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Year 2 - BRS > 10.1 - Disorders of pregnancy & parturition > Flashcards

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

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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
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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

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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)
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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

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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
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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

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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
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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
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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
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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
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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
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13
Q

What are chorionic villi?

A

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

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14
Q

What are the chorionic villi important for?

A

Provide substantial surface area for exchange of gases and nutrients

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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
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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
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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)
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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)

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19
Q

What do spiral arteries do?

A

Spiral arteries provide the maternal blood supply to the endometrium

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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
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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)

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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
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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

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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
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25
Q

How do we diagnose pre-eclampsia? (4)

A
  • 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)
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26
Q

What else happens in severe cases of pre-eclampsia? (3)

A
  • visual disturbances
  • breathlessness
  • risk of eclampsia (seizures)
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27
Q

What happens to foetal movement and amniotic fluid volume in pre-eclampsia?

A

Reduced foetal movement and/or amniotic fluid volume (by ultrasound) in 30% of cases

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28
Q

What are the two subtypes of pre-eclampsia?

A
  • early onset (<34 weeks)
  • late onset (>34 weeks)
29
Q

What is early onset pre-eclampsia associated with? (3)

A
  • associated with foetal and maternal symptoms
  • changes in placental structure
  • reduced placental perfusion
30
Q

What is late onset pre-eclampsia associated with? (4)

A
  • more common (80-90% cases)
  • mostly maternal symptoms
  • foetus generally OK
  • less overt/no placental changes
31
Q

What risks do pre-eclampsia pose to the mother? (4)

A
  • 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
Q

What risks do pre-eclampsia pose to the foetus? (3)

A
  • pre-term delivery
  • reduced foetal growth (inter-uterine growth restriction IUGR/FGR)
  • foetal death (500k/year worldwide)
33
Q

What risk does pre-eclampsia pose to the placenta?

A

Placental abruption - separation of placenta from endometrium

34
Q

What happens normally in placental development in terms of maternal spiral arteries?

A
  • 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
Q

What happens abnormally in placental development in pre-eclampsia, terms of maternal spiral arteries? (Especially early onset PE)

A
  • 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
Q

What is PLGF (placental growth factor)?

A
  • VEGF related
  • pro-angiogenic factor released in large amounts by the placenta
37
Q

What is Flt1 (soluble VEGFR1)?

A
  • 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
Q

What is PLGF and Flt1 like in healthy placenta?

A
  • 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
Q

What is PLGF and Flt1 like in pre-eclampsia placenta?

A
  • 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
Q

What are extracellular vesicles (EVs)?

A
  • 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
Q

What are the roles of extracellular vesicles (EVs)? (2)

A
  • cell signalling: autocrine, paracrine, endocrine
  • homeostasis
42
Q

What changes do you see in extracellular vesicles (EVs) in pre-eclampsia?

A
  • overall increase in EVs in the maternal circulation
  • increase in endothelial-derived EVs (indicative of maternal circulation defects)
  • decrease in placenta-derived EVs
43
Q

What is the possible mechanism of pre-eclampsia using concept of extracellular vesicles (EVs)?

A
  • 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
Q

What have studies shown about extracellular vesicles (EVs) and pre-eclampsia? (2)

A
  • 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
Q

What type of eclampsia are theories about incomplete spiral artery remodelling & extracellular vesicles more relevant to?

A

Early onset PE

46
Q

What causes later onset pre-eclampsia?

A
  • 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
Q

What is the development/stages of pre-eclampsia?

A
  • 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
Q

What happens in stage 1 of pre-eclampsia?

A
  • abnormal placentation
  • proliferative > invasive trophoblasts
  • superficial invasion of EVT and conversion of spiral arteries (not into myometrium)
  • narrow maternal vessels as a consequence
49
Q

What happens in stage 2 of pre-eclampsia?

A
  • maternal syndrome
  • increase in circulating sFlt1 and sEng (more VEGF/PLGF mopped up)
  • increased syncityal debris and pro-inflammatory cytokines in maternal circulation
50
Q

What does systemic vascular dysfunction as a result of pre-eclampsia consist of? (4)

A
  • proteinuria / glomerular endotheliosis (kidney)
  • hypertension
  • visual disturbances / headache / cerebral oedema and seizures (eclampsia)
  • HELLP syndrome / coagulation abnormalities
51
Q

What two ways can we detect pre-eclampsia with?

A
  • PLGF alone
  • Flt-1/PLGF ratio
52
Q

What test is PLGF alone?

A
  • 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
Q

What is Flt-1/PLGF ratio?

A
  • 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
Q

What test for pre-eclampsia has been rolled out throughout NHS from 2021, based on the result of a major clinical trial?

A
  • PLGF level test
  • high sensitivity (>94%, 20-35 weeks gestation)
  • reduced average diagnosis time from 4.1 to 1.9 days
55
Q

What does early diagnosis of pre-eclampsia mean?

A

Reduced maternal adverse events and number of nights spent in high-level neonatal care in test group

56
Q

How might the diagnosis of pre-eclampsia change in the future? (3)

A
  • 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
Q

When is a foetus considered small for gestational age (SGA)?

A

Foetal weight: <10th centile (or 2SD below population normal)

58
Q

When is a foetus considered severe SGA (small for gestational age)?

A

Severe SGA: 3rd centile or less

59
Q

What three groups can small for gestational age (SGA) be subclassified into?

A
  • small throughout pregnancy, but otherwise healthy
  • early growth normal but slows later in pregnancy (FGR/IUGR)
  • non-placental growth restriction (genetic, metabolic, infection)
60
Q

What is intrauterine growth restriction (IUGR) also known as?

A

Foetal growth restriction - FGR

61
Q

What is the difference between IUGR and small for gestational age (SGA)?

A
  • 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
Q

Compare symmetric vs asymmetric IUGR.

A
  • 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
Q

What are the cardiovascular implications of FGR/IUGR?

A
  • 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
Q

What are the respiratory implications of FGR/IUGR?

A

Poor maturation of lungs during foetal life, leading to bronchopulmonary dysplasia and respiratory compromise

65
Q

What are the neurological implications of FGR/IUGR?

A

Long term motor defects and cognitive impairments

66
Q

What leads to foetal growth restriction? (Integrating pre-eclampsia and IUGR)

A
  • 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
Q

What leads to early onset pre-eclampsia +/- foetal growth restriction? (Integrating pre-eclampsia and IUGR)

A
  • 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
Q

What leads to late-onset pre-eclampsia? (Integrating pre-eclampsia and IUGR)

A
  • villous placental vulnerability, stress or ageing –> abnormal maternal systemic vascular adaptation to pregnancy –>
  • exaggerated particle release from placenta, skewed angiomodulatory response

Year 2 - BRS (84 decks)

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