-eclampsia?
- genetic factors (e.g. maternal and foetal sFlt1 SNPs), maternal/environmental factors, immunological factors --> abnormal placentation
- stage 1 - abnormal placentation (1st&2nd trimesters)
- placental ischaemia + oxidative stress? + persistent hypoxia (+ disrupted EVs)--> restricts growth of foetus (especially early onset)
- stage 2 - maternal syndrome (late 2nd&3rd trimesters) - increasing sFlt1 (mopping up PLGF) --> systemic vascular dysfunction
48
What happens in stage 1 of pre-eclampsia?
- abnormal placentation
- proliferative > invasive trophoblasts
- superficial invasion of EVT and conversion of spiral arteries (not into myometrium)
- narrow maternal vessels as a consequence
49
What happens in stage 2 of pre-eclampsia?
- maternal syndrome
- increase in circulating sFlt1 and sEng (more VEGF/PLGF mopped up)
- increased syncityal debris and pro-inflammatory cytokines in maternal circulation
50
What does systemic vascular dysfunction as a result of pre-eclampsia consist of? (4)
- proteinuria / glomerular endotheliosis (kidney)
- hypertension
- visual disturbances / headache / cerebral oedema and seizures (eclampsia)
- HELLP syndrome / coagulation abnormalities
51
What two ways can we detect pre-eclampsia with?
- PLGF alone
- Flt-1/PLGF ratio
52
What test is PLGF alone?
- e.g. Triage test
- rules out PE in next 14 days in women 20-36wk and 6 days
- PLGF < 12pg/ml = test positive, highly abnormal --> increased risk for preterm delivery
- PLGF 12-100 pg/ml = test positive, abnormal --> increased risk for preterm delivery
- PLGF >100 pg/ml = test negative, normal --> unlikely to progress to delivery within 14 days of test
53
What is Flt-1/PLGF ratio?
- 24 weeks to 36 weeks plus 6 days gestation (Flt-1 levels go down towards end of pregnancy so test becomes skewed at later weeks)
- sFlt-1/PLGF ratio <38 = rule out PE
- sFlt1-1/PLGF ratio >38 = increased risk of PE
54
What test for pre-eclampsia has been rolled out throughout NHS from 2021, based on the result of a major clinical trial?
- PLGF level test
- high sensitivity (>94%, 20-35 weeks gestation)
- reduced average diagnosis time from 4.1 to 1.9 days
55
What does early diagnosis of pre-eclampsia mean?
Reduced maternal adverse events and number of nights spent in high-level neonatal care in test group
56
How might the diagnosis of pre-eclampsia change in the future? (3)
- clinical need for diagnostics that identify women at risk of PE early in pregnancy
- examination of circulation cell-free RNA (cfRNA) from liquid biopsy identifies group of transcripts that are predictive of PE in the first trimester
- examination of small molecule metabolites in urine reveals bio-signature associated with PE before symptom onset
57
When is a foetus considered small for gestational age (SGA)?
Foetal weight: <10th centile (or 2SD below population normal)
58
When is a foetus considered severe SGA (small for gestational age)?
Severe SGA: 3rd centile or less
59
What three groups can small for gestational age (SGA) be subclassified into?
- small throughout pregnancy, but otherwise healthy
- early growth normal but slows later in pregnancy (FGR/IUGR)
- non-placental growth restriction (genetic, metabolic, infection)
60
What is intrauterine growth restriction (IUGR) also known as?
Foetal growth restriction - FGR
61
What is the difference between IUGR and small for gestational age (SGA)?
- SGA considers only the foetal/neonatal weight, without any consideration of the in-utero growth and physical characteristics at birth
- IUGR is a clinical definition of foetuses/neonates with clinical features of malnutrition and in-utero growth restriction, irrespective of weight percentile
- thus a baby may be IUGR without being SGA if they show features of malnutrition and growth restriction at birth, but over 10th centile
- similarly, a baby with a birth weight less than 10th percentile will be SGA, not IUGR if there are no features of malnutrition
62
Compare symmetric vs asymmetric IUGR.
- period of insult: earlier gestation vs later gestation
- incidence of total IUGR cases: 20-30% vs 70-80%
- aetiology: genetic disorder or infection intrinsic to foetus vs utero-placental insufficiency
- antenatal scan: all are proportionally reduced vs abdominal circumference decreased; biparietal diameter, head circumference and femur length normal
- cell number: reduced vs normal
- cell size: normal vs reduced
- ponderal index: normal (>2) vs low (<2)
- postnatal anthropometry: reductions in all parameters vs reduction in weight, length and head circumference normal (brain sparing growth)
- difference between head and chest circumferences: <3cm vs >3cm
- features of malnutrition: less pronounced vs more pronounced
- prognosis: poor vs good
63
What are the cardiovascular implications of FGR/IUGR?
- foetal cardiac hypertrophy (foetus reduced O2 supply = vessels go into chronic vasoconstriction to hold O2 in place, continues after birth --> cardiac hypertrophy)
- remodelling of foetal vessels due to chronic vasoconstriction
64
What are the respiratory implications of FGR/IUGR?
Poor maturation of lungs during foetal life, leading to bronchopulmonary dysplasia and respiratory compromise
65
What are the neurological implications of FGR/IUGR?
Long term motor defects and cognitive impairments
66
What leads to foetal growth restriction? (Integrating pre-eclampsia and IUGR)
- genetic causes + abnormal maternal immunological adaptation -->
- villous placental maldevelopment -->
- altered branching of villous tree
- impaired nutrient and/or gas exchange
- syncytial pathology with impaired placental transport efficiency and/or fetoplacental vascular impoverishment
67
What leads to early onset pre-eclampsia +/- foetal growth restriction? (Integrating pre-eclampsia and IUGR)
- trophoblast invasion defect + defective decidualisation + abnormal maternal immunological adaptation -->
- placental bed pathology -->
- vascular malperfusion -->
- stress
- local hypoxia
- hypoxia-reperfusion
- shear damage
- exaggerated particle release
- impaired placental transport efficiency
- villous placental pathology
- altered cell turnover
- skewed angiomodulatory balance
- (also leads to late-onset pre-eclampsia)
68
What leads to late-onset pre-eclampsia? (Integrating pre-eclampsia and IUGR)
- villous placental vulnerability, stress or ageing --> abnormal maternal systemic vascular adaptation to pregnancy -->
- exaggerated particle release from placenta, skewed angiomodulatory response
