Disorders of pregnancy & parturition Flashcards
Describe the structure of the placenta
Fetal vein and fetal artery from the umbilical cord supplying chorionic villus
Maternal vein and artery from spiral arteries supplying intervillous space - lacunae
How do feral demands change through pregnancy on placenta
Histiotrophic form of nutrition - driven by invasion on synsitiotrophoblasts into the endometrium
Break down of glands and nutrients gained from destroying materal surroundings
Switch to haemochorial placenta , where maternal blood supply in contact with chorion
Progressive branching of chorionic villi so more exchange and foetus is putting greater demand on placenta and mother
Placenta is a high metabolic organ
How does fetal growth acceleration happen with changes in support
Embryo-fetal growth during first trimester is relatively limited
Low fetal demand on the placenta
Early embryo nutrition is histiotrophic
Reliant on uterine gland secretions and breakdown of endometrial tissues
Switch to haemotrophic support at start of 2nd trimester
Fetal demands on placenta increase with pregnancy
Achieved in humans through a haemochorial type placenta where maternal blood dir3ctly contacts the fetal membrane (chorionic villi)
Origins of the placenta : early implantation stage ?
Histiotrophic nutrition driven by invasion of synctiotophoblast cells growing out from early planted embryo, invading endometrial tissue and breaking down uterine glands and maternal capillary and deriving nutrients
Then cytotrophoblasts, proliferative cells, dividing so more cells for more syncytiotrophoblasts
To get a haemochorial placenta, cytotrophoblast become important in the development of chorionic villi
How chorionic villi form - 3 phases
They are finger like extensions of the chorionic cytotrophoblast from chorion membrane which then undergo branching
Primary: outgrowth of the cytotrophoblast and branching of these extensions
Secondary: growth of the feral mesoderm into primary villi
Tertiary: growth of the umbilical artery and vein into the villus mesoderm, providing vasculature - outer shell of cytotrophoblasts, mesoderm and then vasculature
Describe the terminal villus microstructure
Convulated knot of vessels and vessel dilation
Slows blood flow enabling exchange between maternal and fetal blood
Whole structure coated with trophoblast
Early pregnancy - 150-200um diameter, approx 10um trophoblast thickness between capillaries and maternal blood
Late pregnancy - villi thin to 40um, vessels move within villi to leave only 1-2um trophoblast separation from maternal blood
How does spiral artery remodelling happen
Non pregnant conditions - endometrium is supplied with convulsed vessels - spiral arteries
Spiral arteries provide the maternal blood supply to the endometrium
Extra villus trophoblast cells coating the villi invade down into the maternal spiral arteries, forming endovascular EVT
Endothelium and smooth muscle is broken down - EVT coat inside of vessels
Conversion: turns the spiral artery into a low pressure, high capacity conduit for maternal blood flow
Explain spiral artery re modelling further
EEVT cell invasion triggers activation of endothelial cells to release chemokines, recruiting immune cells
Immune cells invade spiral artery walls to disrupt vessel walls
EVT cells and immune cells secrete break down normal vessel wall extracellular matrix and smooth muscle, and replace with a new matrix known as fibrinoid
Therefore less spiralised
Failed conversion - smooth muscle remains, immune cells become embedded in vessel wall and vessels occluded by RBCs, still convulated
What are the consequences of failed spiral artery remodelling
Unconverted spiral arteries are vulnerable to pathological change including intimal hyperplasia and atherosis
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 the intravillous space
Atherosis can also occur in basal (non spiral) arteries that would not normally be targeted by trophoblast
What is pre-eclampsia
New onset hypertension (in a previously normotensive woman) BP ≥140 mmHg systolic and/or ≥90 mmHg diastolic
Occurring after 20 weeks’ gestation
Reduced fetal movement and/or amniotic fluid volume (by ultrasound) in 30% cases
Oedema common but not discriminatory for PE
Headache (in around 40% of severe PE patients)
Abdominal pain (in around 15% of severe PE patients)
Visual disturbances, seizures and breathlessness associated with severe PE and risk of eclampsia (seizures)
Describe the early onset form of pre-eclampsia
<34 weeks
Associated with fetal and maternal symptoms
Changes in placental structure
Reduced placental perfusion
Maternal high blood pressure
Protein in urea
Describe the late onset form of pre-eclampsia
More common (80-90% cases)
Mostly maternal symptoms
Fetus generally OK
Less overt/no placental changes
What maternal risk factors pre-dispose to PE?
Previous pregnancy with pre-eclampsia
BMI >30 (esp >35)
Family history
Increased maternal age (>40) and possibly low maternal age (<20?)
Gestational hypertension or previous hypertension
Pre-existing conditions: diabetes, PCOS, renal disease, subfertility,
Autoimmune disease (anti-phospholipid antibodies)
Non-natural cycle IVF?
What are the risks of PE to the mother
damage to kidneys, liver, brain and other organ systems
Possible progression to eclampsia (seizures, loss of consciousness)
HELLP syndrome: Hemolysis, Elevated Liver Enzymes, Low Platelets
Placental abruption (separation of the placenta from the endometrium)
What are the risks of PE to the fetus
Pre-term delivery
Reduced fetal growth (IUGR/FGR)
Fetal death (500,000/year worldwide)
What happens in PE vs normal
Normal:
EVT invasion of maternal spiral arteries through decidua and into myometrium.
EVT become endothelial EVT
Spiral arteries become high capacity
PE (esp early onset):
EVT invasion of maternal spiral arteries is limited to decidual layer and not completely in myometrial layer
Spiral arteries are not extensively remodelled,
Placental perfusion is restricted
What is released by the healthy placenta
PLGF: Placental Growth Factor
VEGF related, pro-angiogenic factor released in large amounts by the placenta.
Towards end of pregnancy declines
Flt1 (soluble VEGFR1)
Soluble receptor for VEGF-like factors which binds soluble angiogenic factors to limit their bioavailabliltiy.
What happens in a healthy placenta
Releases PLGF and VEGF into the maternal circulation. These growth factors bind receptors on the endothelial surface to promote vasodilation, anti-coagulation and ‘healthy’ maternal endothelial cells.
Leads to anticoagulant and vasodilatory factors being released by the healthy endothelial cells
What happens in a pre-eclampsia placenta
Releases less PLGF, Increases release of sFLT1, which acts as a sponge – mopping up PLGF and VEGF and stopping them binding to the endothelial surface receptors. In the absence of these signals, the endothelial cells become dysfunctional.
Procoagulant and vasoconstricting factors released by the dysfunctional endothelial cell
PE: excess production of Flt-1 by distressed placenta leads to reduction of available pro-angiogenic factors in maternal circulation, resulting in endothelial dysfuction
How do you get to the first stage of pre-eclampsia and what is it called?
Abnormal placentation (1st and 2nd trimesters)
Genetic factors
Maternal / environmental factors
Immunological factors (natural killer cells)
Because proliferative > invasive trophoblasts
Superficial invasion
Narrow maternal vessels
What does abnormal placentation lead to
Placental ischemia –> Small for gestational age infant
What can placental ischaemia lead to?
Maternal Syndrome (Late 2nd and 3rd trimester)
-Increase in circulating sFLT1 and sENG
-Systemic vascular dysfunction
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What can placental ischaemia lead to?
Maternal Syndrome (Late 2nd and 3rd trimester)
-Increase in circulating sFLT1 and sENG
-Systemic vascular dysfunction
-
What can placental ischaemia lead to?
Maternal Syndrome (Late 2nd and 3rd trimester)
-Increase in circulating sFLT1 and sENG
-Systemic vascular dysfunction
-Proteinuria
-Hypertension
-Visual disturbance / headache
-HELLP syndrome
What causes later onset PE
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: maternal genetic pre-disposition to cardiovascular disease, which manifests during the ‘stress-test’ of pregnancy.
When a women has high protein urea and high blood pressure and pregnant, what test can be done for pre-eclampsia
PLGR alone:
e.g. Triage test
Rules out PE in next 14 days in women 20-36wks and 6d
PLGF<12 - Highly abnormal, positive test
PLGF 12-100 - Abnormal test, positive test - Increased risk for preterm delivery
PLGF >100 - NORMAL - Unlikely to progress to delivery within 14 days of test
sFlt-1/PlGF ratio:
24 weeks to 36 weeks plus 6 days
<18 - Rule out pre-eclampsia
>18 - Increased risk of pre-eclampsia
What are extracellular vesicles
How do they show PE
EVs are tiny (nano-meter scale) lipd-bilayer laminted vesicles released by almost all cell types
Contain diverse cargos, including mRNAs, proteins and microRNAs (miRNAs) and can influence cell behaviour (locally and at distance)
Changes observed in EV number and composition in PE:
Overall increase in EVs in the maternal circulation
Increase in endothelial-derived EVs (indicative of maternal circulation defects)
Decrease in placenta-derived Evs
Pro-inflammatory cargoes in PE placenta EVs may affect trophoblast invasion, maternal endothelial function
How can PE be managed
If <34 weeks, preferable to try and maintain the pregnancy if possible for benefit of the fetus
If >37 weeks, delivery preferable
In between – case by case basis.
Regular (daily?) monitoring- daily blood pressure and ratio tests every 2 weeks
Anti-hypertensive therapies.
Magnesium sulphate to counter-act seizures
Corticosteroids for <34 weeks to promote fetal lung development before delivery.
How to you prevent PE
Reduce BMI (esp if BMI >35)
Exercise throughout pregnancy (seems to work independent of BMI)
Low-dose asprin (from 11-14 weeks) for high risk groups – but may only prevent early onset.
What are the long term impacts on health due to PE
Elevated risk of cardiovascular disease, type 2 diabetes and renal disease after PE
Roughly 1/8 risk of having pre-eclampsia in next pregnancy (greater if early onset)
What is happening at the moment in terms of PE diagnosis
Clinical need for diagnostics that identify women at risk of PE early, before 20 weeks, in pregnancy (pre-onset)
Examination of circulation cell free RNA (cfRNA) from liquid biopsy identifies group of tr that are predictive of PE in the first trimester, before 12 weeks of gestation
Examination of small molecule metabolites in urine reveals bio-signature associated with PE before symptom onset
What is small for gestational age
Fetal weight: <10th centile (or 2 SD below pop norm)
Severe SGA: 3rd centile or less
Can be subclassified into 3 groups:
Small throughout pregnancy, but otherwise health
Early growth normal but slows later in pregnancy (FGR/IUGR)
Non-placental growth restriction (genetic, metabolic, infection)
SGA vs IUGR/FGR
SGA and Interuterine Growth Restriction (aka Fetal Growth Restriction, FGR) are often used interchangenably, but have distinct definitions
SGA considers only the fetal/neonatal weight without any consideration of the in-utero growth and physical characteristics at birth.
IUGR is a clinical definition of fetuses/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 the show features of malnutrion but and growth restriction at birth
Similarly, a baby with a birth weight less than the 10th percentile will be SGA , not IUGR if there are no features of malnutrition.
Symmetric vs asymmetric IUGR - characteristics
Earlier gestation
Genetic disorder or infection intrinsic
Proportionally reduced
Reduced cell number
Normal cell size
Less pronounced malnutrition features
Poor prognosis
What are the implications of FGR/IUGR
Cardiovascular: fetal cardiac hypertrophy, and re-modelling of fetal vessels due to chronic vasoconstriction
Respiratory: poor maturation of lungs during fetal life, leading to bronchopulmonary dysplasia and respiratory compromise – therefore give corticosteroids
Neurological: long term motor defects and cognitive impairments
