Immunology of pregnancy I & II

Question 1

A young woman had her 9th consecutive miscarriage. Her marriage broke down shortly afterwards.
But within months of finding a new partner, she conceived again and the pregnancy went without a hitch. Why did this happen?

Answer 1

Woman’s immune system took offence to the first choice of partner
over-reacting to the tissue carrying his genes and expelling the fetus.
The fetus is allogenic, its genes are half maternally and half paternally derived.
So it has paternal type antigens which are foreign to the mother. These may be recognised as foreign by the immune system.
Infertility, recurrent miscarriage, premature delivery and a dangerous complication of pregnancy, pre-eclampsia, may be strongly linked to immunological abnormalities.

BUT 350,000 babies are successfully born every day
Half of the fetal genome derives from the father but, unlike a mismatched organ transplant, it isn’t normally rejected.
How does this happen:

Question 2

Immunological problems to solve during pregnancy

Answer 2

1) Fetal tissue is half foreign – so it has to be protected from rejection
2) But the mother’s immune defence must be sufficient during pregnancy to ensure survival of the mother.
3) Fetus often immunologically immature at birth – must have (relies on) maternal antibodies to ensure survival

The maternal/fetal interface is central to overcoming these problems. This interface occurs at the placenta

Question 3

Development of the placenta

Answer 3

The fetus is attached with the umbilical cord
White outer part = myometrium
Pink inner part = decidua
You can see chorionic villi
Can see pools of maternal blood within the intervilus space
This is filled by spiral arteries coming from the maternal blood flow.
The interface at the placenta where it is attached to the uterine wall is key for where the maternal immune system is in contact with the cells from the fetus.

Question 4

Maternal-fetal interface

Answer 4

The maternal-fetal interface is where the mother and babies cells are in direct contact

The cytotrophoblasts can differentiate along two pathways:
They can fuse to become syncytiotrophoblasts
Or they can differentiate to become extravillous trophoblasts
The Extravilous trophoblasts invade into the wall of the decidua and anchor the placenta.
(attached = anchoring villi, not attached = floating villi)

The chorionic villi are bathed in a large pool of maternal blood which is supplied from the maternal blood vessels: the spiral arteries.

Question 5

Three interfaces:

Answer 5

1) Syncytiotrophoblast layer covering the placenta is bathed in maternal blood
2) Where the invading extravilous trophoblast come into contact with decidual immune cells
3) Where the invading Extravilous trophoblast come into contact with decidual blood vessels

It is difficult to study the immunology of pregnancy as most immune cells in the peripheral blood are easily accessible by taking a blood sample. But from where the blood is situated in the interfaces in pregnancy, it is very difficult to investigate this in an ongoing human pregnancy.

Most is know from animal studies, but the physiology of placentation is very different.
The only way to access the maternal fetal interface in human pregnancies is by studying cells isolated from first trimester surgical terminations of pregnancy,
BUT we do not known the outcome and if the pregnancy had developed, would it have been normal.

Question 6

Maternal interface:

1) Syncytiotrophoblast layer covering the placenta is bathed in maternal blood

Answer 6

The syncytiotrophoblast layer that covers the placenta is bathed in maternal blood.
The syncytiotrophoblast is a multi-nucleated layer which arises from fused cytotrophoblasts.
It forms a barrier and performs endocrine functions as well as gas and nutrient exchange from maternal blood (via expression of transport proteins).
There are fetal blood vessels seen in the cross section where there is exchange between the mothers blood and the fetal blood vessels.

The syncytiotrophoblasts are in direct contact with the maternal blood which will contain immune cells:

Question 7

Maternal interface:

2) Invasive extravillous trophoblast are in contact with decidual immune cells

Answer 7

The invasive Extravilous trophoblasts are in contact with the decidual immune cells.
The extravillous trophoblasts are differentiated fetal cells which invade into the maternal decidua to transform maternal spiral arteries.

Seen from the diagram (right):
The chorionic villi (at the top)
The invasive trophoblasts are invading downwards into the decidua and the myometrium.

The invasive Extravilous trophoblasts are somewhat like cancer cells in how they move and invade through tissue.
As they come through, they are heading towards the maternal spiral arteries.
As they come through the decidua they encounter a large infiltration of maternal immune cells:
NK cells, lymphocytes, macrophages.
All of these maternal immune cells could potentially recognise the trophoblast cells which are fetally derived, and therefore would express some of the paternal antigens as foreign. SO… the trophoblasts cells will have to successfully navigate their way through this large infiltration of maternal immune cells, so that they are able to reach the spiral arteries.

Question 8

Maternal-fetal interface:

3) Invasive extravillous trophoblast are in contact with decidual vascular cells

Answer 8

Invasive extravillous trophoblasts are in contact with decidual vascular cells.
The third area where there is direct contact with the fetal trophoblast cells and the maternal blood cells is when they reach the spiral arteries.
The extravillous trophoblast are differentiated fetal cells which invade into the maternal decidua to transform maternal spiral arteries.

As the Extravilous trophoblasts invade they are heading towards the maternal spiral arteries.

In a non pregnant uterus, the spiral arteries are tightly coiled and are spiral in nature.

The spiral arteries are what supply all of the maternal blood to the intervillous space.

As the fetus and the placenta grows these demands increase, so a larger volume of blood needs to be supplied.
This is done through the remodelling of the spiral arteries so that they change from a low flow, high resistance vessel -> to a high flow, low resistance vessel.
The initial stages of this occur early in pregnancy alongside decidualization. This is known as the trophoblast independent remodelling stage.

Some of the immune cells have an important role in this process.
This may explain why the large infiltration of cells is needed.
Part of the trophoblast independent remodelling will be carried out by signals from some of the immune cells present in the decidua.

When the Extravilous trophoblast cells reach the vessel, they cause a loss of vascular smooth muscle layer and a temporary loss of the endothelial layer.
The lumen of the vessel will become much larger and will loose its contractile properties.
This is termed trophoblast dependant remodelling, and allows for a much increased blood supply to the intervillous space.
The trophoblasts start expressing markers of the endothelial cells and will replace the endothelial cells that line the spiral arteries.
As these cells are now fetal cells (lining the inside of the spiral artery), they will then be in direct contact with the maternal blood which is travelling through the spiral arteries.

Question 9

Materal-fetal interface: summary

Answer 9

There will be contact between maternal cells and fetal cells in three areas:

syncytiotrophoblasts lining the chorionic villi will be in contact with maternal blood in the intervillous space
invasive extravillous trophoblasts will be in contact with maternal blood in the spiral arteries (After they have remodelled these vessels)
invasive extravillous trophoblasts will be in contact with infiltrated maternal immune cells in the decidua. (they will have to invade through all of the infiltrated maternal immune cells in the decidua)

Question 10

How do both of these types of trophoblast evade the immune response?

Answer 10

First need to understand how the mother could mount an immune response:

Question 11

Which immune cells are present at the maternal-fetal interface?

Answer 11

In the Decidua:
More than >40% decidual cells are leukocytes in early pregnancy. (large infiltration of immune cells).
Of these cells the predominant type, approximately 70% are NK cells (are a subpopulation of cytotoxic lymphocytes)
NK cells function by cell killing or by cytokine production
Approximately 20% of the immune cells are macrophages
T and B cells make up the remaining 10%

In the Intervillous space and spiral arteries:
The immune cells that are present will be the same as is circulating in the peripheral maternal blood

Question 12

Maternal immune cells: Decidual natural killer cells (dNK)

Answer 12

The predominant type (70%) is the decidual natural killer cells.

dNK cells are different to peripheral blood (pb)NK cells
Their pattern of receptor expression is unique and they are identified by high expression of the protein CD56hiCD16lo peripheral blood NK cells have a low expression of CD56)
They have been identified as being essential to pregnancy in the mouse and they may also play a role in human decidual remodelling through the cytokines which they secrete

V.IMPT:
Note: how different dNK cells are to peripheral blood natural killer cells (pbNK).
When a NK cell is in the decidua, it is no longer a fierce killer cell, instead its role is more to produce cytokines that encourage the important events of placentation such as trophoblast invasion.

Question 13

Maternal immune cells: Macrophages in pregnancy

Answer 13

The 2nd most predominant cell type are the macrophages (about 20% of immune cells in the decidua).
Another immune cell found in the decidua is the macrophage: makes up about 20% of immune cells in the decidua so is the second most abundant immune cell
dMac (decidual macrophages) have a different phenotype to peripheral blood monocytes

Broadly, macrophages may be characterised into two phenotypes M1 and M2:
M1: pro-inflammatory, they secrete TNF-α, IL-6
M2: anti-inflammatory, they secrete IL-10, VEGF

Decidual macrophages are more M2-like than M1
So are more anti-inflammatory in their nature.

Question 14

Immunological tolerance:
How do trophoblast evade the immune response?

Answer 14

There were three different theories from 1953 regarding tolerance of the mothers immune system to the fetus, that mostly still stand today:
Physical separation of the maternal and fetal tissues
Antigenic immaturity of fetal tissues
That the mother is immunologically inert

Question 15

Is there a physical separation of maternal and fetal tissues?

Answer 15

The Fetus is separated from the mother by the fetal trophoblast cells.
Therefore only the fetal trophoblast cells needs to have some tolerance to the mothers immune system
The fetal and maternal circulation is separated
Maternal cells cannot reach the fetus

HOWEVER:
In humans, IgG can cross into the fetal blood via a placental transport mechanism.
Therefore IgG directed against the fetal antigens could also be transferred
This is necessary for the fetal immunity to bacteria and viruses in the first weeks of neonatal life.

Question 16

Why doesn’t the baby get harmed by the separation?

Answer 16

Most fetal blood group and histocompatibility (HCA) antigens are so widely distributed on the fetal cells, tissues and amniotic fluid that any IgG passing in would be diluted out.
Many fetal antigens are also present as soluble forms in the fetal blood and amniotic fluid - IgG would be mopped up by free soluble antigen.
So no tissue damage occurs as there is not enough maternal antibodies left to bind to any of the fetal cells.

So the fetus is separated from the mother, BUT the fetal trophoblast cells are not separated from the maternal immune cells.

Question 17

Is there antigenic immaturity of fetal tissues?

Answer 17

Histocompatibility antigens are the targets for rejection
MHC haplotypes are inherited from both parents and are co-dominantly expressed
There are different classes of MHC molecules:

Class Ia (classical MHC)
HLA-A, HLA-B, HLA-C
They are involved in presenting antigens to CD8+ T cells
Interact with NK cells
They exist in a highly polymorphic form (exist in many forms)

Class Ib (non-classical)
HLA-E, HLA-F, HLA-G
They are minimally polymorphic

Class II
HLA-DP, HLA-DQ, HLA-DR
They are involved in presenting antigen to CD4+ T cells

Question 18

MHC expression by trophoblasts

Answer 18

Syncytiotrophoblasts (lining the chorionic villi) lack both MHC Class I and II antigens.

However: Extravillous trophoblasts lack Class II but express an unusual combination of MHC class I antigens:
HLA-C, HLA-E and HLA-G (non-classical)
So the EVTs are expressing things that can be recognised by the maternal immune cells. So they are NOT antigenically inert.

Question 19

Is the mother immunologically inert?

Answer 19

Maternal blood in pregnancy IS able to respond immunologically to the fetus and fetal cells are detectable in the maternal blood

BUT
Pre-sensitisation to paternal antigen does not prevent pregnancy
The mother has to be able to respond to acute or chronic infections.
Studies in mice show that a pregnant mice will tolerate tumours grafted from the father, but not after delivery of the pups. They will also not tolerate tumours grafted from another mouse. So something is modulating the immune response in pregnancy.

There is neither a generalised or specific depression of maternal immune responsiveness
As the mother still has to continue to fight off infections.
However the quality of the maternal immune response may be what differs.
A local immune regulation is more likely.

Question 20

Theories of immune evasion in the placenta

Answer 20

These are things that occur at a local level as opposed to suppression of the mothers whole immune response:

Role for natural killer cells in the decidua
Selective local induction of programmed cell death in maternal immune cells
Alteration in the cytokine balance
Between a pro-inflammatory and anti-inflammatory environment
Local indoleamine 2,3-dioxygenase synthesis
Complement regulatory proteins

Question 21

Decidual natural killer cells

Answer 21

dNK cells are different to peripheral blood (pb)NK cells
Their pattern of receptor expression is unique and they are identified by having CD56hiCD16lo
They have been identified as being essential to pregnancy in the mouse and they may play a role in human decidual remodelling through the cytokines which they secrete

BUT they still are NK cells which can attack things that are recognised as foreign, so why don’t they attack the fetus? :

Need to consider what the NK cells are expressing on their cell surface that can interact with receptors on the surface of the trophoblast cells.
Key to this is the expression of the MHC molecules: HLA-C, -E and -G

Question 22

How does expression of HLA-C, -E and -G by EVT help immune evasion?

Answer 22

By binding to receptors on NK cells
So the MHC molecules: HLA-C, -E and -G can interact with receptors on the NK cells.

There are 3 types of NK cell receptors:
Killer-cell immunoglobulin-like receptors (KIRs)
CD94/NKG2 receptors
Leukocyte immunoglobulin-like receptor (LILRs)

There are both inhibitory and activating members of these families of receptors.

Question 23

What happens when trophoblasts interact with NK cells:

Answer 23

Binding of HLA class I molecules to inhibitory NK cell receptors inhibits the cytotoxic action of the NK cell, therefore preventing the trophoblast from being attacked.
So by expressing the MHC molecules, the trophoblast is dampening the NK cells response and making it less cytotoxic.

Inhibitory NK receptor:
CD94/NKG2A
KIR2DL/S1
LILRB-1

Trophoblast:
HLA-E
HLA-C
HLA-G

Question 24

Experimental evidence

Answer 24

We know that Inhibitory receptors are expressed at higher levels in uterine NK cells than peripheral blood NK cells
So they are more predisposed to receiving a inhibitory signal
HLA-E has higher affinity for the inhibitory receptor than the activating receptor
More uNK cells are found in women with a history of recurrent pregnancy loss

Question 25

However, trophoblast HLA molecules can also bind to..

Answer 25

Trophoblast HLA molecules can also bind to the activating NK cell receptors
This may alter the NK cytokine repertoire
And may contribute to how the trophoblast behaves
Eg producing growth factors that help them invade more

There are two sides:
There are the inhibitory receptors stopping the NK cells from being killing cells
There is the activating receptors which binding can alter the cytokine repertoire.

Question 26

HLA – G

Answer 26

There has been interest in HLA-G
It exists in different isoforms which are alternately spliced.
It has limited polymorphisms – not many forms (most important is soluble sHLA-G1)
It is thought to be important in fetal development as its expression is restricted throughout the body, and in the placenta it is only expressed in the extravillous trophoblasts.

Question 27

Is there A role for soluble HLA-G

Answer 27

Soluble HLA-G can be released from trophoblasts
In vitro studies have shown that sHLA-G can induce apoptosis in maternal T cells
So this may be an additional way of protecting trophoblasts from attack
IVF study shows that there is an association between the presence of soluble human leukocyte antigen G (sHLA-G) in human embryo culture supernatants (ES) and implantation success.

Question 28

Selective local induction of programmed cell death in maternal immune cells

Answer 28

There are other signalling pathways thought to be involved in selective local induction of programmed cell death in the maternal immune cells.

There is experimental evidence that trophoblasts can induce programmed cell death (apoptosis) in maternal immune cells.

Apoptosis is characterised by cell shrinks, nucleus reorganises, DNA fragments, membranes bleb and cell fragments into membrane bound apoptotic bodies.
Apoptosis is a neat way of cell death as it does not generate lysis of the cells and release of pro inflammatory factors that necrosis induces.
Apoptotic cells are often phagocytosed by cells such as macrophages.

Regulation of apoptosis depends on a balance between pro- and anti-apoptotic factors.

There is evidence that these pathways are important in the maternal immune cells in the decidua:
Fas-Fas L
TRAIL-TRAIL R

Diagram explanation:
There is a fetal trophoblast cell interacting with a maternal immune cell. These are the pathways linked to death receptor signalling:

FasL/Fas pathway:
Trophoblast cells can either express on their cell surface a protein called FasL or they can secrete a soluble form called sFasL.
This can bind to the Fas receptor on the surface of maternal immune cells.
This will trigger a cascade of signalling through fas associated death domain (FADD) protein. This will activate caspases which are enzymes of apoptosis.
So… the interaction of the fetal trophoblast with FasL can lead to cell death of the maternal immune, thereby preventing the cell from attacking the fetal trophoblast.

TRAIL (TNF related apoptosis inducing ligand) pathway:
TRAIL can bind to two different death receptors on the surface of immune cells.
It triggers the same pathway as above, leading to apoptosis.

This was found in studies using KO mice as in mice pregnancy is characterised by extensive infiltration of immune cells, they are prone to small litters and absorption of the foetus.

SO the ability of the trophoblast cell to kill off any attacking maternal immune cells is important.

Question 29

Alteration in the cytokine balance:

Maternal immune cells: The Th1 / Th2 Balance in pregnancy

Answer 29

One of the initial theories of fetal tolerance is the balance between Th1 and Th2 signalling in pregnancy.

T cells differentiate into Th1 or Th2 cells in response to signals given during antigen presentation

Th1 type reaction in placenta mainly generates pro inflammatory responses, activates T cells and NK cells and this type of reaction is correlated with miscarriages.
eg IFNg, IL-2
Th2 type reaction generates non-inflammatory reactions that is consistent with the survival of the fetus.
eg IL-4, IL-6, IL-10, IL-13

It is thought that trophoblasts may be producing cytokines and hormones that act to promote a Th2 balance. (they are making it more non inflammatory by regulating the balance)
BUT it is more complex than this as some pro inflammatory signals are necessary for the initial implantation and trophoblast invasion stage. So it may be that initial in pregnancy you need a more pro-inflammatory environment, shortly after this must be counteracted with a shift to an anti-inflammatory (more Th2) balance. In some pregnancy disorders this shift from Th1 to Th2 does not occur at the correct time.

Question 30

Maternal T Cells

Answer 30

It is now thought that the role of the regulatory t-cell is important too.
There are not many t or b cells present. They are the smallest population of maternal immune cells

BUT skewing the nature of the T cell response to active tolerance rather than an active rejection response is important. The Tregs are key in this
T helpers – Th1, Th2, Th17, Treg

It has been show that sufficient Tregs are needed in the endometrium for implantation and pregnancy
Tregs CD4+CD25+ – are anti-inflammatory, immune suppressive
They can act on other immune cells, produce suppressive cytokines such as TGFb and IL10

How is the balance of getting sufficient regulatory T cells regulated:
Appropriate cytokine balance within the endometrium and signalling from other cells present.
The correct phenotype of other endometrial leukocytes to allow Treg activation
Stabilisation of Treg phenotype by hormones: estrogen and progesterone
Priming of Tregs by male partner seminal fluid stimulates expansion of endometrial Treg population.

Question 31

Indoleamine 2,3-dioxygenase

Answer 31

It is an enzyme that catabolises tryptophan – which is an essential amino acid
The enzyme is synthesised and secreted by syncytiotrophoblasts
It is shown to be essential for successful pregnancy

T cells are very sensitive to the amino acid tryptophan, any decrease in tryptophan is likely to supress T cell proliferation

IDO may break down tryptophan in maternal T cells in the decidua.
This essentially staves them of one essential amino acid.
This can subsequently reduce or inhibit immune response.

This therefore may be a way of the syncytiotrophoblasts targeting some of the t-cells it can come in contact with.

Question 32

Expression of complement regulatory proteins

Answer 32

The complement system is made up of a large number of different plasma proteins that interact with each other to induce inflammatory responses. This makes the cell more susceptible to oxidisation or recognition by phagocytic cells.

There are three different pathways: Classical, Alternative and Lectin pathway
They all converge upon the same enzymatic pathway which leads to the proteins that have and effector function.
We know that components of this system is important as in most models, lacking one of the key complement regulatory proteins, the embryos do not survive.

There are three proteins that have been studied:
CD46 – MCP – membrane co-factor protein
CD55 – DAF – decay accelerating factor
CD59 - MAC-IP- MAC inhibitory protein

Complement regulatory proteins are typically highly expressed in trophoblast cells.

In humans, low levels of these proteins have been linked with pregnancy failure and also preterm birth.
This could be because it is creating an inflammatory state in the uterus.

In normal pregnancies, excessive complement activation is prevented by complement regulatory proteins that are highly expressed on trophoblast membranes (MCP, DAF, and CD59)
This prevents cell lysis

Question 33

Summary: Theories of immune evasion at the maternal – fetal interface

Answer 33

Non-classical expression of HLA antigens may help trophoblast evade the immune response

Forget what you know about immune cells: DECIDUAL immune cells are different!
They may actually be helpful rather than have a killing role.

Trophoblast may promote death of some immune cells

A Th2 (anti-inflammatory) cytokine balance is promoted

Production of IDO by syncytiotrophoblasts may inhibit T cell responses

Complement regulatory proteins are also important.

Question 34

Is there an immunological basis for disorders of pregnancy?

Answer 34

This is a controversial and heavily-researched area
Eg: excessive complement activation with preterm birth.
More of a TH1 (inflammatory) profile being associated with miscarriage

Some incidences of pre-eclampsia and miscarriage may have a basis in maternal-fetal immunological mismatch.
So there is a mismatch between how the immune cell and the trophoblast can communicate through their receptors.

Question 35

Pre-eclampsia

Answer 35

Without pregnancy the spiral arteries are very coiled.
In pregnancy the trophoblast cells invade and remodel the spiral artery in a normal pregnancy down as far as into the myometrium.
In a pre-eclampsia pregnancy there is a failure to remodel the spiral artery sufficiently, as you can see the remodelling only reaches the decidua myometrial boundary.
This means that there is less blood flow coming into the intervillous space through the spiral arteries. This is probably a turbulent blood flow, so there is a less steady supply of oxygen and nutrients to be exchanged across the chorionic villi into the foetal blood vessel.
Therefore it is also related with fetal growth restriction – where babies are smaller than they should be for their gestational age.

Question 36

Evidence that there may be an immunological component to pre-eclampsia:

Answer 36

There is a lower risk of PE with different partner for 2nd pregnancy.
Donor egg pregnancies at higher risk (non-self)
They are totally non self
Prolonged exposure to paternal semen may lower PE risk

Great Obstetric Syndromes (GOS): pre-eclampsia, stillbirth & fetal growth restriction (FGR)

Question 37

NK cells and Pre-eclampsia

Answer 37

Trophoblast cells interact with NK cells (seen in diagram) through their receptors
HLA-C on the trophoblast is the only one of the three trophoblast MHC molecules that is highly polymorphic.

The dNK receptors can be type A or B (KIR-A or KIR-B)
and the HLA-C receptors on the trophoblast can be type C1 or C2

If the match is KIR-A and HLA-C2, pre-eclampsia risk is increased
This may be because this interaction leads to less cytokine production which helps the trophoblast invade
So if the trophoblast cells are not invasive enough then they may not reach the spiral artery in order to cause enough remodelling.

So it is possible that some combinations of paternal HLA-C and maternal KIR receptors are sub optimal for implantation, and therefore will contribute to some diseases such as pre-eclampsia

Question 38

How can we study normal remodelling and determine what is going wrong in PE/FGR?

Answer 38

You can take blood samples from pregnant women, but this will be looking at their peripheral blood immune cells and not their decidual immune cells.

Women who have surgical terminations of pregnancy (TOP), you can obtain tissue from the placenta and decidua, and see immune cells.
BUT the limitations that there is a limited amount of tissue
A GOOD thing is that it is a stage at which all the remodelling processes are active and are going on. So you can see what is going on at this time.
BUT another limitation is that you do not know what the outcome of the pregnancy will be. Would it have developed PE or FGR? As it is in the first trimester of pregnancy.

Used to take samples for chronic villous testing but this is not carried out
Very limited amount of tissue.
But these are pregnancies that are ongoing so you would have known the outcome.

When women give birth
Can look at whole placenta
Can take uterine biopsy – to look at decidua and myometrium
Pros: There is a known outcome, there is lots of tissue
BUT the problem is what is the relevance to the events that are taking place in the first trimester. What is happening in the first trimester is what is setting up the pathology of conditions such as PE.

The trouble is that the clinical symptoms of PE: proteinuria and maternal hypertension don’t show until beyond 20 weeks. So you want to look at tissue before to find a way to predct if a woman will develop PE.

Question 39

First trimester studies of pregnancies with spiral artery related pathologies

Answer 39

Took first trimester tissue from pregnancies characterised by uterine artery doppler resistance indices.
Can do a uterine artery doppler ultrasound
Can relate an event where there is normal remodelling with a percentile from the uterine artery doppler resistance index
When there is abnormal remodelling, and there is a higher resistance spiral artery, this will relate to a higher resistance reading in the uterine artery.

There is correlation between uterine artery blood flow measurements obtained by doppler ultrasound in early pregnancy and the subsequent development of pathologies that relate to poor remodelling.

So a high RI = condition where there is higher resistance utero placental circulation, such as that seen with less spiral artery remodelling.
Women with high RI in doppler scan have a 5 fold higher risk of pregnancy complications.
It is not a good clinical predictor as many will not have complications, but it is useful in studies in the first trimester.

It has also been previously shown that High RI group there was decreased endovascular trophoblast invasion and artery plugging.