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Screening for Sickle Cell Disease (with Prof David Rees) · EHA Unplugged

• 0:04
  Greetings and welcome to EHA Unplugged, the official podcast
• 0:08
  channel of the European Hematology Association EHA.
• 0:12
  I'm Sarah de Fleeker and I'm here in London with David Rees,
• 0:16
  part of our Education Committee at the European Hematology
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  Association. David, could you please
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  introduce yourself? Hi, I'm David Rees.
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  I'm a pediatric hematologist at King's Scottish Hospital and I
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  look after children with sickle cell disease and have been
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  involved in screening and managing them for quite a long
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  time and it was involved in setting up the screening
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  programme in the UK. And we are here to talk about
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  screening today, David. So could you maybe give us a
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  feeling of what you would consider standard of care for or
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  gold standard for for screening in sickle cell disease?
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  Well there's two main points where screening's done. 1 is in,
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  in most countries is antenatally when, when someone's pregnant
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  and you want to identify whether that the baby, the foetus the
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  woman is carrying could be at risk of having sickle cell
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  disease and that's called antenatal screening.
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  And then the other screening is testing babies when they've been
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  born, neonatal screening. And that again is an important
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  factor to try and identify children with sickle cell
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  disease so that they can be treated and managed before they
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  present with complications or even or even die in the in the
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  days before screening. Could you take us through the
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  process, perhaps first of antenatal screening?
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  Well, antenatal screening, it is complicated and it varies a lot
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  on depending on where you are and what the prevalence is, how
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  common the situation is in the UK and lots of area in parts of
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  the UK in cities like London and Birmingham, Manchester where
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  there's a high prevalence and same in European countries.
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  Then the idea is that every woman when she books for
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  pregnancy is also tested to see whether she could carry sickle
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  cell or thalassemia, which involves having a full blood
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  count and also haemoglobin analysis to look for the
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  presence of sickle haemoglobin. And then if she, if she is a
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  sickle carrier or a thalassemia carrier, then the next step
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  would be to invite her partner, even the father of the pregnancy
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  to, to come and be tested also. And if both of those people are
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  carriers that put the the fetus at risk of in developing a
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  significant haemoglobinopathy, then the the couple are
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  counselled regarding that risk. And what the counselling's for
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  depends a bit what country you're in.
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  The idea is to give mothers choice so that they know or
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  couples choice so that they know the they're at risk of having an
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  affected baby. And the choice is really to, you
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  know, involves part of that choice is whether they want to
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  continue the pregnancy and have, you know, have a termination.
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  Obviously that varies quite a lot culturally and in the UK
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  that that is the primary purpose of the antenatal screening
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  programme. In some countries, it's more
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  about choice and giving information so that people can
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  prepare for the possibility of having a a child with a medical
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  condition. I can imagine that's quite a
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  difficult conversation to have. Again, it depends.
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  One key thing is the the and. As it stands, antenatal
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  screening carries a when if you, If both couples are at risk,
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  then the next step is to have prenatal diagnostic testing
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  where you have a, the standard is to, you know, to have an
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  invasive test involving an amniocentesis or chorionic bill
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  of sampling where you put a needle into the womb, which is,
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  well, firstly, I'm comfortable and secondly, does increase the
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  risk of miscarriage by, by a small amount.
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  Probably it's only a very small amount, but it's probably still
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  there. And so the test isn't something
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  people can do casually in the sense that you'll put, you have
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  to be sure that you'll, you want to know this information really.
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  And you have to be sure that the information is going to be
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  useful in the sense that you're putting the, the fetus at risk.
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  And it's not just like a, you know, harmless blood test where,
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  where you get the information. And you can then you, once
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  you've got the information, you can decide what you want to do
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  with it. You have to really think why
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  you're having the test done. People are developing, you know,
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  there are available and they're in development ways of doing the
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  tests by using maternal blood. So in a non invasive way,
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  because there are small amounts of DNA and and cells from the
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  fetus in mother's blood when they're in a mother's blood when
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  they're pregnant. And you can test that, although
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  it's technically still quite difficult to try and identify
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  whether the fetus is is affected by sickle or or not.
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  That can be done, although it's still not 100% sensitive and
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  specific, it's still not of the standard required for a prenatal
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  diagnosis, but it it is being developed and that that is
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  likely to become an important option in the fairly near
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  future. OK.
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  And chorionic villa sampling, can that be done at any point
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  during pregnancy? No, I mean, I think it has to be
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  done, can't be done before about 11 weeks, 10 or 11 weeks.
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  People went through a phase of doing.
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  People used to do it earlier and it caused foetal abnormalities.
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  It caused loss of foetal limbs and things like that.
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  So 11-12 weeks is the earliest it can be done and it can be up
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  to up to about 14 or 15 weeks. And after that, amniocentesis
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  tends to be done where you just take take the fluid out from
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  around the baby. The see, the see, the earlier it
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  can be done, the better in the sense that if you're taking a
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  choice about terminating a pregnancy, that's a much easier
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  decision really. And if you're early on in the
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  pregnancy or certainly termination is much easier in,
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  you know, if you're 8 weeks pregnant compared to 16 weeks
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  pregnant. So it makes makes it a a
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  slightly different choice and a more realistic choice which is
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  where the non invasive testing also has an advantage that can
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  be done earlier. What's the utility of doing
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  invasive tests in in an area or a country where termination
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  might not be an option? Well, I think it's it's a more
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  difficult question. Certainly medical termination
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  is, is an option in many countries.
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  And sometimes, you know, individual mothers may choose to
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  leave the country that they're in and move to a country, you
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  know, to have the termination where the the fetus affected.
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  There is, it is useful information and some people in
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  this country want to know. They know they won't have a
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  termination, but they feel they want to know that they want to
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  prepare themselves mentally for having a baby who could have
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  medical problems. Because sickle cell disease
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  doesn't affect the fetus in the womb and it doesn't really have
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  any clinical cause, any clinical problems till a few months of
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  life at the earliest. There's no strong medical reason
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  for finding out. It doesn't alter how the
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  pregnancy is managed or how the birth is is managed, but if
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  there are some people it is, you know, it's important information
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  and they just want to mentally prepare for having a baby.
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  With that, I think the other important point about it is that
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  I think you can't make any assumptions about what people
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  will choose. And the idea that, you know, if
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  you're Catholic or Muslim, you wouldn't necessarily consider
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  termination isn't individually true.
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  And it's important that, you know, everyone is offered the
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  choices in the same way and you don't have any any
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  preconceptions, certainly. So in most of the world then
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  termination isn't legal. But but, and in most of the
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  world where sickle cell occurs, then it's either not available
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  or not legal. Although medical termination,
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  which we're sort of talking about is, you know, has
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  different rules applying to it. OK, so say a mother hasn't
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  chosen to undergo screening during pregnancy.
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  What would be a reason to screen a child after it?
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  Or a baby once it's born? A neonate.
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  Well, in the UK and I think most people think that it should
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  happen in nearly every country where sickle cell occurs, then
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  every baby is tested so that every baby at birth, you know,
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  after 7 or 8 days of life, a heel prick is tested and that
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  spot of blood is used for looking for lots of conditions
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  like including cystic fibrosis and phenyl cushion area and
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  sickle cell is has been added to that.
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  So every baby is born in the UK who is tested for that.
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  And that's true in in some states in the United States and
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  some some European countries, I think France probably.
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  Now the alternative is to and what used to happen is that you
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  try, you try to identify babies at high risk of having sickle bi
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  where it may be their mothers have been tested all based on
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  their their apparent ethnicity or in in the second is more
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  common in in some parts of the world.
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  It's relatively uncommon in northern Europeans and it's
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  relatively common in families of African origin.
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  So that in some countries people identify high risk pregnancies
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  based on the ethnicity. In the UK that's it was
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  discussed and used to happen, but it's become impractical in
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  that people have caught, you know, it's difficult to know,
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  it's difficult to know what the right question is.
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  And you can't rely on the colour of someone's skin or if they've
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  got a, a funny sounding name. You have to have some objective
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  way and whether you're saying, you know, all four grandparents
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  have to be born in a in a northern European country and
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  some that's not true of many people now in London, the vast
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  majority of people have quite complex and mixed race origins.
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  And it's also quite to do that properly, to use someone's
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  ethnicity to determine the the foetal risk.
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  It takes quite a long time. And in a way it's quicker and
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  cheaper just to do the test because you're, the idea was
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  that you can avoid doing too many blood tests or which were
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  perceived as being expensive by, you know, selecting the babies
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  who are at higher risk. So in the UK it's universal neo
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  national screening physical and I think in and that is, you
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  know, the idea is that that really maybe should be used
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  across Europe and lots of people think that that should apply in
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  every European country. Now that the numbers of people
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  with sickle cell is increasing really across Europe in previous
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  low, low prevalence areas, it's now quite common.
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  And I should say related to that, that E as you E, how are
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  now developing guidelines on this specifically there's a
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  working party to develop guidelines on neonatal, I think
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  just on neonatal screening. So exactly who should be tested
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  and how they should be tested and what you know and whether
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  what country should test really how many, how many affected
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  births do you have to have before it's this sort of thing
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  is included, OK. Do you often find that there are
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  challenges in approaching screening with parents?
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  This screening, yeah, they not hugely.
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  I think there was concern that occasionally, you know, people
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  who have, you know, their parent, they've lived in a
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  certain part of England for all their life and all their
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  ancestors have lived in the same village.
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  And they don't like the idea that they're going to be tested
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  for some disease that is not common in, in, you know,
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  northern Europeans in general. There's not really much
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  resistance to it. As I say, it's part of a more
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  general neonatal screening where lots of conditions are tested
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  for like cystic fibrosis as well.
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  And it sounds very unusual for someone to specifically say, oh,
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  I want all tests, but I don't want to be tested for sickle
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  cell. And the neonatal screening works
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  very well. There's very good coverage in
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  the UK and there's a good system and more than 99% of people have
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  testing done. OK.
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  Do you think there's a reluctance in other parts of the
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  world to adopt this? I think neonatal screening, I
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  think there's a cost to it as the issue.
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  I think in general there's a perception that, you know, if
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  it's a rare disease that you'll test, you know, hundreds of
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  thousands of children not pick up anything.
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  But that is currently done really a phenol cutaneura which
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  is tested for every baby is tested for is incredibly rare.
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  There are, you know, only a handful of cases each year and
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  that's been, whereas in sickles in the UK there are 300 cases a
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  year. And in most European countries
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  there'd be more cases of phenylketonuria, of sickle cell
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  disease and phenylketonuria. And yet people test for
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  phenylketonuria because for historical reasons.
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  The other important thing about testing is there has to be a, an
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  intervention that makes a difference of screening and, and
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  in sickle cell. They're the reason it's
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  important to test babies is that you can start them on penicillin
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  at an early age to protect against infection.
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  And without that, we know that a proportion of children, you
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  know, become very unwell or even die before the diagnosis is
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  made. So it does have a well, it's a
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  good thing to do in itself, probably.
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  But secondly, there is a very practical reason for doing it.
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  Yeah. What other developments could
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  you foresee in the future for when it comes to screening for
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  sickle cell disease? Well, one issue particularly for
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  prenatal diagnosis is that predicting the severity of the
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  the baby. We know sickle cell disease is
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  very variable and some children have, you know, no problems and
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  are completely healthy and others are really quite severely
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  affected and can have strokes and severe complications.
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  And if we could predict, you know, using other genetic
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  markers, you know, whether this was going to be a severely
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  affected or mildly affected child, then that would again, be
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  very useful information for to help parents choose about
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  whether what to do regarding continue continuing the
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  pregnancy. We and others have been trying
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  for a very long time to identify genetic markers that predict
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  severity. And it's still really basically
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  not possible to do that. One or two things that can give
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  you a clue, but they're not specific enough to want to for
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  you want to to use to make a sort of, you know, big decision
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  about whether to continue a pregnancy or not.
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  But with genomic medicine developing and whole genome
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  sequencing starting on on babies and everything, then it may be
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  and more bioinformatic capabilities, it may be possible
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  to give a much more precise direction, which would then add
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  greatly to the value and the the prenatal diagnosis.
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  And so that would be an important way to provide much
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  more valuable information to families.
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  That sounds wonderful. Is there any way to
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  prognosticate in neonates at the moment?
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  OK, it's a good question. And the same arguments apply and
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  the there are crude guidelines really you can identify for
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  example, that boys do less well than girls and you can predict
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  the hemoglobin F level and things like the presence of
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  alpha thalassemia determine outcomes, but to a fairly small
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  extent. I think the issue for that is
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  wise at the moment. There are there are some
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  curative treatments, but they're all quite toxic.
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  They all involve basically, you know, myeloablation and A and a
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  risk of severe complications. So though if you could predict
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  which children are going to have say a stroke, then then you
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  there will be a strong argument for you're giving these quite
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  toxic curative treatments at an early stage.
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  We've tried and others are going to have tried quite hard to
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  predict stroke and identify factors and what, And again,
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  once we found some factors and we haven't found enough to
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  actually, you know, make a, a big decision on, you know,
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  clinical decision where you say, yes, no, we're going to
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  transplant them or not. I think that will change as
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  curative treatment becomes less more widely available and and
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  less toxic then I think it will. We will reach the stage, as I
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  said previously, that that every foetus, every baby had
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  potentially has a curative treatment.
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  So the need to discriminate between severe and mild will
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  become less important. If we were to, you know, get in
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  a time machine and go 50 years in the future, what would you
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  hope for? A screening for sickle cell
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  disease. I think to be honest, the
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  screening is pretty good now. I think every, I think for me, I
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  think every country in Europe should test every baby born for
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  sickle cell disease. And then, you know, more
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  importantly, it's almost where sickle cell is most common in
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  Africa and India, there's almost no neonatal screening.
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  So if you wanted to wish something, it would be that, you
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  know, the neonatal screening had been set up in these countries
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  where it would actually have a huge impact in the, you know,
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  80% of people die in childhood and a large proportion of that
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  is present, preventable by starting penicillin and other
• 16:26
  preventive measures at an early age.
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  So if you could go ahead and say in 50 years you'd really hope
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  that, you know, Nigeria and Congo and India have a national
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  neonatal screening programme and every baby is tested.
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  That would be wonderful. It would.
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  And that would make a real far more difference than we make in
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  the Uki mean make a difference, but you know, you could make a
• 16:45
  huge difference there. OK.
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  And that will become more relevant as curative treatments
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  become available. And that with gene editing, it's
• 16:54
  I think in 50 years, almost certainly that will be, you
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  know, widely available treatment.
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  And so it'll be possible, you know, potentially to, you know,
• 17:03
  cure babies neonatally. And even we're not even further
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  ahead. We're currently looking at
• 17:08
  research doing for doing in utero gene therapy for treating
• 17:12
  fetuses in the womb, which has some advantages.
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  So potentially that our screening could, if that becomes
• 17:20
  a, a feasible and effective way of treating them, it could
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  become quite an effective, you know, the the antenatal
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  screening will become more important so that you can.
• 17:30
  That sounds wonderful it. Does.
• 17:33
  Well, thank you so much for talking to us today and thank
• 17:36
  you to our audience listening to this episode of EHA Unplugged.
• 17:40
  Stay tuned for our next episode.