10.1 - Disorders of pregnancy & parturition Flashcards
How much does the embryo grow in the first trimester?
Embryo-foetal growth during the first trimester is relatively limited
Why is embryo-foetal growth in the first trimester limited?
- 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
As we go from first to second trimester, how does the growth rate of the embryo change?
There is significant increase in rate of foetal growth
What kind of nutritional support does the embryo change to during the second trimester, and why?
- 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)
How do the chorionic villi change throughout pregnancy, and why?
Branching of chorionic villi increases with progression through pregnancy to increase area for exchange, due to increasing foetal demands
Describe what happens in the early implantation stage (origins of the placenta).
- 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
What are foetal membranes? (recap)
Extraembryonic tissues that form a tough but flexible sac encapsulating the foetus and forms the basis of the maternal-foetal interface
Where does the amnion (inner foetal membrane) come from and what does it do? (recap)
- 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
Where does the chorion (outer foetal membrane) come from and what does it do? (recap)
- 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
What does the expansion of the amniotic cavity do (recap)?
- 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
What are allantois and where do they come from (recap)?
- 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
Describe an overview of placental structure.
- 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
What are chorionic villi?
Finger-like extensions of the chorionic cytotrophoblast, which then undergo branching
What are the chorionic villi important for?
Provide substantial surface area for exchange of gases and nutrients
What are the three phases of chorionic villi development?
- 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
Describe the blood network around each villus.
- 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
How do the chorionic villi change from early to late pregnancy?
- 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)
Describe the maternal blood supply to the endometrium (recap).
Uterine artery –> arcuate arteries –> radial arteries –> basal arteries –> spiral arteries (during menstrual cycle endometrial thickening)
What do spiral arteries do?
Spiral arteries provide the maternal blood supply to the endometrium
Describe the process of spiral artery remodelling.
- 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
What is the process of spiral artery remodelling called and what is the end result?
Conversion - turns the spiral artery into a low pressure, high capacity conduit for maternal blood flow (to feed the maternal blood spaces)
How does spiral artery remodelling occur at a cellular level?
- 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
What happens if there is failed conversion (spiral artery remodelling)?
Smooth muscle remains, immune cells become embedded in vessel wall, and vessels occluded by RBCs
What are the consequences of failed spiral artery remodelling?
- 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
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)
What else happens in severe cases of pre-eclampsia? (3)
- visual disturbances
- breathlessness
- risk of eclampsia (seizures)
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
What are the two subtypes of pre-eclampsia?
- early onset (<34 weeks)
- late onset (>34 weeks)
What is early onset pre-eclampsia associated with? (3)
- associated with foetal and maternal symptoms
- changes in placental structure
- reduced placental perfusion
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
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)
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)
What risk does pre-eclampsia pose to the placenta?
Placental abruption - separation of placenta from endometrium
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
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
What is PLGF (placental growth factor)?
- VEGF related
- pro-angiogenic factor released in large amounts by the placenta
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
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
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
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
What are the roles of extracellular vesicles (EVs)? (2)
- cell signalling: autocrine, paracrine, endocrine
- homeostasis
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
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
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)
What type of eclampsia are theories about incomplete spiral artery remodelling & extracellular vesicles more relevant to?
Early onset PE
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)
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
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
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
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
What two ways can we detect pre-eclampsia with?
- PLGF alone
- Flt-1/PLGF ratio
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
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
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
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
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
When is a foetus considered small for gestational age (SGA)?
Foetal weight: <10th centile (or 2SD below population normal)
When is a foetus considered severe SGA (small for gestational age)?
Severe SGA: 3rd centile or less
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)
What is intrauterine growth restriction (IUGR) also known as?
Foetal growth restriction - FGR
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
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
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
What are the respiratory implications of FGR/IUGR?
Poor maturation of lungs during foetal life, leading to bronchopulmonary dysplasia and respiratory compromise
What are the neurological implications of FGR/IUGR?
Long term motor defects and cognitive impairments
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
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)
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
