Disorders of pregnancy Flashcards
fetal growth during first and 2nd trimester
during first trimester its relatively limited as there is low fetal demand on the placenta thus early nutrition is histiotrophic and reliant on uterine gland secretions and breakdown of endometrial tissues
switches to haemotrophic support at second trimester as fetal demands increase with pregnancy
this is achieved by a haemochromial type placenta where we get direct contact with maternal and fetal blood tissue
how do fetal femands change during pregancy
branching of chorionic villi increases with progression through pregnancy to increase area for exchange (increased surface area)
early implantation stage
syncytiotrophoblasts cells invade endometrium
cytotrophoblasts form chorionic villi
what do syncitiotrophoblast cells do and cytotrophoblast cells
Syncytiotrophoblast cells ⇒ assists in histiotrophic feeding
Cytotrophoblasts ⇒ forms the chorionic villi
placenta structure
Foetal side:
- Foetal artery
- Foetal Vein
- Umbilical cord
- Chorionic villi descending into lacunae (intervillous spaces)
Maternal side
- Maternal blood spaces (intervillous spaces)
- Spiral arteries which supply the intervillous space
- These must be despiralised, for high capacity and low resistance
- Cytotrophoblasts important for this
chorionic villi development
Three phases of chorionic villi development:
- Primary ⇒ outgrowth of cytotrophoblast fingers and branching of extension
- Secondary ⇒ growth of foetal mesoderm into the primary villi
- Tertiary ⇒ growth of umbilical artery and umbilical vein, into the villus mesoderm to provide vasculature
Terminal Villus Microstructure
Convoluted knot of vessels, slows blood flow to enable exchange between foetal and maternal blood
Whole thing covered in trophoblast
Early pregnancy ⇒ 150-200 micrometres, trophoblast thickness = 10 micrometres
Late pregnancy ⇒ 40 micrometres, trophoblast thickness = 1-2 micrometres
Spiral Arteries
Penetrate through myometrial and endometrial layers
Provide maternal blood supply to the endometrium
Extra-villus trophoblast (EVT) cells coating the villi invade down into the maternal arteries, forming endovascular EVT
The endothelium and smooth muscle is then broken down, and the EVT coats the inside of the vessels
Conversion occurs where spiral artery is converted into a low pressure high capacity conduit for maternal blood flow
how does spiral artery remodelling occur
- EVT cell invasion triggers endothelial cells to release chemokines, recruiting immune cells
- Immune cells invade spiral artery walls and begin to disrupt vessel walls
- Secretions from EVT cells break down normal vessel wall extracellular matrix, and replace it with a new matrix known as fibrinoid
- ## Immune cells no longer present when remodelling is complete
what happens when spiral artery conversion fails
When conversion fails, smooth muscle remains and immune cells become embedded in vessel wall and the vessels become occluded by RBCs
Consequences of failed spiral artery re-modelling:
- Unconverted spiral arteries are vulnerable to pathological changes, including intimal hyperplasia and atherosis
- This can lad 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 - perturbing blood delivery to the intravillous space
- Atherosis can also occur in the basal (non-spiral) arteries, which would not normally be targeted by trophoblasts
- Inflammatory ⇒ cell debris
Pre-Eclampsia
- affects 2-4% of pregnancies in the West
- higher in developing areas
- Defined as new onset hypertension in a previously normotensive woman
- BP ≥ 140mmHh systolic or 90mmHg diastolic
- Occurs after 20 weeks of gestation
presenttion of pre eclampsia
- 30% may present with reduced foetal movement with or without reduced amniotic fluid volume
- 40% of severe PE patients present with headache
- 15% of severe PE patients present with abdominal pain
- Oedema is common but not discriminatory
- Visual disturbances, breathlessness, and seizures associated with severe PE
- Increased risk of eclampsia (seizures in pregnant women with PE)
types of pre eclampsia
- Early onset (<34 weeks)
- Associated with foetal and maternal symptoms
- Changes in placental structure
- Reduced placental perfusion
- Late onset (>34 weeks)
- Most common (80-90% of cases)
- Mostly maternal symptoms
- Foetus is generally fine
- Less overt with no placental changes → less impact on the foetus
risks of pe to mother
- Damage to kidneys, liver, brain and other organ systems
- Endothelial dysfunction and death to glomerular podocytes due to distressed placental emissions
- Possible progression to eclampsia (seizures and loss of consciousness)
- HELLP syndrome (subtype of Pre-Eclampsia with unknown cause)
- Haemolysis
- Elevated Liver Enzymes
- Low Platelets
- Fatal in 25% of women
- Around 1/3 of cases occur after birth
- Placental abruption
Separation of placenta from endometrium, reduced exchange area
risk of pe to foetus
- Pre-term delivery
- Reduced Foetal Growth (FGR / IUGR)
- Foetal Death (500,000 per year worldwide)
Placental Defects that Underpin PE
In a Normal placenta:
EVT invasion of maternal spiral arteries progresses through the decidua and into the myometrium
EVT become endothelial EVT
Spiral arteries become high capacity
In the PE placenta:
Partial remodelling, but EVT invasion of maternal spiral arteries is limited to the decidual and endometrial layers, not the myometrium
Spiral arteries are therefore not extensively remodelled
Placental perfusion is restricted
Placental ischaemia occurs
what imbalances cause pe
- Placental Growth Factor (PlGF)
VEGF related, pro angiogenic factor released in large amounts by the placenta - Flt1 (soluble VEGFR1)
Soluble VEGF-like factor receptor, binding soluble angiogenic factors and limiting their bioavailability
(VEGF ⇒ Vascular Endothelium Growth Factor)
whats increased in pe
Increased sFlt1 secretion from a pre-eclampsia placenta
This leads to reduced bioavailable PlGF and VEGF (pro-angiogenic factors) in the maternal circulation
- In the absence of these signals, endothelial cells become dysfunctional
extracellular vesicles
Extracellular Vesicles (EVs) are also thought to play a role:
- Tiny (nanometre scale) lipid-bilayer vesicles released by all cell types
- Contain diverse cargo, including mRNA, proteins and microRNAs, which can therefore influence cell behaviour both locally and at a distance
what are the main types of extracellular vesicles
Exosomes and microvesicles are the main two types
what are extracellular cells usually released by
-Stem cells
- Apoptotic cells
- Senescent cells
-young/old donors
what can extracellular vesicles do
Have Autocrine, Paracrine, and Endocrine signalling effects
- small, so many may dock with a target cell and influence cell behaviour
what affect does ev have on pe
- overall increase in extracellular vesicles in maternal circulation in PE
- increase in endothelial-derived EVs and decrease in placenta-derived EVs
- decrease in placental-derived EVs seems contradictory, but may be due to change in composition of these EVs
support for ev mouse study
- EV vesicles from human placenta induced pre-eclampsia like state in mouse studies
Where might placental ev originate from
Placental EVs may be from syncytiotrophoblasts
what might SDEV (syncytiotrophoblast-derived extracellular vesicles) induce
- Dysfunction
- Inflammation
- Hypercoagulation
possible mechanism for ev and pe
placental ischaemia induces trophoblat cell apoptosis and ev release
these enter maternal circulation
they act on endothelial cells to induce dysfunction inflammation and hypercoagulation
collectively they cause pre eclampsia
evidence for pe and ev
In studies, mouse aortas treated with human sPE (severe PE) EVS inhibited vasodilation
- Circulation dysfunction is a hypothesis which is supported by this evidence
Exposure to pre eclamptic EVs also leads to decreased eNOS (endothelial Nitric Oxide Synthase) secretion in human cells
what causes later onset of pe
- Little to no evidence of maternal artery remodelling in late onset PE
- Late onset PE accounts for >80% of cases of PE
- Placental perfusion in late onset PE is normal, and possibly even increased
- Thought to be a result of existing maternal genetic pre-disposition to cardiovascular disease, which manifests during pregnancy due to increased stress on circulation
factors which cause abnormal placentation
genetics
- Maternal and foetal sFlt1 SNPs
- Decidual transcriptome (genes expressed by endometrium at site of implantation, may impact success of spiral artery remodelling)
- Haem Oxygenase Isoform imbalance
- Maternal / Environmental factors
- Smoking
- Diabetes mellitus / hyperglycaemia
- Baseline renal disease or chronic hypertension
- Immunological factors
- Placental Th1 dominance
- Immunogenic HLA-C on trophoblast
- Decidual NK cells
abnormal placenation
- Proliferative trophoblasts > invasive
- Superficial invasion
- Narrower maternal vessels
what does abnormal placentation lead to
This may lead to Placental Ischaemia:
⇒ Oxidative stress (free radicals generated)
⇒ Persistent Hypoxia (changes in gene expression such as increased HIF-1a, HIF-2a, anti-AT1 antibodies
⇒ Changes to extracellular vesicles
what does placental ischaemia change the repertorire of
circulating sFLT1 and sENG increase
which increases syncitial debris and pro inflammatory cytokines in maternal circulation
what does changes to circulating sflt1 cause
systemic vascular dysfunction such as - Proteinuria / glomerular endotheliosis
- Hypertension
- Visual disturbances, headache, cerebral oedema, seizures
- HELLP syndrome and coagulation abnormalities
And also may lead Intrauterine Growth Deficiency
tests for pre eclampsia
Levels of PlGR or Flt-1/PlGFratio may be tested
- PLGF was highly sensitive, >94% at 20-35 weeks gestation
- Rules out PE within the next 14 days
- Reduced average diagnosis time from 4.1 to 1.9 days
- Reduced maternal adverse effects and the number of nights spent in high-level neonatal care
future diagnosis for pe
In the Future, tests are needed to pick this up before the onset:
Examination of circulation cell free RNA (cfRNA) from the liquid biopsy identifies the group of tr that are predictive of PE in the first trimester
Examination of small metabolites in urine reveals bio-signatures associated with PE before symptom onset
small for gestational age
- Foetal weight <10th centile, or 2 standard deviations below the population norm
- Severe SGA = ≤ 3rd centile
3 groups of SGA
Subclasses:
- Small through pregnancy but otherwise healthy
- Early growth normal, but slows later in pregnancy (FGR / IUGR)
- Non-placental growth restriction (genetic, metabolic, or infection related)
sga vs iugr/fgr
SGA considers only the foetal weight without any consideration of the in-utero growth and physical characteristics at birth
IUGR defines foetuses with clinical features of malnutrition and in-utero growth restriction, irrespective of weight percentile
A neonate therefore could be considered IUGR but not SGA
A neonate could also be considered SGA but not IUGR
types of iugr
symmetric and assymetrical
symmetric iugr
- Early gestational cause of growth restriction
- 20-30%
- Caused by genetic disorder or infection intrinsic to the foetus
- Sizes of all features measured in the antenatal scan are proportionally decreased
- Reduced cell number
- Normal cell size
- Normal Ponderal index
- Postnatal anthropometry is reduced in all parameters
- Less than 3cm difference between head and chest in term IUGR
- Less pronounced features of malnutrition
- Poor prognosis
Asymmetrical IUGR
- Later gestational cause of growth restriction
- 70-80%
- Caused by utero-placental insufficiency
- Abdominal circumference decreased in antenatal scan, all other metrics normal in antenatal scan
- Normal cell number
- Reduced cell size
- Low ponderal index
- Reduced weight, but length and head circumference normal in postnatal anthropometry (brain sparing growth)
- More than 3cm difference between head and chest circumference
- More pronounced features of malnutrition
- Good prognosis
Implications of FGR / IUGR
- Cardiovascular ⇒ foetal cardiac hypertrophy, remodelling of foetal vessels due to chronic vasoconstriction
- Respiratory ⇒ poor maturation of lungs during foetal life, bronchopulmonary dysplasia and respiratory compromise as a result
- Neurological ⇒ Long term motor defects or potentially even cognitive impairments
genetic and abnormal maternal immunological adaptation causes for pe/fgr/iugr
causes villous placenta maldevelopment which leads to
-altered branching of villous tree
-impaired nutrient and or gas exchange
-syncythial pathology with impaired placental transport effieciency and or fetalplacental vascular impoverishment
leads to fetal grwoth restriction
trophoblast invasiondefect and defective descidualization and abormal maternal immunological adaptation or abnormal maternal sstemic vascular adaptatonto pregancy causes what between pe and fgr/iugr
placental bed pathology
causes vascular malperfusion
causes
-stress
-local hypoxia
-hypoxia reperfusion
-shear damage
-exaggerated particle release
-impaired placental transport efficiency
-villous placental pathology
-altered cell turnover
-skewed abgiomodulatory balance
causes early onset pe and or fetal growth restriction
abnormal maternal sstemic vascular adaptatonto pregancy or villous placenal vulnerability stress or ageing
causes exaggerated particle release from placenta,skewed angiomodulatory balance
causes late onset pe
What do chorionic villi do
Provide substantial surface area for exchange
Finger like extensions of the chorionic cytotrophoblast which then undergo branching
Levels of PLGF and VEGF in a normal and pre eclampsia placenta
Healthy placenta releases PLGF and VEGF into maternal circulation which bind to receptors on the endothelial surface to promote vasodilation anti coagulation and healthy maternal endothelial cells
In pe sFLT1 is released which acts as a sponge mopping up PLGF and VEGF stopping them from binding to endothelial surface receptors. The the absence of thes signals the endothelial cells become dysfunctional
