Greetings and welcome to EHA Unplugged, the official podcast
channel of the European Hematology Association EHA.
I'm Sarah de Fleeker and I'm here in London with David Rees,
part of our Education Committee at the European Hematology
Association. David, could you please
introduce yourself? Hi, I'm David Rees.
I'm a pediatric hematologist at King's Scottish Hospital and I
look after children with sickle cell disease and have been
involved in screening and managing them for quite a long
time and it was involved in setting up the screening
programme in the UK. And we are here to talk about
screening today, David. So could you maybe give us a
feeling of what you would consider standard of care for or
gold standard for for screening in sickle cell disease?
Well there's two main points where screening's done. 1 is in,
in most countries is antenatally when, when someone's pregnant
and you want to identify whether that the baby, the foetus the
woman is carrying could be at risk of having sickle cell
disease and that's called antenatal screening.
And then the other screening is testing babies when they've been
born, neonatal screening. And that again is an important
factor to try and identify children with sickle cell
disease so that they can be treated and managed before they
present with complications or even or even die in the in the
days before screening. Could you take us through the
process, perhaps first of antenatal screening?
Well, antenatal screening, it is complicated and it varies a lot
on depending on where you are and what the prevalence is, how
common the situation is in the UK and lots of area in parts of
the UK in cities like London and Birmingham, Manchester where
there's a high prevalence and same in European countries.
Then the idea is that every woman when she books for
pregnancy is also tested to see whether she could carry sickle
cell or thalassemia, which involves having a full blood
count and also haemoglobin analysis to look for the
presence of sickle haemoglobin. And then if she, if she is a
sickle carrier or a thalassemia carrier, then the next step
would be to invite her partner, even the father of the pregnancy
to, to come and be tested also. And if both of those people are
carriers that put the the fetus at risk of in developing a
significant haemoglobinopathy, then the the couple are
counselled regarding that risk. And what the counselling's for
depends a bit what country you're in.
The idea is to give mothers choice so that they know or
couples choice so that they know the they're at risk of having an
affected baby. And the choice is really to, you
know, involves part of that choice is whether they want to
continue the pregnancy and have, you know, have a termination.
Obviously that varies quite a lot culturally and in the UK
that that is the primary purpose of the antenatal screening
programme. In some countries, it's more
about choice and giving information so that people can
prepare for the possibility of having a a child with a medical
condition. I can imagine that's quite a
difficult conversation to have. Again, it depends.
One key thing is the the and. As it stands, antenatal
screening carries a when if you, If both couples are at risk,
then the next step is to have prenatal diagnostic testing
where you have a, the standard is to, you know, to have an
invasive test involving an amniocentesis or chorionic bill
of sampling where you put a needle into the womb, which is,
well, firstly, I'm comfortable and secondly, does increase the
risk of miscarriage by, by a small amount.
Probably it's only a very small amount, but it's probably still
there. And so the test isn't something
people can do casually in the sense that you'll put, you have
to be sure that you'll, you want to know this information really.
And you have to be sure that the information is going to be
useful in the sense that you're putting the, the fetus at risk.
And it's not just like a, you know, harmless blood test where,
where you get the information. And you can then you, once
you've got the information, you can decide what you want to do
with it. You have to really think why
you're having the test done. People are developing, you know,
there are available and they're in development ways of doing the
tests by using maternal blood. So in a non invasive way,
because there are small amounts of DNA and and cells from the
fetus in mother's blood when they're in a mother's blood when
they're pregnant. And you can test that, although
it's technically still quite difficult to try and identify
whether the fetus is is affected by sickle or or not.
That can be done, although it's still not 100% sensitive and
specific, it's still not of the standard required for a prenatal
diagnosis, but it it is being developed and that that is
likely to become an important option in the fairly near
future. OK.
And chorionic villa sampling, can that be done at any point
during pregnancy? No, I mean, I think it has to be
done, can't be done before about 11 weeks, 10 or 11 weeks.
People went through a phase of doing.
People used to do it earlier and it caused foetal abnormalities.
It caused loss of foetal limbs and things like that.
So 11-12 weeks is the earliest it can be done and it can be up
to up to about 14 or 15 weeks. And after that, amniocentesis
tends to be done where you just take take the fluid out from
around the baby. The see, the see, the earlier it
can be done, the better in the sense that if you're taking a
choice about terminating a pregnancy, that's a much easier
decision really. And if you're early on in the
pregnancy or certainly termination is much easier in,
you know, if you're 8 weeks pregnant compared to 16 weeks
pregnant. So it makes makes it a a
slightly different choice and a more realistic choice which is
where the non invasive testing also has an advantage that can
be done earlier. What's the utility of doing
invasive tests in in an area or a country where termination
might not be an option? Well, I think it's it's a more
difficult question. Certainly medical termination
is, is an option in many countries.
And sometimes, you know, individual mothers may choose to
leave the country that they're in and move to a country, you
know, to have the termination where the the fetus affected.
There is, it is useful information and some people in
this country want to know. They know they won't have a
termination, but they feel they want to know that they want to
prepare themselves mentally for having a baby who could have
medical problems. Because sickle cell disease
doesn't affect the fetus in the womb and it doesn't really have
any clinical cause, any clinical problems till a few months of
life at the earliest. There's no strong medical reason
for finding out. It doesn't alter how the
pregnancy is managed or how the birth is is managed, but if
there are some people it is, you know, it's important information
and they just want to mentally prepare for having a baby.
With that, I think the other important point about it is that
I think you can't make any assumptions about what people
will choose. And the idea that, you know, if
you're Catholic or Muslim, you wouldn't necessarily consider
termination isn't individually true.
And it's important that, you know, everyone is offered the
choices in the same way and you don't have any any
preconceptions, certainly. So in most of the world then
termination isn't legal. But but, and in most of the
world where sickle cell occurs, then it's either not available
or not legal. Although medical termination,
which we're sort of talking about is, you know, has
different rules applying to it. OK, so say a mother hasn't
chosen to undergo screening during pregnancy.
What would be a reason to screen a child after it?
Or a baby once it's born? A neonate.
Well, in the UK and I think most people think that it should
happen in nearly every country where sickle cell occurs, then
every baby is tested so that every baby at birth, you know,
after 7 or 8 days of life, a heel prick is tested and that
spot of blood is used for looking for lots of conditions
like including cystic fibrosis and phenyl cushion area and
sickle cell is has been added to that.
So every baby is born in the UK who is tested for that.
And that's true in in some states in the United States and
some some European countries, I think France probably.
Now the alternative is to and what used to happen is that you
try, you try to identify babies at high risk of having sickle bi
where it may be their mothers have been tested all based on
their their apparent ethnicity or in in the second is more
common in in some parts of the world.
It's relatively uncommon in northern Europeans and it's
relatively common in families of African origin.
So that in some countries people identify high risk pregnancies
based on the ethnicity. In the UK that's it was
discussed and used to happen, but it's become impractical in
that people have caught, you know, it's difficult to know,
it's difficult to know what the right question is.
And you can't rely on the colour of someone's skin or if they've
got a, a funny sounding name. You have to have some objective
way and whether you're saying, you know, all four grandparents
have to be born in a in a northern European country and
some that's not true of many people now in London, the vast
majority of people have quite complex and mixed race origins.
And it's also quite to do that properly, to use someone's
ethnicity to determine the the foetal risk.
It takes quite a long time. And in a way it's quicker and
cheaper just to do the test because you're, the idea was
that you can avoid doing too many blood tests or which were
perceived as being expensive by, you know, selecting the babies
who are at higher risk. So in the UK it's universal neo
national screening physical and I think in and that is, you
know, the idea is that that really maybe should be used
across Europe and lots of people think that that should apply in
every European country. Now that the numbers of people
with sickle cell is increasing really across Europe in previous
low, low prevalence areas, it's now quite common.
And I should say related to that, that E as you E, how are
now developing guidelines on this specifically there's a
working party to develop guidelines on neonatal, I think
just on neonatal screening. So exactly who should be tested
and how they should be tested and what you know and whether
what country should test really how many, how many affected
births do you have to have before it's this sort of thing
is included, OK. Do you often find that there are
challenges in approaching screening with parents?
This screening, yeah, they not hugely.
I think there was concern that occasionally, you know, people
who have, you know, their parent, they've lived in a
certain part of England for all their life and all their
ancestors have lived in the same village.
And they don't like the idea that they're going to be tested
for some disease that is not common in, in, you know,
northern Europeans in general. There's not really much
resistance to it. As I say, it's part of a more
general neonatal screening where lots of conditions are tested
for like cystic fibrosis as well.
And it sounds very unusual for someone to specifically say, oh,
I want all tests, but I don't want to be tested for sickle
cell. And the neonatal screening works
very well. There's very good coverage in
the UK and there's a good system and more than 99% of people have
testing done. OK.
Do you think there's a reluctance in other parts of the
world to adopt this? I think neonatal screening, I
think there's a cost to it as the issue.
I think in general there's a perception that, you know, if
it's a rare disease that you'll test, you know, hundreds of
thousands of children not pick up anything.
But that is currently done really a phenol cutaneura which
is tested for every baby is tested for is incredibly rare.
There are, you know, only a handful of cases each year and
that's been, whereas in sickles in the UK there are 300 cases a
year. And in most European countries
there'd be more cases of phenylketonuria, of sickle cell
disease and phenylketonuria. And yet people test for
phenylketonuria because for historical reasons.
The other important thing about testing is there has to be a, an
intervention that makes a difference of screening and, and
in sickle cell. They're the reason it's
important to test babies is that you can start them on penicillin
at an early age to protect against infection.
And without that, we know that a proportion of children, you
know, become very unwell or even die before the diagnosis is
made. So it does have a well, it's a
good thing to do in itself, probably.
But secondly, there is a very practical reason for doing it.
Yeah. What other developments could
you foresee in the future for when it comes to screening for
sickle cell disease? Well, one issue particularly for
prenatal diagnosis is that predicting the severity of the
the baby. We know sickle cell disease is
very variable and some children have, you know, no problems and
are completely healthy and others are really quite severely
affected and can have strokes and severe complications.
And if we could predict, you know, using other genetic
markers, you know, whether this was going to be a severely
affected or mildly affected child, then that would again, be
very useful information for to help parents choose about
whether what to do regarding continue continuing the
pregnancy. We and others have been trying
for a very long time to identify genetic markers that predict
severity. And it's still really basically
not possible to do that. One or two things that can give
you a clue, but they're not specific enough to want to for
you want to to use to make a sort of, you know, big decision
about whether to continue a pregnancy or not.
But with genomic medicine developing and whole genome
sequencing starting on on babies and everything, then it may be
and more bioinformatic capabilities, it may be possible
to give a much more precise direction, which would then add
greatly to the value and the the prenatal diagnosis.
And so that would be an important way to provide much
more valuable information to families.
That sounds wonderful. Is there any way to
prognosticate in neonates at the moment?
OK, it's a good question. And the same arguments apply and
the there are crude guidelines really you can identify for
example, that boys do less well than girls and you can predict
the hemoglobin F level and things like the presence of
alpha thalassemia determine outcomes, but to a fairly small
extent. I think the issue for that is
wise at the moment. There are there are some
curative treatments, but they're all quite toxic.
They all involve basically, you know, myeloablation and A and a
risk of severe complications. So though if you could predict
which children are going to have say a stroke, then then you
there will be a strong argument for you're giving these quite
toxic curative treatments at an early stage.
We've tried and others are going to have tried quite hard to
predict stroke and identify factors and what, And again,
once we found some factors and we haven't found enough to
actually, you know, make a, a big decision on, you know,
clinical decision where you say, yes, no, we're going to
transplant them or not. I think that will change as
curative treatment becomes less more widely available and and
less toxic then I think it will. We will reach the stage, as I
said previously, that that every foetus, every baby had
potentially has a curative treatment.
So the need to discriminate between severe and mild will
become less important. If we were to, you know, get in
a time machine and go 50 years in the future, what would you
hope for? A screening for sickle cell
disease. I think to be honest, the
screening is pretty good now. I think every, I think for me, I
think every country in Europe should test every baby born for
sickle cell disease. And then, you know, more
importantly, it's almost where sickle cell is most common in
Africa and India, there's almost no neonatal screening.
So if you wanted to wish something, it would be that, you
know, the neonatal screening had been set up in these countries
where it would actually have a huge impact in the, you know,
80% of people die in childhood and a large proportion of that
is present, preventable by starting penicillin and other
preventive measures at an early age.
So if you could go ahead and say in 50 years you'd really hope
that, you know, Nigeria and Congo and India have a national
neonatal screening programme and every baby is tested.
That would be wonderful. It would.
And that would make a real far more difference than we make in
the Uki mean make a difference, but you know, you could make a
huge difference there. OK.
And that will become more relevant as curative treatments
become available. And that with gene editing, it's
I think in 50 years, almost certainly that will be, you
know, widely available treatment.
And so it'll be possible, you know, potentially to, you know,
cure babies neonatally. And even we're not even further
ahead. We're currently looking at
research doing for doing in utero gene therapy for treating
fetuses in the womb, which has some advantages.
So potentially that our screening could, if that becomes
a, a feasible and effective way of treating them, it could
become quite an effective, you know, the the antenatal
screening will become more important so that you can.
That sounds wonderful it. Does.
Well, thank you so much for talking to us today and thank
you to our audience listening to this episode of EHA Unplugged.
Stay tuned for our next episode.