Disorders of pregnancy & parturition

Question 1

Describe the structure of the placenta

Answer 1

Fetal vein and fetal artery from the umbilical cord supplying chorionic villus

Maternal vein and artery from spiral arteries supplying intervillous space - lacunae

Question 2

How do feral demands change through pregnancy on placenta

Answer 2

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

Question 3

How does fetal growth acceleration happen with changes in support

Answer 3

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)

Question 4

Origins of the placenta : early implantation stage ?

Answer 4

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

Question 5

How chorionic villi form - 3 phases

Answer 5

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

Question 6

Describe the terminal villus microstructure

Answer 6

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

Question 7

How does spiral artery remodelling happen

Answer 7

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

Question 8

Explain spiral artery re modelling further

Answer 8

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

Question 9

What are the consequences of failed spiral artery remodelling

Answer 9

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

Question 10

What is pre-eclampsia

Answer 10

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)

Question 11

Describe the early onset form of pre-eclampsia

Answer 11

<34 weeks
Associated with fetal and maternal symptoms
Changes in placental structure
Reduced placental perfusion

Maternal high blood pressure
Protein in urea

Question 12

Describe the late onset form of pre-eclampsia

Answer 12

More common (80-90% cases)
Mostly maternal symptoms
Fetus generally OK
Less overt/no placental changes

Question 13

What maternal risk factors pre-dispose to PE?

Answer 13

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?

Question 14

What are the risks of PE to the mother

Answer 14

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)

Question 15

What are the risks of PE to the fetus

Answer 15

Pre-term delivery
Reduced fetal growth (IUGR/FGR)
Fetal death (500,000/year worldwide)

Question 16

What happens in PE vs normal

Answer 16

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

Question 17

What is released by the healthy placenta

Answer 17

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.

Question 18

What happens in a healthy placenta

Answer 18

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

Question 19

What happens in a pre-eclampsia placenta

Answer 19

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

Question 20

How do you get to the first stage of pre-eclampsia and what is it called?

Answer 20

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

Question 21

What does abnormal placentation lead to

Answer 21

Placental ischemia –> Small for gestational age infant

Question 22

What can placental ischaemia lead to?

Answer 22

Maternal Syndrome (Late 2nd and 3rd trimester)
-Increase in circulating sFLT1 and sENG
-Systemic vascular dysfunction
-

Question 22

What can placental ischaemia lead to?

Answer 22

Maternal Syndrome (Late 2nd and 3rd trimester)
-Increase in circulating sFLT1 and sENG
-Systemic vascular dysfunction
-

Question 22

What can placental ischaemia lead to?

Answer 22

Maternal Syndrome (Late 2nd and 3rd trimester)
-Increase in circulating sFLT1 and sENG
-Systemic vascular dysfunction
-Proteinuria
-Hypertension
-Visual disturbance / headache
-HELLP syndrome

Question 23

What causes later onset PE

Answer 23

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.

Question 24

When a women has high protein urea and high blood pressure and pregnant, what test can be done for pre-eclampsia

Answer 24

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

Question 25

What are extracellular vesicles How do they show PE

Answer 25

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

Question 26

How can PE be managed

Answer 26

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.

Question 27

How to you prevent PE

Answer 27

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.

Question 28

What are the long term impacts on health due to PE

Answer 28

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)

Question 29

What is happening at the moment in terms of PE diagnosis

Answer 29

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

Question 30

What is small for gestational age

Answer 30

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)

Question 31

SGA vs IUGR/FGR

Answer 31

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.

Question 32

Symmetric vs asymmetric IUGR - characteristics

Answer 32

Earlier gestation Genetic disorder or infection intrinsic Proportionally reduced Reduced cell number Normal cell size Less pronounced malnutrition features Poor prognosis

Question 33

What are the implications of FGR/IUGR

Answer 33

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